Adriamycin-loaded glycyrrhizic acid supramolecular hydrogel for injection as well as preparation method and application of glycyrrhizic acid supramolecular hydrogel
By loading doxorubicin onto glycyrrhizic acid supramolecular hydrogels, the problem of rapid doxorubicin release was solved, achieving long-term sustained release at the tumor site and reduced systemic toxicity, thus providing a new anti-tumor treatment strategy.
Patent Information
- Application Number
- CN202610040804.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2026-01-13
- Publication Date
- 2026-03-20
AI Technical Summary
In existing technologies, the rapid release of doxorubicin leads to the rapid elimination of tumor cells, making it difficult to maintain an effective effect at the tumor site for a long time, and its systemic distribution causes toxic side effects.
A supramolecular hydrogel formed by the self-assembly of glycyrrhizic acid was used as a carrier to load doxorubicin. Through hydrogen bonding, hydrophobicity and π-π stacking, a supramolecular hydrogel of glycyrrhizic acid for injection loaded with doxorubicin was formed, achieving slow release.
Continuous release of doxorubicin at the tumor surgical site for up to 20 days increases the duration of drug action, reduces systemic toxicity and side effects, and enhances anti-tumor efficacy.
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Figure CN121695074A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the pharmaceutical field, specifically relating to an injectable glycyrrhizic acid supramolecular hydrogel loaded with doxorubicin, its preparation method, and its application. Background Technology
[0002] Surgical resection is the core approach to clinical treatment of solid tumors, rapidly reducing the tumor burden through physical removal. However, its limitations are becoming increasingly apparent. First, surgical procedures are limited by visual resolution and operational precision, making it difficult to completely remove aggressively growing micronodules or scattered circulating tumor cells, resulting in a local recurrence rate as high as 30%-50% within 5 years post-surgery, as seen in breast cancer and gliomas. Second, surgical trauma can disrupt the physical barrier of the tumor microenvironment, potentially accelerating the proliferation and metastasis of residual cancer cells. Therefore, developing a novel treatment strategy that can precisely deliver drugs, prolong local action time, and reduce systemic toxicity has become a key breakthrough in postoperative adjuvant therapy for tumors.
[0003] Furthermore, doxorubicin hydrochloride, as the gold standard of anthracycline chemotherapy, can intercalate into DNA base pairs after entering cancer cells, blocking DNA / RNA synthesis, inhibiting topoisomerase II, leading to DNA double-strand breaks, and generating reactive oxygen species (ROS) that disrupt mitochondrial membrane potential. While its remission rate in breast cancer can reach 60%-80%, only 0.01%-0.1% of the drug accumulates in tumor tissue after systemic administration, with the remainder distributed in normal tissues such as the heart or bone marrow, causing myocardial mitochondrial damage or inhibiting hematopoietic stem cells. More challenging is that tumor cells overexpressing P-glycoprotein or P-gp efflux pumps can rapidly clear doxorubicin, leading to multidrug resistance; approximately 50% of patients experience drug resistance and relapse in the later stages of treatment.
[0004] Traditional hydrogels, such as hyaluronic acid and chitosan-based gels, can be used as local drug carriers to achieve sustained release of chemotherapy drugs via intratumoral injection, overcoming the shortcomings of doxorubicin hydrochloride in terms of distribution and rapid clearance by tumor cells. However, burst release is still prone to occur, and the release time remains relatively short, not exceeding 7 days. Summary of the Invention
[0005] The purpose of this invention is to provide an injectable glycyrrhizic acid supramolecular hydrogel loaded with doxorubicin, its preparation method, and its application, in order to solve the technical problem in the prior art where the rapid release of doxorubicin leads to its rapid clearance by tumor cells.
[0006] To solve the above-mentioned technical problems, the present invention adopts the following technical solution: A supramolecular hydrogel of glycyrrhizic acid for injection loaded with doxorubicin includes a carrier and a drug loaded on the carrier, wherein the drug is doxorubicin or doxorubicin hydrochloride, and the carrier is a supramolecular hydrogel formed by the self-assembly of glycyrrhizic acid. The supramolecular hydrogel of glycyrrhizic acid for injection loaded with doxorubicin is formed by using glycyrrhizic acid as a raw material, adding glycyrrhizic acid to a hydrophilic solvent, dissolving it, adding doxorubicin or doxorubicin hydrochloride, heating until dissolved, and cooling to form a hydrogel.
[0007] Furthermore, the hydrophilic solvent includes any one of pure water, physiological saline, and phosphate buffer solution.
[0008] A method for preparing doxorubicin-loaded glycyrrhizic acid supramolecular hydrogels for injection includes the following steps: Glycyrrhizic acid was added to a hydrophilic solvent and sonicated to obtain a glycyrrhizic acid solution. Doxorubicin or doxorubicin hydrochloride is added to a glycyrrhizic acid solution and heated in a water bath at 50-85°C until completely dissolved. Heating is then stopped, and the solution is cooled to 20-37°C to obtain the doxorubicin-loaded glycyrrhizic acid supramolecular hydrogel for injection.
[0009] Furthermore, the mass percentage of glycyrrhizic acid to hydrophilic solvent is 1 mg to 10 mg: 100 mL.
[0010] Furthermore, the mass percentage of the doxorubicin or doxorubicin hydrochloride to the hydrophilic solvent is 0.1 mg to 1 mg: 100 mL.
[0011] Furthermore, the mass percentage of the doxorubicin or doxorubicin hydrochloride to the hydrophilic solvent is 0.1 mg to 1 mg: 100 mL.
[0012] Application of glycyrrhizic acid supramolecular hydrogel loaded with doxorubicin in the preparation of antitumor drugs, which are used after surgical resection of breast cancer.
[0013] The principle of this invention is as follows: This invention presents the first preparation of a supramolecular hydrogel of glycyrrhizic acid for injection loaded with doxorubicin. The hydrogel comprises a carrier and a drug loaded on the carrier, wherein the drug is doxorubicin or doxorubicin hydrochloride. The carrier is a supramolecular hydrogel formed by the self-assembly of glycyrrhizic acid. The supramolecular hydrogel is prepared by adding glycyrrhizic acid to a hydrophilic solvent, dissolving the glycyrrhizic acid, adding doxorubicin or doxorubicin hydrochloride, heating until dissolved, and cooling to form a hydrogel. The hydrogel is formed by the self-assembly of glycyrrhizic acid with hydrogen bonding, hydrophobicity, and π-π stacking after the addition of doxorubicin, and contains only small molecules of glycyrrhizic acid and doxorubicin. The supramolecular hydrogel can slowly release doxorubicin at the surgical site, increasing the duration of action of the drug and reducing systemic toxicity.
[0014] Compared with the prior art, the present invention has the following beneficial effects: (1) This invention provides an injectable glycyrrhizic acid supramolecular hydrogel loaded with doxorubicin, comprising a carrier and a drug loaded on the carrier, wherein the drug is doxorubicin hydrochloride and the carrier is a glycyrrhizic acid supramolecular hydrogel. The constructed injectable glycyrrhizic acid supramolecular hydrogel loaded with doxorubicin slowly releases the drug at the tumor surgical site, with a duration of action in animals up to 20 days, thereby increasing the duration of action of doxorubicin hydrochloride and enhancing the antitumor effect.
[0015] (2) This invention solves the toxic side effects caused by the distribution and dispersion of the antitumor drug doxorubicin hydrochloride and prolongs the duration of action on tumors. Through the synergistic effect of glycyrrhizic acid and doxorubicin, the antitumor effect is increased, providing a new idea for the clinical application of doxorubicin.
[0016] (3) The glycyrrhizic acid used in this invention is a natural product, and the supramolecular hydrogel prepared has the characteristics of low toxicity and good tolerance, and is safe and effective; the glycyrrhizic acid used is low in cost and the hydrogel is easy to synthesize. Attached Figure Description
[0017] Figure 1 This is the structural formula of glycyrrhizic acid and doxorubicin in this invention.
[0018] Figure 2 The transmittance trend line of the liquid generated during the preparation of supramolecular hydrogels using glycyrrhizic acid, doxorubicin, and pure water as a function of time.
[0019] Figure 3 The different states of supramolecular hydrogels during the preparation of supramolecular hydrogels are determined by glycyrrhizic acid content, doxorubicin, and pure water.
[0020] Figure 4 In the image, a is a physical image of the supramolecular hydrogel prepared from glycyrrhizic acid, doxorubicin, and pure water in solution state; b is a physical image of the hydrogel in gel state; c is a thermal image of the solution state; and d is a thermal image of the gel state.
[0021] Figure 5 Hydrogel states prepared in pure water with different ratios of glycyrrhizic acid (GA) and doxorubicin (DOX).
[0022] Figure 6 In the image, a represents the mice injected with the supramolecular hydrogel prepared from glycyrrhizic acid, doxorubicin, and pure water; b represents the mice 10 minutes after subcutaneous injection.
[0023] Figure 7 This is a diagram showing the state of glycyrrhizic acid (GA), doxorubicin (DOX), and pure water during the preparation of supramolecular hydrogels, with and without the addition of DID.
[0024] Figure 8 In vivo imaging images at different time points after subcutaneous injection of glycyrrhizic acid, doxorubicin, pure water and DID into supramolecular hydrogels and free DID in tumor-bearing mice. Detailed Implementation
[0025] The present invention will be further described in detail below with reference to embodiments, but the implementation of the present invention is not limited thereto. Unless otherwise specified, the technical means used in the following embodiments are conventional means well known to those skilled in the art; the experimental methods used are all conventional methods; and the materials, reagents, etc. used are all commercially available.
[0026] Example 1 Weigh out 80 mg of glycyrrhizic acid, 4 mL of pure water, and 4 mg of doxorubicin hydrochloride for later use. The chemical structures of glycyrrhizic acid and doxorubicin hydrochloride are as follows: Figure 1 As shown.
[0027] Glycyrrhizic acid was added to pure water and sonicated for 2 minutes to obtain a glycyrrhizic acid solution. The solution was then heated to 80°C in a water bath at room temperature. Doxorubicin hydrochloride was added and heated until completely dissolved to form a liquid. Heating was stopped, and 3 mL of the liquid was added to a glass dish at 50°C. The dish was then placed in a UV spectrophotometer and measured at 800 nm. The results are as follows: Figure 2 As shown in the figure, the transmittance changed from 100% to 84% over time, indicating that the solution state changed to a hydrogel.
[0028] The remaining liquid was allowed to stand at room temperature until it became a gel, thus obtaining a glycyrrhizic acid supramolecular hydrogel loaded with doxorubicin for injection.
[0029] The glycyrrhizic acid content is 2%, and the doxorubicin content is 0.1%.
[0030] like Figure 3 As shown, glycyrrhizic acid and doxorubicin hydrochloride completely dissolve to form a liquid. When the dissolved liquid is inverted in a container, it flows to the bottom, indicating a liquid state. After heating and cooling, the container is inverted again, and a hydrogel forms and remains in the upper part. The temperatures during the solution and gel states are recorded using a thermal imager. Figure 4 As shown.
[0031] Example 2 Weigh 40 mg of glycyrrhizic acid and add it to 1 mL of pure water. Sonicate the solution for 2 min to obtain a glycyrrhizic acid solution. Heat the glycyrrhizic acid solution to 80°C in a water bath at room temperature and add 1 mg of doxorubicin hydrochloride. Stop heating after complete dissolution and allow the solution to stand at room temperature. The solution will then become a gel and be ready to be injected with doxorubicin supramolecular hydrogel.
[0032] The product contains 4% glycyrrhizic acid and 0.1% doxorubicin. like Figure 5 As shown, after glycyrrhizic acid and doxorubicin hydrochloride are completely dissolved, the container is inverted after dissolution, and a hydrogel forms and remains on the top.
[0033] Example 3 Weigh 40 mg of glycyrrhizic acid and add it to 1 mL of pure water. Sonicate the solution for 2 min to obtain a glycyrrhizic acid solution. Heat the glycyrrhizic acid solution to 80°C in a water bath at room temperature and add 10 mg of doxorubicin hydrochloride. Stop heating after complete dissolution and allow the solution to stand at room temperature. The solution will then become a gel and be ready to be injected with doxorubicin supramolecular hydrogel.
[0034] Among them, glycyrrhizic acid content is 4%, and doxorubicin content is 1%; like Figure 5 As shown, after glycyrrhizic acid and doxorubicin hydrochloride are completely dissolved, the container is inverted after dissolution, and a hydrogel forms and remains on the top.
[0035] Example 4 Weigh 60 mg of glycyrrhizic acid and add it to 1 mL of pure water. Sonicate the solution for 2 min to obtain a glycyrrhizic acid solution. Heat the glycyrrhizic acid solution to 80°C in a water bath at room temperature and add 1 mg of doxorubicin hydrochloride. Stop heating after complete dissolution and allow the solution to stand at room temperature. The solution will then become a gel and be ready to be injected with doxorubicin supramolecular hydrogel.
[0036] The product contains 6% glycyrrhizic acid and 0.1% doxorubicin. like Figure 5 As shown, after glycyrrhizic acid and doxorubicin hydrochloride are completely dissolved, the container is inverted after dissolution, and a hydrogel forms and remains on the top.
[0037] Example 5 Weigh 60 mg of glycyrrhizic acid and add it to 1 mL of pure water. Sonicate the solution for 2 min to obtain a glycyrrhizic acid solution. Heat the glycyrrhizic acid solution to 80°C in a water bath at room temperature and add 10 mg of doxorubicin hydrochloride. Stop heating after the solution is completely dissolved and allowed to stand at room temperature. The solution will then become a gel and be ready to be injected with doxorubicin supramolecular hydrogel.
[0038] Among them, glycyrrhizic acid content is 6%, and doxorubicin content is 1%; like Figure 5 As shown, after glycyrrhizic acid and doxorubicin hydrochloride are completely dissolved, the container is inverted after dissolution, and a hydrogel forms and remains on the top.
[0039] Example 6 A method for preparing an injectable glycyrrhizic acid supramolecular hydrogel loaded with doxorubicin includes the following steps: Weigh 20 mg of glycyrrhizic acid and add it to 1 mL of physiological saline. Sonicate the solution for 2 min to obtain a glycyrrhizic acid solution. Heat the glycyrrhizic acid solution to 80°C in a water bath at room temperature and add 1 mg of doxorubicin hydrochloride. Stop heating after complete dissolution and allow the solution to stand at room temperature. The solution will then become a gel and be ready to inject glycyrrhizic acid supramolecular hydrogel loaded with doxorubicin.
[0040] The saline solution contains 0.9% sodium chloride.
[0041] The glycyrrhizic acid content is 2%, and the doxorubicin content is 0.1%.
[0042] Example 7 A method for preparing an injectable glycyrrhizic acid supramolecular hydrogel loaded with doxorubicin includes the following steps: Weigh 20 mg of glycyrrhizic acid and add it to 1 mL of phosphate buffer. Sonicate the solution for 2 min to obtain a glycyrrhizic acid solution. Heat the glycyrrhizic acid solution to 80°C in a water bath at room temperature and add 1 mg of doxorubicin hydrochloride. Stop heating after complete dissolution and allow the solution to stand at room temperature. The solution will then become a gel and be ready to be injected with doxorubicin supramolecular hydrogel.
[0043] The phosphate buffer solution has a concentration of 10 mM and a pH of 7.4.
[0044] The glycyrrhizic acid content is 2%, and the doxorubicin content is 0.1%.
[0045] Application Example 1 Following Example 7, a non-condensed hydrogel solution was prepared and subcutaneously injected into the axillary region of mice. After 10 minutes, the mice were sacrificed, and the skin was incised to observe the hydrogel morphology. Figure 6 As can be seen, the hydrogel successfully formed in mice. To verify the retention time of the hydrogel in vivo, we need to add DID, which has properties similar to doxorubicin, to the hydrogel to enhance the fluorescence intensity and facilitate detection. Weigh 20 mg of glycyrrhizic acid and add it to 1 mL of physiological saline. After sonication to dissolve, heat it in a water bath to 80°C, add 1 mg of doxorubicin and 50 μg of DID until completely dissolved. After stopping heating, a hydrogel is formed. Figure 7 As shown. Next, a hydrogel liquid was prepared in the same manner and injected into the tumor site of tumor-bearing mice before it solidified. The mice were then photographed using an in vivo imaging system at different time points. The results were analyzed. Figure 8 It can be seen that, compared with free DID, injectable glycyrrhizic acid supramolecular hydrogel loaded with doxorubicin and DID can remain at the tumor site for a longer time.
[0046] The above descriptions are merely embodiments of the present invention, and common knowledge such as specific technical solutions and / or characteristics are not described in detail here. It should be noted that those skilled in the art can make various modifications and improvements without departing from the technical solutions of the present invention, and these should also be considered within the scope of protection of the present invention. These modifications and improvements will not affect the effectiveness of the implementation of the present invention or the practicality of the patent. The scope of protection claimed in this application should be determined by the content of its claims, and the specific embodiments described in the specification can be used to interpret the content of the claims.
Claims
1. A supramolecular hydrogel of glycyrrhizic acid for injection loaded with doxorubicin, characterized in that, The invention includes a carrier and a drug loaded on the carrier, wherein the drug is doxorubicin hydrochloride and the carrier is a supramolecular hydrogel formed by the self-assembly of glycyrrhizic acid. The mass ratio of glycyrrhizic acid to doxorubicin hydrochloride is 1 to 10; The supramolecular hydrogel of glycyrrhizic acid for injection loaded with doxorubicin is made by using glycyrrhizic acid as a raw material, adding glycyrrhizic acid to a hydrophilic solvent, dissolving it, adding doxorubicin hydrochloride, heating until dissolved, and cooling to form a hydrogel.
2. The glycyrrhizic acid supramolecular hydrogel for injection loaded with doxorubicin according to claim 1, characterized in that, The hydrophilic solvent includes any one of pure water, physiological saline, and phosphate buffer solution.
3. The method for preparing doxorubicin-loaded glycyrrhizic acid supramolecular hydrogel for injection according to claim 1, characterized in that, Includes the following steps: Glycyrrhizic acid was added to a hydrophilic solvent and sonicated to obtain a glycyrrhizic acid solution. Doxorubicin hydrochloride was added to a glycyrrhizic acid solution, heated to dissolve, and then the heating was stopped and cooled to 20°C~37°C to obtain the doxorubicin-loaded glycyrrhizic acid supramolecular hydrogel for injection.
4. The method for preparing doxorubicin-loaded glycyrrhizic acid supramolecular hydrogel for injection according to claim 3, characterized in that, The mass percentage of glycyrrhizic acid to hydrophilic solvent is 1 mg to 10 mg: 100 mL.
5. The method for preparing doxorubicin-loaded glycyrrhizic acid supramolecular hydrogel for injection according to claim 3, characterized in that, The heating and melting temperature is 50℃~85℃.
6. The application of the glycyrrhizic acid supramolecular hydrogel for injection loaded with doxorubicin as described in claim 1 in the preparation of antitumor drugs, characterized in that, Anti-tumor drugs are medications used after surgical resection of cancer.
7. The use of the glycyrrhizic acid supramolecular hydrogel for injection loaded with doxorubicin as described in claim 1 in the preparation of antitumor drugs.
8. The application of the glycyrrhizic acid supramolecular hydrogel for injection loaded with doxorubicin according to claim 7 in the preparation of antitumor drugs, characterized in that, The tumor is breast cancer.