Pharmaceutical aqueous solution of CGRP antagonist and solution-type nasal spray

Abstract

A pharmaceutical aqueous solution and a solution-type nasal spray, comprising a specific CGRP antagonist represented by compound 1. By means of the pharmaceutical aqueous solution and solution-type nasal spray, compound 1 can be fully dissolved and prepared into a solution-type formulation, and multiple pharmacokinetic properties of compound 1 can be improved. On the basis of the rapid-release properties and the improved PK properties of the solution-type formulation, the bioavailability can be enhanced and the plasma drug concentration can be increased, which is expected to further reduce the administration dose and improve the medication safety. The present invention is suitable for the treatment, relief, and prevention of acute episodes of migraines and neuropathic pain.

Description

Aqueous solutions and nasal sprays containing CGRP antagonists Technical Field

[0001] This application belongs to the field of pharmaceutical technology, specifically relating to a pharmaceutical aqueous solution and a solution-type nasal spray with improved pharmacokinetic (PK) properties, as well as their preparation method and application. Background Technology

[0002] Calcitonin gene-related peptide (CGRP) is a 37-amino acid polypeptide that primarily functions as a vasodilator in the body. Clinical evidence shows that CGRP levels are elevated in the jugular vein during migraine attacks, and intravenous CGRP injection can induce moderate to severe headaches. CGRP antagonists can alleviate migraine pain and related symptoms [Russo AF. Calcitonin gene-related peptide (CGRP): a new target for migraine. Annu Rev Pharmacol Toxicol. 2015; 55:533-552. doi:10.1146 / annurev-pharmtox-010814-124701]. Zavegepant, also known as vazegepant, is a CGRP antagonist that was marketed in the US by Pfizer in March 2023 as a nasal spray, approved for the acute treatment of migraines in adults with or without aura.

[0003] The prior PCT application PCT / CN2024 / 090110 of this application provides a novel CGRP antagonist compound (hereinafter referred to as "Compound 1") with the following structure: It can effectively inhibit the production of cAMP stimulated by CGRP, and thus can be used as a CGRP antagonist to prevent, alleviate or treat CGRP-related diseases, especially migraines or neuropathic pain.

[0004] Migraines and tension headaches are acute forms of pain, and patients often desire a fast-acting, safe medication to quickly control and relieve the pain. Therefore, improving the pharmacokinetic (PK) properties of drugs, such as achieving a shorter T0... max To shorten the time to peak drug concentration and achieve rapid onset of action, another example is increasing C... max Increasing AUC to improve bioavailability, reduce drug dosage, and enhance drug safety are all of particular clinical significance for migraine and pain indications.

[0005] In practical applications, not all active molecules exhibit high bioavailability, rapid time to peak concentration, and consequently, rapid onset of action after administration. These pharmacokinetic (PK) characteristics are related to the physicochemical and biological properties of the drug's active molecules. The use of penetration enhancers is one method of drug delivery; however, the PK improvement effect after penetration enhancement varies greatly depending on the drug's active molecules, often being unpredictable, and it is rare to see a single penetration enhancer simultaneously and significantly improve multiple PK characteristics.

[0006] Alkyl glycosides are one of the available penetration enhancers. Published Chinese patent applications CN201780081719.4, CN201780044057.3, CN200980157305.0, CN201180053436.1, and CN201980001004.2 disclose studies on the improvement of pharmacokinetic (PK) properties of alkyl glycosides combined with different types of active pharmaceutical ingredients. These results show that the PK improvement results vary significantly for different types of active pharmaceutical ingredients. For example, a rough comparison shows that before and after the combined application of alkyl glycosides: Regarding C... max Some combinations of active molecules showed no change with or without alkyl glycosides, while others showed an increase of approximately 3 times after the application of alkyl glycosides. Regarding AUC, combinations of multiple active molecules showed no change with or without alkyl glycosides, or showed a slight increase of approximately 1.5 times after the application of alkyl glycosides. Regarding T... max In some cases, the combination of active molecules with alkyl glycosides resulted in a 2-fold increase in kinetic energy, while in others, the combination of alkyl glycosides shortened the kinetic profile. Therefore, the exact impact of combining active pharmaceutical ingredients with alkyl glycosides on pharmacokinetic (PK) characteristics is unpredictable.

[0007] The prior PCT application PCT / CN2024 / 120008 of this application provides a pharmaceutical composition that, when administered in combination with an alkyl glycoside, comprises a series of similar compounds including compound 1, and is surprisingly effective in significantly and / or simultaneously improving conditions such as C. max AUC, T max Including multiple pharmacokinetic properties. Based on this, this application further addresses how to improve the pharmacokinetic properties of a specific compound 1 and how to solve the solubility problem of compound 1. Summary of the Invention

[0008] The primary aspect of this application is to provide a pharmaceutical aqueous solution that improves the PK properties of a specific compound 1 and has good solubility for compound 1, and secondly, to provide a solution-type nasal spray with the aforementioned effects suitable for nasal administration.

[0009] In the course of our study of compound 1, we unexpectedly discovered that when compound 1 is used in combination with dodecyl-β-D-maltose glycoside (DDM), it can surprisingly significantly and / or simultaneously improve conditions such as C. max AUC, T max It exhibits multiple PK properties, including [specific PK properties]. Significant improvements in these PK properties, especially simultaneous significant improvements, are of particular clinical importance and value for the emergency treatment, relief, and prevention of migraine and neurogenic headache, the indications for compound 1.

[0010] Further research on compound 1 in this application also revealed that the solubility of compound 1 in water is pH-dependent.

[0011] Therefore, based on the above, the first aspect of this application is to provide a pharmaceutical aqueous solution comprising compound 1, dodecyl-β-D-maltose, an osmotic pressure regulator, a pH buffer, and water, wherein the osmotic pressure regulator comprises sodium chloride, and optionally the pharmaceutical aqueous solution further comprises a pH regulator, particularly wherein the pH value of the pharmaceutical aqueous solution is not greater than 8.5. By controlling the final pH value of the system, compound 1 can be fully dissolved to form a solution. Furthermore, as confirmed by the provided experimental results, the use of compound 1 in combination with DDM can significantly improve several PK properties of the active ingredient, such as C. max AUC 0-inf or T max C. max The significant increase and T max The significant reduction in dosage means that the drug can reach its peak effect rapidly after administration, making it suitable for treating, relieving, or preventing acute attacks of migraines and tension headaches. max and AUC 0-inf The significant improvement in pH can facilitate further reduction in dosage, achieving high efficacy with low dosage and reducing medication safety risks. The addition of succinic acid and / or its salts as pH buffers is expected to stabilize the system's pH, reduce drastic pH fluctuations, and stabilize the formulation composition.

[0012] In some embodiments, to further accelerate the dissolution rate of compound 1 in the system, the pH value of the pharmaceutical aqueous solution is not greater than 7.5, or not greater than 7.0, or 3.0–7.0, or 5.5–7.0, or 6.0–7.0. Considering the human nasal cavity environment, when administering the pharmaceutical aqueous solution through the nasal cavity, it is preferable to control the pH value of the pharmaceutical aqueous solution to 5.5–7.0, especially 6.0–7.0, which is beneficial for adapting to the nasal cavity environment and reducing irritation to the nasal mucosa.

[0013] In some embodiments, the pH buffer in the pharmaceutical aqueous solution includes succinic acid and / or its salts, and the pH adjuster includes sodium hydroxide and / or hydrochloric acid. In some embodiments, the pH buffer in the pharmaceutical aqueous solution includes succinic acid and sodium hydroxide.

[0014] In some embodiments, the pharmaceutical aqueous solution is obtained by a preparation method comprising the following steps:

[0015] 1) Mix pH buffer and water to obtain a buffer solution;

[0016] 2) Add compound 1 to the buffer solution and mix well;

[0017] 3) Continue adding pH adjuster to adjust the pH value of the system to obtain the medicinal aqueous solution;

[0018] Steps 1) through 3) may further include the addition of dodecyl-β-D-maltodextrin, an osmotic pressure regulator, and other excipients; step 3) may also optionally include the addition of water to make up to a final volume.

[0019] In some embodiments, when the concentration of compound 1 in the pharmaceutical aqueous solution is no greater than 2.7 mg / mL, the pH value of the buffer solution after mixing the pH buffer and water is no greater than 6.5; when the concentration of compound 1 in the pharmaceutical aqueous solution is no greater than 6.7 mg / mL, the pH value of the buffer solution after mixing the pH buffer and water is no greater than 6.1; when the concentration of compound 1 in the pharmaceutical aqueous solution is no greater than 13.0 mg / mL, the pH value of the buffer solution after mixing the pH buffer and water is no greater than 5.5; when the concentration of compound 1 in the pharmaceutical aqueous solution is no greater than 50.2 mg / mL, the pH value of the buffer solution after mixing the pH buffer and water is no greater than 5.0; and when the concentration of compound 1 in the pharmaceutical aqueous solution is no greater than 111.6 mg / mL, the pH value of the buffer solution after mixing the pH buffer and water is no greater than 4.1.

[0020] As discovered in this application, the initial pH value of the system (i.e., the buffer aqueous solution used to dissolve Compound 1) before adding Compound 1 has a significant impact on its dissolution capacity and rate. When the initial pH value is greater than 5.5, an oily substance is very likely to appear during the dissolution process of Compound 1. This oily substance is a pale yellow paste with strong adhesion. The appearance of the oily substance is detrimental to the formulation and subsequent commercial production. Therefore, in some embodiments, ideally, the pH value of the buffer aqueous solution after mixing the pH buffer and water is not greater than 5.5, or not greater than 4.0, or between 3.5 and 4.5, and Compound 1 is added only after the pH buffer and water mixture has reached the specified pH value, thus avoiding the appearance of the oily substance. The presence of the pH buffer can stabilize the pH value of the system, preventing excessively drastic changes in the pH value or local pH value when Compound 1 is added, thereby avoiding the appearance of the oily substance at high pH values ​​and enhancing the stability of the system.

[0021] In some embodiments, the concentration of compound 1 in the pharmaceutical aqueous solution is 0.1–100 mg / mL, 2.5–50 mg / mL, 2.5–20 mg / mL, 2.5 mg / mL, 10 mg / mL, or 20 mg / mL. Converted to weight percentages, these are 0.01%–10%, 0.25%–5%, 0.25%–2%, 0.25%, 1%, and 2%, respectively.

[0022] In some embodiments, the weight ratio of the dodecyl-β-D-maltose in the aqueous pharmaceutical solution is 0.05%–20%, 0.05%–10%, 0.05%–5%, 0.1%–5%, 0.1%–0.5%, 0.1%–0.3%, 0.05%, 0.2%, or 5%.

[0023] In some embodiments, the osmotic pressure regulator in the pharmaceutical aqueous solution is 0.7% to 1% by weight, or 0.8% to 1.0%.

[0024] In some embodiments, the pharmaceutical aqueous solution further includes chelating agents and / or preservatives, the chelating agents including disodium edetate (EDTA-2Na), and the preservatives including benzalkonium chloride and / or potassium sorbate.

[0025] In some embodiments, the preservative (e.g., benzalkonium chloride and / or potassium sorbate) in the aqueous pharmaceutical solution is present in a weight ratio of 0% to 0.2%, 0% to 0.008%, or 0% to 0.0075%.

[0026] In some embodiments, the chelating agent (e.g., disodium edetate) in the aqueous pharmaceutical solution is present in a weight ratio of 0% to 0.2%, 0% to 0.15%, or 0% to 0.1%.

[0027] In some embodiments, the pH value of the medicinal aqueous solution is not greater than 7.5, or not greater than 7.0, or 3.0 to 7.0, or 5.5 to 7.0, or 6.0 to 7.0.

[0028] In some embodiments, the pharmaceutical aqueous solution comprises, by weight, 0.01% to 10% of compound 1, 0.05% to 20% of dodecyl-β-D-maltodextrin, 0.7% to 1% of sodium chloride, a pH buffer, a pH adjuster, and water. The pH buffer solution prepared with the pH buffer has a pH value not greater than 6.5, or not greater than 6.0, or not greater than 5.5, or not greater than 5.0, or not greater than 4.0, or 3.5 to 4.5. The pH adjuster adjusts the pH value of the pharmaceutical aqueous solution to not greater than 7.5, or not greater than 7.0, or 3.0 to 7.0, or 5.5 to 7.0, or 6.0 to 7.0.

[0029] In other embodiments, the pharmaceutical aqueous solution comprises, by weight, 0.25% to 5% of compound 1, 0.2% to 5% of dodecyl-β-D-maltodextrin, 0.80% to 1.0% of sodium chloride, a pH buffer, a pH adjuster, and water, wherein the pH buffer is used to prepare a buffered aqueous solution with a pH of 3.5 to 4.5, and the pH adjuster adjusts the pH of the pharmaceutical aqueous solution to 6.0 to 7.0.

[0030] In other embodiments, the pharmaceutical aqueous solution comprises, by weight, 0.25% to 2% of compound 1, 0.2% to 2% of dodecyl-β-D-maltodextrin, 0.80% to 0.83% of sodium chloride, a pH buffer, a pH adjuster, and water, wherein the pH buffer is used to prepare a buffered aqueous solution with a pH of 3.5 to 4.5, and the pH adjuster adjusts the pH of the pharmaceutical aqueous solution to 6.0 to 7.0.

[0031] Based on the aforementioned medicinal aqueous solution, the second aspect of this application also provides a method for preparing the aforementioned medicinal aqueous solution, comprising the following steps:

[0032] 1) Mix pH buffer and water to obtain a buffer solution;

[0033] 2) Add compound 1 to the buffer solution and mix well;

[0034] 3) Continue adding pH adjuster to adjust the pH value of the system to obtain the medicinal aqueous solution;

[0035] Steps 1) through 3) may further include the addition of dodecyl-β-D-maltodextrin, optional osmotic pressure regulator sodium chloride, and other excipients; step 3) may also optionally include the addition of water to make up to volume. Other excipients include, for example, osmotic pressure regulators, chelating agents, preservatives, etc.

[0036] In some implementations, the pH value of the buffer solution in step 1) is not greater than 6.5, or not greater than 6.0, or not greater than 5.5, or not greater than 5.0, or not greater than 4.0, or is 3.5 to 4.5.

[0037] In some embodiments, the preparation method may optionally include adding a pH adjuster in step 1); the pH adjuster added in step 1) adjusts the pH value of the buffer aqueous solution to be no greater than 6.5, or no greater than 6.0, or no greater than 5.5, or no greater than 5.0, or no greater than 4.0, or to 3.5 to 4.5.

[0038] In some embodiments, the pH adjuster added in step 3) adjusts the pH value of the medicinal aqueous solution to be no greater than 8.5, or no greater than 7.5, or no greater than 7.0, or to 3.0-7.0, or to 5.5-7.0, or to 6.0-7.0.

[0039] Based on the aforementioned medicinal aqueous solution, a third aspect of this application also provides a solution-type nasal spray, comprising a nasal spray device and a medicinal aqueous solution contained in any of the aforementioned locations within the nasal spray device. The nasal spray device generally consists of a container, a rubber stopper, and a metering pump. In some embodiments, the container is a borosilicate glass container.

[0040] In an optional embodiment, this application also provides a nasal spray kit, wherein the kit includes a solution-type nasal spray, and the solution-type nasal spray contains an aqueous medicinal solution as described above. In a preferred embodiment, the nasal spray kit further includes a nasal spray device, and the solution-type nasal spray is contained within the nasal spray device.

[0041] In some embodiments, the medicinal aqueous solution in the solution-type nasal spray comprises, by weight, 0.01% to 10% of compound 1, 0.05% to 20% of dodecyl-β-D-maltodextrin, 0.7% to 1% of sodium chloride, a pH buffer, a pH adjuster, and water, wherein the pH buffer is used to prepare a buffered aqueous solution with a pH value not greater than 5.5, and the pH adjuster adjusts the pH value of the medicinal aqueous solution to not greater than 8.5.

[0042] In some other, more specific embodiments, the medicinal aqueous solution in the solution-type nasal spray comprises, by weight, 2% or 0.25% of compound 1, 0.2% of dodecyl-β-D-maltodextrin, 0.80% or 0.83% of sodium chloride, a pH buffer, a pH adjuster, and water, wherein the pH buffer is prepared to a buffered aqueous solution with a pH of 3.5 to 4.5, wherein the pH buffer is optionally prepared from 0.18% succinic acid and 0.032% sodium hydroxide, and the pH adjuster adjusts the pH of the medicinal aqueous solution to 6.0 to 7.0.

[0043] Based on the above, this application also provides the use of the aforementioned aqueous solution or the aforementioned solution-type nasal spray in the preparation of a medicament for the prevention, treatment, or relief of CGRP-mediated and / or regulated diseases. Alternatively, this application provides a method for the prevention, treatment, or relief of CGRP-mediated and / or regulated diseases, comprising administering a therapeutically effective amount of the aforementioned aqueous solution or the aforementioned solution-type nasal spray to a subject requiring prevention, treatment, or relief of the disease. Alternatively, this application also provides the use of the aforementioned aqueous solution or the aforementioned solution-type nasal spray for the prevention, treatment, or relief of CGRP-mediated and / or regulated diseases. In another optional aspect, this application also provides the use of the aforementioned aqueous solution or the aforementioned solution-type nasal spray for the prevention, treatment, or relief of CGRP-mediated and / or regulated diseases. These diseases include, for example, migraines and / or neuropathic pain.

[0044] In this application, when a later technical solution further limits an earlier technical solution, it may only further limit some technical features. In this case, the unlimited technical features may be defined in the earlier technical solution or at any location in this application. Attached Figure Description

[0045] Figure 1 shows the comparison of blood flow inhibition rates of compound 1 and Zavegepant at different time points in test example 6. Detailed Implementation

[0046] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technical intent refer to techniques commonly understood in the art, including variations or equivalent substitutions of techniques that would be obvious to one of ordinary skill in the art.

[0047] Unless otherwise stated, the "%" in this application refers to weight percentage, i.e., "(w / w)%".

[0048] Unless otherwise stated, the terms “comprise”, “comprises”, and “comprising” or their equivalents (contain, contain, containing, include, include, including) used herein are open-ended expressions, meaning that they may cover other unspecified elements, components, and steps in addition to those listed.

[0049] Unless otherwise stated, all figures used herein to represent amounts of components, measurements, or reaction conditions should be understood to be modified by the term "about" in all cases. When used with percentages, the term "about" may mean, for example, ±1%, preferably ±0.5%, more preferably ±0.1%.

[0050] Unless the context clearly indicates otherwise, singular terms in this document cover the plural referents, and vice versa.

[0051] The term “prevention” means administering the pharmaceutical aqueous solution or solution-type nasal spray described in this application to prevent the disease described in this application or one or more symptoms related to the disease, including: preventing the occurrence of the disease or disease state in a subject, particularly when such subjects are susceptible to the disease state but have not yet been diagnosed with the disease state.

[0052] The term "treatment" means administering the pharmaceutical aqueous solution or solution-type nasal spray described in this application to improve or eliminate one or more symptoms of the disease described in this application or related to the disease, including: suppressing the disease or disease state, i.e., curbing its development, or causing the disease or disease state to subside.

[0053] The term "relief" refers to administering the pharmaceutical aqueous solution or solution-type nasal spray described in this application to reduce or decrease one or more symptoms of the disease described in this application or related to the disease, including: reducing the severity of the disease described in this application, delaying the progression of the disease, or reducing the frequency or duration of the disease.

[0054] The term "therapeutic effective amount" means the amount of the present application's aqueous or nasal spray solution used to treat (i) the specific disease, condition, or disorder described herein, (ii) reduce, improve, or eliminate one or more symptoms of the specific disease, condition, or disorder described herein, or (iii) prevent or delay the onset of one or more symptoms of the specific disease, condition, or disorder described herein. The amount of the present application's aqueous or nasal spray solution constituting a "therapeutic effective amount" varies depending on the aqueous or nasal spray solution, the disease state and its severity, the route of administration, and the age of the subject to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and the present disclosure.

[0055] Unless otherwise stated, the terms “patient,” “subject,” and “individual” are used interchangeably in this document and refer to human or non-human animals (e.g., primates, rodents, etc.), such as, but not limited to, mice, rats, guinea pigs, dogs, pigs, chickens, rabbits, monkeys (e.g., rhesus monkeys, cynomolgus monkeys, etc.), humans, etc.

[0056] Unless otherwise stated, the terms “optional” or “optionally” in this document mean that the event or environment described below may, but is not necessarily, occur, including the possibility that the event or environment may or may not occur. For example, “optionally the osmotic pressure regulator includes sodium chloride” means that the osmotic pressure regulator includes sodium chloride or does not include sodium chloride.

[0057] For purposes of description and disclosure, all patents, patent applications and other publications are expressly incorporated herein by reference. These publications are provided only because their publication predates the filing date of this application. All statements regarding the dates of these documents or representations of their contents are based on information available to the applicant and do not constitute any admission of the accuracy of the dates or contents of these documents.

[0058] The present application will be further described below with reference to specific embodiments and effect test data.

[0059] The entire contents of the prior PCT applications PCT / CN2024 / 090110 and PCT / CN2024 / 120008 are incorporated herein by reference and form part of this application. Even though they are incorporated in their entirety, for clarity and completeness, this application also provides a detailed description of Compound 1 and the pharmaceutical composition through the following structural description and detailed embodiments, including preparation, characterization, and activity assays.

[0060] I. Preparation and characterization of compound 1 and its similar compounds (compounds 2, 3, and 4)

[0061] Example 6 of PCT application PCT / CN2024 / 090110 describes the preparation of compound 1, and an example of its preparation process is shown below:

[0062] After synthesizing compound 1, compound 1 can be dispersed in acetonitrile and stirred overnight at room temperature. Filtration yields compound 1 as a powdered solid.

[0063] The mass spectrometry and NMR data of compound 1 obtained are as follows:

[0064] MS(ESI)m / z(M+H) + =660.8.

[0065] 1 H NMR (400MHz, DMSO-d6) δ13.01(s,1H),11.31(s,1H),7.96(s,1H),7.36(s,1H),7.00(s,1H),6.86(s,1H),6.64(d,J=8. 0,1H),4.80-4.72(m,1H),4.14-4.02(m,2H),3.57-3.53(m,1H),3.27-3.18(m,2H),3.14-3.08(m,1H),3.04-3.00(m,2H ),2.98-2.93(m,1H),2.92-2.86(m,1H),2.74-2.60(m,6H),2.56-2.54(m,1H),2.47(s,3H),2.37-2.31(m,1H),2.25-2. 19(m,1H),2.09(s,3H),2.01-1.89(m,4H),1.74-1.61(m,4H),1.55-1.49(m,1H),1.40-1.34(m,2H),1.30-1.13(m,4H).

[0066] Referring to a similar preparation process to Compound 1 mentioned above, the following similar compounds were also prepared in PCT application PCT / CN2024 / 090110:

[0067] II. Bioassay data for compound 1 and / or its similar compounds (compounds 2, 3, 4)

[0068] Test Example 1: Assay for Cellular Functional Antagonism - cAMP Assay

[0069] 1. Experimental Principle

[0070] The CGRP receptor complex is coupled to Gs in the G protein. The binding of CGRP to the CGRP receptor complex leads to the activation of Gs and the production of cAMP (3',5'-cyclic adenosine monophosphate).

[0071] 2. Experimental Objective

[0072] The ability of the compound of this application to inhibit CGRP-stimulated cAMP formation in SK-N-MC cells was determined.

[0073] 3. Experimental Materials

[0074] 3.1 Experimental cell lines:

[0075] SK-N-MC (neuroepithelial tumor cells), source: National Biomedical Experimental Cell Resource Bank.

[0076] 3.2 Reagents and Consumables

[0077] 4. Experimental Procedure

[0078] 4.1 Cell preparation:

[0079] Pre-resuscitate SK-N-MC cells, ensuring the cell confluence is 70%-80% before use.

[0080] 4.2 Prepare sample dilution solution, test compound and α-CGRP (human).

[0081] 4.3 Cell plating and drug effects:

[0082] SK-N-MC cells were digested, centrifuged, resuspended in sample dilution buffer, and seeded into 384-well plates. α-CGRP (human) and the test compound were added to each well, and the mixture was thoroughly mixed by pipetting. The plates were sealed with a sealing film and incubated at 25°C using an ELISA reader.

[0083] 4.4 cAMP assay: Performed according to the LANCE Ultra cAMP Kit instructions. Prepare Eu-cAMP tracer and Ultra-anti-cAMP working solutions in the dark. Add them separately to the wells of the plate and mix well by pipetting. Seal the plate with the sealing film and incubate at 25°C on an ELISA reader.

[0084] 4.5 Use the chemiluminescence module of the fully automated microplate reader to read the luminescence value.

[0085] 4.6 Data Analysis:

[0086] The IC50 value was calculated using a nonlinear formula with the compound concentration (LOG) as the x-axis and inhibition as the y-axis. The results are shown in the table below.

[0087] The IC50 of the compound in inhibiting CGRP-stimulated cAMP production in SK-N-MC cells 50 value

[0088] Test Example 2: In vitro [ 125 Competitive binding assay of CGRP

[0089] 1. Experimental Principle:

[0090] SK-N-MCs endogenously express a CGRP receptor with the same sequence as the human CGRP receptor. Using SK-N-MC cell membrane homogenate as the receptor source, radiolabeled endogenous peptide human α-CGRP was added. 125 [I]CGRP) and compounds competitively bind to this receptor source, washing away unbound portions. 125 After CGRP, the binding of the reaction compound to the receptor can be detected by detecting radioactive signals.

[0091] 2. Experimental materials:

[0092] 2.1 Experimental cell line: SK-N-MC (human neuroepithelial tumor cells), source: Peking Union Medical College Cell Resource Center

[0093] 2.2 Detection equipment: MicroBeta2 (PerkinElmer), UNIFILTER-96-well cell collector (PerkinElmer, C961961)

[0094] 2.3 Experimental Reagents and Consumables

[0095] 2.4 Experimental Procedure

[0096] 2.4.1 Membrane Protein Extraction and Quantification: Fresh SK-N-MC cells were collected. The cell pellet was resuspended in experimental buffer (Tris-HCl 50mM, pH 7.4). The cells were homogenized 10 times using a homogenizer, centrifuged at 1000g, 4℃ for 10 minutes to remove nuclear / mitochondrial debris, and the supernatant tissue homogenate was collected. The supernatant was centrifuged at 50000g, 4℃ for 1 hour, and the supernatant was discarded. The particles were resuspended in an appropriate buffer (Tris-HCl 50mM, pH 7.4), and the protein concentration was determined. The suspension was then aliquoted and stored at -80℃.

[0097] 2.4.2 Determination of Compound Binding Ki (Inhibition Constant): Transfer 1 μl of serially diluted analyte to the assay plate. Add 50 μl of the membrane stock solution (i.e., the suspension prepared in section 2.4.1 above) (15 μg) and 50 μl of a final concentration of 200 pM to the plate. 125I-CGRP (Human), vortex to mix. Add 50 μl of 0.3% PEI to each well of the plate and soak for 1 hour. Filter the reaction mixture using a UNIFILTER-96-well cell collector and wash the plate with pre-cooled buffer (Tris-HCl 50 mM, pH 7.4). After drying the plate, seal the bottom of the plate with Unifilter-96 backing seal tape, add 50 μl of Microscint 20-cocktail to each well, and seal the top of the plate with TopSeal-A sealing film. Capture cells using a MicroBeta2 Reader counting filter. 3 H signal.

[0098] 2.4.3 Data Analysis

[0099] Data were analyzed using Prism 5. A "log(inhibitor) vs. response-variable slope" model was used to fit the data, employing the slope determined in the saturation binding experiment. 125 The Kd value of I-CGRP (Human) is 240.6 pM. Calculations were performed on the compound and... 125 I-CGRP (Human) competitively binds to the IC50 of SK-N-MC cell membranes. 50 And Ki (Ki=IC50 / (1+[L] / Kd), [L]: Radioligand concentration(200pM)).

[0100] 3. Experimental Results

[0101] The Ki values ​​of the compounds binding to the CGRP receptor are shown in the table below:

[0102] Note: Ki ratio = Ki(compound 1) / Ki(Zavegepant).

[0103] Test Example 3: Liver Microsomal Stability Test

[0104] 1. Experimental Objective

[0105] The stability of the compound of this application in rat, monkey, and human liver microsomes was determined.

[0106] 2. Reagents and consumables

[0107] 3. Experimental Procedure

[0108] 3.1 Experimental incubation system

[0109] 3.2 Transfer an appropriate amount of liver microsome solution to a 1 mL 96-well plate, add the test drug solution (or probe substrate solution), and pre-incubate in a 37℃ hot mixer for 5 min. Take two aliquots of the mixture from the system, add 1×PBS instead of NADPH, and take the mixtures out at 0 and 60 min respectively, adding methanol (containing internal standard) to terminate the reaction. Add NADPH to each well of the remaining mixture to start the reaction. Take the mixture from the system at 0, 5, 15, 30, 45, and 60 min for the test group, and at 0, 30, and 60 min for the control group, adding methanol (containing internal standard) to terminate the reaction. Mix all the terminated samples thoroughly, centrifuge at 3800 rpm for 15 min, and take the supernatant for LC-MS / MS analysis.

[0110] 3.3 Data Analysis

[0111] Peak areas were determined from the extracted ion chromatograms. The slope value k was determined by linear regression of the remaining percentage of the parent drug relative to the natural logarithm of the incubation time curve. The in vitro half-life (t) was calculated based on the slope. 1 / 2 ), and calculate the in vitro intrinsic clearance rate (CL) int (expressed in μL / min / mg protein). The calculation formula is as follows: t 1 / 2 =ln2 / k=0.693 / k;CL int =0.693 / t 1 / 2 / Hepatic microsomal protein concentration

[0112] The experimental results are shown in the table below:

[0113] Stability data of the compound in rat, monkey and human liver microsomes.

[0114] Test Example 4: Plasma Protein Binding Rate Test

[0115] 1. Experimental Objective

[0116] The protein binding rate of the compound of this application in rat, monkey and human plasma was determined by balanced dialysis.

[0117] 2. Test substrate

[0118] 3. Experimental Procedure

[0119] 3.1 Rinse the dried dialysis membrane 2-3 times with ultrapure water, then soak it in phosphate buffer for 1 hour. Soak the polytetrafluoroethylene module in 20% ethanol for 30 minutes, blot off surface moisture with lint-free paper, and air dry. Assemble the pretreated dialysis membrane into the dialysis plate according to the product instructions, and add 100 μL of receiving solution (100 mM phosphate buffer solution with 0.002% Tween 80) to one side (receiving chamber) of each dialysis well.

[0120] 3.2 Take plasma and place it in a centrifuge tube. Add the working solution of the analyte to the plasma to a final concentration of 1 μM. Mix by inverting the tube (this step is performed on an ice bath). Take 20 μL of the drug-containing plasma into each of the 96-well sample plates, make two parallel samples, and store them in a -20℃ freezer.

[0121] 3.3 Take another 100 μL of the drug-containing plasma and add it to the other side of the membrane (sample chamber) of the dialysis apparatus, making two parallel portions. Incubate at 37°C with shaking for 6 hours. After 6 hours of incubation, take 20 μL of each sample from the receiving chamber and sample chamber after equilibration to obtain sample B and sample A. Add the corresponding volume of blank plasma or phosphate buffer (containing 0.002% Tween 80) to sample B and sample A respectively, so that the plasma to buffer volume ratio in each sample well is 1:1.

[0122] 3.4 Add 250 μL of methanol solution containing internal standard to all sample wells, mix well, and centrifuge at 3800 rpm for 10 minutes. Take 20 μL of the supernatant, add 180 μL of methanol, vortex to mix, and then analyze by LC-MS / MS.

[0123] 3.5 Data Analysis

[0124] The plasma protein binding rate and recovery rate of the compound in plasma are calculated using the following formula: Free percentage (%) = C B / C A Plasma protein binding rate (f b %) = 1 - Free percentage (%); Recovery rate (%) = (C B +C A ) / C T0

[0125] Where C B C represents the concentration of the compound in the receiving solution after equilibration dialysis. A C represents the concentration of the compound in the plasma after equilibration dialysis; T0 This represents the initial concentration of the compound in plasma.

[0126] The experimental results are shown in the table below:

[0127] Test Example 5: In Vivo Pharmacokinetic Study of the Test Compound Administered by Intravenous and Intranasal Routes to SD Rats

[0128] 1. Experimental Animals

[0129] Species: SD rats, male, SPF grade. Source: Purchased from Chengdu Dashuo Experimental Animal Co., Ltd., Production License Number of Experimental Animals: SCXK(Sichuan) 2020-030. Quantity: 2 for intravenous administration and 4 for intranasal administration.

[0130] 2. Preparation of Test Substances

[0131] 2.1 Weigh an appropriate amount of the drug precisely, add 50 mM succinate buffer (diluted with D5W, pH = 5-6), and ultrasonicate and vortex to mix and dissolve it thoroughly to obtain a dosing solution of 0.2 mg / mL for intravenous injection (IV).

[0132] 2.2 Weigh an appropriate amount of the drug precisely, add 50 mM succinate buffer (diluted with purified water, pH = 5-6), and ultrasonicate and vortex to mix and dissolve it thoroughly to obtain a dosing solution of 10 mg / mL for intranasal (IN) administration.

[0133] 3. Experimental Design

[0134] 4. Blood Sampling Time Points

[0135] 5 min, 10 min, 15 min, 0.5 h, 1 h, 2 h, 4 h, 8 h, 24 h after administration.

[0136] 5. Sample Collection and Handling

[0137] Collect blood through the jugular vein, about 0.2 mL for each sample, anticoagulate with EDTA-K2. After blood sample collection, place it on ice and centrifuge to separate plasma within 2 hours (centrifugation conditions: 6000 g, 5 min, 2-8 °C). The collected plasma samples are stored in a -80 °C refrigerator before analysis, and the remaining plasma samples after analysis are continued to be stored in a -80 °C refrigerator for temporary storage.

[0138] 6. Bioanalysis and Data Processing

[0139] The drug concentration of the specified compound in plasma is determined by LC-MS / MS method, and the main pharmacokinetic parameters are calculated using the Winnolin 8.3 non-compartmental model. When calculating the pharmacokinetic parameters, C max The previous BLQ (including "No peak") is calculated as 0; C max The subsequent BLQ (including "No peak") is not involved in the calculation.

[0140] In vivo pharmacokinetic data of the test compound administered intravenously and intranasally to SD rats

[0141] Test Example 6: In vivo pharmacodynamic study of the test compound on capsaicin-induced changes in blood flow in the forearm skin of cynomolgus monkeys.

[0142] 1. Experimental Principle

[0143] Capsaicin induces the release of CGRP after acting on the skin. CGRP binds to receptors, exerts a vasodilatory effect, and promotes increased blood flow. The test compound inhibits the binding of CGRP to receptors, inhibiting the increase in blood flow caused by the release of CGRP. Blood flow is detected by a blood flow meter to reflect the efficacy of the drug.

[0144] 2. Experimental Procedure

[0145] 2.1 Animal Information:

[0146] Species: Crab-eating macaque, male (5-8 kg), Animal use permit: SYXK(Su)2019-0004, hair removal treatment was performed 3 days before the experiment.

[0147] 2.2 Preparation of test sample:

[0148] Accurately weigh an appropriate amount of drug, dissolve it in sterile physiological saline, and use sonication and vortexing to mix and dissolve it thoroughly to obtain a 0.05 mg / ml drug solution for intravenous (IV) administration.

[0149] 2.3 Pre-test phase: After anesthetizing the animals, a flowmeter was used to scan the blood flow on the inner side of the forearm, and an O-ring was placed on the inner side of the arm, avoiding obvious blood vessels. After confirming the position of the rubber ring, the blood flow rate inside the ring was scanned as the baseline blood flow value. Subsequently, 2 mg of capsaicin was applied inside the rubber ring, and the blood flowmeter recorded the blood flow rate at 10 min, 20 min, and 30 min after capsaicin treatment.

[0150] 2.4 Administration phase: After anesthetizing the monkeys, a rubber band was placed on the same part of the arm. After collecting baseline blood flow data, the test compound (dose: 0.05 mg / kg) was injected intravenously at a dose of 1 ml / kg. After administration, 2 mg of capsaicin was applied to the rubber band. Blood flow was recorded at 10 min, 20 min and 30 min after capsaicin treatment using a blood flow meter.

[0151] 2.5 Data Processing: Blood flow during the pre-test phase is denoted as P, and blood flow in the rubber band at time t is denoted as Pt. t Baseline blood flow is denoted as P0; blood flow during the drug administration phase is denoted as D; and blood flow through the rubber band at time t is denoted as D0. t If the baseline blood flow is denoted as D0, then the blood flow inhibition rate at time t is I. t The calculation formula is as follows: I t=((P) t –P0) / P0–(D t –D0) / D0)*100%

[0152] 3. Experimental Results:

[0153] The blood flow inhibition rates at different time points are shown in Figure 1. At 10 min, the blood flow inhibition rate of compound 1 (Mean = 355.3%) was significantly higher than that of Zavegepant (Mean = 89.7%).

[0154] III. Bioassay data for the combined application of compound 1 and DDM

[0155] Test Example 7: Study on the effect of compound 1 combination DDM or not on PK characteristics in SD rats

[0156] The experimental animals in this test case 7 were also SD rats, and the same experimental design, data collection, and bioanalysis data processing methods and procedures were used as in test case 5.

[0157] In the preparation of the test sample in Test Example 7, a parallel administration solution group with 0.2% dodecyl-β-D-maltose (DDM) was also prepared to compare the changes in rat PK characteristics with the administration solution group without dodecyl-β-D-maltose (DDM).

[0158] The effects of different intranasally administered formulations on rat pharmacokinetic (PK) in Example 7 of this test are shown in the table below:

[0159] Based on the table above, we can see that:

[0160] Compound 1, when combined with DDM, showed surprising and simultaneous significant improvements in several key PK parameters. For example, after the combined application of Compound 1 and DDM: T max The time to peak concentration was reduced from 1 hour to 0.167 hours, a reduction of 83.3%. This ultra-short peak time lays a solid foundation for the rapid onset of action of the drug. max It is greatly increased by 10 times, while the AUC is increased by about 5 times, ensuring a rapid onset concentration while reducing drug dosage and increasing safety.

[0161] For the indications targeted by compound 1, such as migraine and tension headache, rapid relief, treatment, and prevention of acute attacks are particularly important. The T-cell effect resulting from the combined administration of compound 1 and DDM is also crucial. max shorten and C max The remarkable improvement in PK properties demonstrates the enormous clinical potential of this drug formulation for nasal administration.

[0162] Test Example 8: Study on the Influence of Compound 1 in Monkeys with or without DDM on PK Characteristics

[0163] 1. Experimental Animals

[0164] Species: Cynomolgus monkeys, male, 2 - 5 kg. Source: Ankai Yibo (Zhanjiang) Biotechnology Co., Ltd., License number for experimental animal production: SCXK (Guangdong) 2019 - 0046. Quantity: 3 for intravenous administration, 3 for nasal spray administration.

[0165] 2. Preparation of Test Substances

[0166] 2.1 Weigh an appropriate amount of the drug precisely, add 50 mM succinate buffer (diluted with D5W, pH = 5 - 6), and sonicate and vortex to mix and dissolve thoroughly to obtain a dosing solution of 0.5 mg / mL for intravenous injection.

[0167] 2.2 Weigh an appropriate amount of the drug precisely, add Solvent 1: 50 mM succinate buffer (diluted with purified water, pH = 5 - 6), and sonicate and vortex to mix and dissolve thoroughly to obtain a dosing solution of 20 mg / mL. Place it in a nasal spray device for nasal spray administration, 100 μL per spray.

[0168] 2.3 Weigh an appropriate amount of the drug precisely, add Solvent 2: 50 mM succinate buffer containing 0.2% dodecyl - β - D - maltoside (pH = 5 - 6), and sonicate and vortex to mix and dissolve thoroughly to obtain a dosing solution of 20 mg / mL. Place it in a nasal spray device for nasal spray administration, 100 μL per spray.

[0169] 3. Experimental Design

[0170] 4. Blood Sampling Time Points

[0171] 5 min, 10 min, 15 min, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 24 h after administration.

[0172] 5. Sample Collection and Handling

[0173] Collect blood from the saphenous vein or cephalic vein. Collect approximately 0.6 mL for each sample, anticoagulate with EDTA - K2. After blood sample collection, place it on ice and centrifuge to separate plasma within 2 hours (centrifugation conditions: 2000 g, 10 min, 2 - 8°C). The collected plasma samples are stored in a - 80°C refrigerator before analysis, and the remaining plasma samples after analysis are continued to be stored in a - 80°C refrigerator for temporary storage.

[0174] 6. Bioanalysis and Data Processing

[0175] The concentrations of a specified drug compound in plasma were determined using LC-MS / MS, and the main pharmacokinetic parameters were calculated using a Winnolin 8.3 non-compartmental model. When calculating the pharmacokinetic parameters, C... max Previous BLQs (including "No peak") are calculated as 0; C max Subsequent BLQs (including "No peak") will not be included in the calculation.

[0176] In vivo pharmacokinetic data of the test compound administered intravenously and nasally to cynomolgus monkeys

[0177] In vivo pharmacokinetics of different drug combinations administered intranasally in monkeys

[0178] Results analysis:

[0179] Similar to the rat PK characteristic effect study in Test Example 7, the monkey PK characteristic effect study showed that when compound 1 was administered in combination with DDM, several key PK parameters were also surprisingly and simultaneously significantly improved. This was manifested in the following ways: for example, after compound 1 was administered in combination with DDM, C... max It was greatly increased to 52.2 times, while AUC 0-inf Increased to 17.1 times, T max The onset time was reduced from 1 hour to approximately 0.167 hours, a significant reduction of 83.3%. In other words, compared to rats, in monkeys—a species more closely related to humans—the combination of compound 1 and DDM further demonstrated superior improvement in PK characteristics, showing promising clinical application prospects.

[0180] Test Example 9: Study on the effect of different DDM concentrations of compound 1 on PK properties in SD rats

[0181] The experimental animals in this test case 9 were also SD rats, and the same experimental design, data collection, and bioanalysis data processing methods and procedures were used as in test case 5.

[0182] In the preparation of the test sample in Test Example 9, parallel administration solutions with 0.05% and 5% dodecyl-β-D-maltose (DDM) were prepared to compare and observe the changes in rat PK characteristics between the two concentrations of dodecyl-β-D-maltose (DDM) administration solution groups.

[0183] The effects of different DDM concentrations on rat pharmacokinetic (PK) in Test Example 9 are shown in the table below:

[0184] It can be seen from the above table:

[0185] When compound 1 was combined with different concentrations of DDM, several key PK parameters showed surprising, simultaneous, and significant improvements. For example, when compound 1 was combined with 0.05% and 5% alkyl glycosides: T max The time to peak concentration was shortened by 75% and 91.7% respectively, from 1 hour to 0.25 hours and 0.083 hours, indicating that the higher the alkyl glycoside concentration, the shorter the time to peak concentration; C max The concentrations were increased by 6.51 times and 13.3 times, and the AUC was increased by 3.8 times and 3.6 times, ensuring rapid onset of action while reducing drug dosage and increasing safety.

[0186] IV. Formulation Study of Compound 1 in Aqueous Pharmaceutical Solution and Solution-type Nasal Spray

[0187] 1. Solubility Study of Compound 1

[0188] Method for determining saturated solubility: Compound 1 was dissolved in sodium succinate buffer solutions with different pH values ​​(pH 3.0–7.0). Compound 1 was added to sodium succinate buffer solutions with initial pH values ​​of 3.0, 4.0, 5.0, 5.5, 6.0, 6.5, and 7.0, respectively, while stirring. Compound 1 was added gradually until it could not be dissolved. After centrifugation (6000 rpm, 5 min), the supernatant was collected and the content was determined. The results are shown in the table below: Note: 40mM succinate buffer solution was adjusted to the target initial pH (3.0-7.0) by adding sodium hydroxide; the saturated solubility unit mg / g represents the content of compound 1 dissolved in the final drug solution, and all units are calculated as free base.

[0189] Conclusion: Based on the table above, the saturated solubility of compound 1 exhibits a pH-dependent effect, meaning that the lower the pH of the solution, the stronger the solubility. The experiments also revealed that when the initial pH of the buffer solution was greater than 5.5, oil formation was more pronounced.

[0190] 2. Preparation of pharmaceutical aqueous solution and solution-type nasal spray of compound 1

[0191] 1) Prescription design

[0192] Refer to the table below to design the prescriptions for each batch. Note: ① " / " indicates that the corresponding substance is not added to the formula. ② The appropriate amount of sodium hydroxide is the amount added to adjust the pH buffer and appropriate amount of water to the initial pH value.

[0193] 2) Preparation method of pharmaceutical aqueous solution

[0194] Step 1: Prepare a buffer solution with pH buffer and an appropriate amount of water. The initial pH value of the buffer solution is about 4.

[0195] Step 2: Gradually add Compound 1 to the buffer solution and mix well to dissolve. Then add DDM, sodium chloride, and benzalkonium chloride (if any).

[0196] Step 3: Adjust the final pH of the system to 6.0-7.0 using a pH adjuster, and add the remaining water to make up the volume to obtain the corresponding pharmaceutical aqueous solution preparation for each prescription.

[0197] 3) Formulation method of solution-type nasal spray

[0198] The medicinal aqueous solution obtained in step 2) is filled into borosilicate glass containers and sealed with rubber stoppers. A metering pump is then assembled, or it is directly combined with a commercial nasal spray to obtain a solution-type nasal spray formulation.

[0199] For purposes of description and disclosure, all patents, patent applications, and other publications are expressly incorporated herein by reference. These publications are provided solely because their publication predates the filing date of this application. All statements regarding the dates of these documents or representations of their contents are based on information available to the applicant and do not constitute any acknowledgment of the accuracy of the dates or contents of these documents. Furthermore, in any country, any reference to these publications herein does not constitute an endorsement that such publication is part of the general knowledge in the art.

[0200] This application is not limited to the optional embodiments described above, and anyone can derive other various forms of products based on the guidance of this application. The specific embodiments described above should not be construed as limiting the scope of protection of this application, which shall be determined by the claims, and the description can be used to interpret the claims.

Claims

1. A medicinal aqueous solution, wherein, The pharmaceutical aqueous solution comprises compound 1 with the following structure, dodecyl-β-D-maltose, an osmotic pressure regulator, a pH buffer, and water. Optionally, the osmotic pressure regulator comprises sodium chloride, and optionally, the pharmaceutical aqueous solution further comprises a pH regulator, wherein the pH value of the pharmaceutical aqueous solution is not greater than 8.

5.

2. The medicinal aqueous solution according to claim 1, wherein, The pH value of the medicinal aqueous solution is not greater than 7.5, or not greater than 7.0, or 3.0 to 7.0, or 5.5 to 7.0, or 6.0 to 7.

0.

3. The medicinal aqueous solution according to claim 1 or 2, wherein, The pH buffer includes succinic acid and / or its salts, and the pH adjuster includes sodium hydroxide and / or hydrochloric acid.

4. A medicinal aqueous solution according to any one of claims 1-3, wherein, The medicinal aqueous solution is obtained by a preparation method including the following steps: 1) Mix pH buffer and water to obtain a buffer solution; 2) Add compound 1 to the buffer solution and mix well; 3) Continue to add pH adjuster to adjust the pH value of the system to obtain the medicinal aqueous solution; Steps 1) through 3) may further include the addition of dodecyl-β-D-maltodextrin, optional osmotic pressure regulator sodium chloride, and other excipients; step 3) may also optionally include the addition of water to make up to volume.

5. The medicinal aqueous solution according to claim 4, wherein, When the concentration of compound 1 in the pharmaceutical aqueous solution is not greater than 2.7 mg / mL, the pH value of the buffer aqueous solution after mixing the pH buffer and water is not greater than 6.5; When the concentration of compound 1 in the pharmaceutical aqueous solution is not greater than 6.7 mg / mL, the pH value of the buffer aqueous solution after mixing the pH buffer and water is not greater than 6.1; When the concentration of compound 1 in the pharmaceutical aqueous solution is not greater than 13.0 mg / mL, the pH value of the buffer aqueous solution after mixing the pH buffer and water is not greater than 5.5; When the concentration of compound 1 in the pharmaceutical aqueous solution is not greater than 50.2 mg / mL, the pH value of the buffer aqueous solution after mixing the pH buffer and water is not greater than 5.0; When the concentration of compound 1 in the pharmaceutical aqueous solution is not greater than 111.6 mg / mL, the pH value of the buffer aqueous solution after mixing the pH buffer and water is not greater than 4.

1.

6. The medicinal aqueous solution according to claim 4, wherein, The pH value of the buffer solution obtained by mixing the pH buffer and water is not greater than 5.5, or not greater than 4.0, or is between 3.5 and 4.

5.

7. The medicinal aqueous solution according to any one of claims 1-6, wherein, The concentration of compound 1 in the pharmaceutical aqueous solution is 0.1–100 mg / mL, 2.5–50 mg / mL, 2.5–20 mg / mL, 2.5 mg / mL, 10 mg / mL, or 20 mg / mL.

8. The medicinal aqueous solution according to any one of claims 1-7, wherein, The weight ratio of the dodecyl-β-D-maltose in the pharmaceutical aqueous solution is 0.05%–20%, 0.05%–10%, 0.05%–5%, 0.1%–5%, 0.1%–0.5%, 0.1%–0.3%, 0.05%, 0.2%, or 5%.

9. The medicinal aqueous solution according to any one of claims 1-8, wherein, It also includes chelating agents and / or preservatives, the chelating agents including EDTA-2Na, and the preservatives including benzalkonium chloride and / or potassium sorbate.

10. A method for preparing a medicinal aqueous solution according to any one of claims 1 to 9, wherein, Includes the following steps: 1) Mix pH buffer and water to obtain a buffer solution; 2) Add compound 1 to the buffer solution and mix well; 3) Continue to add pH adjuster to adjust the pH value of the system to obtain the medicinal aqueous solution; Steps 1) through 3) may further include the addition of dodecyl-β-D-maltodextrin, optional osmotic pressure regulator sodium chloride, and other excipients; step 3) may also optionally include the addition of water to make up to volume.

11. The preparation method according to claim 10, wherein: Step 1) may optionally include the addition of a pH adjuster; the pH value of the buffer aqueous solution in step 1) is not greater than 6.5, or not greater than 6.0, or not greater than 5.5, or not greater than 5.0, or not greater than 4.0, or is 3.5 to 4.5, or the pH adjuster added in step 1) adjusts the pH value of the buffer aqueous solution to not greater than 6.5, or not greater than 6.0, or not greater than 5.5, or not greater than 5.0, or not greater than 4.0, or is 3.5 to 4.5; the pH adjuster added in step 3) adjusts the pH value of the medicinal aqueous solution to not greater than 8.5, or not greater than 7.5, or not greater than 7.0, or is 3.0 to 7.0, or is 5.5 to 7.0, or is 6.0 to 7.

0.

12. A solution-type nasal spray, wherein, The nasal spray device includes the medicinal aqueous solution of any one of claims 1 to 9 contained in the nasal spray device.

13. The solution-type nasal spray according to claim 12, wherein, The medicinal aqueous solution comprises, by weight, 0.01% to 10% of compound 1, 0.05% to 20% of dodecyl-β-D-maltodextrin, 0.7% to 1% of sodium chloride, a pH buffer, a pH adjuster, and water. The pH value of the buffer solution prepared with the pH buffer is not greater than 5.

5. The pH adjuster adjusts the pH value of the medicinal aqueous solution to be no greater than 8.

5.

14. The solution-type nasal spray according to claim 13, wherein, The medicinal aqueous solution comprises, by weight, 2%, 1%, or 0.25% of compound 1, 0.2% of dodecyl-β-D-maltodextrin, 0.80% or 0.83% of sodium chloride, a pH buffer, a pH adjuster, and water. The pH value of the buffered aqueous solution prepared by the pH buffer is 3.5-4.5, and the pH buffer is optionally prepared from 0.18% succinic acid and 0.032% sodium hydroxide. The pH adjuster adjusts the pH of the medicinal aqueous solution to 6.0-7.

0.

15. A pharmaceutical aqueous solution according to any one of claims 1 to 9 or a solution-type nasal spray according to any one of claims 12 to 14 for the prevention, treatment or relief of diseases mediated and / or regulated by CGRP; preferably, the diseases include migraines and / or neuropathic pain.

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