Pharmaceutical composition containing xanomeline or salt thereof

Abstract

Provided in the present invention is a pharmaceutical composition of xanomeline. The pharmaceutical composition contains xanomeline pamoate and a pharmaceutically acceptable carrier, and can be used for preparing a suspension or a lyophilized formulation for injection. The suspension has a stable particle size, is less likely to experience particle sedimentation, and has a good re-suspension property. The lyophilized formulation is easily resuspended to obtain a uniform suspension. The composition has good stability, can quickly take effect after administration, prolongs the duration of drug action, reduces the administration frequency, reduces the side effects of the drug, and significantly improves the quality of life of patients.

Description

A pharmaceutical composition containing xanomeline or its salt

[0001] This invention claims the priority benefit of the prior application filed by the applicant with the State Intellectual Property Office of China on February 6, 2024, with patent application number CN202410171024.7 and invention name “A pharmaceutical composition containing xanomeline or its salt”. The contents of the above application are incorporated into this text by reference. Technical Field

[0002] The present invention belongs to the field of pharmaceutical compositions, and in particular relates to a pharmaceutical composition containing xanomeline or a salt thereof and an application thereof in preparing a drug for preventing or treating diseases improved by activating muscarinic receptors. Background Art

[0003] Xanomeline, whose chemical name is 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine, is a partial agonist of muscarinic receptors and can be used to treat schizophrenia, Alzheimer's disease, etc.

[0004] Xanomeline is easily absorbed orally, can cross the blood-brain barrier, and has high bioavailability, but it can cause adverse gastrointestinal and cardiovascular reactions. Karuna Therapeutics, Inc. in the United States, has developed an oral combination formulation of xanomeline and trospium chloride in an attempt to mitigate xanomeline's adverse reactions. However, this formulation still requires daily administration, which requires a long period of use. Furthermore, patients with mental illness have poor medication compliance and often forget or refuse to take their medication, which affects treatment effectiveness. Furthermore, the side effects of long-term medication use cause significant pain and inconvenience for patients.

[0005] Therefore, it is necessary to develop a sustained-release injection preparation with good stability that can take effect quickly, prolong the efficacy, reduce the frequency of administration, improve patient compliance, reduce drug side effects, and improve the quality of life of patients. Summary of the Invention

[0006] In order to improve the deficiencies of the prior art, the present invention provides a pharmaceutical composition containing xanomeline, comprising xanomeline pamoxate and a pharmaceutically acceptable carrier.

[0007] According to an embodiment of the present invention, the content of the xanomeline pamoxate is 0.5 to 50 wt % based on the weight of the pharmaceutical composition.

[0008] According to some embodiments of the invention, the content of xanaxine pamoxate is 1 to 45 wt %, such as 3 to 42 wt %, such as 5 to 40 wt %, such as 5 wt %, 6 wt %, 7 wt %, 8 wt %, 9 wt %, 10 wt %, 11 wt %, 12 wt %, 13 wt %, 14 wt %, 15 wt %, 16 wt %, 17 wt %, 18 wt %, 19 wt %, 20 wt %, 21 wt %, 22 wt %, 23 wt %, 24 wt %, 25 wt %, 26 wt %, 27 wt %, 28 wt %, 29 wt %, 30 wt %, 31 wt %, 32 wt %, 33 wt %, 34 wt %, 35 wt %, 36 wt %, 37 wt %, 38 wt %, 39 wt %, 40 wt % or the interval limited by any of these numerical values, based on the weight of the pharmaceutical composition.

[0009] According to an embodiment of the present invention, the pharmaceutically acceptable carrier includes a suspending agent, and the suspending agent is selected from one or more of gums, celluloses, starches, carbomer, polyvinyl pyrrolidone (PVP), dextran and polyethylene glycol (PEG). For example, the suspending agent is selected from sodium carboxymethylcellulose (CMC-Na), calcium carboxymethylcellulose (CMC-Ca), methylcellulose (MC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), hydroxypropyl methylcellulose (HPMC), hydroxypropylethyl cellulose (HPEC), carboxymethyl cellulose, hydroxypropyl methylcellulose phthalate (HPMCP); hydroxyethyl starch (HES); carbomer 980; gum arabic, xanthan gum; polyvinyl pyrrolidone K12 (PVP-K12), polyvinyl pyrrolidone K17 (PVP-K17), polyvinyl pyrrolidone K30 (PVP-K30); dextran 40 (Dextran-40), dextran 70 (Dextran-70); polyethylene glycol 1500 (PEG 1500), polyethylene glycol 4000 (PEG 4000), polyethylene glycol 6000 (PEG 6000) and polyethylene glycol 8000 (PEG 8000) or more.

[0010] According to some embodiments of the present invention, the suspending agent is selected from one or more of HPMC, PEG 4000, PVP-K12, PVP-K17, xanthan gum, CMC-Na, hydroxyethyl cellulose (HEC) and sodium alginate.

[0011] According to an embodiment of the present invention, the content of the suspending agent is 0.1-10wt% based on the weight of the pharmaceutical composition. In some embodiments, the content of the suspending agent is 0.2-8wt%, 0.3-7.5wt%, 0.5-7wt%, 0.8-6.5wt%, 1-6wt%, for example, 0.1wt%, 0.2wt%, 0.5wt%, 0.8wt%, 0.9wt%, 1wt%, 1.2wt%, 1.5wt%, 2wt%, 2.5wt%, 3wt%, 3.5wt%, 4wt%, 5wt%, 5.5wt%, 6wt%, 6.5wt%, 7wt%, 7.5wt% or any interval defined by these values, based on the weight of the pharmaceutical composition.

[0012] According to an embodiment of the present invention, the pharmaceutically acceptable carrier optionally includes a wetting agent. The wetting agent is selected from one or more of polysorbate (Tween), fatty acid sorbitan (Span), poloxamer, tyloxapol, phospholipids, vitamin E polyethylene glycol succinate (TPGS), polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, bile salts, higher fatty alcohol sulfates, sulfonates, higher fatty acid salts and polyethylene glycol stearates. For example, the wetting agent is selected from one or more of Tween 20, Tween 40, Tween 80, poloxamer 188, lecithin, vitamin E polyethylene glycol 2000 succinate (TPGS2000), polyoxyethylene 40 hydrogenated castor oil (RH40), tyloxapol, poloxamer 188, sodium lauryl sulfate (SDS), polyethylene glycol -15 hydroxystearate (HS-15), sodium docusate and sodium oleate.

[0013] According to some embodiments of the present invention, the wetting agent is selected from one or more of Tween 20, Tween 40, Tween 80, lecithin, TPGS, RH40 and tyloxapol.

[0014] According to an embodiment of the present invention, the content of the wetting agent is 0-6wt% based on the weight of the pharmaceutical composition. In some embodiments, the content of the wetting agent is 0.01-5.5wt%, 0.05-5wt%, 0.08-4wt%, 0.1-3wt%, 0.2-2.5wt%, 0.3-2wt%, for example, 0.1wt%, 0.2wt%, 0.5wt%, 0.8wt%, 1.0wt%, 1.2wt%, 1.5wt%, 2wt%, 2.5wt%, 3wt% or any interval defined by these values, based on the weight of the pharmaceutical composition.

[0015] According to an embodiment of the present invention, optionally, the pharmaceutically acceptable carrier further comprises one or more of a pH regulator, an osmotic pressure regulator, and a solvent. The pH regulator is selected from an acid, an alkali, or a buffer salt, such as hydrochloric acid, sulfuric acid, citric acid, tartaric acid, sodium citrate, sodium hydroxide, potassium hydroxide, triethylamine, meglumine, amino acids, phosphate buffer salts (disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, etc.), citric acid buffer salts, tartaric acid buffer salts, malic acid buffer salts, and acetate buffer salts. The osmotic pressure regulator is selected from one or more of sodium chloride, potassium chloride and glycerol, and its dosage is to adjust the osmotic pressure of the pharmaceutical composition to 250-1000mOsm / kg, for example, 250mOsm / kg, 300mOsm / kg, 350mOsm / kg, 400mOsm / kg, 450mOsm / kg, 500mOsm / kg, 550mOsm / kg, 600mOsm / kg, 650mOsm / kg, 700mOsm / kg, 750mOsm / kg, 800mOsm / kg, 850mOsm / kg, 900mOsm / kg, 950mOsm / kg, and 1000mOsm / kg; the solvent is water or vegetable oil, preferably water.

[0016] According to an embodiment of the present invention, the pH adjusting agent is used in an amount to adjust the pH of the pharmaceutical composition to about 4.0-8.5. In some embodiments, the pH of the pharmaceutical composition is adjusted to about 4.5-8.0, 4.5-7.5, 4.0-7.0, or 5.0-7.0. For example, the pH value is selected from 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, or an interval defined by any of these values.

[0017] According to an embodiment of the present invention, the pharmaceutically acceptable carrier optionally includes a filler. The filler may be selected from one or more of mannitol, trehalose, sucrose, glycerol, xylitol, sorbitol, maltose, glucose, starch, and sucralose. The content of the filler is 0-10 wt %, preferably 1-9 wt %, 2-8 wt %, 3-6 wt %, or 4-5 wt %, based on the weight of the pharmaceutical composition.

[0018] According to an embodiment of the present invention, optionally, the pharmaceutically acceptable carrier includes an antibacterial agent, a stabilizer, etc. The antibacterial agent may be selected from one or more of benzyl alcohol, chlorobutanol, etc., and the stabilizer may be selected from one or more of sodium sulfite, sodium bisulfite, and disodium edetate, etc.

[0019] According to an embodiment of the present invention, the xanomeline pamoxate may be selected from one or both of xanomeline pamoxate (Compound II) and xanomeline hemipamoate (Compound III).

[0020] The xanomeline pamoxate may be any crystal or amorphous form, anhydrate, hydrate, or solvate.

[0021] According to an embodiment of the present invention, the xanomeline pamoxate salt can be selected from the following crystalline forms: the xanomeline pamoxate salt shown in formula II is crystalline form A, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.92±0.2°, 8.64±0.2°, 9.88±0.2°, 25.24±0.2° and 26.36±0.2°, and the differential scanning calorimetry curve of the crystalline form A has endothermic peaks at 85.11±5°C and 167.56±5°C; the xanomeline pamoxate salt shown in formula II is crystalline form B, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 7.42±0.2°, 10.29±0.2°, 12.10±0.2°, 24.03±0.2° and 27. 80±0.2°; the xanomeline pamoxate shown in formula III is a D crystal form, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 5.46±0.2°, 11.06±0.2°, 16.56±0.2°, 21.50±0.2° and 21.10±0.2°; the xanomeline pamoxate shown in formula II is an E crystal form, and its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 6.62±0.2°, 8.32±0.2°, 9.60±0.2°, 13.0±0.2° and 16.80±0.2°, and there is no characteristic diffraction peak at about 5.60±0.2°; the differential scanning calorimetry curve of the E crystal form has endothermic peaks at about 84±3°C and 172±3°C.

[0022] According to an embodiment of the present invention, the pharmaceutical composition can be prepared as an oral or parenteral preparation, preferably an injectable preparation, such as a suspension, a lyophilized preparation, etc. Injectable preparations also include but are not limited to microcapsules, nanocapsules, microspheres, nanospheres, microparticles, nanoparticles, polymer-drug conjugates, micelles, liposomes, hydrogels, and other in situ formed depots or implants.

[0023] According to an embodiment of the present invention, the pharmaceutical composition comprises a second pharmaceutically active ingredient, such as trospium chloride.

[0024] In some embodiments, the present invention provides the following pharmaceutical compositions:

[0025] 1) 0.5-50 wt %, preferably 1-40 wt % of xanomeline pamoxate;

[0026] 2) Optionally, 0.05 to 10 wt %, preferably 0.05 to 7.5 wt % of a suspending agent;

[0027] 3) Optionally, a wetting agent 0 to 6 wt%, preferably 0.05 to 5 wt%;

[0028] 4) optionally, a solvent, preferably water;

[0029] 5) optionally, a pH adjuster;

[0030] 6) optionally, an osmotic pressure regulator;

[0031] 7) optionally, a filler;

[0032] 8) Optionally, other pharmaceutically acceptable carriers;

[0033] 9) Optionally, other pharmaceutically active ingredients.

[0034] In some embodiments, based on the weight of the pharmaceutical composition, the content of the xanomeline pamoxate is 5-40 wt %, the content of the suspending agent is 0.1-7.5 wt %, and the content of the wetting agent is 0.05-2 wt %.

[0035] In some embodiments, the suspending agent is selected from HPMC and PEG4000, and the wetting agent is Tween 20.

[0036] In some embodiments, the suspending agent is PVP-K17, and the wetting agent is selected from Tween 20, Tween 80, RH40, TPGS, lecithin, and poloxamer 188.

[0037] In some embodiments, the suspending agent is PVP-K12, and the wetting agent is selected from Tween 20, Tween 80, and tyloxapol.

[0038] In some embodiments, the suspending agent is selected from CMC-Na, hydroxyethyl cellulose, and sodium alginate, and the wetting agent is Tween 80.

[0039] The present invention also provides a method for preparing the pharmaceutical composition, comprising the following steps: 1) dissolving a pharmaceutically acceptable carrier (a suspending agent, a wetting agent, and an optional carrier) in an appropriate amount of solvent (such as water for injection) to obtain a mixed material; 2) adding xanomeline pamoxate to the material of step 1), dispersing the mixture evenly, and processing the mixture to a suitable particle size (for example, using a high-pressure homogenizer); or first processing the xanomeline pamoxate to a suitable particle size, adding the mixture to the material of step 1), and dispersing the mixture evenly; 3) adding solvent (such as water for injection) to adjust the mixture to a target concentration, and packaging the mixture to obtain a suspension.

[0040] In some embodiments, the dosage form of the pharmaceutical composition is a suspension, in which the particle size D of the xanomeline pamoxate is 50 It is 0.1-30μm, for example, 1-25μm, 3-20μm, 5-15μm, 5-10μm; for example, 0.1μm, 0.3μm, 0.5μm, 0.8μm, 1μm, 1.5μm, 2μm, 2.5μm, 3μm, 3.5μm, 4μm, 4.5μm, 5μm, 5.5μm, 6μm, 6.5μm, 7μm, 7.5μm, 8μm, 8.5μm, 9μm, 9.5μm, 10μm, 12μm, 15μm, 18μm, 20μm or an interval range arbitrarily limited by these values.

[0041] In some embodiments, the pharmaceutical composition is in the form of a lyophilized preparation, which can be obtained by freeze-drying the aforementioned suspension. The lyophilized preparation can be in the form of a powder or a block.

[0042] According to one embodiment of the present invention, the freeze-drying conditions are: pre-freezing temperature -45°C, pre-freezing cooling time is 120 minutes, and holding time is 240 minutes; primary drying setting temperature is -15°C, heating time is 420 minutes, and holding time is 300 minutes; analytical drying setting temperature is 25°C, heating time is 300 minutes, and holding time is 180 minutes.

[0043] According to an embodiment of the present invention, the preparation method of the lyophilized preparation comprises the following steps: packaging the prepared xanomeline pamoate suspension, semi-stoppering, lyophilizing, fully stoppering, unpacking, and capping. Lyophilization procedure: pre-freezing temperature -45°C, pre-freezing cooling time of 120 minutes, holding time of 240 minutes; primary drying setting temperature -15°C, heating time of 420 minutes, holding time of 300 minutes; analytical drying setting temperature of 25°C, heating rate of 300 minutes, holding time of 180 minutes. In some embodiments, the pharmaceutical composition is an injection, which is obtained by resuspending the aforementioned lyophilized preparation.

[0044] According to an embodiment of the present invention, the injection can be obtained by resuspending in a certain amount of water for injection or physiological saline. The administration route of the injection includes intramuscular injection, subcutaneous injection, etc.

[0045] In some embodiments, the pharmaceutical composition can be prepared as a sustained-release preparation, for example, releasing a therapeutic amount of the active ingredient xanomeline over a period of at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks or longer after injection.

[0046] According to an embodiment of the present invention, the pharmaceutical composition of the present invention can be administered by subcutaneous or intramuscular injection; preferably, the administration frequency is no more than once a week, for example, the administration frequency is once every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 8 weeks, or longer.

[0047] The present invention also provides use of the pharmaceutical composition in preparing a drug for preventing or treating a disease that can be improved by activating muscarinic receptors.

[0048] The present invention also provides a method for preventing or treating a disease that can be improved by activating muscarinic receptors, comprising administering the pharmaceutical composition of the present invention to a subject in need thereof. The diseases improved by activating muscarinic receptors include schizophrenia, bipolar disorder, Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, Lewy body dementia, movement disorders, drug addiction, pain, neurodegenerative diseases, such as tau disease and synuclein disease, etc. The method comprises administering the pharmaceutical composition of the present invention by injection at a frequency not higher than once a week (e.g., once every 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks or longer). The pharmaceutical composition can be prepared into a sustained-release injectable formulation that provides a therapeutically effective dose of xanomeline over a period of at least one week. Preferably, the method does not require PDSS monitoring. Preferably, the injection is subcutaneous injection, intramuscular injection, etc.

[0049] The present invention also provides a method of administering to a patient a range of about 50 to about 1000 mg of xanomeline or a pharmaceutically acceptable salt thereof per dose.

[0050] In the present invention, when referring to "xanomeline or a pharmaceutically acceptable salt thereof" in a specified amount or range of amounts, it should be meant that the amount of any pharmaceutically acceptable salt of xanomeline is equivalent to the specified amount or range of amounts of xanomeline. The unit preparation (each) of the pharmaceutical composition of the present invention may contain about 10 mg to about 2500 mg of xanomeline or a pharmaceutically acceptable salt thereof equivalent to about 10 mg to about 2500 mg of xanomeline. For example, the preparation contains about 30 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 1000 mg, 1500 mg or 2000 mg of xanomeline or a pharmaceutically acceptable salt thereof.

[0051] In the present invention, "optionally" or "optionally" means that the event or situation described subsequently may or may not occur, and the corresponding implementation methods are all within the scope of the present invention.

[0052] For purposes of this invention, "post-injection delirium / sedation syndrome (PDSS)" is understood to mean a combination of symptoms or conditions as defined in Detke, HC, et al., BMC Psychiatry 2010, 10:43, which is incorporated herein by reference, or as such term is understood by those skilled in the art. For example, symptoms associated with delirium include disorientation, confusion, ataxia, and dysarthria. Symptoms associated with sedation include somnolence, sedation, or other changes in level of consciousness.

[0053] In the present invention, "sustained-release injectable formulation" refers to a dosage form that provides a gradual release of xanomeline over a period of preferably at least one week (e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks or longer). Preferably, although not necessarily, the level of release of xanomeline is relatively constant during this period. Preferably, the dosage form of the present invention releases less than about 40 wt% of xanomeline into human plasma in 1 hour, based on the weight of the administered xanomeline, for example, less than about 35 wt%, 30 wt%, 25 wt%, 20 wt%, 15 wt%, 10 wt%, 5 wt%, 3 wt% or 1 wt% of xanomeline is released into human plasma. The amount of xanomeline released into human plasma can be determined by methods known in the art. Beneficial effects

[0054] The pharmaceutical composition of the present invention has excellent stability and can be used to prepare an injectable suspension or lyophilized formulation. The suspension has a stable particle size, is less susceptible to particle sedimentation, and exhibits excellent resuspensibility. The lyophilized formulation can be quickly resuspended to obtain a uniform suspension. The composition exhibits excellent stability and rapid onset of action after administration, prolonging the duration of drug action, reducing dosing frequency, and lowering drug side effects, significantly improving patients' quality of life. DETAILED DESCRIPTION

[0055] The present invention will be described in further detail below with reference to specific examples. It should be understood that the following examples are merely illustrative and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are encompassed within the scope of protection that the present invention is intended to protect.

[0056] Example

[0057] Experimental materials: Xanomeline pamoxate (Compound II, Crystal Form A), prepared according to the method disclosed in Chinese patent application CN114853750A. Other materials were purchased from commercial sources or prepared by conventional methods in the art, such as water for injection.

[0058] Preparation method of suspension: 1) dissolving a pharmaceutically acceptable carrier (suspending agent, wetting agent and optional excipients) in an appropriate amount of water for injection to obtain a mixed material; 2) adding xanthocyanate to the material of step 1), dispersing evenly, and then processing with a high-pressure homogenizer to a suitable particle size; or first processing xanthocyanate to a suitable particle size, adding it to the material of step 1), and dispersing evenly; 3) adding water for injection to adjust to the target concentration, and packaging to obtain the suspension.

[0059] Preparation of the lyophilized preparation: The prepared xanomeline pamoxate suspension sample was divided into 2 ml / vial portions, partially stoppered, lyophilized, fully stoppered, unpacked, and capped. The lyophilization procedure was as follows: pre-freezing temperature: -45°C, cooling time: 120 minutes, holding time: 240 minutes; primary drying temperature: -15°C, heating time: 420 minutes, holding time: 300 minutes; desorption drying temperature: 25°C, heating time: 300 minutes, holding time: 180 minutes.

[0060] Test method for sedimentation volume ratio of suspension: Use a graduated cylinder to measure 4 ml of each suspension sample, shake and mix, record the height H0 of the suspension before sedimentation, let it stand for 4 hours, record the height Hu of the sedimentation surface after sedimentation, and calculate the sedimentation ratio according to the following formula: Sedimentation volume ratio F = H u / H0.

[0061] Test method for resuspensibility / particle size stability: Place the suspension sample under dry (oven) conditions at 0 days, 25°C, and 40°C for a period of time (e.g., 14 days), then shake 80-120 times within 30 seconds (one reciprocating motion counts as one time), with a shaking amplitude of approximately 25-30 cm. Observe whether the sediment at the bottom of the container is redispersed evenly to examine the resuspensibility of the sample. At the same time, record and observe the appearance characteristics, and use a particle size analyzer (Malvern 3000 laser particle size analyzer) to detect the particle size of the xanomeline pamoate in the suspension. 50 Represents the average particle size of the API in the suspension.

[0062] Method for investigating the resuspension of freeze-dried preparations: Take a sample of the freeze-dried preparation, add an appropriate amount of water for injection (the same volume as before freeze-drying), time it, shake it to mix it evenly (to avoid generating a large number of bubbles that affect observation), record the time required for complete shaking, and measure the pH value and particle size after resuspension.

[0063] In the embodiments, “ / ” indicates that nothing is added or not applicable.

[0064] Example 1: Preparation of Xanomeline Suspension

[0065] The formula is shown in Table 1. The stability test results are shown in Table 2.

[0066] Table 1 Prescription of the present invention

[0067] Table 2 Stability test results

[0068] The results showed that the appearance, particle size and pH of the above-mentioned Xanomeline suspension remained basically stable, and it had good stability, a high sedimentation volume ratio, and good resuspensibility.

[0069] Example 2: Preparation of Xanomeline Suspension

[0070] The formula is shown in Table 3. The stability test results are shown in Table 4.

[0071] Table 3 Prescription of the present invention

[0072] Table 4 Stability test results

[0073] The results showed that the appearance, pH and particle size of the above-mentioned Xanomeline suspension remained basically stable, and it had good stability.

[0074] Example 3 Preparation of Xanomeline Suspension

[0075] The formula is shown in Table 5. The stability test results are shown in Table 6.

[0076] Table 5 Prescription of the present invention

[0077] Table 6 Stability test results

[0078] The results showed that the above-mentioned Xanomeline suspension remained basically stable in appearance and particle size, had good stability, a high sedimentation volume ratio, and good resuspensibility.

[0079] Example 4: Preparation of Xanomeline Suspension

[0080] The formula is shown in Table 7. The stability test results are shown in Table 8.

[0081] Table 7 Prescription of the present invention

[0082] Table 8 Stability test results

[0083] The results showed that the above-mentioned Xanomeline suspension remained basically stable in appearance and particle size, and basically had good stability, a high sedimentation volume ratio, and good resuspensibility.

[0084] Example 5: Preparation of Xanomeline Suspension

[0085] The formula is shown in Table 9. The stability test results are shown in Table 10.

[0086] Table 9 formula of the present invention

[0087] Table 10 Stability test results

[0088] The results showed that the appearance, pH and particle size of the above-mentioned Xanomeline suspension remained basically stable within different pH ranges, and it had good stability, a high sedimentation volume ratio, was not easy to settle, and had good resuspensibility.

[0089] Example 6: Preparation of Xanomeline Suspension and Lyophilized Formulation

[0090] A xanomeline suspension was prepared according to the formulation shown in Table 11 and then lyophilized to obtain a lyophilized preparation. A sample of the lyophilized preparation was resuspended in water for injection to the original suspension volume. The suspension before lyophilization and the resuspended lyophilized preparation were tested, and the test results are shown in Table 12.

[0091] Table 11 Prescription of the present invention

[0092] Table 12 Stability test results

[0093] The results showed that after the above-mentioned Xanomeline suspension was freeze-dried, the freeze-dried preparation could be quickly resuspended to obtain a uniform suspension, and the pH and particle size remained basically stable, indicating good stability.

[0094] Comparative Examples 1-4:

[0095] The comparative example formula of the Xanomeline suspension is shown in Table 13. The stability test results are shown in Table 14.

[0096] Table 13 Comparative Example Formula

[0097] Table 14 Stability test results

[0098] The results showed that when sodium deoxycholate was used as a wetting agent, it was difficult to obtain a uniform suspension (Comparative Example 1); when SDS was used as a wetting agent, the suspension was redispersed after standing, particles adhered to the container wall, and there was a lot of foam in the suspension, making it difficult to obtain a uniform suspension (Comparative Example 2); when PEG1000 was used as a suspending agent, the suspension was difficult to redisperse to obtain a uniform suspension after standing (Comparative Example 3); when Span 20 was used as a wetting agent, the suspension was redispersed after standing, particles adhered to the container wall, and it was difficult to obtain a uniform suspension (Comparative Example 4).

[0099] Comparative Examples 5-8:

[0100] The comparative example formulation of the Xanomeline suspension is shown in Table 15. The stability test results are shown in Table 16.

[0101] Table 15 Comparative Example Formula

[0102] Table 16 Stability test results

[0103] The results show that when Span 40 is used as a wetting agent, the suspension is allowed to stand and redisperse, particles adhere to the container wall, and it is difficult to obtain a uniform suspension (Comparative Example 5). When HS-15 is used as a wetting agent, the suspension is allowed to stand and redisperse, and flakes adhere to the container wall, making it difficult to obtain a uniform suspension (Comparative Example 6). When Carbomer 981 is used as a suspending agent, the particle size of the suspension is significantly increased at both 25°C and 40°C, and the stability is poor (Comparative Example 7). When the pH of the suspension reaches about 8.0, the particle size of the suspension is significantly increased at both 25°C and 40°C, and the stability is poor (Comparative Example 8).

[0104] Test Example 1 Pharmacokinetic Properties Study

[0105] This study aimed to investigate the pharmacokinetic characteristics of xanomeline in Beagle dogs after intramuscular injection of xanomeline pamoxate, with oral administration of xanomeline tartrate as a control.

[0106] Experimental materials: 6 male Beagle dogs (weighing 8-10 kg, purchased from Beijing Masi Biotechnology Co., Ltd.), the suspension of the present invention (Formulation 5 of Example 2), and a control drug (xanomeline tartrate filled in capsules).

[0107] Experimental method: Six male Beagle dogs were randomly divided into two groups, three in each group. The animals were weighed and their weights were recorded before administration. The animals were fasted overnight before administration and resumed feeding 4 hours after administration. Group I: The suspension of the present invention was administered to the dogs by intramuscular injection (im) of the buttocks at a single dose of 10 mg / kg (calculated as xanomeline); 0.8 mL of whole blood was collected from the cephalic vein or saphenous vein at 0 h before administration and 0.5 h, 1 h, 4 h, 8 h, 12 h, 24 h, 48 h, 72 h, 96 h, 120 h and 144 h after administration. Group II: The control drug was administered to Beagle dogs by oral gavage (ig) at a single dose of 10 mg / kg (calculated as xanomeline); 0.8 mL of whole blood was collected from the jugular vein at 0 h before administration and 0.25 h, 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h and 12 h after administration. Blood samples from each group were placed in tubes containing anticoagulant (20 μL of 15% EDTA-K2 solution) and stored on wet ice. Plasma was collected within 0.5 h after centrifugation (3,000 g, 2-8°C, 10 minutes). Plasma was transferred to centrifuge tubes, snap-frozen in dry ice, and then stored in an ultra-low temperature freezer at -60°C or below until LC-MS / MS analysis.

[0108] The drug concentration in K2EDTA anticoagulated dog plasma was determined by LC-MS / MS. The data were statistically processed by Analyst software. TM The pharmacokinetic parameters of each group were calculated using a non-compartmental model to evaluate the pharmacokinetic properties in dogs. The pharmacokinetic data of the suspension of the present invention administered intramuscularly to dogs are shown in Table 17. The pharmacokinetic data of the Xanomelin Tartrate Capsules administered orally to dogs by gavage are shown in Table 18.

[0109] Table 17 Pharmacokinetic parameters of Xanomeline in plasma after intramuscular injection in dogs

[0110] Table 18 Pharmacokinetic parameters of Xanomeline in plasma after oral gavage in dogs

[0111] The results showed that compared with oral administration of xanomeline tartrate, the injection of xanomeline pamoxate suspension of the present invention had a significantly lower T 1 / 2 (half-life), T max (Time to peak) is significantly longer, C max (peak concentration) is stable, can reach therapeutically effective concentration for a long time, and has obvious sustained-release therapeutic effect.

[0112] The present invention is described above by way of examples, but the present invention is not limited to the above examples. According to CN114853750A, Form B of Compound II and Form D of Compound III can also be prepared. Form B of Compound II and methyl acetate are mixed, stirred and slurried at 45 ° C for about 12 hours, cooled, and filtered to obtain Form E of Compound II (refer to CN2024118025219). These crystal forms can be used in the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A pharmaceutical composition containing Xanomeline, characterized in that: The composition comprises xanomeline pamoxate and a pharmaceutically acceptable carrier, wherein the content of xanomeline pamoxate is 0.5-50 wt % based on the weight of the pharmaceutical composition, and the pharmaceutically acceptable carrier comprises a suspending agent and optionally a wetting agent.

2. The pharmaceutical composition according to claim 1, characterized in that The suspending agent is selected from one or more of gums, celluloses, starches, carbomer, PVP, dextran and polyethylene glycol. For example, the suspending agent is selected from one or more of CMC-Na, CMC-Ca, MC, HPC, HEC, HPMC, HPEC, carboxymethyl olefinic acid, HPMCP; HES; carbomer 980; gum arabic, xanthan gum; PVP-K12, PVP-K17, PVP-K30; Dextran-40, Dextran-70; PEG1500, PEG4000, PEG6000 and PEG8000. The suspending agent is further preferably selected from one or more of HPMC, PEG4000, PVP-K12, PVP-K17, xanthan gum, CMC-Na, HEC and sodium alginate.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that The content of the suspending agent is 0.1-10 wt%, 0.2-8 wt%, 0.3-7.5 wt%, or 0.5-7 wt% based on the weight of the pharmaceutical composition.

4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The pharmaceutically acceptable carrier may optionally include a wetting agent, which is selected from one or more of polysorbates, sorbitan fatty acids, poloxamers, tyloxapol, phospholipids, vitamin E polyethylene glycol succinate (TPGS), polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, bile salts, higher fatty alcohol sulfates, sulfonates, higher fatty acid salts and polyethylene glycol stearates, and the wetting agent is further selected from one or more of Tween 20, Tween 40, Tween 80, poloxamer 188, lecithin, vitamin E polyethylene glycol 2000 succinate (TPGS2000), polyoxyethylene 40 hydrogenated castor oil (RH40), tyloxapol, poloxamer 188, docusate sodium and sodium oleate.

5. The pharmaceutical composition according to any one of claims 1 to 4, characterized in that The content of the wetting agent is 0-6 wt %, preferably 0.01-5.5 wt %, 0.05-5 wt %, 0.08-4 wt %, 0.1-3 wt % based on the weight of the pharmaceutical composition.

6. The pharmaceutical composition according to any one of claims 1 to 5, characterized in that The xanomeline pamoxate is selected from compound II and compound III; 7. The pharmaceutical composition according to any one of claims 1 to 6, characterized in that wherein the pharmaceutically acceptable carrier further comprises one or more of a pH regulator, an osmotic pressure regulator, and a solvent, and optionally, a filler; The pH adjuster is selected from an acid, a base or a buffer salt, such as hydrochloric acid, sulfuric acid, citric acid, tartaric acid, sodium citrate, sodium hydroxide, potassium hydroxide, triethylamine, meglumine, amino acids, phosphate buffer, citrate buffer, tartaric acid buffer, malate buffer, acetate buffer; the amount of the pH adjuster is to adjust the pH of the pharmaceutical composition to about 4.0 to 8.5; The osmotic pressure regulator is selected from sodium chloride, potassium chloride, and glycerol; The solvent is water or vegetable oil; The filler is selected from one or more of mannitol, trehalose, sucrose, glycerol, xylitol, sorbitol, maltose, glucose, starch and sucralose.

8. The pharmaceutical composition according to any one of claims 1 to 7, characterized in that The pharmaceutical composition comprises a second pharmaceutically active ingredient, such as trospium chloride.

9. The pharmaceutical composition according to any one of claims 1 to 8, characterized in that The pharmaceutical composition is a suspension or a lyophilized preparation, and the particle size D of the zanomeline pamoate in the suspension is 50 It is 0.1 to 30 μm, preferably 1 to 25 μm, 3 to 20 μm, 5 to 15 μm, and 5 to 10 μm.

10. Use of the pharmaceutical composition according to any one of claims 1 to 9 for preparing a medicament for preventing or treating a disease improved by activating muscarinic receptors, characterized in that: The disease is selected from schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, dementia with Lewy bodies, movement disorders, drug addiction, pain, neurodegenerative disorders such as tauopathies and synucleinopathies.

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