Preparation process of a liquid preparation of a β-lactamase inhibitor

Abstract

The present invention discloses a preparation process of a liquid preparation of a β-lactamase inhibitor. The preparation process disclosed by the present invention includes that a suspension of a β-lactamase inhibitor is prepared into a liquid preparation of a β-lactamase inhibitor through high-pressure homogenization, and the pressure of the high-pressure homogenization is 1-30 K psi; the high-pressure homogenization cycle is 3-57 times; the equipment for the high-pressure homogenization is a high-pressure homogenizer or a microfluidic homogenizer. The liquid preparation of the β-lactamase inhibitor obtained by the preparation process of the present invention is placed for 24 h under natural light conditions at 25°C, and there is no obvious change in the concentration and total impurity content.

Description

Technical Field

[0001] The present invention relates to a preparation process of a liquid preparation of a β-lactamase inhibitor. Background Art

[0002] β-lactam antibiotics have always been the first-choice antibacterial agents in clinical practice. However, the efficacy of current related antibiotics is affected by bacterial β-lactamases, which can develop resistance to penicillins, extended-spectrum cephalosporins, monobactams, and carbapenems. To address β-lactamase-mediated resistance, β-lactamase inhibitors have been introduced into clinical practice, greatly enhancing the efficacy of β-lactams in the treatment of bacterial infections (Clin Microbiol Rev. 2010 Jan; 23(1): 160 - 201). The antibiotic resistance produced by β-lactamases poses more challenges to the efficacy of β-lactam drugs and the categories of antibiotics used clinically. In the past three decades, only a few β-lactamase inhibitors have been introduced to the market (Medchemcomm. 2018 Aug 17; 9(9): 1439 - 1456). β-lactamase inhibitors are clinically available as single-dose and multi-dose incremental injectables and can also be used in combination with other antibacterial drugs. However, β-lactamase inhibitor-like drugs represented by the following general formula are poorly soluble small molecule drugs, and the drugs are prone to precipitation during the storage and use of the injection solution, and have poor stability, which is not conducive to combination with other antibacterial drugs.

[0003]

[0004] The dissolution strategy of poorly soluble drugs is an important issue to be considered in the application of the pharmaceutical industry. Scientists and professionals have explored numerous methods to try to solve such problems. For example, the dissolution of nateglinide (a lipophilic insoluble drug) was improved through nanoparticle and blending technologies (Int J Pharm. 2013 Sep 15; 454(1): 562 - 7); the solubility of insoluble drugs was enhanced by freezing the liquid into spray micronized products to improve physical stability (Pharm Dev Technol. 2003; 8(2): 187 - 97), etc. Although these methods have been proven to increase the solubility of drugs, they currently have great limitations: they are only applicable to small-scale production, the process methods are relatively complex, and the time cycle for developing formulation recipes is long. At present, a relatively mature preparation process still needs to be considered to better solve such problems.

[0005] The high-pressure homogenization process is mainly applied in the biological and pharmaceutical industries. It is a process that uses a homogenizer to break up solid substances in nanoemulsions, liposomes, and nano-suspensions, enabling the solid particles to achieve ultra-fine refinement and form a uniform suspension emulsion. Generally, through mechanical forces such as high-speed shearing, high-frequency oscillation, cavitation, and convective impact, as well as corresponding thermal effects, the solubility of poorly soluble compounds is increased, and the material is in a good state of uniform distribution.

[0006] In the homogenization process, the main forces of the commonly used homogenizer are shear force and pressure. The homogenizers often used in the pharmaceutical and biological industries are mainly high-pressure homogenizers and microfluidic homogenizers. High-pressure homogenizers mainly use the high pressure generated by the pressure system to cause cavitation and turbulent effects to extrude, extend, impact, and break the material. The disadvantages of high-pressure homogenizers are: the design gap of the homogenization valve is large, the homogenization pressure is relatively low, it is easy to be damaged when homogenizing high-hardness particles, and the maintenance difficulty is high. The advantages are: the price is relatively low. High-pressure homogenizers are suitable for processing soft and semi-soft granular materials. Microfluidic homogenizers use channels of about a hundred micrometers to form supersonic jets, and the jets collide with each other to perform extremely strong shearing. The advantages are: it will produce a better particle size distribution effect. The disadvantages are: the flow rate is small, and the cost is relatively high. Among them, the high-pressure homogenization chamber, as the core component, has a unique geometric structure inside, which also affects the homogenization effect of the final product.

[0007] In recent years, nano-suspensions, as a form of injection, have attracted wide attention. Improving the dissolution rate of nano-scale particles - nano-suspensions can solve the problem of poor drug solubility. Due to the large surface area, nano-suspensions not only increase the dissolution rate but also increase the saturation of the solution and improve the bioavailability. Therefore, commercial nano-suspension products, such as Rapamune, Emend, etc., have been rapidly adopted by the pharmaceutical industry. (Pharmaceutical development and technology, 24(10), 1278–1286).

[0008] Whereas, the liquid preparations prepared by the preparation method as Figure 1 shown have a high impurity content and poor drug solubility. There is an urgent need for β-lactamase inhibitors to develop new liquid preparation processes to improve solubility, reduce impurity content, and store stably. Considering that the high-pressure homogenization technology has matured, and the preparation development method of using this technology for β-lactamase inhibitors has not been applied, the high-pressure homogenization process can be used to prepare broad-spectrum antibacterial poorly soluble small molecule compounds of β-lactamase inhibitors. Summary of the Invention

[0009] In order to overcome the problems in the prior art that the liquid preparation of β-lactamase inhibitor has a relatively high impurity content and poor drug solubility, a preparation process for the liquid preparation of β-lactamase inhibitor is provided. The β-lactamase inhibitor obtained by the preparation process of the present invention is placed under natural light at 25 °C for 24 h, and there is no obvious change in the concentration and total impurity content.

[0010] The present invention provides a preparation process for a liquid preparation of a β-lactamase inhibitor, which includes obtaining the liquid preparation of the β-lactamase inhibitor by high-pressure homogenization of a suspension of the β-lactamase inhibitor.

[0011] The pressure of the high-pressure homogenization is 1 - 30 K psi;

[0012] The high-pressure homogenization cycle is 3 - 57 times;

[0013] The equipment for the high-pressure homogenization is a high-pressure homogenizer or a microfluidic homogenizer.

[0014] In one embodiment, the flow rate of the high-pressure homogenization is 50 - 200 ml / min, for example, 100 ml / min.

[0015] In one embodiment, the pressure of the high-pressure homogenization can be 5 - 25 K psi, for example, 5 K psi, 10 K psi, 20 K psi or 25 K psi.

[0016] In one embodiment, the high-pressure homogenization cycle is 3 times, 18 times, 24 times, 27 times, 30 times, 35 times or 57 times.

[0017] In one embodiment, when the pressure of the high-pressure homogenization is 5 K psi, the high-pressure homogenization cycle is 3 times.

[0018] In one embodiment, when the pressure of the high-pressure homogenization is 10 K psi, the high-pressure homogenization cycle is 3 times.

[0019] In one embodiment, when the pressure of the high-pressure homogenization is 20 K psi, the high-pressure homogenization cycle is 3 times or 18 times.

[0020] In one embodiment, when the pressure of the high-pressure homogenization is 20 K psi, the high-pressure homogenization cycle is 24 or 35 times.

[0021] In one embodiment, when the pressure of the high-pressure homogenization is 25 K psi, the high-pressure homogenization cycle is 27, 30 or 57 times.

[0022] In one embodiment, the high-pressure homogenization cycle is 3 times of high-pressure homogenization at a homogenization pressure of 5K psi, then 3 times of high-pressure homogenization at a homogenization pressure of 10K psi, and then the homogenization pressure is increased to 20K psi for 35 times of high-pressure homogenization.

[0023] In one embodiment, the high-pressure homogenization cycle is 3 times of high-pressure homogenization at a homogenization pressure of 5K psi, 3 times of high-pressure homogenization at a pressure of 20K psi, and then the homogenization pressure is increased to 25K psi for 27 times of high-pressure homogenization.

[0024] In one embodiment, the high-pressure homogenization cycle is 3 times of high-pressure homogenization at a pressure of 5K psi, then 3 times of high-pressure homogenization at a pressure of 10K psi, and finally the homogenization pressure is increased to 20K psi for 24 times of high-pressure homogenization.

[0025] In one embodiment, the high-pressure homogenization cycle is 3 times of homogenization at a homogenization pressure of 5K psi, 3 times of homogenization at a homogenization pressure of 10K psi, and an increase in the homogenization pressure to 20K psi for 18 times of high-pressure homogenization.

[0026] In the present invention, the time of the high-pressure homogenization is the conventional homogenization time in the art. Preferably, the time of the high-pressure homogenization is related to the pressure and number of times of the high-pressure homogenization; it is preferably 4.5 - 52 min, such as 4.5 min, 27 min, 36 min, 40 min, and 52 min.

[0027] In the present invention, the single time of the high-pressure homogenization cycle is 1.5 min.

[0028] In the present invention, the β-lactamase inhibitor can be a compound as shown in (A);

[0029]

[0030] In the present invention, the pH value in the suspension is the conventional pH value in the art, and can be, for example, 4 - 5, such as 4.5 or 4.6.

[0031] In the present invention, the temperature of the high-pressure homogenization is the conventional temperature in the art, and can be less than or equal to 55°C, such as 20°C, 27°C, 30°C, 33°C, 35°C, 38°C, 40°C, 48°C, 50°C, or 51°C.

[0032] In the present invention, the particle size of the β-lactamase inhibitor is the conventional particle size in the art, and can be less than or equal to 500 μm, can also be 10 - 200 μm, and can also be 60 - 100 μm, such as 31.78 μm, 60.33 μm, or 100 μm.

[0033] In the present invention, the suspension further comprises sodium sulfobutylether-β-cyclodextrin, citric acid and a base. The base is preferably NaOH.

[0034] In the present invention, in the suspension, the content of the β-lactamase inhibitor liquid preparation is a conventional content in the art, and can be less than or equal to 15 mg / mL; for example, 5.26 mg / mL, 10. mg / mL or 12 mg / mL.

[0035] In the present invention, in the suspension, the content of the citric acid is a conventional content in the art, for example, 0.77 mg / mL.

[0036] In the present invention, in the suspension, the content of the sodium sulfobutylether-β-cyclodextrin is a conventional content in the art, for example, 50.00 mg / mL.

[0037] In the present invention, in the suspension, the content of the base is a conventional content in the art, for example, 6.53 mg / mL.

[0038] In the present invention, the homogenization chamber of the microfluidic homogenizer is Y-shaped or Z-shaped, preferably Y-shaped.

[0039] In the present invention, in the preparation process, after high-pressure homogenization, centrifugation and / or filtration are further included.

[0040] In the present invention, the specification of the filter for filtration is 0.22 μm.

[0041] The present invention also provides an application of high-pressure homogenization in the preparation of a β-lactamase inhibitor liquid preparation, and the conditions of the application are as described in the foregoing preparation process.

[0042] The present invention also provides a β-lactamase inhibitor liquid preparation, and the liquid preparation is prepared by the foregoing preparation process.

[0043] On the basis of not violating the common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain various preferred examples of the present invention.

[0044] The reagents and raw materials used in the present invention are all commercially available.

[0045] The positive and progressive effects of the present invention are as follows: The liquid preparation of the β-lactamase inhibitor prepared by the preparation process of the present invention has no obvious change in concentration and total impurity content after being placed for 24 h under natural light conditions at 25°C. Description of the Drawings

[0046] Figure 1 It is a process flow chart of the original liquid preparation.

[0047] Figure 2 It is the result of the liquid storage stability experiment prepared in Example 1.

[0048] Figure 3 It is the time-varying curve of the total impurity content (RP-HPLC) of the liquid prepared in Example 1.

[0049] Figure 4 Example 2 is about preparing a liquid preparation of Compound A by a high-pressure homogenization process (high-pressure homogenizer).

[0050] Figure 5 Example 3 is about the effect of the high-pressure homogenization process (microfluidizer homogenizer) on the solubility of Compound A.

[0051] Figure 6 Example 3 is about the study on the stability of the liquid after homogenization.

[0052] Figure 7 Example 4 is about the appearance comparison of the homogenized liquid of Compound A prepared by Y-type and Z-type homogenization chambers.

[0053] Figure 8 、 Figure 9 Example 4 is about the effect of the microfluidizer homogenization process with different homogenization chambers (Y-type and Z-type) on the solubility of Compound A.

[0054] Figure 10 、 Figure 11 Example 5 is about the solubility results of Compound A after microfluidizer homogenization with different particle sizes / concentrations. Detailed implementation manners

[0055] The present invention will be further described below by way of examples, but the present invention is not limited to the scope of the described examples. For the experimental methods without specific conditions in the following examples, they are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0056] In this application, the meanings of technical terms are consistent with the common understanding of those skilled in the art, unless otherwise specified. In this application, "a" or its combinations with various quantifiers include both singular and plural meanings, unless specifically stated. In this application, when multiple numerical values, numerical ranges, or their combinations are given to describe the same parameter or variable, it is equivalent to specifically disclosing these numerical values, the end values of the ranges, and the numerical ranges formed by any combination of them. In this application, any numerical value, whether or not it has a approximate modifier such as "about", covers the approximate range that those skilled in the art can understand, such as a range of plus or minus 10% or 5%. In this text, any "embodiment" equally refers to and covers the embodiments of the methods and systems of this application. In this application, one or more technical features in any embodiment can be freely combined with one or more technical features in any other embodiment, and the resulting embodiments also belong to the content disclosed in this application. The weight / volume percentage (% w / v) in this text represents the number of grams (g) per 100 milliliters (100 mL). The molar concentration (M, mol / L) represents the number of moles (mol) of solute contained in each liter (L) of solution. When the dispersed substance is uniformly dispersed in the dispersion medium in the form of molecules, atoms, or ions (particle diameter d < 1 nm), the formed system is called a true solution. A true solution is dispersed in the form of small molecules or ions, is a homogeneous clear solution, and the system is stable. It is also called a solution agent, and the particle size in it is < 1 nm.

[0057] In this application, the "homogenizer" includes various models of equipment known in the art with homogenization functions, such as high-pressure homogenizers and microfluidic homogenizers. High-pressure homogenizers are commonly used equipment in the pharmaceutical, food, and chemical industries, and the selection and use of their models belong to the skills of those skilled in the art.

[0058] In this application, the "homogenization chamber" includes components with various model parameters and different internal structures and belongs to the core component of the high-pressure homogenizer, such as the Y / Z type homogenization chamber. In this application, the "liquid preparation" refers to a liquid dispersion system formed by a drug or a drug and other components dispersed in a liquid solvent in a certain form. "Compound A" refers to one of the compounds of β-lactamase inhibitor (BLI). "API" refers to the active pharmaceutical ingredient, which is any substance or mixture of substances used in the manufacture of drugs. Such substances have pharmacological activity or other direct effects or can affect the function or structure of the body, but cannot be taken directly. Generally, after adding excipients and processing, they are made into drugs that can be used directly. "Placebo" refers to tablets, pills, or injections made of substances without drug efficacy and non-toxic side effects, such as citric acid and sulfobutylether-β-cyclodextrin (SBECD) used in this application.

[0059] In some embodiments, the high-pressure homogenization process of the liquid preparation of the β-lactamase inhibitor broad-spectrum antibacterial poorly soluble small molecule compound referred to in the present application includes any device, tool, or their integration that can achieve a specified one or a group of steps to realize the fact of a high-concentration liquid preparation of the β-lactamase inhibitor broad-spectrum antibacterial poorly soluble small molecule compound.

[0060] The present application will be described in detail through the following exemplary specific embodiments. The following embodiments are only used to help those skilled in the art better understand various inventions of the present application. It should be pointed out that the spirit of the present application and the protection scope of the claims are not limited by the following specific embodiments.

[0061] The material compound A used in the examples was purchased from Chongqing Boren Company;

[0062] The structure of compound A is as follows:

[0063]

[0064] The high-pressure homogenizer (model: NATHOX Lab 3) was purchased from Nathan Technologies; the microfluidic homogenizer (model: M-110EH30) and its accessories, the Y / Z type homogenization chamber, were both purchased from Microfluidics; the constant temperature water bath (model: HWCL-3) was purchased from Greatwall. The dynamic light scattering instrument (model: Malvern ZEN3600) was purchased from Malvern; the clarity detector (model YB-2) was purchased from TianDa TianFa Company.

[0065] Reverse high performance liquid chromatography (RP-HPLC): chromatographic column (3μm, 150mm×4.6mm); through an Agilent high performance liquid chromatograph (model: 1260); mobile phase: A: 0.05% phosphoric acid: (980 mL H2O: 5 mL methanol: 5 mL acetonitrile), B: 0.05% phosphoric acid: (500 mL methanol: 500 mL acetonitrile); flow rate: 1.0 mL / min; detection wavelength: 210 nm. Diluent: pure water.

[0066] In the following examples, the detection conditions for related substances (RP-HPLC) are shown in Table 1 below:

[0067] Table 1:

[0068]

[0069] Example 1 Preparation process of the liquid preparation of compound A

[0070] This example aims to study the physical and chemical properties of the liquid medicine of compound A prepared by the liquid preparation process to evaluate the influence of the liquid preparation process on the liquid medicine.

[0071] Homogeneous liquid formulation: 50.00 mg / mL SBECD, 0.77 mg / mL citric acid, 6.53 mg / mL 1M NaOH, and the feeding concentration of Compound A (batch: PS-12502-105-190002-1) is 5.26 mg / mL.

[0072] Homogenization process: Use a high-pressure homogenizer (Nathan Technologies, model: NATHOX Lab 3); Do not control the temperature during homogenization; Homogenize the freshly prepared suspension of Compound A (150 ml) 3 times at 5K psi pressure with a total cycle time of 4.5 min; Homogenize 3 times at 10K psi pressure with a total cycle time of 4.5 min; Increase the homogenization pressure to 20K psi and homogenize 18 times with a total cycle time of 27 min.

[0073] According to the liquid storage stability study plan shown in Table 2, the liquid formulations were stored at 2 - 8°C and 25°C for 24 hours after preparation. The detection of liquid storage stability includes appearance, pH value, insoluble particles, concentration, and related substances (RP-HPLC). The specific plan is shown in Table 2 below.

[0074] Table 2 Liquid Storage Stability Study Plan of Compound A

[0075]

[0076] X = Appearance, pH, insoluble particles, concentration, and related substances (RP-HPLC)

[0077] The experimental results of the storage stability of Compound A liquid preparation are as Figure 2 shown. The results show that after storage at 2 - 8°C and 25°C for 24 hours, there are no obvious changes in appearance, pH value, insoluble particles, and concentration; There is no obvious increase in total impurities, and the time-variation curve of the total impurity content (RP-HPLC) of the prepared liquid is as Figure 3 shown.

[0078] Example 2 Preparation of Compound A Liquid Preparation by High-Pressure Homogenization Process (High-Pressure Homogenizer)

[0079] In this example, a high-pressure homogenizer of model NATHOX Lab 3 from Nathan Technologies was used to develop a high-pressure homogenization preparation process for Compound A liquid preparation.

[0080] A homogeneous liquid formula was selected: 50.00 mg / mL SBECD (sodium sulfobutyl cyclodextrin), 0.77 mg / mL citric acid, 6.53 mg / mL 1M NaOH, and a feed concentration of 5.26 mg / mL of compound A (batch: PS-12502-105-190002-1).

[0081] The homogenization process adopts the cooling circulating water cooling method to control the homogenization liquid temperature ≤ 50°C; the freshly prepared compound A suspension (150ml) is sampled after a series of homogenization pressures and different homogenization cycles using a high-pressure homogenizer: 5K psi homogenization pressure cycle 3 times, total cycle time 4.5min, 10K psi homogenization pressure cycle 3 times, total cycle time 4.5min, and increase the homogenization pressure to 20K psi homogenization cycle 18 times, total cycle time 27min. After homogenization, some samples are placed at 70°C for 45min. The samples are taken to test the appearance under a clarity detector. The specific high-pressure homogenization process scheme is detailed in Table 3 below.

[0082] Table 3 High-pressure homogenization process (high-pressure homogenizer) for preparing liquid formulations of compound A

[0083]

[0084] X = concentration and related substances (RP-HPLC); Y = temperature; () indicates selected measurement

[0085] " / " means the data does not exist

[0086] The results of the study are summarized in Figure 4 The concentrations of the samples after high-pressure homogenization (homogenization pressure to 20K psi, 18 cycles, 27 min) and after high-pressure homogenization (homogenization pressure to 20K psi, 18 cycles, 27 min) and incubation at 70°C for 45 min were very similar, 5.01 mg / mL and 4.98 mg / mL respectively; however, the results showed that the total impurity content of the former was significantly lower. This shows that in order to ensure that the impurity content of the drug solution is at a low level, the high-temperature heating link should be avoided as much as possible in the liquid preparation process of Compound A.

[0087] Example 3 Preparation of Compound A Solution by High-Pressure Homogenization Process (Microfluidizer) and Evaluation of High-Pressure Homogenization Process

[0088] This example uses the Microfluidics M-110EH microfluidizer to develop a high-pressure homogenization preparation process for the liquid preparation of compound A. The effect of this process on the solubility of compound A is investigated, and the stability of the liquid after homogenization is also investigated. It can also be used to guide and compare the stability differences between the homogenization process and the original liquid preparation (Example 1).

[0089] Select a homogeneous liquid formulation: 50.00 mg / mL SBECD, 0.77 mg / mL citric acid, 6.53 mg / mL 1M NaOH, and a solution of Compound A with a feeding concentration of 10.00 mg / mL (batch: DP3ES001101901).

[0090] High-pressure homogenization process: Use a microfluidizer and a Y-shaped homogenization chamber; control the temperature during homogenization ≤ 50°C; for the freshly prepared suspension of Compound A (150 ml), first homogenize it at 5K psi for 3 cycles with a cycle time of 4.5 min, then at 10K psi for 3 cycles with a cycle time of 4.5 min, and finally increase the homogenization pressure to 20K psi for 24 cycles with a cycle time of 36 min. After filtering the last homogenized liquid using a 0.22 μm filter, place it at 2 - 8°C and under natural light at 25°C for 24H. The specific scheme is shown in Table 4 below.

[0091] Table 4 Study on the effect of high-pressure homogenization process (microfluidizer) on the solubility of Compound A and the storage stability of the homogenized liquid

[0092]

[0093] X = pH, DLS (after filtration), concentration, and related substances (RP-HPLC);

[0094] Y = sample temperature

[0095] The research results are summarized in Figure 5 and Figure 6 . Using a microfluidizer and controlling the microfluidization temperature ≤ 50°C, the feeding concentration of Compound A is increased to 10.00 mg / mL, and the concentration of Compound A continuously increases with the increase of homogenization pressure and the number of homogenization cycles. When the homogenization pressure reaches 20K psi and the number of homogenization cycles is 24 with a cycle time of 36 min, the concentration increases to 9.32 mg / mL; compared with heating at 70°C after high-pressure homogenization, the total impurity content is significantly reduced. During the homogenization process, there is no obvious change in the pH of the selected homogenized sample solution; the results of particle size detection (DLS) show that the homogenized solution of Compound A is a true solution after filtration through a 0.22 μm filter.

[0096] The results of the stability experiment of the homogenized liquid of Compound A show that after filtering the homogenized liquid of Compound A through a 0.22 μm filter, when placed at 5°C under natural light for 24H, there is no obvious change in the concentration and total impurity content; when placed at 25°C under natural light for 24H, there is no obvious change in the concentration and total impurity content.

[0097] In addition, in this example, when the homogenization pressure was 20 K psi and the homogenization cycle was 24 times, the cycle time was 36 min. Compared with the results of the original liquid preparation in Example 1, the total impurities were significantly reduced by 1.03%; when placed under natural light conditions at 25 °C for 24 h, the total impurities were also significantly reduced by 1.51%.

[0098] Example 4 Influence of Microfluidic Homogenization Processes with Different Homogenization Chambers (Y-Type and Z-Type) on the Solubility of Compound A

[0099] In this example, an M-110EH type microfluidic homogenizer from Microfluidics was used, and on this basis, two types of homogenization chambers, Y-type and Z-type, were used; the influence of different homogenization chamber process conditions on the solubility of Compound A was investigated.

[0100] Homogenized liquid formulation: 50.00 mg / mL SBECD, 0.77 mg / mL citric acid, 6.53 mg / mL 1M NaOH, and Compound A with a feeding concentration of 12.00 mg / mL (Batch: D153-2019208-0029-01).

[0101] High-pressure homogenization process: Microfluidic homogenizer; Y-type and Z-type homogenization chambers were used respectively; the temperature was controlled at ≤45 °C during the homogenization process; the freshly prepared suspension of Compound A (150 ml) was homogenized 3 times at a homogenization pressure of 5 K psi, with a cycle time of 4.5 min, homogenized 3 times at a pressure of 20 K psi, and the homogenization pressure was increased to 25 K psi and homogenized 27 times, with a cycle time of 40 min. The specific scheme is shown in Table 5 below.

[0102] Table 5 Influence of Microfluidic Homogenization Processes with Different Homogenization Chambers (Y-Type and Z-Type) on the Solubility of Compound A

[0103]

[0104] X = pH, sample temperature, DLS (after filtration), concentration, and related substances (RP-HPLC);

[0105] The appearance results are as Figure 7 shown. Under the condition of the same feeding concentration of Compound A (12.00 mg / mL) and other unchanged homogenization conditions, when the homogenized liquid reached a relatively clear state: as Figure 8 、 Figure 9 shown, the Z-type homogenization chamber needed to be homogenized to 25K-57 (homogenization pressure (psi) - homogenization cycle (times)), while the Y-type homogenization chamber only needed to be homogenized to 25K-30 (homogenization pressure (psi) - homogenization cycle (times)).

[0106] The influence of different homogenization chambers (Y-type and Z-type) on the solubility of Compound A is as Figure 8 、 Figure 9As shown, compared with the Z-type homogeneous chamber, the concentration of the liquid preparation of Compound A prepared by the microfluidic high-pressure homogenization process using the Y-type homogeneous chamber is significantly higher, and the total impurity content is significantly lower. The results of particle size detection (DLS) show that the homogeneous solutions of Compound A prepared using the two types of homogeneous chambers are true solutions after filtration through a 0.22 μm filter.

[0107] In summary, for Compound A, the microfluidic homogenization process using the Y-type homogeneous chamber has better homogenization effect.

[0108] Solubility of Compound A with Different Particle Sizes after Microfluidic Homogenization in Example 5

[0109] In this example, based on Example 4, a microfluidic homogenizer for Compound A with a Y-type homogeneous chamber was used. The purpose is to illustrate: under the guidance of the optimized homogenization process, the change in the solubility of Compound A with different particle sizes; at the same time, the change in the solubility of Compound A with a particle size of 60.33 μm at two different concentrations after homogenization was investigated.

[0110] Homogeneous liquid formulation: 50.00 mg / mL SBECD, 0.77 mg / mL citric acid, 6.53 mg / mL 1M NaOH, and the feeding concentrations of Compound A with three particle sizes of 31.78 μm, 60.33 μm, and 100.00 μm (batch: Z-D153-20190001-01) are shown in Table 6.

[0111] High-pressure homogenization process: Microfluidics microfluidic homogenizer (model: M-110EH30); during the homogenization process using the Y-type homogeneous chamber, the temperature was controlled at ≤ 45°C; the freshly prepared suspension of Compound A (150 ml) was homogenized and circulated 3 times at a homogenization pressure of 5K psi, with a circulation time of 4.5 min, and then homogenized and circulated 3 times at a homogenization pressure of 10K psi with a circulation time of 4.5 min. After that, the homogenization pressure was increased to 20K psi and homogenized and circulated 35 times with a circulation time of 52 min. The specific scheme is shown in Table 6 below.

[0112] Table 6 Effect of Microfluidic Homogenization Process on Solubility of Compound A with Different Particle Sizes / Concentrations

[0113]

[0114] X = pH, concentration, and related substances (RP-HPLC);

[0115] Y = temperature () indicates selected measurement;

[0116] The effect of the microfluidic homogenization process on the solubility of Compound A with different particle sizes / concentrations is as Figure 10 、 11As shown. On the premise that the microfluidic homogenization process is consistent (i.e., the feeding concentration is 5.30 mg / mL; the homogenization pressure and the number of homogenization cycles are the same; the Y-shaped homogenization chamber is used; the homogenization temperature is controlled ≤ 45°C), the pH of the homogenates of Compound A with three different particle sizes (31.78 μm, 60.33 μm, and 100.00 μm) does not change significantly. After homogenization to 20K - 35 (homogenization pressure (psi) - homogenization cycle (times)) and filtration through a 0.22 μm filter, the concentration of Compound A is 4.55 mg / mL; it shows that different particle sizes in the range of 31 - 100 μm have little difference in the solubility of Compound A. Considering the comprehensive impurity results, the total impurity content of the homogenate of Compound A with a particle size of 60.33 μm is relatively low.

[0117] Select the API with a particle size of 60.33 μm to prepare the liquid preparation of Compound A. By increasing the feeding concentration to 10 mg / mL and using the microfluidic homogenization process (temperature controlled ≤ 45°C), the solubility of Compound A can reach ≥ 5 mg / mL; when using 60.33 μm X, when the feeding concentration is 5.30 mg / mL, homogenized to 20K psi for 35 cycles, and the cycle time is 52 min, the solubility of Compound A is 4.55 mg / mL; when the feeding concentration is 10.00 mg / mL, under the same homogenization conditions, the solubility of Compound A is 8.50 mg / mL.

[0118] The above are only specific application examples of this application and do not constitute any limitation to the protection scope of this application. For those of ordinary skill in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation manners here. All technical solutions formed by equivalent transformation or equivalent substitution that are similar to this kind are within the scope of the protection of the rights of this application.

Claims

1. A process for preparing a liquid preparation of a β-lactamase inhibitor, characterized in that: The invention relates to a liquid preparation of a β-lactamase inhibitor prepared by homogenizing a suspension of the β-lactamase inhibitor under high pressure. The pressure of the high pressure homogenization is 5-20K psi; The high pressure homogenization cycle is 3-35 times; The high-pressure homogenization equipment is a high-pressure homogenizer; Or, when the high-pressure homogenization device is a microfluidizer, the homogenization chamber of the microfluidizer is Y-shaped; The particle size of the β-lactamase inhibitor is 60-100 μm; The β-lactamase inhibitor is a compound as shown in (A), The temperature of the high pressure homogenization is 20-55°C; The suspension also includes 50.00 mg / mL of sodium sulfobutyl cyclodextrin, 0.77 mg / mL of citric acid, and 6.53 mg / mL of NaOH; In the suspension, the content of the β-lactamase inhibitor is less than or equal to 15 mg / mL.

2. The preparation process according to claim 1, characterized in that: It meets one or more of the following conditions: (1) The flow rate of the high pressure homogenization is 50-200 ml / min; (2) The high pressure homogenization cycle is 3 times, 18 times, 24 times, 27 times, 30 times or 35 times.

3. The preparation process according to claim 1, characterized in that: It meets one or more of the following conditions: (1) The flow rate of the high pressure homogenization is 100 ml / min; (2) The pressure of the high-pressure homogenization is 5K psi, 10K psi or 20K psi.

4. The preparation process according to claim 1, characterized in that: It satisfies any one or more of the following: (1) When the pressure of the high-pressure homogenization is 5K psi, the high-pressure homogenization cycle is 3 times; (2) When the pressure of the high-pressure homogenization is 10K psi, the high-pressure homogenization cycle is 3 times; (3) When the pressure of the high-pressure homogenization is 20K psi, the high-pressure homogenization cycle is 3 times or 18 times; (4) When the pressure of the high-pressure homogenization is 20K psi, the high-pressure homogenization cycle is 24 or 35 times; (5) The particle size of the β-lactamase inhibitor is 60.33 μm or 100 μm.

5. The preparation process according to claim 1, characterized in that: It satisfies any of the following: (1) The high-pressure homogenization cycle is 3 cycles of high-pressure homogenization at 5K psi homogenization pressure, 3 cycles of high-pressure homogenization at 10K psi homogenization pressure, and then the homogenization pressure is increased to 20K psi and the high-pressure homogenization is repeated 35 times; (2) The high-pressure homogenization cycle is 3 cycles of high-pressure homogenization at 5K psi homogenization pressure, 3 cycles of high-pressure homogenization at 20K psi pressure, and 27 cycles of high-pressure homogenization at 25K psi pressure; (3) The high-pressure homogenization cycle is 5K psi high-pressure homogenization cycle 3 times, then 10K psi high-pressure homogenization cycle 3 times, and finally the homogenization pressure is increased to 20K psi high-pressure homogenization cycle 24 times; (4) The high-pressure homogenization cycle is 3 cycles at 5K psi homogenization pressure, 3 cycles at 10K psi homogenization pressure, and 18 cycles with the homogenization pressure increased to 20K psi.

6. The preparation process according to claim 1, characterized in that: It meets one or more of the following conditions: (1) The high pressure homogenization time is 4.5-52 minutes; (2) The single time of the high-pressure homogenization cycle is 1.5 min; (3) the pH value of the suspension is 4-5; (4) In the preparation process, the high-pressure homogenization further includes centrifugation and / or filtration.

7. The preparation process according to claim 6, characterized in that: It meets one or more of the following conditions: (1) The high pressure homogenization time is 4.5 min, 27 min, 36 min, 40 min or 52 min; (2) the pH value of the suspension is 4.5 or 4.6; (3) The temperature of the high pressure homogenization is 20°C, 27°C, 30°C, 33°C, 35°C, 38°C, 40°C, 48°C, 50°C or 51°C.

8. The preparation process according to claim 6, characterized in that: In the preparation process, the specification of the filtering filter is 0.22 μm.

9. An application of high pressure homogenization in the preparation of a liquid preparation of a β-lactamase inhibitor, characterized in that: The application conditions are as described in any one of claims 1-8.

10. A β-lactamase inhibitor liquid preparation, characterized in that: The liquid preparation is prepared by the preparation process according to any one of claims 1 to 8.

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