Application of suthiamethoxam in preparation of medicine for treating obstructive sleep apnea

Abstract

The invention relates to the field of medicines, and discloses a pharmaceutical composition for treating obstructive sleep apnea as well as a preparation method and application thereof. The pharmaceutical composition comprises a ternary co-amorphous compound containing zinc ions, and raw materials of the ternary co-amorphous compound comprise suthiamethoxam, L-arginine, a divalent zinc ion donor and a surface stabilizer. Wherein zinc ions form a cross-linked network with the suthiamethoxam and the L-arginine through coordination, so that drug lattices are destroyed, and molecular movement is limited. According to the preparation method, a liquid-assisted high-energy mechanical ball milling process is adopted, a trace amount of coordination catalytic liquid is added to reduce a solid-phase reaction energy barrier, and efficient conversion from a crystalline state to an amorphous state is realized. Through the synergistic effect of multiple components, the saturation solubility and the dissolution rate of the suthiamethoxam are remarkably improved, meanwhile, the coordination crosslinking of zinc ions and the steric hindrance effect of the surface stabilizer are utilized, crystal transformation of an amorphous system is effectively inhibited, and the physical stability and oral bioavailability of the medicine are enhanced.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to the use of succinate in the preparation of a drug for treating obstructive sleep apnea. Background Technology

[0002] Sutamicil is a sulfonamide carbonic anhydrase inhibitor, primarily used clinically to treat partial seizures. Recent medical research indicates that sutamicil can significantly reduce the apnea-hypopnea index in patients with obstructive sleep apnea (OSA) by stimulating respiratory drive and improving upper airway muscle tone, demonstrating its potential as a novel drug for treating OSA.

[0003] However, sulcimetholone is a typical poorly soluble drug. Its active pharmaceutical ingredient exists as a stable crystalline form with high lattice energy at room temperature, resulting in extremely low solubility in physiological pH media. This severely limits the passive diffusion absorption of the drug through gastrointestinal epithelial cells, leading to poor oral bioavailability and large fluctuations in blood drug concentrations, among other clinical application drawbacks. Although the field of drug crystal engineering often employs amorphization strategies—converting drugs from low-energy crystals to high-energy amorphous forms to lower the solubility barrier—the existing sulcimetholone amorphous system is thermodynamically metastable, exhibiting high molecular mobility and a strong tendency to spontaneously lower its Gibbs free energy and revert to a crystalline state. During storage, especially under heat or moisture-absorbing conditions, it is highly susceptible to aging or recrystallization, causing the drug to lose its solubilizing advantage again and failing to meet the requirements for long-term physical stability.

[0004] To address the absorption challenges of poorly soluble drugs, the field of drug crystal engineering often employs an amorphization strategy, transforming the drug from a low-energy crystalline state to a high-energy amorphous state. While amorphous drugs, lacking a long-range ordered lattice structure, can significantly lower the solubility barrier and increase apparent solubility, they exist in a thermodynamically metastable state and have a strong tendency to spontaneously lower their Gibbs free energy and revert to a crystalline state. During storage, especially under heated or hygroscopic conditions, amorphous drugs are highly susceptible to molecular rearrangement and nucleation growth, leading to "aging" or recrystallization and thus losing their solubilizing advantages.

[0005] Current improvements mainly involve preparing polymer solid dispersions or drug-small molecule co-amorphous compounds. For solid dispersions, maintaining drug dispersion stability typically requires the addition of large amounts of hydrophilic polymeric carriers, leading to excessively large final formulation volumes, reduced patient compliance, and the strong hygroscopicity of some polymeric carriers, which in turn accelerates drug crystallization. While existing succinate-based binary co-amorphous systems reduce carrier usage, the intermolecular forces between the drug and ligands are often insufficient, or the system's glass transition temperature is low, resulting in high molecular chain mobility at room temperature, making it difficult to maintain physical stability during long-term storage. Furthermore, conventional preparation processes such as melt-quenching can easily cause degradation of thermosensitive drugs, while solvent evaporation involves the use of large amounts of organic solvents, posing a risk of excessive residual solvent. Summary of the Invention

[0006] The technical problem solved by this invention is that sucimetidine usually exists in crystalline form in the solid state, which has poor water solubility and results in low oral bioavailability; while the amorphous form of sucimetidine prepared by conventional amorphization technology is in a high thermodynamic energy state, which is prone to crystal transformation and its physical stability is difficult to meet the requirements for long-term storage.

[0007] To address the above problems, the present invention provides the following technical solution: First aspect This invention provides a pharmaceutical composition for treating obstructive sleep apnea, employing the following technical solution: A pharmaceutical composition for treating obstructive sleep apnea includes a ternary co-amorphous complex containing zinc ions, wherein the raw materials of the complex are: succinate and L-arginine in a molar ratio of 1:1 to 1:2; a divalent zinc ion donor, wherein the molar ratio of zinc ions of the divalent zinc ion donor to succinate is 0.1:1 to 0.3:1; and a surface stabilizer, wherein the content is 5% to 15% of the total mass of the composition.

[0008] By adopting the above technical solution, the present invention improves the solubility and physical stability of drugs through the synergistic effect of multiple components, and its mechanism of action is as follows: First, L-arginine, as a co-amorphous form, utilizes its amino and guanidinium groups to form hydrogen bonds with the sulfonamide groups in the sucrase molecule, disrupting the original lattice arrangement of sucrase. Following this, divalent zinc ions, acting as coordination centers, accept lone pairs of electrons from the nitrogen and oxygen atoms in sucrase and L-arginine, forming coordinate bonds. The combined effect of hydrogen bonds and coordinate bonds increases intermolecular forces, restricting the rearrangement and nucleation of amorphous molecules and inhibiting crystal transformation.

[0009] Secondly, the cross-linking effect of zinc ions increases the rigidity of the amorphous system and raises its glass transition temperature. The higher transition temperature restricts the movement of molecular chain segments under room temperature and conventional storage conditions, thereby ensuring the thermodynamic and kinetic stability of the amorphous system.

[0010] Finally, the surface stabilizers dispersed in the system adsorb onto the surface of the drug particles, preventing the aggregation of amorphous particles through the steric hindrance effect of the polymer chain segments. Simultaneously, the surface stabilizers improve the wettability of the powder, synergistically enhancing the dissolution rate.

[0011] Preferably, the raw material ratio of the pharmaceutical composition is as follows: the molar ratio of succinate to L-arginine is 1:1.1 to 1:1.5; the molar ratio of zinc ions to succinate is 0.15:1 to 0.25:1; and the content of surface stabilizer is 5% to 10% of the total mass of the composition. Within this ratio range, the coordination between molecules reaches equilibrium, the system has high mixing uniformity, and superior resistance to moisture absorption and aging.

[0012] Preferably, the divalent zinc ion donor is selected from one or a combination of two of anhydrous zinc acetate and zinc gluconate; the surface stabilizer is selected from one or a combination of two of poloxamer 188 and poloxamer 407. The above-mentioned zinc sources have good biocompatibility and are easily dissociated; the above-mentioned types of poloxamer have suitable hydrophilic-lipophilic balance values, which can stabilize the ternary system.

[0013] Second aspect This invention provides a method for preparing the above-mentioned pharmaceutical composition for treating obstructive sleep apnea, using the following technical solution: A method for preparing a pharmaceutical composition for treating obstructive sleep apnea includes the following steps: S1. Preparation of coordination catalyst: Dissolving a zinc ion source in a solvent and subjecting it to ultrasonic treatment at a power of 100W to 300W for 5 minutes to 15 minutes to obtain a coordination catalyst; S2. Solid-phase premixing: Mix succinate, L-arginine, poloxamer 188, and poloxamer 407 evenly to obtain a physically mixed powder; S3. High-energy mechanical ball milling: The physically mixed powder obtained in S2 and grinding balls including zirconia balls are placed in a ball mill jar, and the coordination catalyst prepared in S1 is added to the powder as a grinding aid. The ball milling reaction is carried out to obtain a wet slurry. S4. Curing and drying: The wet slurry is dried to remove the solvent, thus obtaining the pharmaceutical composition.

[0014] By adopting the above technical solution, this invention utilizes liquid-assisted grinding technology to carry out solid-phase reactions, and its preparation principle is as follows: The coordination catalyst added in step S3 forms a liquid film on the surface of the solid particles. This liquid film provides diffusion channels for reactant molecules, reduces the mass transfer resistance of the solid-phase reaction, and allows zinc ions to penetrate and disperse at the interface between sucimeth and arginine.

[0015] High-energy ball milling provides shear and impact forces that create new surfaces and provide the energy needed to break the lattice. Under the combined action of mechanical energy and solvent, the succinimide lattice structure changes and undergoes coordination and recombination with arginine and zinc ions, transforming into a co-amorphous structure.

[0016] Premixing poloxamer and wet milling ensures that the polymer carrier is evenly distributed around the drug molecules, reducing the risk of recrystallization caused by localized drug accumulation.

[0017] Preferably, in step S1, the solvent is a 95% ethanol solution or a mixture of ethanol and water; the volume ratio of the ethanol to water mixture is preferably 9:1. An appropriate amount of water promotes the dissociation of the zinc salt, while ethanol facilitates subsequent drying and removal.

[0018] Preferably, in step S3, the ball milling process parameters are controlled as follows: ball-to-material mass ratio of 20:1 to 50:1, grinding speed of 300 rpm to 500 rpm, and total effective grinding time of 45 minutes to 120 minutes. This parameter range ensures that the input mechanical energy is sufficient to complete the transformation from crystalline to amorphous state, while preventing excessive energy from causing drug degradation.

[0019] Preferably, in step S3, the amount of the coordination catalyst added is controlled to a liquid-to-solid ratio of 0.2 μL / mg to 0.6 μL / mg. This liquid-to-solid ratio control keeps the material in a moist state, ensuring the auxiliary grinding effect and maintaining the shearing efficiency between the grinding balls.

[0020] Preferably, in step S3, the ball milling process is carried out under a protective atmosphere of dry nitrogen, and the grinding temperature is controlled to be ≤30℃. This condition prevents the material from softening or oxidizing due to heat generated during ball milling, ensuring product purity.

[0021] Preferably, in step S4, the drying is vacuum drying, with a drying temperature of 35℃~45℃ and a drying time of 12 hours~24 hours. The low-temperature vacuum environment is beneficial for removing residual solvents while avoiding thermal degradation.

[0022] Preferably, the process further includes step S5, granulation: pulverizing the dried product and passing it through an 80-mesh sieve. This step eliminates agglomeration that occurs during the drying process and improves powder flowability.

[0023] Third aspect This invention provides the application of the above-mentioned pharmaceutical composition for treating obstructive sleep apnea in the preparation of a medicament for treating obstructive sleep apnea, using the following technical solution: The use of a pharmaceutical composition for treating obstructive sleep apnea in the preparation of a medicament for treating obstructive sleep apnea, wherein the medicament is an oral preparation, including tablets, capsules or granules.

[0024] By employing the above technical solution, the ternary co-amorphous complex prepared by this invention exhibits higher saturation solubility and dissolution rate compared to sulcimetidine raw material. The high-energy state of the amorphous state allows the drug to maintain a supersaturated state in physiological media, reducing precipitation and thus improving the absorption efficiency of the drug through the gastrointestinal tract. This pharmaceutical composition can improve the bioavailability of sulcimetidine, which is beneficial for achieving the expected blood drug concentration in the treatment of obstructive sleep apnea.

[0025] This invention provides the use of succinate in the preparation of a medicament for treating obstructive sleep apnea. It has the following beneficial effects: 1. This invention utilizes L-arginine to form a co-amorphous structure with sulcimethicone, disrupting the original stable lattice of sulcimethicone and placing it in a high-energy state. Simultaneously, the surface stabilizer poloxamer is introduced to improve the wettability of the drug powder in aqueous media. This synergistic effect allows the drug to be rapidly released during dissolution and maintain a supersaturated state for a longer period, effectively preventing precipitation due to excessively high concentrations in the gastrointestinal environment. This solves the problem of low oral absorption efficiency of sulcimethicone due to its poor water solubility.

[0026] 2. This invention introduces divalent zinc ions into the succinate-arginine binary system. The empty orbitals of zinc ions form stable coordination bonds with nitrogen and oxygen atoms in the drug and ligand molecules, constructing an intermolecular cross-linking network. This chemical interaction significantly increases the glass transition temperature of the system, restricts the microscopic movement and rearrangement of amorphous molecules, effectively suppresses the tendency of the composition to crystallize under long-term storage or humid and hot conditions, and ensures the quality stability of the drug.

[0027] 3. This invention employs a liquid-assisted high-energy ball milling method, requiring only a trace amount of coordination catalyst to reduce the energy barrier and mass transfer resistance of the solid-phase reaction, achieving complete amorphous transformation under low mechanical energy input and low temperature conditions. This process avoids the potential thermal degradation of drugs caused by traditional melting methods and overcomes the shortcomings of solvent evaporation methods, which require large amounts of organic solvents and are difficult to remove residues. It features high yield, low energy consumption, and good batch-to-batch repeatability. Attached Figure Description

[0028] Figure 1 This is a flowchart of the present invention. Detailed Implementation

[0029] 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. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0030] Example: Please see the appendix Figure 1 This invention provides a drug for treating obstructive sleep apnea, comprising: Sutamicin, also known as Sutamicin in Chinese, is a white crystalline powder with a purity of ≥99.0% and a melting point range of 185℃-187℃, meeting the standards of the British Pharmacopoeia (BP) or the European Pharmacopoeia (EP). L-Arginine, in free base form, is a white crystalline or crystalline powder with a purity ≥99.0% and a loss on drying ≤0.5%, conforming to the standards of the Chinese Pharmacopoeia (ChP). Anhydrous zinc acetate, a white crystalline powder with a purity ≥99.0%, is readily soluble in ethanol and water; Zinc gluconate, white granules or crystalline powder, purity ≥98.0%; Poloxamer 188, trade name Pluronic F68, CAS number 9003-11-6, is a triblock copolymer of polyethylene oxide-polypropylene oxide-polyethylene oxide (PEO-PPO-PEO), with the general chemical formula HO(C2H4O)a(C3H6O)b(C2H4O)aH, where a is approximately 80 and b is approximately 27. The average molecular weight is 7680 Da-9510 Da, the content of ethylene oxide repeating units is 81.8% ± 3.2%, and the appearance is a white fine powder. Anhydrous ethanol, analytical grade, water content ≤0.3%; Anhydrous calcium chloride, analytical grade, white granules, purity ≥96.0%; Magnesium oxide, analytical grade, light white powder, purity ≥98.0%; The medication for treating obstructive sleep apnea is an oral preparation, including tablets, capsules, or granules.

[0031] Example: Example 1: Example 1: This example provides a ternary amorphous composition of succinimide, arginine and poloxamer based on zinc ion coordination crosslinking. The composition ratio is as follows: the molar ratio of succinimide to L-arginine is 1:1.2, the molar ratio of zinc ions to succinimide is 0.2:1, and the content of poloxamer 188 is 10% of the total mass of the composition.

[0032] The preparation method includes the following steps: (1) Preparation of coordination catalyst: Weigh 0.367 g (2.0 mmol) of anhydrous zinc acetate, dissolve it in 3.0 mL of 95% ethanol, with a volume ratio of ethanol to water of 95:5, sonicate at 40 kHz for 15 minutes and supplement with slight heating at about 40 °C until the solid is completely dissolved, and obtain a clear and transparent coordination catalyst.

[0033] (2) Solid-phase premixing: Weigh 2.903g (10.0mmol) of succinyl ether and 2.090g (12.0mmol) of L-arginine, and mix them in a mixer for 3 minutes; then add 0.60g of poloxamer 188 powder and continue mixing for 2 minutes to obtain a physically mixed powder.

[0034] (3) High-energy mechanical ball milling: The above-mentioned physically mixed powder is loaded into a 250mL zirconia ball milling jar, and zirconia grinding balls with a diameter of 5mm are added. The ball-to-material mass ratio is controlled at 30:1. The coordination catalyst prepared in step (1) is uniformly dripped onto the surface of the powder to make the powder wet. The planetary ball mill is started, the speed is set to 400rpm, and the intermittent operation mode is adopted, that is, it runs for 15 minutes and pauses for 5 minutes. The total effective grinding time is 60 minutes.

[0035] (4) Curing and drying: Take out the wet slurry after ball milling, place it in a vacuum drying oven, and dry it for 12 hours at 35℃ and vacuum degree -0.095MPa to remove the solvent.

[0036] (5) Granulation: After drying, the product is pulverized by a pulverizer and passed through an 80-mesh sieve to obtain a white, loose powder of succinimide ternary amorphous composition.

[0037] Example 2: This example provides a ternary amorphous composition of succinimide, arginine and poloxamer based on zinc ion coordination crosslinking. The composition ratio is as follows: the molar ratio of succinimide to L-arginine is 1:1, the molar ratio of zinc ions to succinimide is 0.1:1, and the content of poloxamer 188 is 5% of the total mass of the composition.

[0038] The preparation method is basically the same as in Example 1, except that the amount of raw materials and some process parameters are adjusted: (1) Preparation of coordination catalyst: weigh 0.184 g (1.0 mmol) of anhydrous zinc acetate and dissolve it in 1.5 mL of 95% ethanol; (2) Solid phase premixing: weigh 2.903 g (10.0 mmol) of sutamicil, 1.742 g (10.0 mmol) of L-arginine and 0.25 g of poloxamer 188 powder; (3) High-energy mechanical ball milling: adjust the ball-to-material mass ratio (BPR) to 20:1, adjust the grinding speed to 300 rpm, adjust the total effective grinding time to 45 minutes, and the remaining steps are the same as in Example 1.

[0039] Example 3: This embodiment provides a ternary amorphous composition of succinimide, arginine, and poloxamer based on zinc ion coordination crosslinking. The composition ratio is as follows: the molar ratio of succinimide to L-arginine is 1:2, the molar ratio of zinc ions to succinimide is 0.3:1, and the content of poloxamer 188 is 15% of the total mass of the composition. The preparation method is basically the same as in Example 1, with the only difference being the amount of raw materials and adjustments to some process parameters: (1) Preparation of coordination catalyst: Weigh 0.551 g (3.0 mmol) of anhydrous zinc acetate and dissolve it in 4.0 mL of 95% ethanol.

[0040] (2) Solid-phase premixing: Weigh 2.903g (10.0mmol) of succinyl ether, 3.484g (20.0mmol) of L-arginine and 1.22g of poloxamer 188 powder.

[0041] (3) High-energy mechanical ball mill: The ball mass ratio (BPR) is adjusted to 50:1, the grinding speed is adjusted to 500 rpm, and the total effective grinding time is adjusted to 120 minutes.

[0042] (4) Curing and drying: The drying temperature was adjusted to 45°C and the drying time was adjusted to 24 hours. The remaining steps were the same as in Example 1.

[0043] Example 4: This embodiment provides a ternary amorphous composition of succinate, arginine and poloxamer based on zinc ion coordination crosslinking. The composition ratio is the same as in Example 1, except that zinc gluconate is used as the zinc source.

[0044] The preparation method is basically the same as in Example 1, except for the preparation of the coordination catalyst and the selection of the solvent: In step (1), 0.911 g (2.0 mmol) of zinc gluconate was weighed and dissolved in 5.0 mL of a mixture of ethanol and water (volume ratio 9:1). The solution was then sonicated at 40 kHz for 20 minutes until completely dissolved.

[0045] In step (3), the above-mentioned ethanol and aqueous solution are used as grinding aids, and the amount of other raw materials and process steps are the same as in Example 1.

[0046] Example 5: This embodiment provides a ternary amorphous composition of succinimide, arginine and poloxamer based on zinc ion coordination crosslinking. The composition ratio is the same as in Example 1, except that the amount of grinding aid is adjusted to investigate the parameter range of liquid-assisted grinding.

[0047] The preparation method is basically the same as that in Example 1, except that in step (1), anhydrous zinc acetate is dissolved in 1.2 mL of 95% ethanol to reduce the liquid-solid ratio to about 0.2 μL / mg to form a high-viscosity slurry. In step (3), the grinding speed is set to 450 rpm and the total effective grinding time is set to 90 minutes. The remaining steps are the same as those in Example 1.

[0048] Example 6: This embodiment provides a ternary amorphous composition of succinimide, arginine and poloxamer based on zinc ion coordination crosslinking. The composition ratio is the same as in Example 1, except that a different type of surface stabilizer is used and an inert gas protection process is adopted.

[0049] The preparation method is basically the same as in Example 1, with the only difference being: (1) Raw material substitution: Pluronic F127 was used instead of Pluronic 188, with the same amount of 0.60g.

[0050] (2) Process environment control: In the high-energy mechanical ball milling process in step (3), dry nitrogen gas is introduced into the ball mill jar for protection, and the grinding operation temperature is strictly controlled to not exceed 30°C. The amount of other raw materials and process steps are the same as in Example 1.

[0051] Example 7: This embodiment provides a pharmaceutical composition within the preferred formulation range of the present invention, aiming to verify the stability of the preferred formulation. The component ratios are as follows: the molar ratio of succinylcholine to L-arginine is 1:1.4, the molar ratio of zinc ions to succinylcholine is 0.18:1, and the content of poloxamer 188 is 8% of the total mass of the composition. The preparation method is basically the same as in Example 1, with the following adjustments to the raw material amounts: (1) Preparation of coordination catalyst: Weigh 0.330 g (1.8 mmol) of anhydrous zinc acetate and dissolve it in 2.7 mL of 95% ethanol.

[0052] (2) Solid-phase premixing: Weigh 2.903g (10.0mmol) of succinate, 2.439g (14.0mmol) of L-arginine and 0.49g of poloxamer 188 powder.

[0053] (3) The high-energy mechanical ball milling and subsequent steps are consistent with those in Example 1.

[0054] Example 8: This embodiment provides a pharmaceutical composition (low arginine / high zinc ion) corresponding to the boundary value of the formulation range of the present invention, aiming to verify the cross-linking effect of high zinc ion content at a low co-formed ratio. Its component ratio is: the molar ratio of succinyl ether to L-arginine is 1:1, the molar ratio of zinc ions to succinyl ether is 0.3:1, and the content of poloxamer 188 is 12% of the total mass of the composition. The preparation method is basically the same as in Example 1, with the following adjustments to the raw material amounts: (1) Preparation of coordination catalyst: Weigh 0.551 g (3.0 mmol) of anhydrous zinc acetate and dissolve it in 4.0 mL of 95% ethanol.

[0055] (2) Solid-phase premixing: Weigh 2.903g (10.0mmol) of succinate, 1.742g (10.0mmol) of L-arginine and 0.71g of poloxamer 188 powder.

[0056] (3) The high-energy mechanical ball milling and subsequent steps are consistent with those in Example 1.

[0057] Example 9: This embodiment provides a pharmaceutical composition corresponding to the boundary values ​​of the formulation range of the present invention, aiming to verify the ability to maintain steady-state function under low zinc ion content and high co-formed component ratio. The component ratio is as follows: the molar ratio of sulfomethazone to L-arginine is 1:2, the molar ratio of zinc ions to sulfomethazone is 0.1:1, and the content of poloxamer 188 is 6% of the total mass of the composition. The preparation method is basically the same as in Example 1, with the following adjustments to the raw material amounts: (1) Preparation of coordination catalyst: Weigh 0.184 g (1.0 mmol) of anhydrous zinc acetate and dissolve it in 1.5 mL of 95% ethanol.

[0058] (2) Solid-phase premixing: Weigh 2.903g (10.0mmol) of succinate, 3.484g (20.0mmol) of L-arginine and 0.42g of poloxamer 188 powder.

[0059] (3) The high-energy mechanical ball milling and subsequent steps are consistent with those in Example 1. Comparative Example Comparative Example 1: This comparative example provides sulcimetidine raw material without crystal engineering treatment. The difference from Example 1 is that no grinding and coordination crosslinking treatment was performed, and commercially available sulcimetidine raw material was used directly.

[0060] Comparative Example 2: This comparative example provides a simple physical mixture of the components. The difference from Example 1 is that the high-energy mechanical ball milling in step (3) and the solvent-assisted treatment in step (1) were not carried out in the preparation process. Instead, succinyl ether, L-arginine, anhydrous zinc acetate and poloxamer 188 were mixed uniformly at low speed in a mixer according to the proportions of Example 1, without any mechanical or chemical reaction.

[0061] Comparative Example 3: This comparative example provides a binary co-amorphous system without zinc ions to verify the cross-linking stabilizing effect of zinc ions. Compared with Example 1, the difference is that anhydrous zinc acetate is not added to the raw materials, and only an equal amount of 95% ethanol is used as a grinding aid in step (1). The amount of other raw materials and the preparation process parameters are the same.

[0062] Comparative Example 4: This comparative example provides a system without surface stabilizers to verify the role of poloxamer in maintaining supersaturation. The difference from Example 1 is that poloxamer 188 is not added to the raw materials, and only succinylamine and L-arginine are mixed in step (2). The amount of other raw materials and the preparation process parameters are the same.

[0063] Comparative Example 5: This comparative example provides a system using non-coordinated metal ions to verify the specificity of zinc ions coordinating with sulfonamide groups. The difference from Example 1 is that the raw materials used are equimolar amounts of anhydrous calcium chloride (…). ) to replace anhydrous zinc acetate ( The amounts of other raw materials and preparation process parameters are the same.

[0064] Comparative Example 6: This comparative example provides a system without co-formed L-arginine to verify the skeletal support role of amino acids in the ternary network. The difference from Example 1 is that L-arginine is not added to the raw materials, and only succinyl ether and poloxamer 188 are mixed in step (2), followed by the addition of a zinc-containing solution for grinding. The amount of other raw materials and the preparation process parameters are the same.

[0065] Test Example 1: Experimental steps Solid phase analysis of the samples from each embodiment and comparative example was performed using X-ray diffraction. The test conditions were set as follows: the radiation source was Cu-K. ray( The tube voltage is 40kV and the tube current is 40mA; continuous scanning mode is used, and the scanning range is (2 The scanning angle is 3° to 40°, the step size is 0.02°, and the scanning speed is 5° / min. During sample preparation, an appropriate amount of powder is lightly pressed into the groove of the zero-background silicon sample holder to keep the surface flat. The thermal behavior and glass transition temperature of the sample are studied. Differential scanning calorimetry (DSC) was used for determination. 3-5 mg of sample was weighed and placed in an aluminum crucible, which was then covered and pressed (not sealed). An empty aluminum crucible was used as a reference. Under the protection of high-purity nitrogen at a flow rate of 50 mL / min, the temperature was increased from 25°C to 200°C at a rate of 10°C / min, and the heat flow curve was recorded.

[0066] Table 1 Combining XRPD and DSC test data (see Table 1), the XRPD spectra of Examples 1 to 6 all showed a broad halopattern, and no sharp crystal diffraction peaks of sutometrine or L-arginine were detected; the DSC curves showed only a single glass transition step, indicating that after solvent-assisted grinding, the lattice structure of the raw materials was destroyed, and the components were mixed at the molecular level to form a homogeneous co-amorphous system.

[0067] Comparing thermodynamic parameters, the glass transition temperature of Example 1 ( The temperature was 27.8℃ higher than that of Comparative Example 3. According to the Gordon-Taylor equation theory, this... The positive deviation of the value indicates that there is a stronger intermolecular interaction than conventional hydrogen bonding in the system. The introduced zinc ions form a coordination cross-linking structure with the sucimethamide group and L-arginine guanidine group, which increases the molecular rotational energy barrier and reduces the local migration rate of amorphous molecules.

[0068] In addition, comparative example 5 used calcium ions instead of zinc ions, and the measured... The temperature was 83.2℃, which was higher than that of Comparative Example 3, but significantly lower than that of Example 1. This indicates that the binding strength between calcium ions and susulam is weaker than that between zinc ions, verifying the specific affinity of the susulam molecular structure for zinc ions. The data from the examples show that the ternary coordination system has high thermal rigidity, which is beneficial for suppressing the crystallization phenomenon during storage. The XRPD spectrum of Comparative Example 6 showed sharp crystallization peaks and a melting point significantly higher than that of the active pharmaceutical ingredient. This indicates that in the absence of L-arginine, zinc ions formed a thermodynamically stable crystalline salt or complex with succinate, rather than a high-energy amorphous substance. This confirms that L-arginine plays a key "co-forming" role in the system, disrupting the long-range ordered arrangement of drug molecules by providing abundant hydrogen bonding sites and steric hindrance. It is an essential component for constructing a ternary co-amorphous system.

[0069] Test Example 2: Experimental steps Take appropriate amounts of the samples prepared in Examples 1 to 6 and Comparative Examples 1 to 6, spread them evenly in an open weighing bottle with a thickness of about 3 mm, and place them in a constant temperature and humidity chamber at a temperature of 40℃±2℃ and a relative humidity of 75%±5% for accelerated aging experiments. Samples were taken on days 0, 7, 14, 30 and 60, and detected by X-ray powder diffraction (XRD) as described in Test Example 1. If a sharp diffraction peak appears in the spectrum, it is determined that crystal transformation has occurred, and the duration of maintaining the amorphous morphology is recorded.

[0070] In vitro dissolution was determined according to the basket method in the Chinese Pharmacopoeia. 900 mL of degassed artificial gastric fluid (pH 1.2 hydrochloric acid solution) was used as the medium. The temperature was 37℃±0.5℃ and the rotation speed was 100 rpm. Sample powder equivalent to 200 mg of sucimetholone was weighed and placed into the dissolution vessel in the rotating basket. 5 mL samples were taken at 5 min, 15 min, 30 min, 45 min, 60 min, 120 min and 240 min, and the solution was replenished immediately. The solution was filtered through a 0.45 μm microporous membrane. The absorbance of the filtrate was measured by ultraviolet and visible spectrophotometry at the characteristic absorption wavelength of sucimetholone. The cumulative dissolution percentage (n=6) was calculated.

[0071] Table 2

[0072] Based on the physical stability data and in vitro dissolution kinetics in Table 2, under accelerated conditions of 40℃ / 75%RH, Comparative Example 3, which did not introduce zinc ions, maintained an amorphous state for only about 14 days. Subsequently, XRD patterns detected crystal diffraction peaks, indicating that the simple hydrogen-bonded system underwent phase separation and recrystallization after hygroscopic absorption. Examples 1 to 6 did not detect crystallization peaks during the 60-day test period and maintained an amorphous state. Comparative Example 5, which used calcium ions instead of zinc ions, detected crystallization on day 30. The comparative results show that the coordination between zinc ions and succinate and L-arginine restricts molecular motion and blocks the pathway from amorphous to crystalline state. Moreover, this effect is stronger than the non-specific ionic effect of calcium ions.

[0073] Regarding dissolution performance, the dissolution rate of Comparative Example 4 reached a peak of 89.2% and then dropped to 35.6% within 240 minutes, indicating that the drug rapidly nucleated and precipitated in the medium after dissolution. Examples 1 to 6 with added poloxamer maintained a dissolution rate of over 90% within 240 minutes. The data confirm that poloxamer inhibited the growth of crystal nuclei in the solution through steric hindrance, thus maintaining the supersaturated state of the drug.

[0074] In summary, the composition of the present invention improves the solid-state physical stability by introducing zinc ion coordination and inhibits liquid-phase precipitation in conjunction with surface stabilizers, thereby achieving a simultaneous improvement in the dissolution rate and stability of susulam.

[0075] Test Example 3: The following samples were tested: succinate raw material, L-arginine raw material, physical mixture (mixed according to the ratio of Example 1), sample of Example 1, sample of Comparative Example 3 and sample of Comparative Example 5.

[0076] Fourier transform infrared spectroscopy (FT-IR) testing: A Nicolet iS50 infrared spectrometer was used. Sample preparation was performed using the KBr pellet method, with a sample-to-potassium bromide mass ratio of 1:100. The sample was ground and compressed into pellets. The scanning range was set to 4000. Up to 400 4 resolution The number of scans was 32, and the position of the characteristic absorption peak of each sample in the fingerprint area was determined.

[0077] Differential scanning calorimetry (DSC) testing: A TA Q2000 differential scanning calorimeter was used. Samples of 3.0 mg to 5.0 mg were weighed and placed in an aluminum crucible, which was then sealed with a non-airtight cap. Under a dry nitrogen flow of 50 mL / min, the temperature was increased from 25 °C to 250 °C at a rate of 10 °C / min. The heat flow curve was recorded, and the glass transition temperature (Tg) was calculated. Table 3

[0078] FT-IR spectral data showed that the antisymmetric and symmetric stretching vibration peaks of the sulfonamide group (S=O) in sucimethicone active pharmaceutical ingredient were located at 1332.4°C. and 1166.8 In the spectrum of Example 1, the aforementioned characteristic peaks were shifted to 1316.3. And 1151.4 The wavenumber decreased by 16.1%. and 15.4 The guanidino group (C=N) absorption peak of L-arginine is at 1678.3. Displaced to 1644.2 The shift of the characteristic peak to lower wavenumbers indicates that the oxygen atom of the sulfamethamide group and the nitrogen atom of the L-arginine guanidine group have coordinated with zinc ions, altering the original chemical bond force constants. The peak shift in Comparative Example 3 (without zinc) is smaller than that in Example 1, indicating that the coordination bond strength involving zinc ions is higher than that of hydrogen bonding; the shift amplitude in Comparative Example 5 (calcium ions) is also smaller than that in Example 1, indicating that the coordination binding of zinc ions with this drug system is more tight.

[0079] DSC thermal analysis showed that the physical mixture exhibited endothermic melting peaks at 185.7 °C and 227.9 °C, characteristic of crystalline mixtures. Example 1 showed no melting endothermic peaks, only a single glass transition step at 104.2 °C, indicating that the sample was a homogeneous amorphous body. The Tg of Example 1 (104.2 °C) was higher than that of Comparative Example 3 (76.4 °C) and Comparative Example 5 (83.2 °C). The increased Tg indicates that the coordination network constructed by zinc ions restricts the movement of molecular chain segments, increases the rigidity of the system, and thermodynamically inhibits the transition from the amorphous state to the crystalline state.

[0080] Test Example 4: The samples from Example 1 (Group A), Comparative Example 1 (Suttamicin API) (Group B), Comparative Example 3 (Zinc-free binary system sample) (Group C), and Comparative Example 4 (Surface stabilizer-free sample) (Group D) were selected for comparative testing.

[0081] Saturated solubility and dissolution rate determination: Excess sample powder from each group was added to pH 6.8 phosphate buffer and incubated at 37 ℃ with shaking for 24 hours. The supernatant was filtered through a 0.45 μm filter membrane, and the concentration of sucimethol in the filtrate was determined by high performance liquid chromatography (HPLC) to calculate the saturated solubility. The cumulative dissolution percentage of each sample was also determined at 45 minutes according to the dissolution test method (basket method) in the Chinese Pharmacopoeia.

[0082] Accelerated physical stability assessment: Each group of samples was placed in an open environment at 40 ℃ and 75% relative humidity. Samples were taken at the end of the 6th month and X-ray powder diffraction (XRD) scans were performed. The physical state was determined based on the presence or absence of sharp diffraction peaks.

[0083] Rat Pharmacokinetic Experiment: Twenty-four SD rats were randomly divided into four groups. Each group was administered the sample suspension from group A, B, C, or D by gavage, with the dosage uniformly converted to 20 mg / kg succinate. Blood samples were collected from the orbital venous plexus at 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after administration. Plasma was separated by centrifugation, and plasma concentrations were determined by LC-MS / MS. The peak concentration (Cmax) and area under the curve (AUC0₋₀) were calculated using a non-compartmental model analysis with WinNonlin software. 24h )

[0084] The saturated solubility of group A was 4.82 mg / mL, approximately 26 times that of the active pharmaceutical ingredient (API) in group B (0.18 mg / mL). L-arginine disrupted the crystal structure of sulfomethalin, lowering the lattice energy and allowing the drug molecules to exist in a high-energy amorphous state, thereby increasing apparent solubility. Compared to group D (without surface stabilizer), although its saturated solubility (3.96 mg / mL) was higher than that of the API, its dissolution rate at 45 minutes was only 52.3%, significantly lower than the 98.5% of group A. Poloxamer, as a surface stabilizer, inhibited nucleation and crystal growth in the supersaturated solution during dissolution (parachute effect) by creating steric hindrance through adsorption on the surface of drug particles, thus maintaining a high concentration of drug release.

[0085] Regarding physical stability, after 6 months of accelerated aging, sharp crystal diffraction peaks were detected in group C (zinc-free), indicating that simple hydrogen bonding was insufficient to overcome the high-energy instability of the amorphous system, resulting in phase separation and recrystallization. Group A maintained its amorphous characteristics under the same conditions, confirming that the coordination cross-linking network introduced by zinc ions restricted molecular motion, increased the glass transition temperature of the system, and blocked the crystallization pathway.

[0086] Pharmacokinetic results showed that the AUC value of group A (158.4 μg·h / mL) was significantly higher than that of other groups, being 4.9 times that of group B and 1.4 times that of group C, respectively. Although group D had higher initial solubility, its in vivo absorption was limited due to the lack of precipitation inhibition, resulting in a lower AUC value than group A. This technical solution achieves solid-state stability through zinc ion coordination crosslinking, combined with surface stabilizers to maintain liquid supersaturation, thus solving the problems of poor solubility of succinate, easy crystallization of amorphous drugs, and easy precipitation in vivo, achieving a simultaneous improvement in physical stability and oral bioavailability.

[0087] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A pharmaceutical composition for treating obstructive sleep apnea, characterized in that, A ternary co-amorphous complex consisting of succinate, L-arginine, a divalent zinc ion donor, and a surface stabilizer, wherein the raw materials meet the following ratio: The molar ratio of succinate to L-arginine is 1:1 to 1:

2. A divalent zinc ion donor, wherein the molar ratio of zinc ions to sucimethol in the divalent zinc ion donor is 0.1:1 to 0.3:1; A surface stabilizer, comprising 5% to 15% of the total mass of the composition.

2. The pharmaceutical composition for treating obstructive sleep apnea according to claim 1, characterized in that, The following raw material ratios are included: The molar ratio of succinate to L-arginine is 1:1.1 to 1:1.5; The molar ratio of zinc ions to sucimetholone is 0.15:1 to 0.25:1; The content of the surface stabilizer is 5% to 10% of the total mass of the composition.

3. A pharmaceutical composition for treating obstructive sleep apnea according to claim 1 or 2, characterized in that, The divalent zinc ion donor is selected from one or a combination of two of anhydrous zinc acetate and zinc gluconate; the surface stabilizer is selected from one or a combination of two of poloxamer 188 and poloxamer 407.

4. A method for preparing a pharmaceutical composition for treating obstructive sleep apnea as described in claim 1 or 2, characterized in that, Includes the following steps: S1. Preparation of coordination catalyst: The zinc ion source is dissolved in a solvent and subjected to ultrasonic treatment at a power of 100W to 300W for 5 minutes to 15 minutes to obtain the coordination catalyst; S2. Solid-phase premixing: Mix succinate, L-arginine, poloxamer 188, and poloxamer 407 evenly to obtain a physically mixed powder; S3. High-energy mechanical ball milling: The physically mixed powder obtained in S2 and grinding balls including zirconia balls are placed in a ball mill jar, and the coordination catalyst prepared in S1 is added to the powder as a grinding aid. The ball milling reaction is carried out to obtain a wet slurry. S4. Curing and drying: The wet slurry is dried to remove the solvent, thus obtaining the pharmaceutical composition.

5. A method for preparing a pharmaceutical composition for treating obstructive sleep apnea according to claim 4, characterized in that, In step S1, the solvent is a 95% ethanol solution or a mixture of ethanol and water; the volume ratio of the ethanol to water mixture is preferably 9:

1.

6. A method for preparing a pharmaceutical composition for treating obstructive sleep apnea according to claim 4, characterized in that, In S3, the process parameters for ball milling are controlled as follows: ball-to-material mass ratio is 20:1 to 50:1, grinding speed is 300 rpm to 500 rpm, and total effective grinding time is 45 minutes to 120 minutes.

7. A method for preparing a pharmaceutical composition for treating obstructive sleep apnea according to claim 4, characterized in that, In step S3, the amount of the coordination catalyst added is controlled to have a liquid-to-solid ratio of 0.2 μL / mg to 0.6 μL / mg; or, the ball milling process is carried out under a protective atmosphere of dry nitrogen, and the milling temperature is controlled to be ≤30℃.

8. A method for preparing a pharmaceutical composition for treating obstructive sleep apnea according to claim 4, characterized in that, In step S4, the drying is vacuum drying, the drying temperature is 35℃~45℃, and the drying time is 12 hours~24 hours.

9. A method for preparing a pharmaceutical composition for treating obstructive sleep apnea according to claim 4, characterized in that, Also includes: S5. Granulation: Crush the dried product and pass it through an 80-mesh sieve.

10. The use of the pharmaceutical composition for treating obstructive sleep apnea according to claim 1 or 2 in the preparation of a medicament for treating obstructive sleep apnea, characterized in that, The medication for treating obstructive sleep apnea is an oral preparation, including tablets, capsules, or granules.

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