KR-20260062184-A - Inflammatory condition-specific drug-releasing hydrogel for ocular injection

Abstract

This invention relates to an inflammation-state-specific drug-releasing hydrogel for ocular injection and its uses. According to one aspect, the hydrogel can control the release of a drug specifically in an inflammatory state and allows for direct injection into the eye.

Inventors

• 오승자
• 임매순
• 노현희
• 김혜림

Assignees

• 경희대학교 산학협력단
• 한국과학기술연구원

Dates

Publication Date

20260507

Application Date

20241025

Claims (14)

1. A hydrogel formed by crosslinking hyaluronic acid as a crosslinking agent, A drug is encapsulated inside the above hydrogel, and The above-mentioned crosslinking agent comprises a peptide that is degraded by cathepsins, in a hydrogel.
2. A hydrogel according to claim 1, wherein the hyaluronic acid is DBCO(Dibenzylcyclooctyne)-conjugated hyaluronic acid (DBCO-HA).
3. A hydrogel according to claim 1, wherein the peptide degraded by the cathepsin comprises the amino acid sequence of SEQ ID NO. 1.
4. A hydrogel according to claim 1, wherein when the crosslinking agent is decomposed by cathepsin, the drug is released outside the hydrogel.
5. The hydrogel of claim 1, wherein the hydrogel specifically releases the drug at an inflammatory lesion.
6. A hydrogel according to claim 1, wherein the drug is an EZH2 (Enhancer of zeste homolog 2) inhibitor.
7. The hydrogel of claim 1, wherein the hydrogel is for ocular injection.
8. A drug delivery composition comprising a hydrogel of any one of claims 1 to 7.
9. An anti-inflammatory topical skin composition comprising a hydrogel according to any one of claims 1 to 7.
10. A pharmaceutical composition for treating eye diseases comprising a hydrogel of any one of claims 1 to 7.
11. A pharmaceutical composition according to claim 10, wherein the eye disease is a degenerative retinal disease.
12. (1) Step 1 for preparing DBCO(Dibenzylcyclooctyne)-conjugated hyaluronic acid (DBCO-HA); (2) A second step of mixing the above DBCO-HA and solvent; (3) A third step of mixing the drugs; and (4) A fourth step of adding a crosslinking agent, and A method for preparing a hydrogel, wherein the crosslinking agent comprises a peptide that is degraded by cathepsins.
13. A method according to claim 12, wherein the peptide degraded by the cathepsin comprises the amino acid sequence of SEQ ID NO. 1.
14. The method of claim 12, wherein the drug is an EZH2 (Enhancer of zeste homolog 2) inhibitor.

Description

Inflammatory condition-specific drug-releasing hydrogel for ocular injection The present invention relates to an inflammation-state-specific drug-releasing hydrogel for ocular injection and the use thereof, wherein the hydrogel capable of controlling the release of a drug specifically in an inflammation-state, a composition for drug delivery, anti-inflammation, or treatment of eye diseases comprising the same, and a method for manufacturing the hydrogel. Retinitis Pigmentosa (RP) is an outer retinal degenerative disease that can lead to photoreceptor cell death and severe vision loss. While effectively controlling inflammation within the retina can slow disease progression, efficient anti-inflammatory treatment strategies are still lacking. Effective resolution of inflammation contributes to preventing disease progression and promoting healing. While most past research focused on immediate inflammation reduction, timely inflammation control has become increasingly important, as recent studies have reported that appropriate management tailored to the severity of inflammation can lower drug side effects and enhance therapeutic efficacy. A crucial regulatory factor in resolving the inflammatory environment is the modulation of macrophage plasticity, and converting inflammatory macrophages (M1) into anti-inflammatory macrophages (M2) is a key element in controlling the transition to the resolution phase of the inflammatory process. Epigenetic modulation can serve as an effective strategy for altering macrophage phenotypes due to its potent efficacy in regulating macrophage plasticity, which possesses target specificity and reversibility. Therefore, alleviating inflammatory responses through the epigenetic modulation of macrophages can be a novel therapeutic strategy in clinical applications. However, since drugs for epigenetic modulation have very short half-lives and the epigenome is regulated sensitively by the environment, these drugs must be delivered to the epigenome in a timely manner to maximize their intended effects. Consequently, to control inflammation through the effective epigenetic modulation of macrophages, a drug delivery system capable of delivering drugs to macrophages at a timely rate specific to the inflammatory state is required. Hydrogels possess high biocompatibility due to their high water content, porous structure, and similarity to the extracellular matrix. Due to these characteristics, they are being extensively studied in biomedical fields such as drug delivery systems and tissue engineering. Meanwhile, there is a lack of research on drug delivery systems capable of releasing drugs specifically in response to inflammatory conditions and allowing for ocular injection. Figure 1a shows the mRNA expression levels of inflammatory markers measured at 3 weeks (PW3) and 7 weeks (PW7) after birth in wild-type (wild-type, wt₀ ) and retinal degeneration (retinal degeneration 10, rd10₀ ) mouse models. (Mean ± SD; n = 3) Figure 1b shows the mRNA expression levels of cathepsin L, S, and B at 3 weeks (PW3) and 7 weeks (PW7) after birth in normal ( wt ) and retinal degeneration ( rd10 ) mouse models. (Mean ± SD; n = 3) Figure 1c shows the activity of cathepsin L, S, and B measured at 3 weeks (PW3) and 7 weeks (PW7) after birth in normal ( wt ) and retinal degeneration ( rd10 ) mouse models. (Mean ± SD; n = 3) Figure 1d shows the results of immunofluorescence staining of inflammatory markers at 3 weeks (PW3) and 7 weeks (PW7) after birth in normal ( wt ) and retinal degeneration ( rd10 ) mouse models. Figure 1e shows the results of immunofluorescence staining of cathepsin L, S, and B at 3 weeks (PW3) and 7 weeks (PW7) after birth in normal ( wt ) and retinal degeneration ( rd10 ) mouse models. Figure 2a is a schematic diagram showing the manufacturing process of an inflammatory responsive hydrogel (IRH). Figure 2b shows that the rate of IRH degradation varies depending on the amount of cathepsin secreted in the inflammatory microenvironment. Figure 3a is a schematic diagram illustrating the structure of a hydrogel (IRH) in which crosslinking is formed by the connection of a cathepsin-cleavable peptide crosslinker and DBCO-HA. Figure 3b shows the results of analyzing the chemical composition of the prepared DBCO-HA using 1H -NMR. Figure 3c shows the storage modulus (G'; solid line symbol) and loss modulus (G”; hollow symbol) of IRH at four different concentrations (0.25, 0.5, 1, 2 mM) of cathepsin-degradable crosslinker. Figure 3d shows the measured Young's count values of IRH at three different concentrations (0.25, 0.5, 1 mM) of cathepsin-degradable crosslinker. Figure 3e shows the scanning electron microscope (SEM) results of IRH at three different concentrations (0.25, 0.5, 1 mM) of cathepsin-degradable crosslinker. Figure 3f shows the measured permeability values of IRH at three different concentrations (0.25, 0.5, 1 mM) of cathepsin-degradable crosslinker. Figures 3g and 3h show the cytotoxicity