An indomethacin small molecule hydrogel and a preparation method thereof

Abstract

The application belongs to the technical field of medicine, and particularly discloses a small-molecule indometacin hydrogel and a preparation method thereof. The small-molecule hydrogel is obtained by mixing indometacin and a small-molecule ligand, adding a small amount of deionized water, and oscillating. The small-molecule hydrogel has the advantages of solubility and permeability, with the small-molecule ligand as a matrix. The formed small-molecule hydrogel can significantly improve the solubility and dissolution / release rate of indometacin. Compared with indometacin crystals, the water solubility of the two small-molecule hydrogels of indometacin-meglumine and arginine is increased by 506 times and 479 times, respectively, and the cumulative release rate at 2h is increased by 2.67 times and 3.05 times, respectively. Meanwhile, the small-molecule hydrogel significantly promotes the membrane permeability of indometacin, enhances the development potential of indometacin in oral and transdermal applications, and provides a new preparation idea for solving the solubility and permeability defects of non-steroidal anti-inflammatory drugs and other poorly soluble drugs.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine, and particularly discloses an indometacin small-molecule hydrogel and a preparation method thereof. BACKGROUND

[0002] Indometacin (IND), with a chemical name of 2-methyl-1-(4-chlorobenzoyl)-5-methoxy-1H-indole-3-acetic acid, has a chemical structure as shown in the following formula:

[0003]

[0004] Indometacin, also known as indometacin, is a non-corticosteroid anti-inflammatory analgesic and antipyretic drug with strong effect, belonging to aryl acetic acid non-steroidal anti-inflammatory drugs. By inhibiting cyclooxygenase to reduce prostaglandin synthesis, the formation of inflammatory tissue pain nerve impulses is prevented, and inflammatory reactions are inhibited. However, indometacin belongs to the biological classification system (BCS) II drug, and has poor solubility and low in vivo absorption, which limits its clinical therapeutic effect.

[0005] The existing indometacin gel (trade name: Votalin) for treating muscle and joint pain is composed of indometacin, hydroxypropyl methylcellulose, polycarboxylic acid and other high molecular materials. So far, the research on drug hydrogel mainly focuses on designing and preparing drug macromolecular gel by introducing macromolecular matrix (such as hyaluronic acid, chitosan, sodium alginate, poloxamer, etc.), and elucidating its formation mechanism and related therapeutic applications. However, the design and related research on small-molecule gel system of drugs are very few. SUMMARY

[0006] The purpose of the present application is to provide an indometacin small-molecule hydrogel, especially an indometacin-meglumine hydrogel and an indometacin-arginine hydrogel. That is, by uniformly mixing indometacin with small-molecule ligands at a certain molar ratio, adding a small amount of deionized water, and simply oscillating, a new type of indometacin small-molecule hydrogel is successfully prepared. Compared with indometacin crystals, the solubility and dissolution / release of indometacin in the small-molecule hydrogel are significantly improved. In addition, compared with the commercially available indometacin hydrogel, the new type of small-molecule hydrogel significantly promotes the membrane permeability of indometacin in the skin and gastrointestinal tract, significantly enhances the pharmaceutical properties of indometacin, expands the further practical application of indometacin, and is expected to provide a new idea for the development of other small-molecule poorly soluble drug preparation products.

[0007] In the formula, the molecular weight of indometacin and the small-molecule ligand is less than 1000 Da.

[0008] The small molecule ligand includes meglumine, arginine, glutamic acid, glutamine, citrulline, piperazine, proline, tryptophan, theanine, ornithine, lysine, aspartic acid or histidine.

[0009] The small molecule ligand is preferably meglumine or arginine.

[0010] The molar ratio of indomethacin to the small molecule ligand is 1:5-5:1, preferably 1:2-2:1, and most preferably 1:1.

[0011] The amount of deionized water is 50-600 μL, preferably 100-300 μL, and most preferably 200 μL, based on the total mass of 1 g of indomethacin and the small molecule ligand.

[0012] The oscillation temperature is 10-60°C, preferably 20-30°C, and most preferably 25°C, and the oscillation time is 1-20 min, preferably 3-10 min, and most preferably 5 min.

[0013] The indomethacin small molecule hydrogel prepared in the application has a typical three-dimensional network structure in the interior of the gel according to the scanning electron microscope results.

[0014] The prepared hydrogel is frozen in a -80°C refrigerator, and then the sample is transferred to a vacuum freeze dryer for drying for 24 h to obtain indomethacin small molecule dry gel.

[0015] The X-ray powder diffraction pattern shows that the crystal diffraction peaks of the drug and the ligand in the two dry gels are basically disappeared, showing amorphous diffraction rings or very weak crystal diffraction peaks.

[0016] The differential scanning calorimetry analysis confirms that the two dry gel samples both show a single glass transition temperature (50.45°C and 69.89°C).

[0017] The solubility of indomethacin crystals, indomethacin-ligand physical mixtures and the two indomethacin hydrogels is determined, and the results show that the two indomethacin-meglumine and indomethacin-arginine hydrogels can significantly increase the solubility of indomethacin in water.

[0018] The cumulative release test under the leak tank condition confirms that the two indomethacin-meglumine and indomethacin-arginine hydrogels can significantly improve the cumulative release rate of indomethacin.

[0019] The release test under the non-leak tank condition shows that the two indomethacin-meglumine and indomethacin-arginine hydrogels exhibit supersaturation release behavior and can maintain a high supersaturation concentration for a long time.

[0020] Compared with the existing indomethacin commercial gel, the indomethacin-meglumine and indomethacin-arginine hydrogels can significantly promote the membrane permeability of indomethacin in the simulated skin and gastrointestinal environment.

[0021] Advantages:

[0022] The present application prepares a new small molecule hydrogel system of indomethacin and small molecule ligands, which has good solubility and dissolution release advantage, and significantly enhances the membrane permeability of indomethacin. The prepared two hydrogels are expected to develop into a new gel preparation product of indomethacin, and also provide a new design idea for the development of other new gel drugs. BRIEF DESCRIPTION OF DRAWINGS

[0023] Figure 1 (A) sample figure and (B) SEM figure of the indomethacin-meglumine hydrogel and the indomethacin-arginine hydrogel prepared in Example 1 (a: indomethacin-meglumine hydrogel, b: indomethacin-arginine hydrogel);

[0024] Figure 2 Rheological test figure of the indomethacin-meglumine hydrogel prepared in Example 1 (a: strain sweep, b: frequency sweep);

[0025] Figure 3 Rheological test figure of the indomethacin-arginine hydrogel prepared in Example 1 (a: strain sweep, b: frequency sweep);

[0026] Figure 4 X-ray powder diffraction (XRPD) figure of the dry gel prepared from the indomethacin-meglumine hydrogel in Example 1;

[0027] Figure 5 X-ray powder diffraction (XRPD) figure of the dry gel prepared from the indomethacin-arginine hydrogel in Example 1;

[0028] Figure 6 Differential scanning calorimetry (DSC) figure of the indomethacin-meglumine dry gel prepared in Example 1;

[0029] Figure 7 Differential scanning calorimetry (DSC) figure of the indomethacin-arginine dry gel prepared in Example 1;

[0030] Figure 8 Infrared spectrum (FTIR) figure of the indomethacin-meglumine dry gel prepared in Example 1;

[0031] Figure 9 Infrared spectrum (FTIR) figure of the indomethacin-arginine dry gel prepared in Example 1

[0032] Figure 10 Cumulative release profiles of the indomethacin-meglumine hydrogel and the indomethacin-arginine hydrogel prepared in Example 1;

[0033] Figure 11 Non-fitting-bath release profiles of the indomethacin-meglumine hydrogel and the indomethacin-arginine hydrogel prepared in Example 1;

[0034] Figure 12 Phase solubility diagram of indomethacin in different concentrations of ligand aqueous solution (indomethacin: IND, meglumine: MEG, arginine: ARG);

[0035] Figure 13 Simulated gastrointestinal permeation diagram of the indomethacin-meglumine hydrogel and the indomethacin-arginine hydrogel prepared in Example 1;

[0036] Figure 14 Simulated skin permeation diagram of the indomethacin-meglumine hydrogel and the indomethacin-arginine hydrogel prepared in Example 1. DETAILED DESCRIPTION

[0037] The application will be further described below with reference to examples.

[0038] Example 1

[0039] 647 mg of indomethacin and 353 mg of meglumine, 672.5 mg of indomethacin and 327.5 mg of arginine were weighed into two 10 mL vials, respectively, and mixed at 25°C with a suspension instrument, 200 μL of deionized water was added, and oscillated for 5 min, to obtain two homogeneous yellow gel samples.

[0040] Example 2

[0041] 478.2 mg of indomethacin and 521.8 mg of meglumine, 506.6 mg of indomethacin and 493.4 mg of arginine were weighed into two 10 mL vials, respectively, and mixed at 25°C with a suspension instrument, 200 μL of deionized water was added, and oscillated for 5 min, to obtain two homogeneous yellow gel samples.

[0042] Example 3

[0043] 785.7 mg of indomethacin and 214.3 mg of meglumine, 804.2 mg of indomethacin and 195.8 mg of arginine were weighed into two 10 mL vials, respectively, and mixed at 25°C with a suspension instrument, 200 μL of deionized water was added, and oscillated for 5 min, to obtain two homogeneous yellow gel samples.

[0044] Example 4

[0045] Indomethacin, 647 mg and meglumine, 353 mg; indomethacin, 672.5 mg and arginine, 327.5 mg were weighed into two 10 mL vials and mixed using a suspension apparatus at 20 °C. 200 μL of deionized water was added and the samples were shaken for 5 min to obtain two homogeneous yellow gels.

[0046] Example 5:

[0047] Indomethacin, 647 mg and meglumine, 353 mg; indomethacin, 672.5 mg and arginine, 327.5 mg were weighed into two 10 mL vials and mixed using a suspension apparatus at 30 °C. 200 μL of deionized water was added and the samples were shaken for 5 min to obtain two homogeneous yellow gels.

[0048] Example 6

[0049] Indomethacin, 647 mg and meglumine, 353 mg; indomethacin, 672.5 mg and arginine, 327.5 mg were weighed into two 10 mL vials and mixed using a suspension apparatus at 25 °C. 100 μL of deionized water was added and the samples were shaken for 5 min to obtain two homogeneous yellow gels.

[0050] Example 7

[0051] Indomethacin, 647 mg and meglumine, 353 mg; indomethacin, 672.5 mg and arginine, 327.5 mg were weighed into two 10 mL vials and mixed using a suspension apparatus at 25 °C. 300 μL of deionized water was added and the samples were shaken for 5 min to obtain two homogeneous yellow gels.

[0052] Example 8

[0053] Indomethacin, 647 mg and meglumine, 353 mg; indomethacin, 672.5 mg and arginine, 327.5 mg were weighed into two 10 mL vials and mixed using a suspension apparatus at 25 °C. 200 μL of deionized water was added and the samples were shaken for 3 min to obtain two homogeneous yellow gels.

[0054] Example 9

[0055] Indomethacin, 647 mg and meglumine, 353 mg; indomethacin, 672.5 mg and arginine, 327.5 mg were weighed into two 10 mL vials and mixed using a suspension apparatus at 25 °C. 200 μL of deionized water was added and the samples were shaken for 7 min to obtain two homogeneous yellow gels.

[0056] Example 10

[0057] Indomethacin, 672.5 mg and arginine, 327.5 mg were weighed into two 10 mL vials and mixed using a suspension apparatus at 25 °C. 200 μL of deionized water was added and the samples were shaken for 10 min to obtain two homogeneous yellow gels.

[0058] Example 11

[0059] Indomethacin, 672.5 mg and arginine, 327.5 mg were weighed into two 10 mL vials and mixed using a suspension apparatus at 25 °C. 200 μL of deionized water was added and the samples were shaken for 10 min to obtain two homogeneous yellow gels.

[0060] Example 12

[0061] Indomethacin, 672.5 mg and arginine, 327.5 mg were weighed into two 10 mL vials and mixed using a suspension apparatus at 25 °C. 200 μL of deionized water was added and the samples were shaken for 10 min to obtain two homogeneous yellow gels.

[0062] Example 13

[0063] Indomethacin, 672.5 mg and arginine, 327.5 mg were weighed into two 10 mL vials and mixed using a suspension apparatus at 25 °C. 200 μL of deionized water was added and the samples were shaken for 10 min to obtain two homogeneous yellow gels.

[0064] Example 14

[0065] Indomethacin, 672.5 mg and arginine, 327.5 mg were weighed into two 10 mL vials and mixed using a suspension apparatus at 25 °C. 200 μL of deionized water was added and the samples were shaken for 10 min to obtain two homogeneous yellow gels.

[0066] Comparative Example

[0067] Indomethacin and ligand (meglumine and arginine) powders were weighed in a 1 : 1 molar ratio into a 10 mL vial and mixed by vortexing for 10 min to obtain a physical mixture of indomethacin-ligand.

[0068] Test Example 1: The indometacin-meglumine hydrogel and the indometacin-arginine hydrogel prepared in Example 1 were tested as follows.

[0069] 1. Scanning Electron Microscopy (SEM)

[0070] Instrument: TM4000 Tabletop Scanning Electron Microscope (HITACHI, Japan)

[0071] Probe current: 20 μA

[0072] Accelerating voltage: 15 kV

[0073] Counting time: 60 s

[0074] Measurement results: The scanning electron microscope sample image of the indometacin-meglumine hydrogel is shown in Figure 1 B. As can be seen from Figure 1 B, the indometacin-meglumine hydrogel and the indometacin-arginine hydrogel exhibit a typical three-dimensional network structure of a gel, and there are obvious pores inside.

[0075] 2. Rheology test

[0076] Instrument: Kinexus pro rotational rheometer (Malvern, Britain)

[0077] Parallel plate diameter: 20 mm

[0078] Measurement gap: 1 mm

[0079] Temperature: 25 °C

[0080] Strain sweep: Frequency: 1 Hz Range: 0.1% ~ 1000%

[0081] Frequency sweep: Strain: 0.1% Range: 0.1 ~ 100 rad·s -1

[0082] Measurement results: The rheology test results of the indometacin-meglumine hydrogel in Example 1 are shown in Figure 2 . As can be seen from Figure 2 a, G' and G" remain almost unchanged at 10% strain, indicating that the structure of the indometacin-meglumine hydrogel is not destroyed. When the strain exceeds 10%, the values of G' and G" decrease sharply with the change of the applied strain, and the viscoelastic signal is reversed (G" > G'), indicating that the structure of the indometacin-meglumine hydrogel is significantly destroyed. The angular frequency sweep was performed in the range of 0.1 ~ 100 rad·s -1 , and the strain was 0.1% (within the linear viscoelastic region). The indometacin-meglumine hydrogel exhibits significant elasticity, and the values of G' and G" increase with the increase of the frequency Figure 2 b).

[0083] The rheological test results of the indomethacin-arginine hydrogel in Example 1 are shown in Figure 3 . It is known from Figure 3 that 30% strain is defined as the upper boundary of the linear rheological region of the indomethacin-arginine hydrogel. When the boundary is exceeded (>30% strain), the hydrogel transitions to a liquid-like behavior due to G" being greater than G'. Figure 3 b).

[0084] 3. Powder X-ray Diffraction (XRPD)

[0085] Instrument: SmartLab (9) X-ray diffractometer (Rigaku, Japan)

[0086] Target: Cu-Ka radiation

[0087] Wavelength:

[0088] Tube voltage: 40 KV

[0089] Tube current: 40 mA

[0090] Step size: 0.02°

[0091] Scan speed: 4° / min

[0092] Scan range; 2 theta, 3-50°

[0093] The results of the powder X-ray diffraction analysis of the indomethacin-meglumine and indomethacin-arginine dry gels prepared from the hydrogel samples in Example 1 are shown in Figure 4 and Figure 5 . It is known from Figure 4 that the crystalline diffraction peaks in the powder X-ray diffraction pattern of the indomethacin-meglumine dry gel are all disappeared, and replaced by a single diffuse amorphous diffraction ring.

[0094] The XRPD pattern of the indomethacin-arginine dry gel shows weak characteristic diffraction peaks, and the crystalline diffraction peaks in the indomethacin-arginine dry gel are significantly weakened compared to the indomethacin crystal and the arginine crystal Figure 5 ).

[0095] 4. Differential Scanning Calorimetry (DSC)

[0096] Instrument: Hitachi SIIDSC7020 (Hitachi, Japan)

[0097] Range: 25-260°C

[0098] Heating rate: 10℃ / min

[0099] Measurement results: The DSC test results of indomethacin-meglumine xerogel and indomethacin-arginine xerogel prepared from the hydrogel sample in Example 1 are as follows: Figure 6 and Figure 7 As shown. Figure 6 and Figure 7 It can be seen that the glass transition temperatures of indomethacin-meglumine xerogel and indomethacin-arginine xerogel are 50.45℃ and 69.89℃, respectively, and the crystal melting peaks of the original drug and ligand basically disappear.

[0100] 5. Infrared spectroscopy (FTIR)

[0101] Instrument: Nicolet iS50 Fourier transform infrared spectrometer (Thermo, American)

[0102] Range: 4000-400cm -1

[0103] Scan times: 64 times

[0104] Measurement results: Figure 8 It can be seen that the infrared spectrum wave number (cm -1 ) are: 3458.3, 3334.9, 3113.1, 3078.3, 1674.2, 1643.3, 1521.8, 1456.2, 1417.6, 1400.3, 1352.1, 1240.2, 1186.2, 1159.2, 1081.8, 1043.4, 837.1, 779.2, 746.4, 677.0 and 553.6.

[0105] like Figure 9 As shown in the figure, the infrared spectrum wave number (cm -1 ) are: 3456.4, 3323.3, 3111.2, 2943.3, 2839.2, 1664.5, 1597.0, 1529.5, 1454.3, 1419.6, 1400.3, 1352.1, 1319.3, 1290.3, 1240.2, 1188.1, 1163.0, 1087.8, 912.3, 873.7, 840.9, 779.2, 709.8, 638.4 and 551.6.

[0106] Compared with the indomethacin-meglumine hydrogel and indomethacin-arginine hydrogel and their xerogels in Example 1, the two kinds of indomethacin hydrogels prepared in Examples 2-10 exhibit the same or similar gel morphology, microstructure and rheological behavior. The xerogels prepared from the hydrogels in Examples 2-10 exhibit the same or similar XRPD, DSC and FTIR spectra.

[0107] Test Example 2: Solubility determination of the indomethacin-meglumine hydrogel and indomethacin-arginine hydrogel prepared in Comparative Example 1 and Examples 1, 3, 5, 9 was carried out as follows:

[0108] 1. Solubility determination

[0109] Indomethacin crystals, indomethacin-meglumine physical mixture, indomethacin-arginine physical mixture, indomethacin-meglumine hydrogel and indomethacin-arginine hydrogel were taken in 10 mL centrifuge tubes in parallel in five portions, 5 ml of deionized water was added respectively, and placed in a constant temperature shaking bed for shaking for 24 h (200 rpm, 37°C). 2 mL of supernatant was taken, filtered with a 0.22 μm water phase microporous filter, and then determined by high performance liquid chromatography (HPLC) to calculate the solubility of the drug in deionized water.

[0110] The high performance liquid chromatography conditions are as follows:

[0111] Instrument: Agilent-1260 high performance liquid chromatograph

[0112] Column: Ultimate XB-C18 (4.6 mm x 250 mm, 5 μm)

[0113] Mobile phase: acetonitrile-water phase (0.3% phosphoric acid) = 30:70 (V / V)

[0114] Flow rate: 1.0 mL / min

[0115] Detection wavelength: 228 nm

[0116] Determination results: The solubility of the indomethacin-meglumine hydrogel and indomethacin-arginine hydrogel in deionized water in Examples 1, 3, 5, 9, 11 and 13 is shown in Table 1. As can be seen from Table 1, compared with single indomethacin crystals (3.7 μg / mL), the solubility of the indomethacin-meglumine hydrogel in Example 1 is increased by 506 times, reaching 1874.81 μg / mL, and the solubility of the indomethacin-arginine hydrogel is increased by 479 times, reaching 1774.64 μg / mL.

[0117] Table 1. Water solubility of indomethacin crystals, indomethacin-ligand physical mixture and indomethacin hydrogel

[0118]

[0119] Test Example 3: Release test of the indometacin-meglumine hydrogel and the indometacin-arginine hydrogel prepared in Example 1 under sink condition was carried out as follows:

[0120] Indometacin crystals, physical mixture of indometacin and meglumine crystals, physical mixture of indometacin and arginine crystals, indometacin-meglumine hydrogel and indometacin-arginine hydrogel (containing an amount of drug equivalent to 1.8 mg of indometacin) prepared in Example 1 were weighed respectively, in parallel for 5 times. According to the second method of General Test 0931 in Chinese Pharmacopoeia 2020 edition, the release test under sink condition was carried out by slurry method. The release medium was water, the medium temperature was 37℃, the medium volume was 900 mL, and the rotation speed was 100 rpm. 2 mL of sample was taken at 2, 5, 10, 15, 20, 30, 45, 60, 90 and 120 min, and 2 mL of constant temperature medium was supplemented at the same time. The removed liquid was passed through a 0.22 μm water phase microporous filter membrane, and 10 μL of the filtrate was taken for HPLC analysis.

[0121] The determination results: the cumulative release rate curves of the indometacin-meglumine hydrogel and the indometacin-arginine hydrogel in Example 1 under sink condition are shown in Figure 10 It can be seen from Figure 10 that the release of the two hydrogels of indometacin was always significantly higher than that of indometacin crystals throughout the release test. At 20 min, compared with the cumulative release rate (2.11%) of indometacin crystals, the cumulative release rates of the indometacin-meglumine hydrogel and the indometacin-arginine hydrogel were 51.13% and 54.42% respectively, which were about 24.23 times and 25.79 times of that of indometacin crystals; at 120 min, the cumulative release rates of the indometacin-meglumine hydrogel and the indometacin-arginine hydrogel were 58.21% and 61.88% respectively, which were about 2.87 times and 3.05 times of that of indometacin crystals (20.30%).

[0122] Test Example 4: Release test of the indometacin-meglumine hydrogel and the indometacin-arginine hydrogel of Example 1 under non-sink condition was carried out as follows:

[0123] Take an appropriate amount of indomethacin crystal, indomethacin and meglumine crystal physical mixture, indomethacin and arginine crystal physical mixture, indomethacin-meglumine gel in Example 1 and indomethacin-arginine hydrogel (containing an amount of drug equivalent to 40 mg of indomethacin), respectively, in parallel for 5 times. According to the second method of 0931 in Chinese Pharmacopoeia 2020 edition, the non-bypass release degree was evaluated by slurry method. The release medium was water, the medium temperature was 37℃, the medium volume was 200 mL, and the rotation speed was 100 rpm. 2 mL was taken out at 5, 10, 20, 30, 45, 60, 90, 120, 240, 360, 480 and 720 min, and 2 mL constant temperature medium was supplemented at the same time. The liquid was filtered through a 0.22 μm water phase microporous filter membrane, and 10 μL of the filtrate was taken for HPLC analysis.

[0124] The determination results: the non-bypass release curves of indomethacin, indomethacin-meglumine physical mixture and indomethacin-meglumine hydrogel in Example 1 are shown in Figure 11 Figure 11 It can be seen that the release concentration of indomethacin crystal is low at 120 min, which is 5.24 μg / mL, and then tends to be saturated. While the release concentrations of indomethacin-meglumine physical mixture and indomethacin-meglumine hydrogel are significantly improved, which are 116.71 μg / mL and 167.03 μg / mL, respectively. During the whole test process, indomethacin-meglumine physical mixture and indomethacin-meglumine hydrogel show supersaturation release behavior and maintain high supersaturation concentration for a long time. After 720 min, the release concentration of indomethacin in indomethacin-meglumine hydrogel reaches 161.95 μg / mL, which is 20.82 times and 1.31 times of that of indomethacin crystal (7.78 μg / mL) and indomethacin-meglumine physical mixture (123.74 μg / mL), respectively.

[0125] Figure 11 It can be seen that the indomethacin-arginine hydrogel in Example 1 shows similar supersaturation release behavior as the indomethacin-meglumine hydrogel. At 720 min, the release concentration of indomethacin in indomethacin-arginine hydrogel is 158.73 μg / mL, which is 20.40 times and 1.34 times of that of indomethacin crystal (7.78 μg / mL) and indomethacin-arginine physical mixture (118.27 μg / mL), respectively.

[0126] Test Example 5: The phase solubility of indomethacin crystal in different concentrations of meglumine aqueous solution and arginine aqueous solution was determined, as follows:

[0127] Instrument: SHZ-82JT constant temperature oscillator (LIANGYOU, China)

[0128] ​​Excess indomethacin powder was added to 5 mL of different concentrations of meglumine aqueous solution and arginine aqueous solution, respectively, in parallel with 5 replicates, and the phase solubility test was performed in a constant temperature oscillator at 37°C, 200 rpm for 24 h. 2 mL of supernatant was passed through a 0.45 μm water phase microporous filter, and the indomethacin concentration was determined by an HPLC system.

[0129] The determination results: the phase solubility of indomethacin in different concentrations of meglumine aqueous solution and arginine aqueous solution is as follows Figure 12 The solubility of indomethacin increases non-linearly with the increase of the concentration of meglumine or arginine, showing a typical 1:1A N complexation behavior, with a negative deviation at a higher concentration of meglumine or arginine.

[0130] Test Example 6: In vitro permeability determination of indomethacin-meglumine hydrogel and indomethacin-arginine hydrogel prepared in Example 1 was compared with commercially available indomethacin hydrogel (Kowa Company, Ltd., Japan), as follows:

[0131] Instrument: TP-6 intelligent transdermal diffusion instrument (Jingtuo, Tianjin, China)

[0132] Indomethacin hydrogel trade name: Wante Li (Kowa, Japan)

[0133] The prepared indomethacin-meglumine hydrogel, indomethacin-arginine hydrogel and commercially available indomethacin hydrogel (containing an amount of drug equivalent to 20 mg of indomethacin) were placed on the artificial membrane in the donor chamber, in parallel with 5 replicates.

[0134] Simulated gastrointestinal permeation: synthetic cellulose acetate membrane (0.45 μm) was placed in the middle of the two chambers of the transdermal diffusion cell to simulate gastrointestinal permeation. Each receptor chamber was filled with 15 mL of pH 6.8 phosphate buffer, and the water bath temperature was maintained at 37°C, and stirred at a speed of 350 rpm with a magnetic stirrer. At appropriate time intervals (0.5, 1, 2, 4, 6, 8, 10, 12, 24 h), 0.7 mL of receptor fluid was removed, and then 0.7 mL of fresh fluid was added. The fluid drawn from the receptor chamber was filtered with a 0.22 μm water phase microporous filter, and then the membrane cumulative permeation rate of indomethacin was determined by an HPLC system

[0135] Simulated skin permeation: The membrane was mounted horizontally between the donor and receptor chambers of the diffusion cell with the lipid layer facing upwards to simulate skin permeation. Each receptor chamber was filled with 15 mL of 30% ethanol in phosphate buffer (pH 7.4) and maintained at 37°C in a water bath with magnetic stirring at 350 rpm. At appropriate time intervals (0.5, 1, 2, 4, 6, 8, 10, 12, 24 h), 0.7 mL of the receptor fluid was removed and replaced with 0.7 mL of fresh fluid. The fluid withdrawn from the receptor chamber was filtered through a 0.22 μm water phase micropore filter and then assayed for indomethacin membrane cumulative permeation rate using the HPLC system.

[0136] Results: In the study of gastrointestinal permeability, Figure 13 ), the cumulative permeation rate of indomethacin-meglumine hydrogel and indomethacin-arginine hydrogel was significantly higher than that of the commercial indomethacin hydrogel (p < 0.0001), as shown in Table 2 and Figure 13 It can be seen that the maximum cumulative permeation amount of indomethacin-meglumine hydrogel at 8 h was 6883.82 ± 230.35 μg·cm -2 (the maximum steady-state permeation rate J was 33.53%·h -1 ), and the maximum cumulative permeation amount of indomethacin-arginine hydrogel at 8 h was 6338.37 ± 159.68 μg·cm -2 (the maximum steady-state permeation rate J was 30.90%·h -1 ), which were 39.35 and 36.23 times that of the commercial indomethacin hydrogel (the maximum cumulative permeation amount at 8 h was 174.93 ± 38.53 μg·cm -2 ), respectively.

[0137] In the transdermal test, the maximum transdermal amount of the two prepared indomethacin hydrogels at 10 h was 5240.56 ± 198.30 μg·cm -2 (the maximum steady-state permeation rate J was 26.65%·h -1 ) and 4379.45 ± 234.23 μg·cm -2 (the maximum steady-state permeation rate J was 24.07%·h -1 ), which were 8.02 and 6.70 times that of the commercial indomethacin hydrogel (the maximum cumulative permeation amount at 8 h was 653.46 ± 26.34 μg·cm -2 ), respectively. Figure 14

[0138] Table 2 Cumulative permeation rate of indomethacin hydrogel in simulated gastrointestinal and skin environments

[0139]

[0140] ​

[0141] **** p < 0.0001 compared to commercially available indomethacin hydrogel.

Claims

1. A method for preparing indomethacin small molecule hydrogel, characterized in that: The preparation method of the small molecule hydrogel is as follows: indomethacin and a small molecule ligand are uniformly mixed, deionized water is added, and the mixture is shaken to react to obtain a yellow gel-like small molecule hydrogel; The small molecule ligand is: meglumine or arginine; The molar ratio of indomethacin to the small molecule ligand is 1:5 to 5:

1.

2. The method for preparing the indomethacin small molecule hydrogel according to claim 1, wherein: The molecular weights of the indomethacin and the small molecule ligand are both less than 1000 Da.

3. The method for preparing the indomethacin small molecule hydrogel according to claim 1, wherein: Based on the total mass of indomethacin and small molecule ligand being 1 g, the amount of deionized water added was 50-600 μL.

4. The method for preparing the indomethacin small molecule hydrogel according to claim 1, wherein: The shaking reaction temperature is 10-60°C, and the shaking time is 1-20 min.

5. An indomethacin small molecule hydrogel prepared according to the method according to any one of claims 1 to 4.

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