Etodolac micromolecular hydrogel and preparation method thereof

Abstract

The invention relates to the technical field of medicines, and particularly discloses etodolac micromolecular hydrogel and a preparation method thereof, the hydrogel is prepared from etodolac and three micromolecular ligands (meglumine, arginine and lysine) respectively, the morphological characteristics, thermodynamic properties, intermolecular interaction and dissolution and dissolution effects of the hydrogel are verified through SEM (scanning electron microscope), rheological tests, DSC (differential scanning calorimetry), XRPD (X-ray powder diffraction), FTIR (Fourier transform infrared spectroscopy) and dissolution and dissolution tests. The preparation method is simple and comprises the following steps: mixing etodolac with a small molecule ligand, adding a small amount of deionized water, and oscillating. The formed hydrogel can significantly improve the solubility and dissolution rate / release rate of the etodolac, compared with an etodolac crystal, the solubility and dissolution rate / release rate of the hydrogel in water are significantly superior to those of a single crystal drug and a physical mixture thereof, and the hydrogel has the potential of improving the bioavailability of the etodolac, and can be used for preparing an etodolac drug. The invention provides a new preparation thought for solving the dissolvability defect of indissolvable drugs and drug combination.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and specifically discloses an etodolac small molecule hydrogel and a preparation method thereof. Background Art

[0002] Gel is a special dispersion system with a three-dimensional network structure and solid-like rheological behavior. It can be divided into polymer gel and organic small molecule gel (Mw<3000Da) according to the molecular weight of the gel factor.

[0003] Compared with polymer gels, small molecule gels have theoretical advantages such as thermoreversibility, thixotropy, biocompatibility and biodegradability, and have great application potential in the fields of medical engineering and tissue engineering. However, in the process of drug development, this application potential has not met actual expectations. Some crystalline or amorphous drugs aggregate to form viscous gel clumps during the manufacturing or dissolution process, further reducing the performance of the drug. For example, lenvatinib mesylate and amorphous curcumin form viscoelastic hydrogels when in contact with aqueous media, which significantly hinders their in vitro dissolution and limits their in vivo absorption and therapeutic effects. Therefore, existing research on small molecule gels mainly focuses on the gel formation mechanism and degelation strategies (such as crystal engineering technology, formulation design, preparation process optimization, etc.) to eliminate the adverse effects of gelation, but does not involve deeper research on binary or even multi-component gels and related formation mechanisms.

[0004] Etodolac, chemical name is (±) 1,8-diethyl-1,3,4,9-tetrahydrofurano[3,4-b]indole-1-acetic acid, chemical structure is: Etodolac belongs to the aromatic acetic acid class of nonsteroidal anti-inflammatory drugs, mainly used for acute or long-term treatment of osteoarthritis and rheumatoid arthritis, and is mainly prepared into tablets or capsules in clinical practice. Its main mechanism of action is to reduce prostaglandin synthesis by inhibiting cyclooxygenase, stop the formation of pain nerve impulses in inflammatory tissues, and thus inhibit the occurrence of inflammatory reactions. However, etodolac 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. Summary of the invention

[0005] The object of the present invention is to provide a novel etodolac small molecule hydrogel. In the novel etodolac small molecule hydrogel of the present invention, the selected ligands are all small molecule substances with a molecular weight of less than 1000 Da, including meglumine, arginine, lysine, glutamic acid, glutamine, citrulline, piperine, proline, tryptophan, theanine, ornithine, histidine and aspartic acid, preferably meglumine, arginine or lysine.

[0006] The three preferred novel etodolac small molecule hydrogels are etodolac-methylglucamine hydrogel, etodolac-arginine hydrogel and etodolac-lysine hydrogel. Compared with single etodolac crystals, the three hydrogels significantly improve the solubility and dissolution / release of etodolac in water, and are expected to be developed into soft capsules and transdermal preparations, etc., which can promote the development of new preparations of etodolac and further therapeutic applications.

[0007] Another object of the present invention is to provide a method for preparing three novel hydrogels, namely, etodolac-meglumine hydrogel, etodolac-arginine hydrogel and etodolac-lysine hydrogel. Etodolac is uniformly mixed with three small molecule ligands (meglumine, arginine and lysine), respectively, and a certain amount of deionized water is added, followed by simple shaking to prepare the hydrogels.

[0008] The mass volume ratio of the total mass of etodolac and the ligand to deionized water is: 1 g: 50-600 μL, preferably 1 g: 100-300 μL, and most preferably 1 g: 200 μL.

[0009] The molar ratio of etodolac to meglumine, etodolac to arginine, and etodolac to lysine is 1:(0.2-5), preferably 1:(0.2-2), and most preferably 1:1.

[0010] The shaking time is 1 to 20 min, preferably 3 to 10 min, and most preferably 5 min.

[0011] The preparation temperature is 10-60°C, preferably 20-30°C, most preferably 25°C.

[0012] Scanning electron microscopy results of etodolac-methylglucamine hydrogel, etodolac-arginine hydrogel and etodolac-lysine hydrogel showed a typical three-dimensional network structure inside the gel; rheological results showed that they could still maintain a good gel state within a certain strain range and meet application requirements.

[0013] After the prepared hydrogel was placed in a -80°C refrigerator for freezing, the sample was transferred to a vacuum freeze dryer and dried for 24 hours to obtain etodolac-methylglucamine xerogel, etodolac-arginine xerogel and etodolac-lysine xerogel.

[0014] The X-ray powder diffraction patterns of etodolac-methylglucamine xerogel, etodolac-arginine xerogel and etodolac-lysine xerogel showed that the crystal diffraction peaks of the drug and ligand in the three xerogels basically disappeared, showing amorphous diffraction rings or very few weak crystal diffraction peaks; differential scanning calorimetry analysis confirmed that the three xerogel samples all showed a single glass transition temperature (91.4°C, 84.4°C and 68.3°C).

[0015] By measuring the solubility of etodolac crystals, etodolac-ligand physical mixture and etodolac hydrogels, the results showed that etodolac-methylglucamine, etodolac-arginine and etodolac-lysine hydrogels can significantly increase the solubility of etodolac in water.

[0016] By conducting cumulative release tests under sink conditions, it was confirmed that the three hydrogels, etodolac-meglumine, etodolac-arginine and etodolac-lysine, can significantly improve the cumulative release rate of etodolac.

[0017] Beneficial effects:

[0018] The present invention prepares etodolac with three small molecule ligands respectively into novel small molecule hydrogels, which have good solubility and dissolution release advantages. The three prepared hydrogels are expected to be developed into novel gel preparation products of etodolac (such as soft capsules, transdermal preparations, etc.), and also provide new design ideas for the development of novel gels for other drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 The (A) sample image and (B) SEM image of the etodolac-meglumine hydrogel, etodolac-arginine hydrogel and etodolac-lysine hydrogel prepared in Example 1 (a: etodolac-meglumine hydrogel, b: etodolac-arginine hydrogel, c: etodolac-lysine hydrogel);

[0020] Figure 2 This is a rheological test graph of the etodolac-methylglucamine hydrogel prepared in Example 1 (a: strain sweep, b: frequency sweep);

[0021] Figure 3 This is a rheological test graph of the etodolac-arginine hydrogel prepared in Example 1 (a: strain sweep, b: frequency sweep);

[0022] Figure 4 This is a rheological test graph of the etodolac-lysine hydrogel prepared in Example 1 (a: strain sweep, b: frequency sweep);

[0023] Figure 5 is a powder X-ray diffraction (XRPD) pattern of the xerogel prepared from the etodolac-meglumine hydrogel in Example 1;

[0024] Figure 6 is a powder X-ray diffraction (XRPD) pattern of the xerogel prepared from the etodolac-arginine hydrogel in Example 1;

[0025] Figure 7 is a powder X-ray diffraction (XRPD) pattern of the xerogel prepared from the etodolac-lysine hydrogel in Example 1;

[0026] Figure 8 is a differential scanning calorimetry (DSC) graph of the etodolac-meglumine xerogel prepared in Example 1;

[0027] Fig. 9 is a differential scanning calorimetry (DSC) graph of the etodolac-arginine xerogel prepared in Example 1;

[0028] Fig.10 is the differential scanning calorimetry (DSC) diagram of the etodolac-lysine xerogel prepared in Example 1

[0029] Fig.11 is an infrared spectrum (FTIR) of the etodolac-meglumine xerogel prepared in Example 1;

[0030] Fig.12 This is the infrared spectrum (FTIR) of the etodolac-arginine xerogel prepared in Example 1

[0031] Fig.13 This is the infrared spectrum (FTIR) of the etodolac-lysine xerogel prepared in Example 1.

[0032] Fig.14 are the cumulative release curves of (A) etodolac-meglumine hydrogel, (B) etodolac-arginine hydrogel, and (C) etodolac-lysine hydrogel prepared in Example 1;

[0033] Fig.15 are the non-sink release curves of (A) etodolac-meglumine hydrogel, (B) etodolac-arginine hydrogel, and (C) etodolac-lysine hydrogel prepared in Example 1;

[0034] Fig.16 It is the phase solubility diagram of etodolac in aqueous solutions of ligands with different concentrations (etodolac: Etodolac, meglumine: MEG, arginine: ARG, lysine: LYS). DETAILED DESCRIPTION

[0035] The present invention will be further described below in conjunction with the embodiments.

[0036] Example 1

[0037] 595.5 mg of etodolac and 404.5 mg of meglumine, 622.6 mg of etodolac and 377.4 mg of arginine, and 662.8 mg of etodolac and 337.2 mg of lysine were weighed and placed in three 10 mL vials, mixed using a suspension mixer at 25° C., 200 μL of deionized water was added, and the mixture was shaken for 5 min to obtain three gel samples.

[0038] Embodiment 2:

[0039] 424.0 mg of etodolac and 576.0 mg of meglumine, 452.0 mg of etodolac and 548.0 mg of arginine, and 459.7 mg of etodolac and 504.3 mg of lysine were weighed respectively into three 10 mL vials, mixed with a suspension mixer at 25° C., 200 μL of deionized water was added, and the mixture was shaken for 5 min to obtain three gel samples.

[0040] Embodiment 3:

[0041] 746.5 mg of etodolac and 253.54 mg of meglumine, 767.4 mg of etodolac and 232.6 mg of arginine, and 797.2 mg of etodolac and 202.8 mg of lysine were weighed respectively into three 10 mL vials, mixed at 25° C. using a suspension mixer, and 200 μL of deionized water was added and shaken for 5 min to obtain three gel samples.

[0042] Embodiment 4:

[0043] 595.5 mg of etodolac and 404.5 mg of meglumine, 622.6 mg of etodolac and 377.4 mg of arginine, and 662.8 mg of etodolac and 337.2 mg of lysine were weighed into three 10 mL vials, mixed at 20°C using a suspension mixer, 200 μL of deionized water was added, and the mixture was shaken for 5 min to obtain three gel samples.

[0044] Embodiment 5:

[0045] 595.5 mg of etodolac and 404.5 mg of meglumine, 622.6 mg of etodolac and 377.4 mg of arginine, and 662.8 mg of etodolac and 337.2 mg of lysine were weighed into three 10 mL vials, mixed at 30°C using a suspension mixer, 200 μL of deionized water was added, and the mixture was shaken for 5 min to obtain three gel samples.

[0046] Embodiment 6:

[0047] 595.5 mg of etodolac and 404.5 mg of meglumine, 622.6 mg of etodolac and 377.4 mg of arginine, and 662.8 mg of etodolac and 337.2 mg of lysine were weighed respectively into three 10 mL vials, mixed at 25°C using a suspension mixer, 100 μL of deionized water was added, and the mixture was shaken for 5 min to obtain three gel samples.

[0048] Embodiment 7:

[0049] 595.5 mg of etodolac and 404.5 mg of meglumine, 622.6 mg of etodolac and 377.4 mg of arginine, and 662.8 mg of etodolac and 337.2 mg of lysine were weighed into three 10 mL vials, mixed at 25°C using a suspension mixer, 300 μL of deionized water was added, and the mixture was shaken for 5 min to obtain three gel samples.

[0050] Embodiment 8:

[0051] 595.5 mg of etodolac and 404.5 mg of meglumine, 622.6 mg of etodolac and 377.4 mg of arginine, and 662.8 mg of etodolac and 337.2 mg of lysine were weighed into three 10 mL vials, mixed at 25°C using a suspension mixer, 200 μL of deionized water was added, and the mixture was shaken for 3 min to obtain three gel samples.

[0052] Embodiment 9:

[0053] 595.5 mg of etodolac and 404.5 mg of meglumine, 622.6 mg of etodolac and 377.4 mg of arginine, and 662.8 mg of etodolac and 337.2 mg of lysine were weighed respectively into three 10 mL vials, mixed at 25°C using a suspension mixer, 200 μL of deionized water was added, and the mixture was shaken for 7 min to obtain three gel samples.

[0054] Embodiment 10:

[0055] 595.5 mg of etodolac and 404.5 mg of meglumine, 622.6 mg of etodolac and 377.4 mg of arginine, and 662.8 mg of etodolac and 337.2 mg of lysine were weighed respectively into three 10 mL vials, mixed with a suspension mixer at 25°C, 200 μL of deionized water was added, and the mixture was shaken for 10 min to obtain three gel samples.

[0056] Embodiment 11:

[0057] Weigh 661.37 mg of etodolac and 338.63 mg of glutamic acid, place in a 10 mL vial, mix with a suspension mixer at 25° C., add 200 μL of deionized water, and shake for 10 min to obtain an etodolac-glutamic acid combination sample.

[0058] Embodiment 12:

[0059] Weigh 655.31 mg of etodolac and 344.69 mg of histidine, place in a 10 mL vial, mix with a suspension mixer at 25°C, add 200 μL of deionized water, and shake for 10 min to obtain an etodolac-histidine sample.

[0060] Test Example 1: The etodolac-meglumine hydrogel, etodolac-arginine hydrogel and etodolac-lysine hydrogel prepared in Example 1 were tested as follows:

[0061] 1. Scanning electron microscope (SEM)

[0062] Instrument: TM4000 desktop scanning electron microscope (HITACHI, Japan)

[0063] Probe current: 20μA

[0064] Accelerating voltage: 15 kV

[0065] Counting time: 60s

[0066] Test results: Sample images of three types of etodolac hydrogels and SEM samples are shown in Figure 1 .Depend on Figure 1 B shows that the etodolac-methylglucamine hydrogel, the etodolac-arginine hydrogel and the etodolac-lysine hydrogel present a typical three-dimensional network structure of gel, with many obvious pores inside. The three etodolac hydrogels prepared in Examples 2 to 10 exhibit the same or similar gel morphology and microstructure.

[0067] 2. Rheological test

[0068] Instrument: Kinexus pro rotational rheometer (Malvern, the Great Britain)

[0069] Parallel plate diameter: 20mm

[0070] Measuring gap: 1mm

[0071] Temperature: 25℃

[0072] Strain sweep: Frequency: 1Hz Range: 0.1%~1000%

[0073] Frequency sweep: Strain: 10% Range: 0.1~100rad·s -1

[0074] Test results: The rheological test results of the etodolac-meglumine hydrogel in Example 1 are shown in Figure 2 .Depend on Figure 2It can be seen from a that under the strain of 0.1-10%, the storage modulus G′ and loss modulus G″ can maintain a high value, indicating that the viscoelastic performance of the etodolac-methylglumine hydrogel is stable within this range. When the strain exceeds 10%, the G′ and G″ values ​​decrease sharply with the increase of the applied strain, and the viscoelastic signal reverses (G″>G′), indicating that the internal structure of the etodolac-methylglumine hydrogel begins to collapse, resulting in a gradual weakening of the elastic and viscous responses. In the range of 0.1-100 rad·s -1 Angular frequency sweep was performed in the range of 0.1 to 50 rad·s. When the strain was 10% (in the linear viscoelastic region), the G′ and G″ of the etodolac-meglumine hydrogel showed dependence on the applied frequency. -1 In the frequency range of G′>G″, when the frequency exceeds 50rad·s -1 , the values ​​of G′ and G″ fluctuate greatly, and the stability of the gel structure is affected ( Figure 2 b).

[0075] The rheological test results of the etodolac-arginine hydrogel in Example 1 are as follows: Figure 3 .Depend on Figure 3 As can be seen from Fig. 1, with the increase of strain, both G′ and G″ show a trend of first increasing and then decreasing, indicating that the structure of the etodolac-arginine hydrogel changes under the action of shear strain. The 10% strain is defined as the upper boundary of the linear rheological region of the etodolac-arginine hydrogel. When exceeding this boundary (>10% strain), the hydrogel turns into liquid-like behavior because G″ is greater than G′. The etodolac-arginine hydrogel has reasonable hydrogel strength, and G′ and G″ are less dependent on the applied frequency. The G′ measured in the frequency range is greater than G″ ( Figure 3 b).

[0076] The rheological test results of the etodolac-lysine hydrogel in Example 1 are as follows: Figure 4 .Depend on Figure 4 It can be seen from Figure 1 that under low shear strain (<5%), G′ and G″ remain almost unchanged, indicating that the etodolac-lysine hydrogel can maintain structural stability, and this range is called the linear viscoelastic region of the etodolac-lysine hydrogel. When the strain is greater than 5%, the G′ and G″ values ​​decrease with the increase of the applied strain, and show G″>G′, indicating that the etodolac-lysine hydrogel yields and the gel structure is destroyed, showing the rheological behavior of the liquid. In the range of 0.1 to 100 rad·s -1 In the dynamic frequency scanning range, G′ is always greater than G″, and the etodolac-lysine hydrogel exhibits significant elasticity ( Figure 4 b).

[0077] The three types of etodolac hydrogels prepared in Examples 2 to 10 exhibited the same or similar rheological behaviors.

[0078] 3. Powder X-ray Diffraction (XRPD)

[0079] Instrument: SmartLab (9) X-ray diffractometer (Rigaku, Japan)

[0080] Target: Cu-Kα radiation

[0081] wavelength:

[0082] Tube voltage: 40KV

[0083] Tube current: 40mA

[0084] Step size: 0.02°

[0085] Scanning speed: 4° / min

[0086] Scanning range: 2θ, 3-40°

[0087] Measurement results: The powder X-ray diffraction analysis results of the etodolac-meglumine xerogel, etodolac-arginine xerogel and etodolac-lysine xerogel prepared from the hydrogel samples in Example 1 are as follows: Figure 5 to Figure 7 As shown. Figure 5 It can be seen that the powder X-ray diffraction pattern of the etodolac-methylglucamine dry gel has basically disappeared at 3-40° crystal diffraction peaks, which are replaced by a single diffuse amorphous diffraction ring. The XRPD patterns of the etodolac-arginine dry gel and the etodolac-lysine dry gel show weaker characteristic diffraction peaks, indicating that the crystallinity in the etodolac-arginine dry gel and the etodolac-lysine dry gel is less, and the dry gel samples mainly exist in an amorphous form ( Figure 6-7 ). The xerogels prepared from the etodolac hydrogels in Examples 2 to 10 exhibited the same or similar XRPD patterns.

[0088] 4. Differential Scanning Calorimetry (DSC)

[0089] Instrument: Hitachi SIIDSC7020 (Hitachi, Japan)

[0090] Range: 25~260℃

[0091] Heating rate: 10℃ / min

[0092] Test results: The DSC test results of the etodolac-meglumine xerogel, etodolac-arginine xerogel and etodolac-meglumine-lysine xerogel prepared from the hydrogel sample in Example 1 are as follows: Figures 8 to 10 As shown. Figures 8 to 10It can be seen that the DSC spectra of the etodolac-methylglucamine xerogel, etodolac-arginine xerogel and etodolac-lysine xerogel in Example 1 show that the endothermic melting peak of etodolac disappears, and have a single glass transition temperature of 91.4° C., 84.4° C. and 68.3° C. respectively. The xerogels prepared from the etodolac hydrogels in Examples 2 to 10 show similar DSC spectra, showing the disappearance of the melting peak and the presence of a single glass transition temperature.

[0093] 5. Infrared spectroscopy (FTIR)

[0094] Instrument: Nicolet iS50 Fourier transform infrared spectrometer (Thermo, American)

[0095] Range: 4000~400cm -1

[0096] Scan times: 64 times

[0097] Measurement results: It can be seen from Figure 11 that the infrared spectrum wave number (cm -1 ) are: 3344.86, 2966.79, 2933.88, 1746.02, 1674.2, 1570.36, 1463.40, 1398.03, 1303.95, 1303.95, 1264.36, 1173.29, 1075.57, 1046.04, 958.21, 891.63 and 858.93.

[0098] like Fig.12 As shown, the infrared spectrum wave number (cm -1 ) are: 3343.61, 2967.43, 2347.03, 1744.88, 1636.03, 1554.94, 1465.16, 1397.41, 1264.02, 1200.60, 1176.38, 1106.92, 1072.86, 1045.57, 988.21, 958.58, 891.96, 844.40, 749.78, 747.45, 706.75, 647.79 and 552.40.

[0099] like Fig.13 As shown, the infrared spectrum wave number (cm -1) are: 3344.89, 2965.28, 2347.06, 1744.51, 1642.06, 1578.07, 1459.43, 1396.93, 1264.39, 1139.70, 1106.23, 1073.40, 1047.07, 957.31, 859.93, 792.84, 745.64, 707.17, 646.94, 550.74 and 429.02.

[0100] Compared with the xerogels of the etodolac-meglumine hydrogel, the etodolac-arginine hydrogel and the etodolac-lysine hydrogel in Example 1, the xerogels exhibited the same or similar FTIR spectra.

[0101] Test Example 2: The solubility of the physical mixture of etodolac and the ligand, the etodolac-meglumine hydrogel prepared in Examples 1, 3, 5, and 9, the etodolac-arginine hydrogel, the etodolac-lysine hydrogel, and the etodolac-glutamate composition and the etodolac-histidine composition prepared in Examples 11 and 12 were measured, as follows:

[0102] The physical mixture of etodolac and the ligand is prepared by weighing the drug and the ligand powder in a molar ratio of 1:1, placing the mixture in a 10 mL vial, and vortexing the mixture for 10 minutes to uniformly mix the two powders, thereby obtaining the physical mixture of etodolac-ligand.

[0103] Excess etodolac crystals, etodolac-meglumine physical mixture, etodolac-arginine physical mixture, etodolac-lysine physical mixture, etodolac-meglumine hydrogel, etodolac-arginine hydrogel, etodolac-lysine hydrogel, etodolac-glutamate composition and etodolac-histidine composition were weighed and placed in 10 mL centrifuge tubes in 3 parallel portions. 5 ml of deionized water was added to each of the tubes and shaken in a constant temperature shaker 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.

[0104] The HPLC conditions were as follows:

[0105] Instrument: Agilent-1260 High Performance Liquid Chromatograph

[0106] Chromatographic column: Ultimate XB-C18 (4.6mm×250mm, 5μm)

[0107] Mobile phase: acetonitrile-water phase (0.3% phosphoric acid) = 30:70 (V / V)

[0108] Flow rate: 1.0mL / min

[0109] Detection wavelength: 228nm

[0110] Measurement results: The solubility comparison of the etodolac-meglumine hydrogel, etodolac-arginine hydrogel and etodolac-lysine hydrogel in Examples 1, 3, 5 and 9, and the etodolac-glutamate composition and etodolac-histidine composition in Examples 11 and 12 in deionized water is shown in Table 1.

[0111] Table 1 Water solubility of etodolac crystals, etodolac-ligand physical mixture and etodolac hydrogel

[0112]

[0113]

[0114] It can be seen from Table 1 that compared with single etodolac crystals (96.33 μg / mL), the solubility of the etodolac-meglumine hydrogel in Example 1 increased by 20.84 times to 2008.46 μg / mL, the solubility of the etodolac-arginine hydrogel increased by 16.85 times to 1623.31 μg / mL, and the solubility of the etodolac-lysine hydrogel increased by 19.24 times to 1854.34 μg / mL. However, the etodolac-glutamate and etodolac-histidine combinations in Examples 11 and 12 had no significant effect on the solubility of etodolac because the two combinations could not form gels.

[0115] Test Example 3: The release test under sink conditions was performed on the etodolac-meglumine hydrogel, etodolac-arginine hydrogel and etodolac-lysine hydrogel prepared in Example 1, as follows:

[0116] Weigh etodolac crystals, physical mixture of etodolac and meglumine crystals, physical mixture of etodolac-arginine, physical mixture of etodolac-lysine, etodolac-meglumine hydrogel in Example 1, etodolac-arginine hydrogel and etodolac-lysine hydrogel (equivalent to etodolac 17.3 mg) respectively, in parallel in 3 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 sink was carried out by the slurry method. The release medium was deionized water, the medium temperature was 37 ° C, the medium volume was 900 mL, and the speed was 100 rpm. Sample 2 mL at 2, 5, 10, 15, 20, 30, 45, 60, 90 and 120 min, and add 2 mL of isothermal and equal volume dissolution medium at the same time. Take out the liquid and pass it through a 0.22 μm aqueous microporous filter membrane, and take 10 μL of the filtrate for HPLC analysis.

[0117] Determination results: The cumulative release rate curves of the etodolac-meglumine hydrogel, the etodolac-arginine hydrogel and the etodolac-lysine hydrogel under sink conditions in Example 1 are as follows: Fig.14 As shown. Fig.14 It can be seen that in the entire release test, the release of the three types of etodolac hydrogels was always significantly higher than that of etodolac crystals. At 20 minutes, compared with the cumulative release rate of etodolac crystals (13.31%), the cumulative release rates of etodolac-meglumine hydrogel, etodolac-arginine hydrogel and etodolac-lysine hydrogel were 71.74%, 63.60% and 68.81%, respectively, which were about 5.39 times, 4.78 times and 5.16 times that of etodolac crystals; at 120 minutes, the cumulative release rates of etodolac-meglumine hydrogel, etodolac-arginine hydrogel and etodolac-lysine hydrogel were 80.67%, 71.96% and 73.01%, respectively, which were about 1.78 times, 1.59 times and 1.61 times that of etodolac crystals (45.22%).

[0118] Test Example 4: The release experiment under non-sink conditions was conducted on the etodolac-meglumine hydrogel, the etodolac-arginine hydrogel and the etodolac-lysine hydrogel of Example 1, as follows:

[0119] Weigh a certain amount of etodolac crystals, a physical mixture of etodolac and meglumine crystals, a physical mixture of etodolac and arginine crystals, a physical mixture of etodolac and lysine crystals, etodolac-meglumine hydrogel, etodolac-arginine hydrogel and etodolac-lysine hydrogel (equivalent to 400 mg etodolac) in Example 1, and 3 parallel portions. According to the second method of 0931 of the fourth general rule of the 2020 edition of the Chinese Pharmacopoeia, the non-sink release was evaluated by the slurry method. The release medium was deionized water, the medium temperature was 37 ° C, the medium volume was 200 mL, and the speed was 100 rpm. Samples of 2 mL were taken at 5, 10, 20, 30, 45, 60, 90, 120, 240, 360, 480 and 720 min, and 2 mL of isothermal and equal volume dissolution medium was added at the same time. The liquid was taken out and passed through a 0.22 μm aqueous microporous filter membrane, and 10 μL of the filtrate was taken for HPLC analysis.

[0120] Test results: The non-sink release curves of etodolac, etodolac-meglumine physical mixture and etodolac-meglumine hydrogel in Example 1 are compared as shown in FIG. Fig.15 As shown. Fig.15It can be seen that the release concentration of etodolac crystals at 90 min was low, 84.28 μg / mL, and then tended to saturation. The release concentrations of etodolac-meglumine physical mixture and etodolac-meglumine hydrogel increased significantly, reaching 1201.94 μg / mL and 1561.97 μg / mL, respectively. Throughout the experiment, etodolac-meglumine physical mixture and etodolac-meglumine hydrogel showed supersaturated release behavior and maintained high supersaturated concentrations for a long time. After 720 min, the etodolac release concentration of etodolac-meglumine hydrogel reached 1543.77 μg / mL, which were 15.71 times and 1.29 times that of etodolac crystals (98.27 μg / mL) and etodolac-meglumine physical mixture (1193.46 μg / mL), respectively (15A).

[0121] Depend on Fig.15 B It can be seen that the etodolac-arginine hydrogel in Example 1 exhibits a supersaturated release behavior similar to that of the etodolac-methylglucamine hydrogel. At 720 min, the etodolac release concentration in the etodolac-arginine hydrogel was 1743.61 μg / mL, which was 17.74 times and 1.28 times that of the etodolac crystals (98.27 μg / mL) and the etodolac-arginine physical mixture (1356.86 μg / mL), respectively. The etodolac release concentration of the etodolac-lysine hydrogel in Example 1 was 1671.58 μg / mL, which was 17.01 times and 1.18 times that of the etodolac crystals (98.27 μg / mL) and the etodolac-lysine physical mixture (1410.17 μg / mL), respectively. Fig.15 C).

[0122] Test Example 5: The phase solubility of etodolac crystals in aqueous solutions of meglumine, arginine and lysine at different concentrations was determined as follows:

[0123] Instrument: SHZ-82JT constant temperature oscillator (LIANGYOU, China)

[0124] Excess etodolac powder was added to 5 mL of different concentrations of meglumine aqueous solution, arginine aqueous solution and lysine aqueous solution in three parallel portions, and the phase solubility test was performed by shaking in a constant temperature oscillator at 37°C and 200 rpm for 24 h. 2 mL of the supernatant was filtered through a 0.45 μm aqueous microporous filter membrane, and the etodolac concentration was determined by an HPLC system.

[0125] Test results: The solubility of etodolac in different concentrations of meglumine aqueous solution, arginine aqueous solution and lysine aqueous solution is as follows: Fig.16 The solubility of etodolac increases nonlinearly with increasing concentrations of meglumine, arginine, or lysine, showing a typical 1:1AN The complexation behavior of the type is negatively deviated when the concentrations of meglumine, arginine and lysine are high (>6.25mM). Since there is a complexation reaction between etodolac and the three selected ligands meglumine, arginine and lysine, the solubility of the physical mixture of etodolac and the three ligands and the hydrogel is significantly improved compared with the etodolac crystal. However, there is no complexation between etodolac and the two ligands of glutamic acid and histidine, so the solubility of etodolac in the combination is not significantly improved (Table 1). The three hydrogels of etodolac formed in the present invention significantly enhance the solubility and dissolution of etodolac, and maintain the supersaturation degree for a long time, which is expected to promote the in vivo absorption of etodolac.

Claims

1. An etodolac small molecule hydrogel, characterized in that: The etodolac small molecule hydrogel is prepared by mixing etodolac with a small molecule ligand, adding deionized water and shaking.

2. The etodolac small molecule hydrogel according to claim 1, characterized in that: The small molecule ligands are meglumine, arginine or lysine.

3. The etodolac small molecule hydrogel according to claim 1, characterized in that: The molecular weights of etodolac and the small molecule ligand are both less than 1000 Da.

4. The etodolac small molecule hydrogel according to claim 1, characterized in that: The molar ratio of etodolac to the small molecule ligand is 1:0.2-5.

5. The etodolac small molecule hydrogel according to claim 1, characterized in that: The volume ratio of the total mass of etodolac and the small molecule ligand to deionized water is 1 g: 50-600 μL.

6. The etodolac small molecule hydrogel according to claim 1, characterized in that: The mixing temperature is 10-60°C and the shaking time is 1-20 min.

Images