Indometacin micromolecular hydrogel and preparation method thereof

Abstract

The invention belongs to the technical field of medicines, and particularly discloses indometacin micromolecular hydrogel and a preparation method thereof. The micromolecular hydrogel is prepared by mixing indometacin and a micromolecular ligand, adding a small amount of deionized water and oscillating. The micromolecular hydrogel takes a micromolecular ligand as a matrix, and has the advantages of solubility and permeability. The formed micromolecular hydrogel can significantly improve the solubility and dissolution rate / release rate of indometacin, and compared with an indometacin crystal, the water solubility of the two micromolecular hydrogel of indometacin-meglumine / arginine is respectively improved by 506 times and 479 times, and the accumulated release rates in 2 hours are respectively improved by 2.67 times and 3.05 times. Meanwhile, the membrane permeability of the indometacin is remarkably promoted by the small-molecule hydrogel, the development potential of oral administration and transdermal application of the indometacin is enhanced, and a new preparation idea is provided for solving the dissolvability and permeability defects of non-steroidal anti-inflammatory drugs and other insoluble drugs.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines and specifically discloses an indomethacin small molecule hydrogel and a preparation method thereof. Background Art

[0002] Indometacin (IND), chemical name is 2-methyl-1-(4-chlorobenzoyl)-5-methoxy-1H-indole-3-acetic acid, and its chemical structure is shown in the following formula:

[0003]

[0004] Indomethacin, also known as indomethacin, is a strong non-corticoid anti-inflammatory, antipyretic and analgesic drug, belonging to the aromatic acetic acid class of non-steroidal anti-inflammatory drugs. It inhibits cyclooxygenase to reduce prostaglandin synthesis, stop the formation of pain nerve impulses in inflammatory tissues, and inhibit inflammatory reactions. However, indomethacin belongs to the Class II drug of the Biopharmaceutics Classification System (BCS), has poor solubility and low absorption in the body, which limits its clinical therapeutic effect.

[0005] The currently available indomethacin gel (trade name: Vantel) is used to treat muscle and joint pain. It is composed of indomethacin and various polymer materials such as hydroxypropyl methylcellulose and polycarboxyvinyl. So far, the research on drug hydrogels has mainly focused on designing and preparing drug macromolecular gels by introducing macromolecular matrices (such as hyaluronic acid, chitosan, sodium alginate, poloxamer, etc.), and clarifying their formation mechanism and related therapeutic applications. However, there are very few designs and related studies on small molecule gel systems for drugs. Summary of the invention

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

[0007] Among them, the molecular weights of indomethacin and small molecule ligands are both less than 1000Da.

[0008] Small molecule ligands include: meglumine, arginine, glutamic acid, glutamine, citrulline, piperine, 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 to 5:1, preferably 1:2 to 2:1, and most preferably 1:1.

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

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

[0013] The indomethacin small molecule hydrogel prepared by the present invention has a typical three-dimensional network structure as shown by scanning electron microscopy results, and a good gel state can be maintained within a certain strain range, which can meet application requirements.

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

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

[0016] Differential scanning calorimetry analysis confirmed that both xerogel samples exhibited a single glass transition temperature (50.45°C and 69.89°C).

[0017] By measuring the solubility of indomethacin crystals, indomethacin-ligand physical mixture and two indomethacin hydrogels, the results showed that indomethacin-meglumine and indomethacin-arginine hydrogels can significantly increase the solubility of indomethacin in water.

[0018] By conducting cumulative release tests under sink conditions, it was confirmed that the two hydrogels, indomethacin-methylglucone and indomethacin-arginine, can significantly improve the cumulative release rate of indomethacin.

[0019] By conducting release tests under non-sink conditions, the two hydrogels, indomethacin-methylglucone and indomethacin-arginine, showed supersaturated release behavior and could maintain high supersaturated concentrations for a long time.

[0020] Through membrane permeability tests, it was found that compared with the existing commercially available indomethacin gel, the two hydrogels, indomethacin-meglumine and indomethacin-arginine, can significantly promote the membrane permeability of indomethacin in simulated skin and gastrointestinal environments.

[0021] Beneficial effects:

[0022] The present invention prepares indomethacin and a small molecule ligand into a new small molecule hydrogel system, which has good solubility and dissolution release advantages and significantly enhances the membrane permeability of indomethacin. The two prepared hydrogels are expected to be developed into new gel preparation products of indomethacin, and also provide new design ideas for the development of new gels for other drugs. BRIEF DESCRIPTION OF THE DRAWINGS

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

[0024] Figure 2 This is a rheological test graph of the indomethacin-methylglucamine hydrogel prepared in Example 1 (a: strain sweep, b: frequency sweep);

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

[0026] Figure 4 is a powder X-ray diffraction (XRPD) pattern of the xerogel prepared from the indomethacin-meglumine hydrogel in Example 1;

[0027] Figure 5 is a powder X-ray diffraction (XRPD) pattern of the xerogel prepared from the indomethacin-arginine hydrogel in Example 1;

[0028] Figure 6 is a differential scanning calorimetry (DSC) graph of the indomethacin-meglumine xerogel prepared in Example 1;

[0029] Figure 7 is a differential scanning calorimetry (DSC) graph of the indomethacin-arginine xerogel prepared in Example 1;

[0030] Figure 8 is an infrared spectrum (FTIR) of the indomethacin-meglumine xerogel prepared in Example 1;

[0031] Fig. 9 This is the infrared spectrum (FTIR) of the indomethacin-arginine xerogel prepared in Example 1.

[0032] Fig.10 is the cumulative release curve of the indomethacin-meglumine hydrogel and the indomethacin-arginine hydrogel prepared in Example 1;

[0033] Fig.11 is the non-sink release curve of the indomethacin-meglumine hydrogel and the indomethacin-arginine hydrogel prepared in Example 1;

[0034] Fig.12 is the phase solubility diagram of indomethacin in aqueous solutions with different ligand concentrations (indomethacin: IND, meglumine: MEG, arginine: ARG);

[0035] Fig.13 is a simulated gastrointestinal permeation diagram of the indomethacin-meglumine hydrogel and the indomethacin-arginine hydrogel prepared in Example 1;

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

[0037] The present invention will be further described below in conjunction with the embodiments.

[0038] Example 1

[0039] Weigh 647 mg of indomethacin and 353 mg of meglumine, 672.5 mg of indomethacin and 327.5 mg of arginine respectively into two 10 mL vials, mix them evenly with a suspension mixer at 25°C, add 200 μL of deionized water, and shake for 5 minutes to obtain two homogeneous yellow gel samples.

[0040] Example 2

[0041] Weigh 478.2 mg of indomethacin and 521.8 mg of meglumine, 506.6 mg of indomethacin and 493.4 mg of arginine respectively into two 10 mL vials, mix them evenly with a suspension mixer at 25°C, add 200 μL of deionized water, and shake for 5 minutes 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 respectively and placed in two 10 mL vials, mixed with a suspension mixer at 25°C, 200 μL of deionized water was added, and shaken for 5 minutes to obtain two homogeneous yellow gel samples.

[0044] Example 4

[0045] Weigh 647 mg of indomethacin and 353 mg of meglumine, 672.5 mg of indomethacin and 327.5 mg of arginine respectively into two 10 mL vials, mix them evenly with a suspension mixer at 20°C, add 200 μL of deionized water, and shake for 5 minutes to obtain two homogeneous yellow gel samples.

[0046] Embodiment 5:

[0047] Weigh 647 mg of indomethacin and 353 mg of meglumine, 672.5 mg of indomethacin and 327.5 mg of arginine respectively and put them into two 10 mL vials, mix them with a suspension mixer at 30°C, add 200 μL of deionized water, and shake for 5 minutes to obtain two homogeneous yellow gel samples.

[0048] Example 6

[0049] Weigh 647 mg of indomethacin and 353 mg of meglumine, 672.5 mg of indomethacin and 327.5 mg of arginine respectively into two 10 mL vials, mix them evenly with a suspension mixer at 25°C, add 100 μL of deionized water, and shake for 5 minutes to obtain two homogeneous yellow gel samples.

[0050] Example 7

[0051] Weigh 647 mg of indomethacin and 353 mg of meglumine, 672.5 mg of indomethacin and 327.5 mg of arginine respectively into two 10 mL vials, mix them evenly with a suspension mixer at 25°C, add 300 μL of deionized water, and shake for 5 minutes to obtain two homogeneous yellow gel samples.

[0052] Example 8

[0053] Weigh 647 mg of indomethacin and 353 mg of meglumine, 672.5 mg of indomethacin and 327.5 mg of arginine respectively into two 10 mL vials, mix them evenly with a suspension mixer at 25°C, add 200 μL of deionized water, and shake for 3 minutes to obtain two homogeneous yellow gel samples.

[0054] Example 9

[0055] Weigh 647 mg of indomethacin and 353 mg of meglumine, 672.5 mg of indomethacin and 327.5 mg of arginine respectively into two 10 mL vials, mix them evenly with a suspension mixer at 25°C, add 200 μL of deionized water, and shake for 7 minutes to obtain two homogeneous yellow gel samples.

[0056] Example 10

[0057] Weigh 647 mg of indomethacin and 353 mg of meglumine, 672.5 mg of indomethacin and 327.5 mg of arginine respectively and put them into two 10 mL vials, mix them with a suspension mixer at 25°C, add 200 μL of deionized water, and shake for 10 minutes to obtain two homogeneous yellow gel samples.

[0058] Embodiment 11

[0059] Weigh 708.6 mg of indomethacin and 291.4 mg of glutamic acid, 710 mg of indomethacin and 290 mg of glutamine respectively into two 10 mL vials, mix them evenly with a suspension mixer at 25 °C, add 200 μL of deionized water, and shake for 5 min to obtain two heterogeneous yellow gel samples, in which some drug or ligand powder still exists.

[0060] Example 12

[0061] Weigh 756.6 mg of indomethacin and 243.4 mg of proline, 636.6 mg of indomethacin and 363.4 mg of tryptophan respectively into two 10 mL vials, mix them evenly with a suspension mixer at 25 °C, add 200 μL of deionized water, and shake for 5 min to obtain two heterogeneous yellow gel samples, in which some drug or ligand powder still exists.

[0062] Example 13

[0063] 672.5 mg of indomethacin and 327.5 mg of theanine, 556.3 mg of indomethacin and 443.7 mg of piperine were weighed into two 10 mL vials, mixed with a suspension mixer at 25 °C, 200 μL of deionized water was added, and oscillated for 5 min. The drug and the ligand were dispersed in the form of powder, and a homogeneous gel sample could not be formed.

[0064] Embodiment 14

[0065] 703 mg of indomethacin and 297 mg of histidine, 709.9 mg of indomethacin and 290.1 ​​mg of lysine were weighed into two 10 mL vials, mixed with a suspension mixer at 25°C, 200 μL of deionized water was added, and oscillated for 5 minutes. The drug and the ligand were dispersed in the form of powder and could not form a homogeneous gel sample.

[0066] Comparative Example

[0067] Indomethacin and ligand (methylglumine and arginine) powders were weighed in a molar ratio of 1:1, placed in a 10 mL vial, and vortexed for 10 min to uniformly mix the two powders to obtain an indomethacin-ligand physical mixture.

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

[0069] 1. Scanning electron microscope (SEM)

[0070] Instrument: TM4000 desktop scanning electron microscope (HITACHI, Japan)

[0071] Probe current: 20μA

[0072] Accelerating voltage: 15 kV

[0073] Counting time: 60s

[0074] Measurement results: The scanning electron microscope sample of indomethacin-meglumine gel is shown in Figure 1 B. By Figure 1 B shows that the indomethacin-methylglucamine hydrogel and indomethacin-arginine hydrogel present a typical three-dimensional network structure of the gel with obvious pores inside.

[0075] 2. Rheological test

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

[0077] Parallel plate diameter: 20mm

[0078] Measuring gap: 1mm

[0079] Temperature: 25℃

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

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

[0082] Test results: The rheological test results of the indomethacin-methylglumine hydrogel in Example 1 are shown in Figure 2 .Depend on Figure 2 It can be seen from Figure 1 that G' and G" remain almost unchanged at 10% strain, indicating that the structure of the indomethacin-methylglucamine hydrogel is not damaged. When the strain exceeds 10%, the G' and G" values ​​decrease sharply with the change of the applied strain, and the viscoelastic signal reverses (G">G'), indicating that the structure of the indomethacin-methylglucamine hydrogel is significantly damaged. -1 The angular frequency was swept in the range of 0.1% strain (in the linear viscoelastic region). The indomethacin-meglumine hydrogel showed significant elasticity, and the G' and G" values ​​increased with increasing frequency ( Figure 2 b).

[0083] The rheological test results of the indomethacin-arginine hydrogel in Example 1 are as follows: Figure 3 .Depend on Figure 3 It can be seen from a that 30% strain is defined as the upper boundary of the linear rheological region of indomethacin-arginine hydrogel. When this boundary is exceeded (>30% strain), the hydrogel turns into liquid-like behavior because G" is greater than G'. Indomethacin-arginine hydrogel has reasonable hydrogel strength, and G' has little dependence on the applied frequency. The G' measured in the frequency range is greater than and G" ( Figure 3 b).

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

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

[0086] Target: Cu-Kα radiation

[0087] wavelength:

[0088] Tube voltage: 40KV

[0089] Tube current: 40mA

[0090] Step size: 0.02°

[0091] Scanning speed: 4° / min

[0092] Scanning range: 2θ, 3-50°

[0093] Measurement results: The powder X-ray diffraction analysis results of the indomethacin-methylglucamine xerogel and indomethacin-arginine xerogel prepared from the hydrogel sample in Example 1 are as follows: Figure 4 and Figure 5 .Depend on Figure 4 It can be seen that the crystal diffraction peaks in the powder X-ray diffraction pattern of indomethacin-methylglumine xerogel all disappeared, and were replaced by a single diffuse amorphous diffraction ring.

[0094] The XRPD pattern of indomethacin-arginine xerogel showed weak characteristic diffraction peaks. Compared with indomethacin crystals and arginine crystals, the crystal diffraction peaks in indomethacin-arginine xerogel were significantly weakened ( Figure 5 ).

[0095] 4. Differential Scanning Calorimetry (DSC)

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

[0097] Range: 25-260℃

[0098] Heating rate: 10℃ / min

[0099] Measurement results: The DSC test results of indomethacin-methylglucamine 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-methylglucamine 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 spectral wavenumber (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 Fig. 9 As shown, 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-methylglumine hydrogel and indomethacin-arginine hydrogel and their xerogels in Example 1, the two indomethacin hydrogels prepared in Examples 2 to 10 exhibited the same or similar gel morphology, microstructure and rheological behavior. The xerogels prepared from the hydrogels in Examples 2 to 10 exhibited the same or similar XRPD, DSC and FTIR spectra.

[0107] Test Example 2: The solubility of the indomethacin-methylglucamine hydrogel and the indomethacin-arginine hydrogel prepared in Comparative Example 1, Examples 1, 3, 5, and 9 was measured 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 placed in 10 mL centrifuge tubes, and 5 parallel portions were added with 5 ml of deionized water respectively. The tubes were placed in a constant temperature shaker and shaken for 24 h (200 rpm, 37 ° C). 2 mL of the supernatant was taken and filtered with a 0.22 μm aqueous microporous filter membrane, and then measured by high performance liquid chromatography (HPLC) to calculate the solubility of the drug in deionized water.

[0110] The HPLC conditions were as follows:

[0111] Instrument: Agilent-1260 High Performance Liquid Chromatograph

[0112] Chromatographic column: Ultimate XB-C18 (4.6mm×250mm, 5μm)

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

[0114] Flow rate: 1.0mL / min

[0115] Detection wavelength: 228nm

[0116] Measurement results: The solubility comparison of 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 shown in Table 1, compared with single indomethacin crystals (3.7 μg / mL), the solubility of indomethacin-meglumine hydrogel in Example 1 increased by 506 times to 1874.81 μg / mL, and the solubility of indomethacin-arginine hydrogel increased by 479 times to 1774.64 μg / mL.

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

[0118]

[0119] Test Example 3: The indomethacin-meglumine hydrogel and indomethacin-arginine hydrogel prepared in Example 1 were subjected to a release test under sink conditions, as follows:

[0120] Weigh indomethacin crystals, physical mixture of indomethacin and meglumine crystals, physical mixture of indomethacin and arginine crystals, indomethacin-meglumine hydrogel and indomethacin-arginine hydrogel (containing an amount of drug equivalent to 1.8 mg of indomethacin) in Example 1, respectively, and parallel 5 portions. According to the second method of 0931 of the fourth general rule of the 2020 edition of the Chinese Pharmacopoeia, the release test under the condition of the leak tank was carried out by the slurry method. The release medium is water, the medium temperature is 37 ° C, the medium volume is 900 mL, and the speed is 100 rpm. Sample 2 mL at 2, 5, 10, 15, 20, 30, 45, 60, 90 and 120 min, and add 2 mL of constant temperature medium at the same time. The removed liquid passed through a 0.22 μm aqueous phase microporous filter membrane, and 10 μL of the filtrate was taken for HPLC analysis.

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

[0122] Test Example 4: A release experiment was conducted on the indomethacin-meglumine hydrogel and the indomethacin-arginine hydrogel of Example 1 under non-sink conditions, as follows:

[0123] Weigh a certain amount of indomethacin crystals, a physical mixture of indomethacin and meglumine crystals, a physical mixture of indomethacin and arginine crystals, indomethacin-meglumine gel and indomethacin-arginine hydrogel (containing an amount of drug equivalent to 40 mg of indomethacin) in Example 1, and 5 parallel portions. According to the second method of 0931 of the fourth general rule of the 2020 edition of the Chinese Pharmacopoeia, the non-leakage release was evaluated by the slurry method. The release medium is water, the medium temperature is 37 ° C, the medium volume is 200 mL, and the speed is 100 rpm. Sample 2 mL at 5, 10, 20, 30, 45, 60, 90, 120, 240, 360, 480 and 720 min, and add 2 mL of constant temperature medium at the same time. The removed liquid passes through a 0.22 μm aqueous phase microporous filter membrane, and 10 μL of the filtrate is taken for HPLC analysis.

[0124] Determination results: The non-sink release curves of indomethacin, indomethacin-meglumine physical mixture and indomethacin-meglumine hydrogel in Example 1 are compared as shown in FIG. Fig.11 As shown. Fig.11 It can be seen that the release concentration of indomethacin crystals at 120 minutes was low, 5.24μg / mL, and then tended to saturation. The release concentrations of indomethacin-meglumine physical mixture and indomethacin-meglumine hydrogel increased significantly, reaching 116.71μg / mL and 167.03μg / mL, respectively. Throughout the experiment, indomethacin-meglumine physical mixture and indomethacin-meglumine hydrogel showed supersaturated release behavior and maintained a high supersaturated concentration for a long time. After 720 minutes, the indomethacin release concentration of indomethacin-meglumine hydrogel reached 161.95μg / mL, which were 20.82 times and 1.31 times that of indomethacin crystals (7.78μg / mL) and indomethacin-meglumine physical mixture (123.74μg / mL), respectively.

[0125] Depend on Fig.11 It can be seen that the indomethacin-arginine hydrogel in Example 1 exhibits a supersaturated release behavior similar to that of the indomethacin-meglumine hydrogel. At 720 min, the indomethacin release concentration of the indomethacin-arginine hydrogel is 158.73 μg / mL, which is 20.40 times and 1.34 times that of the indomethacin crystals (7.78 μg / mL) and the indomethacin-arginine physical mixture (118.27 μg / mL), respectively.

[0126] Test Example 5: The phase solubility of indomethacin crystals in aqueous solutions of meglumine and arginine at different concentrations 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 5 parallel portions, and shaken in a constant temperature oscillator at 37°C and 200 rpm for 24 h for phase solubility test. 2 mL of supernatant was filtered through a 0.45 μm aqueous microporous filter membrane, and the indomethacin concentration was determined using an HPLC system.

[0129] Test results: The solubility of indomethacin in different concentrations of meglumine aqueous solution and arginine aqueous solution is as follows: Fig.12 The solubility of indomethacin increased nonlinearly with increasing concentrations of meglumine or arginine, showing a typical 1:1 A N type complexation behavior, with a negative deviation at higher concentrations of meglumine or arginine.

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

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

[0132] Indomethacin hydrogel Trade name: Vanteli (Kowa, Japan)

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

[0134] Simulated gastrointestinal permeation: A synthetic cellulose acetate membrane (0.45 μm) was placed between 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, the water bath temperature was maintained at 37°C, and stirred at 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 taken out, and then 0.7 mL of fresh fluid was added. The liquid extracted from the receptor chamber was filtered with a 0.22 μm aqueous microporous filter membrane, and then the membrane cumulative permeability of indomethacin was determined using an HPLC system.

[0135] Simulated Skin Penetration: The membrane was installed horizontally between the donor chamber and the receptor chamber of the diffusion cell, with the lipid layer facing up, to simulate skin penetration. Each receptor chamber was filled with 15 mL of 30% ethanol in phosphate buffer (pH 7.4), the water bath temperature was maintained at 37°C, and the magnetic stirrer was stirred at 350 rpm. 0.7 mL of the receptor solution was taken out at appropriate time intervals (0.5, 1, 2, 4, 6, 8, 10, 12, 24 h), and then 0.7 mL of fresh liquid was added. The liquid extracted from the receptor chamber was filtered with a 0.22 μm aqueous microporous filter membrane, and then the membrane cumulative permeability of indomethacin was determined using an HPLC system.

[0136] Results: In the study of gastrointestinal permeability ( Fig.13 ), the cumulative permeability of indomethacin-meglumine hydrogel and indomethacin-arginine hydrogel was significantly higher than that of commercial indomethacin hydrogel (p < 0.0001), as shown in Table 2 and Fig.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 permeability J is 33.53%·h -1 ), the maximum cumulative permeability of indomethacin-arginine hydrogel at 8 h was 6338.37±159.68 μg·cm -2 (The maximum steady-state permeability J is 30.90%·h -1 ), commercially available indomethacin hydrogel (maximum cumulative permeation at 8 h was 174.93±38.53 μg·cm -2 ) are 39.35 times and 36.23 times.

[0137] In the transdermal test, the maximum transdermal amounts of the two prepared indomethacin hydrogels were 5240.56±198.30μg·cm at 10h, respectively. -2 (The maximum steady-state permeability J is 26.65%·h -1 ) and 4379.45±234.23μg·cm -2 (The maximum steady-state permeability J is 24.07%·h -1 ), commercially available indomethacin hydrogel (maximum cumulative permeation at 8 h was 653.46±26.34 μg·cm -2 ) is 8.02 times and 6.70 times ( Fig.14 ).

[0138] Table 2 Cumulative permeation of indomethacin hydrogel in simulated gastrointestinal tract and skin environment

[0139]

[0140]

[0141] ****p<0.0001, compared with commercial indomethacin hydrogel.

Claims

1. A method for preparing an 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 a yellow gel-like small molecule hydrogel is obtained by oscillating the mixture.

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

3. The method for preparing the indomethacin small molecule hydrogel according to claim 1, characterized in that: The small molecule ligand is: meglumine, arginine, glutamic acid, glutamine, citrulline, piperine, proline, tryptophan, theanine, ornithine, lysine, aspartic acid or histidine.

4. The method for preparing the indomethacin small molecule hydrogel according to claim 1, characterized in that: The small molecule ligand is: meglumine or arginine.

5. The method for preparing the indomethacin small molecule hydrogel according to claim 1, characterized in that: The molar ratio of indomethacin to the small molecule ligand is 1:5 to 5:

1.

6. The method for preparing the indomethacin small molecule hydrogel according to claim 1, characterized in that: Based on the total mass of indomethacin and the small molecule ligand being 1 g, the amount of deionized water added is 50 to 600 μL.

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

8. An indomethacin small molecule hydrogel prepared according to the method according to any one of claims 1 to 7.

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