Ketoprofen in-situ co-amorphous composition

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a ketoprofen in-situ co-amorphous composition. The co-amorphous composition is prepared from ketoprofen, lysine, arginine and meglumine, and homogeneous disordered arrangement can be spontaneously formed when the co-amorphous composition is in contact with an aqueous medium (including a dissolution process). Through powder X-ray diffraction, differential scanning calorimetry and Fourier infrared spectroscopic analysis, the three combinations can be subjected to in-situ co-amorphization in contact with a trace aqueous medium or in a dissolution process, so that the solubility and the dissolution rate of ketoprofen are remarkably improved, and the oral absorption and treatment effects of ketoprofen are expected to be enhanced. Meanwhile, the degree of in-situ co-amorphization is closely related to composition molar ratio, contact time, medium pH and temperature. The invention provides a new preparation thought for mediating in-situ co-amorphous generation of ketoprofen through prescription composition and design and improving the defects of drug solubility and dissolution rate.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and particularly relates to a ketoprofen in-situ co-amorphous composition. Background Art

[0002] Most of the drugs under development are poorly water-soluble drugs. Low drug solubility and dissolution rate are the main reasons for the low oral bioavailability of drugs, which restricts the clinical therapeutic effect of drugs. At present, an effective strategy to improve drug solubility and dissolution rate is to convert crystalline drugs into their amorphous form. However, the amorphous form is a thermodynamically unstable system and is prone to recrystallization during production, storage and dissolution, resulting in the loss of the advantages of amorphization.

[0003] Drugs and polymer carriers are usually prepared into amorphous solid dispersions (ASDs) of drugs. ASDs can, to a certain extent, suppress the risk of recrystallization of drugs during storage and dissolution. However, sometimes the miscibility of drugs and polymers is poor. In order to meet the formulation requirements, a large amount of high molecular weight polymers are usually added, resulting in a large final medication volume / mass. In addition, hydrophilic high molecular weight polymers such as hydroxypropyl methylcellulose (HPMC) and polyvinyl pyrrolidone (PVP) are often used in ASDs, which easily absorb moisture in the environment, causing ASD to phase separate and causing recrystallization of amorphous drugs. In recent years, drug co-amorphization has been used as an alternative technology to form a single homogeneous drug co-amorphous system by combining drugs with low molecular weight ligands (such as amino acids, organic acids, low molecular weight sugars and other ligands) using the principles and methods of crystal engineering. The drug and ligand form a single homogeneous drug co-amorphous system through intermolecular non-covalent bonds (mainly hydrogen bonds) between the drug and the ligand. This is an effective strategy to stabilize single amorphous drugs and overcome the limitations of ASD. However, it is still unstable during storage and production, and there is a risk of recrystallization, which affects solubility.

[0004] The above-mentioned drug ASD or co-amorphous system is a thermodynamically metastable system, and there is still a risk of recrystallization during production and storage, and its preparation process requires a lot of exploration and repeated experiments, which is time-consuming and laborious. In recent years, in situ co-amorphization of drugs through prescription design has been introduced to overcome the challenges of drug stability and production and manufacturing. The in situ co-amorphization process occurs before or during drug administration. Through microwave, laser irradiation, etc., the drug and ligand spontaneously form a co-amorphous system, avoiding the production and physical stability problems of the drug. It is a very effective formulation strategy to solve the problem of drug solubility. However, the operation process of microwave and laser irradiation is cumbersome, and the cost and energy consumption are high. Therefore, it is particularly necessary to find a simple method that does not require photothermal and other conditions to induce and can spontaneously form in situ co-amorphous during administration.

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

[0006]

[0007] Ketoprofen mainly inhibits the biosynthesis of inflammatory substances such as prostaglandins (PGs), leukotrienes (LTs) and thromboxanes (TXs) by reversibly inhibiting the activity of cyclooxygenase (COXs) proinflammatory peptides or lipoxygenase (LOXs), thereby reducing the release of bradykinin, thereby exerting its good antipyretic, analgesic and anti-inflammatory effects, and also has a certain inhibitory effect on platelet adhesion and aggregation reactions. It is widely used in the clinic to treat various rheumatoid arthritis, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis pain, rheumatic arthritis, as well as dysmenorrhea, toothache, postoperative pain, cancer pain and acute renal colic. Ketoprofen belongs to BCS II drugs in the biopharmaceutics classification system, and has poor water solubility, which affects the oral absorption of drugs. Therefore, improving its solubility and dissolution will help improve its oral absorption. Summary of the invention

[0008] The object of the present invention is to provide a composition in which ketoprofen is co-amorphized with three ligands (lysine, arginine, and meglumine) respectively in situ. The three compositions can co-amorphize by themselves when in contact with an aqueous medium (including the dissolution process), that is, co-amorphize in situ, thereby effectively enhancing the solubility and dissolution rate of the poorly soluble drug ketoprofen and avoiding the risk of recrystallization in the process of drug amorphous preparation.

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

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

[0011] The present invention uniformly mixes ketoprofen and a ligand, and then uses a tablet press to compress the mixture for 10 seconds under a pressure of 10 MPa to form a tablet dosage form, which is convenient for investigating the formation process and influencing factors of in-situ co-amorphization. The compressed tablet can spontaneously undergo in-situ co-amorphization when in contact with an aqueous medium (including a dissolution process), which can significantly improve the solubility and dissolution rate of ketoprofen, and avoids the preparation of amorphous drug preparations and the exploration of process parameters, as well as stability problems during storage.

[0012] The three ketoprofen in-situ co-amorphous compositions of the present invention are prepared 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] The present invention investigates the degree of in-situ co-amorphization of three ketoprofen in-situ co-amorphous composition tablets after contacting a trace amount of aqueous medium (10-400uL) based on the total mass of the tablet formed by ketoprofen and the ligand being 100mg. The preferred amount of aqueous medium is 20-200uL, and the most preferred is 50uL.

[0014] The present invention investigates 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 to 120 minutes of contact with an aqueous medium.

[0015] The present invention investigates the in-situ co-amorphization degree of three ketoprofen in-situ co-amorphous composition tablets at different temperatures of 0-50°C.

[0016] The present invention also investigates the in situ co-amorphization degree of three ketoprofen in situ co-amorphous composition tablets when in contact with aqueous media of different pH values ​​of 1 to 8.

[0017] The present invention uses powder X-ray diffraction analysis to confirm that after the three ketoprofen in-situ co-amorphous composition tablets are in contact with an aqueous medium, the crystal diffraction peaks gradually decrease until they disappear.

[0018] The invention uses differential scanning calorimetry analysis to confirm that after the three ketoprofen in-situ co-amorphous composition tablets are in contact with an aqueous medium, the endothermic melting peaks of the crystals disappear and a single glass transition temperature appears.

[0019] The invention uses Fourier infrared spectroscopy analysis to confirm that after the three ketoprofen in-situ co-amorphous composition tablets are in contact with an aqueous medium, potential intermolecular interactions occur between ketoprofen and ligands.

[0020] Beneficial effects of the present invention:

[0021] The present invention aims at the water solubility defect of ketoprofen. By introducing ligand components (lysine, arginine and meglumine), three ketoprofen in situ co-amorphous compositions are obtained. The compositions can undergo co-amorphization by themselves when in contact with an aqueous medium (including the dissolution process), effectively improving the solubility and dissolution rate of the poorly soluble drug ketoprofen, achieving the potential for enhancing the oral absorption of the poorly soluble drug, while avoiding the risk of crystallization in the process of preparing amorphous drug preparations, and providing a new and simple idea for the prescription design of poorly soluble drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 is the powder X-ray diffraction pattern of the ketoprofen-lysine composition tablets in Example 1-3 that underwent in-situ co-amorphization (a: ketoprofen: lysine 1:1, b: ketoprofen: lysine 1:3, c: ketoprofen: lysine 3:1);

[0023] Figure 2 is the powder X-ray diffraction pattern of the ketoprofen-arginine combination tablets in Example 1-3 that underwent in-situ co-amorphization (a: ketoprofen: arginine 1:1, b: ketoprofen: arginine 1:3, c: ketoprofen: arginine 3:1);

[0024] Figure 3 is the powder X-ray diffraction pattern of the ketoprofen-meglumine combination tablets in Example 1-3 that underwent 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 spectra of the ketoprofen-lysine composition tablets in Example 1-3 that underwent in-situ co-amorphization at 120 min (a: ketoprofen: lysine 1:1, b: ketoprofen: lysine 1:3, c: ketoprofen: lysine 3:1);

[0026] Figure 5 The differential scanning calorimetry spectra of the ketoprofen-arginine combination tablets in Example 1-3 that underwent in-situ co-amorphization at 120 min (a: ketoprofen: arginine 1:1, b: ketoprofen: arginine 1:3, c: ketoprofen: arginine 3:1);

[0027] Figure 6 The differential scanning calorimetry spectra of the ketoprofen-meglumine combination tablets in Example 1-3 that underwent in-situ co-amorphization at 120 min (a: ketoprofen: meglumine 1:1, b: ketoprofen: meglumine 1:3, c: ketoprofen: meglumine 3:1);

[0028] Figure 7 These are infrared spectra of three ketoprofen in situ co-amorphous composition tablets in Example 1 that underwent in situ co-amorphization at different times (a: ketoprofen: lysine 1:1, b: ketoprofen: arginine 1:1, c: ketoprofen: meglumine 1:1);

[0029] Figure 8 The powder X-ray diffraction patterns of the three ketoprofen in situ co-amorphous composition tablets in Examples 8-10 that underwent in situ co-amorphization at different temperatures (a: ketoprofen: arginine 1:1, b: ketoprofen: lysine 1:1, c: ketoprofen: meglumine 1:1);

[0030] Fig. 9 are powder X-ray diffraction patterns of the three ketoprofen in situ co-amorphous composition tablets in Examples 11-16 that underwent in situ co-amorphization in contact with different pH media (a: ketoprofen: arginine 1:1, b: ketoprofen: lysine 1:1, c: ketoprofen: meglumine 1:1);

[0031] Fig.10 is a characteristic dissolution rate graph of three ketoprofen in situ co-amorphous compositions in Examples 1-3;

[0032] Fig.11 It is the phase solubility diagram of ketoprofen in aqueous solutions of ligands with different concentrations (a: ketoprofen-lysine combination, b: ketoprofen-arginine combination, c: ketoprofen-meglumine combination). DETAILED DESCRIPTION

[0033] The present invention will be further described below in conjunction with the embodiments.

[0034] Example 1

[0035] Take ketoprofen 3.175g and lysine 1.825g, ketoprofen 2.967g and arginine 2.033g, ketoprofen 2.829g and meglumine 2.171g respectively and be placed in 10mL centrifuge tube, mix (10min) in vortex mixer, obtain ketoprofen-ligand physical mixture.Take 100mg physical mixture respectively at each time, use tablet press to carry out tabletting, under 10MPa pressure, suppress 10s, take out after making into the regular disc of smooth surface without damage for subsequent use.5 groups of compressed discs (3 per group) are placed in airtight box, under 25 ℃ of temperature conditions, every surface drips identical deionized water 50uL, takes out and carries out freeze drying 24h respectively at 10,30,60,90,120min, analyzes its original position amorphization degree.

[0036] Example 2

[0037] Take ketoprofen 1.835g and lysine 3.165g, ketoprofen 1.637g and arginine 3.363g, ketoprofen 1.514g and meglumine 3.486g respectively and be placed in 10mL centrifuge tube, mix (10min) in vortex mixer, obtain ketoprofen-ligand physical mixture.Take 100mg physical mixture respectively at every turn, use tablet press to carry out tabletting, under 10MPa pressure, suppress 10s, take out after making into the regular disc of smooth surface without damage for subsequent use.5 groups of compressed discs (3 in every group) are placed in airtight box, under 25 ℃ of temperature conditions, every surface drips identical deionized water 50uL, takes out and carries out freeze drying 24h when 10,30,60,90,120min respectively, analyzes its original position amorphization degree.

[0038] Example 3

[0039] Take ketoprofen 4.196g and lysine 0.804g, ketoprofen 4.071g and arginine 0.930g, ketoprofen 3.981g and meglumine 1.019g respectively and be placed in 10mL centrifuge tube, mix (10min) in vortex mixer, obtain ketoprofen-ligand physical mixture.Take 100mg physical mixture respectively at every turn, use tablet press to carry out tabletting, under 10MPa pressure, suppress 10s, take out after making into the regular disc of smooth surface without damage for subsequent use.5 groups of compressed discs (3 in every group) are placed in airtight box, under 25 ℃ of temperature conditions, every surface drips identical deionized water 50uL, takes out and carries out freeze drying 24h when 10,30,60,90,120min respectively, analyzes its original position amorphization degree.

[0040] Example 4

[0041] Take ketoprofen 4.7282g and lysine 0.2718g, ketoprofen 4.679g and arginine 0.321g, ketoprofen 4.643g and meglumine 0.357g respectively and be placed in 10mL centrifuge tube, mix (10min) in vortex mixer, obtain ketoprofen-ligand physical mixture.Take 100mg physical mixture respectively at each time, use tablet press to carry out tabletting, under 10MPa pressure, suppress 10s, take out after making into the regular disc of smooth surface without damage for subsequent use.5 groups of compressed discs (3 in every group) are placed in airtight box, under 25 ℃ of temperature conditions, every surface drips identical deionized water 50uL, takes out and carries out freeze drying 24h when 10,30,60,90,120min respectively, analyzes its original position amorphization degree.

[0042] Example 5

[0043] Take ketoprofen 0.74g and lysine 4.26g, ketoprofen 0.673g and arginine 4.363g, ketoprofen 0.575g and meglumine 4.425g respectively and be placed in 10mL centrifuge tube, mix (10min) in vortex mixer, obtain ketoprofen-ligand physical mixture.Take 100mg physical mixture respectively at each time, use tablet press to carry out tabletting, under 10MPa pressure, suppress 10s, take out after making into the regular disc of smooth surface without damage for subsequent use.5 groups of compressed discs (3 in every group) are placed in airtight box, under 25 ℃ of temperature conditions, every surface drips identical deionized water 50uL, takes out and carries out freeze drying 24h when 10,30,60,90,120min respectively, analyzes its original position amorphization degree.

[0044] Example 6

[0045] Take ketoprofen 3.175g and lysine 1.825g, ketoprofen 2.967g and arginine 2.033g, ketoprofen 2.829g and meglumine 2.171g respectively and be placed in 10mL centrifuge tube, mix (10min) in vortex mixer, obtain ketoprofen-ligand physical mixture.Take 100mg physical mixture respectively at each time, use tablet press to carry out tabletting, under 10MPa pressure, suppress 10s, take out after making into the regular disc of smooth surface without damage for subsequent use.5 groups of compressed discs (3 in every group) are placed in airtight box, under 25 ℃ of temperature conditions, every surface drips identical deionized water 10uL, takes out and carries out freeze drying 24h when 10,30,60,90,120min respectively, analyzes its original position amorphization degree.

[0046] Example 7

[0047] Take ketoprofen 3.175g and lysine 1.825g, ketoprofen 2.967g and arginine 2.033g, ketoprofen 2.829g and meglumine 2.171g respectively and be placed in 10mL centrifuge tube, mix (10min) in vortex mixer, obtain ketoprofen-ligand physical mixture.Take 100mg physical mixture respectively at each time, use tablet press to carry out tabletting, under 10MPa pressure, suppress 10s, take out after making into the regular disc of smooth surface without damage for subsequent use.5 groups of compressed discs (3 per group) are placed in airtight box, under 25 ℃ of temperature conditions, every surface drips identical deionized water 400uL, takes out and carries out freeze drying 24h respectively at 10,30,60,90,120min, analyzes its original position amorphization degree.

[0048] Example 8

[0049] Take ketoprofen 3.175g and lysine 1.825g, ketoprofen 2.967g and arginine 2.033g, ketoprofen 2.829g and meglumine 2.171g respectively and be placed in 10mL centrifuge tube, mix (10min) in vortex mixer, obtain ketoprofen-ligand physical mixture.Take 100mg physical mixture respectively at each time, use tablet press to carry out tabletting, under 10MPa pressure, suppress 10s, make into smooth surface without damaged regular disc and take out for use.5 groups of compressed discs (3 per group) are placed in airtight box, under 4 ℃ of temperature conditions, every surface drips identical deionized water 50uL, takes out and carries out freeze drying 24h when 10,30,60,90,120min respectively, analyzes its original position amorphization degree.

[0050] Example 9

[0051] Weigh ketoprofen 3.175g and lysine 1.825g, ketoprofen 2.967g and arginine 2.033g, ketoprofen 2.829g and meglumine 2.171g respectively and be placed in 10mL centrifuge tube, mix (10min) in vortex mixer, obtain ketoprofen-ligand physical mixture.Take 100mg physical mixture respectively at each time.Use tabletting machine to carry out tabletting, under 10MPa pressure, suppress 10s, take out after making into the regular disc with smooth surface and no damage for standby use.5 groups of compressed discs (3 per group) are placed in airtight box, under 37 ℃ of temperature conditions, every surface drips identical deionized water 50uL, takes out and carries out freeze drying 24h when 10,30,60,90,120min respectively, analyzes its original position amorphization degree.

[0052] Example 10

[0053] Weigh ketoprofen 3.175g and lysine 1.825g, ketoprofen 2.967g and arginine 2.033g, ketoprofen 2.829g and meglumine 2.171g respectively and be placed in 10mL centrifuge tube, mix (10min) in vortex mixer, obtain ketoprofen-ligand physical mixture.Take 100mg physical mixture respectively at each time.Use tabletting machine to carry out tabletting, under 10MPa pressure, suppress 10s, take out after making into the regular disc with smooth surface and no damage for standby use.5 groups of compressed discs (3 per group) are placed in airtight box, under 50 ℃ of temperature conditions, every surface drips identical deionized water 50uL, takes out and carries out freeze drying 24h respectively at 10,30,60,90,120min, analyzes its original position amorphization degree.

[0054] Embodiment 11

[0055] Weigh ketoprofen 3.175g and lysine 1.825g, ketoprofen 2.967g and arginine 2.033g, ketoprofen 2.829g and meglumine 2.171g respectively and be placed in 10mL centrifuge tube, mix (10min) in vortex mixer, obtain ketoprofen-ligand physical mixture.Take 100mg physical mixture respectively at each time.Use tabletting machine to carry out tabletting, under 10MPa pressure, suppress 10s, take out after making into the regular disc with smooth surface and no damage for standby use.5 groups of compressed discs (3 per group) are placed in airtight box, under 25 ℃ of temperature conditions, every surface drips pH1.2 buffer 50uL, takes out and carries out freeze drying 24h when 10,30,60,90,120min respectively, analyzes its original position amorphization degree.

[0056] Example 12

[0057] Weigh ketoprofen 3.175g and lysine 1.825g, ketoprofen 2.967g and arginine 2.033g, ketoprofen 2.829g and meglumine 2.171g respectively and be placed in 10mL centrifuge tube, mix (10min) in vortex mixer, obtain ketoprofen-ligand physical mixture.Take 100mg physical mixture respectively at each time.Use tabletting machine to carry out tabletting, under 10MPa pressure, suppress 10s, take out after making into the regular disc with smooth surface and no damage for standby use.5 groups of compressed discs (3 per group) are placed in airtight box, under 25 ℃ of temperature conditions, every surface drips pH3.0 buffer 50uL, takes out and carries out freeze drying 24h when 10,30,60,90,120min respectively, analyzes its original position amorphization degree.

[0058] Embodiment 13

[0059] Weigh ketoprofen 3.175g and lysine 1.825g, ketoprofen 2.967g and arginine 2.033g, ketoprofen 2.829g and meglumine 2.171g respectively and be placed in 10mL centrifuge tube, mix (10min) in vortex mixer, obtain ketoprofen-ligand physical mixture.Take 100mg physical mixture respectively at each time.Use tabletting machine to carry out tabletting, under 10MPa pressure, suppress 10s, take out after making into the regular disc with smooth surface and no damage for standby use.5 groups of compressed discs (3 per group) are placed in airtight box, under 25 ℃ of temperature conditions, every surface drips pH4.5 buffer 50uL, takes out and carries out freeze drying 24h when 10,30,60,90,120min respectively, analyzes its original position amorphization degree.

[0060] Embodiment 14

[0061] Weigh ketoprofen 3.175g and lysine 1.825g, ketoprofen 2.967g and arginine 2.033g, ketoprofen 2.829g and meglumine 2.171g respectively and be placed in 10mL centrifuge tube, mix (10min) in vortex mixer, obtain ketoprofen-ligand physical mixture.Take 100mg physical mixture respectively at every turn.Use tabletting machine to carry out tabletting, under 10MPa pressure, suppress 10s, take out after making into the regular disc of smooth surface without damage for subsequent use.5 groups of compressed discs (3 per group) are placed in airtight box, under 25 ℃ of temperature conditions, every surface drips pH5.4 buffer 50uL, takes out and carries out freeze drying 24h when 10,30,60,90,120min respectively, analyzes its original position amorphization degree.

[0062] Embodiment 15

[0063] Weigh ketoprofen 3.175g and lysine 1.825g, ketoprofen 2.967g and arginine 2.033g, ketoprofen 2.829g and meglumine 2.171g respectively and be placed in 10mL centrifuge tube, mix (10min) in vortex mixer, obtain ketoprofen-ligand physical mixture.Take 100mg physical mixture respectively at each time.Use tabletting machine to carry out tabletting, under 10MPa pressure, suppress 10s, take out after making into the regular disc with smooth surface and no damage for standby use.5 groups of compressed discs (3 per group) are placed in airtight box, under 25 ℃ of temperature conditions, every surface drips pH6.8 buffer 50uL, takes out and carries out freeze drying 24h when 10,30,60,90,120min respectively, analyzes its original position amorphization degree.

[0064] Example 16

[0065] Weigh ketoprofen 3.175g and lysine 1.825g, ketoprofen 2.967g and arginine 2.033g, ketoprofen 2.829g and meglumine 2.171g respectively and be placed in 10mL centrifuge tube, mix (10min) in vortex mixer, obtain ketoprofen-ligand physical mixture.Take 100mg physical mixture respectively at each time.Use tabletting machine to carry out tabletting, under 10MPa pressure, suppress 10s, take out after making into the regular disc with smooth surface and no damage for standby use.5 groups of compressed discs (3 per group) are placed in airtight box, under 25 ℃ of temperature conditions, every surface drips pH7.4 buffer 50uL, takes out and carries out freeze drying 24h when 10,30,60,90,120min respectively, analyzes its original position amorphization degree.

[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 them in a vortex mixer (10 min) to obtain a ketoprofen-ligand physical mixture. Then take an excess of the physical mixture and put it into a centrifuge tube containing 4 mL of deionized water. Three parallel portions are placed in a shaker at 37° C. and 200 rpm for 24 hours. Take 1 mL of the supernatant and filter it through a 0.45 μm microporous membrane. The saturated solubility of the sample is determined by high performance liquid chromatography.

[0068] Comparative Example 2

[0069] Weigh 3.167 g of ketoprofen and 1.833 g of glutamic acid, place in a 10 mL centrifuge tube, and mix in a vortex mixer (10 min) to obtain a ketoprofen-ligand physical mixture. Then take excess physical mixture and put it into a centrifuge tube containing 4 mL of deionized water, and place it in a shaker at 37 ° C and 200 rpm for 24 hours. Take 1 mL of the supernatant and pass it through a 0.45 μm microporous filter membrane, and measure the saturated solubility of the sample by high performance liquid chromatography.

[0070] Comparative Example 3

[0071] Weigh 3.703 g of ketoprofen and 1.297 g of alanine, place in a 10 mL centrifuge tube, and mix in a vortex mixer (10 min) to obtain a ketoprofen-ligand physical mixture. Then take excess physical mixture and put it into a centrifuge tube containing 4 mL of deionized water, and place it in a shaker at 37 ° C and 200 rpm for 24 hours. Take 1 mL of the supernatant and pass it through a 0.45 μm microporous filter membrane, and measure the saturated solubility of the sample by high performance liquid chromatography.

[0072] Comparative Example 4

[0073] Weigh 3.422 g of ketoprofen and 1.578 g of valine, place in a 10 mL centrifuge tube, and mix in a vortex mixer (10 min) to obtain a ketoprofen-ligand physical mixture. Then take excess physical mixture and put it into a centrifuge tube containing 4 mL of deionized water, and place it in a shaker at 37 ° C and 200 rpm for 24 hours. Take 1 mL of the supernatant and pass it through a 0.45 μm microporous filter membrane, and measure the saturated solubility of the sample by high performance liquid chromatography.

[0074] Test Example 1: The in-situ co-amorphization degree of the three ketoprofen-ligand compositions of 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] Tube voltage: 40KV

[0080] Tube current: 40mA

[0081] Step size: 0.02°

[0082] Scanning speed: 4° / min

[0083] Scanning range: 2θ, 5-40°

[0084] Test results: Figure 1-3 After the ketoprofen-lysine composition, ketoprofen-arginine composition and ketoprofen-meglumine composition tablets in Example 1 were exposed to an aqueous medium, the crystal diffraction peaks of the three combinations gradually weakened over time until they disappeared, indicating that in-situ co-amorphization could occur spontaneously. The three ketoprofen and 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 combination, the ambient temperature and the pH of the medium.

[0085] Among them, in Examples 1-3, the molar ratio of ketoprofen to ligand in the three ketoprofen-ligand compositions significantly affects the degree of in situ co-amorphization of the composition tablets after contacting the aqueous medium. When the molar ratio of ketoprofen to ligand is 1:1, a good in situ co-amorphization trend is shown ( Figure 1-3 ).

[0086] In Examples 8-10, the powder X-ray diffraction patterns of the three ketoprofen-ligand compositions at different temperatures are as follows: Figure 8 As shown by Figure 8 It can be seen that under the same amount of medium and the same time, as the temperature increases, the degree of decrease of the characteristic crystal diffraction peak of the composition is more significant, 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 to 8) are as follows: Fig. 9 As shown by Fig. 9 It can be seen that, at the same time, as the pH value of the medium increases, the degree of decrease of the characteristic crystal diffraction peak of the composition is more significant, 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 calorimeter (Hitachi Profile, Japan)

[0090] Range: 25-250℃

[0091] Heating rate: 10℃ / min

[0092] Test results: Figure 4-6As shown, at 120 min, the melting endothermic peaks of the original ketoprofen crystals and the ligands of the three ketoprofen-ligand composition tablets weakened or disappeared, indicating that the three composition tablets underwent in-situ co-amorphization after contacting 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] Scan times: 32 times

[0097] Measurement results: The Fourier transform infrared spectra of the in-situ co-amorphization of three ketoprofen-ligand combination tablets are shown in Figure 7 As shown by Figure 7 a It can be seen that the infrared absorption spectrum of the in situ co-amorphous composite of ketoprofen-lysine combination with a molar ratio of 1:1 at 120 min is 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, 550.8 cm -1 There is an absorption peak.

[0098] Depend on Figure 7 b It can be seen that the infrared absorption spectrum of the in situ co-amorphous composite of ketoprofen-arginine combination with a molar ratio of 1:1 at 120 min is 3366.6, 1597.6, 1384.7, 1352.8, 1280.1, 1106.9, 990.3, 775.8, 731.9, 655.2, 617.9 cm -1 There is an absorption peak.

[0099] Depend on Figure 7 c It can be seen that the infrared absorption spectrum of the in situ co-amorphous composite of ketoprofen-meglumine combination with a molar ratio of 1:1 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, 643.4 cm -1 There is an absorption peak.

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

[0101] 1. Solubility determination

[0102] The excess ketoprofen crystals, ketoprofen-lysine, ketoprofen-arginine and ketoprofen-meglumine in Example 1, Examples 4-5 and Comparative Examples 1-4 and other drug-ligand compositions with the same molar ratio were respectively put into centrifuge tubes containing 4 mL of deionized water, and three parallel portions were placed in a shaker at 37 ° C and 200 rpm for 24 h. 1 mL of the supernatant was taken and passed through a 0.45 μm microporous filter membrane, and the saturated solubility of different samples was determined by high performance liquid chromatography.

[0103] The HPLC conditions were as follows:

[0104] Instrument: Agilent 1260 High Performance Liquid Chromatograph

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

[0106] Mobile phase: acetonitrile-0.3% phosphoric acid water = 50:50 (V / V)

[0107] Flow rate: 1.0mL / min

[0108] Detection wavelength: 220nm

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

[0110]

[0111] Test results: As shown in Table 1, the solubility of ketoprofen crystals in water is 209.43ug / mL. Compared with ketoprofen crystals, the solubility of ketoprofen in the ketoprofen-lysine combination, ketoprofen-arginine combination and ketoprofen-meglumine combination at a ratio of 1:1 was significantly improved, by 6.28 times, 6.08 times and 7.03 times, respectively. The other combinations had little effect on the solubility of ketoprofen.

[0112] 2. Determination of characteristic dissolution rate

[0113] Weigh 250 mg of ketoprofen crystals, ketoprofen-lysine combination, ketoprofen-arginine combination, ketoprofen-meglumine combination, respectively, in parallel, use a tablet press to compress, press at 10 MPa pressure for 10 s, make a smooth and undamaged regular disc, and then take it out for use. Use beeswax as a mold and place the tablet in beeswax so that only one circular surface is in contact with the dissolution medium. According to the second method (paddle method) device of the 2020 edition of the Chinese Pharmacopoeia, 0931. The medium temperature is 37 ° C, the medium volume is 900 mL, the speed is 50 rpm, and the dissolution medium is water. During the test, 2 mL was sampled at 2, 5, 10, 15, 20, 30, 45, 60, 90 and 120 min, and 2 mL of constant temperature medium was added at the same time. The removed liquid was filtered with a 0.45 μm aqueous microporous filter membrane and analyzed by high performance liquid chromatography. The intrinsic dissolution rate is determined by the dissolution amount (mg / cm -2 )-time (min) regression curve.

[0114] Test results: The characteristic dissolution rate results of ketoprofen crystals and ketoprofen-ligand compositions with different molar ratios are as follows: Fig.10 As shown. As can be seen from the figure, when the ligand component is introduced, all ketoprofen-ligand compositions show significantly enhanced dissolution rates. And the molar ratio of the composition has a significant effect on the characteristic dissolution rate of ketoprofen. Among them, the dissolution rate of the ketoprofen-ligand composition with a molar ratio of 3:1 is weaker than that of the composition with a molar ratio of 2:1. Compared with the compositions with a molar ratio of 3:1 and 2:1, the ketoprofen-ligand compositions with a molar ratio of 1:1 to 1:3 all show high dissolution rates. Among them, in the first 15 minutes, the characteristic dissolution rates of the ketoprofen-lysine composition, ketoprofen-arginine composition, and ketoprofen-methylglucamine composition with a molar ratio of 1:1 are 999.712 times, 617.011 times, and 1274.682 times that of ketoprofen crystals.

[0115] Test Example 3: Phase solubility test was performed on the three ketoprofen-ligand compositions of Example 1, as follows:

[0116] Weigh 2.9238g of lysine, 3.5038g of arginine, and 3.9042g of meglumine, add 200mL of deionized water into a 250mL beaker, and then dilute step by step to prepare lysine, arginine, and meglumine solutions of different concentrations (100, 50, 25, 12.5, 6.25, 3.125, 1.5625, 0.78, 0.39, 0.19, 0.09, 0.04mM). Weigh an excess of ketoprofen into a 5mL centrifuge tube, drop 4mL of the above-mentioned ligand solution of different concentrations, and repeat 3 times. Seal the centrifuge tube and place it in a constant temperature shaker at 37°C and 200rpm for 24h, then take 1mL of the sample, filter it with a 0.45μm microporous filter membrane, and analyze it by high performance liquid chromatography.

[0117] Test results: The phase solubility of ketoprofen crystal drug in aqueous solution with different concentrations of ligand is as follows: Fig.11 As shown in the figure, the solubility of ketoprofen crystal drug increases nonlinearly with the increase of ligand solution concentration. The solubility of ketoprofen deviates negatively when the ligand concentration is high, showing a typical 1:1A N Since intermolecular complexation reaction occurs between ketoprofen and the selected ligand 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 compositions are spontaneously formed by ketoprofen and lysine, meglumine or arginine, respectively, upon contact with an aqueous medium.

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

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 10:1 to 1:

10.

4. 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.

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

6. The ketoprofen in situ co-amorphous composition according to claim 1, characterized in that: The contact time of ketoprofen and lysine, meglumine or arginine with the aqueous medium is 0 to 120 minutes.

7. The ketoprofen in situ co-amorphous composition according to claim 1, characterized in that: The ambient temperature of the contact between ketoprofen and lysine, meglumine or arginine and the aqueous medium is 0 to 50°C.

8. The ketoprofen in situ co-amorphous composition according to claim 1, characterized in that: When ketoprofen and lysine, meglumine or arginine are in contact with an aqueous medium, the pH value of the medium is 1 to 8.

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