A high-dissolution poltezonide solid preparation and a preparation method thereof

Abstract

The application belongs to the technical field of medical preparations, and particularly relates to a high-dissolution solid preparation of multitarget and a preparation method thereof. The solid preparation is composed of 5-20% of multitarget, 10-30% of alkaline amino acid, 40-70% of hydrophilic filler, 2-10% of disintegrant, 0.1-1% of metal ion complexing agent and 0.5-2% of lubricant according to percentage by weight. The multitarget and the alkaline amino acid form a co-amorphous state in a molar ratio of 1:1 to 1:3. The preparation method comprises the following steps: dissolving the multitarget and the alkaline amino acid in an organic solvent containing volatile acid, removing the solvent under reduced pressure to obtain a co-amorphous substance, mixing the co-amorphous substance with the hydrophilic filler, the disintegrant and the metal ion complexing agent, and mixing the mixture with the lubricant after dry granulation and then compressing the mixture into tablets. The application eliminates the lattice energy limitation of the multitarget, realizes supersaturated dissolution, inhibits recrystallization during storage, maintains stable dissolution curve, improves drug loading capacity, and avoids damage to the amorphous state caused by moisture and heat through dry granulation.

Description

Technical Field

[0001] This invention belongs to the field of medical preparation technology, specifically a high-dissolution dotenorazole solid dosage form and its preparation method. Background Technology

[0002] Dotenorazole is a poorly soluble drug. To improve its in vitro dissolution rate and in vivo bioavailability, conventional techniques often employ micronization or the preparation of solid dispersions using polymeric carriers. Micronization reduces drug particle size and increases specific surface area through mechanical shearing. Solid dispersion preparation typically involves mixing dotenorazole with a water-soluble polymeric carrier such as povidone or copovidone, and then using hot-melt extrusion or spray drying processes to disperse the drug in an amorphous form within the carrier, disrupting the drug's original crystal structure and increasing the dissolution rate.

[0003] Based on the above implementation methods, existing polymeric carrier solid dispersions are prone to phase separation under high temperature and humidity environments. Drug molecule migration leads to recrystallization, and the drug transforms from an amorphous state to a stable crystalline form, causing a decrease in the solubility of solid dosage forms. Simultaneously, the polymeric carrier constitutes a large proportion of the system, resulting in low drug loading in solid dosage forms, which cannot meet the requirements for high-dose drug administration. Existing technologies suffer from insufficient recrystallization inhibition by polymeric carriers and low drug loading in solid dosage forms. Summary of the Invention

[0004] To address the shortcomings of existing dotenoroxetine polymeric carrier solid dispersions, such as easy recrystallization under high temperature and humidity conditions leading to decreased dissolution and low drug loading in solid dosage forms due to large amounts of polymeric carrier, this invention provides a high-dissolution dotenoroxetine solid dosage form and its preparation method.

[0005] To address the aforementioned technical problems, this invention provides a high-dissolution dotenoradine solid dosage form, comprising, by weight percentage: 5%-20% dotenoradine, 10%-30% basic amino acids, 40%-70% hydrophilic filler, 2%-10% disintegrant, 0.1%-1% metal ion chelating agent, and 0.5%-2% lubricant; the dotenoradine and the basic amino acids exist in a co-amorphous form in the solid dosage form, wherein the molar ratio of the dotenoradine to the basic amino acids in the co-amorphous form is 1:1 to 1:3; the basic amino acid is arginine or lysine; the hydrophilic filler comprises water-soluble fillers and porous fillers; the disintegrant comprises superdisintegrants and capillary disintegrants; and the lubricant is sodium stearate fumarate.

[0006] Dotenoroxetine is a weakly acidic drug containing acidic groups such as carboxyl groups in its molecular structure. These groups can form ionic bonds with the amino groups in basic amino acid molecules. Simultaneously, non-covalent interactions such as hydrogen bonds and van der Waals forces also exist between the two molecules. When dotenoroxetine and basic amino acids form a co-amorphous form in a specific molar ratio, the original crystal lattice structure of dotenoroxetine is completely destroyed. The drug molecules are no longer bound by lattice energy, allowing for rapid dissolution in the dissolution medium and the formation of a supersaturated solution. Basic amino acids, acting as co-amorphous forming agents, "anchor" dotenoroxetine molecules to the amorphous network through intermolecular interactions, effectively limiting drug molecule migration and rearrangement, and significantly inhibiting the transformation of dotenoroxetine to a stable crystalline form during storage. Using basic amino acids instead of traditional polymeric carriers significantly reduces the proportion of carriers in the formulation, thereby significantly increasing the drug loading of dotenoroxetine.

[0007] Furthermore, in the above technical solution, the molar ratio of dotenorazole to the basic amino acid in the amorphous form is 1:2; the basic amino acid is L-arginine; the metal ion complexing agent is disodium ethylenediaminetetraacetate or calcium disodium ethylenediaminetetraacetate; the weight percentage of disodium ethylenediaminetetraacetate or calcium disodium ethylenediaminetetraacetate is 0.2%-0.5%; the X-ray powder diffraction pattern of the amorphous form has no characteristic crystallization diffraction peaks in the 2θ angle range of 5° to 40°; the differential scanning calorimetry pattern of the amorphous form has no melting endothermic peak of dotenorazole in the range of 120° to 150°.

[0008] In practice, when the molar ratio of dotenoramide to L-arginine is 1:2, the acidic groups in the dotenoramide molecule can form the most stable ionic bond with the guanidinium group in the L-arginine molecule. At this point, the glass transition temperature of the co-amorphous state is the highest, and the physical stability is optimal. The absence of characteristic crystallization diffraction peaks in X-ray powder diffraction patterns and the absence of melting endothermic peaks in differential scanning calorimetry are direct evidence of the formation of the co-amorphous state, indicating that dotenoramide has been completely converted to the amorphous state. Disodium ethylenediaminetetraacetate or disodium calcium ethylenediaminetetraacetate, as metal ion complexing agents, can chelate trace metal ions introduced into the formulation raw materials and during the production process, preventing these metal ions from catalyzing oxidation, hydrolysis, and other degradation reactions of the dotenoramide molecule, thereby improving the chemical stability of the formulation.

[0009] Furthermore, in the above technical solution, the water-soluble filler in the hydrophilic filler is mannitol or xylitol, and the porous filler is a microcrystalline cellulose colloidal silica co-treated product; the weight ratio of the water-soluble filler to the porous filler is 3:1 to 1:1; the weight percentage of colloidal silica in the microcrystalline cellulose colloidal silica co-treated product is 2%-5%; and the bulk density of the porous filler is 0.25 g / mL to 0.35 g / mL.

[0010] In practice, water-soluble fillers such as mannitol or xylitol possess excellent water solubility and compressibility, enabling them to dissolve rapidly in the dissolution medium, forming hydrophilic channels and promoting water penetration into the formulation. Microcrystalline cellulose and colloidal silica co-treated materials exhibit abundant porous structures and a large specific surface area, allowing them to adsorb amorphous materials and prevent amorphous material aggregation during preparation and storage. Simultaneously, they increase the contact area between the drug and the dissolution medium, accelerating drug dissolution. Controlling the weight ratio of water-soluble filler to porous filler within the range of 3:1 to 1:1 balances the dissolution rate and compressibility of the formulation; controlling the bulk density of the porous filler within the range of 0.25 g / mL to 0.35 g / mL ensures sufficient adsorption capacity and good flowability.

[0011] Furthermore, in the above technical solution, the super disintegrant in the disintegrant is crospovidone, and the capillary disintegrant is low-substituted hydroxypropyl cellulose; the weight ratio of crospovidone to low-substituted hydroxypropyl cellulose is 2:1 to 1:2; the disintegrant is added to the solid dosage form by means of internal addition and external addition, wherein the internally added disintegrant accounts for 60%-80% of the total weight of the disintegrant, and the externally added disintegrant accounts for 20%-40% of the total weight of the disintegrant.

[0012] In practice, crospovidone, as a superdisintegrant, primarily disintegrates the formulation through the swelling force generated by its rapid expansion upon contact with water; low-substituted hydroxypropyl cellulose, as a capillary disintegrant, primarily draws water into the formulation rapidly through capillary action. When used in a weight ratio of 2:1 to 1:2, the two can exert a synergistic disintegrating effect, significantly accelerating the disintegration rate of the formulation. By combining internal and external addition of disintegrants, internally added disintegrants promote intraparticle disintegration, while externally added disintegrants promote interparticle disintegration, thereby achieving rapid and uniform disintegration of the formulation.

[0013] Furthermore, in the above technical solution, the particle size distribution characteristics of the co-amorphous morphology are: D90 less than or equal to 50 micrometers, D50 less than or equal to 20 micrometers; the angle of repose of the co-amorphous morphology is less than or equal to 35 degrees; the weight percentage of dotenoroxetine is 10%-15%; and the weight percentage of the basic amino acid is 15%-25%.

[0014] In practice, controlling the particle size distribution of the amorphous form within the aforementioned range ensures a sufficiently large specific surface area while avoiding poor flowability and dust issues caused by excessively small particle sizes. An angle of repose less than or equal to 35 degrees indicates good flowability of the amorphous form, which is beneficial for subsequent mixing and granulation processes. Controlling the weight percentage of domperidone at 10%-15% and the weight percentage of basic amino acids at 15%-25% maximizes the drug loading of the formulation while ensuring the formation of the amorphous form and physical stability.

[0015] Furthermore, in the above technical solution, the solid formulation further includes a surfactant, the surfactant having a weight percentage of 0.5%-2%; the surfactant is sodium dodecyl sulfate or polysorbate 80; the surfactant is premixed with the co-amorphous form to form an adsorption mixture; and the lubricant has a weight percentage of 0.8%-1.5%.

[0016] In practice, sodium dodecyl sulfate or polysorbate 80, as surfactants, can reduce the interfacial tension between dotenoramide and the dissolution medium, thereby improving the solubility and dissolution rate of dotenoramide. Premixing the surfactant with the amorphous material to form an adsorption mixture allows the surfactant to be evenly distributed on the surface of the amorphous material, better exerting its solubilizing effect. Controlling the weight percentage of the lubricant, sodium stearate fumarate, within the range of 0.8%-1.5% can effectively reduce the friction between the particles and the die during tableting, preventing sticking and tablet cracking, while also avoiding a decrease in solubility due to excessive lubricant usage.

[0017] Furthermore, the present invention also provides a method for preparing a high-dissolution dotenoradine solid dosage form, the method comprising the following steps: S1, dissolving dotenoradine and basic amino acids in an organic solvent containing volatile acid to form a clear solution; S2, removing the organic solvent from the clear solution under reduced pressure to obtain a co-amorphous compound of dotenoradine and basic amino acids; S3, mixing the co-amorphous compound with a hydrophilic filler, an internal disintegrant, and a metal ion complexing agent to obtain a mixed powder; S4, dry granulating the mixed powder to obtain dry granulated particles; S5, mixing the dry granulated particles with an external disintegrant and a lubricant and then compressing them into tablets to obtain the high-dissolution dotenoradine solid dosage form.

[0018] Adding volatile acids to the organic solvent promotes proton transfer between dotenoramide and basic amino acids, making it easier for them to form ionic bonds, thus facilitating the formation of the amorphous form. Using reduced pressure to remove the solvent allows for rapid removal of the organic solvent at lower temperatures, avoiding the damage to dotenoramide and basic amino acids caused by high temperatures, while also preventing solvent residue. Subsequent dry granulation and tableting avoids the damage to the amorphous form caused by the humid and hot environment during wet granulation, effectively maintaining the physical stability of the amorphous form and preventing recrystallization of dotenoramide during preparation.

[0019] Furthermore, in the above preparation method, in step S1, the organic solvent is a mixed solvent of dichloromethane and methanol, and the volume ratio of dichloromethane to methanol is 3:1 to 1:1; the volatile acid is formic acid or glacial acetic acid, and the volume percentage of the volatile acid in the organic solvent is 0.5%-2%; the dissolution temperature is 30°C to 45°C; and the solid content of the clarified solution is 10%-20%.

[0020] In practice, a mixed solvent of dichloromethane and methanol can simultaneously dissolve dotenoramide and basic amino acids. Optimal dissolution is achieved by controlling the volume ratio of the two solvents to be between 3:1 and 1:1. Formic acid or glacial acetic acid, as volatile acids, can be removed along with the organic solvent during subsequent depressurization, leaving no residue in the formulation. Controlling the dissolution temperature between 30°C and 45°C accelerates the dissolution rate while preventing dotenoramide degradation due to excessively high temperatures. Maintaining the solid content of the clarified solution within the range of 10%-20% ensures a suitable viscosity, which is beneficial for subsequent solvent removal and prevents residual crystals in the amorphous phase due to excessively high solid content.

[0021] Furthermore, in the above preparation method, in step S4, the pressure of the dry granulation roller is 3MPa to 8MPa, the gap between the rollers is 1.5mm to 3.0mm, and the mesh size of the granulation screen is 0.8mm to 1.2mm; in step S3, the amorphous material is first mixed with the porous filler in the hydrophilic filler, and then mixed with the water-soluble filler in the hydrophilic filler; the mixing time is 10 minutes to 20 minutes.

[0022] In practice, controlling the pressure of the rollers in dry granulation within the range of 3MPa to 8MPa ensures that the mixed powder forms particles with suitable hardness, while avoiding excessive pressure that could cause amorphous transformation. Controlling the roller gap and the granulation screen aperture within these ranges yields particles with uniform size distribution. Pre-mixing the amorphous material with a porous filler allows the filler to fully adsorb the amorphous material, preventing agglomeration. Then, mixing it with a water-soluble filler ensures uniform mixing of all components. Controlling the mixing time within the range of 10 to 20 minutes improves production efficiency while ensuring uniform mixing.

[0023] Furthermore, in the above preparation method, in step S5, the dry granulation particles are first mixed with the added disintegrant for 5 to 10 minutes, and then mixed with the lubricant for 2 to 5 minutes; the relative humidity of the tableting environment is less than or equal to 40%; the main pressure of the tableting is 5 kN to 15 kN; the X-ray powder diffraction pattern of the amorphous material before tableting has no characteristic crystalline diffraction peaks in the 2θ angle range of 5° to 40°.

[0024] In practice, the dry-granulated granules are first mixed with the added disintegrant, and then mixed with the lubricant. This avoids the lubricant coating the disintegrant surface and affecting its disintegration effect. Controlling the mixing time within the above-mentioned range ensures uniform mixing of all components and avoids granule breakage due to excessive mixing time. Controlling the relative humidity of the tableting environment to less than or equal to 40% prevents the amorphous material from absorbing moisture and recrystallizing. Controlling the main tableting pressure within the range of 5kN to 15kN produces tablets with suitable hardness and brittleness, while avoiding excessive pressure that could cause crystal transformation of the amorphous morphology. The X-ray powder diffraction pattern of the amorphous material before tableting shows no characteristic crystallization diffraction peaks, indicating that domperidone remains in an amorphous state throughout the preparation process, ensuring the dissolution performance of the formulation.

[0025] Compared with the prior art, the beneficial effects of the present invention are as follows: 1. This invention involves reacting dotenoroxetine with basic amino acids in a molar ratio of 1:1 to 1:3 to form a co-amorphous state, disrupting the original crystal lattice structure of dotenoroxetine, eliminating lattice energy constraints, and achieving a supersaturated dissolution state. The basic amino acids interact with dotenoroxetine molecules, limiting their migration and rearrangement, inhibiting recrystallization during storage, and maintaining a stable dissolution profile. By using basic amino acids instead of polymeric carriers, the amount of carrier in the system is reduced, increasing the drug loading of the solid dosage form.

[0026] 2. This invention, based on the co-amorphous form, combines a water-soluble filler with a porous filler. The porous filler adsorbs the co-amorphous material, increasing the contact area between the drug and the dissolution medium. Superdisintegrants and capillary disintegrants are added internally and externally in proportion to accelerate water penetration into the solid dosage form and particle disintegration. A metal ion chelating agent is added to prevent metal ions from catalyzing drug degradation. In the preparation method, the drug and amino acids are dissolved in an organic solvent containing volatile acids. The solvent is removed under reduced pressure to form the co-amorphous material. Subsequently, dry granulation and tableting are used to avoid damage to the co-amorphous form under humid and hot conditions, maintaining the physical stability of the amorphous form. Detailed Implementation

[0027] The present invention will be further described in detail below with reference to embodiments. Those skilled in the art can reproduce the technical solution of the present invention and achieve its claimed technical effects based on the content disclosed in this specification. It should be noted that the following embodiments are only used to explain the present invention and are not intended to limit the scope of protection of the present invention. Any non-substantial improvements and adjustments made based on the core concept of the present invention should fall within the scope of protection of the present invention.

[0028] Example 1: This example provides a high-dissolution dotenoradine solid dosage form, which, by weight percentage, comprises: 12% dotenoradine, 10% L-arginine, 46.33% mannitol, 23.17% microcrystalline cellulose-colloidal silica co-treated product (colloidal silica weight percentage 3%, bulk density 0.30 g / mL), 3% crospovidone, 3% low-substituted hydroxypropyl cellulose, 0.3% disodium EDTA, 1% sodium dodecyl sulfate, and 1.2% sodium stearate fumarate. The molar ratio of dotenoradine to L-arginine is 1:2.01, and the amorphous particle size distribution is D90 = 32 μm, D50 = 15 μm, and angle of repose 32 degrees.

[0029] Its preparation method includes the following steps: S1. Add 120g dotenorazole and 100g L-arginine to 1470mL of mixed solvent, which is prepared by mixing dichloromethane and methanol in a volume ratio of 2:1 and contains 1% glacial acetic acid by volume; stir at 35°C until completely dissolved to form a clear solution with a solid content of 15%. S2. Transfer the above clear solution to a rotary evaporator and remove the organic solvent by vacuum distillation at 40℃ and -0.09MPa until constant weight is obtained to obtain a co-amorphous compound of dotenoroxetine and L-arginine; pulverize the co-amorphous compound and pass it through a 100-mesh sieve for later use. S3. Mix the above amorphous material with 231.7g of microcrystalline cellulose colloidal silica co-treated material for 10 minutes, then add 463.3g of mannitol, 24g of crospovidone, 24g of low-substituted hydroxypropyl cellulose, and 3g of disodium ethylenediaminetetraacetate, and continue mixing for 10 minutes to obtain a mixed powder. S4. Feed the mixed powder into a dry granulator, set the pressure of the pressure roller to 5MPa, the gap between the pressure rollers to 2.0mm, and the mesh size of the granulation screen to 1.0mm to obtain dry granulated granules. S5. Mix the dry-granulated granules with 6g of cross-linked povidone and 6g of low-substituted hydroxypropyl cellulose for 7 minutes, then add 12g of sodium stearate fumarate and mix for 3 minutes; compress the tablets under the conditions of 35% relative humidity and 10kN main compression pressure to obtain 1000 tablets of high-dissolution dotenoradine solid dosage form.

[0030] Example 2: The only difference between this example and Example 1 is that: the weight percentage of dotenoroxetine is 18%, the weight percentage of L-arginine is 7.5%, and the molar ratio of the two is 1:1.02; the weight percentage of mannitol is 42.83%, and the weight percentage of the microcrystalline cellulose colloidal silica co-treated product is 21.17%. The remaining components and preparation methods are the same as in Example 1.

[0031] Example 3: The only difference between this example and Example 1 is that: the weight percentage of dotenorazole is 10%, the weight percentage of L-arginine is 12.5%, and the molar ratio of the two is 1:2.99; the weight percentage of mannitol is 47.67%, and the weight percentage of the microcrystalline cellulose colloidal silica co-treated product is 23.83%. The remaining components and preparation methods are the same as in Example 1.

[0032] Example 4: The only difference between this example and Example 1 is that the basic amino acid is replaced with L-lysine, which accounts for 8.37% by weight and has a molar ratio of 1:2.03 with dotenorazole; the weight percentage of mannitol is 47.96%; and the weight percentage of the microcrystalline cellulose colloidal silica co-treated product is 23.97%. The remaining components and preparation methods are the same as in Example 1.

[0033] Example 5: The only difference between this example and Example 1 is that the water-soluble filler is replaced with xylitol, with a weight percentage of 46.33%. The remaining components and preparation methods are the same as in Example 1.

[0034] Example 6: The only difference between this example and Example 1 is that the disintegrant composition is 4% crospovidone and 2% low-substituted hydroxypropyl cellulose, with a weight ratio of 2:1; the internal disintegrant is 3.2g crospovidone and 1.6g low-substituted hydroxypropyl cellulose, and the external disintegrant is 0.8g crospovidone and 0.4g low-substituted hydroxypropyl cellulose. All other components and preparation methods are the same as in Example 1.

[0035] Example 7: The only difference between this example and Example 1 is that the disintegrant composition is 2% crospovidone and 4% low-substituted hydroxypropyl cellulose, with a weight ratio of 1:2; the internal disintegrant is 1.6g crospovidone and 3.2g low-substituted hydroxypropyl cellulose, and the external disintegrant is 0.4g crospovidone and 0.8g low-substituted hydroxypropyl cellulose. All other components and preparation methods are the same as in Example 1.

[0036] Example 8: The only difference between this example and Example 1 is that the metal ion complexing agent is replaced with calcium disodium ethylenediaminetetraacetate, with a weight percentage of 0.3%. The remaining components and preparation methods are the same as in Example 1.

[0037] Example 9: The only difference between this example and Example 1 is that the surfactant is replaced with polysorbate 80, which accounts for 1% by weight. The remaining components and preparation methods are the same as in Example 1.

[0038] Example 10: The only difference between this example and Example 1 is that the mixed solvent in step S1 is prepared by mixing dichloromethane and methanol in a volume ratio of 3:1. The remaining components and preparation methods are the same as in Example 1.

[0039] Example 11: The only difference between this example and Example 1 is that the pressure of the roller in the dry granulation process in step S4 is 3 MPa. All other components and preparation methods are the same as in Example 1.

[0040] Example 12: The only difference between this example and Example 1 is that the main pressure for tablet compression in step S5 is 15 kN. All other components and preparation methods are the same as in Example 1.

[0041] Comparative Example 1: The only difference between this comparative example and Example 1 is that L-arginine is not added, the weight percentage of dotenorazole is 22%, the weight percentage of mannitol is 46.33%, and the weight percentage of the microcrystalline cellulose colloidal silica co-treated product is 23.17%. The remaining components and preparation methods are the same as in Example 1.

[0042] Comparative Example 2: This comparative example uses the polymer carrier solid dispersion technology described in the background art. Its components are: 12% dotenorazole, 30% povidone K30, 46.33% mannitol, 23.17% microcrystalline cellulose, 3% crospovidone, 3% low-substituted hydroxypropyl cellulose, and 1.2% sodium stearate fumarate.

[0043] The preparation method is as follows: 120g of dotenorazole and 300g of povidone K30 are dissolved in 80% ethanol aqueous solution to prepare a solution with a solid content of 15%; a solid dispersion is prepared by spray drying, with an inlet air temperature of 120℃ and an outlet air temperature of 60℃; the obtained solid dispersion is mixed with the remaining excipients according to steps S3 to S5 of Example 1, granulated and tableted.

[0044] Comparative Example 3: The only difference between this comparative example and Example 1 is that: the weight percentage of dotenoroxetine is 12%, the weight percentage of L-arginine is 16.7%, and the molar ratio of the two is 1:3.35, which exceeds the range of 1:1 to 1:3; the weight percentage of mannitol is 42.13%, and the weight percentage of the microcrystalline cellulose colloidal silica co-treated product is 21.07%. The remaining components and preparation methods are the same as in Example 1.

[0045] Comparative Example 4: The only difference between this comparative example and Example 1 is that glacial acetic acid is not added in step S1. The remaining components and preparation methods are the same as in Example 1.

[0046] Test method: Dissolution determination: Method II (paddle method) of General Chapter 0931, Part IV, Chinese Pharmacopoeia 2025 Edition was adopted. The dissolution medium was 900 mL of pH 6.8 phosphate buffer, the rotation speed was 50 rpm, and the temperature was 37℃. Samples were taken at 5, 10, 15, 30, and 45 minutes, and the dissolution amount of dotenoradine was determined by high performance liquid chromatography. The cumulative dissolution rate over 45 minutes was calculated.

[0047] Accelerated stability test: The formulations of each example and comparative example were placed at 40℃±2℃ and 75%±5% relative humidity for 6 months. Samples were taken at 0 months and 6 months respectively, and the cumulative dissolution rate was measured over 45 minutes. The crystal form change in the range of 5° to 40°2θ was detected by X-ray powder diffraction (XRD).

[0048] Related substances determination: Related substances in the sample after 6 months of accelerated testing were determined by high performance liquid chromatography, and the total impurity content was calculated by area normalization.

[0049] The test results are shown in Table 1: Table 1 Performance test results of each embodiment and comparative example

[0050] Results analysis: All embodiments achieved a dissolution rate of over 95% at 0 months and 45 minutes, significantly higher than Comparative Example 1 (35.6%), Comparative Example 2 (82.5%), Comparative Example 3 (88.3%), and Comparative Example 4 (76.4%). This indicates that the present invention disrupts the crystal structure of the drug by forming a co-amorphous form of dotenoradine and basic amino acids, eliminating lattice energy constraints and achieving rapid drug dissolution. Comparative Example 1 did not add basic amino acids, and dotenoradine existed in a crystalline state with extremely low dissolution; Comparative Example 4 did not add volatile acids, resulting in incomplete formation of the co-amorphous form, with some drug remaining in a crystalline state, leading to a significant decrease in dissolution.

[0051] After 6 months of accelerated testing, the dissolution rate at 45 minutes remained above 92% for all examples, and no characteristic crystallization peaks were observed in XRD analysis. However, the dissolution rate of Comparative Example 1 decreased to 28.3%, showing a strong characteristic crystallization peak; the dissolution rate of Comparative Example 2 decreased to 56.7%, showing a significant characteristic crystallization peak; the dissolution rate of Comparative Example 3 decreased to 65.2%, showing a weak characteristic crystallization peak; and the dissolution rate of Comparative Example 4 decreased to 42.8%, showing a significant characteristic crystallization peak. This indicates that the ionic bonds and non-covalent interactions formed between the basic amino acid and dotenoradine molecules in this invention can effectively limit the migration and rearrangement of drug molecules, significantly inhibiting the tendency for recrystallization during storage. Comparative Example 2 used a traditional polymer carrier, which is prone to phase separation under high temperature and high humidity conditions, leading to drug recrystallization; the molar ratio of Comparative Example 3 exceeded the range defined in this invention, resulting in insufficient intermolecular interactions and an inability to effectively inhibit recrystallization.

[0052] The total impurity content of all embodiments after 6 months of accelerated testing was below 0.15%, significantly lower than that of Comparative Example 1 (0.21%) and Comparative Example 2 (0.18%). This indicates that the metal ion chelating agent added in this invention can effectively chelate trace metal ions, preventing them from catalyzing drug degradation and improving the chemical stability of the formulation. In Comparative Example 1, the drug had high crystallinity and a small specific surface area, but due to the lack of protection from basic amino acids, the impurity content was still relatively high; in Comparative Example 2, the polymer carrier was prone to degradation under high temperature and high humidity conditions, thus accelerating drug degradation.

[0053] Examples 2 to 9, by replacing the types of excipients or adjusting the proportions of core components, and Examples 10 to 12, by adjusting the preparation process parameters, all achieved dissolution performance and stability comparable to Example 1. This demonstrates that the technical solution of the present invention has good robustness and can stably achieve the expected technical effects within a defined range.

[0054] In summary, this invention solves the technical problems of easy recrystallization, unstable dissolution, and low drug loading in the prior art by forming a co-amorphous form of dotenoradine with basic amino acids and combining it with specific excipient combinations and preparation processes.

Claims

1. A high-dissolution tenolorai solid dosage form, characterized in that, The solid dosage form comprises the following components by weight percentage: Dotenoxetine 5%-20%, basic amino acids 10%-30%, hydrophilic fillers 40%-70%, disintegrants 2%-10%, metal ion complexing agents 0.1%-1%, lubricants 0.5%-2%; The dotenoramide and the basic amino acid exist in the solid dosage form in a co-amorphous form, wherein the molar ratio of the dotenoramide to the basic amino acid in the co-amorphous form is 1:1 to 1:

3. The basic amino acid is arginine or lysine; The hydrophilic filler includes water-soluble fillers and porous fillers; The disintegrant includes superdisintegrants and capillary disintegrants; The lubricant is sodium stearate fumarate.

2. The high-dissolution dotenoradine solid dosage form according to claim 1, characterized in that, The molar ratio of dotenorazole to the basic amino acid in the co-amorphous form is 1:2; The basic amino acid is L-arginine; The metal ion complexing agent is disodium ethylenediaminetetraacetate or disodium calcium ethylenediaminetetraacetate. The weight percentage of disodium ethylenediaminetetraacetate or calcium disodium ethylenediaminetetraacetate is 0.2%-0.5%; The X-ray powder diffraction pattern of the amorphous morphology has no characteristic crystalline diffraction peaks in the 2θ angle range of 5° to 40°. The differential scanning calorimeter of the amorphous form showed no melting endothermic peak of dotenorazole in the temperature range of 120°C to 150°C.

3. The high-dissolution tenolorai solid dosage form according to claim 1, characterized in that, The water-soluble filler in the hydrophilic filler is mannitol or xylitol, and the porous filler is a microcrystalline cellulose colloidal silica co-treated product. The weight ratio of the water-soluble filler to the porous filler is 3:1 to 1:1; The weight percentage of colloidal silica in the microcrystalline cellulose colloidal silica co-treated product is 2%-5%; The bulk density of the porous filler is from 0.25 g / mL to 0.35 g / mL.

4. The high-dissolution dotenoradine solid dosage form according to claim 1, characterized in that, The super-disintegrant in the disintegrant is crospovidone, and the capillary disintegrant is low-substituted hydroxypropyl cellulose. The weight ratio of the cross-linked polyvinylpyrrolidone to the low-substituted hydroxypropyl cellulose is 2:1 to 1:2; The disintegrant is added to the solid dosage form by means of internal addition and external addition, wherein the internally added disintegrant accounts for 60%-80% of the total weight of the disintegrant, and the externally added disintegrant accounts for 20%-40% of the total weight of the disintegrant.

5. The high-dissolution dotenoradine solid dosage form according to claim 1, characterized in that, The particle size distribution characteristics of the amorphous morphology are D90 less than or equal to 50 micrometers and D50 less than or equal to 20 micrometers. The angle of repose of the co-amorphous form is less than or equal to 35 degrees; The weight percentage of dotenoroxetine is 10%-15%; The basic amino acids comprise 15%-25% by weight.

6. The high-dissolution dotenoradine solid dosage form according to claim 1, characterized in that, The solid dosage form further includes a surfactant, wherein the surfactant comprises 0.5%-2% by weight. The surfactant is sodium dodecyl sulfate or polysorbate 80; The surfactant and the co-amorphous form are premixed to form an adsorption mixture; The lubricant has a weight percentage of 0.8%-1.5%.

7. A method for preparing a high-dissolution tenoloretine solid dosage form, characterized in that, The method includes the following steps: S1. Dissolve dotenorazole and basic amino acids in an organic solvent containing volatile acid to form a clear solution; S2. Remove the organic solvent from the clarified solution under reduced pressure to obtain a co-amorphous compound of dotenoroxetine and basic amino acids; S3. The co-amorphous material is mixed with a hydrophilic filler, an internal disintegrant, and a metal ion complexing agent to obtain a mixed powder; S4. The mixed powder is subjected to dry granulation to obtain dry granulated particles; S5. The dry-granulated granules are mixed with an added disintegrant and lubricant and then compressed into tablets to obtain the high-dissolution dotenoradine solid dosage form.

8. The method for preparing high-dissolution tenoloretine solid dosage form according to claim 7, characterized in that, In step S1, the organic solvent is a mixture of dichloromethane and methanol, and the volume ratio of dichloromethane to methanol is 3:1 to 1:

1. The volatile acid is formic acid or glacial acetic acid, and the volume percentage of the volatile acid in the organic solvent is 0.5%-2%. The melting temperature is 30°C to 45°C; The solid content of the clarified solution is 10%-20%.

9. The method for preparing high-dissolution tenolactate solid dosage form according to claim 7, characterized in that, In step S4, the pressure of the rollers in the dry granulation process is 3MPa to 8MPa, the gap between the rollers is 1.5mm to 3.0mm, and the mesh size of the granulation screen is 0.8mm to 1.2mm. In step S3, the co-amorphous material is first mixed with the porous filler in the hydrophilic filler, and then mixed with the water-soluble filler in the hydrophilic filler; The mixing time is 10 to 20 minutes.

10. The method for preparing high-dissolution tenoloretine solid dosage form according to claim 7, characterized in that, In step S5, the dry granulated particles are first mixed with the added disintegrant for 5 to 10 minutes, and then mixed with the lubricant for 2 to 5 minutes. The relative humidity of the environment where the tablets are compressed is less than or equal to 40%; The main pressure of the tablet compression is 5kN to 15kN; The X-ray powder diffraction pattern of the amorphous material before tableting showed no characteristic crystalline diffraction peaks in the 2θ angle range of 5° to 40°.

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