Solid dispersion of compound and use thereof

Abstract

Disclosed is a solid dispersion of a rifamycin-quinazolinone conjugated molecule, which comprises a rifamycin-quinazolinone conjugated molecule shown in formula (I) and a polymer carrier. The polymer carrier comprises one or a combination of more of hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl cellulose (HPC), polypropylene resin, and polyvinyl pyrrolidone (PVP). FIG. 1: AA%%%Formula (I)

Description

Solid dispersion of compound and use thereof Technical Field

[0001] The present application relates to the field of medical technology, and in particular to a solid dispersion of a rifamycin-quinolizinone coupled molecule and its application. Background Art

[0002] Rifamycin-quinolizinone conjugate molecules, as shown in the structure of formula (I) of this specification, are semi-synthetic broad-spectrum antibiotics. They are composed of rifamycin and quinolizinone pharmacophores connected by stable covalent bonds and are novel antibacterial drugs with a multi-target mechanism of action. Rifamycin-quinolizinone conjugate molecules can selectively act with DNA-dependent RNA polymerases to inhibit the transcription process of bacterial DNA. At the same time, by acting with DNA topoisomerases (including DNA gyrase and DNA topoisomerase IV), they prevent the mutual conversion between DNA topoisomers and inhibit the replication, recombination and transcription process of DNA. Through the synergistic effect of the conjugated pharmacophores, rifamycin-quinolizinone conjugate molecules can effectively inhibit the single-resistant or multi-resistant clinical strains that have already formed and greatly reduce the frequency of bacterial resistance. Patent CN109453166A discloses a solid dispersion of a rifamycin-quinolizinone conjugate molecule. Although its solubility is greatly improved in a dissolution medium at pH 4.5 compared to the API, the prior art still lacks a formulation of the rifamycin-quinolizinone conjugate molecule with high solubility, high stability, and reliable efficacy in dissolution media such as simulated fasting gastric juice and fasting intestinal fluid (FaSSGF-FaSSIF, which simulates the release process of ASD into the body and can better simulate the in vivo dissolution process compared to a dissolution medium at pH = 4.5). Summary of the Invention

[0003] A solid dispersion of a rifamycin-quinolizinone conjugate molecule, comprising a rifamycin-quinolizinone conjugate molecule represented by formula (I) and a polymer carrier; wherein the polymer carrier comprises one or a combination of hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl cellulose (HPC), polypropylene resin, and polyvinyl pyrrolidone (PVP);

[0004] In some embodiments, the rifamycin-quinolizinone conjugate molecule accounts for 20%-50% of the total mass of the solid dispersion, the polymeric carrier accounts for 50%-80% of the total mass of the solid dispersion, and the total of the rifamycin conjugate molecule and the polymeric carrier does not exceed or equal to 100% of the total mass of the solid dispersion. For example, the rifamycin-quinolizinone conjugate molecule may account for 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49% or 50% of the total mass of the solid dispersion. For example, the polymer carrier accounts for 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79% or 80% of the total mass of the solid dispersion. In the above situation, the total amount of the rifamycin conjugate molecule and the polymer carrier is no more than or equal to 100% of the total mass of the solid dispersion; for example, the total amount of the rifamycin conjugate molecule and the polymer carrier accounts for 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the total mass of the solid dispersion.

[0005] In some preferred embodiments, the polymer carrier accounts for 62%±10% of the total mass of the solid dispersion.

[0006] In some embodiments, the polymeric carrier comprises hydroxypropylmethylcellulose acetate succinate of grade LG (HPMCAS-LG) and / or hydroxypropylmethylcellulose acetate succinate of grade MG (HPMCAS-MG).

[0007] In some embodiments, the polymer carrier comprises polyvinyl pyrrolidone grade K60 (PVP K60) and / or polyvinyl pyrrolidone grade K90 (PVP K90).

[0008] In some embodiments, the polymeric carrier comprises hydroxypropyl methylcellulose phthalate grade HP-55 (HPMCP HP-55), hydroxypropyl methylcellulose phthalate grade 55S (HPMCP 55S), and / or hydroxypropyl methylcellulose phthalate grade HP-50 (HPMCP HP-50).

[0009] In some embodiments, the polymer carrier comprises polyacrylic acid resin Eudragit EPO, polyacrylic acid resin Eudragit L100-55, polyacrylic acid resin Eudragit L100, and / or polyacrylic acid resin Eudragit S100.

[0010] In some embodiments, the solid dispersion component further comprises a functional excipient, and the total weight of the functional excipient, the rifamycin-quinolizinone conjugate molecule, and the polymer carrier is no more than or equal to 100% of the total mass of the solid dispersion.

[0011] In some embodiments, the functional excipient accounts for 0-10% of the total mass of the solid dispersion. For example, the functional excipient can account for 0% (excluding functional excipients), 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10% of the total mass of the solid dispersion.

[0012] In some embodiments, the functional excipient is selected from one or more of poloxamer, Tween 20, polyoxyethylene 40 hydrogenated castor oil, and vitamin E polyethylene glycol succinate (VE-TPGS).

[0013] In some embodiments, the solid dispersion is formulated in a solvent that is a combination of one or more of tetrahydrofuran (THF), dichloromethane (DCM), ethanol, ethyl acetate, acetone, methyl isobutyl ketone, and methanol.

[0014] In some embodiments, the solvent is a solvent combination formed of dichloromethane and methanol.

[0015] In some embodiments, the solid dispersion is configured with an antioxidant, and the amount of the antioxidant is 0.05%-2% of the total weight of the solid dispersion. For example, the amount of the antioxidant can be 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9% or 2% of the total weight of the solid dispersion.

[0016] In some preferred embodiments, the amount of the oxidant is 0.1%-1% of the total mass of the solid dispersion.

[0017] In some embodiments, the antioxidant is selected from one or more of L-ascorbyl palmitate, vitamin C, butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, vitamin E, sodium formaldehyde sulfoxylate dihydrate, and citric acid.

[0018] In some embodiments, the solid dispersion has an XRPD pattern substantially similar to the solid dispersion shown by any one of the diffraction lines in FIG. 3A , FIG. 7 , or FIG. 11 .

[0019] In some embodiments, the solid dispersion has a thermogram substantially similar to Figures 3N-3P, Figure 10A, or Figure 12C.

[0020] On the other hand, the present application provides a pharmaceutical composition comprising the solid dispersion described herein and one or more pharmaceutically acceptable excipients selected from fillers, disintegrants, binders, buffers, tonicity agents, stabilizers, diluents, lubricants, glidants, antioxidants, solubilizers and surfactants.

[0021] In some embodiments, the pharmaceutical composition is a solid preparation selected from microgranules, granules, tablets, capsules, pellets, powders, and films.

[0022] On the other hand, the present application provides use of the solid dispersion described herein or the pharmaceutical composition described herein in the preparation of a drug for treating bacterial infection and / or bacterial metabolism-related diseases in the human body. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] The specific features of the inventions of this application are set forth in the appended claims. The features and advantages of the inventions of this application can be better understood by referring to the exemplary embodiments described in detail below and the accompanying drawings. A brief description of the drawings is as follows:

[0024] Figures 1A-1D show the characterization results of the compound of formula (I) by PLM, XRPD, DSC and TGA, respectively.

[0025] Figures 2A-2B show the powder X-ray diffraction patterns (XRPD) of Formulations 2 to 10 (Figure 2A) and the dynamic solubility patterns of Formulations 1 to 10 in FeSSIF-V2 buffer for 2 hours (Figure 2B) in the polymer carrier screening experiment.

[0026] FIG3A shows the XRPD results of Formulations 11 to 16 in the polymer carrier screening experiment ( FIG3A ).

[0027] 3B-3D show the TGA curve, mDSC curve and polarized light microscopy (PLM) graph of Formulation 11, respectively.

[0028] 3E-3G show the TGA curve, mDSC curve and polarized light microscopy (PLM) graph of Formulation 12, respectively.

[0029] 3H-3J show the TGA curve, mDSC curve, and polarized light microscopy (PLM) graph of Formulation 13, respectively.

[0030] 3K-3M show the TGA curve, mDSC curve, and polarized light microscopy (PLM) graph of Formulation 14, respectively.

[0031] 3N-3P show the TGA curve, mDSC curve, and polarized light microscopy (PLM) graph of Formulation 15, respectively.

[0032] 3Q-3S show the TGA curve, mDSC curve, and polarized light microscopy (PLM) graph of Formulation 16, respectively.

[0033] FIG4 shows the two-step dissolution profiles of Formulation 1, Formulations 11 to 16, and the compound of formula (I) (API) in FaSSGF-FaSSIF in the polymer carrier screening experiment.

[0034] Figure 5 shows the two-step dissolution profiles of API, physical mixture of API and carrier material, and amorphous solid dispersion (ASD) in FaSSGF-FaSSIF during the polymer carrier screening experiment.

[0035] 6A-6C show XRPD overlays of the stability samples of Formulation 1, Formulations 11-14, and Formulations 15 and 16 in the polymer carrier screening experiment.

[0036] Figure 7 shows the XRPD overlay of Formulation 18-Formulation 20 in the drug loading optimization experiment.

[0037] Figure 8 shows the two-step dissolution profiles of Formulation 1, Formulation 14, and Formulation 18-Formulation 20 in FaSSGF-FaSSIF during the drug loading optimization experiment.

[0038] Figure 9 shows the XRPD overlay of the stability samples of Formulation 18 and Formulation 20 in the drug loading optimization experiment.

[0039] 10A-10C show the mDSC curves (upper) and PLM graphs (lower) of Formulations 18-20 in the drug loading optimization experiment.

[0040] FIG11 shows an XRPD overlay of Formulations 30 to 34 in the antioxidant screening experiment.

[0041] 12A-12E show the mDSC curves (upper) and PLM graphs (lower) of Formulations 30-34 in the antioxidant screening experiment.

[0042] Figures 13A-13C show the XRPD overlays of the stability samples of Formulations 30-34 placed at 25°C for 4 weeks, the stability samples of Formulations 30-34 placed at 5°C for 4 weeks, and the stability sample of Formulation 30 filled with nitrogen and an oxygen absorber in the antioxidant screening experiment.

[0043] 14A-14D show the XRPD pattern ( FIG. 14A ), PLM pattern ( FIG. 14B ), TGA curve ( FIG. 14C ), and mDSC curve ( FIG. 14D ) of the scaled-up preparation of Formulation 32. FIG. DETAILED DESCRIPTION

[0044] To provide a clearer understanding of the technical features, objectives, and beneficial effects of the present invention, the following detailed description of the technical solution of the present invention is provided. However, this description should not be construed as limiting the scope of the present invention. The experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents and materials described are commercially available unless otherwise specified.

[0045] As used in this specification, "similar" or "similar" in reference to forms exhibiting similar properties as, for example, XRPD, IR, Raman spectroscopy, DSC, TGA, NMR, SSNMR, etc., means that the polymorphs or co-crystals can be identified by the method and can range from similar to substantially similar, as long as the material identified by the method has the variability expected by a person skilled in the art (based on experimental variations including, for example, the instrument used, time of day, humidity, season, pressure, room temperature, etc.).

[0046] Polymorphism as used herein refers to the occurrence of different crystalline forms of a single compound in different hydration states (e.g., the properties of some compounds and complexes). Therefore, polymorphs are different solids with the same molecular formula, but each polymorph can have unique physical properties. Therefore, a single compound can result in a variety of polymorphs, each of which has different and unique physical properties, such as solubility curves, melting point temperatures, hygroscopicity, particle shape, density, fluidity, compactability, and / or X-ray diffraction peaks. The solubility of each polymorph can vary, so identifying the presence of pharmaceutical polymorphs is necessary for providing a drug with a predictable solubility curve. It is desirable to investigate all solid forms of a drug including all polymorphs and to determine the stability, dissolution, and fluidity of each polymorph. The polymorphs of a compound can be distinguished in the laboratory by X-ray diffraction spectra and by other methods such as infrared spectroscopy.

[0047] Example

[0048] Example 1

[0049] Solvent Screening for Solid Dispersions

[0050] (1) Physical characterization of rifamycin-quinolizinone conjugate molecules

[0051] The rifamycin-quinolizinone conjugate represented by formula (I) was characterized by PLM, XRPD, DSC, and TGA. The PLM image (Figure 1A) revealed irregular blocky crystals, consistent with the characteristic peaks in the XRPD pattern (Figure 1B). The compound exhibited a weight loss of 0.422% at 150°C and a melting point of 193.10°C (Figures 1C-1D).

[0052] (2) Solvent screening

[0053] To identify solvents suitable for spray drying, this example tested the solubility of the compound of formula (I) in various organic solvents at 25°C. Approximately 2 mg of the drug substance was weighed into a 2 mL HPLC vial. Solvent was then gradually added until the final volume reached 1 mL or no particles were visible to the naked eye. The total solvent volume was recorded to calculate the approximate solubility.

[0054] The results shown in Table 1 indicate that the compound of formula (I) has good solubility in tetrahydrofuran, dichloromethane (DCM), and DCM:MeOH = 1:1 (v / v), and DCM:MeOH = 1:1 (v / v) is recommended for spray drying due to its high solubility and easier removal of residual solvent.

[0055] Table 1 Solubility of compounds of formula (I) in organic solvents

[0056] 1 Reference standard: ICH Guideline for residual solvents Q3C(R3).

[0057] 2 :Reference value: CN109453166A.

[0058] Example 2

[0059] Polymer carrier screening

[0060] A binary amorphous solid dispersion (ASD) can be prepared by solvent evaporation of a rifamycin-quinolizinone conjugate molecule represented by formula (I) and a polymer in a solvent. The polymer is selected from hydroxypropyl methylcellulose acetate succinate (HPMCAS) grades MG, HG, and LG, hydroxypropyl methylcellulose phthalate (HPMCP) grade 55, hydroxypropyl cellulose grade L, polypropylene resins (Eudragit EPO and Eudragit L100-55), and polyvinyl pyrrolidone (PVP) grade K90. The solvent is selected from methanol, dichloromethane, or methanol:dichloromethane (1:1, v:v). The ratio of the compound of formula (I) to the polymer is 20:80 (by weight).

[0061] Preparation Method 1: Approximately 10 mg of the compound of formula (I) (API) and 40 mg of polymer were weighed into a glass vial. 1 mL of solvent was added to completely dissolve the mixture to obtain a clear solution. The clear solution was rapidly evaporated at 60°C until dry to obtain a solid dispersion (Formulas 3 to 10). An amorphous sample of the compound of formula (I) was prepared using the same method as a control (Formula 2).

[0062] The prepared samples were characterized by XRPD, and no crystalline diffraction peaks were observed for all samples ( FIG2A ), indicating that the samples existed in an amorphous state.

[0063] Preparation Method 2: Approximately 20 mg of the compound of formula (I) and 80 mg of the polymer were weighed into a glass vial. 1 mL of solvent was added to completely dissolve the mixture to obtain a clear solution. The clear solution was rapidly evaporated at 60°C until dry to obtain a solid dispersion (Formulas 3 to 10). An amorphous sample of the compound of formula (I) was prepared using the same method as a control (Formula 2).

[0064] The prepared samples were subjected to solubility testing in FeSSIF-V2 (pH 5.8) buffer, a simulated intestinal fluid buffer, at 37°C for 2 hours. The results are shown in Table 2 and Figure 2B. The results show that compared with the polymer carrier Eudragit EPO (Formulation 8) used in CN109453166A, the polymer carriers HPMCAS-LG, 80% HPMCAS-MG, HPMCP HP-55, Eudragit L100-55, and PVP K90 had significant solubilization effects and better crystallization inhibition capabilities. Among them, HPMCAS-LG and PVP K90 had the best solubilization effects.

[0065] Table 2 Dissolution of fast solvent evaporation products in FeSSIF-V2 for 2 hours

[0066] Example 3

[0067] Preparation of Amorphous Solid Dispersion (ASD) by Spray Drying

[0068] Based on the results of polymer and solvent screening, three polymers—PVP K90, HPMCAS-LG, and Eudragit EPO—were selected as carriers, and a DCM:MeOH (v / v) ratio of 1:1 was used as the solvent system for spray drying. Furthermore, 8% by weight of vitamin E polyethylene glycol succinate (VE-TPGS) was added and spray-dried using the same method to further investigate the possibility of adding a solubilizer.

[0069] The detailed preparation process parameters are shown in the table below. ASD-Eudragit EPO and ASD-HPMCAS-LG with or without VE-TPGS were vacuum dried at 40°C for 18 hours. ASD-PVP K90 with and without VE-TPGS was vacuum dried at 40°C for 24 hours before subsequent characterization.

[0070] In this example, PLM, XRPD, mDSC, and TGA were performed on formulations 11 to 16 (the results are shown in Table 3 and Figure 3). The PLM and XRPD results showed that all six ASDs were amorphous. gThe glass transition temperature (GST) was 126.13°C, 104.90°C for ASD-HPMCAS-LG-VE-TPGS, 71.93°C and 115.86°C for ASD-Eudragit EPO, 60.29°C and 100.49°C for ASD-Eudragit EPO-VE-TPGS, 107.81°C for ASD-PVP K90, and 113.75°C for ASD-PVP K90-VE-TPGS. The weight loss rate of ASD at 150°C was 0.407%-7.792%.

[0071] Table 3 ASD characterization results of Formulations 11-16

[0072] In order to evaluate the in vitro ASD release performance of the compound of formula (I), Formulations 11-16 were subjected to a two-step dissolution experiment in simulated fasting gastric fluid-fasting intestinal fluid (FaSSGF-FaSSIF), and the compound of formula (I) molecule and a physical mixture (20% API + 72% HPMCAS-LG + 8% VE-TPGS, Formulation 17) were subjected to a two-step dissolution experiment as a control.

[0073] The results of Figures 4, 5 and Table 4 show that all ASDs can significantly improve the 240-minute solubility of the API in the FaSSGF-FaSSIF system. Among them, compared with ASD-Eudragit EPO (Formula 12) with the addition of VE-TPGS, ASD-PVP K90 (Formula 16) and ASD-HPMCAS-LG (Formula 14) with the addition of VE-TPGS also showed a better ability to increase the concentration of the API in the FaSSGF-FaSSIF system. In addition, the two-step dissolution solubility of Formula 14 is much better than that of its control physical mixture (Formula 17), which further illustrates that the products of the embodiments of the present disclosure can improve the solubility of existing formulas in the FaSSGF-FaSSIF system and improve bioavailability.

[0074] Table 4 Two-step dissolution results of formula 1, formula 11 to formula 17 in FaSSGF-FaSSIF

[0075] The stability of Formulations 11-16 was investigated. Formulation 1 (control) and Formulations 11-16 were stored at 25°C / 60% RH (open) and 5°C (closed) for 4 weeks. After 4 weeks, samples were collected for XRPD characterization (Figure 6) and content and related substance determination. Formulations 11-16 remained amorphous after 4 weeks at 25°C / 60% RH (open) and 5°C (closed), demonstrating good physical stability. Formulations 11-16 showed a significant increase in total impurities after 4 weeks at 25°C / 60% RH (open), primarily due to oxidative impurities. Formulations 16 and 14 exhibited superior chemical stability compared to other formulations, such as Formulation 12. However, due to the high viscosity of dissolved PVP K90, Formulation 16 produced flocculent material during spray drying, making it impossible to collect the spray-dried product. The spray-dried product could only be collected at very low concentrations (API concentration of 2.5 mg / mL).

[0076] Table 5 4-week stability results of Formulation 1, Formulation 11-Formulation 16

[0077] Example 4

[0078] Drug loading optimization

[0079] Approximately 2 g of the compound of formula (I) (API) and HPMCAS-LG were prepared in a DCM:MeOH (1:1, v:v) solvent with 8% by weight of vitamin E polyethylene glycol succinate (VE-TPGS). ASDs were prepared by spray drying at drug loadings of 30%, 40%, and 50%. The spray drying parameters are shown in the table below. A secondary drying step was performed after spray drying.

[0080] The samples were observed under a polarizing microscope and characterized by XRPD after preparation. No crystal diffraction peaks or birefringence were observed for all samples, indicating that the samples existed in an amorphous state (Figure 7). The samples were also characterized by mDSC, and the results showed that there was only one T for Formulations 18-20. g The temperatures were 100.07°C, 108.69°C, and 113.12°C, respectively ( Figure 10 ).

[0081] Table 6 ASD characterization results of Formulations 18-20

[0082] Formulations 18-20 were subjected to two-step dissolution experiments in FaSSGF-FaSSIF, with the compound of Formula (I) as a control. The dissolution results are shown in Table 7 and Figure 8. All formulations significantly increased the solubility of the API, with Formulation 18 (30% drug loading) demonstrating the best two-step dissolution results.

[0083] Table 7 Two-step dissolution results of Formulation 14, Formulation 18-Formulation 20 in FaSSGF-FaSSIF

[0084] To investigate the stability of ASDs prepared with varying drug loadings, Formulations 18-20 were stored at 25°C / 60% RH (open) and 5°C (closed) for four weeks. After four weeks, samples were collected for XRPD characterization and content and related substance analysis (results shown in Figure 9 and Table 8). Formulations 18-20 remained amorphous after four weeks at 25°C / 60% RH (open) and 5°C (closed), demonstrating good physical stability. Formulations 18-20 exhibited an increase in total impurities after four weeks at 25°C / 60% RH (open), primarily due to oxidative impurities. No significant differences in chemical stability were observed among the formulations with varying drug loadings.

[0085] Table 8 4-week stability results of Formulation 14, Formulation 18-Formulation 20

[0086] Example 5

[0087] Antioxidant screening

[0088] To reduce the oxidative degradation rate of the compound of formula (I) (API) and the production of oxidative impurities, the use of several antioxidants, including L-ascorbyl palmitate, vitamin C, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, sodium formaldehyde sulfoxylate dihydrate, and citric acid, was investigated. 1% (by weight, based on the API) of each antioxidant was added to a solution of the compound of formula (I) in a methanol:dichloromethane (1:1, v:v) solvent. Each solution was stored at 5°C and 25°C for 10 days. The effects of related substances and oxidative impurities were investigated. The results are shown in Table 9.

[0089] Table 9 Antioxidant screening stability results

[0090] Note: LOQ stands for limit of quantitation (0.05%).

[0091] As can be seen from the above table, for Formulation 21 stored at 5°C for 5 days, the oxidation impurities increased from 0.09% to 0.13%, and the total impurities increased from 0.37% to 0.42%. For Formulation 21 stored at 5°C for 10 days, the oxidation impurities increased from 0.09% to 0.20%, and the total impurities increased from 0.37% to 0.48%. This shows that the solution of the compound of formula (I) can maintain chemical stability within 5 days at 5°C, but has poor chemical stability at 25°C. Compared with other antioxidants, the addition of the antioxidants L-ascorbyl palmitate and vitamin C can significantly improve the stability of the formulation, and the oxidation degradation situation is significantly improved. Among them, the growth of oxidation impurities and total impurities in Formulation 22 and Formulation 23 is the smallest. For Formulation 22 stored at 5°C for 10 days, the oxidation impurities were still <LOQ, and the total impurities remained unchanged. Stored at 25°C for 3 days, the oxidation impurities were still <LOQ, and the total impurities increased from 0.27% to 0.33%. Stored at 25°C for 5 days, the oxidation impurities were still <LOQ, and the total impurities increased from 0.27% to 0.37%. For Formulation 23 stored at 5°C for 10 days, the oxidation impurities were still <LOQ, and the total impurities remained unchanged. Stored at 25°C for 3 days, the oxidation impurities were still <LOQ, and the total impurities increased from 0.28% to 0.35%. Stored at 25°C for 5 days, the oxidation impurities were still <LOQ, and the total impurities increased from 0.28% to 0.38%. This shows that Formulation 22 and Formulation 23 can maintain chemical stability within 10 days at 5°C and within 3 days at 25°C. In the examples of this application, by comparing the types of antioxidants, the products of the examples of the present disclosure can improve the degradation of oxidation impurities in the existing formulation and the situation of low formulation stability.

[0092] Approximately 2 g of the compound of formula (I) with a drug loading of 30% was combined with HPMCAS-LG, Eudragit EPO, a methanol:dichloromethane (DCM:MeOH = 1:1, v:v) solvent system, and 8% vitamin E polyethylene glycol succinate (VE-TPGS, by weight). Antioxidants vitamin C, L-ascorbyl palmitate, or sodium formaldehyde sulfoxylate dihydrate at 1% (1% of the API, by weight) were added respectively, and ASD was prepared by spray drying. The spray drying process parameters are shown in the following table. Secondary drying was carried out after spray drying.

[0093] The samples produced were observed under a polarized light microscope after preparation and characterized by XRPD. No crystalline diffraction peaks and birefringence were observed for all samples, indicating that the samples exist in an amorphous state (Figure 11). And the samples were characterized by mDSC. For Formulations 30 - 34, there was only one T g temperature, which were 107.59°C, 107.05°C, 101.80°C, 100.99°C, and 102.10°C respectively (Figure 12).

[0094] Table 10 Characterization results of formulations 30-34

[0095] To investigate stability, Formulations 30-34 were stored at 25°C (closed) and 5°C (closed) for four weeks. After four weeks, samples were taken for XRPD characterization (Figure 13) and for content and related substances. To investigate the effect of an external oxygen absorber on formulation stability, a new packaging option was added to Formulation 30, which contained nitrogen and an external oxygen absorber and desiccant. The remaining packaging options were not nitrogen-filled but only contained a desiccant. The results in Table 11 show that Formulations 30-34 remained amorphous after four weeks at 25°C (closed) and 5°C (closed), demonstrating good physical stability. Formulation 32 exhibited superior chemical stability compared to the other formulations. Nitrogen filling and the addition of an external oxygen absorber significantly inhibited the growth of impurities.

[0096] Table 11 4-week stability results of Formulations 30-34

[0097] Note: LOQ stands for limit of quantitation (0.05%).

[0098] Example 6

[0099] Antibacterial activity of the compounds of this application against related strains

[0100] Strain Preparation: As shown in the table below, all strains were obtained from the American Type Culture Collection (ATCC) and stored frozen at -80°C. Two days prior to antimicrobial activity testing, strains were revived. A small amount of the frozen bacteria was scraped with a sterile inoculating loop and streaked onto solid culture medium (TSA + 5% defibrinated sheep blood). The culture was then incubated at 35±2°C in a suitable atmosphere for 20-48 hours. A single pure colony was then picked from the resuscitation medium with a sterile inoculating loop and streaked onto solid culture medium again. The culture was then incubated under suitable conditions for 20-48 hours.

[0101] Prepare bacterial suspension: Pick 5-10 bacterial colonies from the solid culture medium and resuspend them in 5 mL of normal saline. Adjust the bacterial suspension to 0.5 McFarland (1-2×10 8 CFU / ml, the strains tested by broth dilution method were diluted 100 times with the corresponding broth (10 6 CFU / mL, the strains tested by agar dilution method were diluted 10 times with normal saline (10 7 CFU / mL) and set aside.

[0102] Broth dilution method MIC determination: The test compounds were dissolved in DMSO to prepare a 5120 μg / mL stock solution. The compounds were serially diluted to prepare a series of compound dilution working solutions (twice the final test concentration). 50 μL of the series of compound dilution working solutions were pipetted into the corresponding 96-well plates using a dispenser. 50 μL of the diluted bacterial suspension was added to each well, and the inoculum size was approximately 5 × 10 4 CFU / well. Read the number after 20-24 hours of incubation according to the bacterial culture conditions in the table above.

[0103] Agar dilution method MIC determination: The test compounds were dissolved in DMSO, and the compounds were serially diluted to prepare a series of compound dilution solutions (100 times the final test concentration). Columbia culture medium containing 5% defibrinated sheep blood was used for anaerobic susceptibility testing. All culture media were prepared and stored according to the agar method of CLSIM07. 200 μL of compound dilution solution was added to melted Columbia blood agar balanced in a 45°C to 50°C water bath. The agar and drug solution were thoroughly mixed and poured onto a horizontal surface. The plate was allowed to solidify and then used. 3 μL of bacterial suspension was drawn up using a spray gun and inoculated into the compound dilution plate. The final inoculum size was approximately 10 4 The inoculated agar plate was placed in an anaerobic box containing a GasPak bag and incubated at 35-37°C under anaerobic conditions for 46-48 hours before reading.

[0104] Table 12 Minimum inhibitory concentration (MIC) results of test compounds against specific strains (unit: μg / mL)

[0105] According to the results in Table 12, the compounds of the present application have high antibacterial activity against common pathogens or conditional pathogens, and have good selectivity for probiotics (Bifidobacterium bifidum). The compounds of the present application can prevent or treat human bacterial infections and / or bacterial metabolism-related diseases by inhibiting pathogens or conditional pathogens.

Claims

1. A solid dispersion of a rifamycin-quinolizinone conjugate molecule, comprising a rifamycin-quinolizinone conjugate molecule of formula (I) and a polymer carrier; in, The polymer carrier comprises one or a combination of hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl cellulose (HPC), polypropylene resin, and polyvinyl pyrrolidone (PVP).

2. The solid dispersion according to claim 1, wherein the rifamycin-quinolizinone conjugate molecules account for 20%-50% of the total mass of the solid dispersion, the polymer carrier accounts for 50%-80% of the total mass of the solid dispersion, and the total of the rifamycin conjugate molecules and the polymer carrier does not exceed or equal to 100% of the total mass of the solid dispersion. 3 . The solid dispersion according to claim 1 , wherein the polymer carrier accounts for 62%±10% of the total mass of the solid dispersion. 4 . The solid dispersion according to claim 1 , wherein the polymer carrier comprises hydroxypropyl methylcellulose acetate succinate (HPMCAS-LG) of grade LG and / or hydroxypropyl methylcellulose acetate succinate (HPMCAS-MG) of grade MG. 5 . The solid dispersion according to claim 1 , wherein the polymer carrier comprises polyvinyl pyrrolidone of grade K60 (PVP K60) and / or polyvinyl pyrrolidone of grade K90 (PVP K90).

6. The solid dispersion according to claim 1 or 2, wherein the polymer carrier comprises hydroxypropyl methylcellulose phthalate of grade HP-55 (HPMCP HP-55), hydroxypropyl methylcellulose phthalate of grade 55S (HPMCP 55S), and / or hydroxypropyl methylcellulose phthalate of HP-50 (HPMCP HP-50).

7. The solid dispersion according to claim 1 or 2, wherein the polymer carrier comprises polyacrylic acid resin Eudragit EPO, polyacrylic acid resin Eudragit L100-55, polyacrylic acid resin Eudragit L100, and / or polyacrylic acid resin Eudragit S100.

8. The solid dispersion according to any one of claims 1 to 7, further comprising a functional excipient, wherein the total weight of the functional excipient, the rifamycin-quinolizinone conjugate molecule and the polymer carrier does not exceed or equal to 100% of the total weight of the solid dispersion. 9 . The solid dispersion according to claim 8 , wherein the functional excipient accounts for 0-10% of the total mass of the solid dispersion.

10. The solid dispersion according to claim 8 or 9, wherein the functional excipient is selected from one or more of poloxamer, Tween 20, polyoxyethylene 40 hydrogenated castor oil and vitamin E polyethylene glycol succinate (VE-TPGS).

11. The solid dispersion according to any one of claims 1 to 10, which is formulated in a solvent, wherein the solvent is a combination of one or more of tetrahydrofuran (THF), dichloromethane (DCM), ethanol, ethyl acetate, acetone, methyl isobutyl ketone and methanol. The solid dispersion according to claim 11 , wherein the solvent is a solvent combination formed by dichloromethane and methanol.

13. The solid dispersion according to any one of claims 1 to 12, which is prepared together with an antioxidant, wherein the amount of the antioxidant is 0.05% to 2% of the total mass of the solid dispersion. The solid dispersion according to claim 13 , wherein the amount of the oxidant is 0.1% to 1% of the total mass of the solid dispersion.

15. The solid dispersion according to claim 14, wherein the antioxidant is selected from one or more of L-ascorbyl palmitate, vitamin C, butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, vitamin E, sodium formaldehyde sulfoxylate dihydrate, and citric acid.

16. The solid dispersion according to any one of claims 1 to 15, which has an XRPD pattern substantially similar to the solid dispersion shown by any one of the diffraction lines in Figure 3A, Figure 7 or Figure 11.

17. The solid dispersion of any one of claims 1-16, having a thermogram substantially similar to Figures 3N-3P, Figure 10A, or Figure 12C.

18. A pharmaceutical composition comprising the solid dispersion according to any one of claims 1 to 17, and one or more pharmaceutically acceptable excipients selected from fillers, disintegrants, binders, buffers, tonicity agents, stabilizers, diluents, lubricants, glidants, antioxidants, solubilizers, and surfactants. The pharmaceutical composition according to claim 18, which is a solid preparation selected from microgranules, granules, tablets, capsules, dripping pills, powders and films.

20. Use of the solid dispersion according to any one of claims 1 to 17, or the pharmaceutical composition according to claim 18 or 19, in the preparation of a medicament for treating bacterial infection and / or bacterial metabolism-related diseases in the human body.

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