Ibuprofen in-situ co-amorphous composition and oral solid preparation thereof

Abstract

The invention belongs to the technical field of medicines, and particularly relates to an ibuprofen in-situ co-amorphous composition and an oral solid preparation thereof. The composition is prepared from ibuprofen, lysine, arginine or meglumine in proportion. The composition can spontaneously trigger in situ co-amorphization between ibuprofen and ligands under high humidity conditions or when contacted with an aqueous medium (including a dissolution process). The composition can significantly improve the apparent solubility and the dissolution rate of the indissolvable drug ibuprofen. Meanwhile, due to the addition of the auxiliary materials, the composition has good compatibility with various auxiliary materials, can keep a relatively high in-situ co-amorphization degree, and can be mixed with various auxiliary materials to prepare various ibuprofen solid preparations (such as tablets, capsules, powder, granules and the like). Through a humidity response type in-situ amorphization strategy, a new preparation thought and effective guidance are provided for solving the dissolvability and dissolution defects of ibuprofen and other indissolvable drugs.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and particularly relates to an ibuprofen in-situ co-amorphous composition and an oral solid preparation thereof. Background Art

[0002] Ibuprofen, a nonsteroidal anti-inflammatory drug (NSAID), chemically known as 2-(4-isobutylphenyl) propionic acid, has multiple pharmacological actions: It inhibits inflammatory responses by reducing prostaglandin synthesis, lowering local vascular permeability and leukocyte infiltration, thereby reducing tissue swelling and redness, thus exerting its anti-inflammatory effects. It also exerts its analgesic effects by inhibiting the release of inflammatory mediators and neuronal activation, reducing pain signal transmission, thereby alleviating pain perception. It also exerts its antipyretic effects by affecting the hypothalamic thermoregulatory center, reducing prostaglandin synthesis in the hypothalamus, thereby lowering body temperature. Clinically, ibuprofen is indicated for fever, mild to moderate pain (including postoperative pain), menstrual pain, headaches, and pain caused by kidney stones. It is also used for rheumatoid arthritis, juvenile idiopathic arthritis, pericarditis, and patent ductus arteriosus. Ibuprofen belongs to BCS II class drugs in the biopharmaceutics classification system and has poor water solubility, which affects the oral absorption of the drug. Therefore, improving its solubility and dissolution rate will help improve its oral absorption.

[0003] Currently, various strategies (such as nanoparticles, liposomes, amorphous solid dispersions, and cyclodextrin inclusion complexes) aim to improve the solubility / dissolution rate of poorly soluble drugs. However, these strategies often face drawbacks such as complex preparation processes, poor physical stability, low drug loading, and high excipient usage leading to an increased risk of toxic side effects. This has limited further drug development. In recent years, in situ drug co-amorphization through formulation design has been introduced to overcome challenges in drug stability and manufacturing. In situ co-amorphization technology spontaneously forms a uniform amorphous system through intermolecular interactions (primarily hydrogen bonds) between the drug and ligand molecules. Currently, most methods use laser irradiation, magnetic induction, and microwave irradiation to achieve in situ drug co-amorphization. However, these methods often face high costs, high energy consumption, biosafety, and difficulties in scale-up. Therefore, it is particularly necessary to provide a low-cost and low-energy method for in situ drug co-amorphization.

[0004] Solid preparations are the most widely circulated and used dosage forms on the market, and are usually composed of a main drug and excipients. Commonly used solid dosage forms include powders, granules, tablets, capsules, etc., which account for a large proportion of pharmaceutical preparations. Compared with liquid preparations, solid preparations have significant advantages: good physical and chemical stability, low production and manufacturing costs, and easy to take and carry; the pretreatment of the preparation process undergoes the same unit operations to ensure uniform mixing and accurate dosage of the drugs, and there is a close connection between the dosage forms. It is worth noting that when solid drugs exert their effects in the human body, they must first complete the dissolution process, then penetrate the physiological membrane, and finally be absorbed into the blood circulation system. However, the solubility and dissolution rate of commercially available ibuprofen tablets and ibuprofen capsules are relatively low, resulting in slow onset of the drug and difficulty in quickly relieving patients' pain, fever and other discomfort symptoms. Summary of the Invention

[0005] The present invention aims to provide a composition in which ibuprofen and three ligands (lysine, arginine, meglumine) are co-amorphized in situ. By uniformly mixing ibuprofen and the ligands in a specific molar ratio and pressing them into tablets, the resulting tablets can spontaneously undergo co-amorphization under high humidity conditions or when in contact with an aqueous medium (including a dissolution process). This humidity-responsive in situ co-amorphization strategy can effectively enhance the solubility and dissolution rate of the poorly soluble drug ibuprofen. At the same time, the in situ co-amorphous composition can be used as a prescription composition for ibuprofen solid preparations, promoting the development of ibuprofen solid preparations with high solubility / dissolution rate to achieve good oral absorption and therapeutic effects of ibuprofen.

[0006] To achieve the above object, the present invention adopts the following technical solutions:

[0007] The ibuprofen-ligand in situ co-amorphous composition of the present invention comprises an ibuprofen-lysine composition, an ibuprofen-meglumine composition or an ibuprofen-arginine composition, wherein ibuprofen and a ligand are mixed and tableted, and then spontaneously undergo in situ co-amorphization under the driving and induction of aqueous medium conditions.

[0008] The specific method of the present invention is to uniformly mix ibuprofen and a ligand, then compress the mixture using a tablet press at a constant pressure of 10 MPa for 10 seconds to produce a tablet dosage form. This provides a model system for systematically studying the formation mechanism and key influencing factors of humidity / water-responsive in situ co-amorphization. The compressed tablets, upon contact with an aqueous medium (including dissolution), can undergo an in situ transformation from a crystalline to a co-amorphous phase, validating the effectiveness of spontaneous in situ co-amorphization of ibuprofen compositions.

[0009] The degree of in situ co-amorphization of three ibuprofen in situ co-amorphous composition tablets after exposure to trace amounts of aqueous medium (10-400 μL) was investigated, based on a total mass of 100 mg of ibuprofen and ligand-formed tablets. Ibuprofen and ligand were mixed in a molar ratio of 5:1 to 1:5.

[0010] The present invention also investigates the degree of in situ co-amorphization of three ibuprofen in situ co-amorphous composition tablets at different time points within the range of 0 to 120 minutes of contact with an aqueous medium; the degree of in situ co-amorphization at different temperatures of 0 to 50°C; and the degree of in situ co-amorphization when contacting aqueous media with different pH values of 1 to 8.

[0011] The present invention uniformly mixes ibuprofen and a ligand, and the formed mixture can spontaneously undergo in-situ co-amorphization under high humidity conditions when multiple pharmaceutical excipients are added. The pharmaceutical excipients include: polyvinyl pyrrolidone, microcrystalline cellulose, hydroxypropyl cellulose, sodium hydroxymethyl cellulose, hypromellose, polyethylene glycol, sucrose, glucose, D-mannitol, lactose, starch, etc.

[0012] Oral solid preparations include tablets, capsules, powders, and granules.

[0013] Beneficial effects of the present invention:

[0014] The present invention addresses the defect of ibuprofen's poor water solubility and designs three ibuprofen in situ co-amorphous compositions (ibuprofen-lysine composition, ibuprofen-arginine composition, and ibuprofen-meglumine composition) through a drug combination method. These compositions achieve a dynamic conversion of crystals to a high-energy co-amorphous phase under high humidity conditions or when in contact with an aqueous medium and during medication. Furthermore, the in situ co-amorphization improves the solubility and dissolution of ibuprofen. On the other hand, the one-step molding method circumvents the problems of complex preparation processes and poor physical stability. Furthermore, the compositions can be used for the development of oral solid preparations of ibuprofen, providing new ideas for the formulation development of ibuprofen and other BSC II / IV poorly soluble drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 The powder X-ray diffraction patterns of the ibuprofen-lysine composition tablets in Examples 1-3 during the in situ co-amorphization process (a: ibuprofen:lysine 1:2, b: ibuprofen:lysine 1:1, c: ibuprofen:lysine 2:1);

[0016] Figure 2 The powder X-ray diffraction patterns of the ibuprofen-arginine composition tablets in Examples 1-3 during the in situ co-amorphization process (a: ibuprofen:arginine 1:2, b: ibuprofen:arginine 1:1, c: ibuprofen:arginine 2:1);

[0017] Figure 3 is the powder X-ray diffraction pattern of the ibuprofen-meglumine combination tablet in Example 1-3 during the in situ co-amorphization process (a: ibuprofen:meglumine 1:2, b: ibuprofen:meglumine 1:1);

[0018] Figure 4 Differential scanning calorimetry spectra of the ibuprofen crystals, lysine crystals, ibuprofen-lysine physical mixture, and ibuprofen-lysine composition tablets in Examples 1-3 undergoing in situ co-amorphization at 120 min (a: ibuprofen:lysine 1:2, b: ibuprofen:lysine 1:1, c: ibuprofen:lysine 2:1);

[0019] Figure 5 Differential scanning calorimetry spectra of the ibuprofen crystals, arginine crystals, ibuprofen-arginine physical mixture, and ibuprofen-arginine combination tablets in Examples 1-3 undergoing in situ co-amorphization at 120 min (a: ibuprofen:arginine 1:2, b: ibuprofen:arginine 1:1, c: ibuprofen:arginine 2:1);

[0020] Figure 6 Differential scanning calorimetry spectra of the ibuprofen crystals, meglumine crystals, ibuprofen-meglumine physical mixture, and ibuprofen-meglumine combination tablets in Examples 1-3 undergoing in situ co-amorphization at 120 min (a: ibuprofen:meglumine 1:2, b: ibuprofen:meglumine 1:1, c: ibuprofen:meglumine 2:1);

[0021] Figure 7 Powder X-ray diffraction patterns of the three ibuprofen in situ co-amorphous composition tablets in Examples 6-8 that underwent in situ co-amorphization at different temperatures (a: ibuprofen:lysine 1:1, b: ibuprofen:arginine 1:1, c: ibuprofen:meglumine 1:1);

[0022] Figure 8 Powder X-ray diffraction patterns of the three ibuprofen in situ co-amorphous composition tablets in Examples 9-14 that underwent in situ co-amorphization in contact with media of different pH values (a: ibuprofen:lysine 1:1, b: ibuprofen:arginine 1:1, c: ibuprofen:meglumine 1:1);

[0023] Figure 9 IR spectra of the three ibuprofen in situ co-amorphous composition tablets in Examples 1-3 at different time points of in situ co-amorphization (a: ibuprofen:lysine 1:1, b: ibuprofen:arginine 1:1, c: ibuprofen:meglumine 1:1);

[0024] Figure 10 is the non-sink condition dissolution profile of the three ibuprofen in situ co-amorphous compositions in Examples 1-3;

[0025] Figure 11It is the phase solubility diagram of ibuprofen in aqueous solutions of ligands with different concentrations (a: ibuprofen-lysine combination, b: ibuprofen-arginine combination, c: ibuprofen-meglumine combination).

[0026] Figure 12 Polarized light microscopy images of three ibuprofen-ligand compositions (molar ratio of 1:1) before and after contact with water for 120 min.

[0027] Figure 13 This is a polarizing microscope image of the three ibuprofen-ligand compositions in Example 15 mixed with a variety of different pharmaceutical excipients at a mass ratio of 10:1 and then in contact with water for 120 minutes.

[0028] Figure 14 This is a polarizing microscope image of the three ibuprofen-ligand compositions in Example 15 mixed with a variety of different pharmaceutical excipients at a mass ratio of 1:10 and then in contact with water for 120 minutes. DETAILED DESCRIPTION

[0029] The present invention will be further described below with reference to specific embodiments.

[0030] Example 1

[0031] Three compositions (ibuprofen 0.585 g and lysine 0.415 g, ibuprofen 0.542 g and arginine 0.458 g, and ibuprofen 0.507 g and meglumine 0.493 g) in a 1:1 molar ratio were weighed and placed in a 5 mL centrifuge tube and shaken for 10 minutes to mix thoroughly, yielding ibuprofen-ligand physical mixtures. Accurately weighing 100 mg of each physical mixture, the mixture was placed in a mold and compressed using a tablet press at a constant pressure of 10 MPa for 10 seconds to form smooth, undamaged, regular discs (13 mm diameter). The compressed discs (three parallel discs) were placed in a sealed box and 50 μL of deionized water was evenly dripped onto each disc at 25°C. The discs were removed at predetermined time points (30, 60, and 120 minutes) and freeze-dried for 24 hours. The degree of in situ amorphization was analyzed.

[0032] Example 2

[0033] Three compositions (ibuprofen 0.414 g and lysine 0.586 g, ibuprofen 0.372 g and arginine 0.628 g, ibuprofen 0.346 g and meglumine 0.654 g) with a molar ratio of 1:2 were weighed respectively, and the in situ amorphization preparation steps were the same as in Example 1.

[0034] Example 3

[0035] Three compositions (ibuprofen 0.738 g and lysine 0.262 g, ibuprofen 0.703 g and arginine 0.297 g, ibuprofen 0.679 g and meglumine 0.321 g) with a molar ratio of 2:1 were weighed respectively, and the in situ amorphization preparation steps were the same as in Example 1.

[0036] Example 4

[0037] An ibuprofen-ligand physical mixture was obtained as in Example 1, and tablets were pressed as in Example 1. The pressed tablets (three in parallel) were placed in a sealed box. 10 μL of deionized water was evenly dripped onto each tablet at 25°C. The tablets were removed at predetermined time points of 30, 60, and 120 minutes, freeze-dried for 24 hours, and analyzed for their in situ amorphization degree.

[0038] Example 5

[0039] An ibuprofen-ligand physical mixture was obtained as in Example 1, and tablets were pressed as in Example 1. The pressed tablets (three in parallel) were placed in a sealed box. 400 μL of deionized water was evenly dripped onto each tablet at 25°C. The tablets were removed at predetermined time points of 30, 60, and 120 minutes, freeze-dried for 24 hours, and their in situ amorphization degree was analyzed.

[0040] Example 6

[0041] An ibuprofen-ligand physical mixture was obtained as in Example 1, and tablets were pressed as in Example 1. The pressed tablets (three in parallel) were placed in a sealed box. 50 μL of deionized water was evenly dripped onto each tablet at 4°C. The tablets were removed at predetermined time points of 30, 60, and 120 minutes, freeze-dried for 24 hours, and their in situ amorphization degree was analyzed.

[0042] Example 7

[0043] An ibuprofen-ligand physical mixture was obtained as in Example 1, and tablets were pressed as in Example 1. The pressed tablets (three in parallel) were placed in a sealed box. 50 μL of deionized water was evenly dripped onto each tablet at 37°C. The tablets were removed at predetermined time points of 30, 60, and 120 minutes, freeze-dried for 24 hours, and analyzed for their in situ amorphization degree.

[0044] Example 8

[0045] An ibuprofen-ligand physical mixture was obtained as in Example 1, and pellets were pressed as in Example 1. The pellets (three in parallel) were placed in a sealed box. 50 μL of deionized water was evenly dripped onto each pellet at 50°C. The pellets were removed at predetermined time points (30, 60, and 120 minutes) and freeze-dried for 24 hours. The in situ amorphization degree was then analyzed.

[0046] Example 9

[0047] An ibuprofen-ligand physical mixture was obtained as in Example 1, and pellets were pressed as in Example 1. The pellets (three in parallel) were placed in a sealed box. 50 μL of pH 1.2 buffer was evenly dripped onto each pellet at 25°C. The pellets were removed at predetermined time points of 30, 60, and 120 minutes, freeze-dried for 24 hours, and analyzed for their in situ amorphization degree.

[0048] Example 10

[0049] An ibuprofen-ligand physical mixture was obtained as in Example 1, and tablets were pressed as in Example 1. The pressed tablets (three in parallel) were placed in a sealed box. 50 μL of pH 3.0 buffer was evenly dripped onto each tablet at 25°C. The tablets were removed at predetermined time points of 30, 60, and 120 minutes, freeze-dried for 24 hours, and analyzed for their in situ amorphization degree.

[0050] Example 11

[0051] An ibuprofen-ligand physical mixture was obtained as in Example 1, and pellets were pressed as in Example 1. The pellets (three in parallel) were placed in a sealed box. 50 μL of pH 4.5 buffer was evenly dripped onto each pellet at 25°C. The pellets were removed at predetermined time points of 30, 60, and 120 minutes, freeze-dried for 24 hours, and analyzed for their in situ amorphization degree.

[0052] Example 12

[0053] An ibuprofen-ligand physical mixture was obtained as in Example 1, and pellets were pressed as in Example 1. The pellets (three in parallel) were placed in a sealed box. 50 μL of pH 5.4 buffer was evenly dripped onto each pellet at 25°C. The pellets were removed at predetermined time points of 30, 60, and 120 minutes, freeze-dried for 24 hours, and analyzed for their in situ amorphization degree.

[0054] Example 13

[0055] An ibuprofen-ligand physical mixture was obtained as in Example 1, and tablets were pressed as in Example 1. The pressed tablets (three in parallel) were placed in a sealed box. 50 μL of pH 6.8 buffer was evenly dripped onto each tablet at 25°C. The tablets were removed at predetermined time points of 30, 60, and 120 minutes, freeze-dried for 24 hours, and analyzed for their in situ amorphization degree.

[0056] Example 14

[0057] An ibuprofen-ligand physical mixture was obtained as in Example 1, and pellets were pressed as in Example 1. The pellets (three in parallel) were placed in a sealed box. 50 μL of pH 7.4 buffer was evenly dripped onto each pellet at 25°C. The pellets were removed at predetermined time points of 30, 60, and 120 minutes, freeze-dried for 24 hours, and analyzed for their in situ amorphization degree.

[0058] Test Example 1: The in situ co-amorphization degree of the three ibuprofen-ligand compositions in the examples was tested as follows:

[0059] 1. Powder X-ray diffraction

[0060] Powder X-ray diffraction was performed using a SmartLab9 X-ray diffractometer (Rigaku, Japan) with Cu-Kα palladium as the emission source. The tube voltage was set to 40 kV, the tube current was set to 40 mA, the step size was set to 0.02°, the scanning speed was set to 4° / min, and the scanning range (2θ) was 5–40°.

[0061] Measurement results: In Examples 1-3, the effects of different molar ratios on the degree of in-situ co-amorphization of ibuprofen were investigated. Figure 1-3 As shown, the molar ratio of ibuprofen to ligand in the three ibuprofen-ligand compositions significantly affects the degree of in situ co-amorphization of the tablets after contact with an aqueous medium. A 1:1 ibuprofen-lysine molar ratio, a 1:1 ibuprofen-arginine molar ratio, and a 1:1 ibuprofen-meglumine molar ratio all exhibited favorable in situ co-amorphization trends after contact with an aqueous medium for 30 minutes, 1:1 ibuprofen-meglumine molar ratio, and 1:1 ibuprofen-meglumine molar ratio for 120 minutes. However, a 2:1 ibuprofen-meglumine molar ratio resulted in a sticky mass that could not be analyzed by PXRD.

[0062] In Examples 6-8, the effect of different temperatures on the degree of in-situ co-amorphization of ibuprofen was investigated. The powder X-ray diffraction patterns of three ibuprofen-ligand compositions (molar ratio 1:1) at different temperatures are shown in FIG. Figure 7 As shown. Figure 7Under the same medium conditions and time, the intensity of the characteristic crystal diffraction peak of the composite material decreases significantly with increasing ambient temperature, indicating that temperature has a significant impact on the in situ co-amorphization process. The higher the temperature, the greater the degree of in situ co-amorphization and the more pronounced the transition of the crystal structure to an amorphous state.

[0063] In Examples 9-14, the effects of buffer solutions with different pH values on the degree of in-situ co-amorphization of ibuprofen were investigated. The powder X-ray diffraction patterns of three ibuprofen-ligand compositions (molar ratio 1:1) at different pH values (pH range 1-8) are shown in FIG. Figure 8 As shown. Figure 8 It can be seen that compared with ultrapure water conditions, the three ibuprofen-ligand compositions have stronger crystal diffraction peak intensities under acidic or alkaline conditions. It is possible that the acidic or alkaline medium changes the ionic microenvironment, resulting in a lower degree of in situ co-amorphization.

[0064] In general, the molar ratio of ibuprofen to ligand, the contact time between the composition tablet and the medium, the pH of the medium, and the temperature all have an impact on the degree of in situ co-amorphization.

[0065] 2. Differential Scanning Calorimetry

[0066] About 5 mg each of ibuprofen crystals, ibuprofen-ligand physical mixture, and in-situ co-amorphous complex at 120 min were placed in an aluminum crucible and analyzed using a HITACHIDSC 7020 differential scanning calorimeter (Hitachi Profile, Japan). Under nitrogen protection, the temperature was raised from 25°C to 250°C at a heating rate of 10°C / min.

[0067] Determination results: Differential scanning calorimetry analysis results are as follows Figure 4-6 As shown, at 120 minutes, the characteristic melting endothermic peaks of the original ibuprofen crystals and ligands significantly weakened or even disappeared in the three ibuprofen-ligand combination tablets. This thermodynamic phenomenon indicates that the long-range ordered structure of the drug-ligand combination undergoes dissociation upon contact with an aqueous medium, forming a co-amorphous phase with metastable properties. This confirms that the three combination tablets can undergo in situ co-amorphization under high humidity conditions and after contact with an aqueous medium.

[0068] 3. Infrared spectroscopy

[0069] The interactions between the co-amorphous complexes were analyzed using a Thermo Scientific Nicolet iS50 Fourier transform infrared spectrometer (Thermo Fisher Scientific, America). Appropriate amounts of ibuprofen crystals, ibuprofen-ligand physical mixtures, and the in situ co-amorphous complex formed at 120 min (molar ratio 1:1) were thoroughly ground with potassium bromide and pressed into thin sheets at a pressure of approximately 1000 pis for analysis. The scanning range was 4000–500 cm. -1 , with 4cm -1 Scan 32 times at a resolution of 100 nm.

[0070] Measurement results: The Fourier transform infrared spectra of the three ibuprofen-ligand combination tablets in situ co-amorphization are shown in Figure 2. Figure 9 As shown by Figure 9 It can be seen from a that the infrared absorption spectrum of the in situ co-amorphous composite of ibuprofen-lysine combination with a molar ratio of 1:1 at 30 min is 3444.3, 2955.83, 2825.86, 2713.83, 1633.81, 1360.44, 1109.48, 988.48, 782.33, and 612.04 cm -1 There is an absorption peak at.

[0071] Depend on Figure 9 b It can be seen that the infrared absorption spectrum of the in situ co-amorphous composite of ibuprofen-arginine combination with a molar ratio of 1:1 at 120 min is 3403.86, 2737.86, 2069.53, 1596.81, 1352.29, 1105.46, 986.69, 779.44, and 614.1 cm -1 There is an absorption peak at.

[0072] Depend on Figure 9 c It can be seen that the infrared absorption spectrum of the in situ co-amorphous composite of ibuprofen-meglumine combination with a molar ratio of 1:1 at 120 min is 3403.21, 2954.49, 2828.85, 2712.18, 1626.28, 1361.54, 1101.28, 984.62, 769.23, 616.67 cm -1 There is an absorption peak at.

[0073] Test Example 2: Apparent solubility test of the ibuprofen crystals and three ibuprofen-ligand compositions in Example 1: The excess ibuprofen crystals and three ibuprofen-ligand compositions in Example 1 were respectively placed in a centrifuge tube containing 4 mL of deionized water, and three parallel portions were placed in a shaker at 37°C and 200 rpm and shaken for 24 hours. 1 mL of the supernatant was taken and passed through a 0.22 μm microporous filter membrane, and the apparent solubility of different samples was determined by high performance liquid chromatography.

[0074] The HPLC conditions were as follows:

[0075] Instrument: Agilent 1260 High Performance Liquid Chromatograph

[0076] Chromatographic column: Ultimate XB-C18 (4.6 mm × 250 mm, 5 μm)

[0077] Mobile phase: acetonitrile-0.3% phosphoric acid water = 70:30 (V / V)

[0078] Flow rate: 1.0 mL / min

[0079] Detection wavelength: 220nm

[0080] Table 1 shows the solubility of ibuprofen crystals and ibuprofen-ligand combinations. The equilibrium solubility of the combination system was significantly different from that of ibuprofen crystals. The solubility of ibuprofen crystals in water was 56.65 μg / mL, while the solubility of the ibuprofen-lysine, ibuprofen-arginine, and ibuprofen-meglumine combinations in water was 1312.75, 1213.88, and 1391.34 μg / mL, respectively. These solubilities represent increases of 23.17, 21.43, and 24.56 times, respectively, compared to ibuprofen crystals.

[0081] Table 1 Solubility of ibuprofen crystals and ibuprofen-ligand compositions

[0082]

[0083] Test Example 3: Non-sink dissolution test was performed on the ibuprofen crystals and three ibuprofen-ligand compositions in Example 1, as follows:

[0084] A certain amount of ibuprofen crystals and ibuprofen-ligand composition were weighed respectively, and 3 parallel portions were taken. According to the second method of 0931 of the fourth general rule of the 2020 edition of the Chinese Pharmacopoeia, the non-sink release evaluation was performed by the slurry method. The release medium was water, the medium temperature was 37 ° C, the volume was 200 mL, and the rotation speed was 100 rpm. 2 mL of samples were taken at 5, 10, 20, 30, 45, 60, 90, 120, 240, 360, 480 and 720 min, and 2 mL of constant temperature medium was added at the same time. The removed liquid passed through a 0.22 μm microporous filter membrane and was analyzed by high performance liquid chromatography.

[0085] Test results: The non-sink dissolution results of ibuprofen crystals and ibuprofen-ligand combination are as follows: Figure 10As shown. The ibuprofen-ligand composition reached dissolution equilibrium in approximately 4 hours, with the dissolution concentrations of the ibuprofen-lysine composition, ibuprofen-arginine composition, and ibuprofen-meglumine composition at this time being approximately 807.88, 792.62, and 727.74 μg / mL, respectively. The ibuprofen crystals reached a maximum dissolution concentration of 59.19 μg / mL in approximately 4 hours. Compared to ibuprofen crystals, the dissolution concentrations of the ibuprofen-lysine composition, ibuprofen-arginine composition, and ibuprofen-meglumine composition increased by 13.65, 13.39, and 12.29 times, respectively, and maintained supersaturation for a long time.

[0086] Test Example 4: Phase solubility test of the three ibuprofen-ligand compositions of Example 1:

[0087] 2.924 g of lysine, 3.504 g of arginine, and 3.904 g of meglumine were weighed separately and added to 200 mL of deionized water in a 250 mL beaker. These solutions were then diluted serially to prepare solutions of varying concentrations (100, 50, 25, 12.5, 6.25, 3.125, 1.5625, 0.78, 0.39, 0.19, 0.09, and 0.04 mM). An excess of ibuprofen was weighed into a 5 mL centrifuge tube, and 4 mL of the ligand solution of varying concentrations was added dropwise. Three replicates were prepared. The tubes were sealed and placed in a thermostatic shaker at 37°C and 200 rpm for 24 hours. A 1 mL sample was then taken, filtered through a 0.22 μm microporous membrane, and analyzed by high-performance liquid chromatography.

[0088] Determination results: The solubility results of the three ibuprofen-ligand combinations are as follows: Figure 11 As shown. With the increase of ligand concentration, the concentration of ibuprofen crystals increased significantly, but when the concentration of the ligand solution was 0.05M, the dissolution of ibuprofen crystals tended to equilibrium. When the ligand concentration exceeded this threshold, the solubility curve showed a negative deviation, and the result was consistent with the typical 1:1A N This indicates that a complexation reaction occurs between ibuprofen and the ligand molecule. This intermolecular complexation allows ibuprofen to maintain a constant high concentration effect during the dissolution process, thereby potentially improving the oral bioavailability of the poorly soluble drug ibuprofen.

[0089] Example 15

[0090] Various excipients (polyvinyl pyrrolidone, microcrystalline cellulose, hydroxypropyl cellulose, sodium hydroxymethyl cellulose, hypromellose, sucrose, glucose, etc.) were added to a physical mixture of ibuprofen and a ligand (lysine, arginine, and meglumine) (molar ratio 1:1) to induce in situ amorphization. The mass ratio of the composition to the excipient was 10:1 to 1:10. Each accurately weighed 100 mg of the composition-excipient mixture was placed in a mold and compressed using a tablet press at a constant pressure of 10 MPa for 10 seconds to form smooth, undamaged, regular discs (13 mm diameter). The compressed discs (three parallel discs) were placed in a sealed box. At 25°C, 50 μL of deionized water was evenly added to each disc. After 120 minutes, the discs were removed and freeze-dried for 24 hours. The samples were then placed on glass slides and thoroughly dispersed with liquid paraffin. The samples were then observed at a magnification of 4×10, and the degree of disappearance of crystalline birefringence was recorded.

[0091] The results showed that the ibuprofen-lysine composition, ibuprofen-arginine composition and ibuprofen-meglumine composition with a molar ratio of 1:1 showed obvious crystal birefringence ( Figure 12 The polarizing microscopy results of the spontaneous in situ co-amorphization of the three ibuprofen-ligand compositions under high humidity conditions after the addition of various pharmaceutical excipients are shown in Figure 2. Figure 13 、 Figure 14 As shown. After adding various pharmaceutical excipients and contacting with a trace amount of deionized water, polarized light observation for 120 minutes revealed that the mixture after adding the excipients exhibited similar polarization phenomena as the original composition after 120 minutes of contact with water. The ibuprofen-ligand composition still exhibited a high degree of in-situ co-amorphization after the addition of the excipients, and the amount of excipients used had little effect on the degree of in-situ co-amorphization. Therefore, this in-situ co-amorphous composition can be used as a formulation component for solid dosage forms and is expected to be suitable for various solid dosage forms (tablets, capsules, powders, granules, etc.) to improve the solubility and dissolution rate of ibuprofen.

Claims

1. An application of an ibuprofen in-situ co-amorphous composition, characterized in that: The ibuprofen in situ co-amorphous composition is used for preparing oral solid preparations.

2. The use of the ibuprofen in situ co-amorphous composition according to claim 1, characterized in that: The ibuprofen in-situ co-amorphous composition is formed spontaneously under the driving and induction of an aqueous medium after ibuprofen and a ligand are mixed and compressed into tablets.

3. The use of the ibuprofen in situ co-amorphous composition according to claim 2, characterized in that: The ligand is lysine, arginine or meglumine, and the molar ratio of ibuprofen to the ligand is 5:1 to 1:

5.

4. The use of the ibuprofen in situ co-amorphous composition according to claim 2, characterized in that: Based on 100 mg of the composition, the amount of the aqueous medium used is 10 to 400 μL.

5. The use of the ibuprofen in situ co-amorphous composition according to claim 2, characterized in that: The time for driving and inducing the aqueous medium is 0 to 120 minutes.

6. The use of the ibuprofen in situ co-amorphous composition according to claim 2, characterized in that: The ambient temperature during aqueous medium driving and induction is 0-50°C.

7. The use of the ibuprofen in situ co-amorphous composition according to claim 2, characterized in that: The pH value of the medium during aqueous medium driving and induction is 1-8.

8. The use of the ibuprofen in situ co-amorphous composition according to claim 1, characterized in that: The preparation method of the oral solid preparation is as follows: a physical mixture of ibuprofen and a ligand is added with pharmaceutical excipients and mixed evenly, and then an amorphous oral solid preparation is spontaneously formed under the driving and induction of an aqueous medium.

9. The use of the ibuprofen in situ co-amorphous composition according to claim 8, characterized in that: Pharmaceutical excipients include: Polyvinylpyrrolidone, microcrystalline cellulose, hydroxypropyl cellulose, sodium hydroxymethyl cellulose, hypromellose, polyethylene glycol, sucrose, glucose, D-mannitol, lactose, starch.

10. The use of the ibuprofen in situ co-amorphous composition according to claim 1, characterized in that: Oral solid preparations include tablets, capsules, powders, and granules.

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