Co-amorphous substance containing LBQ657 as well as preparation method and application of co-amorphous substance

Abstract

The invention relates to the technical field of pharmacy, and provides a co-amorphous substance containing LBQ657 as well as a preparation method and application of the co-amorphous substance containing LBQ657, the co-amorphous substance containing LBQ657 has a single glass transition temperature and comprises an olmesartan medoxomil-LBQ657 co-amorphous substance or an olmesartan-LBQ657 co-amorphous substance; when the co-amorphous substance containing the LBQ657 is an olmesartan medoxomil-LBQ657 co-amorphous substance, the glass transition temperature Tg1 is 65 + / -5 DEG C; and when the co-amorphous substance containing LBQ657 is an olmesartan-LBQ657 co-amorphous substance, the glass transition temperature Tg2 is 80 + / -5 DEG C. According to the technical scheme, the problems of poor solubility, low inherent dissolution rate and insufficient bioavailability of a traditional drug combination scheme in the related technology are solved.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to co-amorphous compounds containing LBQ657, their preparation methods, and applications. Background Technology

[0002] Inappropriate activation of the renin-angiotensin-aldosterone system (RAAS) is one of the pathological mechanisms underlying cardiovascular and metabolic diseases such as hypertension, heart failure, atherosclerosis, and diabetic nephropathy. Angiotensin II receptor antagonists (ARBs) exert potent antihypertensive and target organ protective effects by selectively blocking the binding of angiotensin II to angiotensin receptors (AT1 receptors). Olmesartan and its prodrug olmesartan medoxomil, as a class of ARBs, have a longer half-life and exhibit better effects on arteriosclerosis and myocardial hypertrophy, and are superior to other ARBs.

[0003] Angiotensin receptor-neprilysin inhibitors (ARNIs) simultaneously inhibit neprilysin (NEP) and AT1 receptors. Due to their unique mechanism of action, they have achieved significant efficacy in the treatment of essential hypertension and heart failure, prolonging survival and improving quality of life for heart failure patients. LBQ657, as a key active ingredient in ARNIs that inhibits neprilysin, plays a crucial role in their pharmacological effects.

[0004] As treatment concepts have evolved from single-target blockade to multi-pathway synergistic effects, combination therapy has gained favor among researchers. However, traditional solutions, such as simply physically mixing the active ingredients of two drugs or preparing compound formulations, often suffer from problems such as poor solubility, low inherent dissolution rate, and insufficient bioavailability. Summary of the Invention

[0005] This invention proposes a co-amorphous compound containing LBQ657, its preparation method, and its application, which solves the problems of poor solubility, low inherent dissolution, and insufficient bioavailability in traditional combination drug regimens in related technologies.

[0006] The technical solution of the present invention is as follows: This invention proposes co-amorphous compounds containing LBQ657 with a single glass transition temperature, including olmesartan medoxomil-LBQ657 co-amorphous compounds or olmesartan-LBQ657 co-amorphous compounds. When the co-amorphous compound containing LBQ657 is the olmesartan medoxomil-LBQ657 co-amorphous compound, the glass transition temperature Tg1 is 65±5℃. When the co-amorphous compound containing LBQ657 is the olmesartan-LBQ657 co-amorphous compound, the glass transition temperature Tg2 is 80±5℃.

[0007] As a further technical solution, the co-amorphous material containing LBQ657 exhibits a single hump in the X-ray powder diffraction pattern using Cu-Kα radiation within the range of 2θ values ​​of 5° to 40°.

[0008] The present invention also proposes a method for preparing the co-amorphous compound containing LBQ657, comprising the following steps: adding an angiotensin II receptor antagonist and LBQ657 to a solvent, extracting, removing the solvent, and obtaining the co-amorphous compound containing LBQ657; The angiotensin II receptor antagonists include olmesartan medoxomil or olmesartan.

[0009] As a further technical solution, the molar ratio of the angiotensin II receptor antagonist to LBQ657 is 1:1.

[0010] As a further technical solution, the mass-to-volume ratio of the sum of the angiotensin II receptor antagonist and LBQ657 to the solvent is 5-8 mg:1 mL.

[0011] As a further technical solution, the solvent includes methanol or ethanol.

[0012] As a further technical solution, the extraction is performed using ultrasonic extraction, wherein the ultrasonic extraction frequency is 30~50kHz, the power is 90~110W, and the time is 30~40min.

[0013] As a further technical solution, a rotary evaporation method is used to remove the solvent.

[0014] The present invention also proposes the application of the LBQ657-containing co-amorphous compound or the LBQ657-containing co-amorphous compound prepared by the above preparation method in the preparation of drugs for treating hypertension and / or arteriosclerosis.

[0015] The present invention also provides a pharmaceutical composition comprising the LBQ657-containing co-amorphous compound or the LBQ657-containing co-amorphous compound prepared by the aforementioned preparation method; and Pharmaceutically acceptable carrier.

[0016] As a further technical solution, the daily dosage of the co-amorphous compound containing LBQ657 is 10~1000mg.

[0017] The beneficial effects of this invention are as follows: In this invention, the co-amorphous compound containing LBQ657 exhibits a single glass transition temperature, indicating that olmesartan medoxomil or olmesartan forms an amorphous supramolecular system with LBQ657. The synergistic effect of this supramolecular system at the molecular level results in excellent solubility, inherent dissolution rate, and bioavailability of the co-amorphous compound containing LBQ657. Furthermore, compared to conventional physical mixing or combination therapy, the co-amorphous compound containing LBQ657 can achieve the same therapeutic effect as a combination therapy through single-agent administration. Attached Figure Description

[0018] The present invention will now be described in further detail with reference to the accompanying drawings and specific embodiments.

[0019] Figure 1 X-ray powder diffraction pattern; In the figure: A represents the spectrum of the CO-M group, and B represents the spectrum of the CO-L group; Figure 2 This is a Fourier transform infrared spectrum; In the figure: A represents the spectrum of the CO-M group, and B represents the spectrum of the CO-L group; Figure 3 Raman spectrum; In the figure: A represents the spectrum of the CO-M group, and B represents the spectrum of the CO-L group; Figure 4 This is a temperature-modulated differential scanning calorimetry (DSC) spectrum; In the figure: Tg is the glass transition temperature; Figure 5 A diagram of dynamic characteristic parameters; In the figure: A is the root mean square deviation diagram; B is the radius of gyration diagram; C is the solvent accessible surface area diagram; D is the hydrogen bond quantity diagram; Figure 6 A snapshot of the simulation results for CO-M and CO-L; In the figure: A represents a simulated snapshot of CO-M, and B represents a simulated snapshot of CO-L; Figure 7 Equilibrium solubility diagrams of OM, LBQ657 and CO-M in media with pH=1, pH=4 and pH=6.8; In the figure: A represents the equilibrium solubility diagram of component OM in CO-M group; B represents the equilibrium solubility diagram of component LBQ657 in CO-M group. Figure 8 Equilibrium solubility diagrams of OLM, LBQ657 and CO-L in media with pH=1, pH=4 and pH=6.8; In the figure: A represents the equilibrium solubility diagram of the OLM component in the CO-L group; B represents the equilibrium solubility diagram of the LBQ657 component in the CO-L group. Figure 9 The intrinsic dissolution rates of OM, LBQ657, and CO-M in media at pH=1, pH=4, and pH=6.8 are plotted. In the figure: A represents the inherent dissolution rate of the OM component in the CO-M group; B represents the inherent dissolution rate of the LBQ657 component in the CO-M group. Figure 10 The intrinsic dissolution rates of OLM, LBQ657, and CO-L in media at pH=1, pH=4, and pH=6.8 are plotted. In the figure: A represents the inherent dissolution rate of the OLM component in the CO-L group; B represents the inherent dissolution rate of the LBQ657 component in the CO-L group. Figure 11 The drug concentration-time curves of OM and LBQ657 components in rat plasma are shown. In the figure: A represents the drug concentration-time curve of the OM component in the CO-M group; B represents the drug concentration-time curve of the LBQ657 component in the CO-M group. Figure 12 The drug concentration-time curves of OLM and LBQ657 components in rat plasma are shown. In the figure: A represents the drug concentration-time curve of OLM component in the CO-L group; B represents the drug concentration-time curve of LBQ657 component in the CO-L group. Figure 13 The drug concentration-time curves of OM and LBQ657 components in beagle plasma are shown. In the figure: A represents the drug concentration-time curve of the OM component in the CO-M group; B represents the drug concentration-time curve of the LBQ657 component in the CO-M group. Figure 14 The drug concentration-time curves of OLM and LBQ657 components in beagle plasma are shown. In the figure: A represents the drug concentration-time curve of OLM component in the CO-L group; B represents the drug concentration-time curve of LBQ657 component in the CO-L group. Detailed Implementation

[0020] To enable those skilled in the art to better understand the technical solutions in the embodiments of the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. All other embodiments obtained by those skilled in the art based on the embodiments in the specific embodiments of the present invention should fall within the protection scope of the embodiments of the present invention.

[0021] It should be understood that, unless the context clearly indicates otherwise, the terms "comprising," "including," or "having" as used herein refer to the presence of a particular element, but do not exclude the presence or addition of one or more other elements. Furthermore, "comprising" and / or "including" as used herein specify the presence of shapes, numbers, steps, operations, members, elements, and / or combinations thereof, and do not exclude the presence or addition of one or more other shapes, numbers, operations, elements, and / or combinations thereof. Some embodiments of the present invention are described in detail below with reference to the accompanying drawings. Where there is no conflict between the embodiments, the following embodiments and features described therein can be combined with each other. The steps in the following method embodiments are for illustrative purposes only and are not intended to limit the present invention.

[0022] In this invention, the numerical range indicated by "~" refers to the range of values ​​specified as the lower and upper limits, respectively, before or after the term. When multiple values ​​for the upper or lower limit of any numerical range are mentioned, the range disclosed herein can be understood as a range with any one of the mentioned upper limits as its upper limit and any one of the mentioned lower limits as its lower limit.

[0023] Olmesartan medoxomil and olmesartan, as angiotensin II receptor antagonists, can produce a synergistic effect when used in combination with LBQ657 in diseases such as hypertension and heart failure. However, traditional combination therapy methods, such as simply physically mixing the two active ingredients or preparing compound formulations, often suffer from problems such as poor solubility, low inherent dissolution rate, and insufficient bioavailability.

[0024] Supramolecular technology combines two or more components through intermolecular forces (such as hydrogen bonding, electrostatic interactions, hydrophobic interactions, and π-π stacking) to form supramolecular systems with specific structures and functions. Supramolecular technology can improve the undesirable physicochemical properties of each component, achieving synergistic effects at the molecular level.

[0025] Based on this, the present invention combines supramolecular technology with combination drug therapy to construct two dual-target supramolecular systems: olmesartan medoxomil-LBQ657 co-amorphous compound and olmesartan-LBQ657 co-amorphous compound. The aim is to develop a drug delivery system that can achieve the purpose of combination drug therapy by improving the solubility, inherent dissolution and bioavailability of the drug.

[0026] To make the objectives, technical solutions, and advantages of the present invention clearer, the following will describe the co-amorphous compound containing LBQ657, its preparation method, and its application through specific embodiments.

[0027] According to a first aspect of the present invention, the present invention provides co-amorphous compounds containing LBQ657, including olmesartan medoxomil-LBQ657 co-amorphous compounds or olmesartan-LBQ657 co-amorphous compounds.

[0028] This invention utilizes supramolecular technology to construct two LBQ657-containing co-amorphous compounds through hydrogen bonds formed between the C=O groups in the olmesartan ester or olmesartan structure and the OH groups in the LBQ657 structure. The LBQ657-containing co-amorphous compounds have an amorphous crystal structure, composed of randomly arranged molecules, and lack a unique crystal lattice. The co-amorphous compounds containing LBQ657 exhibit the following characteristics: (1) They have a single glass transition temperature; the crystallization diffraction peaks disappear, there are no sharp characteristic peaks, and only a single hump is displayed; (2) Hydrogen bonding exists, that is, the stretching vibrations of the C=O groups in the olmesartan medoxomil or olmesartan structures of the co-amorphous compounds shift to a higher field, and the stretching vibrations of the OH groups in the LBQ657 structure shift to a higher field; (3) Compared with olmesartan medoxomil, olmesartan, or LBQ657 standards, the intensity, width, and position of the Raman peaks of the co-amorphous compounds containing LBQ657 change, with CO-M values ​​ranging from 555 to 905 cm⁻¹. 1 The Raman peak widens within the range, and reaches 1710cm. 1 The Raman peak disappears at this location, and the CO-L value is between 522 and 950 cm. 1 1337~1550cm 1 The Raman peaks decrease and broaden within the range of 2900~3100 cm⁻¹. -1 The Raman peaks at the specified locations broaden significantly. This indicates that olmesartan medoxomil or olmesartan forms a co-amorphous compound with LBQ657. The glass transition temperature can be characterized by differential scanning calorimetry (DSC) or temperature-modulated differential scanning calorimetry (TMDC); the crystallization diffraction peaks can be characterized by X-ray powder diffraction; the hydrogen bonds can be characterized by Fourier transform infrared spectroscopy; and the Raman peaks can be characterized by Raman spectroscopy.

[0029] In one embodiment of the present invention, the LBQ657-containing amorphous compound has a single glass transition temperature. When the LBQ657-containing amorphous compound is an olmesartan medoxomil-LBQ657 amorphous compound, the glass transition temperature Tg1 is 65±5℃; when the LBQ657-containing amorphous compound is an olmesartan-LBQ657 amorphous compound, the glass transition temperature Tg2 is 80±5℃. Considering that fluctuations in the accuracy of the testing instrument or the testing environment may cause the measurement results to deviate from the true value during glass transition temperature testing, the allowable error for glass transition temperature testing is generally ±5℃.

[0030] In one embodiment of the present invention, the X-ray powder diffraction pattern of the LBQ657-containing amorphous compound under Cu-Kα radiation exhibits a single hump within the 2θ range of 5° to 40°. The hump, also known as a "steamer peak," is a characteristic feature of X-ray powder diffraction patterns known in the art, where the diffraction intensity exhibits a continuous distribution resembling a camel hump, without sharp crystalline diffraction peaks. This diffraction phenomenon indicates that the LBQ657-containing amorphous compound possesses amorphous structural characteristics.

[0031] According to a second aspect of the present invention, the present invention also provides a method for preparing the above-mentioned co-amorphous compound containing LBQ657, comprising the following steps: adding an angiotensin II receptor antagonist and LBQ657 to a solvent, extracting, removing the solvent, and obtaining a co-amorphous compound containing LBQ657; the angiotensin II receptor antagonist includes olmesartan medoxomil or olmesartan.

[0032] In this invention, the molar ratio of angiotensin II receptor antagonist to LBQ657 is 1:1. The mass-to-volume ratio of the sum of the mass of angiotensin II receptor antagonist and LBQ657 to the solvent is 5-8 mg:1 mL, for example, including but not limited to 5 mg:1 mL, 6 mg:1 mL, 7 mg:1 mL, and 8 mg:1 mL. Within this range, the angiotensin II receptor antagonist and LBQ657 can be fully dissolved in the solvent, which is beneficial for the formation of a co-amorphous compound containing LBQ657. To ensure a fast evaporation rate and low solvent residue, the solvent can be selected from methanol or ethanol, preferably methanol. To improve the extraction effect, ultrasonic extraction can be used, with an ultrasonic frequency of 30-50 kHz, an ultrasonic power of 90-110 W, and an extraction time of 30-40 min. On the one hand, in order to accelerate solvent evaporation, remove solvent efficiently and quickly, and improve preparation efficiency; on the other hand, in order to avoid the instability of the co-amorphous structure containing LBQ657 due to high-temperature evaporation, the solvent is removed by rotary evaporation, and the preferred temperature for rotary evaporation is 36~40℃.

[0033] According to a third aspect of the present invention, the present invention also proposes the use of the above-described LBQ657-containing co-amorphous compound or the LBQ657-containing co-amorphous compound prepared by the above-described preparation method in the preparation of medicaments for treating hypertension and / or arteriosclerosis.

[0034] According to a fourth aspect of the invention, the invention also provides a pharmaceutical composition comprising the above-described co-amorphous compound containing LBQ657 and a pharmaceutically acceptable carrier.

[0035] In this invention, the pharmaceutical composition can be prepared according to methods known in the art. For example, it can be formulated into any dosage form suitable for human or animal use by combining the LBQ657-containing amorphous compound of this invention with one or more pharmaceutically acceptable solid or liquid excipients and / or adjuvants. The content of the LBQ657-containing amorphous compound of this invention in its pharmaceutical composition is typically 0.1 to 95 wt%. The pharmaceutical composition of this invention can be administered in unit dose form via enteral or non-enteric routes, such as oral, intravenous, intramuscular, or subcutaneous injection. The preferred dosage form is a solid dosage form. Solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, etc.), capsules (including hard capsules, soft capsules, enteric-coated capsules, etc.), granules, powders, microcapsules, drops, suppositories, films, patches, aerosols, and sprays, etc. When preparing tablets, various excipients known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, and flow aids. Diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, dicalcium phosphate, calcium carbonate, etc.; humectants can be water, ethanol, isopropanol, etc.; binders can be starch paste, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, gum arabic paste, gelatin paste, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; disintegrants can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, croscarmellose, croscarmellose sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, etc.; lubricants and flow aids can be talc, silica, stearates, tartaric acid, liquid paraffin, polyethylene glycol, etc. In addition, colorants, preservatives, flavorings, tasters, or other additives can be added to pharmaceutical preparations if necessary.

[0036] In this invention, the dosage of the pharmaceutical composition containing LBQ657 coamorphous material can vary widely depending on the nature and severity of the disease to be prevented or treated, the individual circumstances of the patient or animal, the route of administration, and the dosage form. The dosage can be administered as a single unit or divided into several units; generally, the daily dose, based on the LBQ657 coamorphous material, can be 10-1000 mg.

[0037] The present invention will now be described in detail with reference to examples. The embodiments of the invention described below can be modified in various ways, and therefore the scope of the invention should not be construed as limited to the embodiments described in detail below. Examples are provided to help those skilled in the art to more readily understand the invention.

[0038] In the following examples, olmesartan medoxomil, olmesartan, and LBQ657 were all from Aladdin Chemical Co., Ltd.

[0039] Example 1 The preparation method of olmesartan medoxomil-LBQ657 co-amorphous compound includes the following steps: 50.00 mg of a physical mixture containing olmesartan medoxomil (OM) and LBQ657 (molar ratio of 1:1) is placed in a 100 mL round-bottom flask, 10 mL of methanol is added, and the mixture is ultrasonically extracted at room temperature at a frequency of 50 kHz and a power of 110 W for 30 min to completely dissolve the medoxomil. The solvent is evaporated by rotating at 40 °C for 20 min (rotation speed of 50 rpm), and the mixture is dried under vacuum to obtain the olmesartan medoxomil-LBQ657 co-amorphous compound.

[0040] Example 2 The preparation method of olmesartan-LBQ657 co-amorphous compound includes the following steps: 80.00 mg of a physical mixture containing olmesartan (OLM) and LBQ657 (molar ratio of 1:1) is placed in a 100 mL round-bottom flask, 10 mL of methanol is added, and ultrasonic extraction is performed at room temperature at a frequency of 30 kHz and a power of 90 W for 40 min to completely dissolve the compound. The solvent is evaporated by rotating at 40 °C for 20 min (rotation speed of 50 rpm), and the compound is dried under vacuum to obtain olmesartan-LBQ657 co-amorphous compound.

[0041] Unless otherwise specified, in the following experimental examples: OM represents olmesartan medoxomil; OLM represents olmesartan; CO-M represents the olmesartan medoxomil-LBQ657 co-amorphous compound prepared in Example 1; CO-L represents the olmesartan-LBQ657 co-amorphous compound prepared in Example 2; PM represents physical mixture.

[0042] Experimental Example 1: Structural Characterization (1) X-ray powder diffraction detection OM, OLM, LBQ657, CO-M, and CO-L were placed on the stage, and the X-ray powder diffraction patterns of their respective samples were measured. The scanning range was 5° to 40° (2θ), the step size was 0.02°, and the scanning speed was 10° / min.

[0043] X-ray powder diffraction pattern as follows Figure 1 As shown in the figure, OM and LBQ657 have obvious characteristic diffraction peaks, while the X-ray powder diffraction pattern of CO-M only shows a single hump without sharp characteristic peaks, and the crystalline diffraction peaks disappear, preliminarily indicating the formation of a co-amorphous state; OLM and LBQ657 have obvious characteristic diffraction peaks, while the X-ray powder diffraction pattern of CO-L only shows a single hump without sharp characteristic peaks, and the crystalline diffraction peaks disappear, preliminarily indicating the formation of a co-amorphous state.

[0044] (2) Fourier transform infrared spectroscopy detection Fourier transform infrared (FTIR) spectra of OM, OLM, LBQ657, CO-M, and CO-L were measured using the KBr pellet method on a Fourier transform infrared spectrometer. A blank KBr pellet was used as a reference during the test, with a resolution of 4 cm⁻¹. -1 Scanning range 4000~400cm -1 The total number of scans is 40, and the signals are accumulated and averaged.

[0045] Fourier transform infrared spectrum as follows Figure 2 As shown in the figure, the stretching vibration of the C=O group in the CO-M structure attributed to olmesartan medoxomil changes from 1706 cm⁻¹. -1 Moved to 1718cm -1 Shifting to higher fields; the stretching vibration of the OH group in the LBQ657 structure shifts from 3329 cm⁻¹ -1 The shift to a higher field indicates that the C=O group in the olmesartan medoxomil structure of CO-M and the OH group in the LBQ657 structure participate in hydrogen bond formation. The stretching vibration attributable to the C=O group in the olmesartan structure in CO-L shifts from 1637 cm⁻¹ to 1637 cm⁻¹. -1 Moved to 1716cm -1 The stretching vibrations of the OH groups in the LBQ657 structure shift to higher fields, moving from 3328 cm⁻¹. -1 The shift towards a higher field indicates that the C=O group in the olmesartan structure of CO-L and the OH group in the LBQ657 structure participate in the formation of hydrogen bonds.

[0046] (3) Raman spectroscopy detection OM, OLM, LBQ657, CO-M, and CO-L were measured using a Raman imaging spectrometer in the range of 3500–400 cm⁻¹. -1 Raman spectra within the range. Excitation wavelength was 638 nm; RTD time was 1 s, and the scans were performed three times and averaged.

[0047] Raman spectra as follows Figure 3 As shown in the figure, compared with the Raman spectra of OM, OLM, and LBQ657, the Raman peak intensity, width, and position of CO-M and CO-L have changed: CO-M is in the range of 555~905 cm⁻¹. 1 The Raman peak widens within the range, and reaches 1710cm. 1 The Raman peak disappears at 522-950 cm; CO-L is between 522 and 950 cm. 1 1337~1550cm 1The Raman peaks decreased and broadened within the range of CO-M and CO-L Raman spectra; and the 2900~3100 cm⁻¹ peaks were also wider. -1 The Raman peaks at the point of origin show a significant broadening, indicating the formation of a disordered structure.

[0048] (4) Temperature-modulated differential scanning calorimetry detection 4 mg each of CO-M and CO-L were accurately weighed into aluminum crucibles. Using an empty crucible as a reference, the temperature-modulated differential scanning calorimetry (DSC) spectra of each sample were measured. The parameters were: temperature: 0–250 °C; heating rate: 2.000 K / min; period: 60 seconds; amplitude: 0.5 K.

[0049] Temperature-modulated differential scanning calorimetry (DSC) spectra are as follows: Figure 4 As shown in the figure, both the reversible heat flow signal curves of CO-M and CO-L exhibit an endothermic step and a single glass transition temperature Tg, proving the formation of amorphous states in both systems.

[0050] Experimental Example 2: Molecular Dynamics Simulation The molecular dynamics simulation system was constructed in a closed environment with a system temperature set at 300K and all system pressures maintained at standard atmospheric pressure (1 bar). Periodic boundary conditions were set centered on the target structure, and the minimum distance between the structure edge and the simulation box edge was controlled to 1.0 nm. AMBEff14SB was used as the ionic force field parameter; ligand atoms OM, OLM, and LBQ657 were parameterized using the GAFF force field; the water molecule model used was the TIP3P model. After the initial simulation system was built, the steepest descent algorithm was used to minimize the energy of all atoms to eliminate unreasonable atomic spatial arrangements within the system. Subsequently, under the constrained system position, two equilibrium simulations were performed sequentially: first, a 1000 ps NVT (constant number-volume-temperature) equilibrium simulation, followed by a 1000 ps NPT (constant number-pressure-temperature) equilibrium simulation. After completing the NVT and NPT equilibrium simulations, a 100 ns final dynamics simulation was performed on the system with a simulation step size of 2 fs. During the simulation, a linear constraint algorithm was used to limit the covalent bond length, while long-range electrostatic interactions were calculated using the particle mesh Ewald method. After all simulations were completed, the kinetic characteristic parameters of the system, such as radius of gyration (RG), root mean square deviation (RMSD), solvent accessible surface area (SASA), and number of hydrogen bonds (H-Bond Number), were analyzed and calculated.

[0051] Dynamic characteristic parameter diagram as follows Figure 5As shown in the figure, through RMSD and RG analysis of the structure, both CO-M and CO-L converged after 40 ns of simulation, and RG converged to around 1.15 nm. The low RMSD and RG values ​​demonstrate the structural stability of the two co-amorphous systems. Analysis of the changes in SASA and hydrogen bond numbers shows that, as the simulation progresses, the area exposed to the solvent for both systems converges to around 45 nm. 2 Nearby, the hydrogen bonds of the two co-amorphous systems also converged after 40 ns, with CO-L converging to around 15 bonds and CO-M converging to around 10 bonds, proving the stability of the two co-amorphous systems.

[0052] Simulation snapshots of CO-M and CO-L are shown below. Figure 6 As shown, it can be seen that the overall clusters actually begin to form at 20 ns, and the overall clusters are basically formed at 40 ns.

[0053] Experimental Example 3: Solubility Determination The equilibrium solubility of CO-M and CO-L in hydrochloric acid solution (pH=1), acetate buffer (pH=4), and phosphate buffer (pH=6.8) was determined using the shake-flask method. Excess sample was added to each shake flask containing 10 mL of the aforementioned medium, and the flasks were placed on an air bath shaker at a constant temperature of 37°C and a rotation speed of 150 rpm. -1 Shake until the concentrations of olmesartan or olmesartan medoxomil and LBQ657 in the solution no longer change; this is considered a saturated solution. After equilibration for 72 hours, the suspension is drawn up with a disposable syringe and filtered through a 0.22 μm microporous membrane. The equilibrium solubility of OM, OLM, LBQ657, CO-M, and CO-L is determined by high performance liquid chromatography. All experiments are performed in triplicate.

[0054] The equilibrium solubility diagrams of OM, LBQ657, and CO-M in hydrochloric acid solution at pH 1, acetate buffer at pH 4, and phosphate buffer at pH 6.8 are shown below. Figure 7 As shown, the equilibrium solubility of the OM component and LBQ657 component of CO-M in phosphate buffer at pH 6.8 is approximately 4.07 times and 2.40 times that of the physical mixture, respectively. This indicates that the solubility of the co-amorphous component is significantly better than that of the physical mixture.

[0055] The equilibrium solubility diagrams of OLM, LBQ657, and CO-L in hydrochloric acid solution at pH 1, acetate buffer at pH 4, and phosphate buffer at pH 6.8 are shown below. Figure 8As shown, the equilibrium solubility of the OLM component of CO-L in phosphate buffer at pH 6.8 is approximately 1.44 times that of the physical mixture; and the equilibrium solubility of the LBQ657 component of CO-L in acetate buffer at pH 4 is approximately 1.32 times that of the physical mixture. This indicates that the solubility of the co-amorphous component is significantly better than that of the physical mixture.

[0056] Experimental Example 4: Determination of Inherent Dissolution Accurately weigh OM, LBQ657, PM (a physical mixture of OM and LBQ657), and CO-M samples (where PM and CO-M are each equivalent to 55.8 mg OM and 38.3 mg LBQ657, and each contains 10 mg hydroxypropyl methylcellulose as a binder); accurately weigh OLM, LBQ657, PM (a physical mixture of OLM and LBQ657), and CO-L samples (where PM and CO-L are each equivalent to 44.6 mg OLM and 38.3 mg LBQ657, and each contains 10 mg hydroxypropyl methylcellulose as a binder). Compress the drug powder into tablets at 180 kg pressure for 2 min. Connect the tableted drug, along with the mold, to the lower end of the rotating shaft, ensuring that only one side of the tablet is in contact with the dissolution medium. Determine the inherent dissolution rate of the drug using a rotary dissolution apparatus. The rotating shaft speed is 50 r / min, and the temperature is 37 °C. Hydrochloric acid solution (pH=1), acetate buffer (pH=4), and phosphate buffer (pH=6.8) were used as dissolution media. At 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, and 60 min, 2 mL of sample solution was collected and replenished immediately with an equal volume of dissolution media at the same temperature. The samples were filtered through a 0.22 μm microporous membrane, appropriately diluted, and their concentrations were determined by high-performance liquid chromatography (HPLC). All experiments were performed in triplicate. The drug concentrations at different time points were calculated, and their intrinsic dissolution rate (IDR) was calculated. IDR is the slope of the OM / LBQ657 content per unit area versus time curve.

[0057] The inherent solubility of OM, LBQ657 and CO-M in the above-mentioned media at pH=1, pH=4 and pH=6.8 is as follows: Figure 9 According to Table 1, in hydrochloric acid solution medium at pH=1, the IDR value of the OM component in CO-M is approximately 69.5 times and 71.5 times that of OM and the physical mixture, respectively. In acetate buffer medium at pH=4, the IDR value of the LBQ657 component in CO-M is approximately 3.18 times and 1.89 times that of LBQ657 and the physical mixture, respectively. This indicates that the inherent dissolution rate of the co-amorphous component is better than that of the physical mixture.

[0058] Table 1 IDR values of the CO-M group in different pH buffers (μg / mol / cm 2 / min)

[0059] PM-OM is the intrinsic dissolution rate of the OM component of PM (physical mixture of OM and LBQ657); CO-M-OM is the intrinsic dissolution rate of the OM component of CO-M; PM-LBQ657 is the intrinsic dissolution rate of the LBQ657 component of PM (physical mixture of OM and LBQ657); CO-M-LBQ657 is the intrinsic dissolution rate of the LBQ657 component of CO-M.

[0060] The intrinsic dissolution rates of OLM, LBQ657, and CO-L in the above media with pH = 1, pH = 4, and pH = 6.8 are as Figure 10 shown in Table 2. In the acetic acid buffer medium with pH = 4, the IDR values of the OLM component in CO-L are approximately 2.25 times and 3.40 times the IDR values of OLM and the physical mixture, respectively. In the acetic acid buffer medium with pH = 4, the IDR values of the LBQ657 component in CO-L are approximately 6.52 times and 6.56 times the IDR values of LBQ657 and the physical mixture, respectively. This indicates that the intrinsic dissolution rate of the co-amorphous form is better than that of the physical mixture.

[0061] Table 2 IDR values of the CO-L group in different pH buffers (mg / cm 2 / min)

[0062] PM-OLM is the intrinsic dissolution rate of the OLM component of PM (physical mixture of OLM and LBQ657); CO-L-OLM is the intrinsic dissolution rate of the OLM component of CO-L; PM-LBQ657 is the intrinsic dissolution rate of the LBQ657 component of PM (physical mixture of OLM and LBQ657); CO-L-LBQ657 is the intrinsic dissolution rate of the LBQ657 component of CO-L.

[0063] Experimental Example 5 Pharmacokinetic Determination of CO-M and CO-L (1) Pharmacokinetic Determination of CO-M and CO-L in Rats Forty-eight male SD rats weighing 250 ± 25 g were selected as test animals (Hebei Experimental Animal Center, SPF, license number: SCXK (Hebei) 2023-008). They were fasted from 12 h before the experiment until the end of the experiment and had free access to water. All animal facilities complied with the requirements of the International Association for Assessment and Accreditation of Laboratory Animal Care. The feeding environment for the experimental animals was: temperature 22~24°C, relative humidity 50 ± 5%, 12 h of light followed by 12 h of darkness.

[0064] Twenty-four SD rats were randomly divided into four groups of six each. Each group was orally administered OM, LBQ657, PM (a physical mixture of OM and LBQ657), and CO-M, respectively, and housed in an environment with a temperature of 22–24℃ and a relative humidity of 50±5%. Before the experiment, the rats were weighed and the dosage was calculated (equivalent to OM 55.8 mg / kg and LBQ657 38.3 mg / kg). The rats were fasted for 12 hours prior to administration, but had free access to water. A single gavage administration was performed, and 0.3 mL of blood was collected from the orbital sinus at 5 min, 10 min, 15 min, 30 min, 45 min, 1 h, 1.5 h, 2 h, 3 h, 5 h, 8 h, 12 h, and 24 h. The blood samples were collected in anticoagulant tubes containing dried heparin and centrifuged at 3500 rpm for 10 min at 4℃. The plasma supernatant was collected and stored at -20℃. After processing, 10 μL of the supernatant was accurately injected into the liquid chromatograph, and the chromatogram was recorded. Plot a drug concentration-time curve with blood collection time on the x-axis and the concentrations of OM and LBQ657 components in the plasma sample on the y-axis, and calculate the AUC. 0-t C max t 1 / 2 and T max Pharmacokinetic parameters were determined and statistical analysis was performed. The final results were set at a significance level of 0.05, and a p-value < 0.05 was considered statistically significant.

[0065] The drug concentration-time curves of the OM and LBQ657 components in rat plasma are shown below. Figure 11 As shown. AUC 0-t C max t 1 / 2 and T max As shown in Tables 3 and 4. For the OM component, compared to PM and OM, t 1 / 2 The half-life was advanced by approximately 3.24 hours and 1.57 hours, respectively, and the C of CO-M... max It is approximately 1.78 times and 2.09 times that of PM and OM, respectively, and the AUC of CO-M 0-t The bioavailability of CO-M was approximately 1.32 times that of PM and 1.72 times that of OM, respectively. This indicates that CO-M has higher bioavailability compared to OM alone or the physical blend of both, PM. For the LBQ657 component, CO-M, compared to PM and LBQ657, showed significantly higher bioavailability. 1 / 2 The half-life was advanced by approximately 3.20 hours and 6.33 hours, respectively, and the C of CO-M... max It is approximately 1.57 times and 1.53 times that of PM and LBQ657, respectively, with an AUC of 0-t The improvement was not significant. The results indicate that preparing LBQ657 into a co-amorphous form reduced the drug's half-life in vivo and improved its bioavailability.

[0066] Table 3. Mean pharmacokinetic parameters of OM components in rats after CO-M administration (n=6, ±sd)

[0067] In Table 3, * This indicates p < 0.05 (vs. OM). ** This indicates p < 0.01 (vs. OM). # This indicates that p < 0.05 (vs. PM).

[0068] Table 4. Mean pharmacokinetic parameters of LBQ657 component in rats after CO-M group administration (n=6, ±sd)

[0069] In Table 4, * This indicates that p < 0.05 (vs. LBQ657).

[0070] Twenty-four SD rats were randomly divided into four groups of six each. Each group was orally administered OLM, LBQ657, PM (a physical blend of OLM and LBQ657), and CO-L, respectively. The rats were housed in an environment with a temperature of 22–24°C and a relative humidity of 50 ± 5%. Before the experiment, the rats were weighed and the dosage was calculated (equivalent to 44.6 mg / kg OLM and 38.3 mg / kg LBQ657). The rats were fasted for 12 hours prior to administration, but had free access to water. A single gavage administration was performed. At 5 min, 10 min, 15 min, 30 min, 45 min, 1 h, 1.5 h, 2 h, 3 h, 5 h, 8 h, 12 h, and 24 h, 0.3 mL of blood was collected from the orbital sinus into anticoagulant tubes containing dried heparin. The tubes were centrifuged at 3500 rpm for 10 min at 4°C, and the plasma supernatant was stored at -20°C. After processing, 10 μL of the supernatant from the plasma sample was precisely measured and injected into the liquid chromatograph, and the chromatogram was recorded. A drug concentration-time curve was plotted with blood collection time on the x-axis and the concentrations of the OLM and LBQ657 components in the plasma sample on the y-axis, and the AUC was calculated. 0-t C max t 1 / 2 and T max Pharmacokinetic parameters were determined and statistical analysis was performed. The final results were set at a significance level of 0.05, and a p-value < 0.05 was considered statistically significant.

[0071] The drug concentration-time curves of OLM and LBQ657 components in rat plasma are shown below. Figure 12 As shown. AUC 0-t C max t 1 / 2 and T maxAs shown in Tables 5 and 6. For the OLM component, the C of CO-L max The AUC of CO-L is approximately 2.08 times that of PM and 2.58 times that of OLM, respectively. 0-t The CO-L concentrations were approximately 2.68 times and 4.57 times higher than those of PM and OLM, respectively. These results indicate that CO-L has higher bioavailability compared to OLM alone or the physical blend of both, PM. For the LBQ657 component, CO-L, compared to PM and LBQ657, showed significantly higher bioavailability. 1 / 2 The half-life was advanced by approximately 3.02 hours and 9.82 hours, respectively, and the C of CO-L... max It is approximately 1.46 times and 2.11 times that of PM and LBQ657, respectively, with CO-L AUC 0-t These figures are approximately 1.50 times and 1.68 times that of PM and LBQ657, respectively. The results indicate that preparing LBQ657 into a co-amorphous form reduces the drug's half-life in vivo and improves its bioavailability.

[0072] Table 5. Mean pharmacokinetic parameters of OLM components in rats after CO-L administration (n=6, ±sd)

[0073] In Table 5, * This indicates p < 0.05 (vs. OLM). ** This indicates p < 0.01 (vs. OLM). # This indicates p < 0.05 (vs. PM). ## This indicates that p < 0.01 (vs. PM).

[0074] Table 6. Mean pharmacokinetic parameters of LBQ657 component in rats after CO-L administration (n=6, ±sd)

[0075] In Table 6, * This indicates p < 0.05 (vs. LBQ657). ** This indicates that p < 0.01 (vs. LBQ657). # This indicates that p < 0.05 (vs. PM).

[0076] (2) Pharmacokinetic determination of CO-M and CO-L in beagle dogs Beagle dogs, ordinary grade, male, 8 in number, aged between 10 and 11 months, with a body weight of about 10 kg (purchased from Beijing Keyu Animal Breeding Center Co., Ltd., animal license number: SCXK (Lu) 2023 0008). In this experiment, a four-formulation four-cycle crossover experimental design was adopted. The 8 Beagle dogs were randomly divided into 4 groups, with 2 dogs in each group. They took the formulations in a crossover manner in 4 cycles, and each Beagle dog received 4 different drug treatments in sequence. The washout period was 7 days.

[0077] The 8 Beagle dogs were fasted overnight for 12 h before the experiment. The four groups of Beagle dogs were respectively intragastrically administered OM, LBQ657, PM (physical blend of OM and LBQ657), and CO-M capsules (equivalent to 13.4 mg / kg of OM and 11.5 mg / kg of LBQ657) on an empty stomach with 20 mL of water in the early morning of the next day. After taking the medicine, the Beagle dogs' mouths were checked to confirm that the test drugs were completely swallowed. About 1 mL of blood was taken from the hind limb vein at 0.25 h, 0.5 h, 0.75 h, 1 h, 1.5 h, 2 h, 3 h, 5 h, 8 h, and 12 h after drug administration. The washout period was 7 days, and then the four groups of Beagle dogs exchanged the drugs they took, and the above research steps were repeated.

[0078] The venous blood of the Beagle dogs collected was placed in an anticoagulant tube containing dry heparin, centrifuged at 3500 rpm for 10 min at 4 °C, and the plasma supernatant was stored at -20 °C. After the plasma samples were processed, 10 μL of the supernatant was precisely measured and injected into the liquid chromatograph, and the chromatogram was recorded. Taking the blood sampling time as the abscissa and the concentrations of the OM component and LBQ657 component in the plasma samples as the ordinate, the drug concentration-time curve was plotted, and the AUC 0-t , C max , t 1 / 2 and T max and other pharmacokinetic parameters were calculated and statistically analyzed. The final results were based on a test level of 0.05, and when p < 0.05, it was considered that there was a statistical difference.

[0079] The drug concentration-time curves of the OM component and LBQ657 component in the plasma of the Beagle dogs measured are as Figure 13 shown. The AUC 0-t , C max , t 1 / 2 and T max are shown in Table 7 and Table 8. For the OM component, the C max of CO-M was about 1.30 times and 1.54 times that of PM and OM respectively, and the AUC 0-t of CO-M was about 1.62 times and 1.85 times that of PM and OM respectively. The results showed that CO-M had a higher bioavailability compared with the single drug OM or the physical blend PM of the two. For the LBQ657 component, compared with PM and LBQ657, the t 1 / 2The half-life was advanced by approximately 0.92 hours and 1.31 hours, T max The time to peak concentration was advanced by approximately 1.03 h and 0.65 h, respectively. These results indicate that preparing LBQ657 into a co-amorphous form reduces both the drug's half-life and time to peak concentration in vivo.

[0080] Table 7. Mean pharmacokinetic parameters of OM component in beagle dogs after CO-M group administration (n=8, ±sd)

[0081] In Table 7, * This indicates p < 0.05 (vs. OM). ** This indicates p < 0.01 (vs. OM). *** This indicates that p < 0.001 (vs. OM). # This indicates p < 0.05 (vs. PM). ## This indicates that p < 0.01 (vs. PM). ### This indicates that p < 0.001 (vs. PM).

[0082] Table 8. Mean pharmacokinetic parameters of LBQ657 in beagle dogs after CO-M group administration (n=8, ±sd)

[0083] In Table 8, * This indicates p < 0.05 (vs. LBQ657). # This indicates p < 0.05 (vs. PM). ## This indicates that p < 0.01 (vs. PM).

[0084] Eight beagle dogs were fasted overnight for 12 hours before the experiment. The following morning, the four groups of beagle dogs were administered OLM, LBQ657, PM (a physical blend of OLM and LBQ657), and CO-L capsules (equivalent to 13.4 mg / kg OLM and 11.5 mg / kg LBQ657) via gavage with 20 mL of water on an empty stomach. After administration, the dogs' mouths were examined to confirm complete swallowing of the test drugs. Approximately 1 mL of blood was collected from the hind limb vein at 0.25 h, 0.5 h, 0.75 h, 1 h, 1.5 h, 2 h, 3 h, 5 h, 8 h, and 12 h after administration. A 7-day washout period was maintained, after which the four groups of beagle dogs were rotated through drug administration, and the above research procedures were repeated.

[0085] The collected beagle dog venous blood was placed in anticoagulant tubes containing dried heparin and centrifuged at 3500 rpm for 10 min at 4°C. The plasma supernatant was then stored at -20°C. After processing, 10 μL of the supernatant was precisely measured and injected into the liquid chromatograph, and the chromatogram was recorded. A drug concentration-time curve was plotted with blood collection time on the x-axis and the concentrations of OLM and LBQ657 components in the plasma sample on the y-axis, and the AUC was calculated. 0-t C max t 1 / 2 and T max Pharmacokinetic parameters were determined and statistical analysis was performed. The final results were set at a significance level of 0.05, and a p-value < 0.05 was considered statistically significant.

[0086] The drug concentration-time curves of the OLM and LBQ657 components in beagle plasma were measured as follows: Figure 14 As shown. AUC 0-t C max t 1 / 2 and T max As shown in Tables 9 and 10. For the OLM component, the C of CO-L max The AUC of CO-L is approximately 1.85 times that of PM and 2.00 times that of OLM, respectively. 0-t The results showed that CO-L had approximately 2.20 times and 3.41 times the bioavailability of PM and OLM, respectively. This indicates that CO-L has higher bioavailability compared to OM alone or the physical blend of both, PM. For the LBQ657 component, CO-L, compared to PM and LBQ657, had significantly higher bioavailability. 1 / 2 The half-life was advanced by approximately 1.19 h and 2.89 h, respectively, and the C of CO-L... max The AUC of CO-L is approximately 1.73 times that of PM and 1.58 times that of LBQ657, respectively. 0-t The bioavailability of CO-L was approximately 1.39 times that of PM and 1.27 times that of LBQ657, respectively. These results indicate that CO-L has higher bioavailability compared to LBQ657 alone or the physical blend of both, PM.

[0087] Table 9. Mean pharmacokinetic parameters of OLM components in beagle dogs after CO-L administration (n=8, ±sd)

[0088] In Table 9, * This indicates p < 0.05 (vs. OLM). ** This indicates p < 0.01 (vs. OLM). *** This indicates p < 0.001 (vs. OLM). # This indicates p < 0.05 (vs. PM). ##This indicates that p < 0.01 (vs. PM).

[0089] Table 10 Mean pharmacokinetic parameters of LBQ657 component in beagle dogs after CO-L group administration (n=8, ±sd)

[0090] In Table 10, * This indicates p < 0.05 (vs. LBQ657). # This indicates that p < 0.05 (vs. PM).

[0091] The above are merely preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A co-amorphous compound containing LBQ657, characterized in that, Having a single glass transition temperature, including olmesartan medoxomil-LBQ657 co-amorphous or olmesartan-LBQ657 co-amorphous; When the co-amorphous compound containing LBQ657 is the olmesartan medoxomil-LBQ657 co-amorphous compound, the glass transition temperature Tg1 is 65±5℃. When the co-amorphous compound containing LBQ657 is the olmesartan-LBQ657 co-amorphous compound, the glass transition temperature Tg2 is 80±5℃.

2. The co-amorphous material containing LBQ657 according to claim 1, characterized in that, The co-amorphous material containing LBQ657 exhibits a single hump in the X-ray powder diffraction pattern using Cu-Kα radiation within the range of 2θ values ​​from 5° to 40°.

3. The method for preparing the co-amorphous compound containing LBQ657 according to any one of claims 1 to 2, characterized in that, Includes the following steps: Angiotensin II receptor antagonist and LBQ657 were added to a solvent, extracted, and the solvent was removed to obtain the co-amorphous compound containing LBQ657. The angiotensin II receptor antagonists include olmesartan medoxomil or olmesartan.

4. The method for preparing the co-amorphous compound containing LBQ657 according to claim 3, characterized in that, The molar ratio of the angiotensin II receptor antagonist to LBQ657 is 1:

1.

5. The method for preparing the co-amorphous compound containing LBQ657 according to claim 3, characterized in that, The mass-to-volume ratio of the sum of the angiotensin II receptor antagonist and LBQ657 to the solvent is 5-8 mg:1 mL; Preferably, the solvent includes methanol or ethanol.

6. The method for preparing the co-amorphous compound containing LBQ657 according to claim 3, characterized in that, The extraction was performed using ultrasonic extraction, with a frequency of 30-50 kHz, a power of 90-110 W, and a time of 30-40 min.

7. The method for preparing the co-amorphous compound containing LBQ657 according to claim 3, characterized in that, The solvent was removed by rotary evaporation.

8. The use of the co-amorphous compound containing LBQ657 according to any one of claims 1 to 2 or the co-amorphous compound containing LBQ657 prepared by the preparation method according to any one of claims 3 to 7 in the preparation of a medicament for treating hypertension and / or arteriosclerosis.

9. A pharmaceutical composition, characterized in that, Includes the co-amorphous material containing LBQ657 as described in any one of claims 1-2, or the co-amorphous material containing LBQ657 prepared by the preparation method described in any one of claims 3-7; and Pharmaceutically acceptable carrier.

10. A pharmaceutical composition according to claim 9, characterized in that, The daily dose of the co-amorphous compound containing LBQ657 is 10-1000 mg.

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