Berberine tauroursodeoxycholate compositions and methods thereof

Abstract

The present invention provides berberine tauroursodeoxycholate (BTUDC), pharmaceutical compositions and methods of use thereof for the treatment, amelioration and / or prevention of Parkinson's disease or related diseases and conditions as monotherapy or in combination with other agents or as an adjuvant. The present invention also provides pharmaceutical compositions of berberine (BBR) and tauroursodeoxycholic acid (TUDCA) and methods of use thereof for the treatment, alleviation and / or prevention of Parkinson's disease or related diseases and conditions as monotherapy or in combination with other agents or as an adjuvant.

Description

Priority claims and related patent applications

[0001] This application claims the benefit of priority to U.S. Provisional Application Serial No. 63 / 446,004, filed on February 15, 2023, and Chinese Patent Application No. 2024101662972, filed on February 6, 2024, all of which are incorporated herein by reference in their entirety. Technical Field

[0002] The present invention generally relates to pharmaceutical compositions and methods for their therapeutic use. Specifically, the present invention relates to berberine tauroursodeoxycholate (BTUDC), pharmaceutical compositions, and methods of their use as monotherapy, in combination with other agents, or as an adjunct for treating, alleviating, and / or preventing central nervous system (CNS) diseases and conditions, such as Parkinson's disease and amyotrophic lateral sclerosis (ALS), or related diseases and conditions. The present invention also relates to pharmaceutical compositions of berberine (BBR) and tauroursodeoxycholic acid (TUDCA), and methods of their use as monotherapy, in combination with other agents, or as an adjunct for treating, alleviating, and / or preventing Parkinson's disease or related diseases and conditions. Background Art

[0003] Degenerative neurological diseases (or neurodegenerative diseases) affect millions of people worldwide. These diseases include a range of conditions that primarily affect neurons in the brain. Neurons are the basic units that make up the nervous system, including the brain and spinal cord. Neurons generally cannot regenerate or be replaced after being damaged or dying. Examples of neurodegenerative diseases that affect the CNS include Parkinson's disease, Alzheimer's disease, Huntington's disease, and ALS. Currently, neurodegenerative diseases are incurable and debilitating conditions that result in the progressive degeneration and / or death of nerve cells.

[0004] Parkinson's disease is a long-term degenerative disorder of the central nervous system that causes involuntary or uncontrollable movements and difficulty with balance and coordination. Symptoms usually develop gradually and worsen over time. Early symptoms include tremors, stiffness, slow movements, and difficulty walking. As the disease progresses, patients may have difficulty walking and speaking. Cognitive and behavioral problems such as depression, anxiety, and apathy may also occur in many patients. Parkinson's disease dementia becomes common in the late stages of the disease. Parkinson's disease patients may also have problems with their sleep and sensory systems. As the disease progresses, patients may have difficulty walking and speaking. (Sveinbjornsdottir 2016 "The clinical symptoms of Parkinson's disease" J. Neurochem. 139(Suppl 1):318–324; "Parkinson's Disease Information Page Nat'l Inst. Neurol. Dis. & Stroke, https: / / www.ninds.nih.gov / health- information / disorders / parkinsons-disease .)

[0005] Currently, there is no cure or effective treatment for Parkinson's disease. Treatment is usually aimed at reducing the effects of symptoms. Initial treatment options include levodopa (L-DOPA), MAO-B inhibitors, and dopamine agonists. These drugs become less effective as the disease progresses and produce side effects characterized by involuntary muscle movements. In severe cases where medications are ineffective, deep brain stimulation using surgically placed microelectrodes has been used to reduce motor symptoms. Diet and some forms of rehabilitation have shown some effectiveness in improving symptoms. (Samii, et al. 2004 "Parkinson's disease" Lancet 363(9423):1783–1793; Armstrong, et al. 2020 "Diagnosis and Treatment of Parkinson's Disease: A Review" JAMA 323(6):548–560; Barichella, et al. 2009 "Majornutritional issues in the management of Parkinson's disease"MovementDisorders24(13):1881–1892.)

[0006] Currently available therapeutic agents and methods for treating Parkinson's disease are still insufficient. There is an urgent need for a new, safe and effective treatment method. Summary of the Invention

[0007] In one aspect, the present invention generally relates to salts having formula (I):

[0008] In another aspect, the present invention generally relates to a solid form of a compound of formula (I), i.e., Form A, wherein its X-ray powder diffraction (XRPD) pattern comprises one or more characteristic diffraction peaks at the following 2θ angles when using a Cu-Kα ray source: 4.62°, 9.32°, 17.02°±0.2°.

[0009] In another aspect, the present invention generally relates to pharmaceutical compositions comprising BTUDC and a pharmaceutically acceptable excipient, carrier, or diluent.

[0010] In another aspect, the present invention generally relates to pharmaceutical compositions comprising a solid form disclosed herein and a pharmaceutically acceptable excipient, carrier, or diluent.

[0011] In yet another aspect, the present invention generally relates to unit dosage forms of pharmaceutical compositions comprising the BTUDC disclosed herein.

[0012] In yet another aspect, the present invention generally relates to a method for alleviating, preventing, or treating a neurodegenerative disease, comprising administering to a subject in need thereof a pharmaceutical composition comprising BTUDC.

[0013] In yet another aspect, the present invention generally relates to a method for alleviating, preventing, or treating Parkinson's disease, comprising administering to a subject in need thereof a pharmaceutical composition comprising BTUDC.

[0014] In yet another aspect, the present invention generally relates to a method for alleviating, preventing, or treating a neurodegenerative disease, comprising administering to a subject in need thereof a pharmaceutical composition comprising BBR and TUDCA.

[0015] In yet another aspect, the present invention generally relates to a method for alleviating, preventing, or treating Parkinson's disease, comprising administering to a subject in need thereof a pharmaceutical composition comprising BBR and TUDCA.

[0016] In yet another aspect, the present invention generally relates to the use of BTUDC for treating neurodegenerative diseases or related diseases or conditions.

[0017] In yet another aspect, the present invention generally relates to the use of BTUDC for treating Parkinson's disease or a related disease or condition.

[0018] In yet another aspect, the present invention generally relates to the use of BTUDC for the manufacture of a medicament for preventing or treating a neurodegenerative disease or a related disease or condition.

[0019] In yet another aspect, the present invention generally relates to the use of BTUDC for the manufacture of a medicament for preventing or treating Parkinson's disease or a related disease or condition.

[0020] In yet another aspect, the present invention generally relates to the use of BBR and TUDCA for treating a neurodegenerative disease or a related disease or condition.

[0021] In yet another aspect, the present invention generally relates to the use of BBR and TUDCA for treating Parkinson's disease or a related disease or disorder.

[0022] In yet another aspect, the present invention generally relates to the use of BBR and TUDCA for the manufacture of a medicament for preventing or treating a neurodegenerative disease or a related disease or condition.

[0023] In yet another aspect, the present invention generally relates to the use of BBR and TUDCA for the manufacture of a medicament for preventing or treating Parkinson's disease or a related disease or condition.

[0024] In yet another aspect, the present invention generally relates to methods for preparing the BTUDC salts disclosed herein.

[0025] In yet another aspect, the present invention generally relates to methods for preparing the solid forms disclosed herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 For BTUDC's exemplary 1 H NMR spectrum.

[0027] Figure 2 For TUDCA's exemplary 1 H NMR spectrum.

[0028] Figure 3 For example, BBR-Cl 1 HNMR spectrum.

[0029] Figure 4 Schematic diagram of the asymmetric structural unit.

[0030] Figure 5 Schematic diagram of the crystal unit cell structure.

[0031] Figure 6 Exemplary results are presented regarding the effects of a test article on the number of ipsilateral rotations within 30 minutes of apomorphine injection in rats induced by stereotactic injection of 6-hydroxydopamine (6-OHDA).

[0032] Figure 7 Figure 1 is an exemplary result regarding the effect of the test article on the balance beam test time in rats induced by stereotaxic injection of 6-OHDA.

[0033] Figure 8 Exemplary results are presented regarding the effects of the test article on the number of foot slips in the balance beam test in rats induced by stereotactic injection of 6-OHDA.

[0034] Figure 9 Figure 1 is an exemplary result regarding the effect of the test article on rotarod test time in rats induced by stereotaxic injection of 6-OHDA.

[0035] Figure 10 Exemplary results are presented regarding the effects of the test article on peak grip force in a grip strength test in rats induced by stereotactic injection of 6-OHDA.

[0036] Figure 11 is an exemplary XRPD pattern of Form A.

[0037] Figure 12 Exemplary DSC and TGA curves of Form A.

[0038] Figure 13 An exemplary XRPD comparison of a crystalline transformation of Form A.

[0039] Figure 14 This is an example of a fast DVS isotherm of form A.

[0040] Figure 15 Figures 2 and 3 are exemplary XRPDs of Form A before and after rapid DVS.

[0041] Figure 16 An exemplary XRPD of a Form A single crystal sample.

[0042] Figure 17 is an exemplary XRPD pattern of Form A stability study.

[0043] Figure 18 Exemplary data are presented regarding the effects of test article on the number of ipsilateral rotations within 30 minutes of apomorphine injection in rats induced by stereotactic injection of 6-OHDA.

[0044] Figure 19 Exemplary data are presented regarding the effects of a test article on peak grip force in a grip strength test in rats induced by stereotactic injection of 6-OHDA.

[0045] Figure 20 Exemplary data are presented regarding the effects of test article on time on the rotarod test in rats induced by stereotaxic injection of 6-OHDA.

[0046] Figure 21 Figure 2 is an exemplary data on the time it takes to cross a balance beam.

[0047] Figure 22The following are exemplary data regarding the number of foot slips on the balance beam.

[0048] Figure 23 are exemplary data regarding immunofluorescence staining of tyrosine hydroxylase (TH) in the striatum (Str) and substantia nigra (SN) brain regions of PD model rats 21 days after administration.

[0049] Figure 24 Figure 2 is exemplary data regarding fluorescence intensity analysis of tyrosine hydroxylase (TH)-positive cells in the Str brain region of rats 21 days after stereotactic injection of 6-OHDA into the brain.

[0050] Figure 25 Figure 2 is exemplary data regarding fluorescence intensity analysis of tyrosine hydroxylase (TH)-positive cells in the Str brain region of rats 21 days after stereotactic injection of 6-OHDA into the brain.

[0051] Figure 26 are exemplary data regarding the results of immunofluorescence staining of microglia (Iba1) in the Str and SN brain regions of PD model rats 21 days after administration.

[0052] Figure 27 Figure 2 is an exemplary data analysis regarding the count of microglia (Iba1)-positive cells in the Str brain region of rats on day 21 after stereotaxic injection of 6-OHDA.

[0053] Figure 28 Figure 2 is an exemplary data analysis regarding the count of microglia (Iba1)-positive cells in the SN brain region of rats on day 21 after stereotactic injection of 6-OHDA in the brain.

[0054] Figure 29 Figure 2 is an exemplary data analysis of Elisa test results for IL-1β, IL-6, and TNF-α in rat cerebrospinal fluid 21 days after administration.

[0055] Figure 30 For example, BTUDC prepared by method 2 1 H NMR spectrum.

[0056] Figure 31 is an exemplary XRPD pattern of BTUDC prepared by Method 1.

[0057] Figure 32 Exemplary TGA and DSC of BTUDC prepared by Method 1.

[0058] Figure 33 This is an exemplary online temperature-swing experiment of BTUDC prepared by Method 1. definition

[0059] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. Abbreviations used herein have their conventional meanings in the fields of chemistry and biology. The chemical structures and formulae set forth herein are constructed according to standard rules of chemical valence known in the chemical art.

[0060] As used in this disclosure, the following words and phrases are generally intended to have the meanings set forth below unless expressly indicated otherwise or the context in which the following words and phrases are used indicates otherwise.

[0061] In this specification and the appended claims, the singular forms "a," "an," and "the," include plural referents unless the context clearly dictates otherwise.

[0062] Unless the context clearly indicates otherwise, the term "and / or" is used in the present invention to mean "and" or "or".

[0063] As used herein, "at least" of a particular value is understood to mean that value and all values ​​greater than that value.

[0064] Applicants' disclosure is herein described in terms of preferred embodiments with reference to the accompanying drawings, wherein like numerals represent identical or similar elements. Reference throughout this specification to "one embodiment" or "an embodiment" or similar language means that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases "in one embodiment," "in an embodiment," and similar language throughout this specification may, but do not necessarily, all refer to the same embodiment.

[0065] The term "comprising," when used to define compositions and methods, is intended to mean that the compositions and methods include the listed elements, but not to exclude other elements. The term "consisting essentially of," when used to define compositions and methods, shall mean that the compositions and methods include the listed elements, and exclude other elements that are of any substantial significance to the compositions and methods. For example, "consisting essentially of" refers to the administration of the pharmacologically active agents that are explicitly listed, and excludes pharmacologically active agents that are not explicitly listed. The term "consisting essentially of" does not exclude pharmacologically inactive or inert agents, such as pharmaceutically acceptable excipients, carriers, or diluents. The term "consisting of," when used to define compositions and methods, shall mean excluding trace elements and substantial method steps of other ingredients. Embodiments defined by each of these transition terms are within the scope of the present invention.

[0066] Throughout this specification, when compositions and kits are described as having, including, or comprising particular components, or when processes and methods are described as having, including, or comprising particular steps, it is contemplated that there are additionally compositions and kits of the invention that consist essentially of, or consist of, the components, and that there are processes and methods according to the invention that consist essentially of, or consist of, the processing steps.

[0067] In this application, when an element or component is considered to be included in and / or selected from a list of elements or components, it should be understood that the element or component may be any one of the elements or components, or the element or component may be selected from two or more of the elements or components.

[0068] Unless otherwise specified or obvious from the context, as used herein, the term "about" should be understood as within the normal tolerance range in the art, for example, within 2 standard deviations of the mean. About can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05% or 0.01% of the stated value. Unless the context clearly dictates otherwise, all numerical values ​​provided herein are modified by the term "about".

[0069] In this specification, variables or parameters are disclosed in groups or ranges. Specifically, the description should include every subcombination of the members of these groups and ranges. For example, a range of 1 to 16 is understood to include any number, combination of numbers, or subrange within the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

[0070] As used herein, "XRPD" refers to X-ray powder diffraction. An XRPD diagram is an xy graph in which 2θ (diffraction angle) is plotted on the x-axis and intensity is plotted on the y-axis. These are diffraction peaks that can be used to characterize crystalline materials. Diffraction peaks are typically represented and referred to by their positions on the x-axis rather than the diffraction peak intensity on the y-axis, because diffraction peak intensity may be particularly sensitive to sample orientation (see Pharmaceutical Analysis, Lee & Web, pp. 255-257 (2003)). Therefore, those skilled in the art typically do not use intensity to characterize crystalline materials.

[0071] As used herein, the term "2θ value" or "2θ" refers to the peak position in degrees based on the experimental setup of an X-ray diffraction experiment and is a commonly used abscissa unit in a diffraction pattern. The experimental setup requires that if diffraction occurs when an incident light beam forms an angle θ with a certain lattice plane, the reflected light beam is recorded at an angle 2θ. It should be understood that references herein to a particular 2θ value for a particular solid form are intended to mean the 2θ value (in degrees) as measured using the X-ray diffraction experimental conditions described herein.

[0072] As with any data measurement, XRPD data may have variability. In addition to the variability of the diffraction peak intensity, there may also be variability in the position of the diffraction peak on the x-axis. However, when reporting the position of the diffraction peak for the purpose of characterization, this variability can generally be taken into account. This variability in the position of the diffraction peak along the x-axis can come from several aspects. One such source can be sample preparation. Samples of the same crystalline material prepared under different conditions can produce slightly different diffraction patterns. Factors such as particle size, moisture content, solvent content, temperature and orientation can all affect how the sample diffracts X-rays. Another source of variability is instrument parameters. Different X-ray powder diffractometers operate using different parameters and can result in slightly different diffraction patterns from the same crystalline material. Similarly, different software packages process XRPD data in different ways, which can also lead to variability. These and other sources of variability are known to those of ordinary skill in the art. Because of these sources of variability, the value of each X-ray diffraction peak may be preceded by the term "about" or by an appropriate range to limit the experimental variability (e.g., ±0.1°, ±0.2°, ±0.3°, ±0.4°, ±0.5°, etc.).

[0073] Crystalline forms, such as the crystalline forms of compounds of formula (I) are easily determined by XRPD. Data from X-ray powder diffraction can be used to characterize crystalline forms in a variety of ways. For example, the entire X-ray powder diffraction pattern output from a diffractometer can be used to characterize the crystalline form (e.g., of a compound of formula (I)). However, a smaller subset of these data may also be suitable for and used to characterize these crystalline forms. In fact, typically even a single X-ray powder diffraction peak can be used to characterize this crystalline form. With regard to the crystalline form of a compound of formula (I), any one or more of the peaks in the X-ray powder diffraction pattern can be used to characterize the crystalline form of a compound of formula (I) disclosed herein.

[0074] The term "characteristic peak," when referring to a peak in an XRPD pattern of a crystalline form of a given chemical entity (e.g., a crystalline form of a compound of Formula (I)), refers to a collection of specific diffraction peaks whose values ​​include a range of 2θ values ​​(e.g., 0°-40°) that are, as a whole, characteristic of that particular crystalline form.

[0075] Differential scanning calorimetry (DSC) curves can be particularly sensitive to sample preparation and parameters. Consequently, there can be variability in the DSC data (e.g., the location of the onset temperature and the highest peak temperature). Due to these sources of variability, each temperature value based on the DSC data may be preceded by the term "about" or by an appropriate range defining the experimental variability (e.g., ±0.5°C, ±1°C, ±3°C, ±4°C, ±5°C, etc.).

[0076] As used herein, the term "crystalline" refers to any solid material that exhibits three-dimensional order, which gives a distinctive X-ray powder diffraction (XRPD) pattern with well-defined peaks compared to amorphous solid materials.

[0077] As used herein, the term "amorphous" refers to any solid material that lacks three-dimensional order. In some cases, amorphous solids can be characterized by known techniques including XRPD crystallography, solid-state nuclear magnetic resonance (ssNMR) spectroscopy, DSC, or some combination of these techniques. Amorphous solids typically give a dispersed XRPD pattern consisting of one or two broad peaks (i.e., peaks with a base width of about 5° 2θ or greater).

[0078] As used herein, the term "polymorph" refers to different crystalline forms of the same compound, and includes, but is not limited to, other solid-state molecular forms of the same compound, including hydrates (e.g., bound water present in the crystalline structure) and solvates (e.g., bound solvent other than water).

[0079] As used herein, the term "substantially the same" with respect to X-ray powder diffraction peak positions and / or patterns means taking into account typical peak position and intensity variability. For example, it will be understood by those skilled in the art that peak position (2θ) will show a certain variability, typically up to 0.1 to 0.2 degrees of variability, as well as variability on the device used to measure diffraction. In addition, it will be understood by those skilled in the art that relative peak intensity will show inter-device variability and variability due to crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be used only as a qualitative indicator. Similarly, as used herein, "substantially the same" with respect to DSC is also intended to encompass variability associated with these analytical techniques known to those skilled in the art.

[0080] As used herein, the term "stable" refers to a compound that is not substantially altered when subjected to conditions that allow its production, detection, recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when stored at 40° C. or less, in the absence of moisture or other chemically reactive conditions, for at least one week, preferably at least one month, more preferably at least six months, and even more preferably at least one year.

[0081] As used herein, the term "solvate" refers to a crystalline solid adduct that contains a stoichiometric or non-stoichiometric amount of solvent incorporated into the crystal structure. When the solvent is tightly bound to the drug, the resulting complex will have a well-defined stoichiometry that is independent of humidity. However, when the solvent is weakly bound, as in channel solvates and hygroscopic compounds, the solvent content will depend on humidity and drying conditions. In such cases, the complex is generally non-stoichiometric. If the incorporated solvent is water, such an adduct is referred to as a "hydrate." Thus, the term "hydrate" describes a solvate comprising a drug substance and a stoichiometric or non-stoichiometric amount of water.

[0082] As used herein, when the term "anhydrous" or "anhydrate" refers to a crystalline form (e.g., a crystalline form of a compound of formula (I)), it is meant that no water molecules form part of the unit cell of the crystalline form. The anhydrous crystalline form may still contain water molecules that do not form part of the unit cell of the anhydrous crystalline form (e.g., as residual solvent molecules left in the production of the crystalline form). In a preferred embodiment, water may account for about 0.5% of a sample of the anhydrous form by weight of the total composition. In a more preferred embodiment, water may account for about 0.2% of a sample of the anhydrous form by weight of the total composition. In some embodiments, a sample of the anhydrous crystalline form of a compound of formula (I) does not contain water molecules, e.g., does not contain a detectable amount of water.

[0083] As used herein, a "pharmaceutical composition" refers to a therapeutically active agent in combination with one or more pharmaceutically acceptable excipients, carriers, or diluents, making the composition particularly suitable for in vivo or ex vivo diagnostic or therapeutic use.

[0084] As used herein, the term "pharmaceutically acceptable excipient, carrier, or diluent" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, vehicle, solvent, or encapsulating material, that is involved in carrying or transporting a subject's drug from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffered saline; and other nontoxic, compatible substances used in pharmaceutical formulations. Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-polypropylene oxide copolymers, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0085] As used herein, the term "subject " refers to any animal (for example, mammal), including but not limited to people, non-human primates, rodents, etc., which will become the recipient of specific treatment. Generally, the terms "subject" and "patient" are used interchangeably herein, referring to human subjects. Considering "subject" applied to include but not limited to people (i.e., male or female of any age group, such as children's subjects (for example, infants, children, teenagers) or adult subjects (for example, young people, middle-aged people or the elderly)) and / or non-human animals, for example, mammals such as primates (for example, cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats and / or dogs. In certain embodiments, the subject is a person. In certain embodiments, the subject is a non-human animal.

[0086] As used herein, "administering" means oral administration, pulmonary administration, intramuscular administration, intrathecal administration, intranasal administration or subcutaneous administration, or implanting a sustained-release device, for example, a mini-osmotic pump, to a subject. Administration can be by any route, including transmucosal (e.g., oral, sublingual, palate, gum, nose, vagina, rectum or) administration. Parenteral administration includes, for example, intramuscular and subcutaneous administration. Other modes of delivery include, but are not limited to, the use of liposome formulations, etc. "Co-administering" means that the compositions described herein are administered while, just before, or just after administering one or more other therapies (e.g., therapeutic agents, chemotherapeutic agents, or treatment of neurodegenerative diseases). The compound of formula (I) can be administered alone or can be co-administered to a patient. Co-administration is intended to include administering a compound (one or more compounds or agents) alone or in combination, simultaneously or sequentially. Therefore, when desired, the preparation can also be combined with other active substances (e.g., to reduce metabolic degradation).

[0087] As used herein, the terms "disease," "disorder," and "condition" are used interchangeably herein.

[0088] As used herein, the term "treatment", "alleviation" or "prevention" disease or condition refers to improving such disease before or after it occurs. Compared to equivalent untreated controls, measured by any standard technique, such alleviation or prevention degree is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95% or 100%. The term "treatment (treat, treating and treatment)" is considered to occur when a subject suffers from a specific disease, disease or the patient's condition, which reduces the severity of the disease, disease or the patient's condition, or slows down or slows down the progress of the disease, disease or the patient's condition ("therapeutic treatment"), and also considers the action ("preventive treatment") that occurs before the subject starts to suffer from a specific disease, disease or the patient's condition. In one embodiment, provided herein is a compound that is considered to be used in a therapeutic treatment method, which plays a role when the subject suffers from a specific disease, disease or the patient's condition, and causes the severity of the disease, disease or the patient's condition to be reduced, or the progress of the disease, disease or the patient's condition to be slowed down or slowed down. In an alternative embodiment, the compounds provided herein are contemplated for use in methods of prophylactic treatment, which methods are effected before a subject becomes afflicted with a particular disease, disorder, or condition, and which result in preventing the disease, disorder, or condition, or one or more symptoms associated with the disease, disorder, or condition, or preventing the recurrence of the disease, disorder, or condition.

[0089] As used herein, the term "effective amount" of an active agent refers to an amount sufficient to elicit a desired biological response. As will be appreciated by those of ordinary skill in the art, the effective amount of a compound of the invention may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the patient.

[0090] After preparation, the compounds of the present invention are preferably isolated and purified to obtain compositions containing an amount equal to or greater than 95% by weight ("substantially pure") and then used or formulated as described herein. In certain embodiments, the purity of the compounds of the present invention exceeds 99%. DETAILED DESCRIPTION

[0091] The present invention is based, in part, on compositions of BTUDC and combinations of BBR and TUDCA, and methods of using the same for treating neurodegenerative diseases, particularly Parkinson's disease.

[0092] Berberine (5,6-dihydro-9,10-dimethoxybenzo[g]-1,3-dioxolbenzo[5,6-a]quinolizine) is an isoquinoline alkaloid isolated from plants such as Coptis chinensis. It has a long history of medicinal use in China for the treatment of various gastrointestinal diseases.

[0093] Berberine is found in a variety of plants such as Berberis, Goldenseal, Rhizoma Coptidis, Corkwood, Coptis Rhizome, Tinospora cordifolia, Poppy, and California Poppy. Berberine broth has been used for digestive tract diseases (including travelers' diarrhea). Berberine broth has a broad spectrum of activity and has multiple modes of action. Previous studies on berberine have reported that it exhibits antiviral, anti-inflammatory, and hepatoprotective benefits, as well as reducing oxidative stress. For example, berberine has shown antiviral activity, such as against influenza, hepatitis C, cytomegalovirus, and alphavirus. (Neag, et al. 2018 "Berberine: Botanical Occurrence, Traditional Uses, ExtractionMethods, and Relevance in Cardiovascular, Metabolic, Hepatic, and RenalDisorders" Front. Pharmacol., 21 August Sec. Ethnopharmacology vol.9; "Berberine" Altern.Med.Rev.2000Apr.5(2):175-7.)

[0094] Berberine is commercially available as its chloride, sulfate, or tannate salts, with berberine hydrochloride being used in nearly all previous studies. The low bioavailability of currently available forms of berberine makes its use in the treatment of chronic and systemic diseases very challenging.

[0095] Tauroursodeoxycholic acid (TUDCA), also known as ursodeoxycholic acid or taurine diol, is a naturally occurring hydrophilic bile acid.

[0096] TUDCA has been used to treat chronic cholestatic liver disease and cholelithiasis. Studies have shown that TUDCA can inhibit apoptosis in different cell types by stabilizing mitochondrial membranes or regulating the expression of specific upstream targets of apoptosis. Recently, glycine-conjugated TUDCA has been reported to inhibit nitrite production and prevent matrix metallopeptidase 9 activation in a cell model of superoxide dismutase 1 neurodegeneration. Studies have been conducted to collect preliminary safety and efficacy data on the long-term biological effects of TUDCA in patients who have received treatment for ALS. (Hofmann 1999 “The continuingimportance of bile acids in liver and intestinal disease” Arch.Intern.Med.159:2647–2658; Rodrigues, et al. 2001 “The therapeutic effects of ursodeoxycholic acid as an anti-apoptotic agent” Expert Opin. Investig.Drugs 10:1243–1253; Vaz, et al. al. "Glycoursodeoxycholic acid reduces matrix metalloproteinase-9and caspase-9activation in a cellular model of superoxide dismutase-1neurodegeneration" Mol.Neurobiol.2014; Elia, etal.2016 "Tauroursodeoxycholic acid in the treatment of patients with amyotrophic lateral sclerosis" Eur.J.Neurol.23(1):45–52.)

[0097] BTUDC, first discovered by the present applicant and disclosed herein, is an ionic salt of BBR and TUDCA and is represented by the following formula:

[0098] Without wishing to be bound by theory, BTUDC and the combination of BBR and TUDCA may alleviate or improve one or more symptoms of neurodegenerative diseases, particularly Parkinson's disease. In addition, BTUDC and the combination of BBR and TUDCA may effectively reduce, delay and / or stop the progression of Parkinson's disease.

[0099] More specifically, the present invention relates to BTUDC, which synergistically combines the beneficial effects of TUDCA and BBR. Thus, the present invention provides a unique method for treating neurodegenerative diseases, particularly Parkinson's disease, alone or in combination with other available treatments or therapies. Thus, the present invention provides a new strategy for treating neurodegenerative diseases, particularly Parkinson's disease.

[0100] In one aspect, the present invention generally relates to salts having formula (I):

[0101] In certain embodiments, the BTUDC salt is in substantially pure form.

[0102] In certain embodiments, the BTUDC salt is characterized by a purity of about 90% (eg, about 95%, about 98%, about 99%) or greater.

[0103] In certain embodiments, the BTUDC salt is prepared by an acid-base reaction between BBR (or a salt thereof) and TUDCA (or a salt thereof).

[0104] In another aspect, the present invention generally relates to a solid form of a compound of formula (I), i.e., Form A, wherein its X-ray powder diffraction (XRPD) pattern comprises one or more characteristic diffraction peaks at the following 2θ angles when using a Cu-Kα ray source: 4.62°, 9.32°, 17.02°±0.2°.

[0105] In certain embodiments, the XRPD pattern of the solid form further comprises one or more characteristic diffraction peaks at the following 2θ angles when using a Cu-Ka radiation source: 5.96°, 6.23°, 15.19°±0.2°.

[0106] In certain embodiments, the XRPD pattern of the solid form comprises characteristic diffraction peaks at the following 2θ angles when using a Cu-Ka radiation source: 4.62°, 5.96°, 6.23°, 9.32°, 15.19°, 17.02°±0.2°.

[0107] In certain embodiments, the XRPD pattern of the solid form further comprises one or more characteristic diffraction peaks at the following 2θ angles when using a Cu-Ka radiation source: 11.99°, 12.56°, 12.90°±0.2°.

[0108] In certain embodiments, the XRPD pattern of the solid form comprises characteristic diffraction peaks at the following 2θ angles when using a Cu-Ka radiation source: 4.62°, 5.96°, 6.23°, 9.32°, 11.99°, 12.56°, 12.90°, 13.32°, 14.25°, 14.88°, 15.19°, 17.02°, 17.51°, 17.73°, 18.02°, 21.39°, 24.25°, 24.71°±0.2°.

[0109] In certain embodiments, the XRPD pattern of the solid form comprises characteristic diffraction peaks at the following 2θ angles: Table 1. 2θ angle values ​​of XRPD patterns

[0110] In certain embodiments, when using a Cu-Ka radiation source, the XRPD pattern of the solid form is Figure 11 The diagrams shown in are essentially the same.

[0111] In certain embodiments, the differential scanning calorimetry (DSC) curve of Form A comprises an endotherm with a peak at about 280°C.

[0112] In certain embodiments, the thermogravimetric analysis (TGA) curve of Form A comprises a weight loss from about 0.5% to about 3% from room temperature to about 150°C.

[0113] In certain embodiments, the solid form is an anhydrate.

[0114] In certain embodiments, the solid form is a hydrate having formula (II). In certain embodiments, the solid form is a hydrate having up to 2 H2O molecules per BTUDC molecule (i.e., BTUDC:H2O=1:x, wherein x is a number in the range of 0 to 2, preferably a number in the range of 0.3 to 1.5, and further preferably a number in the range of 0.5 to 1.2).

[0115] In certain embodiments, solid forms include hydrates and anhydrates.

[0116] In certain embodiments, the solid form is a crystalline form.

[0117] In another aspect, the present invention generally relates to pharmaceutical compositions comprising BTUDC and a pharmaceutically acceptable excipient, carrier, or diluent.

[0118] In another aspect, the present invention generally relates to pharmaceutical compositions comprising a solid form disclosed herein and a pharmaceutically acceptable excipient, carrier, or diluent.

[0119] In yet another aspect, the present invention generally relates to unit dosage forms of pharmaceutical compositions comprising the BTUDC disclosed herein.

[0120] In yet another aspect, the present invention generally relates to a method for alleviating, preventing, or treating a neurodegenerative disease, comprising administering to a subject in need thereof a pharmaceutical composition comprising BTUDC.

[0121] In yet another aspect, the present invention generally relates to a method for alleviating, preventing, or treating Parkinson's disease, comprising administering to a subject in need thereof a pharmaceutical composition comprising BTUDC.

[0122] In yet another aspect, the present invention generally relates to a method for alleviating, preventing, or treating a neurodegenerative disease, comprising administering to a subject in need thereof a pharmaceutical composition comprising BBR and TUDCA.

[0123] In yet another aspect, the present invention generally relates to a method for alleviating, preventing, or treating Parkinson's disease, comprising administering to a subject in need thereof a pharmaceutical composition comprising BBR and TUDCA.

[0124] In certain embodiments, the method results in reduction or improvement of one or more symptoms of Parkinson's disease.

[0125] In certain embodiments, the method results in an improvement in the effect of substantia nigra lesions.

[0126] In certain embodiments, the method results in ameliorating chronic neuroinflammation.

[0127] In certain embodiments, the method results in a delay in progression of Parkinson's disease.

[0128] In certain embodiments, the method results in halting the progression of Parkinson's disease.

[0129] In certain embodiments, the method results in reversal of the progression of Parkinson's disease.

[0130] In certain embodiments, the method further comprises administering to the subject a second therapeutic agent.

[0131] In certain embodiments, the second therapeutic agent is selected from levodopa (L-DOPA), a MAO-B inhibitor, and a dopamine agonist.

[0132] In yet another aspect, the present invention generally relates to the use of BTUDC for treating neurodegenerative diseases or related diseases or conditions.

[0133] In yet another aspect, the present invention generally relates to the use of BTUDC for treating Parkinson's disease or a related disease or condition.

[0134] In yet another aspect, the present invention generally relates to the use of BTUDC for the manufacture of a medicament for preventing or treating a neurodegenerative disease or a related disease or condition.

[0135] In yet another aspect, the present invention generally relates to the use of BTUDC for the manufacture of a medicament for preventing or treating Parkinson's disease or a related disease or condition.

[0136] In yet another aspect, the present invention generally relates to the use of BBR and TUDCA for treating a neurodegenerative disease or a related disease or condition.

[0137] In yet another aspect, the present invention generally relates to the use of BBR and TUDCA for treating Parkinson's disease or a related disease or disorder.

[0138] In yet another aspect, the present invention generally relates to the use of BBR and TUDCA for the manufacture of a medicament for preventing or treating a neurodegenerative disease or a related disease or condition.

[0139] In yet another aspect, the present invention generally relates to the use of BBR and TUDCA for the manufacture of a medicament for preventing or treating Parkinson's disease or a related disease or condition.

[0140] In certain embodiments of the methods disclosed herein, BTUDC is administered at a daily dosage ranging from about 25 mg to about 3,500 mg for a period of about 1 week to about 2 years.

[0141] In certain embodiments of the methods disclosed herein, the total amount of BBR and TUDCA is administered at a daily dosage ranging from about 25 mg to about 3,500 mg for a period of about 1 week to about 2 years.

[0142] In certain embodiments, the weight ratio of BBR to TUDCA is in a range from about 10:1 to about 1:10.

[0143] In yet another aspect, the present invention generally relates to a method for preparing a BTUDC salt disclosed herein, comprising: dissolving tauroursodeoxycholic acid in ethanol; adding an aqueous solution of NaHCO3 to obtain a sodium tauroursodeoxycholate solution; dissolving berberine hydrochloride in hot water to obtain a berberine hydrochloride solution; adding the berberine hydrochloride solution dropwise to the sodium tauroursodeoxycholate solution; stirring the combined solution at about 60° C. to about 80° C. to react; and cooling the combined solution to obtain berberine tauroursodeoxycholate. In certain embodiments, the method further comprises crystallizing the berberine tauroursodeoxycholate.

[0144] In yet another aspect, the present invention generally relates to a method for preparing a solid form disclosed herein, comprising: adding an aqueous solution of sodium tauroursodeoxycholate to an aqueous solution of berberine hydrochloride to form a combined solution; mixing the combined solution; and cooling the combined solution to obtain a solid form.

[0145] In yet another aspect, the present invention generally relates to a method for preparing a solid form disclosed herein, comprising: adding an aqueous solution of tauroursodeoxycholic acid to an aqueous solution of berberine hydrochloride to form a combined solution; mixing the combined solution; and cooling the combined solution to obtain a solid form.

[0146] Possible formulations include those suitable for oral, sublingual, buccal, parenteral (e.g., subcutaneous, intramuscular or intravenous), rectal, topical (including transdermal), intranasal and inhalation administration. The most suitable mode of administration for a particular patient will depend on the nature and severity of the disease or condition being treated or the nature of the therapy being used and the nature of the active compound. Example Characterization methods Nuclear magnetic resonance (NMR)

[0147] NMR characterizations were performed on a Bruker AVANCE NEO 400 (Bruker, GER).Samples were prepared by dissolving 3 mg-5 mg of solid in methanol-d4. X-ray powder diffraction (XRPD)

[0148] Standard XRPD patterns were collected using a Panalytical EMPYREAN (PANalytical, UK). The X-ray source was a Cu tube operating at 45 kV and 40 mA. Powder samples were prepared on a zero-background Si support using manual beam pressure to maintain a flat surface. Each sample was analyzed from 3° to 45° (2θ) with an effective step size of 0.013° 2θ. The measurement time for each sample was 3.5 min.

[0149] Crystal transformation was heated using an online variable temperature XRPD Malvern PANalytical Aeris (MalvernPanalytical, UK). The X-ray source was a Cu tube, and the operating conditions were 40 kV and 7.5 mA. Powder samples were prepared on a zero-background Si stand using manual light pressure to keep the sample surface flat. Each sample was analyzed from 3° to 40° (2θ) with an effective step size of 0.02° 2θ. The measurement time for each sample was 13 min. The sample was placed on a BTS500 hot stage (Anton Paar, AT) to collect XRPD at room temperature, heated to the target temperature at 20°C / min and held for 10 minutes before XRPD analysis. The sample was then cooled to room temperature and characterized by XRPD. Thermogravimetric analysis (TGA)

[0150] Thermogravimetric analysis (TGA) was performed on a TA Instruments Discovery 550 (TA, US). Each sample was placed in a pre-tared platinum pan and heated from room temperature to the set temperature at a heating rate of 10°C / min under a nitrogen atmosphere. The nitrogen purge was 40 mL / min at the balance and 60 mL / min at the furnace. Differential Scanning Calorimetry (DSC)

[0151] DSC analysis was performed on a TA Instruments Discovery 250 (TA, US). Indium was used for calibration of the instrument temperature and cell constant. During each analysis, the DSC cell was maintained under a nitrogen purge of 50 mL / min. The sample was placed on a Tzero airtight pan with a pinhole and heated from 25°C to the set temperature at a rate of 10°C / min. Polarized Light Microscopy (PLM)

[0152] Polarized light microscopic images of the crystals were captured on a Nikon Ci-POL445 polarizing microscope (Nikon, JP) under appropriate objectives. Oil was used for observation in some samples. Single crystal X-ray diffraction (SCXRD)

[0153] SCXRD was collected using XtaLAB Synergy R (DW system, HyPix). The X-ray source was Cu Kα A suitable single crystal was selected and mounted on a glass fiber. The crystal was maintained at a stable temperature of 296 K during data collection. Preliminary inspection, data collection, and analysis were performed using the CrysAlisPro software package.

[0154] The unit cell parameters and orientation matrix used for data collection were retrieved and refined by CrysAlisPro using 33,656 diffraction points within the range of 2.32° <θ < 76.01°. The final data integrity was 99.95% (θ = 66.97°). Data Restoration

[0155] Each image frame was integrated using CrysAlisPro 1.171.42.84a (Rigaku Oxford Diffraction, 2023). A total of 56,856 diffraction points were collected, including 8,736 independent diffraction points. Multi-scan absorption correction was performed using spherical harmonics as implemented in the SCALE3 ABSPACK scaling algorithm. The absorption coefficient μ for this material is 1.201 mm. -1 , and the minimum and maximum transmittances are 0.7952 and 0.8893. The intensity-based Rint value is 5.26%. Single crystal structure analysis and refinement

[0156] The structure was solved in space group P21 using the intrinsic phase method with the SHELXS-97 (Sheldrick, 1990) structure solution program and using Olex2 as a graphical interface. 2 The model was refined using the SHELXS-97 (Sheldrick, 1990) version using the full-matrix least squares method. All non-hydrogen atoms were refined anisotropically. The positions of all hydrogen atoms were calculated and refined using the riding model. Single crystal structure diagram

[0157] The crystal structure and thermal ellipsoid diagram were drawn using Olex2 software. Example 1. Synthesis (Method 1) and Characterization of BTUDC

[0158] Tauroursodeoxycholic acid (1 equivalent) was dissolved in ethanol, and an aqueous NaHCO3 solution (0.95 equivalents to 1.5 equivalents) was added, and the mixture was stirred for 15 minutes to 60 minutes to react to obtain a sodium tauroursodeoxycholate solution.

[0159] Dissolve berberine hydrochloride in hot water. Add the berberine hydrochloride solution dropwise to the sodium tauroursodeoxycholate solution at 60-80°C and stir at 60-80°C for at least 10 minutes. Cool the solution. Filter and dry the precipitate to obtain berberine tauroursodeoxycholate.

[0160] Exemplary of the resulting BTUDC 1 H NMR spectra are provided by Figure 1 For comparison, TUDCA and BBR chloride 1 HNMR spectra are provided in Figure 2 and Figure 3 middle. Single crystal growth and structure confirmation

[0161] The obtained BTUDC sample was used as a raw material, added to methanol / water (1 / 1, V / V), stirred until the solid was completely dissolved and filtered, and the resulting clear solution was left open at room temperature until volatilization to obtain a solid. The PLM image showed that the solid was a cluster and needle-shaped crystal. The needle-shaped crystals obtained were tested by single crystal X-ray diffraction (SCXRD) and the diffraction data were analyzed to obtain the crystal structure. The crystallographic data and refinement parameters of the crystals are detailed in Table 2. The schematic diagram of the asymmetric structural unit is provided in Figure 4 middle. Figure 5 Schematic diagram of the BTUDC single crystal unit cell. Table 2. Crystallographic data and refinement parameters *O11 and O12 were not hydrotreated. **Molecular weight of O11 and O12 without hydrogenation treatment

[0162] The results show that the crystal belongs to the monoclinic system, P21 space group, and the unit cell parameters { α=90°, β=109.5641(12)°, γ=90°, The single crystal structure shows that the asymmetric structural unit of the crystal structure contains a berberine salt of tauroursodeoxycholic acid and two water molecules with a salt ratio of 1:1, and the occupancy ratios of these two water molecules are 0.45 (O11) and 0.38 (O12), respectively; the chemical structure of the crystal is shown below. According to the analysis results, the hydrate is a hydrate with a non-fixed stoichiometric ratio, and the number of water molecules can vary within a certain range, for example, within a range of 0 to 2. Example 2. Synthesis (Method 2) and Characterization of BTUDC

[0163] Tauroursodeoxycholic acid (1 eq) was added to water and stirred until dissolved. An aqueous solution of NaHCO3 (0.95 eq-1.5 eq) was added and stirred for at least 10 minutes to obtain a sodium tauroursodeoxycholate solution.

[0164] Dissolve berberine hydrochloride in hot water. Add the sodium tauroursodeoxycholate solution at 60°C-80°C and stir at 60°C-80°C for at least 10 minutes. Cool the solution. Filter the mixture. Wash and dry the filter cake to obtain berberine tauroursodeoxycholate.

[0165] Exemplary of the resulting BTUDC 1 HNMR spectra are provided by Figure 30 middle. Crystal form characterization

[0166] The synthesized BTUDC is named as Form A (Form A), and its XRPD diffraction and other relevant characterization data are shown in Figure 11-Figure 15 PLM images showed that Form A was short rod-shaped particles with a particle size generally less than 10 μm; XRPD results showed that it was a crystalline solid. TGA results showed that there was a 1.2% weight loss during heating to 150°C, and decomposition could occur above 300°C. DSC results showed the presence of a broad endothermic signal from room temperature to 80°C (peak at 43°C) and an endothermic peak at approximately 280°C. Thermal crystallization experiments showed that the crystalline form remained unchanged during heating to 150°C and returning to room temperature, and NMR results showed that the sample was consistent with the reference spectrum. Fast dynamic vapor sorption (DVS) results showed that the adsorption weight increased by approximately 0.74% at 95% relative humidity, the adsorption weight increased by approximately 0.46% at 80% relative humidity, and the desorption weight increased by approximately 0.49%. XRPD results showed that the crystalline shape of the sample did not change after the DVS test compared to before the test. KF titration results showed that the batch of samples had a moisture content of 2.4%.

[0167] The BTUDC raw material and single crystal sample obtained from Example 1 were subjected to XRPD characterization, and the results are shown in Figure 31 and Figure 16 Based on the comparison of XRPD results, it can be seen that the single crystal sample of Example 1 belongs to the same crystalline type as Form A. Therefore, from the characterization results of Form A and the structural analysis of the single crystal structure of BTUDC, it is determined that Form A is a hydrate with a non-fixed stoichiometric ratio. Other relevant characterization data of the BTUDC raw material obtained from Example 1 are shown in Figure 32-Figure 33 middle.

[0168] The stability of Form A was studied under high temperature (60°C), high humidity (25°C / 92.5% RH), light (25°C / 4500 Lux) and accelerated (40°C / 75% RH) conditions. Samples were taken at 7 days and 15 days for XRPD characterization and HPLC testing, respectively. The results are shown in Tables 3-4 and Figure 17XRPD results showed that Form A was stable under high temperature, high humidity, light, and accelerated conditions for 15 days without undergoing crystalline transformation. HPLC results showed that the chemical purity of Form A remained unchanged when exposed to high temperature, high humidity, and accelerated conditions for 15 days. However, the chemical purity of Form A decreased significantly when exposed to light for 15 days. Table 3. Stability study of Form A Table 4. HPLC analysis for stability studies of Form A Information related to the preparation of animal test articles raw material Table 5. Information about raw materials Preparation information

[0169] Preparation of 0.5% sodium carboxymethylcellulose (0.5% CMC-Na): 0.5 g of CMC-Na was added to purified water and stirred until a clear solution was obtained, and water was added to a final volume of 100 mL. Table 6. Test product information

[0170] Preparation of PD modeling agent: 20 μg of 6-hydroxydopamine (6-OHDA) was dissolved in 8 μL of 0.9% saline (containing 0.02% ascorbic acid). Animal models

[0171] Rats were anesthetized with isoflurane inhalation; the head was fixed to prevent movement and the brain surface was adjusted to be flat; the head was shaved, and a skin incision was made along the sagittal suture to expose the bregma point; a glass electrode was positioned at the anterior bregma, and the axis of the coordinate monitor was zeroed to locate the brain regions of the SN and Str based on the coordinates, where SN: AP = -5.0 mm; ML = -1.9 mm; DV = -8.5 mm, Str: AP = +0.5 mm; ML = -3.0 mm; DV = -6.0 mm. (8.5 mm, Str: AP = +0.5 mm; ML = -3.0 mm; DV = -6.0 mm); after slowly inserting the needle and positioning it at the SN and Str, wait for 10 minutes, and then administer 6-OHDA at a rate of 0.4 μL / min for 10 minutes, with 4 μL each in the SN and Str regions of each animal. The needle was then slowly withdrawn 10 minutes after drug administration to establish the PD rat model. Information on methods for modeling surgical PD can also be found in the literature, which embodies injection sites at local areas of SN and Str, respectively (Sokoudi, et al. 2022 Physiol. Res. 71(4):551-560; Haddadi, et al. 2013 Neuroscience Letters 555, 106-111.). Test Method 1. Apomorphine-asymmetric rotation test

[0172] Three weeks after modeling and administration, the animals were tested. 0.5 mg / kg apomorphine was injected intraperitoneally. The number of rotations per rat was recorded over 30 minutes, with the rat rotating in place using the lateral forelimb as a support point toward the side contralateral to the injury. Information on the apomorphine-asymmetric rotation test can be found in the literature (Ximenes et al. 2015 J Neurodegener Dis. 2015:313702). 2. Balance beam test

[0173] The rats were placed on a balance beam. The time it took for the rats to cross the balance beam and the number of foot slips (the feet left the top of the balance beam) were recorded. The average of the two successful crossing times and the number of foot slips was used to assess the rats' motor balance ability. Information about the balance beam can also be found in the literature (Allbutt, et al. 2007 J Neurosci Methods 159 (2): 195-202; Fine, et al. 2014 Brain Res. 1574: 96-104). 3. Grip test

[0174] The animal is placed on a platform with both forelimbs placed on a gripping bar. The tail of the animal is then grasped and pulled straight back until the pulling force exceeds its gripping force. After the animal loses its gripping force, the preamplifier automatically records the maximum gripping force. After the measurement is completed, the average value of the maximum gripping force of each group of animals is calculated to assess the motor muscle capacity of the rat. Information on grip strength testing can also be found in the literature (Jeyasingham, et al. 2001 Brain Res Bull. 55 (4): 541-8). 4. Rotarod Test

[0175] The rotation speed of the rotarod fatigue tester was set to 20 rpm / min, and the test time was 5 min. Animals were placed on the rotarod in batches for testing, and the time each animal stayed on the rod was recorded to assess the rat's motor coordination ability. Information about the rotarod test can also be found in the literature (Bohlen, et al. 2009 J Neurosci Methods 178(1):10-4). 6. Perfusion-Fixation-Sugar Sedimentation-Slicing (Str / SN Brain Region)

[0176] After anesthetizing the rat, the abdominal cavity and thoracic cavity were opened with straight scissors to expose the heart. First, the blood was flushed out with normal saline perfusion, and then paraformaldehyde was used for perfusion and initial fixation. The head was cut off, the skull was carefully opened with forceps, the brain tissue was removed, and it was placed in paraformaldehyde solution for fixation for 24 hours; on the second day, the brain tissue was removed and placed in 20% sucrose solution for 24 hours; on the third day, the brain tissue was removed and placed in 30% sucrose solution for 24 hours; on the fourth day, the brain tissue was removed and placed in 35% sucrose solution for 24 hours (the time was appropriately extended or the concentration was increased according to the sugar deposition in the brain tissue); the brain tissue was removed, embedded in OCT embedding medium, and cut into 16 μm thick brain slices using a freezing microtome. 7. Immunofluorescence staining (TH, Iba-1)

[0177] Immunohistochemical staining for TH and Iba-1 was performed on sections. Sections were rewarmed for 30 minutes and blocked with 50 μL of 10% serum + 0.3% Triton X-100 for 1 hour at room temperature. Sections were shaken out and the primary antibody (diluted in PBS) was added and incubated overnight at 4°C. The sections were rewarmed for 30 minutes and the primary antibody was removed (3 times for 5 minutes in PBS). Secondary antibody (diluted in PBS) was added under backlight and incubated at room temperature for 2 hours. The secondary antibody was removed (3 times for 5 minutes in PBS). 4',6-diamidino-2-phenylindole (DAPI) was added and incubated at room temperature for 10 minutes. The DAPI was removed (3 times for 5 minutes in PBS). The sections were sealed with 70% glycerol to avoid air bubbles. Sections were observed and photographed under a microscope. The target brain region was essentially the same for each section. After imaging, the number or area of ​​signals across the entire section was counted using ImageJ. 8. Elisa test (IL-6, IL-1β, TNF-α)

[0178] Cerebrospinal fluid was directly extracted by inserting a needle into the foramen magnum, and the supernatant was collected after centrifugation for ELISA testing. The kits were from Shanghai Enzyme Link. The product codes for IL-6, IL-1β, and TNF-α were ml064292, ml037361, and ml002859, respectively. Samples were processed according to the ELISA kit instructions. A blank well was used as the zero setting, and the absorbance (OD) of each well was measured at a wavelength of 450 nm. Sample concentrations were calculated based on the standard curve and the OD values. 9. Statistics

[0179] SPSS software was used for statistical analysis (one-way analysis of variance, with p < 0.05 considered significant), and Graph Pad software was used to create images based on the SPSS analysis results. Histological examinations were plotted using Adobe Photoshop software. Significant statistical differences (p < 0.001), highly significant statistical differences (p < 0.01), and statistically significant differences (p < 0.05) were observed. Example 2. Tolerability and efficacy test of rat Parkinson's disease (PD) model induced by 6-OHDA injection

[0180] Animal models : The PD model was established by stereotaxic injection of 6-OHDA into the brain of Sprague-Dawley rats. 1. Methods:

[0181] In this study, 16 Sprague Dawley (SD) male rats weighing 180g-220g were used. After one week of adaptive feeding, 6-OHDA was stereotactically injected unilaterally into the substantia nigra (SN) and striatum (Str) brain regions to establish a PD model. The rats were randomly divided into two groups of 8 rats each. One group of rats was administered the test compound BTUDC 500mg / kg (QD, po), while the other group of rats, a model group, was administered an equal volume of 0.5% CMC-Na (QD, po) to the test compound group. Animals were administered once daily for 21 consecutive days starting from the second day after modeling to evaluate the tolerability and therapeutic potential of BTUDC in the 6-OHDA PD model. 2. General status observation :

[0182] The body weight and food intake of the rats were collected and recorded every day, and the animals were observed in their cages. 3. Behavioral testing:

[0183] After 21 days of drug administration, the following tests were performed: apomorphine-asymmetric rotation test, balance beam test, grip strength test, and rotarod test. 4. Results:

[0184] During the test period, animals in each group were in good condition, with no abnormal or unexpected deaths. Both the drug-treated and model groups showed weight loss on Day 1 after modeling due to surgical trauma, and began to steadily gain weight on Day 2 after the trauma gradually recovered, with similar weight changes between the two groups. Four days after modeling, food intake steadily increased in both the drug-treated and model groups, and food intake stabilized from Day 5 onwards. Tolerability and efficacy :

[0185] Figures 6-10 Figure 4 shows exemplary results from various experiments involving ipsilateral rotation, beam crossing time, beam foot slips, time on the bar, and grip strength tests.

[0186] On day 21 after stereotaxic injection of 6-OHDA, all rats showed in situ rotation behavior on the contralateral side of the injury using the rotating forelimb as a support point after apomorphine (APO) induction, indicating that the model has been successfully established. Within 30 minutes, there was no statistically significant difference in the number of ipsilateral rotations between the test compound group and the model group (p>0.05). Table 7. After 21 days of treatment, the effects of the test compounds on the number of ipsilateral rotations were determined within 30 minutes of apomorphine injection. ring. Group dose Number of same-side rotations Model solvent 126.380±31.681 Test compound 500 mg / kg / day 109.000±23.670

[0187] During the entire study period, there were no significant differences in body weight and food intake data between the model control group and the test compound treatment group. In addition, compared with the model group, no mortality or moribundity associated with the test compound was noted in the test compound treatment group, nor was abnormal animal status noted, indicating that the test compound was well tolerated in the PD rat model. Compared with the model group, after 21 consecutive days of treatment with the test compound, the rats in the test compound group showed a significant reduction in the time to pass through the balance beam test (p < 0.001) and a significant reduction in the number of foot slips (p < 0.001), a significant extension of the time on the rod in the rotating rod test (p < 0.001), and a significant increase in the peak grip force in the grip test (p < 0.001). Table 8. After 21 days of compound treatment, behavioral examination of PD rats induced by 6-OHDA stereotaxic injection (balanced Wood test, rotating rod test, grip strength test) Note: Compared with the model group, ***P<0.001

[0188] This study demonstrated that the test compounds were well tolerated by the PD rat model and that the test compounds exhibited beneficial effects in Parkinson's disease model animals induced by stereotaxic injection of 6-OHDA into the substantia nigra and striatum of rats. Example 3. Pharmacodynamic study on Parkinson's disease

[0189] Animal models : The PD model was established by stereotaxic injection of 6-OHDA into the brain of Sprague-Dawley rats.

[0190] Experimental methods:Select 70 180g-220g SD male rats, adaptive feeding one week, set up PD model by stereotactic unilateral injection of 6-OHDA in substantia nigra (SN) and corpus striatum (Str) region, and be randomly divided into five groups according to its body weight, these five groups comprise Madopar group (Madopar, 50mg / kg), BTUDC-L group (BTUDC, 100mg / kg), BTUDC-M group (BTUDC, 500mg / kg) and BTUDC-H group (BTUDC, 1000mg / kg), wherein every group has 10 animals.Choose other 10 SD male rats and carry out sham-operated control group operation (only 4 μ L contain 0.02% ascorbic acid 0.9%NS localization injection to SN and Str brain region during modeling), as sham-operated control group.From the second day of modeling (first day of administration, D1), by oral gavage mode, once a day continuous administration medicine, keep 21 days.During administration phase, carry out general state observation. At the end of the dosing period, the tolerability of the test article in this model was assessed, and behavioral tests including apomorphine-asymmetric rotation test, balance beam test, rotarod test, and grip strength test, immunofluorescence staining (TH, Iba1), and analysis of inflammatory factors in cerebrospinal fluid were performed to evaluate the pharmacodynamic effects of the test article. The inflammatory factors tested included interleukin-6 (1L-6), interleukin-1β (1L-1β), and tumor necrosis factor α (TNF-α). Inflammation assays were performed in a total of four groups (including sham control group, model group, Madopar group, and BTUDC-H group). Table 9. Dosing volume: 10mL / kg

[0191] 1. General Observation: During the drug administration period, body weight, food intake test and cage observation were performed every 3 days.

[0192] 2. Behavioral test: 21 days after administration, behavioral test was carried out starting on the second day.

[0193] 3. Histochemical test: After the behavioral test, cerebrospinal fluid was collected from each animal (N=10), the supernatant was collected by centrifugation, and stored at -80°C for Elisa test (IL-6, IL-1β, TNF-α). Then, animals in each group (N=5) were randomly selected, and the striatum on the modeling side was taken for neurotransmitter content detection. The remaining animals (N=5) underwent cardiac perfusion, and after perfusion, fixation, precipitation, and sectioning, they were used for immunofluorescence staining, photographed, and the number or area of ​​signals were counted using ImageJ software.

[0194] 4. Data Analysis: After summarizing the data and counting them, they were analyzed using SPSS statistical software (one-way ANOVA, p < 0.05 was considered a significant difference), and images were drawn using Graph Pad software based on the results of SPSS analysis. Histological examination results were generated using Adobe Photoshop software. result

[0195] The results of the rotation test of APO-induced PD model rats are shown in Figure 18 After APO induction, rats in each administration group and model group showed the behavior of turning in place toward the opposite side of the injury using the rotating forelimb as a support point. Compared with the sham-operated control group, the rats in the model group rotated in a circle within 30 minutes after apomorphine injection. The number of rotations increased significantly (p < 0.001), indicating that the model has been successfully established. Compared with the model group, the rats in the BTUDC-H group injected with apomorphine had significantly fewer rotations within 30 minutes, indicating that BTUDC has the potential to protect neurons in the brain. Table 10. Results of behavioral tests (grasp strength test, rotarod test, and balance beam test) of PD model rats Notes: Mean ± SEM, N = 10; *** - p < 0.001 relative to the model; ** - p < 0.01 relative to the model; * - p < 0.05 relative to the model.

[0196] The results of the grip strength test of PD model rats are shown in Figure 19 and Table 10. Compared with the model group, the peak grip force of rats in each administration group (G3-G6) was significantly higher than that in the model group, and the difference was extremely significant (p < 0.001). Different doses of BTUDC administration group increased the peak grip force in a dose-dependent manner.

[0197] The results of the rotarod test of PD rats are shown in Figure 20 The time spent on the rod by rats in each administration group (G3-G6) was significantly longer than that in the model group; the effect of different doses of BTUDC administration groups on prolonging the time spent on the rod was dose-dependent, among which the time spent on the rod by the medium and high doses of BTUDC groups was statistically significantly longer than that in the model group (p < 0.001).

[0198] The results of the time it takes for PD rats to pass the balance beam in the balance beam test are shown in Figure 21 Compared with the model group, the time for rats in each administration group (G3-G6) to pass the balance beam was significantly shorter than that in the model group (p < 0.01); the effect of different doses of BTUDC on prolonging the time to pass the balance beam was dose-dependent.

[0199] The results of the number of foot slips of PD rats in the balance beam test are shown in Figure 22 Compared with the model group, the number of times the rats in each administration group (G3-G6) slipped on the balance beam was significantly less than that in the model group (p < 0.05); the effect of different doses of BTUDC on increasing the number of times the rats slipped on the balance beam was dose-dependent. Table 11. Results of TH staining and Iba-1 staining in the Str and SN brain regions Notes: Mean ± SEM, N = 15; *** - p < 0.001 versus model; ** - p < 0.01 versus model; * - p < 0.05 versus model; 5 animals per group; three sections of each animal were used for TH staining and Iba-1 staining statistics, N = 5*3.

[0200] The results of TH staining are shown in Figure 23 The results of TH staining of the fluorescence intensity in the brain region of rat Str after 21 days of administration are shown in Tables 11 and Figure 24 The results of TH staining for the number of positive cells in the SN brain region of rats 21 days after administration are shown in Tables 11 and Figure 25 Compared with the sham-operated control group, the fluorescence intensity of TH staining in the Str brain region and the number of TH-positive cells in the SN brain region in the model group rats were significantly reduced, and the difference was extremely significant (p < 0.001). Compared with the model group, the fluorescence intensity of TH staining in the Str brain region of rats in each administration group (G4-G6) was significantly higher than that in the model group (p < 0.05), and the number of TH-positive cells in the SN brain region of the BTUDC-H group was significantly more than that in the model group (p < 0.001). The effect of BTUDC on increasing the TH fluorescence intensity in the Str brain region and the number of TH-positive cells in the SN brain region of 6-OHDA rats is dose-related. The above results show that BTUDC has a beneficial effect in improving substantia nigra lesions and has a neuronal protective effect.

[0201] The results of Iba-1 staining are shown in Figure 26 The results of Iba-1 staining of the number of positive cells in the rat Str brain region 21 days after administration are shown in FIG. Figure 27 The results of the number of positive cells are shown in Figure 28Compared with the model group, the number of Iba1-positive cells in the Str brain region of rats in each administration group (G4-G6) was significantly lower than that in the model group (p < 0.05). The number of Iba1-positive cells in the SN brain region of the BTUDC-H group was significantly lower than that in the model group (p < 0.001). The effect of BTUDC on improving the number of Iba1-positive cells in the Str and SN brain regions of 6-OHDA rats showed a certain dose-related effect, indicating that BTUDC has the potential to improve chronic neuroinflammation and has a neuroprotective effect. Table 12. Elisa test results of IL-1β / IL-6 / TNF-α in rat cerebrospinal fluid after 21 days of administration Notes: Mean ± SEM, n = 10; *-p < 0.05, **-p < 0.01, ***-p < 0.001 relative to the model

[0202] The results of the Elisa test for IL-1β in rat cerebrospinal fluid after 21 days of administration are shown in Tables 12 and Figure 29 middle.

[0203] The results of the Elisa test of 1L-6 in rat cerebrospinal fluid after 21 days of administration are shown in Tables 12 and Figure 30 middle.

[0204] The results of ELISA analysis of TNF-α in rat cerebrospinal fluid after 21 days of administration are shown in Figure 31 middle.

[0205] In summary, animals tolerated BTUDC up to 1000mg / kg well and showed no significant abnormalities in weight gain or food intake compared to animals in other groups. BTUDC showed beneficial effects in various behavioral tests such as grip strength test, rotarod test, and balance beam test, and the beneficial effects were dose-dependent, and the improvement effects in the medium and high dose groups reached statistical significance. In addition, BTUDC also increased the number and intensity of tyrosine hydroxylase-positive cells and reduced the number of microglia. BTUDC dose-dependently increased the fluorescence intensity of tyrosine hydroxylase (TH)-positive cells in the Str brain region, and the high dose BTUDC group significantly increased the number of TH-positive cells in the SN brain region. All BTUDC-treated groups significantly reduced the number of microglia (Iba1) in the Str brain region. The high dose BTUDC group significantly reduced the number of microglia (Iba1) in the SN brain region.

[0206] Applicants' disclosure is herein described in terms of preferred embodiments with reference to the accompanying drawings, wherein like numerals represent identical or similar elements. Reference throughout this specification to "one embodiment" or "an embodiment" or similar language means that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases "in one embodiment," "in an embodiment," and similar language throughout this specification may, but do not necessarily, all refer to the same embodiment.

[0207] The features, structures or characteristics of the applicant's disclosure may be combined in any suitable manner in one or more embodiments. In the description herein, many specific details are described to provide a thorough understanding of the embodiments of the present invention. However, those skilled in the relevant art will recognize that the applicant's compositions and / or methods may be practiced without one or more specific details, or practiced with other methods, components, materials, etc. In other cases, well-known structures, materials or operations are not shown or described in detail to avoid obscuring aspects of the present disclosure.

[0208] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. The methods described herein can be performed in any order that is logically possible, except for the specific order disclosed. References

[0209] References and citations to other documents, such as patents, patent applications, patent publications, periodicals, books, papers, and web content are incorporated throughout this disclosure. All of these documents are hereby incorporated by reference in their entirety for all purposes. Any material or portion thereof that is considered to be incorporated by reference herein but conflicts with existing definitions, statements, or other public materials clearly set forth herein is incorporated only to the extent that no conflict occurs between the incorporated material and the present disclosure. In the event of a conflict, the conflict will be resolved in a manner that is beneficial to the present disclosure as a preferred disclosure. equivalent

[0210] The representative examples are intended to help illustrate the present invention and are not intended to, and should not be construed as, limiting the scope of the present invention. Indeed, various modifications of the present invention and many other embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art in light of the entire disclosure herein, including the present examples and the references to the scientific and patent literature contained herein. These examples contain important additional information, illustrations, and guidance that may be suitable for the practice of the present invention in its various embodiments and their equivalents.

Claims

1. A salt of formula (I):

2. A salt in substantially pure form, wherein the salt is represented by formula (I):

3. The salt of claim 2, wherein the salt is characterized by a purity equal to or greater than 95%.

4. The salt according to any one of claims 1 to 3, wherein the salt is prepared by an acid-base reaction between berberine (BBR) and tauroursodeoxycholic acid (TUDCA).

5. A solid form of a compound of formula (I), i.e., Form A, wherein its X-ray powder diffraction (XRPD) pattern comprises one or more characteristic diffraction peaks at the following 2θ angles when using a Cu-Kα ray source: 4.62°, 9.32°, 17.02°±0.2°.

6. The solid form according to claim 5, wherein the XRPD pattern of the solid form further comprises one or more characteristic diffraction peaks at the following 2θ angles: 5.96°, 6.23°, 15.19°±0.2° when using a Cu-Ka ray source.

7. The solid form of claim 5, wherein the XRPD pattern of the solid form comprises characteristic diffraction peaks at the following 2θ angles: 4.62°, 5.96°, 6.23°, 9.32°, 15.19°, 17.02°±0.2° when using a Cu-Ka ray source.

8. The solid form of claim 7, wherein the XRPD pattern of the solid form further comprises one or more of characteristic diffraction peaks at the following 2θ angles: 11.99°, 12.56°, 12.90°±0.2° when using a Cu-Ka ray source.

9. The solid form of claim 5, wherein the XRPD pattern of the solid form comprises characteristic diffraction peaks at the following 2θ angles when using a Cu-Ka radiation source: 4.62°, 5.96°, 6.23°, 9.32°, 11.99°, 12.56°, 12.90°, 13.32°, 14.25°, 14.88°, 15.19°, 17.02°, 17.51°, 17.73°, 18.02°, 21.39°, 24.25°, 24.71°±0.2°.

10. The solid form of any one of claims 5 to 9, wherein a differential scanning calorimetry (DSC) curve of the solid form comprises an endothermic peak having a peak at about 280°C.

11. The solid form of any one of claims 5 to 10, wherein a thermogravimetric analysis (TGA) profile of the solid form comprises a weight loss from about 0.5% to about 3% from room temperature to 150°C.

12. The solid form of any one of claims 5 to 11, wherein the solid form is characterized by a BTUDC:H2O ratio of 1:X, wherein X is a number in the range of 0 to 2.

13. The solid form of claim 12, wherein the solid form is an anhydrate.

14. The solid form of claim 12, wherein the solid form is a hydrate having at most 2 H2O molecules per BTUDC molecule.

15. The solid form of any one of claims 5 to 14, wherein the solid form is a crystalline form.

16. A pharmaceutical composition comprising the salt according to any one of claims 1 to 4 and a pharmaceutically acceptable excipient, carrier or diluent.

17. A pharmaceutical composition comprising the solid form according to any one of claims 5 to 15 and a pharmaceutically acceptable excipient, carrier or diluent.

18. A unit dosage form comprising the pharmaceutical composition according to claim 16 or 17.

19. A method for alleviating, preventing or treating a neurodegenerative disease, comprising administering to a subject in need thereof a pharmaceutical composition comprising the salt according to any one of claims 1 to 4.

20. A method for alleviating, preventing or treating a neurodegenerative disease, the method comprising administering to a subject in need thereof a pharmaceutical composition comprising the solid form according to any one of claims 5 to 15.

21. A method for alleviating, preventing or treating Parkinson's disease, comprising administering to a subject in need thereof a pharmaceutical composition comprising the salt according to any one of claims 1 to 4.

22. A method for alleviating, preventing or treating Parkinson's disease, the method comprising administering to a subject in need thereof a pharmaceutical composition comprising the solid form according to any one of claims 5 to 15.

23. The method of claim 21 or 22, wherein one or more symptoms of Parkinson's disease are reduced or improved.

24. The method of claim 23, wherein progression of Parkinson's disease is delayed.

25. The method of claim 23, wherein progression of Parkinson's disease is arrested.

26. The method of claim 23, wherein the progression of Parkinson's disease is reversed.

27. The method of any one of claims 19 to 26, wherein a dose of about 25 mg to about 3,500 mg is administered to the subject daily.

28. The method of any one of claims 19 to 27, further comprising administering to the subject a second therapeutic agent.

29. The method of claim 28, wherein the second therapeutic agent is selected from the group consisting of levodopa (L-DOPA), a MAO-B inhibitor, and a dopamine agonist.

30. Use of berberine tauroursodeoxycholate (BTUDC) for treating neurodegenerative diseases or related diseases or conditions.

31. Use of BTUDC for treating Parkinson's disease or related diseases or conditions.

32. Use of BTUDC for the manufacture of a medicament for preventing or treating a neurodegenerative disease or a related disease or condition.

33. Use of BTUDC for the manufacture of a medicament for the prevention or treatment of Parkinson's disease or a related disease or condition.

34. The use according to any one of claims 30 to 33, wherein the BTUDC is in the solid form according to any one of claims 5 to 15.

35. A method for alleviating, preventing or treating a neurodegenerative disease, the method comprising administering to a subject in need thereof a pharmaceutical composition comprising berberine (BBR) and tauroursodeoxycholic acid (TUDCA).

36. A method for alleviating, preventing or treating Parkinson's disease, the method comprising administering to a subject in need thereof a pharmaceutical composition comprising berberine (BBR) and tauroursodeoxycholic acid (TUDCA).

37. The method of claim 36, wherein one or more symptoms of Parkinson's disease are reduced or improved.

38. The method of claim 36, wherein progression of Parkinson's disease is delayed.

39. The method of claim 36, wherein progression of Parkinson's disease is arrested.

40. The method of claim 36, wherein the progression of Parkinson's disease is reversed.

41. The method of any one of claims 35 to 40, wherein a dosage of about 25 mg to about 3,500 mg of BBR and TUDCA is administered to the subject daily.

42. The method of any one of claims 35 to 41, further comprising administering to the subject a second therapeutic agent.

43. The method of claim 42, wherein the second therapeutic agent is selected from the group consisting of levodopa (L-DOPA), a MAO-B inhibitor, and a dopamine agonist.

44. Use of berberine (BBR) and tauroursodeoxycholic acid (TUDCA) for treating neurodegenerative diseases or related diseases or conditions.

45. Use of berberine (BBR) and tauroursodeoxycholic acid (TUDCA) for treating Parkinson's disease or a related disease or condition.

46. ​​Use of berberine (BBR) and tauroursodeoxycholic acid (TUDCA) for the manufacture of a medicament for preventing or treating a neurodegenerative disease or a related disease or condition.

47. Use of berberine (BBR) and tauroursodeoxycholic acid (TUDCA) for the manufacture of a medicament for preventing or treating Parkinson's disease or a related disease or condition.

48. A method for preparing a salt according to any one of claims 1 to 4, comprising: Dissolve tauroursodeoxycholic acid in ethanol; Add an aqueous solution of NaHCO3 to obtain a sodium tauroursodeoxycholate solution; dissolving berberine hydrochloride in hot water to obtain a berberine hydrochloride solution; adding the berberine hydrochloride solution dropwise to the sodium tauroursodeoxycholate solution; stirring the combined solution at about 60° C. to about 80° C.; as well as The combined solutions were cooled to obtain berberine tauroursodeoxycholate.

49. The method of claim 48, further comprising: Crystallization of berberine tauroursodeoxycholate.

50. A method for preparing a solid form according to any one of claims 5 to 15, comprising: adding the aqueous solution of sodium tauroursodeoxycholate to the aqueous solution of berberine hydrochloride to form a combined solution; mixing the combined solutions; as well as The mixed combined solution was cooled to obtain the solid form.

51. A method for preparing a solid form according to any one of claims 5 to 15, comprising: adding the aqueous tauroursodeoxycholic acid solution to the aqueous berberine hydrochloride solution to form a combined solution; mixing the combined solutions; as well as The mixed combined solution was cooled to obtain the solid form.

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