Mabloxvir oral solution as well as preparation method and application thereof

Abstract

The invention discloses a macloxvir oral solution as well as a preparation method and application thereof, and belongs to the technical field of medical chemistry. The invention aims to solve the technical problems that the existing macloxvir preparation is inconvenient to take, slow in absorption, low in bioequivalence, tedious in preparation process and the like. The key point of the technical scheme is as follows: the oral solution of the macarovir comprises the following components: the macarovir, hydroxypropyl-beta-cyclodextrin, a flavoring agent, a pH regulator and water for injection, and the substitution degree of the hydroxypropyl-beta-cyclodextrin is 3.0-7.0.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry technology, specifically relating to a mabaloxavir oral solution, its preparation method, and its application. Background Technology

[0002] Baloxavir was jointly developed by Shionogi & Co., Ltd. of Japan, Genentech, and Roche Pharmaceuticals. Dosage forms include tablets, granules, and dry suspensions. Baloxavir ester is a novel prodrug that, through metabolism (hydrolysis), is converted into the active form of baloxavir. This active form selectively inhibits a cap-dependent endonuclease, an influenza virus-specific enzyme in the acidic (PA) subunit of the viral RNA polymerase complex, thereby inhibiting influenza virus replication.

[0003] Currently, commercially available mabaloxavir dosage forms mainly include tablets and dry suspensions. The bioequivalence of tablets is greatly affected by the particle size of the raw materials, which has a narrow acceptable range and is difficult to control precisely. Furthermore, tablets exhibit excessively high resolution deviations (RSDs) in standard media, making it difficult to compare the quality of self-made formulations with reference formulations. Considering the inconvenience of administration for children, the elderly, bedridden patients, patients with swallowing difficulties, and those with limited access to water, both tablets and dry suspensions are not suitable for their use.

[0004] Relevant patent documents retrieved: This document, published in China (CN120643538A) on September 16, 2025, discloses a mabaloxavir direct-administered granule and its preparation method. It improves the taste and achieves direct swallowability by adding flavoring agents and using multi-layer coating technology. By controlling the particle size of the raw materials and the type and amount of excipients, the resulting mabaloxavir direct-administered granules exhibit excellent dissolution performance. The addition of stabilizers ensures excellent stability. This invention provides a mabaloxavir direct-administered granule that can be taken in divided doses directly. Its formulation process is stable and controllable, with excellent dissolution performance, good taste, good masking effect, and good stability, making it suitable for large-scale production and possessing good market prospects.

[0005] Relevant non-patent literature retrieved: The journal is titled "Journal of Liaocheng University (Natural Science Edition)", the article is titled "Advances in the Prediction and Performance Optimization of Miscibility of Amorphous Solid Dispersions Based on Polymer Selection", Volume 38 (06), and the publication date is March 12, 2025. This review focuses on the key influence of polymer selection on amorphous solid dispersion (ASD) systems, systematically summarizes the prediction and characterization techniques of drug-polymer miscibility, and details the performance optimization strategies in various aspects such as recrystallization inhibition, dissolution enhancement and stability improvement. This provides a theoretical basis for the rational design of ASD and promotes its widespread application in the delivery of poorly soluble drugs.

[0006] The prior art represented by the aforementioned documents has at least the following unresolved technical problems or defects: The stability of the aforementioned patented mabaloxavir direct-acting granules is poor, and the preparation process is cumbersome, resulting in high pharmaceutical costs. Relevant evidence includes accelerated and long-term experimental test results of the mabaloxavir direct-acting granules.

[0007] Therefore, there is an urgent need in the field to provide a mabaloxavir oral solution that is convenient to take, rapidly absorbed, highly bioequivalent, has good bioequivalence, and is simple to prepare and low in cost. Summary of the Invention

[0008] The purpose of this invention is to provide: A marbaloxavir oral solution, its preparation method and application, and related technologies, to solve the technical problems of existing marbaloxavir preparations, such as inconvenience in administration, slow absorption, low bioequivalence, and cumbersome preparation processes, or a combination thereof.

[0009] Terminology Explanation: Unless otherwise defined, all technical terms in this invention have the same meanings as commonly understood by one of ordinary skill in the art to which the subject matter of the claims pertains. Unless otherwise stated, all patents, patent inventions, and disclosures referenced in this invention are incorporated herein by reference in their entirety. If multiple definitions exist for terms in this invention, the definitions in this chapter shall prevail.

[0010] It should be understood that the above brief description and the following detailed description are exemplary and for illustrative purposes only, and do not limit the subject matter of the invention in any way. In this invention, the singular is used in conjunction with the plural unless otherwise specifically stated. It should also be noted that, unless otherwise stated, the use of “or” or “or” means “and / or”. Furthermore, the use of the term “comprising” and other forms such as “including,” “containing,” and “contains” are not limiting.

[0011] The definition of standard chemical terms can be found in the reference "Medicinal Chemistry, Chemical Industry Press, 3rd Edition, 2016".

[0012] Unless otherwise stated, conventional methods within the scope of the art, such as stability evaluation methods, shall be used.

[0013] Unless specifically defined, the use of various commercially available products in this invention employs standard techniques. For example, it may be carried out using the manufacturer's instructions for use with the reagent kit, or in accordance with methods known in the art or the description of this invention. The techniques and methods described herein can generally be implemented according to conventional methods well known in the art, based on the descriptions in the various summary and more specific documents cited and discussed in this specification.

[0014] The terms “optional / arbitrary” or “optionally / arbitrarily” mean that the event or situation described below may or may not occur, including both the occurrence and non-occurrence of the event or situation.

[0015] The term "hydroxypropyl-β-cyclodextrin" as used in this invention refers to: [a compound with the molecular formula (C...]]. 42 H 70 O 35 The chemical substance )-HX+(C3H7O2)X is a white powder that is highly soluble in water and also soluble in 50% ethanol and methanol. It has some relative hygroscopicity. It is non-irritating to muscles and is an ideal solubilizer and excipient for injectable drugs.

[0016] The term "flavoring agent" as used in this invention refers to pharmaceutical excipients used to improve or mask unpleasant odors and tastes of drugs, making it difficult for patients to detect strong bitterness (or other unpleasant odors such as spiciness or irritation). Flavoring agents generally include four categories: sweeteners, flavoring agents, gelling agents, and effervescent agents.

[0017] The term "pH adjuster" as used in this invention, also known as an acidity regulator, refers to substances used to maintain or change the acidity or alkalinity of food. It is primarily used to control the acidifiers, alkalis, and buffering salts required in food.

[0018] The term "water for injection" as used in this invention refers to water obtained by distillation of purified water, also known as redistilled water, which must meet the bacterial endotoxin test requirements stipulated in the Chinese Pharmacopoeia. Its preparation, storage, and dispensing must be carried out under conditions that prevent the production of bacterial endotoxins. This water has a melting point of 0°C and a boiling point of 100°C. Storage tanks and pipelines must be made of non-toxic and corrosion-resistant materials (such as 316L stainless steel), avoiding dead corners and blind pipes. Hydrophobic sterilizing filters must be installed at the vents of the storage tanks, and high-temperature insulation or low-temperature storage methods must be used to control microbial growth.

[0019] In a first aspect, the present invention provides: A mabaloxavir oral solution comprises the following components: mabaloxavir, hydroxypropyl-β-cyclodextrin, flavoring agent, pH adjuster, and water for injection, wherein the degree of substitution of the hydroxypropyl-β-cyclodextrin is 3.0-7.0.

[0020] Technical features include: degree of substitution of hydroxypropyl-β-cyclodextrin, flavoring agents, pH adjusters, and component content.

[0021] The preferred technical feature “degree of substitution of hydroxypropyl-β-cyclodextrin” is 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5 or 7.

[0022] The technical feature “degree of substitution of hydroxypropyl-β-cyclodextrin” is further preferably 3.5-5.5.

[0023] The pharmaceutical excipient used in this invention is hydroxypropyl-β-cyclodextrin, a highly water-soluble β-cyclodextrin (β-CD) derivative. It is stable in alkaline media, but can be cleaved under strong acids; it crystallizes well in aqueous and alcoholic solutions; it has no fixed melting point, decomposing at approximately 200°C, and exhibits good thermal stability; it is non-hygroscopic, but readily forms various stable hydrates; its hydrophobic cavities can embed various organic compounds, forming inclusion complexes and altering the physicochemical properties of the included compounds.

[0024] The technical feature "flavoring agent" is selected from one or more of the following: cyclamate, sucralose, acesulfame potassium, steviol glycoside, aspartame, sematriol, glycyrrhizin, asparagine methyl ester, potassium dihydrothiazide, sodium cyclohexanesulfonate, saccharin, sodium saccharin, calcium saccharin, sorbitol, mannitol, fructose, sucrose, maltose, isomaltose, glucose, hydrogenated glucose syrup, xylitol, caramel, and honey.

[0025] The preferred "flavoring agent" is cyclamate, sucralose, aspartame, or fructose.

[0026] Among them, the technical feature "flavoring agent" is further preferably sucralose.

[0027] The technical feature "pH adjuster" is selected from one or more of the following: sodium dihydrogen phosphate, citric acid, sodium carbonate, sodium bicarbonate, hydrochloric acid, sulfuric acid, sodium hydroxide, potassium hydroxide, and disodium hydrogen phosphate.

[0028] The preferred technical feature "pH adjuster" is sodium dihydrogen phosphate, citric acid, sodium carbonate, or sodium bicarbonate.

[0029] Among them, the technical feature "pH adjuster" is further preferably sodium bicarbonate.

[0030] The oral solution of mabaloxavir contains the following components per 100 mL: mabaloxavir 0.1-0.4 g, hydroxypropyl-β-cyclodextrin 1-10 g, flavoring agent 0.5-3.5 g, and pH adjuster 0.01-1.0 g.

[0031] The mabaloxavir oral solution comprises the following components per 100 mL: mabaloxavir 0.2-0.4 g, hydroxypropyl-β-cyclodextrin 2-6 g, flavoring agent 1-2 g, and pH adjuster 0.1-1.0 g.

[0032] Based on further solutions to the technical problems of the present invention, or simultaneous solutions to multiple technical problems, the preferred solution in the technical solution provided in the first aspect of the present invention includes: The first preferred embodiment is that the degree of substitution of the hydroxypropyl-β-cyclodextrin is 3.5-5.5. This technical solution not only solves the technical problems of "existing mabaloxavir formulations being inconvenient to take, slow to absorb, and having low bioequivalence", but also further solves the technical problem of "existing mabaloxavir formulations having cumbersome preparation processes".

[0033] The second preferred embodiment: the flavoring agent is selected from one or more of the following: cyclamate, sucralose, acesulfame potassium, steviol glycosides, aspartame, sematrandole, glycyrrhizin, asparagine methyl ester, potassium dihydrothiazide, sodium cyclohexanesulfonate, saccharin, sodium saccharin, calcium saccharin, sorbitol, mannitol, fructose, sucrose, maltose, isomaltose, glucose, hydrogenated glucose syrup, xylitol, caramel, and honey. This technical solution, in addition to addressing the technical problems of "existing mabaloxavir preparations being inconvenient to take, slow to absorb, and having low bioequivalence," further solves the technical problem of "existing mabaloxavir preparations having cumbersome preparation processes."

[0034] The third preferred option: the pH adjuster is selected from one or more of sodium dihydrogen phosphate, citric acid, sodium carbonate, sodium bicarbonate, hydrochloric acid, sulfuric acid, sodium hydroxide, potassium hydroxide, and disodium hydrogen phosphate. This technical solution, in addition to addressing the technical problems of "existing mabaloxavir preparations being inconvenient to take, slow to absorb, and having low bioequivalence," further solves the technical problem of "existing mabaloxavir preparations having cumbersome preparation processes."

[0035] The fourth preferred embodiment: Each 100 mL of the mabaloxavir oral solution comprises the following components: mabaloxavir 0.1-0.4 g, hydroxypropyl-β-cyclodextrin 1-10 g, flavoring agent 0.5-3.5 g, and pH adjuster 0.01-1.0 g. This technical solution, in addition to addressing the technical problems of "existing mabaloxavir formulations being inconvenient to take, slow to absorb, and having low bioequivalence," further solves the technical problem of "existing mabaloxavir formulations having cumbersome preparation processes."

[0036] The fifth preferred embodiment: Each 100 mL of the mabaloxavir oral solution comprises the following components: mabaloxavir 0.2-0.4 g, hydroxypropyl-β-cyclodextrin 2-6 g, flavoring agent 1-2 g, and pH adjuster 0.1-1.0 g. This technical solution, in addition to addressing the technical problems of "existing mabaloxavir formulations being inconvenient to take, slow to absorb, and having low bioequivalence," further solves the technical problem of "existing mabaloxavir formulations having cumbersome preparation processes."

[0037] Secondly, the present invention provides: The preparation method of the above-mentioned mabaloxavir oral solution includes the following steps: (1) First, dissolve hydroxypropyl-β-cyclodextrin in a portion of water for injection, then add mabaloxavir and stir well to obtain a mixed solution; (2) Dissolve the flavoring agent in the mixed solution, add pH adjuster to adjust pH, and finally add the remaining water for injection to obtain the final product.

[0038] The technical features include: the temperature of the water for injection in step (1), the pH value adjusted in step (2), and the post-treatment of adding the remaining water for injection in step (2).

[0039] The technical feature “temperature of water for injection in step (1)” is selected from 50-80℃.

[0040] The preferred temperature of the water for injection in step (1) is 50°C, 55°C, 60°C, 65°C, 70°C, 75°C or 80°C.

[0041] The temperature of the water for injection described in step (1) is further preferably 60-70℃.

[0042] Among them, the technical feature “the pH value adjusted in step (2)” is selected from: 3-8.

[0043] The preferred pH value in step (2) is 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 or 8.

[0044] The technical feature “the pH value adjusted in step (2)” is further preferably 4-7.

[0045] In step (2), the remaining water for injection is added and then filtered.

[0046] It also includes technical features: the material of the filter element.

[0047] The technical feature "filter material" is selected from: PES, PVDF or PP.

[0048] Among them, the preferred technical feature "filter material" is PES.

[0049] It also includes technical features: the pore size of the filter element.

[0050] The technical feature “pore size of the filter element” is selected from: 0.45 μm.

[0051] Based on further solutions to the technical problems of the present invention, or simultaneous solutions to multiple technical problems, the preferred solution in the technical solution provided in the second aspect of the present invention includes: The first preferred option is that the temperature of the water for injection in step (1) is 50-80℃. This technical solution solves the technical problem that "existing mabaloxavir preparations are inconvenient to take, have slow absorption, and low bioequivalence". It further solves the technical problem that "existing mabaloxavir preparations have complicated preparation processes".

[0052] The second preferred solution: In step (2), the pH is adjusted to 3-8; after adding the remaining water for injection, filtration is performed, and the filter element material is PES, PVDF or PP, and the pore size of the filter element is 0.45 μm. This technical solution not only solves the technical problems of "existing mabaloxavir preparations being inconvenient to take, slow to absorb, and having low bioequivalence", but also further solves the technical problem of "existing mabaloxavir preparations having cumbersome preparation processes".

[0053] Thirdly, the present invention provides: The above-mentioned mabaloxavir oral solution is used in the preparation of drugs for treating influenza A virus infection.

[0054] Embodiments 1-7 of this invention at least support the protection scope of claim 1.

[0055] Regarding the claim 1: The technical feature “Mabaloxavir oral solution comprises the following components: mabaloxavir, hydroxypropyl-β-cyclodextrin, flavoring agent, pH adjuster, and water for injection” is derived from the corresponding technical features in the foregoing explanation and / or Examples 1-7 of this invention: “A mabaloxavir oral solution is composed of the following components: 2 g mabaloxavir, 40 g hydroxypropyl-β-cyclodextrin (degree of substitution 4.0), 20 g cyclamate, 4 g sodium dihydrogen phosphate, and water for injection to a final volume of 2000 mL”; “A mabaloxavir oral solution is composed of the following components: 4 g mabaloxavir, 80 g hydroxypropyl-β-cyclodextrin (degree of substitution 5.0), 40 g sucralose, 10 g citric acid, and water for injection to a final volume of 2000 mL”; “A mabaloxavir oral solution is composed of the following components: 8 g mabaloxavir, 120 g hydroxypropyl-β-cyclodextrin (degree of substitution 5.5)”. "A mabaloxavir oral solution, comprising: 8 g mabaloxavir, 20 g aspartame, 8 g citric acid, and water for injection to a final volume of 2000 mL"; "A mabaloxavir oral solution, comprising: 8 g mabaloxavir, 100 g hydroxypropyl-β-cyclodextrin (degree of substitution 4.5), 40 g sucralose, 10 g sodium bicarbonate, and water for injection to a final volume of 2000 mL"; "A mabaloxavir oral solution, comprising: 8 g mabaloxavir, 60 g hydroxypropyl-β-cyclodextrin (degree of substitution 4.5), 40 g fructose, 8 g sodium carbonate, and water for injection to a final volume of 2000 mL", etc., are summarized from the common characteristic "components of mabaloxavir oral solution". Therefore, based on reasonable presumption, those skilled in the art can determine that the subordinate concepts of the technical feature "Mabaloxavir oral solution comprises the following components: mabaloxavir, hydroxypropyl-β-cyclodextrin, flavoring agent, pH adjuster and water for injection", the technical means that are essentially equivalent to "Mabaloxavir oral solution comprises the following components: mabaloxavir, hydroxypropyl-β-cyclodextrin, flavoring agent, pH adjuster and water for injection", and the technical means that can replace "Mabaloxavir oral solution comprises the following components: mabaloxavir, hydroxypropyl-β-cyclodextrin, flavoring agent, pH adjuster and water for injection" based on the existing level of technology and conventional technical means and common knowledge, should all fall within the protection scope of claim 1.

[0056] The technical feature “the degree of substitution of the hydroxypropyl-β-cyclodextrin is 3.0-7.0” is summarized from the corresponding technical features in the foregoing explanation and / or Examples 1-7 of this invention, such as 40 g of hydroxypropyl-β-cyclodextrin (degree of substitution 4.0), 5.0 g of hydroxypropyl-β-cyclodextrin (degree of substitution 5.0), 120 g of hydroxypropyl-β-cyclodextrin (degree of substitution 5.5), and 60 g of hydroxypropyl-β-cyclodextrin (degree of substitution 4.5), through the common feature “degree of substitution of hydroxypropyl-β-cyclodextrin”. Therefore, those skilled in the art can reasonably presume that the subordinate concepts of the technical feature "the degree of substitution of the hydroxypropyl-β-cyclodextrin is 3.0-7.0", the essentially equivalent technical means of "the degree of substitution of the hydroxypropyl-β-cyclodextrin is 3.0-7.0", and the technical means that can replace "the degree of substitution of the hydroxypropyl-β-cyclodextrin is 3.0-7.0" based on the existing technical level and conventional technical means and common knowledge should all fall within the protection scope of claim 1. For example, if the degree of substitution of "the hydroxypropyl-β-cyclodextrin" is replaced with 3.0, 7.0, etc. while other technical features remain unchanged, it still falls within the protection scope of claim 1 of this invention.

[0057] Embodiments 1-7 of this invention at least support the protection scope of claim 2.

[0058] The technical feature “the degree of substitution of the hydroxypropyl-β-cyclodextrin is 3.5-5.5” is summarized from the corresponding technical features in the foregoing explanation and / or Examples 1-7 of this invention, such as 40 g of hydroxypropyl-β-cyclodextrin (degree of substitution 4.0), 5.0 g of hydroxypropyl-β-cyclodextrin (degree of substitution 5.0), 120 g of hydroxypropyl-β-cyclodextrin (degree of substitution 5.5), and 60 g of hydroxypropyl-β-cyclodextrin (degree of substitution 4.5), through the common feature “degree of substitution of hydroxypropyl-β-cyclodextrin”. Therefore, those skilled in the art can reasonably presume that the subordinate concepts of the technical feature "the degree of substitution of the hydroxypropyl-β-cyclodextrin is 3.5-5.5", the essentially equivalent technical means of "the degree of substitution of the hydroxypropyl-β-cyclodextrin is 3.5-5.5", and the technical means that can replace "the degree of substitution of the hydroxypropyl-β-cyclodextrin is 3.5-5.5" based on the existing technical level and conventional technical means and common knowledge should all fall within the protection scope of claim 2. For example, replacing "the degree of substitution of the hydroxypropyl-β-cyclodextrin" with 3.5 while keeping other technical features unchanged still falls within the protection scope of claim 2 of this invention.

[0059] Embodiments 1-7 of this invention at least support the protection scope of claim 3.

[0060] The technical feature “the flavoring agent is selected from one or more of the following: cyclamate, sucralose, acesulfame potassium, steviol glycoside, aspartame, sematrandole, glycyrrhizin, asparagine methyl ester, potassium dihydrothiazide, sodium cyclohexanesulfonate, saccharin, sodium saccharin, calcium saccharin, sorbitol, mannitol, fructose, sucrose, maltose, isomaltose, glucose, hydrogenated glucose syrup, xylitol, caramel, and honey” is summarized from the corresponding technical features of 40 g sucralose, 40 g fructose, 10 g cyclamate, and 20 g aspartame in the foregoing explanation and / or Examples 1-7 of this invention, using the common feature “flavoring agent”. Therefore, those skilled in the art can reasonably presume that the technical feature "the flavoring agent is selected from one or more of cyclamate, sucralose, acesulfame potassium, steviol glycoside, aspartame, sematrandole, glycyrrhizin, asparagine methyl ester, potassium dihydrothiazide, sodium cyclohexanesulfonate, saccharin, sodium saccharin, calcium saccharin, sorbitol, mannitol, fructose, sucrose, maltose, isomaltose, glucose, hydrogenated glucose syrup, xylitol, caramel, and honey" and "the flavoring agent is selected from one or more of cyclamate, sucralose, sodium dihydrothiazide, calcium saccharin, sodium saccharin, calcium saccharin, sorbitol, mannitol, fructose, sucrose, maltose, isomaltose, glucose, hydrogenated glucose syrup, xylitol, caramel, and honey" The following are subordinate concepts of "one or more of the following: cyclamate, sucralose, acesulfame potassium, steviol glycosides, aspartame, sematrandole, glycyrrhizin, asparagine methyl ester, potassium dihydrothiazide, sodium cyclohexanesulfonate, saccharin, sodium saccharin, calcium saccharin, sorbitol, mannitol, fructose, sucrose, maltose, isomaltose, glucose, hydrogenated glucose syrup, xylitol, caramel, and honey"; and "the flavoring agent is selected from cyclamate, sucralose, acesulfame potassium, steviol glycosides, aspartame, sematrandole, glycyrrhizin, asparagine methyl ester, potassium dihydrothiazide, sodium cyclohexanesulfonate, saccharin, calcium saccharin, sorbitol, mannitol, fructose, sucrose, maltose, isomaltose, glucose, hydrogenated glucose syrup, xylitol, caramel, and honey". The technical means are basically equivalent to "one or more of methyl phenylalanine, potassium dihydrothiazide, sodium cyclohexanesulfonate, saccharin, sodium saccharin, calcium saccharin, sorbitol, mannitol, fructose, sucrose, maltose, isomaltose, glucose, hydrogenated glucose syrup, xylitol, caramel and honey", and can replace "the flavoring agent selected from cyclamate, sucralose, acesulfame potassium, steviol glycoside, aspartame, thomatose, glycyrrhizin, asparagine" within the scope of conventional technical means and common knowledge based on the existing technical level. The technical means of "one or more of phenylalanine methyl ester, potassium dihydrothiazide, sodium cyclohexanesulfonate, saccharin, sodium saccharin, calcium saccharin, sorbitol, mannitol, fructose, sucrose, maltose, isomaltose, glucose, hydrogenated glucose syrup, xylitol, caramel and honey" should all fall within the protection scope of claim 3. For example, if the flavoring agent is replaced with acesulfame potassium, potassium dihydrothiazide, etc., while other technical features remain unchanged, it still falls within the protection scope of claim 3 of this invention.

[0061] Embodiments 1-7 of this invention at least support the protection scope of claim 4.

[0062] The technical feature "the pH adjuster is selected from one or more of sodium dihydrogen phosphate, citric acid, sodium carbonate, sodium bicarbonate, hydrochloric acid, sulfuric acid, sodium hydroxide, potassium hydroxide, and disodium hydrogen phosphate" is derived from the corresponding technical features of 4 g sodium dihydrogen phosphate, 10 g citric acid, 10 g sodium bicarbonate, and 8 g sodium carbonate in the foregoing explanation and / or Examples 1-7 of this invention, summarized by the common feature "pH adjuster". Therefore, those skilled in the art can reasonably infer that the technical feature "the pH adjuster is selected from one or more of sodium dihydrogen phosphate, citric acid, sodium carbonate, sodium bicarbonate, hydrochloric acid, sulfuric acid, sodium hydroxide, potassium hydroxide, and disodium hydrogen phosphate", and the subordinate concept of "the pH adjuster is selected from one or more of sodium dihydrogen phosphate, citric acid, sodium carbonate, sodium bicarbonate, hydrochloric acid, sulfuric acid, sodium hydroxide, potassium hydroxide, and disodium hydrogen phosphate", and the concept of "the pH adjuster is selected from one or more of sodium dihydrogen phosphate, citric acid, sodium carbonate, sodium bicarbonate, hydrochloric acid, sulfuric acid, sodium hydroxide, potassium hydroxide, and disodium hydrogen phosphate", are all related to the concept of "the pH adjuster is selected from sodium dihydrogen phosphate, citric acid, sodium carbonate, sodium bicarbonate, hydrochloric acid, sulfuric acid, sodium hydroxide, etc." The technical means that are essentially equivalent to "one or more of potassium hydroxide and disodium hydrogen phosphate", and the technical means that can replace "the pH adjuster is selected from one or more of sodium dihydrogen phosphate, citric acid, sodium carbonate, sodium bicarbonate, hydrochloric acid, sulfuric acid, sodium hydroxide, potassium hydroxide and disodium hydrogen phosphate" based on the existing technical level and conventional technical means and common knowledge, should all fall within the protection scope of claim 4. For example, if "the pH adjuster" is replaced with sulfuric acid, sodium hydroxide, etc. while other technical features remain unchanged, it still falls within the protection scope of claim 4 of this invention.

[0063] Embodiments 1-7 of this invention at least support the protection scope of claim 5.

[0064] The technical feature “The mabaloxavir oral solution comprises the following components per 100 mL: mabaloxavir 0.1-0.4 g, hydroxypropyl-β-cyclodextrin 1-10 g, flavoring agent 0.5-3.5 g, and pH adjuster 0.01-1.0 g” is consistent with the corresponding technical feature in the foregoing explanation and / or Examples 1-7 of this invention: “A mabaloxavir oral solution is composed of the following components: mabaloxavir 2 g, hydroxypropyl-β-cyclodextrin (degree of substitution 4.0) 40 g, cyclamate 20 g, sodium dihydrogen phosphate 4 g, and water for injection to a final volume of 2000 mL”; “A mabaloxavir oral solution is composed of the following components: mabaloxavir 4 g, hydroxypropyl-β-cyclodextrin (degree of substitution 5.0) 80 g, sucralose 40 g, citric acid 10 g, and water for injection to a final volume of 2000 mL”; “A mabaloxavir oral solution is composed of the following components: mabaloxavir 4 g, hydroxypropyl-β-cyclodextrin (degree of substitution 5.0) 80 g, sucralose 40 g, citric acid 10 g, and water for injection to a final volume of 2000 mL”. "mL"; "A mabaloxavir oral solution, composed of the following components: 8 g mabaloxavir, 120 g hydroxypropyl-β-cyclodextrin (degree of substitution 5.5), 20 g aspartame, 8 g citric acid, and water for injection to a final volume of 2000 mL"; "A mabaloxavir oral solution, composed of the following components: 8 g mabaloxavir, 100 g hydroxypropyl-β-cyclodextrin (degree of substitution 4.5), 40 g sucralose, 10 g sodium bicarbonate, and water for injection to a final volume of 2000 mL"; "A mabaloxavir oral solution, composed of the following components: 8 g mabaloxavir, 60 g hydroxypropyl-β-cyclodextrin (degree of substitution 4.5), 40 g fructose, 8 g sodium carbonate, and water for injection to a final volume of 2000 mL", etc., are summarized from the common feature "mass-volume ratio of each component in the mabaloxavir oral solution".Therefore, those skilled in the art can reasonably presume that the technical feature "the mabaloxavir oral solution comprises the following components per 100 mL: mabaloxavir 0.1-0.4 g, hydroxypropyl-β-cyclodextrin 1-10 g, flavoring agent 0.5-3.5 g, and pH adjuster 0.01-1.0 g" and "the mabaloxavir oral solution comprises the following components per 100 mL: mabaloxavir 0.1-0.4 g, hydroxypropyl-β-cyclodextrin 1-10 g, flavoring agent 0.5-3.5 g, and pH adjuster 0.01-1.0 g" are subordinate concepts, as are "the mabaloxavir oral solution comprises the following components per 100 mL: mabaloxavir 0.1-0.4 g, hydroxypropyl-β-cyclodextrin 1-10 g, flavoring agent 0.5-3.5 g, and pH adjuster 0.01-1.0 g". The technical means that are basically equivalent to “g”, and the technical means that can replace “the following components are included in every 100 mL of the mabaloxavir oral solution: mabaloxavir 0.1-0.4 g, hydroxypropyl-β-cyclodextrin 1-10 g, flavoring agent 0.5-3.5 g and pH adjuster 0.01-1.0 g” based on the existing technical level, conventional technical means, and common knowledge, should all fall within the protection scope of claim 5. For example, if the content of each component in the mabaloxavir oral solution is replaced with “the following components are included in every 100 mL of the mabaloxavir oral solution: mabaloxavir 0.25 g, hydroxypropyl-β-cyclodextrin 9 g, flavoring agent 2.5 g and pH adjuster 0.08 g” while other technical features remain unchanged, it still falls within the protection scope of claim 5 of this invention.

[0065] Embodiments 1-7 of this invention at least support the protection scope of claim 6.

[0066] The technical feature “The mabaloxavir oral solution comprises the following components per 100 mL: mabaloxavir 0.2-0.4 g, hydroxypropyl-β-cyclodextrin 2-6 g, flavoring agent 1-2 g and pH adjuster 0.1-1.0 g” is consistent with the corresponding technical features in the foregoing explanation and / or Examples 1-7 of this invention: “A mabaloxavir oral solution is composed of the following components: mabaloxavir 2 g, hydroxypropyl-β-cyclodextrin (degree of substitution 4.0) 40 g, cyclamate 20 g, sodium dihydrogen phosphate 4 g and water for injection to make up to 2000 mL”; “A mabaloxavir oral solution is composed of the following components: mabaloxavir 4 g, hydroxypropyl-β-cyclodextrin (degree of substitution 5.0) 80 g, sucralose 40 g, citric acid 10 g and water for injection to make up to 2000 mL”; “A mabaloxavir oral solution is composed of the following components: mabaloxavir 8 ... "A mabaloxavir oral solution, comprising: 8 g mabaloxavir, 100 g hydroxypropyl-β-cyclodextrin (degree of substitution 4.5), 40 g sucralose, 10 g sodium bicarbonate, and water for injection to a final volume of 2000 mL"; "A mabaloxavir oral solution, comprising: 8 g mabaloxavir, 60 g hydroxypropyl-β-cyclodextrin (degree of substitution 4.5), 40 g fructose, 8 g sodium carbonate, and water for injection to a final volume of 2000 mL", etc., are summarized from the common characteristic "mass-volume ratio of each component in the mabaloxavir oral solution". Therefore, those skilled in the art can reasonably presume that the technical feature "the mabaloxavir oral solution comprises the following components per 100 mL: mabaloxavir 0.2-0.4 g, hydroxypropyl-β-cyclodextrin 2-6 g, flavoring agent 1-2 g and pH adjuster 0.1-1.0 g" and "the mabaloxavir oral solution comprises the following components per 100 mL: mabaloxavir 0.2-0.4 g, hydroxypropyl-β-cyclodextrin 2-6 g, flavoring agent 1-2 g and pH adjuster 0.1-1.0 g" are subordinate concepts, as are "the mabaloxavir oral solution comprises the following components per 100 mL: mabaloxavir 0.2-0.4 g, hydroxypropyl-β-cyclodextrin 2-6 g, flavoring agent 1-2 g and pH adjuster 0.1-1.0 g". The technical means that are basically equivalent to “g”, and the technical means that can replace “the following components are included in every 100 mL of the mabaloxavir oral solution: mabaloxavir 0.2-0.4 g, hydroxypropyl-β-cyclodextrin 2-6 g, flavoring agent 1-2 g and pH adjuster 0.1-1.0 g” based on the existing technical level and conventional technical means and common knowledge, should all fall within the protection scope of claim 6.

[0067] Embodiments 1-7 of this invention at least support the protection scope of claim 7.

[0068] The technical feature “The preparation method of the mabaloxavir oral solution includes the following steps: (1) First, dissolve hydroxypropyl-β-cyclodextrin in a portion of water for injection, then add mabaloxavir, stir well, and obtain a mixed solution; (2) Then dissolve the flavoring agent in the mixed solution, add a pH adjuster to adjust the pH, and finally add the remaining water for injection to obtain the solution,” according to the foregoing explanation and / or the corresponding technical feature in Examples 1-7 of this invention, “Dissolve hydroxypropyl-β-cyclodextrin in 80% of the prescription dosage of water for injection (60°C water bath), add mabaloxavir while stirring until completely dissolved to obtain a mixed solution; then add cyclamate to the above mixed solution and stir until completely dissolved; then add sodium dihydrogen phosphate to adjust the pH to 3.5, and finally add water for injection to make up to 2000 mL, and then filter the solution after making up to 2000 mL through a 0.45 μm filter.” After filtration through a PES filter cartridge, the solution is filled to obtain the following: Hydroxypropyl-β-cyclodextrin is dissolved in 80% of the prescription volume of water for injection (80°C water bath), and mabaloxavir is added while stirring until completely dissolved to obtain a mixed solution; sucralose is then added to the above mixture and stirred until completely dissolved; citric acid is added to adjust the pH to 4.0, and finally water for injection is added to bring the volume to 2000 mL. The final volume of the solution is then filtered through a 0.45 μm PVDF filter cartridge and filled to obtain the following: Hydroxypropyl-β-cyclodextrin is dissolved in 80% of the prescription volume of water for injection (70°C water bath), and mabaloxavir is added while stirring until completely dissolved to obtain a mixed solution; aspartame is then added to the above mixture and stirred until completely dissolved; citric acid is added to adjust the pH to 5.0, and finally water for injection is added to bring the volume to 2000 mL. The final volume of the solution is then filtered through a 0.45 μm PVDF filter cartridge and filled to obtain the following: After filtration through a PES filter cartridge, the solution is filled to obtain the following: Hydroxypropyl-β-cyclodextrin is dissolved in 80% of the prescription volume of water for injection (60°C water bath), and mabaloxavir is added while stirring until completely dissolved to obtain a mixed solution; sucralose is then added to the above mixture and stirred until completely dissolved; sodium bicarbonate is added to adjust the pH to 5.5, and finally water for injection is added to bring the volume to 2000 mL. The final volume of the solution is then filtered through a 0.45 μm PES filter cartridge and filled to obtain the following: Hydroxypropyl-β-cyclodextrin is dissolved in 80% of the prescription volume of water for injection (70°C water bath), and mabaloxavir is added while stirring until completely dissolved to obtain a mixed solution; cyclamate is then added to the above mixture and stirred until completely dissolved; citric acid is added to adjust the pH to 3.0, and finally water for injection is added to bring the volume to 2000 mL. The final volume of the solution is then filtered through a 0.45 μm PES filter cartridge and filled to obtain the following: After filtration by PVDF filter cartridges, the solution is filled to obtain the product. The preparation method of "Mabaloxavir oral solution" is summarized by common characteristics.Therefore, those skilled in the art can reasonably presume that the technical feature “the preparation method of the mabaloxavir oral solution includes the following steps: (1) first dissolve hydroxypropyl-β-cyclodextrin in a portion of water for injection, then add mabaloxavir, stir well, and obtain a mixed solution; (2) then dissolve the flavoring agent in the mixed solution, add a pH adjuster to adjust the pH, and finally add the remaining water for injection to obtain the solution” and “the preparation method of the mabaloxavir oral solution includes the following steps: (1) first dissolve hydroxypropyl-β-cyclodextrin in a portion of water for injection, then add mabaloxavir, stir well, and obtain a mixed solution; (2) then dissolve the flavoring agent in the mixed solution, add a pH adjuster to adjust the pH, and finally add the remaining water for injection to obtain the solution” are subordinate concepts, and “the preparation method of the mabaloxavir oral solution includes the following steps, ... The preparation method includes the following steps: (1) dissolving hydroxypropyl-β-cyclodextrin in a portion of water for injection, then adding mabaloxavir, stirring well to obtain a mixed solution; (2) dissolving the flavoring agent in the mixed solution, adding a pH adjuster to adjust the pH, and finally adding the remaining water for injection to obtain the solution. The preparation method of the mabaloxavir oral solution, which is basically equivalent to the preparation method of the oral solution of the present invention and can replace the preparation method of the oral solution of the mabaloxavir within the scope of conventional technical means and common knowledge, includes the following steps: (1) dissolving hydroxypropyl-β-cyclodextrin in a portion of water for injection, then adding mabaloxavir, stirring well to obtain a mixed solution; (2) dissolving the flavoring agent in the mixed solution, adding a pH adjuster to adjust the pH, and finally adding the remaining water for injection to obtain the oral solution of the mabaloxavir oral solution. All of these technical means should fall within the protection scope of claim 7.

[0069] Embodiments 1-7 of this invention at least support the protection scope of claim 8.

[0070] The technical feature “the temperature of the water for injection in step (1) is 50-80℃” is derived from the common feature “temperature of water for injection” by the corresponding technical features of 60℃ water bath, 80℃ water bath, and 70℃ water bath in the foregoing explanation and / or Examples 1-7 of this invention. Therefore, those skilled in the art can reasonably infer that the technical feature “the temperature of the water for injection in step (1) is 50-80℃”, the subordinate concept of “the temperature of the water for injection in step (1) is 50-80℃”, the technical means that are basically equivalent to “the temperature of the water for injection in step (1) is 50-80℃”, and the technical means that can replace “the temperature of the water for injection in step (1) is 50-80℃” based on the existing technical level and conventional technical means and common knowledge, should all fall within the protection scope of claim 8. For example, if the “temperature of water for injection” is replaced with 55℃, 65℃, etc., while other technical features remain unchanged, it still falls within the protection scope of claim 8 of this invention.

[0071] Embodiments 1-7 of this invention at least support the protection scope of claim 9.

[0072] The technical feature “In step (2), the pH is adjusted to 3-8; after adding the remaining water for injection, filtration is performed, and the filter element material is PES, PVDF or PP, and the pore size of the filter element is 0.45 μm” is summarized from the common features in the foregoing explanation and / or Examples 1-7 of this invention, such as “adding sodium dihydrogen phosphate to adjust the pH to 3.5, and finally adding water for injection to make up to 2000 mL, filtering the drug solution after making up to 2000 mL through a 0.45 μm PES filter element and then filling it”; “adding citric acid to adjust the pH to 4.0, and finally adding water for injection to make up to 2000 mL, filtering the drug solution after making up to 2000 mL through a 0.45 μm PVDF filter element and then filling it”; “adding citric acid to adjust the pH to 5.0, and finally adding water for injection to make up to 2000 mL, filtering the drug solution after making up to 2000 mL through a 0.45 μm PES filter element and then filling it”. Therefore, those skilled in the art can reasonably infer that the technical feature “in step (2), the pH is adjusted to 3-8; after adding the remaining water for injection, filtration is performed, the filter element material is PES, PVDF or PP, and the pore size of the filter element is 0.45 μm” is a subordinate concept, and ... The technical means that are basically equivalent to “μm” and can be replaced by “in step (2), the pH is adjusted to 3-8; after adding the remaining water for injection, filtration is performed, the filter material is PES, PVDF or PP, and the pore size of the filter is 0.45 μm” based on the existing technical level and conventional technical means and common knowledge, should all fall within the protection scope of claim 9. For example, if other technical features remain unchanged, replacing it with “in step (2), the pH is adjusted to 6.5; after adding the remaining water for injection, filtration is performed, the filter material is PES, and the pore size of the filter is 0.45 μm”, etc., still falls within the protection scope of claim 9 of this invention.

[0073] Embodiments 1-7 of this invention at least support the protection scope of claim 10.

[0074] The beneficial effects of this invention are as follows: The present invention has at least the following beneficial effects: (1) Compared with the prior art, the mabaloxavir oral solution of the present invention has better technical effects in terms of quality stability and bioequivalence.

[0075] According to experimental tests, the present invention improves the quality stability from one month in the prior art to more than six months.

[0076] According to experimental tests, the present invention increases the bioequivalence from 85% in the prior art to over 99%.

[0077] (2) Currently, mabaloxavir is available in tablet and dry suspension formulations, but no oral solution formulation is available. This invention provides a mabaloxavir oral solution, which uses hydroxypropyl-β-cyclodextrin with a specific degree of substitution as an excipient and limits the dosage range of each component. This not only helps to form a stable solution formulation, but also improves the stability and bioequivalence of the formulation, enabling the drug to take effect more quickly and shortening the treatment cycle.

[0078] Furthermore, based on the present invention: Based on the comparison of Examples 1-7 and Comparative Examples 1-3, this invention employs a combination of technical means, such as "a mabaloxavir oral solution comprising the following components: mabaloxavir, hydroxypropyl-β-cyclodextrin, flavoring agent, pH adjuster, and water for injection," and "the degree of substitution of the hydroxypropyl-β-cyclodextrin is 3.0-7.0," achieving new technical effects: solving the technical problems of existing mabaloxavir preparations, such as inconvenience in administration, slow absorption, low bioequivalence, and cumbersome preparation processes. The combined technical effect is superior to the sum of the effects of each individual technical means. Detailed Implementation

[0079] The following non-limiting embodiments are intended to enable those skilled in the art to gain a more comprehensive understanding of the present invention, but do not limit the invention in any way. The following content is merely an exemplary description of the scope of protection claimed by the present invention, and those skilled in the art can make various changes and modifications to the present invention based on the disclosed content, and such changes should also fall within the scope of protection claimed by the present invention.

[0080] The present invention will be further described below by way of specific embodiments. Unless otherwise specified, all instruments, devices, equipment, reagents, products, etc., used in the embodiments of the present invention are obtained through conventional commercial means.

[0081] Marbaloxavir was purchased from Nanchang Changyou Pharmaceutical Technology Co., Ltd.

[0082] Example 1 A mabaloxavir oral solution comprises the following components: 2 g mabaloxavir, 40 g hydroxypropyl-β-cyclodextrin (degree of substitution 4.0), 20 g cyclamate, 4 g sodium dihydrogen phosphate, and water for injection to a final volume of 2000 mL.

[0083] The preparation method of the above-mentioned mabaloxavir oral solution is as follows: Hydroxypropyl-β-cyclodextrin was dissolved in 80% of the prescription volume of water for injection (60°C water bath). Marbaloxavir was added while stirring until completely dissolved to obtain a mixed solution. Cyclamate was then added to the above mixture and stirred until completely dissolved. Sodium dihydrogen phosphate was added to adjust the pH to 3.5. Finally, water for injection was added to bring the volume to 2000 mL. The final volume was filtered through a 0.45 μm PES filter before being filled into vials.

[0084] Example 2 A mabaloxavir oral solution comprises the following components: 4 g mabaloxavir, 80 g hydroxypropyl-β-cyclodextrin (degree of substitution 5.0), 40 g sucralose, 10 g citric acid, and water for injection to a final volume of 2000 mL.

[0085] The preparation method of the above-mentioned mabaloxavir oral solution is as follows: Hydroxypropyl-β-cyclodextrin was dissolved in 80% of the prescription dosage of water for injection (80°C water bath). Marbaloxavir was added while stirring until completely dissolved to obtain a mixed solution. Sucralose was then added to the above mixture and stirred until completely dissolved. Citric acid was added to adjust the pH to 4.0. Finally, water for injection was added to bring the volume to 2000 mL. The final volume was filtered through a 0.45 μm PVDF filter before being filled into vials.

[0086] Example 3 A mabaloxavir oral solution comprises the following components: 8 g mabaloxavir, 120 g hydroxypropyl-β-cyclodextrin (degree of substitution 5.5), 20 g aspartame, 8 g citric acid, and water for injection to a final volume of 2000 mL.

[0087] The preparation method of the above-mentioned mabaloxavir oral solution is as follows: Hydroxypropyl-β-cyclodextrin was dissolved in 80% of the prescription volume of water for injection (70°C water bath). Marbaloxavir was added while stirring until completely dissolved to obtain a mixed solution. Aspartame was then added to the above mixture and stirred until completely dissolved. Citric acid was added to adjust the pH to 5.0. Finally, water for injection was added to bring the volume to 2000 mL. The final volume was filtered through a 0.45 μm PES filter before being filled into vials.

[0088] Example 4 A mabaloxavir oral solution comprises the following components: 8 g mabaloxavir, 100 g hydroxypropyl-β-cyclodextrin (degree of substitution 4.5), 40 g sucralose, 10 g sodium bicarbonate, and water for injection to a final volume of 2000 mL.

[0089] The preparation method of the above-mentioned mabaloxavir oral solution is as follows: Hydroxypropyl-β-cyclodextrin was dissolved in 80% of the prescription volume of water for injection (60°C water bath). Marbaloxavir was added while stirring until completely dissolved to obtain a mixed solution. Sucralose was then added to the above mixture and stirred until completely dissolved. Sodium bicarbonate was added to adjust the pH to 5.5. Finally, water for injection was added to bring the volume to 2000 mL. The final solution was filtered through a 0.45 μm PES filter and then filled into vials to obtain the final product.

[0090] Example 5 A mabaloxavir oral solution comprises the following components: 8 g mabaloxavir, 60 g hydroxypropyl-β-cyclodextrin (degree of substitution 4.5), 40 g fructose, 8 g sodium carbonate, and water for injection to a final volume of 2000 mL.

[0091] The preparation method of the above-mentioned mabaloxavir oral solution is as follows: Hydroxypropyl-β-cyclodextrin was dissolved in 80% of the prescription volume of water for injection (80°C water bath). Marbaloxavir was added while stirring until completely dissolved to obtain a mixed solution. Fructose was then added to the above mixture and stirred until completely dissolved. Sodium carbonate was added to adjust the pH to 5.5. Finally, water for injection was added to bring the volume to 2000 mL. The final volume was filtered through a 0.45 μm PES filter before being filled into vials.

[0092] Example 6 A mabaloxavir oral solution comprises the following components: 8 g mabaloxavir, 200 g hydroxypropyl-β-cyclodextrin (degree of substitution 5.0), 70 g sucralose, 20 g citric acid, and water for injection to a final volume of 2000 mL.

[0093] The preparation method of the above-mentioned mabaloxavir oral solution is as follows: Hydroxypropyl-β-cyclodextrin was dissolved in 80% of the prescription volume of water for injection (70°C water bath). Marbaloxavir was added while stirring until completely dissolved to obtain a mixed solution. Sucralose was then added to the above mixture and stirred until completely dissolved. Citric acid was added to adjust the pH to 7.0. Finally, water for injection was added to bring the volume to 2000 mL. The final volume was filtered through a 0.45 μm PVDF filter before being filled into vials.

[0094] Example 7 A mabaloxavir oral solution comprises the following components: 2 g mabaloxavir, 20 g hydroxypropyl-β-cyclodextrin (degree of substitution 5.0), 10 g cyclamate, 0.2 g citric acid, and water for injection to a final volume of 2000 mL.

[0095] The preparation method of the above-mentioned mabaloxavir oral solution is as follows: Hydroxypropyl-β-cyclodextrin was dissolved in 80% of the prescription volume of water for injection (70°C water bath). Marbaloxavir was added while stirring until completely dissolved to obtain a mixed solution. Cyclamate was then added to the above mixture and stirred until completely dissolved. Citric acid was added to adjust the pH to 3.0. Finally, water for injection was added to bring the volume to 2000 mL. The final volume was filtered through a 0.45 μm PVDF filter before being filled into vials.

[0096] Comparative Example 1 Compared to Example 4, the only difference is that hydroxypropyl-β-cyclodextrin is replaced with sodium dodecyl sulfate; all other components and contents remain the same. Specifically: A mabaloxavir oral solution comprises the following components: 8 g mabaloxavir, 100 g sodium dodecyl sulfate, 40 g sucralose, 10 g sodium bicarbonate, and water for injection to a final volume of 2000 mL.

[0097] The preparation method of the above-mentioned mabaloxavir oral solution is as follows: Sodium dodecyl sulfate was dissolved in 80% of the prescription dosage of water for injection (60°C water bath). Marbaloxavir was added while stirring until completely dissolved to obtain a mixed solution. Sucralose was then added to the above mixture and stirred until completely dissolved. Sodium bicarbonate was added to adjust the pH to 5.5. Finally, water for injection was added to bring the volume to 2000 mL. The final volume was filtered through a 0.45 μm PES filter before being filled into vials.

[0098] Comparative Example 2 Compared to Example 4, the only difference is that the pH of the solution is adjusted to 8.5; all other components and their contents remain the same. Specifically: A mabaloxavir oral solution comprises the following components: 8 g mabaloxavir, 100 g hydroxypropyl-β-cyclodextrin (degree of substitution 4.5), 40 g sucralose, 15 g sodium bicarbonate, and water for injection to a final volume of 2000 mL.

[0099] The preparation method of the above-mentioned mabaloxavir oral solution is as follows: Hydroxypropyl-β-cyclodextrin was dissolved in 80% of the prescription volume of water for injection (60°C water bath). Marbaloxavir was added while stirring until completely dissolved to obtain a mixed solution. Sucralose was then added to the above mixture and stirred until completely dissolved. Sodium bicarbonate was added to adjust the pH to 8.5. Finally, water for injection was added to bring the volume to 2000 mL. The final volume was filtered through a 0.45 μm PES filter before being filled into vials.

[0100] Comparative Example 3 Compared to Example 4, the only difference is that the degree of substitution of hydroxypropyl-β-cyclodextrin is 7.5; all other components and their contents are the same. Specifically: A mabaloxavir oral solution comprises the following components: 8 g mabaloxavir, 100 g hydroxypropyl-β-cyclodextrin (degree of substitution 7.5), 40 g sucralose, 10 g sodium bicarbonate, and water for injection to a final volume of 2000 mL.

[0101] The preparation method of the above-mentioned mabaloxavir oral solution is as follows: Hydroxypropyl-β-cyclodextrin was dissolved in 80% of the prescription volume of water for injection (60°C water bath). Marbaloxavir was added while stirring until completely dissolved to obtain a mixed solution. Sucralose was then added to the above mixture and stirred until completely dissolved. Sodium bicarbonate was added to adjust the pH to 5.5. Finally, water for injection was added to bring the volume to 2000 mL. The final solution was filtered through a 0.45 μm PES filter and then filled into vials to obtain the final product.

[0102] Detection Example 1 Key quality tests were performed on the mabaloxavir oral solutions prepared in Examples 1-7 and Comparative Examples 1-3, respectively, using high performance liquid chromatography (HPLC).

[0103] Verification of technical effectiveness and / or analysis of solutions to technical problems: The test results of mabaloxavir oral solutions in Examples 1-7 and Comparative Examples 1-3 are shown in Table 1. It can be seen that the mabaloxavir oral solutions in the examples all meet the requirements.

[0104] Table 1. Detection results of mabaloxavir oral solution

[0105] Detection Example 2 According to Appendix 9001 of the 2025 edition of the Chinese Pharmacopoeia, Volume IV, "Guiding Principles for Stability Testing of Raw Materials and Preparations", accelerated stability tests (temperature 40±2℃, relative humidity 75±5%, storage for 6 months, and sampling at 1, 3 and 6 months) were conducted on the samples prepared by Example 4 of the optimal combination and Comparative Examples 1-3.

[0106] Verification of technical effectiveness and / or analysis of solutions to technical problems: The stability test results are shown in Table 2. The stability test results show that the mabaloxavir oral solution prepared using the prescription process of Example 4 of the present invention is of stable quality; the mabaloxavir oral solution prepared using the prescription process of Comparative Examples 1-3 of the present invention is of unstable quality.

[0107] Table 2 Accelerated Test Results

[0108] Detection Example 3 This experiment compared the bioequivalence of mabaloxavir oral solution, homemade mabaloxavir tablets (using conventional wet granulation process), and commercially available mabaloxavir tablets (trade name: Xofluza) in Beagle dogs.

[0109] Laboratory animals: 15 Beagle dogs.

[0110] Experimental drugs: Mabaloxavir oral solution prepared in Example 4 (specification: 80 mg / 20 mL); self-made mabaloxavir tablets (specification: 40 mg); commercially available mabaloxavir tablets (trade name: Xofluza, specification: 40 mg).

[0111] Experimental Methods: This experiment consisted of two test groups and one control group, with five dogs in each group. Animals in the test groups were administered 10 mL of the mabaloxavir oral solution (40 mg mabaloxavir) from Example 4, or one self-made mabaloxavir tablet (40 mg mabaloxavir), along with 20 mL of water. Animals in the control group were administered one commercially available mabaloxavir tablet (40 mg mabaloxavir) along with 20 mL of water. All administration was oral, and the experiment was a single-cycle design. Blood samples were collected from the animals before administration and at 15 min, 30 min, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12 h, 24 h, 48 h, and 72 h after administration to test the blood concentration of mabaloxavir and calculate pharmacokinetic parameters.

[0112] Verification of technical effectiveness and / or analysis of solutions to technical problems: The pharmacokinetic parameters were tested and the results are shown in Table 3. A GMR (geometric mean ratio) closer to 100% indicates better bioequivalence. It can be seen that the bioequivalence of the mabaloxavir oral solution in Example 4 is better than that of the self-made mabaloxavir tablets.

[0113] Table 3 Pharmacokinetic parameters of mabaloxavir oral solution

[0114] In summary, the mabaloxavir oral solution provided by this invention has a simple preparation process and good bioequivalence.

[0115] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A mabaloxavir oral solution, characterized in that, It comprises the following components: mabaloxavir, hydroxypropyl-β-cyclodextrin, flavoring agent, pH adjuster and water for injection, wherein the degree of substitution of the hydroxypropyl-β-cyclodextrin is 3.0-7.

0.

2. The mabaloxavir oral solution according to claim 1, characterized in that, The degree of substitution of the hydroxypropyl-β-cyclodextrin is 3.5-5.

5.

3. The mabaloxavir oral solution according to claim 1, characterized in that, The flavoring agent is selected from one or more of the following: cyclamate, sucralose, acesulfame potassium, steviol glycoside, aspartame, sematriol, glycyrrhizin, asparagine methyl ester, potassium dihydrothiazide, sodium cyclohexanesulfonate, saccharin, sodium saccharin, calcium saccharin, sorbitol, mannitol, fructose, sucrose, maltose, isomaltose, glucose, hydrogenated glucose syrup, xylitol, caramel, and honey.

4. The mabaloxavir oral solution according to claim 1, characterized in that, The pH adjuster is selected from one or more of sodium dihydrogen phosphate, citric acid, sodium carbonate, sodium bicarbonate, hydrochloric acid, sulfuric acid, sodium hydroxide, potassium hydroxide, and disodium hydrogen phosphate.

5. The marbaloxavir oral solution according to claim 1, characterized in that, The oral solution of mabaloxavir contains the following components per 100 mL: mabaloxavir 0.1-0.4 g, hydroxypropyl-β-cyclodextrin 1-10 g, flavoring agent 0.5-3.5 g, and pH adjuster 0.01-1.0 g.

6. The mabaloxavir oral solution according to claim 5, characterized in that, The mabaloxavir oral solution comprises the following components per 100 mL: mabaloxavir 0.2-0.4 g, hydroxypropyl-β-cyclodextrin 2-6 g, flavoring agent 1-2 g, and pH adjuster 0.1-1.0 g.

7. A method for preparing mabaloxavir oral solution according to any one of claims 1-6, characterized in that, Includes the following steps: (1) First, dissolve hydroxypropyl-β-cyclodextrin in a portion of water for injection, then add mabaloxavir and stir well to obtain a mixed solution; (2) Dissolve the flavoring agent in the mixed solution, add pH adjuster to adjust pH, and finally add the remaining water for injection to obtain the final product.

8. The preparation method according to claim 7, characterized in that, The temperature of the water for injection in step (1) is 50-80℃.

9. The preparation method according to claim 7, characterized in that, In step (2), the pH is adjusted to 3-8; after adding the remaining water for injection, filtration is performed, and the filter element material is PES, PVDF or PP, and the pore size of the filter element is 0.45 μm.

10. The use of the mabaloxavir oral solution as described in any one of claims 1-6 in the preparation of an anti-influenza A virus infection drug.

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