Etoricoxib small molecule hydrogel and preparation method thereof

Abstract

This invention relates to the field of pharmaceutical technology, specifically disclosing an etodoxa acid small molecule hydrogel and its preparation method. The hydrogel is prepared by mixing etodoxa acid with three small molecule ligands (glucamine, arginine, and lysine). The morphological characteristics, thermodynamic properties, intermolecular interactions, and dissolution effects of the hydrogel were verified using SEM, rheological testing, DSC, XRPD, FTIR, and dissolution experiments. The preparation method is simple, involving mixing etodoxa acid with the small molecule ligands, adding a small amount of deionized water, and shaking. The resulting hydrogel significantly improves the solubility and dissolution / release rate of etodoxa acid. Compared to etodoxa acid crystals, the hydrogel exhibits significantly better solubility, dissolution / release rate in water than individual crystalline drugs or their physical mixtures, demonstrating the potential to improve the bioavailability of etodoxa acid. This provides a new formulation strategy for addressing the solubility defects of poorly soluble drugs and for combination drug use.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and specifically discloses an etordosulfuric acid small molecule hydrogel and its preparation method. Background Technology

[0002] Gels are special dispersion systems with three-dimensional network structures and solid-like rheological behavior. They can be classified into polymeric gels and small organic molecule gels (Mw<3000Da) according to the molecular weight of the gelling factor.

[0003] Compared to polymeric gels, small molecule gels possess theoretical advantages such as thermal reversibility, thixotropy, biocompatibility, and biodegradability, showing great potential for applications in fields like medical engineering and tissue engineering. However, in drug development, this potential has not met expectations. Some crystalline or amorphous drugs aggregate into viscous gel clusters during manufacturing or dissolution, further reducing drug performance. For example, lenvatinib mesylate and amorphous curcumin form viscoelastic hydrogels upon contact with aqueous media, significantly hindering their in vitro dissolution and limiting their in vivo absorption and therapeutic effects. Therefore, current research on small molecule gels mainly focuses on gel formation mechanisms and degelation strategies (such as crystal engineering, formulation design, and process optimization) to eliminate the adverse effects of gelation, without delving into deeper studies of binary or even multi-component gels and their related formation mechanisms.

[0004] Etodolac, chemically named (±)1,8-diethyl-1,3,4,9-tetrahydrofurano[3,4-b]indole-1-acetic acid, has the following chemical structure: Etodoxacin belongs to the arylaceous acid class of nonsteroidal anti-inflammatory drugs (NSAIDs) and is mainly used for the acute or long-term treatment of osteoarthritis and rheumatoid arthritis. Clinically, it is primarily formulated as tablets or capsules. Its main mechanism of action is to inhibit cyclooxygenase, thereby reducing prostaglandin synthesis and suppressing the formation of pain nerve impulses in inflamed tissues, thus inhibiting the inflammatory response. However, etodoxacin is classified as a Biopharmaceutics Class II drug, exhibiting poor solubility and low in vivo absorption, which limits its clinical therapeutic efficacy. Summary of the Invention

[0005] The purpose of this invention is to provide a novel eostoic acid small molecule hydrogel. In this novel eostoic acid small molecule hydrogel, the selected ligands are all small molecules 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] Three novel etodoxa acid small molecule hydrogels were selected: etodoxa acid-glucamine hydrogel, etodoxa acid-arginine hydrogel, and etodoxa acid-lysine hydrogel. Compared to single etodoxa acid crystals, these three hydrogels significantly improve the solubility and dissolution / release rate of etodoxa acid in water, and are expected to be developed into soft capsules and transdermal formulations, which can promote the development of novel etodoxa acid formulations and further therapeutic applications.

[0007] Another objective of this invention is to provide methods for preparing three novel hydrogels: etoduolic acid-glucamine hydrogel, etoduolic acid-arginine hydrogel, and etoduolic acid-lysine hydrogel. Etoduolic acid is uniformly mixed with each of the three small molecule ligands (glucamine, arginine, and lysine), and a certain amount of deionized water is added, followed by simple shaking to prepare the hydrogel.

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

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

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

[0011] The preparation temperature is 10–60℃, preferably 20–30℃, and most preferably 25℃.

[0012] Etoduolic acid-glucamine hydrogel, etoduolic acid-arginine hydrogel, and etoduolic acid-lysine hydrogel were observed to exhibit a typical three-dimensional network structure within the gel under scanning electron microscopy. Rheological results showed that the gels maintained a good gel state within a certain strain range, meeting the application requirements.

[0013] After freezing the prepared hydrogels at -80°C, the samples were transferred to a vacuum freeze dryer and dried for 24 hours to obtain etodoxa acid-glucamine dry gel, etodoxa acid-arginine dry gel, and etodoxa acid-lysine dry gel.

[0014] X-ray powder diffraction patterns of etodulic acid-glucamine dry gel, etodulic acid-arginine dry gel, and etodulic acid-lysine dry gel showed that the crystal diffraction peaks of the drug and ligands in the three dry gels were basically gone, showing amorphous diffraction rings or very few weak crystal diffraction peaks. Differential scanning calorimetry analysis confirmed that the three dry gel samples all showed a single glass transition temperature (91.4℃, 84.4℃, and 68.3℃).

[0015] By measuring the solubility of three hydrogels—ethotoic acid crystals, ethotoic acid-ligand physical mixtures, and ethotoic acid—the results showed that the three hydrogels—ethotoic acid-glucamine, ethotoic acid-arginine, and ethotoic acid-lysine—can significantly increase the solubility of ethotoic acid in water.

[0016] Cumulative release experiments under trough conditions confirmed that three hydrogels—ethotoic acid-glucamine, ethotoic acid-arginine, and ethotoic acid-lysine—can significantly improve the cumulative release rate of ethotoic acid.

[0017] Beneficial effects:

[0018] This invention prepares novel small molecule hydrogels by fusing etodoxa acid with three different small molecule ligands. These hydrogels exhibit excellent solubility and dissolution-release properties. The three hydrogels prepared are expected to be developed into novel gel formulations of etodoxa acid (such as soft capsules, transdermal formulations, etc.), and also provide new design ideas for the development of novel gels for other drugs. Attached image description:

[0019] Figure 1 These are (A) sample images and (B) SEM images of the etoduolic acid-glucamine hydrogel, etoduolic acid-arginine hydrogel, and etoduolic acid-lysine hydrogel prepared in Example 1 (a: etoduolic acid-glucamine hydrogel, b: etoduolic acid-arginine hydrogel, c: etoduolic acid-lysine hydrogel).

[0020] Figure 2 The rheological test diagrams of the etodoxa acid-glucamine hydrogel prepared in Example 1 are as follows (a: strain scan, b: frequency scan).

[0021] Figure 3 These are rheological test diagrams of the eosin-arginine hydrogel prepared in Example 1 (a: strain scan, b: frequency scan);

[0022] Figure 4 The rheological test diagrams of the lysine hydrogel prepared in Example 1 are as follows: (a: strain scan, b: frequency scan).

[0023] Figure 5 This is the powder X-ray diffraction (XRPD) pattern of the dry gel prepared from the etodoxa acid-glucamine hydrogel in Example 1;

[0024] Figure 6 This is the powder X-ray diffraction (XRPD) pattern of the dry gel prepared by the etordosulfate-arginine hydrogel in Example 1;

[0025] Figure 7 This is the powder X-ray diffraction (XRPD) pattern of the dry gel prepared from the eosin-lysine hydrogel in Example 1;

[0026] Figure 8 This is a differential scanning calorimetry (DSC) chromatogram of the etodoxa acid-glucamine dry gel prepared in Example 1;

[0027] Figure 9 This is a differential scanning calorimetry (DSC) chromatogram of the etidoside-arginine dry gel prepared in Example 1;

[0028] Figure 10 This is a differential scanning calorimetry (DSC) image of the etoposide-lysine dry gel prepared in Example 1.

[0029] Figure 11 This is the Fourier Transform Infrared (FTIR) spectrum of the etodoxa acid-glucamine dry gel prepared in Example 1;

[0030] Figure 12 This is the Fourier Transform Infrared (FTIR) spectrum of the etoritol acid-arginine dry gel prepared in Example 1.

[0031] Figure 13 This is the Fourier Transform Infrared (FTIR) spectrum of the etodo acid-lysine dry gel prepared in Example 1.

[0032] Figure 14 The cumulative release curves of (A) etoduolic acid-glucamine hydrogel, (B) etoduolic acid-arginine hydrogel and (C) etoduolic acid-lysine hydrogel prepared in Example 1 are shown.

[0033] Figure 15 The non-leakage release curves of (A) etoduolic acid-glucamine hydrogel, (B) etoduolic acid-arginine hydrogel and (C) etoduolic acid-lysine hydrogel prepared in Example 1 are shown.

[0034] Figure 16 This is a solubility diagram of etodolac in aqueous solutions of ligands at different concentrations (etodolac, meglumine, arginine, lysine). Detailed Implementation

[0035] The present invention will be further described below with reference to the embodiments.

[0036] Example 1

[0037] Weigh out 595.5 mg of etodoxacin and 404.5 mg of meglumine, 622.6 mg of etodoxacin and 377.4 mg of arginine, and 662.8 mg of etodoxacin and 337.2 mg of lysine into three 10 mL vials, mix them thoroughly with a suspension mixer at 25 °C, add 200 μL of deionized water, and shake for 5 min to obtain three gel-like samples.

[0038] Example 2:

[0039] Weigh out 424.0 mg of etodoxacin and 576.0 mg of meglumine, 452.0 mg of etodoxacin and 548.0 mg of arginine, and 459.7 mg of etodoxacin and 504.3 mg of lysine into three 10 mL vials, mix them thoroughly with a suspension mixer at 25 °C, add 200 μL of deionized water, and shake for 5 min to obtain three gel-like samples.

[0040] Example 3:

[0041] Weigh out 746.5 mg of etodoxacin and 253.54 mg of meglumine, 767.4 mg of etodoxacin and 232.6 mg of arginine, and 797.2 mg of etodoxacin and 202.8 mg of lysine into three 10 mL vials, mix them thoroughly with a suspension mixer at 25 °C, add 200 μL of deionized water, and shake for 5 min to obtain three gel-like samples.

[0042] Example 4:

[0043] Weigh out 595.5 mg of etodoxacin and 404.5 mg of meglumine, 622.6 mg of etodoxacin and 377.4 mg of arginine, and 662.8 mg of etodoxacin and 337.2 mg of lysine into three 10 mL vials, mix them thoroughly with a suspension mixer at 20 °C, add 200 μL of deionized water, and shake for 5 min to obtain three gel-like samples.

[0044] Example 5:

[0045] Weigh out 595.5 mg of etodoxacin and 404.5 mg of meglumine, 622.6 mg of etodoxacin and 377.4 mg of arginine, and 662.8 mg of etodoxacin and 337.2 mg of lysine into three 10 mL vials, mix them thoroughly with a suspension mixer at 30 °C, add 200 μL of deionized water, and shake for 5 min to obtain three gel-like samples.

[0046] Example 6:

[0047] Weigh out 595.5 mg of etodoxacin and 404.5 mg of meglumine, 622.6 mg of etodoxacin and 377.4 mg of arginine, and 662.8 mg of etodoxacin and 337.2 mg of lysine into three 10 mL vials, mix them thoroughly with a suspension mixer at 25 °C, add 100 μL of deionized water, and shake for 5 min to obtain three gel-like samples.

[0048] Example 7:

[0049] Weigh out 595.5 mg of etodoxacin and 404.5 mg of meglumine, 622.6 mg of etodoxacin and 377.4 mg of arginine, and 662.8 mg of etodoxacin and 337.2 mg of lysine into three 10 mL vials, mix them thoroughly with a suspension mixer at 25 °C, add 300 μL of deionized water, and shake for 5 min to obtain three gel-like samples.

[0050] Example 8:

[0051] Weigh out 595.5 mg of etodoxacin and 404.5 mg of meglumine, 622.6 mg of etodoxacin and 377.4 mg of arginine, and 662.8 mg of etodoxacin and 337.2 mg of lysine into three 10 mL vials, mix them thoroughly with a suspension mixer at 25 °C, add 200 μL of deionized water, and shake for 3 min to obtain three gel-like samples.

[0052] Example 9:

[0053] Weigh out 595.5 mg of etodoxacin and 404.5 mg of meglumine, 622.6 mg of etodoxacin and 377.4 mg of arginine, and 662.8 mg of etodoxacin and 337.2 mg of lysine into three 10 mL vials, mix them thoroughly with a suspension mixer at 25 °C, add 200 μL of deionized water, and shake for 7 min to obtain three gel-like samples.

[0054] Example 10:

[0055] Weigh out 595.5 mg of etodoxacin and 404.5 mg of meglumine, 622.6 mg of etodoxacin and 377.4 mg of arginine, and 662.8 mg of etodoxacin and 337.2 mg of lysine into three 10 mL vials, mix them thoroughly with a suspension mixer at 25 °C, add 200 μL of deionized water, and shake for 10 min to obtain three gel-like samples.

[0056] Example 11:

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

[0058] Example 12:

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

[0060] Test Example 1: The etoduolic acid-glucamine hydrogel, etoduolic acid-arginine hydrogel, and etoduolic acid-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: 15kV

[0065] Counting time: 60s

[0066] Results: Sample images and scanning electron microscope images of the three hydrogels of etodoxa acid are shown below. Figure 1 .Depend on Figure 1 As shown in B, the etodoxa acid-glucamine hydrogel, etodoxa acid-arginine hydrogel, and etodoxa acid-lysine hydrogel exhibit a typical three-dimensional network structure with numerous obvious pores inside. The three etodoxa acid hydrogels prepared in Examples 2-10 show 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] Measurement gap: 1mm

[0071] Temperature: 25℃

[0072] Strain scan: Frequency: 1 Hz; Range: 0.1%–1000%

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

[0074] Test results: The rheological test results of the etoposide-glucamine hydrogel in Example 1 are shown in [the table below]. Figure 2 .Depend on Figure 2As can be seen from a, within the strain range of 0.1–10%, the storage modulus G′ and loss modulus G″ maintain relatively high values, indicating that the viscoelastic performance of the etodo acid-glucamine hydrogel is stable within this range. When the strain exceeds 10%, the values ​​of G′ and G″ decrease sharply with increasing applied strain, and the viscoelastic signal reverses (G″>G′), indicating that the internal structure of the etodo acid-glucamine hydrogel begins to collapse, leading to a gradual weakening of elastic and viscous responses. Within the strain range of 0.1–100 rad·s -1 Angular frequency scanning was performed within the range of 0.1–50 rad·s, with a strain of 10% (within the linear viscoelastic region). The G′ and G″ of the eosin-glucamine hydrogel exhibited dependence on the applied frequency. -1 Within the frequency range, G′>G″, when the frequency exceeds 50 rad·s -1 The values ​​of G′ and G″ fluctuate greatly, affecting the stability of the gel structure. Figure 2 b).

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

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

[0077] The three hydrogels of etodo acid prepared in Examples 2-10 exhibited the same or similar rheological behavior.

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

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

[0080] Target: Cu-Kα radiation

[0081] wavelength:

[0082] Pipe pressure: 40KV

[0083] Pipe current: 40mA

[0084] Step size: 0.02°

[0085] Scanning speed: 4° / min

[0086] Scan range; 2θ, 3-40°

[0087] Test results: The powder X-ray diffraction analysis results of the etoduolic acid-glucamine dry gel, etoduolic acid-arginine dry gel, and etoduolic acid-lysine dry gel prepared from the hydrogel samples in Example 1 are as follows: Figures 5-7 As shown. By Figure 5 It can be seen that the crystalline diffraction peaks in the 3–40° range of the etoduolic acid-glucamine dry gel essentially disappear, replaced by a single, diffuse amorphous diffraction ring. The XRPD patterns of the etoduolic acid-arginine dry gel and the etoduolic acid-lysine dry gel show weaker characteristic diffraction peaks, indicating that these dry gels have low crystallinity and exist primarily in an amorphous form. Figure 6-7 The dry gels prepared from the etodo acid hydrogels in Examples 2-10 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 etoduolic acid-glucamine dry gel, etoduolic acid-arginine dry gel, and etoduolic acid-glucamine-lysine dry gel prepared from the hydrogel samples in Example 1 are as follows: Figures 8-10 As shown. By Figures 8-10It can be seen that in Example 1, the DSC spectra of the etodulic acid-glucamine dry gel, etodulic acid-arginine dry gel, and etodulic acid-lysine dry gel show the disappearance of the endothermic melting peak of etodulic acid, and they have a single glass transition temperature of 91.4℃, 84.4℃, and 68.3℃, respectively. The dry gels prepared from the etodulic acid hydrogels in Examples 2 to 10 exhibit similar DSC spectra, showing the disappearance of the melting peak and the presence of a single glass transition temperature.

[0093] 5. Fourier Transmission Infrared Spectroscopy (FTIR)

[0094] Instrument: Nicolet iS50 Fourier Transform Infrared Spectrometer (Thermo, American)

[0095] Range: 4000~400cm -1

[0096] Number of scans: 64

[0097] Measurement results: As shown in 11, the infrared spectral wavenumber (cm²) of the etodoxa acid-glucamine dry gel prepared from the hydrogel sample in Example 1 is... -1 The values ​​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 Figure 12 As shown, the infrared spectral wavenumber (cm²) of the etidoside-arginine dry gel prepared from the hydrogel sample in Example 1 is... -1 The values ​​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 Figure 13 As shown, the infrared spectral wavenumber (cm²) of the hydrogel sample prepared in Example 1, consisting of an etoposide-lysine dry gel, is... -1The values ​​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 dry gels of etoduolic acid-glucamine hydrogel, etoduolic acid-arginine hydrogel and etoduolic acid-lysine hydrogel in Example 1, they exhibited the same or similar FTIR spectra.

[0101] Test Example 2: The solubility of physical mixtures of etodu acid and ligands, including etodu acid-glucamine hydrogels, etodu acid-arginine hydrogels, etodu acid-lysine hydrogels prepared in Examples 1, 3, 5, and 9, and etodu acid-glutamic acid and etodu acid-histidine compositions prepared in Examples 11 and 12, was determined as follows:

[0102] The physical mixture of etodoxa acid and ligand is prepared by weighing the drug and ligand powders in a molar ratio of 1:1, placing them in a 10 mL vial, and vortexing for 10 min to uniformly mix the two powders.

[0103] Excess amounts of etoduolic acid crystals, etoduolic acid-glucamine physical mixture, etoduolic acid-arginine physical mixture, etoduolic acid-lysine physical mixture, etoduolic acid-glucamine hydrogel, etoduolic acid-arginine hydrogel, etoduolic acid-lysine hydrogel, etoduolic acid-glutamic acid composition, and etoduolic acid-histidine composition were weighed separately and placed in 10 mL centrifuge tubes in triplicate. 5 mL of deionized water was added to each tube, and the tubes were shaken in a constant temperature shaker for 24 h (200 rpm, 37 °C). 2 mL of the supernatant was collected, filtered through a 0.22 μm aqueous microporous membrane, and analyzed by high-performance liquid chromatography (HPLC) to calculate the solubility of the drug in deionized water.

[0104] The high-performance liquid chromatography (HPLC) conditions are as follows:

[0105] Instrument: Agilent-1260 High Performance Liquid Chromatography (HPLC)

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

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

[0108] Flow rate: 1.0 mL / min

[0109] Detection wavelength: 228nm

[0110] The results are shown in Table 1. The solubility of the etoduolic acid-glucamine hydrogel, etoduolic acid-arginine hydrogel, and etoduolic acid-lysine hydrogel in Examples 1, 3, 5, and 9, and the etoduolic acid-glutamic acid composition and etoduolic acid-histidine composition in Examples 11 and 12 in deionized water are compared.

[0111] Table 1. Water solubility of Etodu acid crystals, Etodu acid-ligand physical mixtures, and Etodu acid hydrogels

[0112]

[0113]

[0114] As shown in Table 1, compared with single etodo acid crystals (96.33 μg / mL), the solubility of the etodo acid-glucamine hydrogel in Example 1 increased by 20.84 times to 2008.46 μg / mL, the solubility of the etodo acid-arginine hydrogel increased by 16.85 times to 1623.31 μg / mL, and the solubility of the etodo acid-lysine hydrogel increased by 19.24 times to 1854.34 μg / mL. However, the combinations of etodo acid-glutamic acid and etodo acid-histidine in Examples 11 and 12 had no significant effect on the solubility of etodo acid because these two combinations could not form a gel.

[0115] Test Example 3: Release tests were conducted under leaky conditions on the etoduolic acid-glucamine hydrogel, etoduolic acid-arginine hydrogel, and etoduolic acid-lysine hydrogel prepared in Example 1, as follows:

[0116] Three replicates were weighed for each of the following: etoduolic acid crystals, a physical mixture of etoduolic acid and meglumine crystals, a physical mixture of etoduolic acid and arginine, a physical mixture of etoduolic acid and lysine, and the etoduolic acid-meglumine hydrogel, etoduolic acid-arginine hydrogel, and etoduolic acid-lysine hydrogel from Example 1 (equivalent to 17.3 mg of etoduolic acid). Release tests were conducted under leaky conditions using the slurry method according to Method II, General Chapter 0931, Part IV of the 2020 edition of the Chinese Pharmacopoeia. The release medium was deionized water at 37°C, with a volume of 900 mL and a rotation speed of 100 rpm. 2 mL samples were taken at 2, 5, 10, 15, 20, 30, 45, 60, 90, and 120 min, and 2 mL of isothermal and equal-volume dissolution medium was added simultaneously. The collected solution was filtered through a 0.22 μm aqueous microporous membrane, and 10 μL of the filtrate was analyzed by HPLC.

[0117] Test results: The cumulative release rate curves of etoduolic acid-glucamine hydrogel, etoduolic acid-arginine hydrogel, and etoduolic acid-lysine hydrogel under the drain conditions in Example 1 are shown below. Figure 14 As shown. By Figure 14 It can be seen that throughout the release test, the release rates of the three hydrogels of etodulic acid were consistently significantly higher than those of etodulic acid crystals. At 20 min, compared with the cumulative release rate of etodulic acid crystals (13.31%), the cumulative release rates of etodulic acid-glucamine hydrogel, etodulic acid-arginine hydrogel, and etodulic acid-lysine hydrogel were 71.74%, 63.60%, and 68.81%, respectively, which were approximately 5.39 times, 4.78 times, and 5.16 times that of etodulic acid crystals. At 120 min, the cumulative release rates of etodulic acid-glucamine hydrogel, etodulic acid-arginine hydrogel, and etodulic acid-lysine hydrogel were 80.67%, 71.96%, and 73.01%, respectively, which were approximately 1.78 times, 1.59 times, and 1.61 times that of etodulic acid crystals (45.22%).

[0118] Test Example 4: Release experiments were conducted on the etoduolic acid-glucamine hydrogel, etoduolic acid-arginine hydrogel, and etoduolic acid-lysine hydrogel from Example 1 under non-leakage conditions, as follows:

[0119] A certain amount of etodoxa acid crystals, a physical mixture of etodoxa acid and meglumine crystals, a physical mixture of etodoxa acid and arginine crystals, a physical mixture of etodoxa acid and lysine crystals, and the etodoxa acid-meglumine hydrogel, etodoxa acid-arginine hydrogel, and etodoxa acid-lysine hydrogel (equivalent to 400 mg etodoxa acid) from Example 1 were weighed in triplicate. According to Method II of General Chapter 0931, Part IV of the 2020 edition of the Chinese Pharmacopoeia, the non-leaking release rate was evaluated using the slurry method. The release medium was deionized water, the medium temperature was 37℃, the medium volume was 200 mL, and the rotation speed was 100 rpm. 2 mL samples 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 simultaneously. The extracted solution was filtered through a 0.22 μm aqueous microporous membrane, and 10 μL of the filtrate was analyzed by HPLC.

[0120] Test results: The non-leaking release curves of etodu acid, the physical mixture of etodu acid and meglumine, and the etodu acid-meglumine hydrogel in Example 1 are compared as follows: Figure 15 As shown. By Figure 15It was found that the release concentration of etodoxa acid crystals was relatively low at 90 min, at 84.28 μg / mL, and then tended to saturate. The release concentrations of the etodoxa acid-meglumine physical mixture and the etodoxa acid-meglumine hydrogel were significantly increased, reaching 1201.94 μg / mL and 1561.97 μg / mL, respectively. Throughout the experiment, both the etodoxa acid-meglumine physical mixture and the etodoxa acid-meglumine hydrogel exhibited supersaturated release behavior and maintained high supersaturated concentrations for a prolonged period. After 720 min, the etodoxa acid release concentration of the etodoxa acid-meglumine hydrogel reached 1543.77 μg / mL, which was 15.71 times and 1.29 times that of the etodoxa acid crystals (98.27 μg / mL) and the etodoxa acid-meglumine physical mixture (1193.46 μg / mL), respectively (15A).

[0121] Depend on Figure 15 As shown in B, the etoduolic acid-arginine hydrogel in Example 1 exhibited a similar supersaturated release behavior to the etoduolic acid-glucamine hydrogel. At 720 min, the etoduolic acid release concentration in the etoduolic acid-arginine hydrogel was 1743.61 μg / mL, which was 17.74 times and 1.28 times that of the etoduolic acid crystals (98.27 μg / mL) and the etoduolic acid-arginine physical mixture (1356.86 μg / mL), respectively. In contrast, the etoduolic acid release concentration of the etoduolic acid-lysine hydrogel in Example 1 was 1671.58 μg / mL, which was 17.01 times and 1.18 times that of the etoduolic acid crystals (98.27 μg / mL) and the etoduolic acid-lysine physical mixture (1410.17 μg / mL), respectively. Figure 15 C).

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

[0123] Instrument: SHZ-82JT Thermostatic Oscillator (LIANGYOU, China)

[0124] Excess etodoxa acid powder was added to 5 mL of aqueous solutions of meglumine, arginine, and lysine of different concentrations, in triplicate. The solutions were shaken at 37°C and 200 rpm for 24 h in a constant temperature shaker for phase solubility testing. 2 mL of the supernatant was filtered through a 0.45 μm aqueous microporous membrane, and the concentration of etodoxa acid was determined by HPLC.

[0125] Results: The phase solubility of etoposide in different concentrations of meglumine aqueous solution, arginine aqueous solution, and lysine aqueous solution is as follows: Figure 16 The solubility of etoposide increases non-linearly with increasing concentrations of meglumine, arginine, or lysine, exhibiting a typical 1:1 A / B ratio.N The complexation behavior of etoduolic acid showed a negative bias at high concentrations of meglumine, arginine, and lysine (>6.25 mM). Due to the complexation reaction between etoduolic acid and the three selected ligands meglumine, arginine, and lysine, the solubility of the physical mixture and hydrogel of etoduolic acid with the three ligands was significantly improved compared to etoduolic acid crystals. However, there was no complexation reaction between etoduolic acid and the ligands glutamic acid and histidine, therefore the solubility of etoduolic acid in these combinations was not significantly improved (Table 1). The three hydrogels of etoduolic acid formed in this invention significantly enhanced the solubility and dissolution rate of etoduolic acid and maintained a long-term supersaturation level, which is expected to promote the in vivo absorption of etoduolic acid.

Claims

1. A small molecule hydrogel with a specific acidity, characterized in that, The etodo acid small molecule hydrogel is prepared by mixing etodo acid with a small molecule ligand, adding deionized water and shaking; wherein the small molecule ligand is meglumine, arginine or lysine; the molar ratio of etodo acid to small molecule ligand is 1:0.2~5; the mixing temperature is 10~60 ℃ and the shaking time is 1~20 min.

2. The eosinophilic acid small molecule hydrogel according to claim 1, characterized in that, The molecular weights of the etodu acid and the small molecule ligand are all less than 1000 Da.

3. The eosinophilic acid small molecule hydrogel according to claim 1, characterized in that, The total mass ratio of the etoposide acid and the small molecule ligand to the volume ratio of deionized water was 1 g: 50~600 μL.

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