Pyrimidine derivative-containing pharmaceutical composition and use thereof

Abstract

The present invention relates to a pyrimidine derivative-containing pharmaceutical composition and use thereof. The pharmaceutical composition comprises compound 1 as an active ingredient, and further comprises an alkaline reagent and a solubilizer, wherein the molar ratio of the active ingredient to the total amount of the alkaline reagent and the solubilizer is 1:0.80-3.50. The pharmaceutical combination of the present invention can effectively improve the solubility of compound 1 and ensure the stable release of compound 1 in vivo and in vitro, significantly improving the bioavailability of pharmaceutical formulations. The present invention provides a feasible solution for enabling the clinical use of compound 1.

Description

A pharmaceutical composition containing a pyrimidine derivative and its application Technical Field

[0001] This invention belongs to the field of medicine, and in particular, this invention relates to a pharmaceutical composition containing a pyrimidine derivative and its application. Background Technology

[0002] Influenza (flu) is an acute respiratory infectious disease caused by the influenza virus, which is more common in winter and spring. Clinically, it is characterized by systemic symptoms such as high fever, fatigue, headache, and body aches, as well as milder respiratory symptoms. It is one of the major public health problems facing humanity. Influenza viruses are RNA viruses, classified into four types: A, B, C, and D. While the clinical symptoms of influenza caused by these types are similar, their etiological and epidemiological characteristics differ significantly. Type A influenza can cause global pandemics.

[0003] Influenza has a rapid onset, and although most cases are self-limiting, some patients develop severe illness due to complications such as pneumonia or exacerbation of underlying diseases. A small number of critically ill cases progress rapidly and can lead to death from complications such as acute respiratory distress syndrome (ARDS), acute necrotizing encephalopathy, or multiple organ failure. Severe influenza mainly occurs in high-risk groups such as the elderly, young children, obese individuals, pregnant women, and those with chronic underlying diseases, but it can also occur in the general population.

[0004] Currently, there are two main types of drugs used clinically to treat influenza: M2 channel protein inhibitors, represented by amantadine and rimantadine, and neuraminidase inhibitors, represented by oseltamivir and zanamivir. However, the emergence of drug-resistant strains, such as seasonal H3N2, and highly pathogenic avian influenza A (H1N1), H5N1, and H7N9 in 2009, has significantly diminished the clinical value of these two types of drugs. Therefore, the development of antiviral drugs that can provide cross-protection against different influenza virus subtypes has attracted considerable attention. With the extensive development of biological and structural-functional studies of influenza virus proteins, especially after the successful resolution of the crystal structures of relevant functional domains in influenza virus RNA polymerase, drug design and screening targeting influenza virus RNA polymerase have gradually gained attention.

[0005] Influenza virus RNA polymerase is a complex composed of three subunits: PB1, PB2, and PA. It is an important regulatory protein in the life cycle of influenza A virus, and the gene sequences encoding each subunit of the polymerase are highly conserved. Among them, the PB2 subunit is an important component of influenza virus RNA polymerase. It can recognize and "grab" the 5'-capped primer of the host cell pre-mRNA, and then the PA subunit, which has endonuclease activity, cleaves 10-13 nucleotides of the pre-mRNA. Using viral RNA (vRNA) as a template, viral mRNA synthesis is initiated under the action of PB1, thereby inhibiting multiple functions of the viral life cycle genome, such as transcription and replication, to achieve the effect of resisting influenza A virus.

[0006] Onradivir, CAS number 2200336-20-3, has the following structure:

[0007] Patent WO2018 / 041263A1 discloses a series of pyrimidine derivatives with RNA polymerase inhibitory activity, which exhibit excellent antiviral activity against the A / Weiss / 43(H1N1) influenza virus strain in in vitro experiments, with an EC50% (50% effective concentration). 50 At the nanomolar (nM) level, it is significantly lower than similar compounds targeting the same target, and it also showed good antiviral activity against influenza A virus H1N1 in in vivo animal experiments. Among them, WX-216 (compound 1) has excellent antiviral activity against influenza virus. Further studies have found that its in vitro antiviral activity against influenza virus is more than 1000 times that of oseltamivir, and it is considered to have good prospects for drug development.

[0008] Although preparing target compounds into formulations suitable for clinical use is an essential step in drug development, it is still impossible for those skilled in the art to predict which properties of the compound will be improved to achieve clinical use. Preparing WX-216 (compound 1) into a pharmaceutical composition that meets the requirements for clinical use is a technical problem that needs to be solved in the prior art. Summary of the Invention

[0009] The first objective of this invention is to provide a pharmaceutical composition containing onradivir (compound 1) as an active ingredient, which can effectively improve the solubility of compound 1, ensure the stable release of compound 1 in vivo and in vitro, and significantly improve the bioavailability of the pharmaceutical preparation, thus facilitating the realization of the clinical therapeutic effect of compound 1.

[0010] The above-mentioned objective of the present invention is achieved through the following technical solution:

[0011] A pharmaceutical composition containing compound 1 as an active ingredient, wherein the pharmaceutical composition comprises the active ingredient, an alkaline reagent, and a solubilizer; the molar ratio of the active ingredient to the total amount of the alkaline reagent and solubilizer is 1:0.80 to 3.50; the alkaline reagent is selected from one or a mixture of at least two of sodium hydroxide, potassium hydroxide, calcium hydroxide, and magnesium hydroxide in any proportion; the solubilizer is selected from one or a mixture of at least two of meglumine, arginine, histidine, lysine, glycine, glycerol, diethanolamine, choline, and theobromine in any proportion.

[0012] Onradivir (compound 1) exhibits poor solubility. While conventional formulation methods, such as using the active pharmaceutical ingredient as a salt, micronization, and adding surfactants to solubilize it, can increase its solubility to some extent and even improve its in vitro dissolution, the improvement in its in vivo release and bioavailability remains low, thus affecting its prospects for clinical application. Therefore, to prepare compound 1 into a formulation suitable for clinical use, it is necessary not only to address its solubility but also to ensure stable release both in vitro and in vivo, and, more importantly, to guarantee the bioavailability of the drug formulation in vivo.

[0013] Specifically, to simultaneously improve the in vivo and in vitro bioavailability of compound 1, the molar ratio of the active ingredient to the alkaline reagent in the pharmaceutical composition of this application is 1:0.30–2.00; preferably 1:0.45–1.50; more preferably 1:0.50–1.35. The molar ratio of the active ingredient to the cosolvent in the pharmaceutical composition of this application is 1:0.07–1.50; preferably 1:0.08–1.00; more preferably 1:0.09–0.90.

[0014] While addressing the solubility problem of Compound 1, the applicant accidentally discovered that using only alkaline reagents or only solubilizers, while improving the solubility of Compound 1, did not significantly improve its dissolution performance in formulations. Worse still, when using only alkaline reagents, the resulting solution exhibited poor stability, with solid precipitation and even gelation (coagulation) occurring upon prolonged exposure to air or stirring, hindering the stable release of Compound 1 in vivo. The inventors creatively discovered that by simultaneously adding both alkaline reagents and solubilizers, both the solubility and in vitro dissolution performance of Compound 1 can be improved, while also enhancing its in vivo bioavailability.

[0015] Furthermore, in the pharmaceutical composition containing compound 1 as the active ingredient provided by this invention, the amount of the active ingredient and the total amount (molar ratio) of the alkaline reagent and solubilizer have a significant impact on its solubility and dissolution effect. The inventors have occasionally discovered that the stability of the dissolution performance of compound 1 is closely related to the stability of its dissolution effect. For example, when the total amount of alkaline reagent and solubilizer is too small, compound 1 dissolves poorly or even not at all, resulting in severe turbidity; correspondingly, compound 1 has poor dissolution in the pharmaceutical formulation. Therefore, to ensure the dissolution of compound 1, it is first necessary to ensure that the solubility of compound 1 is in a suitable state. Through numerous experiments, the inventors surprisingly discovered that controlling the molar ratio of the active ingredient to the total amount of alkaline reagent and solubilizer within the range of 1:0.80 to 3.50 results in better solubility of the active ingredient, better stability of the dissolved solution, and promotes stable release of the active ingredient in vitro and in vivo, and significantly improves its bioavailability. Taking into account the bioavailability of the active ingredient in Compound 1 and ensuring other drug-making and preparation process indicators, in the pharmaceutical composition of this application, the recommended molar ratio of the active ingredient to the total amount of alkaline reagent and cosolvent is 1:1.00 to 2.50; preferably 1:1.05 to 1.50; more preferably 1:1.08 to 1.33. Within the above range, the solubility and bioavailability of the active ingredient can be effectively improved, and the drug-making indicators such as the stability of the obtained pharmaceutical composition are in a better state.

[0016] In the pharmaceutical composition described in this application, the alkaline reagent is selected from one or a mixture of at least two of sodium hydroxide, potassium hydroxide, calcium hydroxide, and magnesium hydroxide in any proportion; preferably, it is a mixture of sodium hydroxide, potassium hydroxide, or both in any proportion. In one embodiment of the present invention, the alkaline reagent used is sodium hydroxide. In another embodiment of the present invention, the alkaline reagent used is potassium hydroxide.

[0017] In the pharmaceutical composition described in this application, the cosolvent is selected from one or a mixture of at least two of meglumine, arginine, histidine, lysine, glycine, glycerol, diethanolamine, choline, and theobromine in any proportion; preferably, the cosolvent is a composition of one or at least two of meglumine, arginine, histidine, and lysine in any proportion; more preferably, the cosolvent is a mixture of meglumine, arginine, or both in any proportion. In one embodiment of the present invention, the cosolvent used is meglumine. In another embodiment of the present invention, the cosolvent used is arginine.

[0018] In some embodiments of the present invention, the molar ratio of the active ingredient to the total amount of alkaline reagent and cosolvent is approximately 1:1.05, 1:1.08, 1:1.10, 1:1.25, 1:1.45, or 1:1.54.

[0019] In some embodiments of the present invention, the molar ratio of the active ingredient to the alkaline reagent is 1:0.50-1.25, 1:0.50-1.15, or 1:0.50-1.05.

[0020] In some embodiments of the present invention, the molar ratio of the active ingredient to the cosolvent is 1:0.08-0.90, 1:0.08-0.85, or 1:0.08-0.80.

[0021] In one embodiment of the present invention, the alkaline reagent is selected from sodium hydroxide, and the co-solvent is selected from meglumine; the molar ratio of the active ingredient to sodium hydroxide and meglumine is approximately 1:0.50:0.75.

[0022] In one embodiment of the present invention, the molar ratio of the active ingredient to sodium hydroxide and meglumine is approximately 1:0.5:0.75.

[0023] In one embodiment of the present invention, the alkaline reagent is selected from potassium hydroxide, and the co-solvent is selected from meglumine; the molar ratio of the active ingredient to potassium hydroxide and meglumine is approximately 1:0.50:0.75.

[0024] In one embodiment of the present invention, the alkaline reagent is selected from sodium hydroxide, and the co-solvent is selected from arginine; the molar ratio of the active ingredient to sodium hydroxide and arginine is approximately 1:0.50:0.75.

[0025] In one embodiment of the present invention, the alkaline reagent is selected from sodium hydroxide, and the co-solvent is selected from meglumine; the molar ratio of the active ingredient to sodium hydroxide and meglumine is approximately 1:1.00:0.25.

[0026] In one embodiment of the present invention, the alkaline reagent is selected from potassium hydroxide, and the co-solvent is selected from meglumine; the molar ratio of the active ingredient to potassium hydroxide and meglumine is approximately 1:1.00:0.25.

[0027] In one embodiment of the present invention, the alkaline reagent is selected from sodium hydroxide, and the co-solvent is selected from arginine; the molar ratio of the active ingredient to sodium hydroxide and arginine is approximately 1:1.00:0.25.

[0028] In one embodiment of the present invention, the alkaline reagent is selected from sodium hydroxide, and the co-solvent is selected from meglumine; the molar ratio of the active ingredient to sodium hydroxide and meglumine is approximately 1:1.00:0.10.

[0029] In one embodiment of the present invention, the alkaline reagent is selected from potassium hydroxide, and the co-solvent is selected from meglumine; the molar ratio of the active ingredient to potassium hydroxide and meglumine is approximately 1:1.00:0.10.

[0030] In one embodiment of the present invention, the alkaline reagent is selected from sodium hydroxide, and the co-solvent is selected from arginine; the molar ratio of the active ingredient to sodium hydroxide and arginine is approximately 1:1.00:0.10.

[0031] Compound 1, as the active ingredient of the drug, may take the form of its free acid, hydrate, or solvate, among other things. Unless otherwise specified, all mass values ​​mentioned in this invention refer to the mass of the free base (acid equivalent), and all hydrates / solvates refer to the mass on an anhydrous basis.

[0032] Depending on the formulation and / or preparation process and / or clinical administration requirements, the pharmaceutical composition containing compound 1 may be further optionally supplemented with a pharmaceutically acceptable carrier, which includes, but is not limited to, one or at least two of the following in any proportion: fillers, disintegrants, binders, solubilizers, and lubricants / flow aids.

[0033] The pharmaceutical composition containing compound 1 can also be prepared into dosage forms (formulas) commonly used in this field according to clinical administration needs, including but not limited to liquid dosage forms, solid dosage forms, and semi-solid dosage forms. Based on the release mechanism and / or dispersion system, it can be further subdivided into tablets (including plain tablets, sugar-coated tablets, regular tablets, sustained-release tablets, dispersible tablets, effervescent tablets, orally disintegrating tablets, sublingual tablets, multilayer tablets, and fast-release tablets), pellets, capsules, granules, fine powders, powders, solutions, syrups, etc. Tablets are preferred.

[0034] According to clinical medication needs, the pharmaceutical composition of compound 1 can be prepared into a specification of 1-1000mg / unit dosage form, such as 50mg, 100mg, 200mg, 400mg, depending on the specific circumstances such as dosage, frequency of administration, and target population. The unit dosage form refers to the smallest package, such as per tablet, per capsule, per sachet, per vial, etc.

[0035] When the pharmaceutical composition is prepared into a pharmaceutical formulation, the active ingredient comprises 5% to 60% of the total weight of the formulation, preferably 15% to 55%, and more preferably 30% to 50%.

[0036] Regarding the preparation process of the pharmaceutical composition containing compound 1, those skilled in the art can use well-known methods, such as direct mixing or granulation / compression molding.

[0037] The present invention provides a process for preparing a pharmaceutical composition containing compound 1, comprising the step of mixing the active ingredient with an alkaline reagent and a solubilizer.

[0038] This invention discloses a preparation process for a pharmaceutical composition containing compound 1, including a granulation process. The granulation method is a conventional granulation method in the art, such as spray drying granulation, fluidized bed granulation, wet granulation, or dry granulation. The granulation process may involve adding a pharmaceutically acceptable carrier, depending on the formulation and / or preparation process and / or clinical administration requirements.

[0039] In a preferred embodiment of the present invention, the pharmaceutical composition is prepared by wet granulation, comprising the steps of mixing compound 1, a basic reagent and a cosolvent and / or mixing with a pharmaceutically acceptable carrier.

[0040] In a preferred embodiment of the present invention, the pharmaceutical composition is prepared by a fluidized bed method, comprising the steps of dissolving compound 1, an alkaline reagent and a cosolvent, and / or mixing with a pharmaceutically acceptable carrier to prepare a granulation solution, introducing the solution into a fluidized bed granulator, and spraying the solution onto a pharmaceutically acceptable carrier in the fluidized bed.

[0041] The pharmaceutically acceptable carrier described in this invention has no particular limitation in dosage and can be adjusted by conventional means according to what is known in the art or in combination with prescription requirements.

[0042] For the purposes of this invention, if the pharmaceutical composition contains the aforementioned pharmaceutically acceptable carrier, the pharmaceutically acceptable carrier includes a filler; the weight ratio of the active ingredient to the filler relative to the active ingredient is 1:0.050-50.000; preferably 1:0.50-5.000; more preferably 1:0.60-2.000.

[0043] For the purposes of this invention, if the pharmaceutical composition contains the aforementioned pharmaceutically acceptable carrier, the pharmaceutically acceptable carrier includes a binder; the weight ratio of the active ingredient to the binder relative to the weight of the active ingredient is 1:0.001-0.200; preferably 1:0.010-0.150; more preferably 1:0.020-0.120.

[0044] For the purposes of this invention, if the pharmaceutical composition contains the aforementioned pharmaceutically acceptable carrier, the pharmaceutically acceptable carrier includes a disintegrant; the weight ratio of the active ingredient to the disintegrant relative to the weight of the active ingredient is 1:0.005-0.500; preferably 1:0.010-0.400; more preferably 1:0.040-0.300.

[0045] For the purposes of this invention, if the pharmaceutical composition contains the aforementioned pharmaceutically acceptable carrier, the pharmaceutically acceptable carrier includes a lubricant / flow aid; the weight ratio of the active ingredient to the lubricant / flow aid is 1:0.001-0.200 relative to the weight of the active ingredient; preferably 1:0.005-0.100; more preferably 1:0.008-0.080.

[0046] For the purposes of this invention, if the pharmaceutical composition contains the aforementioned pharmaceutically acceptable carrier, the pharmaceutically acceptable carrier includes a solubilizer; the weight ratio of the active ingredient to the solubilizer relative to the weight of the active ingredient is 1:0.001-0.050; preferably 1:0.002-0.030; more preferably 1:0.003-0.020.

[0047] If a filler is required, the filler includes one or a mixture of at least two of the following in any proportion: microcrystalline cellulose, lactose, sucrose, starch or its derivatives (including pregelatinized starch), dextrin, powdered sugar, mannitol, sorbitol, xylitol, erythritol, maltitol, calcium carbonate, magnesium carbonate, calcium phosphate, calcium sulfate, and kaolin (H2Al2Si2O8·H2O·Al2O3·2SiO2·3H2O); or the filler may be microcrystalline cellulose or lactose. A mixture of one or more of the following in any proportion: sucrose, starch or its derivatives (including pregelatinized starch), dextrin, powdered sugar, mannitol, sorbitol, xylitol, erythritol, maltitol, calcium carbonate, magnesium carbonate, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, kaolin (H2Al2Si2O8·H2O·Al2O3·2SiO2·3H2O), maltose, isomaltose, glucose, trehalose, dextran, fructose, galactose, maltodextrin, etc.

[0048] If an adhesive is required, the adhesive includes a mixture of one or more of the following in any proportion: hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, polyvinylpyrrolidone (Povidone), gum arabic, gelatin, tragacanth gum, xanthan gum, sodium alginate, etc.; or the adhesive includes a mixture of one or more of the following in any proportion: hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone (Povidone), gum arabic, gelatin, tragacanth gum, xanthan gum, sodium alginate, etc.

[0049] If a disintegrant is required, the disintegrant includes a mixture of one or more of sodium carbonate, sodium bicarbonate, dry starch, croscarmellose sodium, croscarmellose (croscarmellose), sodium hydroxymethyl starch, sodium hydroxypropyl starch, low-substituted hydroxypropyl cellulose, chitosan, etc., in any proportion; the disintegrant includes a mixture of one or more of sodium carbonate, sodium bicarbonate, dry starch, croscarmellose sodium, croscarmellose (croscarmellose), sodium hydroxymethyl starch, sodium hydroxypropyl starch, low-substituted hydroxypropyl cellulose, chitosan, etc., in any proportion.

[0050] If a lubricant / flow aid is required, the lubricant / flow aid includes one or a mixture of at least two of the following: talc, micronized silica gel, silica (including colloidal silica), powdered cellulose, magnesium trisilicate, hydrated sodium aluminosilicate, stearic acid, magnesium stearate, calcium stearate, zinc stearate, sodium stearate fumarate, hydrogenated vegetable oil, sodium dodecastearyl fumarate, glyceryl monostearate, and glyceryl palmitate, in any proportion.

[0051] If a solubilizer is required, the solubilizer includes one or more of polyethylene glycol, propylene glycol, glycerin, Tween, sodium dodecyl sulfate (SDS), cyclodextrin, polyoxyethylene castor oil, sesame oil, olive oil, soybean oil, peppermint oil, corn oil, vitamin E, etc., mixed in any proportion.

[0052] It should be noted that, in this application, those skilled in the art will understand that the aforementioned fillers and adhesives are not limited to their respective uses (functions) as described, but may also be used for other purposes. For example, the adhesive may be used as a filler, or the filler may be used as an adhesive, etc.

[0053] Depending on the nature of the active ingredient and / or the formulation method, those skilled in the art will understand that, in addition to the fillers, binders, disintegrants, and lubricants / flow aids described above, the pharmaceutical compositions of the present invention may also include other components. Examples of such other components include various additives that can be used as pharmaceutical excipients, such as flavoring agents, coloring agents, pH adjusters, preservatives, antioxidants, buffers, chelating agents, curing agents, sweeteners, and flavorings. If desired, those skilled in the art can select appropriate dosages based on the properties of the active ingredient and each excipient.

[0054] Depending on the nature of the active ingredient and / or the formulation method, those skilled in the art will understand that pharmaceutical compositions may also be coated or uncoated using known methods. If coating is required, this step not only provides a sealed coating layer to the tablet core, effectively preventing direct contact between the tablet core and air and moisture, thereby reducing the risk of drug degradation, but also helps to isolate any unpleasant odors the drug may have, thus improving patient compliance.

[0055] Adding certain additives to the coating material to suit specific coating requirements is something that can be easily determined by those skilled in the art based on experience. For example, plasticizers, colorants, and masking agents can be added to the coating solution, including but not limited to gelatin, gum arabic, alginate, cellulose acetate phthalate, ethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, acrylic resin, polyvinylpyrrolidone, and polyethylene glycol. These can be used alone or in combination to form single-layer or multi-layer (two or more layers) coating structures. In this invention, a gastrointestinal-soluble film coating is preferred. The weight gain after coating is 0.5-8%, preferably 1-6%, and more preferably 2-5%.

[0056] Coating can be performed using known methods. For example, using a pot coating device, a fluidized bed coating device, an aerated rotary drum coating device, or a rotary coating method, the coating base is dispersed in water or an organic solvent, and then the dissolved coating base is sprayed.

[0057] The present invention also relates to the use of the pharmaceutical composition of the present invention in the preparation of a medicament for treating influenza virus infection. Specifically, the medicament is an antiviral drug for influenza. More specifically, the antiviral drug is a drug for treating influenza caused by a highly pathogenic avian influenza virus. More specifically, the antiviral drug is a drug for treating influenza A.

[0058] The present invention has the following advantages and beneficial effects compared with the prior art:

[0059] 1. A pharmaceutical composition is provided, which improves the dissolution effect of compound 1 and significantly enhances the bioavailability of compound 1 in animals by adding specific types and amounts of alkaline reagents and solubilizers to the formulation, thus providing a feasible path for its development into a clinical drug.

[0060] 2. A series of methods for preparing the pharmaceutical compositions of this application are provided;

[0061] 3. To provide the pharmaceutical use of the pharmaceutical composition of this application in the preparation of a drug for treating anti-influenza virus. Attached Figure Description

[0062] Figure 1 shows the case where compound 1, sodium hydroxide, and diethylamine in a molar ratio of 4:2:3, do not dissolve when mixed.

[0063] Figure 2 shows the insolubility of compound 1 when the molar ratio of sodium hydroxide to triethylamine is 4:2:4.

[0064] Figure 3 shows the dissolution of compound 1 and sodium hydroxide in a molar ratio of 1:1.25.

[0065] Figure 4 shows the solidification of compound 1 and sodium hydroxide after they were mixed and dissolved in a molar ratio of 1:1.25 and then stirred overnight in a sealed and open manner (left: solidification after stirring overnight in a sealed manner; right: solidification after stirring overnight in an open manner).

[0066] Figure 5 shows the results of mixing and dissolving compound 1, sodium hydroxide, and meglumine in molar ratios (from left to right) of 4:4:1, 4:1:4, and 4:4:0.4, until the mixture is clear. Detailed Implementation

[0067] The present invention will now be described in further detail with reference to embodiments and accompanying drawings. However, the embodiments of the invention are not limited thereto, nor does this imply any adverse limitation on the invention. The present invention has been described in detail herein, and specific embodiments thereof have also been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope thereof.

[0068] Experiment 1: Effects of different alkaline reagents and cosolvents on the solubility of compound 1

[0069] At room temperature, with 4 mol of compound 1 as 1 equivalent, add the alkaline reagent and co-solvent in 13-20 mL of water according to the molar equivalent content of compound 1 in Table 1, stir, and observe the dissolution of compound 1. The results are summarized in Table 1.

[0070] Table 1: Effects of different alkaline reagents and co-solvents on the solubility of compound 1 (Experimental results)

[0071] Note [1]: The stability refers to the change in appearance of the mixture after mixing compound 1, alkaline reagent and / or meglumine in water, and stirring and leaving it overnight (about 6-12 hours) in a sealed and open manner.

[0072] Table 1 shows that diethylamine and triethylamine, when used as co-solvents (Sample 1 and Sample 2), did not improve the solubility of Compound 1; Compound 1 remained insoluble. The solubility of Compound 1 mixed with sodium hydroxide using ethylenediamine and triethylamine as co-solvents is shown in Figures 1 and 2, respectively. However, using meglumine or arginine as co-solvents significantly improved the solubility of Compound 1, resulting in uniform dispersion (turbidity) or even clear dissolution in water. Therefore, different co-solvents have different effects on the solubility of Compound 1.

[0073] When the total molar ratio of compound 1 to the basic reagent and co-solvent is 1:0.80–3.50, the solubility of compound 1 can be improved while the resulting solution system exhibits good stability, remaining stable even after stirring. In the sample, when the total molar ratio of the basic reagent and co-solvent to compound 1 is 0.75, which is below 0.80, compound 1 cannot dissolve.

[0074] In Sample 4, without adding a co-solvent, the solubility of Compound 1 was not significantly improved by adding only 1 equivalent of the alkaline reagent sodium hydroxide, and it remained severely turbid or insoluble. In Sample 5, the addition of only 1.25 equivalents of the alkaline reagent sodium hydroxide promoted the dissolution of Compound 1 (as shown in Figure 3), but the stability of the solution system was poor, and solidification occurred after stirring and standing overnight (as shown in Figure 4). Specifically, this manifested as a clear solution being formed during solution preparation and fresh preparation (as shown in Figure 3), but solidification due to solid precipitation occurred after a longer period of time (such as overnight) (as shown in Figure 4). This phenomenon was caused by the instability of the solution system and may potentially affect the dissolution behavior of the formulation, a situation that needs to be avoided in formulation research / design. Therefore, it can be seen that adding an alkaline reagent alone, by adjusting the amount of alkaline reagent, can improve the solubility of Compound 1, but the stability of the solution system is poor, leading to unstable drug release. Furthermore, the applicant's further research showed that adding only an alkaline reagent did not significantly improve the in vitro dissolution of the drug composition.

[0075] In Sample 10, without adding an alkaline reagent, adding only about 1.07 equivalents of a cosolvent improved the solubility of Compound 1, achieving a uniformly dispersed and turbid state. In Samples 11 and 12, further increasing the cosolvent content further improved the solubility of the compound, and the system showed good stability with no significant changes after stirring. However, further research by the applicant revealed that simply adding a cosolvent did not significantly improve the in vitro dissolution of the pharmaceutical composition. Therefore, it is evident that the presence of a cosolvent in the pharmaceutical composition of this application has a certain impact on the stability of the solubility system of Compound 1.

[0076] Furthermore, when both an alkaline reagent and a co-solvent are added simultaneously, their respective amounts also affect the improvement in the solubility and stability of compound 1. The molar ratio of compound 1 to the alkaline reagent is 1:0.30–2.00; preferably 1:0.45–1.50; the molar ratio of compound 1 to the co-solvent is 1:0.07–1.50; preferably 1:0.08–1.00, which allows compound 1 to be uniformly dispersed in water (turbidity, clear dissolution); more preferably, compound 1 can dissolve clearly. Figure 5 shows the clear dissolution of compound 1 when mixed with sodium hydroxide and meglumine (from left to right) at molar ratios of 4:4:1, 4:1:4, and 4:4:0.4, indicating improved solvent stability.

[0077] In summary, controlling the total amount of alkaline reagents and solubilizers, as well as adding specific types of solubilizers, are key factors in ensuring the stable dissolution of compound 1 in the pharmaceutical composition of this application. The presence of alkaline reagents and solubilizers can synergistically improve the solubility of compound 1 and further ensure the stable release of compound 1 in vitro and in vivo in the pharmaceutical formulation.

[0078] In repeated experiments, researchers replaced the alkaline reagent sodium hydroxide with potassium hydroxide, calcium hydroxide, and magnesium hydroxide, and obtained consistent experimental results.

[0079] Experiment 2: Preparation of a pharmaceutical composition containing compound 1

[0080] Example 1: Preparation of tablets containing compound 1

[0081] The prescription composition of each tablet: (mg / tablet)

[0082] Preparation method: Sodium hydroxide, meglumine and active ingredients are stirred until fully dissolved / dispersed evenly in water, dried, and then mixed with other excipients and compressed into tablets.

[0083] Example 2: Preparation of tablets containing compound 1

[0084] The prescription composition of each tablet: (mg / tablet)

[0085] Preparation method: Sodium hydroxide, meglumine and active ingredients are stirred until fully dissolved or evenly dispersed in water to form a granulation solution. The granulation solution is then prepared into a solid by spray drying. Other excipients are added and mixed. After tableting, the tablets are coated with a gastrointestinal film.

[0086] Example 3: Preparation of tablets containing compound 1

[0087] The prescription composition of each tablet: (mg / tablet)

[0088] Preparation method: Sodium hydroxide, meglumine, and the active ingredient are stirred until fully dissolved / uniformly dispersed in water to prepare the granulation solution. Sorbitol (filler), binder, and disintegrant anhydrous sodium carbonate / crosslinked carboxymethyl cellulose (CMC) are added to a fluidized bed granulation vessel, and granulation is completed in a fluidized bed granulator with the above granulation solution. The remaining filler (microcrystalline cellulose), CMC, and lubricant are added and mixed to obtain a final mixed granule, which is then compressed into tablets.

[0089] Example 4: Preparation of tablets containing compound 1

[0090] The prescription composition of each tablet: (mg / tablet)

[0091] Preparation method: Sodium hydroxide, meglumine, compound 1, and binder are stirred until fully dissolved / uniformly dispersed in water to prepare the granulation solution. The filler and disintegrant are added to a fluidized bed granulation pot, and granulation is completed in a fluidized bed granulator with the above granulation solution. A lubricant is added and mixed to obtain total mixed granules, which are then compressed into tablets and coated with a gastrointestinal film.

[0092] Example 5: Preparation of tablets containing compound 1

[0093] The prescription composition of each tablet: (mg / tablet)

[0094] Preparation method: Sodium hydroxide, meglumine, compound 1, and binder are stirred until fully dissolved / uniformly dispersed in water to prepare the granulation solution. The filler and disintegrant are added to a fluidized bed granulation pot, and granulation is completed in a fluidized bed granulator with the above granulation solution. A lubricant is added and mixed to obtain total mixed granules, which are then compressed into tablets and coated with a gastrointestinal film.

[0095] Example 6: Preparation of tablets containing compound 1

[0096] The prescription composition of each tablet: (mg / tablet)

[0097] Preparation method: Sodium hydroxide, meglumine, compound 1, and binder are stirred until fully dissolved / uniformly dispersed in water to prepare the granulation solution. The filler and disintegrant are added to a fluidized bed granulation pot, and granulation is completed in a fluidized bed granulator with the above granulation solution. A lubricant is added and mixed to obtain total mixed granules, which are then compressed into tablets and coated with a gastrointestinal film.

[0098] Examples 7-12: Preparation of tablets containing compound 1

[0099] The prescription composition of each tablet: (mg / tablet)

[0100] Preparation method: Alkaline reagent, co-solvent, and compound 1 are stirred until fully dissolved / uniformly dispersed in water to prepare the granulation solution. Filler, binder, and disintegrant are added to a fluidized bed granulation vessel, and granulation is completed in a fluidized bed granulator with the above granulation solution. Lubricant is added and mixed to obtain total mixed granules, which are then compressed into tablets and coated with a gastrointestinal film.

[0101] Examples 13 and 14: Preparation of granules containing compound 1

[0102] The prescription composition of each sachet of granules: (mg / granule)

[0103] Preparation method: Sodium hydroxide, meglumine, and compound 1 are stirred until fully dissolved / uniformly dispersed in water. The mixture is then wet-granulated with fillers / binders and disintegrants, dried, sized, and finally mixed with flavoring agents and taste enhancers. The resulting granules are completely soluble and mixable in warm water.

[0104] Examples 15 and 16: Preparation of capsules containing compound 1

[0105] The prescription composition of each capsule: (mg / capsule)

[0106] Preparation method: Sodium hydroxide, meglumine, compound 1 and hydroxypropyl methylcellulose are stirred until fully dissolved in water to form a granulation solution. The filler and part of the disintegrant are added to a fluidized bed granulation pot and granulated with the above granulation solution in a fluidized bed granulator. After fluidized drying, drug-containing granules are obtained. The mixture is then mixed evenly with the remaining disintegrant and lubricant to obtain total mixed granules, which are then filled into capsules.

[0107] Comparative Example 1: Preparation of tablets containing compound 1

[0108] The prescription composition of each tablet: (mg / tablet)

[0109] In the tablet formulation of Comparative Example 1, compound 1 was micronized without the presence of alkaline reagents and cosolvents.

[0110] Preparation method: Micronized active ingredients, fillers and partially cross-linked sodium carboxymethyl cellulose are mixed, added to a granulation solution containing binders and wet granulated. After drying, lubricant and disintegrant are mixed and tableted.

[0111] Comparative Example 2: Preparation of tablets containing compound 1

[0112] The prescription composition of each tablet: (mg / tablet)

[0113] In the tablet formulation of Comparative Example 2, no alkaline reagents or cosolvents were included, and a surfactant was added as a solubilizer.

[0114] Preparation method: The micronized active ingredient is mixed with a portion of microcrystalline cellulose and croscarmellose sodium, and a granulation solution containing binder and solubilizer sodium dodecyl sulfate is added. The mixture is then wet-granulated, dried, and then mixed with a lubricant and a portion of microcrystalline cellulose and croscarmellose sodium, and finally compressed into tablets.

[0115] Comparative Example 3: Preparation of tablets containing compound 1

[0116] The prescription composition of each tablet: (mg / tablet)

[0117] In the tablet formulation of Comparative Example 3, no alkaline reagents or solubilizers were used. The active pharmaceutical ingredient of Compound 1 and the filler lactose were co-micronized, and a surfactant was added.

[0118] Preparation method: The co-micronized active ingredients and lactose are mixed with some microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose, and then wet-granulated with a granulation solution containing binder and solubilizer sodium dodecyl sulfate. After drying, the mixture is further mixed with lubricant, remaining filler and disintegrant, and then tableted.

[0119] Comparative Example 4: Preparation of tablets containing compound 1

[0120] The prescription composition of each tablet: (mg / tablet)

[0121] The tablet formulation of Comparative Example 4 did not contain a solubilizer, and the molar ratio of Compound 1 to the alkaline reagent sodium hydroxide was 1:1.25.

[0122] Preparation method: Potassium hydroxide and Compound 1 are stirred until fully dissolved. The filler, binder, and disintegrant are added to a fluidized bed granulation vessel, and granulation is completed in a fluidized bed granulator with the uniformly dispersed solution. A lubricant is added and mixed to obtain a total mixed granule, which is then compressed into tablets.

[0123] Comparative Example 5: Preparation of tablets containing compound 1

[0124] The prescription composition of each tablet: (mg / tablet)

[0125] The tablet formulation of Comparative Example 5 did not contain any alkaline reagents, but a surfactant was added as a solubilizer, and the molar ratio of compound 1 to the solubilizer arginine was 1:1.50.

[0126] The active ingredient is mixed with a cosolvent, lactose, a portion of microcrystalline cellulose and croscarmellose sodium, and then wet-granulated with a granulation solution containing sodium dodecyl sulfate. After drying, it is mixed with a lubricant, the remaining microcrystalline cellulose and croscarmellose sodium, and then tableted.

[0127] Experiment 4: In vitro dissolution study

[0128] Dissolution test: The dissolution method was performed according to the second method (paddle method) of Part IV, Chinese Pharmacopoeia 2020 edition; the dissolution medium environment was 50 rpm and 900 mL of 0.3% SDS + pH 6.8 phosphate buffer. The cumulative dissolution results (RSD ≤ 5%) after 45 min are shown in Table 2 below.

[0129] Table 2: Dissolution test results of pharmaceutical compositions containing Compound 1

[0130] Analysis of the in vitro dissolution results shows that micronization of the raw material, addition of SDS for solubilization, and addition of alkaline reagents and co-solvents within the scope of this invention can all improve the in vitro dissolution effect of compound 1. The dissolution rate is greater than 85% within 45 minutes, which basically meets the requirements for clinical drug development.

[0131] In Examples 1-12, the formulations contained alkaline reagents and co-solvents within the scope of this invention, and the dissolution within 45 minutes basically met the requirements.

[0132] In the formulation of Comparative Example 4, only 1.25 equivalents of alkaline reagent (sodium hydroxide) were added. Combined with the aforementioned analysis of solubility performance, although adding excessive alkaline reagent can improve the solubility of compound 1, it does not improve its in vitro dissolution effect. The in vitro dissolution effect is poor, with about 32% dissolving within 45 minutes, which is difficult to meet the requirements for clinical drug development.

[0133] As shown in Comparative Example 5, adding only 1.50 equivalents of the solubilizer (arginine) and SDS for solubilization, compared to adding only an alkaline reagent (Comparative Example 4), although it can improve drug dissolution to some extent, the dissolution rate is only about 73% within 45 minutes, which is still insufficient. Therefore, it can be concluded that in the pharmaceutical composition of this application, the presence of the solubilizer has a significant impact on the in vitro dissolution of the drug, and works synergistically with the alkaline reagent to improve the in vitro dissolution effect.

[0134] In the formulations of Comparative Examples 1-3, micronizing the raw materials or excipients and adding SDS as a solubilizer in the formulation can achieve complete dissolution of Compound 1 in vitro. However, further research by the applicant found that the improved methods of micronizing the raw materials or excipients and adding SDS as a solubilizer in the formulation did not significantly improve the bioavailability of Compound 1 in vivo, thus limiting its clinical application prospects.

[0135] Experiment 5: Canine Oral Bioavailability Study

[0136] The applicant studied the pharmacokinetic behavior of compound 1 and the systemic exposure (AUC) after single oral administration of 1, 5, and 15 mg / kg of compound 1 to male and female beagle dogs. 0-last and C max (Peak drug concentration) increases with increasing dose, from 1 mg / kg to 5 mg / kg and from 5 mg / kg to 15 mg / kg, C in male and female beagles max and AUC 0-last Basically, the dosage increases proportionally. Furthermore, after a single oral administration to both male and female beagle dogs, the AUC of the three dosage groups... 0-last and C max No significant gender differences were observed.

[0137] To further understand the pharmacokinetic behavior of the pharmaceutical composition containing compound 1 in animals, oral bioavailability studies were conducted on the tablets obtained in Examples 1 and 3 and Comparative Examples 1-3 in dogs. The dosage of the samples in Examples 1 and 1-3 was approximately 5 mg / kg (QD), and the dosage of the sample in Example 3 was approximately 20 mg / kg (QD). The results are as follows:

[0138] Table 3: Results of canine oral bioavailability study of drug compositions containing compound 1

[0139] Analysis of Comparative Examples 1-3 shows that in Comparative Example 1, micronization of the active pharmaceutical ingredient resulted in an absolute bioavailability of only about 11%; in Comparative Example 2, the bioavailability was about 16% after adding the surfactant SDS for solubilization; and after further co-micronization of the filler (lactose), the bioavailability was about 19%. This indicates that micronization of the active pharmaceutical ingredient, addition of solubilizers, and co-micronization of the filler (lactose) do not significantly improve in vivo bioavailability. The bioavailability of the resulting samples was all below 20%, making them unsuitable for further development as clinical formulations.

[0140] The results of Examples 1 and 3 show that the addition of the alkaline reagent and cosolvent of the present invention can significantly improve the bioavailability of the active ingredient in vivo, with an absolute bioavailability of more than 40%, which is more than twice that of other improvement methods (Comparative Examples 1-3). Moreover, the active pharmaceutical ingredient does not need to be micronized or contain undesirable surfactants, demonstrating process advantages that exceed conventional expectations.

[0141] In summary, by adding specific types and amounts of alkaline reagents and solubilizers, this invention can synergistically improve the solubility of compound 1, ensuring not only its full dissolution in the in vitro environment but also its release and absorption in vivo, significantly improving its bioavailability in vivo. This allows the active ingredient of compound 1 to be prepared into a suitable pharmaceutical composition, providing a feasible solution for the clinical use of compound 1.

[0142] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises active ingredient compound 1, an alkaline reagent, and a cosolvent, wherein the molar ratio of the active ingredient to the total amount of the alkaline reagent and cosolvent is 1:0.80–3.50; wherein the alkaline reagent is selected from one or a mixture of at least two of sodium hydroxide, potassium hydroxide, calcium hydroxide, and magnesium hydroxide in any proportion; the cosolvent is selected from one or a mixture of at least two of meglumine, arginine, histidine, lysine, glycine, glycerol, diethanolamine, choline, and theobromine in any proportion; and compound 1 is a compound with the following structure:

2. The pharmaceutical composition according to claim 1, characterized in that, The molar ratio of the active ingredient to the total amount of alkaline reagent and cosolvent is 1:1.00 to 2.50; preferably 1:1.05 to 1.50; more preferably 1:1.08 to 1.

33.

3. The pharmaceutical composition according to claim 1, characterized in that, The molar ratio of the active ingredient to the alkaline reagent is 1:0.30 to 2.00; preferably 1:0.45 to 1.50; more preferably 1:0.50 to 1.

35.

4. The pharmaceutical composition according to claim 1, characterized in that, The molar ratio of the active ingredient to the cosolvent is 1:0.07 to 1.50; preferably 1:0.08 to 1.00; more preferably 1:0.09 to 0.

90.

5. The pharmaceutical composition according to claim 1, characterized in that, The alkaline reagent is selected from sodium hydroxide, potassium hydroxide, or a mixture of the two in any proportion.

6. The pharmaceutical composition according to claim 1, characterized in that, The co-solvent is a mixture of one or more of meglumine, arginine, histidine, and lysine in any proportion.

7. The pharmaceutical composition according to claim 1, characterized in that, The molar ratio of the active ingredient to the total amount of alkaline reagent and cosolvent is approximately 1:1.05, 1:1.08, 1:1.10, 1:1.25, 1:1.45 or 1:1.

54.

8. The pharmaceutical composition according to claim 1, characterized in that, The molar ratio of the active ingredient to the alkaline reagent is 1:0.50-1.25, 1:0.50-1.15, or 1:0.50-1.

05.

9. The pharmaceutical composition according to claim 1, characterized in that, The molar ratio of the active ingredient to the cosolvent is 1:0.08-0.90, 1:0.08-0.85, or 1:0.08-0.

80.

10. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition also includes at least one pharmaceutically acceptable carrier.

11. The pharmaceutical composition according to claim 10, characterized in that, The pharmaceutically acceptable carriers include one or at least two of the following: fillers, disintegrants, binders, solubilizers, and lubricants, in any proportion.

12. The pharmaceutical composition according to claim 11, characterized in that, The filler includes microcrystalline cellulose, lactose, sucrose, starch or its derivatives, pregelatinized starch, dextrin, powdered sugar, mannitol, sorbitol, xylitol, erythritol, maltitol, calcium carbonate, dicalcium phosphate, magnesium carbonate, calcium phosphate, calcium sulfate, kaolin, maltose, isomaltose, glucose, trehalose, dextran, fructose, galactose, and maltodextrin, or a mixture of one or more of these in any proportion.

13. The pharmaceutical composition according to claim 11, characterized in that, The weight ratio of the active ingredient to the filler is 1:0.050-50.000; preferably 1:0.50-5.000; more preferably 1:0.60-2.

000.

14. The pharmaceutical composition according to claim 11, characterized in that, The adhesive comprises one or more of the following: hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxyethylcellulose, ethylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, gum arabic, gelatin, tragacanth gum, xanthan gum, and sodium alginate, mixed in any proportion.

15. The pharmaceutical composition according to claim 11, characterized in that, The weight ratio of the active ingredient to the binder is 1:0.001-0.200; preferably 1:0.010-0.150; more preferably 1:0.020-0.

120.

16. The pharmaceutical composition according to claim 11, characterized in that, The disintegrant includes sodium carbonate, sodium bicarbonate, dry starch, croscarmellose sodium, croscarmellose polyvinylpyrrolidone, sodium hydroxymethyl starch, sodium hydroxypropyl starch, low-substituted hydroxypropyl cellulose, and chitosan, or a mixture of at least two of these in any proportion.

17. The pharmaceutical composition according to claim 11, characterized in that, The weight ratio of the active ingredient to the disintegrant is 1:0.005-0.500; preferably 1:0.010-0.400; more preferably 1:0.040-0.

300.

18. The pharmaceutical composition according to claim 11, characterized in that, The lubricant comprises one or a mixture of at least two of the following in any proportion: talc, micronized silica gel, silica, colloidal silica, powdered cellulose, magnesium trisilicate, hydrated sodium aluminosilicate, stearic acid, magnesium stearate, calcium stearate, zinc stearate, sodium stearate fumarate, hydrogenated vegetable oil, sodium dodecyl stearate fumarate, glyceryl monostearate, and glyceryl palmitate.

19. The pharmaceutical composition according to claim 11, characterized in that, The weight ratio of the active ingredient to the lubricant is 1:0.001-0.200; preferably 1:0.005-0.100; more preferably 1:0.008-0.

080.

20. The pharmaceutical composition according to claim 11, characterized in that, The solubilizer includes a mixture of one or more of polyethylene glycol, propylene glycol, glycerin, Tween, sodium lauryl sulfate, cyclodextrin, polyoxyethylene castor oil, sesame oil, olive oil, soybean oil, peppermint oil, corn oil, and vitamin E in any proportion.

21. The pharmaceutical composition according to claim 11, characterized in that, The weight ratio of the active ingredient to the solubilizer is 1:0.001-0.050; preferably 1:0.002-0.030; more preferably 1:0.003-0.

020.

22. The pharmaceutical composition according to claim 1, characterized in that, The dosage forms of the pharmaceutical composition include liquid dosage forms, solid dosage forms, and semi-solid dosage forms.

23. The pharmaceutical composition according to claim 22, characterized in that, The dosage form of the pharmaceutical composition is tablets, microcapsules, capsules, granules, fine powder, powder, solution, or syrup.

24. Use of the pharmaceutical composition according to any one of claims 1 to 23 in the preparation of a medicament for treating influenza viruses.

25. The use according to claim 24, characterized in that, The antiviral drugs mentioned are drugs for treating influenza or drugs for influenza caused by highly pathogenic avian influenza viruses.

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