CN-121987571-A - Application of sulteume in preparation of medicines for treating obstructive sleep apnea

CN121987571ACN 121987571 ACN121987571 ACN 121987571ACN-121987571-A

Abstract

The application relates to the field of medicines, and discloses a pharmaceutical composition for treating obstructive sleep apnea, and a preparation method and application thereof. The pharmaceutical composition comprises a ternary co-amorphous complex containing zinc ions, and the raw materials of the ternary co-amorphous complex comprise Shu Sai Mei, L-arginine, a divalent zinc ion donor and a surface stabilizer. Wherein zinc ions form a cross-linked network with the sultebuthimide and the L-arginine through coordination, destroy the crystal lattice of the medicine and limit the movement of molecules. The preparation method adopts a liquid-assisted high-energy mechanical ball milling process, and reduces the solid-phase reaction energy barrier by adding a micro-coordination catalytic liquid, so as to realize the high-efficiency conversion from crystalline state to amorphous state. The application obviously improves the saturated solubility and the dissolution rate of Shu Sai Mei through the multicomponent synergistic effect, and simultaneously utilizes the coordination crosslinking of zinc ions and the steric hindrance effect of a surface stabilizer to effectively inhibit the crystal transformation of an amorphous system and enhance the physical stability and the oral bioavailability of the medicine.

Inventors

LI LIZHONG
LI LITONG
LIU KAIQIANG
HOU JIANRONG
LI XINSHENG
LI SHUTIAN
LI RUNBAO

Assignees

山西普德药业有限公司

Dates

Publication Date: 20260508
Application Date: 20260126

Claims (10)

1. A pharmaceutical composition for treating obstructive sleep apnea, which is characterized by comprising a ternary co-amorphous complex formed by Shu Sai m, L-arginine, a divalent zinc ion donor and a surface stabilizer, wherein the following raw materials are mixed according to the following proportion: Shu Sai Mei and L-arginine in a molar ratio of 1:1 to 1:2; A divalent zinc ion donor having a molar ratio of zinc ions to Shu Sai mex of 0.1:1 to 0.3:1; A surface stabilizer in an amount of 5% to 15% of the total mass of the composition.
2. The pharmaceutical composition for treating obstructive sleep apnea according to claim 1, comprising the following raw materials: Shu Sai molar ratio of mei to L-arginine is 1:1.1 to 1:1.5; the molar ratio of zinc ions to Shu Sai Mei 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. The pharmaceutical composition for treating obstructive sleep apnea according to claim 1 or 2, wherein the divalent zinc ion donor is selected from one or a combination of two of anhydrous zinc acetate and zinc gluconate, and the surface stabilizer is selected from one or a combination of two of poloxamer 188 and poloxamer 407.
4. A method of preparing a pharmaceutical composition for the treatment of obstructive sleep apnea according to claim 1 or 2, comprising the steps of: S1, preparing a coordination catalytic liquid, namely dissolving a zinc ion source in a solvent, and performing ultrasonic treatment with the power of 100-300W for 5-15 minutes to obtain the coordination catalytic liquid; s2, solid phase premixing, namely uniformly mixing Shu Sai Mei, L-arginine, poloxamer 188 and poloxamer 407 to obtain physical mixed powder; s3, performing high-energy mechanical ball milling, namely placing the physical mixed powder obtained in the step S2 and grinding balls comprising zirconia balls into a ball milling tank, adding the coordination catalyst liquid prepared in the step S1 into the powder as a grinding aid, and performing ball milling reaction to obtain wet slurry; S4, solidifying and drying, namely drying the wet slurry to remove the solvent, thus obtaining the pharmaceutical composition.
5. The method for preparing a pharmaceutical composition for treating obstructive sleep apnea according to claim 4, wherein in S1, the solvent is a 95% ethanol solution or a mixed solution of ethanol and water, and the volume ratio of the ethanol to the water mixed solution is preferably 9:1.
6. The method for preparing the pharmaceutical composition for treating obstructive sleep apnea according to claim 4, wherein in the step S3, the ball milling process parameters are controlled to be that the ball mass ratio is 20:1-50:1, the grinding speed is 300-500 rpm, and the total effective grinding time is 45-120 minutes.
7. The method for preparing a pharmaceutical composition for treating obstructive sleep apnea according to claim 4, wherein in the step S3, the addition amount of the coordination catalyst liquid is controlled to be 0.2-0.6. Mu.L/mg, or the ball milling process is performed under a protective atmosphere filled with dry nitrogen, and the milling temperature is controlled to be less than or equal to 30 ℃.
8. The method for preparing a pharmaceutical composition for treating obstructive sleep apnea according to claim 4, wherein in S4, the drying is vacuum drying, the drying temperature is 35 ℃ to 45 ℃, and the drying time is 12 hours to 24 hours.
9. The method of preparing a pharmaceutical composition for treating obstructive sleep apnea of claim 4, further comprising: s5, finishing, namely crushing the dried product and sieving the crushed product with a 80-mesh sieve.
10. Use of a pharmaceutical composition for the treatment of obstructive sleep apnea according to claim 1 or 2, in the manufacture of a medicament for the treatment of obstructive sleep apnea, wherein the medicament for the treatment of obstructive sleep apnea is an oral formulation, comprising a tablet, a capsule or a granule.

Description

Application of sulteume in preparation of medicines for treating obstructive sleep apnea Technical Field The invention relates to the technical field of medicines, in particular to an application of sultiamide in preparing a medicine for treating obstructive sleep apnea. Background Sultehime is a sulfonamide carbonic anhydrase inhibitor and is mainly used for treating partial epileptic seizure clinically. Recent medical research shows that sultebuthimide can stimulate respiratory drive, improve upper airway muscle tone, remarkably reduce the apnea hypopnea index of patients with Obstructive Sleep Apnea (OSA), and has potential to be a new medicine for treating OSA. However, shu Sai is a typical indissolvable drug, and the bulk drug exists in a stable crystal form with high lattice energy at normal temperature, so that the solubility of the bulk drug in a physiological pH value medium is extremely low, the passive diffusion and absorption of the drug through gastrointestinal epithelial cells are severely limited, and the clinical application defects of poor oral bioavailability, large blood concentration fluctuation and the like are caused. Although amorphous strategies are often adopted in the field of pharmaceutical crystal engineering, i.e. the conversion of drugs from low-energy crystals to high-energy amorphous forms to lower the dissolution energy barrier, the existing Shu Sai m amorphous systems are in a thermodynamically metastable state and have a high molecular mobility with a strong tendency to spontaneously lower the gibbs free energy and revert to the crystalline state. Aging or recrystallization is very easy to occur during the storage process, particularly under the condition of heating or moisture absorption, so that the medicine loses the solubilization advantage again and cannot meet the requirement of long-acting physical stability of the medicine. In order to solve the problem of absorption of poorly soluble drugs, the field of drug crystal engineering often adopts an amorphization strategy, i.e., the conversion of a drug from a low-energy state crystal to a high-energy state amorphous body. Although amorphous drugs can significantly reduce the dissolution energy barrier and increase apparent solubility due to the lack of long-range ordered lattice structure, they are thermodynamically metastable and have a strong tendency to spontaneously reduce the gibbs free energy to revert to the crystalline state. Amorphous drugs are highly susceptible to molecular rearrangement and nucleation growth during storage, particularly under heated or hygroscopic conditions, resulting in "aging" or recrystallization, thereby losing their solubilizing advantage. Current improvements include mainly the preparation of polymer solid dispersions or drug-small molecule co-amorphous forms. For solid dispersions, to maintain the dispersion stability of the drug, a large amount of hydrophilic polymeric carrier is usually added, which results in an excessively large volume of the final formulation, reduced patient compliance, and a portion of the polymeric carrier has a strong hygroscopicity, which in turn accelerates the crystal transformation of the drug. However, the existing Shu Sai Mei binary co-amorphous system reduces the dosage of the carrier, but the intermolecular force between the drug and the ligand is often not strong enough, or the glass transition temperature of the system is low, so that the molecular chain segment still has higher movement capability at room temperature, and the physical stability is difficult to maintain in long-term storage. In addition, conventional preparation processes such as melt quenching tend to cause degradation of heat sensitive drugs, while solvent evaporation involves the use of large amounts of organic solvents, with the risk of exceeding the residual solvents. Disclosure of Invention The technical problem solved by the invention is that Shu Sai Mei medicine usually exists in a crystal form in a solid state, the water solubility is poor, the oral bioavailability is low, the Shu Sai Mei amorphous body prepared by the conventional amorphization technology is in a thermodynamic high-energy state, the crystal transformation is easy to occur, and the physical stability is difficult to meet the long-term storage requirement. In order to solve the problems, the invention provides the following technical scheme: First aspect The invention provides a pharmaceutical composition for treating obstructive sleep apnea, which adopts the following technical scheme: a pharmaceutical composition for treating obstructive sleep apnea comprises a ternary co-amorphous complex containing zinc ions, wherein the ternary co-amorphous complex comprises Shu Sai Mei and L-arginine in a molar ratio of 1:1 to 1:2, a divalent zinc ion donor in a molar ratio of 0.1:1 to 0.3:1, and a surface stabilizer, wherein the content of the surface stabilizer is 5 to 15 percent of the total mass of the compositio