Preparation method of petal-shaped drug-loaded hydrogel
By forming a petal-like structure through esterification within the hydrogel backbone, the drug is chemically bonded to a three-dimensional network, solving the compatibility and release instability problems of traditional hydrogels. This enables controlled release and targeted delivery of the drug, improving therapeutic efficacy and safety.
Patent Information
- Application Number
- CN202511478347.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-10-16
- Publication Date
- 2026-01-02
AI Technical Summary
Traditional hydrogels have poor compatibility when loaded with hydrophobic drugs, leading to drug leakage or precipitation, unstable release behavior, difficulty in achieving precise pharmacokinetic control, and easy disintegration in the gastrointestinal environment, resulting in uneven drug distribution and toxic side effects.
Drugs are bonded to the hydrogel framework through esterification to form a petal-like structure. This structure is then embedded into a three-dimensional network using chemical bonding, enabling controlled and sustained drug release and enhancing structural stability to resist the gastrointestinal environment.
This approach achieves stable drug release, avoids the toxic side effects of excessively high initial drug concentrations, ensures the stability of targeted drug delivery and therapeutic concentration, and improves bioavailability and therapeutic efficacy.
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Figure CN121243056A_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the field of biological medicine, and in particular to a preparation method of petal-shaped drug-loaded hydrogel. BACKGROUND
[0002] In the field of biological medicine, traditional hydrogels are mainly composed of hydrophilic polymer networks, which have significant differences in physical and chemical properties with hydrophobic drugs, resulting in poor compatibility between them. During the loading process, hydrophobic drugs are difficult to disperse effectively and remain stably in the hydrophilic skeleton, and are prone to leakage or precipitation during preparation or storage. This inherent limitation not only limits the amount of drugs that can be carried by unit dose hydrogel, affecting the therapeutic effect, but also forces the increase of drug frequency or dosage in clinical application, potentially increasing the cost and side effect risk of medication.
[0003] Existing hydrogels mostly rely on simple physical embedding or weak interaction drug loading, and the release behavior of drugs is strongly dependent on the swelling, diffusion and degradation processes of the gel network, which are easily disturbed by the complex environment in the body (such as pH, ionic strength, enzymes). This excessive dependence on the environment makes the release rate difficult to predict and reproduce, and it is difficult to achieve a smooth transition from rapid release to slow release, let alone program complex release curves (such as pulse release or constant release), thus limiting its application in treatment scenarios that require precise pharmacokinetic control.
[0004] When using oral or other systemic administration routes, traditional hydrogel carriers need to pass through the strong acid environment of the stomach and the complex digestive fluid environment of the small intestine before reaching the target lesion (such as the colon). During this process, the gel structure may be dissolved or disintegrated too early, resulting in a large amount of drug being released and absorbed in non-target sites. This not only causes waste of drugs and reduces the effective drug concentration at the lesion, but also may cause unnecessary toxic side effects due to the distribution of drugs in non-target tissues, ultimately leading to low treatment efficiency and difficulty in meeting the needs of targeted therapy for diseases in the digestive tract (such as ulcerative colitis). SUMMARY
[0005] In view of the problems in the background art, a preparation method of petal-shaped drug-loaded hydrogel is proposed. The petal-shaped drug-loaded hydrogel realizes controlled release and sustained release of drugs by bonding the drugs to the interior of the gel skeleton rather than the surface, effectively avoiding the burst release problem of traditional drug loading methods.
[0006] The present application provides a preparation method of petal-shaped drug-loaded hydrogel, wherein 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride is used as a coupling reagent, 1-methylimidazole is used as a reaction base and catalyst, and dimethyl sulfoxide is used as a solvent, an esterification reaction is carried out between carboxyl of a poorly soluble drug and hydroxyl of inulin and inulin derivatives, and then drug-loaded nanoparticles are obtained through precipitation, washing and drying; finally, the petal-shaped drug-loaded hydrogel is obtained through dissolving and heating treatment of the drug-loaded nanoparticles.
[0007] Preferably, the poorly soluble drug includes, but is not limited to, indole 3 acetic acid or indole 3 propionic acid.
[0008] Preferably, the preparation steps of the petal-shaped drug-loaded hydrogel are as follows: The inulin is added into a dimethyl sulfoxide solution to obtain a viscous solution; the indole 3 acetic acid, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride and 1-methylimidazole are added into the viscous solution to obtain a reaction mixture; the esterified inulin is washed and dried to obtain drug-loaded nanoparticles; and the petal-shaped drug-loaded hydrogel is obtained through dissolving and heating treatment of the drug-loaded nanoparticles.
[0009] Preferably, the preparation steps of the petal-shaped drug-loaded hydrogel are as follows: The inulin is added into a dimethyl sulfoxide solution to obtain a viscous solution; the indole 3 acetic acid, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride and 1-methylimidazole are added into the viscous solution to obtain a reaction mixture; the esterified inulin is washed and dried to obtain drug-loaded nanoparticles; and the petal-shaped drug-loaded hydrogel is obtained through dissolving and heating treatment of the drug-loaded nanoparticles.
[0010] Preferably, the preparation steps of the petal-shaped drug-loaded hydrogel are as follows: The inulin is added into a dimethyl sulfoxide solution to obtain a viscous solution; the indole 3 acetic acid, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride and 1-methylimidazole are added into the viscous solution to obtain a reaction mixture; the esterified inulin is washed and dried to obtain drug-loaded nanoparticles; and the petal-shaped drug-loaded hydrogel is obtained through dissolving and heating treatment of the drug-loaded nanoparticles.
[0011] Preferably, the preparation steps of the petal-shaped drug-loaded hydrogel are as follows: Incorporation of indole-3-propionic acid into inulin: 0.1 g of inulin was added to 2 mL of dimethyl sulfoxide solution and continuously stirred at 50 °C for 2 h to obtain a viscous solution; indole-3-propionic acid, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride and 1-methylimidazole were added to the viscous solution in a molar ratio of 0.1-1:1.2:2 to obtain a reaction mixture; after the reaction mixture was stirred at room temperature for 24 h, the esterified inulin was precipitated with absolute ethanol and washed 2-8 times, and dried at 35-40 °C to obtain drug-loaded nanoparticles; 300 mg-400 mg of the drug-loaded nanoparticles were dissolved in 1.0 mL of deionized water, heated at 70 °C for 1-5 min, and stored at 4 °C for 12 h, and finally petal-shaped drug-loaded hydrogels were obtained.
[0012] Compared with the prior art, the present application has the following beneficial technical effects: in terms of drug release kinetics, the present application exhibits significant advantages. The drug of the conventional hydrogel is mostly loaded on the surface layer of the material, and is easily diffused rapidly due to the concentration gradient after contacting with the medium, resulting in burst release of the drug. The petal-shaped structure constructed in the present application successfully embeds the drug molecules into the three-dimensional network framework of the hydrogel by chemical bonding, instead of simply physically attaching to the surface layer. This unique "core drug storage" mode fundamentally changes the drug release path. The drug can only be slowly and continuously released to the external environment after the hydrogel framework is gradually degraded or swelled in a specific environment. The in vitro release experiment data fully confirm this point: at the key time point of 4h, the drug release rate of the unmodified physical mixed hydrogel group is as high as 98%, showing a typical burst release; while the hydrogel of the present application only releases about 50% of the drug, and the release curve is more gentle, effectively avoiding the risk of toxic side effects caused by the initial high drug concentration, while ensuring stable treatment concentration in the subsequent period, thereby greatly improving the safety and effectiveness of the drug. In terms of in vivo targeting and lesion site enrichment ability, the present application realizes precise drug delivery. Oral drug delivery targeting the colon has always been a major challenge in the field of formulations, and the difficulty lies in maintaining the structural integrity of the drug while passing through the complex physiological environment of the stomach, small intestine, etc., and accurately reaching the colon lesion site for release. The petal-shaped hydrogel prepared in the present application has structural stability, which can effectively resist the harsh environment of the upper gastrointestinal tract and reduce drug leakage during transportation. The in vivo imaging results clearly reveal its targeting mechanism: the fluorescence signal of the control group gel appears in large quantities in the small intestine, indicating that the carrier disintegrates too early or the drug leaks, resulting in insufficient drug reaching the colon; in contrast, the fluorescence signal of the hydrogel group of the present application is weak in the small intestine, and most of the fluorescence specifically accumulates in the caecum and colon tissues. This not only proves that the carrier can successfully deliver the drug to the target area, but also implies that it may have the "intelligent" property of structural responsive disintegration under the action of colon enzymes or specific pH environment, thereby achieving site-specific and time-specific release of the drug, greatly improving the bioavailability of the drug, and providing an ideal formulation solution for the treatment of local intestinal diseases such as ulcerative colitis. BRIEF DESCRIPTION OF DRAWINGS
[0013] Figure 1 (a) scanning electron microscope image and (b) infrared spectrum of the IN-IAA drug-loaded nanoparticles in Example 1 are shown. Figure 2 The scanning electron microscope image of the IN-IAA gel in Example 1 is shown. Figure 3 The scanning electron microscope image of the IN-IPA drug-loaded nanoparticles in Example 2 is shown. Figure 4 The scanning electron microscope image of the IN-IPA gel in Example 2 is shown. Figure 5 Release profile of the gel in the presence of esterase and beta glucosidase; Figure 6 In vivo imaging of different groups. DETAILED DESCRIPTION
[0014] Example 1, the embodiment proposes a preparation method of petal-shaped drug-loaded hydrogel, 0.1 g inulin is added into dimethyl sulfoxide (2 mL), continuously stirred at 50 °C for 2 h to obtain a clear viscous solution. Indole-3-acetic acid (IAA), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride and 1-methylimidazole are added into the solution at a molar ratio of 1:1.2:2. The reaction mixture is stirred at room temperature for 24 h. The esterified inulin is precipitated and washed with anhydrous ethanol for 4 times. IN-IAA is obtained after drying at 40 °C, and infrared and scanning electron microscopy characterization is carried out, as shown in Figure 1 Compared with the IN spectrum, the IN-IAA spectrum has some characteristic absorption peaks similar to IAA, at 1720 cm -1 is the stretching vibration of C=O, at 1270 cm -1 is the stretching vibration of C-O-C, indicating the formation of ester bond. At the same time, the scanning electron microscopy results show that there is obvious nanoparticle formation, indicating the successful preparation of drug-loaded nanoparticles.
[0015] 300 mg IN-IAA is dissolved in 1.0 mL deionized water, then heated at 70 °C for 1-5 min, and stored at 4 °C for 12 h to obtain petal-shaped drug-loaded hydrogel IN-IAA gel, and transmission electron microscopy characterization is carried out, as shown in Figure 2 The results show petal-like shape, indicating the successful preparation of the gel.
[0016] Example 2, the embodiment proposes a preparation method of petal-shaped drug-loaded hydrogel, 0.1 g inulin is added into dimethyl sulfoxide (2 mL), continuously stirred at 50 °C for 2 h to obtain a clear viscous solution. Indole-3-propionic acid (IPA), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride and 1-methylimidazole are added into the solution at a molar ratio of 1:1.2:2. The reaction mixture is stirred at room temperature for 24 h. The esterified inulin is precipitated and washed with anhydrous ethanol for 4 times. IN-IPA is obtained after drying at 40 °C, and transmission electron microscopy characterization is carried out, as shown in Figure 3 indicating the successful preparation of drug-loaded nanoparticles.
[0017] 300 mg IN-IAA is dissolved in 1.0 mL deionized water, then heated at 70 °C for 1-5 min, and stored at 4 °C for 12 h to obtain petal-shaped drug-loaded hydrogel IN-IAA gel, and transmission electron microscopy characterization is carried out, as shown in Figure 4As shown, the results show petal-like shape, indicating the successful preparation of the gel.
[0018] In the detection example, according to the preparation method of the petal-shaped drug-loaded hydrogel in Example 1, the dialysis bag (3000 Da) containing IN-IAA gel was added to PBS containing esterase and β-glucosidase and shaken (37℃, 100 rpm), and the release of IAA in the preparation was investigated, and samples were taken at 0.5h, 1h, 2h, 4h, 8h and 12h and high performance liquid chromatography was used to detect the drug concentration. The results are shown in Figure 5 As shown, in the IN / IAA group without chemical bond modification, about 98% of the drug was released within 4h. However, the gel in the present application released about 50% of the drug within 4h, so the petal-shaped hydrogel in the present application can prolong the drug release time and avoid premature drug release.
[0019] The present application further uses carboxyl-modified Cy5.5 as a fluorescent dye to investigate the distribution of IN-IAA gel in mice. Six 6-8 week old C57BL / 6 mice were selected, 3 in each group, and each mouse was given 100 µL IN-Cy5.5 gel or IN / Cy5.5 gel by gavage; at 8h, the mice were sacrificed and the colon tissue was removed, washed with sterile PBS, placed in a dish, and placed in a live imaging instrument for photography and storage. The results are shown in Figure 6 As shown, the fluorescence of the control group gel leaks more in the small intestine, resulting in the drug failing to reach the colon site, while the petal-shaped gel group of the present application has more fluorescence accumulated in the cecum and colon site to exert the drug effect.
[0020] The embodiments of the present application are described in detail above in combination with the drawings, but the present application is not limited thereto, and various changes can be made within the knowledge of those skilled in the art without departing from the spirit of the present application.
Claims
1. A method for preparing a petal-shaped drug-loaded hydrogel, characterized in that, Using 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride as a coupling agent, 1-methylimidazole as a reaction base and catalyst, and dimethyl sulfoxide as a solvent, the carboxyl group of the poorly soluble drug was used to carry out an esterification reaction with the hydroxyl group of inulin and inulin derivatives. After precipitation, washing, and drying, drug-loaded nanoparticles were obtained. Finally, the nanoparticles were dissolved and heated to obtain a petal-shaped drug-loaded hydrogel.
2. The method for preparing the petal-shaped drug-loaded hydrogel according to claim 1, characterized in that, Poorly soluble drugs include, but are not limited to, indole-3-acetic acid or indole-3-propionic acid.
3. The method for preparing the petal-shaped drug-loaded hydrogel according to claim 2, characterized in that, The steps are as follows: Inulin was added to a dimethyl sulfoxide solution to obtain a viscous solution; indole-3-acetic acid, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1-methylimidazole were added to the viscous solution to obtain a reaction mixture; the esterified inulin was washed and dried to obtain indole-3-acetic acid-loaded nanoparticles; the obtained nanoparticles were dissolved and heated to obtain a petal-shaped drug-loaded hydrogel.
4. The method for preparing the petal-shaped drug-loaded hydrogel according to claim 3, characterized in that, 0.1 g of inulin was added to 2 mL of dimethyl sulfoxide solution and stirred continuously at 50 °C for 2 h to obtain a viscous solution. Indole-3-acetic acid, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1-methylimidazole were added to the viscous solution at a molar ratio of 0.1-1:1.2:2 to obtain a reaction mixture. After stirring the reaction mixture at room temperature for 24 h, the esterified inulin was precipitated and washed 2-8 times with anhydrous ethanol and dried at 35-40 °C to obtain drug-loaded nanoparticles. 300 mg-400 mg of drug-loaded nanoparticles were dissolved in 1.0 mL of deionized water, heated at 70 °C for 1-5 min, and stored at 4 °C for 12 h to obtain a petal-shaped drug-loaded hydrogel.
5. The method for preparing the petal-shaped drug-loaded hydrogel according to claim 2, characterized in that, The steps are as follows: Inulin was added to a dimethyl sulfoxide solution to obtain a viscous solution; indole-3-propionic acid, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1-methylimidazole were added to the viscous solution to obtain a reaction mixture; the esterified inulin was precipitated and washed with anhydrous ethanol and dried to obtain indole-3-propionic acid-loaded nanoparticles; the obtained nanoparticles were dissolved and heated to finally obtain a petal-shaped drug-loaded hydrogel.
6. The method for preparing the petal-shaped drug-loaded hydrogel according to claim 5, characterized in that, The steps are as follows: 0.1 g of inulin was added to 2 mL of dimethyl sulfoxide solution and stirred continuously at 50 °C for 2 h to obtain a viscous solution. Indole-3-propionic acid, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1-methylimidazole were added to the viscous solution at a molar ratio of 0.1-1:1.2:2 to obtain a reaction mixture. After stirring the reaction mixture at room temperature for 24 h, the esterified inulin was precipitated and washed 2-8 times with anhydrous ethanol and dried at 35-40 °C to obtain drug-loaded nanoparticles. 300 mg-400 mg of drug-loaded nanoparticles were dissolved in 1.0 mL of deionized water, heated at 70 °C for 1-5 min, and stored at 4 °C for 12 h to obtain a petal-shaped drug-loaded hydrogel.