Ketoprofen in situ co-amorphous compositions

Abstract

The application belongs to the technical field of medicine, and particularly relates to a ketoprofen in-situ co-amorphous composition. The co-amorphous composition is composed of ketoprofen, lysine, arginine and meglumine, and can spontaneously form a homogeneous disordered arrangement when contacting with an aqueous medium (including a dissolution process). Through powder X-ray diffraction, differential scanning calorimetry and Fourier infrared spectroscopy analysis, the three compositions can be co-amorphized in-situ when contacting with a trace amount of aqueous medium or in a dissolution process, so that the solubility and dissolution rate of ketoprofen are significantly improved, and the oral absorption and therapeutic effect of ketoprofen are expected to be enhanced. Meanwhile, the degree of in-situ co-amorphization is closely related to the molar ratio of the composition, the contacting time, the pH and the temperature of the medium. The application mediates the occurrence of in-situ co-amorphization of ketoprofen through prescription composition and design, improves the solubility and dissolution defects of the drug, and provides a new preparation idea.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to an in-situ co-amorphous composition of ketoprofen. Background Technology

[0002] Most drugs under development are poorly water-soluble, and low solubility and dissolution rate are the main reasons for their low oral bioavailability, thus limiting their clinical efficacy. Currently, an effective strategy to improve drug solubility and dissolution rate is to convert crystalline drugs into their amorphous form. However, amorphous forms are thermodynamically unstable systems and are prone to recrystallization during production, storage, and dissolution, leading to the loss of the advantages of amorphization.

[0003] Drugs are typically prepared into amorphous solid dispersions (ASDs) by combining drugs with polymer carriers. ASDs can, to some extent, suppress the risk of recrystallization during storage and dissolution. However, sometimes the miscibility between the drug and the polymer is poor. To meet formulation requirements, large amounts of high-molecular-weight polymers are often added, resulting in a larger final drug volume / mass. Furthermore, hydrophilic polymers, such as hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP), are often used in ASDs, easily absorbing moisture from the environment and promoting phase separation, leading to recrystallization of the amorphous drug. In recent years, co-amorphous drug formulations have emerged as an alternative technology. By combining drugs with low-molecular-weight ligands (such as amino acids, organic acids, low-molecular-weight sugars, and other ligands), and utilizing crystal engineering principles and methods, a single homogeneous co-amorphous drug system is formed between the drug and ligand through intermolecular non-covalent interactions (mainly hydrogen bonds). This is an effective strategy for stabilizing single amorphous drugs and overcoming the limitations of ASDs. However, instability still exists during storage and production, with the risk of recrystallization, affecting solubility.

[0004] The aforementioned drug ASD or co-amorphous systems are thermodynamically metastable systems, still subject to recrystallization risks during production and storage. Furthermore, their preparation processes require extensive trial and error, which is time-consuming and labor-intensive. In recent years, in-situ co-amorphization of drugs through formulation design has been introduced to overcome challenges in drug stability and manufacturing. The in-situ co-amorphization process occurs before or during drug administration. Through microwave or laser irradiation, the drug and ligand spontaneously form a co-amorphous system, avoiding production and physical stability issues. This is a very effective formulation strategy for solving drug solubility problems. However, microwave and laser irradiation processes are cumbersome, costly, and energy-intensive. Therefore, finding a simple method that does not require photothermal induction and can spontaneously form an in-situ co-amorphous system during administration is particularly necessary.

[0005] Ketoprofen (KET) is an excellent 2-arylpropionic acid nonsteroidal anti-inflammatory drug. Its chemical name is α-methyl-3-benzoylphenylacetic acid, and its chemical structure is shown in the following formula:

[0006]

[0007] Ketoprofen primarily exerts its antipyretic, analgesic, and anti-inflammatory effects by reversibly inhibiting the activity of cyclooxygenases (COXs) and pro-inflammatory peptides or lipoxygenases (LOXs), thereby inhibiting the biosynthesis of pro-inflammatory substances such as prostaglandins (PGs), leukotrienes (LTs), and thromboxanes (TXs), reducing bradykinin release, and thus exhibiting certain inhibitory effects on platelet adhesion and aggregation. Clinically, it is widely used to treat various types of rheumatoid arthritis, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis pain, rheumatoid arthritis, as well as dysmenorrhea, toothache, postoperative pain, cancer pain, and acute renal colic. Ketoprofen belongs to the BCSII class of drugs in the biopharmaceutics classification system. Its poor water solubility affects oral absorption; therefore, improving its solubility and dissolution rate will help improve its oral absorption. Summary of the Invention

[0008] The purpose of this invention is to provide compositions in which ketoprofen undergoes in-situ co-amorphization with three ligands (lysine, arginine, and meglumine). These three compositions can spontaneously undergo co-amorphization upon contact with an aqueous medium (including the dissolution process), i.e., in-situ co-amorphization, thereby effectively enhancing the solubility and dissolution rate of the poorly soluble drug ketoprofen and avoiding the risk of recrystallization during the preparation of amorphous drug formulations.

[0009] The technical solution adopted by the present invention to achieve the above objectives is as follows:

[0010] The ketoprofen-ligand in situ co-amorphous composition of the present invention is spontaneously formed by ketoprofen and lysine, meglumine or arginine respectively in contact with an aqueous medium (including the dissolution process).

[0011] This invention involves uniformly mixing ketoprofen with a ligand, then compressing the mixture into tablets at 10 MPa for 10 seconds using a tablet press. This facilitates the investigation of the in-situ co-amorphization formation process and influencing factors. The compressed tablets spontaneously undergo in-situ co-amorphization upon contact with an aqueous medium (including the dissolution process), significantly improving the solubility and dissolution rate of ketoprofen. Furthermore, it avoids the challenges of preparing amorphous drug formulations, determining process parameters, and addressing stability issues during storage.

[0012] The three ketoprofen in situ co-amorphous compositions of the present invention are made by mixing ketoprofen and ligand in a molar ratio of 10:1 to 1:10. The molar ratio of ketoprofen to ligand is preferably 3:1 to 1:3, and most preferably 1:1.

[0013] This invention investigated the degree of in-situ co-amorphization of three ketoprofen in-situ co-amorphous composition tablets after contact with a trace amount of aqueous medium (10-400 μL), based on a total tablet mass of 100 mg formed by ketoprofen and its ligand. Preferably, the amount of aqueous medium used was 20-200 μL, and most preferably 50 μL.

[0014] This invention investigated the degree of in-situ co-amorphization of three ketoprofen in-situ co-amorphous composition tablets at different time points within the range of 0–120 min of contact with an aqueous medium.

[0015] This invention investigated the degree of in-situ co-amorphization of three ketoprofen in-situ co-amorphous composition tablets at different temperatures ranging from 0 to 50°C.

[0016] This invention also investigated the degree of in-situ co-amorphization of three ketoprofen in-situ co-amorphous composition tablets in contact with aqueous media of different pH values ​​(1–8).

[0017] This invention, through powder X-ray diffraction analysis, confirms that the crystal diffraction peaks of three ketoprofen in situ co-amorphous composition tablets gradually decrease until they disappear after contact with an aqueous medium.

[0018] This invention, through differential scanning calorimetry analysis, confirms that after contact with an aqueous medium, the endothermic melting peak of the crystals in the three ketoprofen in situ co-amorphous composition tablets disappears, and a single glass transition temperature appears.

[0019] This invention, through Fourier transform infrared spectroscopy analysis, confirms that after contact with an aqueous medium, potential intermolecular interactions occur between ketoprofen and its ligands in three ketoprofen in situ co-amorphous composition tablets.

[0020] The beneficial effects of this invention are:

[0021] This invention addresses the water solubility deficiency of ketoprofen by introducing ligand components (lysine, arginine, and meglumine) to obtain three in-situ co-amorphous compositions for ketoprofen. These compositions can spontaneously undergo co-amorphization upon contact with an aqueous medium (including the dissolution process), effectively improving the solubility and dissolution rate of the poorly soluble drug ketoprofen, thereby enhancing the potential for oral absorption of poorly soluble drugs. Simultaneously, it avoids the crystallization risk during the preparation of amorphous drug formulations, providing a new and convenient approach for the formulation design of poorly soluble drugs. Attached Figure Description

[0022] Figure 1 These are powder X-ray diffraction patterns of the ketoprofen-lysine composition tablets in Examples 1-3 after in-situ co-amorphization (a: ketoprofen:lysine 1:1, b: ketoprofen:lysine 1:3, c: ketoprofen:lysine 3:1).

[0023] Figure 2 These are powder X-ray diffraction patterns of the ketoprofen-arginine composition tablets in Examples 1-3 after in-situ co-amorphization (a: ketoprofen:arginine 1:1, b: ketoprofen:arginine 1:3, c: ketoprofen:arginine 3:1);

[0024] Figure 3 These are powder X-ray diffraction patterns of the ketoprofen-meglumine composition tablets in Examples 1-3 after in-situ co-amorphization (a: ketoprofen:meglumine 1:1, b: ketoprofen:meglumine 1:3, c: ketoprofen:meglumine 3:1);

[0025] Figure 4 The differential scanning calorimetry (DSC) spectra of the ketoprofen-lysine composition tablets in Examples 1-3 after 120 min of in-situ co-amorphization are shown (a: ketoprofen:lysine 1:1, b: ketoprofen:lysine 1:3, c: ketoprofen:lysine 3:1).

[0026] Figure 5 These are differential scanning calorimeters of the ketoprofen-arginine composition tablets in Examples 1-3 after 120 min of in-situ co-amorphization (a: ketoprofen:arginine 1:1, b: ketoprofen:arginine 1:3, c: ketoprofen:arginine 3:1).

[0027] Figure 6 The differential scanning calorimetry (DSC) spectra of the ketoprofen-meglumine combination tablets in Examples 1-3 after 120 min of in-situ co-amorphization are shown (a: ketoprofen:meglumine 1:1, b: ketoprofen:meglumine 1:3, c: ketoprofen:meglumine 3:1).

[0028] Figure 7 The infrared spectra of the three ketoprofen in situ co-amorphous composition tablets in Example 1 at different times after in situ co-amorphization (a: ketoprofen: lysine 1:1, b: ketoprofen: arginine 1:1, c: ketoprofen: meglumine 1:1).

[0029] Figure 8 These are powder X-ray diffraction patterns of tablets containing the three ketoprofen in situ co-amorphous compositions in Examples 8-10 at different temperatures after in situ co-amorphization (a: ketoprofen: arginine 1:1, b: ketoprofen: lysine 1:1, c: ketoprofen: meglumine 1:1).

[0030] Figure 9 These are powder X-ray diffraction patterns of tablets containing three ketoprofen in situ co-amorphous compositions in Examples 11-16, which underwent in situ co-amorphization in contact with media of different pH values ​​(a: ketoprofen: arginine 1:1, b: ketoprofen: lysine 1:1, c: ketoprofen: meglumine 1:1).

[0031] Figure 10 This is a characteristic dissolution rate diagram of the three ketoprofen in situ co-amorphous compositions in Examples 1-3;

[0032] Figure 11 This is a phase solubility diagram of ketoprofen in aqueous solutions of ligands at different concentrations (a: ketoprofen-lysine composition, b: ketoprofen-arginine composition, c: ketoprofen-meglumine composition). Detailed Implementation

[0033] The present invention will be further described below with reference to the embodiments.

[0034] Example 1

[0035] 3.175 g of ketoprofen and 1.825 g of lysine, 2.967 g of ketoprofen and 2.033 g of arginine, and 2.829 g of ketoprofen and 2.171 g of meglumine were weighed and placed in 10 mL centrifuge tubes, respectively, and mixed in a vortex mixer (10 min) to obtain ketoprofen-ligand physical mixtures. 100 mg of each physical mixture was taken and compressed into tablets using a tablet press at 10 MPa for 10 s to form smooth, undamaged, and regular round tablets. Five groups of compressed tablets (3 tablets per group) were placed in a sealed box at 25 °C, and 50 μL of the same amount of deionized water was added to the surface of each tablet. The tablets were then freeze-dried for 24 h at 10, 30, 60, 90, and 120 min, respectively, and the degree of in-situ amorphization was analyzed.

[0036] Example 2

[0037] 1.835 g of ketoprofen and 3.165 g of lysine, 1.637 g of ketoprofen and 3.363 g of arginine, and 1.514 g of ketoprofen and 3.486 g of meglumine were weighed and placed in 10 mL centrifuge tubes, respectively, and mixed in a vortex mixer (10 min) to obtain ketoprofen-ligand physical mixtures. 100 mg of each physical mixture was taken and compressed into tablets using a tablet press at 10 MPa for 10 s to form smooth, undamaged, regular round tablets. Five groups of compressed tablets (3 tablets per group) were placed in a sealed box at 25 °C, and 50 μL of the same amount of deionized water was added to the surface of each tablet. The tablets were then freeze-dried for 24 h at 10, 30, 60, 90, and 120 min, respectively, and the degree of in-situ amorphization was analyzed.

[0038] Example 3

[0039] 4.196 g of ketoprofen and 0.804 g of lysine, 4.071 g of ketoprofen and 0.930 g of arginine, and 3.981 g of ketoprofen and 1.019 g of meglumine were weighed and placed in 10 mL centrifuge tubes, respectively, and mixed in a vortex mixer (10 min) to obtain ketoprofen-ligand physical mixtures. 100 mg of each physical mixture was taken and compressed into tablets using a tablet press at 10 MPa for 10 s to form smooth, undamaged, and regular round tablets. Five groups of compressed tablets (3 tablets per group) were placed in a sealed box at 25 °C, and 50 μL of the same amount of deionized water was added to the surface of each tablet. The tablets were then freeze-dried for 24 h at 10, 30, 60, 90, and 120 min, respectively, and the degree of in-situ amorphization was analyzed.

[0040] Example 4

[0041] 4.7282 g of ketoprofen and 0.2718 g of lysine, 4.679 g of ketoprofen and 0.321 g of arginine, and 4.643 g of ketoprofen and 0.357 g of meglumine were weighed into 10 mL centrifuge tubes and mixed in a vortex mixer (10 min) to obtain ketoprofen-ligand physical mixtures. 100 mg of each physical mixture was taken and compressed into tablets using a tablet press at 10 MPa for 10 s to form smooth, undamaged, regular round tablets. Five groups of compressed tablets (3 tablets per group) were placed in a sealed box at 25 °C. 50 μL of the same amount of deionized water was added to the surface of each tablet. The tablets were then freeze-dried for 24 h at 10, 30, 60, 90, and 120 min, and the degree of in-situ amorphization was analyzed.

[0042] Example 5

[0043] 0.74 g of ketoprofen and 4.26 g of lysine, 0.673 g of ketoprofen and 4.363 g of arginine, and 0.575 g of ketoprofen and 4.425 g of meglumine were weighed into 10 mL centrifuge tubes and mixed in a vortex mixer (10 min) to obtain ketoprofen-ligand physical mixtures. 100 mg of each physical mixture was taken and compressed into tablets using a tablet press at 10 MPa for 10 s to form smooth, undamaged, regular round tablets. Five groups of compressed tablets (3 tablets per group) were placed in a sealed box at 25 °C. 50 μL of the same amount of deionized water was added to the surface of each tablet. The tablets were then freeze-dried for 24 h at 10, 30, 60, 90, and 120 min, and the degree of in-situ amorphization was analyzed.

[0044] Example 6

[0045] 3.175 g of ketoprofen and 1.825 g of lysine, 2.967 g of ketoprofen and 2.033 g of arginine, and 2.829 g of ketoprofen and 2.171 g of meglumine were weighed and placed in 10 mL centrifuge tubes, respectively, and mixed in a vortex mixer (10 min) to obtain ketoprofen-ligand physical mixtures. 100 mg of each physical mixture was taken and compressed into tablets using a tablet press at 10 MPa for 10 s to form smooth, undamaged, regular round tablets. Five groups of compressed tablets (3 tablets per group) were placed in a sealed box at 25 °C, and 10 μL of the same amount of deionized water was added to the surface of each tablet. The tablets were then freeze-dried for 24 h at 10, 30, 60, 90, and 120 min, respectively, and the degree of in-situ amorphization was analyzed.

[0046] Example 7

[0047] 3.175 g of ketoprofen and 1.825 g of lysine, 2.967 g of ketoprofen and 2.033 g of arginine, and 2.829 g of ketoprofen and 2.171 g of meglumine were weighed and placed in 10 mL centrifuge tubes, respectively, and mixed in a vortex mixer (10 min) to obtain ketoprofen-ligand physical mixtures. 100 mg of each physical mixture was taken and compressed into tablets using a tablet press at 10 MPa for 10 s to form smooth, undamaged, regular round tablets. Five groups of compressed tablets (3 tablets per group) were placed in a sealed box at 25 °C, and 400 μL of the same amount of deionized water was added to the surface of each tablet. The tablets were then freeze-dried for 24 h at 10, 30, 60, 90, and 120 min, respectively, and the degree of in-situ amorphization was analyzed.

[0048] Example 8

[0049] 3.175 g of ketoprofen and 1.825 g of lysine, 2.967 g of ketoprofen and 2.033 g of arginine, and 2.829 g of ketoprofen and 2.171 g of meglumine were weighed and placed in 10 mL centrifuge tubes, respectively, and mixed in a vortex mixer (10 min) to obtain ketoprofen-ligand physical mixtures. 100 mg of each physical mixture was taken and compressed into tablets using a tablet press at 10 MPa for 10 s to form smooth, undamaged, regular round tablets. Five groups of compressed tablets (3 tablets per group) were placed in a sealed box at 4 °C, and 50 μL of the same amount of deionized water was added to the surface of each tablet. The tablets were then freeze-dried for 24 h at 10, 30, 60, 90, and 120 min, respectively, and the degree of in-situ amorphization was analyzed.

[0050] Example 9

[0051] 3.175 g of ketoprofen and 1.825 g of lysine, 2.967 g of ketoprofen and 2.033 g of arginine, and 2.829 g of ketoprofen and 2.171 g of meglumine were weighed into 10 mL centrifuge tubes and mixed in a vortex mixer for 10 min to obtain ketoprofen-ligand physical mixtures. 100 mg of the physical mixture was taken each time. Tableting was performed using a tablet press at 10 MPa for 10 s to form smooth, undamaged, regular round tablets. Five groups of three tablets were placed in a sealed box at 37 °C, and 50 μL of the same amount of deionized water was added to the surface of each tablet. The tablets were then freeze-dried for 24 h at 10, 30, 60, 90, and 120 min, and the degree of in-situ amorphization was analyzed.

[0052] Example 10

[0053] Weigh out 3.175g of ketoprofen and 1.825g of lysine, 2.967g of ketoprofen and 2.033g of arginine, and 2.829g of ketoprofen and 2.171g of meglumine, respectively, and place them in 10mL centrifuge tubes. Mix thoroughly in a vortex mixer (10min) to obtain ketoprofen-ligand physical mixtures. Take 100mg of the physical mixture each time. Compress the mixture using a tablet press at 10MPa for 10s to form smooth, undamaged, and regular round tablets. Place 5 groups (3 tablets per group) of the compressed tablets in a sealed box. At 50℃, add 50µL of the same amount of deionized water to the surface of each tablet. Remove the tablets at 10, 30, 60, 90, and 120min and freeze-dry for 24h. Analyze the degree of in-situ amorphization.

[0054] Example 11

[0055] Weigh out 3.175g of ketoprofen and 1.825g of lysine, 2.967g of ketoprofen and 2.033g of arginine, and 2.829g of ketoprofen and 2.171g of meglumine, respectively, and place them in 10mL centrifuge tubes. Mix thoroughly in a vortex mixer (10min) to obtain ketoprofen-ligand physical mixtures. Take 100mg of the physical mixture each time. Compress the mixture using a tablet press at 10MPa for 10s to form smooth, undamaged, and regular round tablets. Place 5 groups (3 tablets per group) of the compressed tablets in a sealed box. At 25℃, add 50uL of pH 1.2 buffer solution to the surface of each tablet. Remove the tablets at 10, 30, 60, 90, and 120min and freeze-dry for 24h. Analyze the degree of in-situ amorphization.

[0056] Example 12

[0057] Weigh out 3.175 g of ketoprofen and 1.825 g of lysine, 2.967 g of ketoprofen and 2.033 g of arginine, and 2.829 g of ketoprofen and 2.171 g of meglumine, respectively, and place them in 10 mL centrifuge tubes. Mix thoroughly in a vortex mixer (10 min) to obtain ketoprofen-ligand physical mixtures. Take 100 mg of the physical mixture each time. Compress the mixture using a tablet press at 10 MPa for 10 s to form smooth, undamaged, and regular round tablets. Place 5 groups (3 tablets per group) of the compressed tablets in a sealed box. At 25 °C, add 50 μL of pH 3.0 buffer solution to the surface of each tablet. Remove the tablets at 10, 30, 60, 90, and 120 min and freeze-dry for 24 h. Analyze the degree of in-situ amorphization.

[0058] Example 13

[0059] Weigh out 3.175g of ketoprofen and 1.825g of lysine, 2.967g of ketoprofen and 2.033g of arginine, and 2.829g of ketoprofen and 2.171g of meglumine, respectively, and place them in 10mL centrifuge tubes. Mix thoroughly in a vortex mixer (10min) to obtain ketoprofen-ligand physical mixtures. Take 100mg of the physical mixture each time. Compress the mixture using a tablet press at 10MPa for 10s to form smooth, undamaged, and regular round tablets. Place 5 groups (3 tablets per group) of the compressed tablets in a sealed box. At 25℃, add 50uL of pH 4.5 buffer solution to the surface of each tablet. Remove the tablets at 10, 30, 60, 90, and 120min and freeze-dry for 24h. Analyze the degree of in-situ amorphization.

[0060] Example 14

[0061] Weigh out 3.175g of ketoprofen and 1.825g of lysine, 2.967g of ketoprofen and 2.033g of arginine, and 2.829g of ketoprofen and 2.171g of meglumine, respectively, and place them in 10mL centrifuge tubes. Mix thoroughly in a vortex mixer (10min) to obtain ketoprofen-ligand physical mixtures. Take 100mg of the physical mixture each time. Compress the mixture using a tablet press at 10MPa for 10s to form smooth, undamaged, and regular round tablets. Place 5 groups (3 tablets per group) of the compressed tablets in a sealed box. At 25℃, add 50uL of pH5.4 buffer solution to the surface of each tablet. Remove the tablets at 10, 30, 60, 90, and 120min and freeze-dry for 24h. Analyze the degree of in-situ amorphization.

[0062] Example 15

[0063] Weigh out 3.175g of ketoprofen and 1.825g of lysine, 2.967g of ketoprofen and 2.033g of arginine, and 2.829g of ketoprofen and 2.171g of meglumine, respectively, and place them in 10mL centrifuge tubes. Mix thoroughly in a vortex mixer (10min) to obtain ketoprofen-ligand physical mixtures. Take 100mg of the physical mixture each time. Compress the mixture using a tablet press at 10MPa for 10s to form smooth, undamaged, and regular round tablets. Place 5 groups (3 tablets per group) of the compressed tablets in a sealed box. At 25℃, add 50uL of pH 6.8 buffer solution to the surface of each tablet. Remove the tablets at 10, 30, 60, 90, and 120min and freeze-dry for 24h. Analyze the degree of in-situ amorphization.

[0064] Example 16

[0065] Weigh out 3.175g of ketoprofen and 1.825g of lysine, 2.967g of ketoprofen and 2.033g of arginine, and 2.829g of ketoprofen and 2.171g of meglumine, respectively, and place them in 10mL centrifuge tubes. Mix thoroughly in a vortex mixer (10min) to obtain ketoprofen-ligand physical mixtures. Take 100mg of the physical mixture each time. Compress the mixture using a tablet press at 10MPa for 10s to form smooth, undamaged, and regular round tablets. Place 5 groups (3 tablets per group) of the compressed tablets in a sealed box. At 25℃, add 50uL of pH 7.4 buffer solution to the surface of each tablet. Remove the tablets at 10, 30, 60, 90, and 120min and freeze-dry for 24h. Analyze the degree of in-situ amorphization.

[0066] Comparative Example 1

[0067] Weigh 2.448 g of ketoprofen and 2.552 g of leucine, place them in a 10 mL centrifuge tube, and mix thoroughly in a vortex mixer (10 min) to obtain a ketoprofen-ligand physical mixture. Then, take an excess of the physical mixture and add it to a centrifuge tube containing 4 mL of deionized water. Perform triplicate of these steps, and shake in a shaker at 37 °C and 200 rpm for 24 h. Take 1 mL of the supernatant and filter it through a 0.45 μm microporous membrane. Determine the saturated solubility of the sample using high-performance liquid chromatography (HPLC).

[0068] Comparative Example 2

[0069] Weigh 3.167 g of ketoprofen and 1.833 g of glutamic acid into a 10 mL centrifuge tube and mix thoroughly in a vortex mixer (10 min) to obtain a ketoprofen-ligand physical mixture. Then, take an excess of the physical mixture and add it to a centrifuge tube containing 4 mL of deionized water. Perform triplicate mixing and shake in a shaker at 37 °C and 200 rpm for 24 h. Take 1 mL of the supernatant and filter it through a 0.45 μm microporous membrane. Determine the saturated solubility of the sample using high-performance liquid chromatography (HPLC).

[0070] Comparative Example 3

[0071] Weigh 3.703 g of ketoprofen and 1.297 g of alanine into a 10 mL centrifuge tube and mix thoroughly in a vortex mixer (10 min) to obtain a ketoprofen-ligand physical mixture. Then, take an excess of the physical mixture and add it to a centrifuge tube containing 4 mL of deionized water. Perform triplicate of these steps and shake in a shaker at 37 °C and 200 rpm for 24 h. Take 1 mL of the supernatant and filter it through a 0.45 μm microporous membrane. Determine the saturated solubility of the sample using high-performance liquid chromatography (HPLC).

[0072] Comparative Example 4

[0073] Weigh 3.422 g of ketoprofen and 1.578 g of valine into a 10 mL centrifuge tube and mix thoroughly in a vortex mixer (10 min) to obtain a ketoprofen-ligand physical mixture. Then, take an excess of the physical mixture and add it to a centrifuge tube containing 4 mL of deionized water. Perform triplicate of these steps and shake in a shaker at 37 °C and 200 rpm for 24 h. Take 1 mL of the supernatant and filter it through a 0.45 μm microporous membrane. Determine the saturated solubility of the sample using high-performance liquid chromatography (HPLC).

[0074] Test Example 1: The degree of in-situ co-amorphization of the three ketoprofen-ligand compositions in Example 1 was tested, as follows:

[0075] 1. Powder X-ray diffraction

[0076] Instrument: SmartLab9 X-ray diffractometer (Rigaku, Japan)

[0077] Target: Cu-Kα radiation

[0078] wavelength:

[0079] Pipe pressure: 40KV

[0080] Pipe current: 40mA

[0081] Step size: 0.02°

[0082] Scanning speed: 4° / min

[0083] Scan range; 2θ, 5-40°

[0084] Measurement results: such as Figure 1-3 In Example 1, the ketoprofen-lysine, ketoprofen-arginine, and ketoprofen-meglumine tablets, after contact with an aqueous medium, showed, through powder X-ray diffraction analysis, that the crystal diffraction peaks of the three combinations gradually weakened and eventually disappeared over time, indicating that spontaneous in-situ co-amorphization could occur. The three ketoprofen-ligand compositions in Examples 8-16 exhibited the same or similar in-situ co-amorphization behavior, and the degree of in-situ co-amorphization was closely related to the molar ratio of the combinations, the ambient temperature, and the pH of the medium.

[0085] In Examples 1-3, the molar ratio of ketoprofen to ligand in the three ketoprofen-ligand compositions significantly affected the degree of in-situ co-amorphization of the tablets after contact with an aqueous medium. When the molar ratio of ketoprofen to ligand was 1:1, a good in-situ co-amorphization trend was observed. Figure 1-3 ).

[0086] In Examples 8-10, the powder X-ray diffraction patterns of the three ketoprofen-ligand compositions at different temperatures are shown below. Figure 8 As shown, by Figure 8 It can be seen that, under the same medium volume and the same time, the decrease of the characteristic crystal diffraction peaks of the composition is more significant with the increase of temperature, indicating that temperature has a significant effect on in-situ co-amorphization, and the higher the temperature, the higher the degree of in-situ co-amorphization.

[0087] In Examples 11-16, the powder X-ray diffraction patterns of the three ketoprofen-ligand compositions at different pH values ​​(pH range 1-8) are shown below. Figure 9 As shown, by Figure 9 It can be seen that, under the same time conditions, the decrease in the characteristic crystal diffraction peaks of the composition is more significant as the pH value of the medium increases, indicating that the pH value of the medium affects the degree of in-situ co-amorphization of the ketoprofen composition.

[0088] 2. Differential scanning calorimetry

[0089] Instrument: HITACHIDSC 7020 Differential Scanning Thermal Analyzer (Hitachi Profile, Japan)

[0090] Range: 25-250℃

[0091] Heating rate: 10℃ / min

[0092] Measurement results: such as Figure 4-6As shown, at 120 min, the melting endothermic peaks of the proto-ketoprofen crystals and ligands in the three ketoprofen-ligand combination tablets weakened or disappeared, indicating that the three combination tablets underwent in-situ co-amorphization behavior after contact with the aqueous medium.

[0093] 3. Fourier transform infrared spectroscopy

[0094] Instrument: Thermo Scientific Nicolet iS50 Fourier Transform Infrared Spectrometer (Thermo Fisher Scientific, America)

[0095] Range: 4000-400cm -1

[0096] Number of scans: 32

[0097] Determination results: The Fourier transform infrared spectra of the three ketoprofen-ligand combination tablets after in-situ co-amorphization are shown below. Figure 7 As shown, by Figure 7 As shown in Figure a, the infrared absorption spectra of the 1:1 molar ratio ketoprofen-lysine combination, at 120 min, for the in-situ co-amorphous complex are 3382.3, 2942.4, 1649.1, 1572.1, 1448.2, 1393.1, 1358.9, 1319.4, 1248.4, 1179.8, 1139.7, 998.3, 880.3, 720.8, 643.5, and 550.8 cm⁻¹. -1 There is an absorption peak at that point.

[0098] Depend on Figure 7 As shown in b, the infrared absorption spectra of the 1:1 molar ratio ketoprofen-arginine combination, at 120 min, for the in-situ co-amorphous complex are 3366.6, 1597.6, 1384.7, 1352.8, 1280.1, 1106.9, 990.3, 775.8, 731.9, 655.2, and 617.9 cm⁻¹. -1 There is an absorption peak at that point.

[0099] Depend on Figure 7 As shown in c, the infrared absorption spectrum of the in-situ co-amorphous complex of the 1:1 molar ratio ketoprofen-meglumine combination at 120 min is 3378.4, 2336.6, 1655.4, 1574.2, 1448.2, 1394.1, 1284.5, 1081.2, 955.1, 882.5, 721.1, and 643.4 cm⁻¹. -1 There is an absorption peak at that point.

[0100] Test Example 2: The solubility and characteristic dissolution rate of the ketoprofen crystals and three ketoprofen-ligand compositions from Example 1 were tested, as follows:

[0101] 1. Solubility determination

[0102] Excess ketoprofen crystals, ketoprofen-lysine, ketoprofen-arginine, and ketoprofen-meglumine compositions, and other drug-ligand compositions in the same molar ratio from Examples 1, 4-5, and Comparative Examples 1-4 were added to centrifuge tubes containing 4 mL of deionized water, three in parallel. The tubes were shaken in a shaker at 37°C and 200 rpm for 24 h. 1 mL of the supernatant was filtered through a 0.45 μm microporous membrane, and the saturated solubility of different samples was determined by high performance liquid chromatography.

[0103] The high-performance liquid chromatography (HPLC) conditions are as follows:

[0104] Instrument: Agilent 1260 high performance liquid chromatograph

[0105] Column: Ultimate XB-C18 (4.6mm × 250mm, 5μm)

[0106] Mobile phase: Acetonitrile - 0.3% phosphoric acid solution = 50:50 (v / v)

[0107] Flow rate: 1.0 mL / min

[0108] Detection wavelength: 220nm

[0109] Table 1. Solubility of ketoprofen in water (n=3)

[0110]

[0111] Results: As shown in Table 1, the solubility of ketoprofen crystals in water was 209.43 μg / mL. Compared to ketoprofen crystals, the solubility of ketoprofen was significantly increased in the 1:1 ratios of ketoprofen-lysine, ketoprofen-arginine, and ketoprofen-meglumine, increasing by 6.28 times, 6.08 times, and 7.03 times, respectively. Other compositions had little effect on the solubility of ketoprofen.

[0112] 2. Determination of characteristic dissolution rate

[0113] 250 mg of ketoprofen crystals, ketoprofen-lysine combination, ketoprofen-arginine combination, and ketoprofen-meglumine combination were weighed in triplicate and compressed into tablets using a tablet press at 10 MPa for 10 seconds to form smooth, undamaged, and regular round tablets. The tablets were then placed in beeswax molds, ensuring only one circular surface was in contact with the dissolution medium. The apparatus was prepared according to General Chapter 0931, Method II (Paddle Method) of the 2020 edition of the Chinese Pharmacopoeia. The medium temperature was 37℃, the medium volume was 900 mL, the rotation speed was 50 rpm, and the dissolution medium was water. During the experiment, 2 mL samples were taken at 2, 5, 10, 15, 20, 30, 45, 60, 90, and 120 min, and 2 mL of constant temperature medium was added simultaneously. The extracts were filtered through a 0.45 μm aqueous microporous membrane and analyzed by high-performance liquid chromatography (HPLC). Characteristic dissolution rate via dissolution amount (mg / cm³) -2 The slope of the regression curve is calculated from the time (min).

[0114] Test results: The characteristic dissolution rates of ketoprofen crystals and ketoprofen-ligand compositions with different molar ratios are as follows: Figure 10 As shown in the figure, the introduction of ligand components significantly enhanced the dissolution rate of all ketoprofen-ligand compositions. Furthermore, the molar ratio of the compositions significantly affected the characteristic dissolution rate of ketoprofen. Specifically, the dissolution rate of the ketoprofen-ligand composition with a molar ratio of 3:1 was weaker than that of the composition with a molar ratio of 2:1. Compared to compositions with molar ratios of 3:1 and 2:1, ketoprofen-ligand compositions with molar ratios of 1:1 to 1:3 all exhibited high dissolution rates. In the first 15 minutes, the characteristic dissolution rates of the ketoprofen-lysine composition, ketoprofen-arginine composition, and ketoprofen-meglumine composition with a molar ratio of 1:1 were 999.712 times, 617.011 times, and 1274.682 times that of ketoprofen crystals, respectively.

[0115] Test Example 3: The phase solubility of the three ketoprofen-ligand compositions from Example 1 was tested, as follows:

[0116] Weigh 2.9238 g of lysine, 3.5038 g of arginine, and 3.9042 g of meglumine, respectively, and add them to 200 mL of deionized water in a 250 mL beaker. Then, dilute stepwise to prepare solutions of lysine, arginine, and meglumine at different concentrations (100, 50, 25, 12.5, 6.25, 3.125, 1.5625, 0.78, 0.39, 0.19, 0.09, and 0.04 mM). Weigh excess ketoprofen into a 5 mL centrifuge tube, and add 4 mL of each of the above-mentioned ligand solutions at different concentrations. Perform triplicate. Seal the centrifuge tubes and place them in a constant temperature shaker at 37℃ and 200 rpm for 24 h. Take a 1 mL sample, filter it through a 0.45 μm microporous membrane, and analyze it by high-performance liquid chromatography (HPLC).

[0117] Results of the determination: The phase solubility of ketoprofen crystals in aqueous solutions of ligands at different concentrations is as follows: Figure 11 As shown in the figure, the solubility of ketoprofen crystals increases non-linearly with increasing ligand concentration. The solubility of ketoprofen deviates negatively at high ligand concentrations, exhibiting a typical 1:1 A / B ratio. N Type complexation. Due to the intermolecular complexation reaction between ketoprofen and the selected ligands during the dissolution process, the solubility and dissolution rate of the three ketoprofen-ligand compositions are significantly improved.

Claims

1. A ketoprofen in situ co-amorphous composition, characterized in that, The co-amorphous composition is spontaneously formed by ketoprofen with lysine, meglumine, or arginine respectively upon contact with an aqueous medium; The molar ratio of ketoprofen to lysine, meglumine, or arginine is 10:1 to 1:

10.

2. The ketoprofen in situ co-amorphous composition according to claim 1, characterized in that, Contact with aqueous media involves a dissolution process.

3. The ketoprofen in situ co-amorphous composition according to claim 1, characterized in that, The molar ratio of ketoprofen to lysine, meglumine, or arginine is 3:1 to 1:

3.

4. The ketoprofen in situ co-amorphous composition according to claim 1, characterized in that, The amount of aqueous medium added is 10~400uL.

5. The ketoprofen in situ co-amorphous composition according to claim 1, characterized in that, The contact time between ketoprofen and lysine, meglumine or arginine and the aqueous medium is 10-120 min.

6. The ketoprofen in situ co-amorphous composition according to claim 1, characterized in that, The ambient temperature for contact between ketoprofen and lysine, meglumine, or arginine and aqueous media is 25~50℃.

7. The ketoprofen in situ co-amorphous composition according to claim 1, characterized in that, When ketoprofen and lysine, meglumine or arginine come into contact with an aqueous medium, the pH of the medium should be between 1 and 8.

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