Hydrogel kit capable of being rapidly dissolved as required and method of using same

Abstract

A hydrogel kit capable of being rapidly dissolved as required and a method of using same. The hydrogel kit comprises a gel system and a dissolving liquid, and the gel system and the dissolving liquid are used in a volume ratio of 1:(2-10). The co-action of the aldehyde group-capped star-shaped multi-arm polyethylene glycol gel system and the dissolving liquid of the water-soluble amino compound can realize rapid degradation of the gel. In addition, the pH value of the dissolving liquid of the water-soluble amino compound is controlled to be 3-7.5, which can realize the low-temperature rapid degradation of the gel system, thereby greatly expanding the application range of the gel and reducing the side effects of long-term foreign body irritation for patients.

Description

A hydrogel kit capable of rapid dissolution on demand and its use method Technical Field

[0001] The present invention relates to a hydrogel kit capable of rapid dissolution on demand and a method for using the kit, and particularly to the field of pharmaceutical preparations. Background Art

[0002] Hydrogels are polymer materials with high water content and excellent biocompatibility. In recent years, they have been increasingly applied in the medical field. Due to their excellent biocompatibility, hydrogels are widely used in tissue isolation, tissue repair, sustained drug release, wound dressings, medical aesthetics, and scar repair. However, due to their inherent gel properties, hydrogels degrade slowly within the body. If hydrogels are not quickly removed after completing their functional tasks and remain in the body for a long time, they can easily cause inflammation caused by foreign bodies. Furthermore, hydrogels in tissue isolation, wound dressings, and scar repair require rapid removal after completing their functional tasks, otherwise they will affect further tissue repair and growth. Hydrogels can also experience implant misalignment during in vitro and in vivo applications, necessitating removal. However, since most hydrogels are implanted via minimally invasive in situ injections or because they strongly adhere to the tissue at the implantation site, hydrogel removal presents significant resistance. Therefore, rapid and non-destructive hydrogel removal is a pressing technical challenge in clinical applications.

[0003] Chinese invention patent CN115737535A discloses a controllable degradable nanocomposite gel, its preparation method and application. The aminophenylboronic acid-modified hyaluronic acid cross-linked polyvinyl alcohol / hydrogel-liposome achieves clinical precision treatment by regulating the internal configuration changes through dynamic aminophenylboronic acid ester covalent bonds and hyaluronic acid skeleton under hydrolysis, completing the automatic degradation after the release of nanomedicine. However, the nanocomposite gel requires a long degradation time and there is a risk of foreign body inflammation. Chinese invention patent CN202011119562.X discloses a degradable medical hydrogel. By adopting aldehyde-terminated star-shaped multi-arm polyethylene glycol and optimizing the number of arms and molecular weight range of the star-shaped multi-arm polyethylene glycol, a hydrogel with short-term degradability is obtained. However, degradation still takes several days to a year, and the degradation rate is slow.

[0004] Summary of the Invention

[0005] In order to increase the degradation rate of the hydrogel and achieve rapid and lossless dissolution, the first aspect of the present invention provides a hydrogel kit that can be quickly dissolved on demand, comprising a gel system and a dissolving solution, wherein the volume ratio of the gel system to the dissolving solution is 1:(2-10).

[0006] As a preferred embodiment, the gel system comprises an aldehyde derivative aqueous solution and a polyamine aqueous solution, and the volume ratio of the aldehyde derivative aqueous solution to the polyamine aqueous solution is 1:(0-10).

[0007] As a preferred embodiment, the volume ratio of the aldehyde derivative aqueous solution to the polyamine aqueous solution is 1:(0.5-2).

[0008] As a preferred embodiment, the aldehyde derivative aqueous solution is selected from a combination of one or more of a polyethylene glycol aldehyde derivative aqueous solution, an oxidized sodium carboxymethyl cellulose aqueous solution, an oxidized sodium alginate aqueous solution, and an oxidized sodium dextran sulfate aqueous solution.

[0009] As a preferred embodiment, the aqueous solution of the polyethylene glycol aldehyde derivative is an aldehyde-terminated star-shaped multi-arm polyethylene glycol, and the number of arms of the aldehyde-terminated star-shaped multi-arm polyethylene glycol is 4-8.

[0010] As a preferred embodiment, the weight average molecular weight of the aldehyde-terminated star-shaped multi-arm polyethylene glycol is 2000-5000 Da.

[0011] As a preferred embodiment, the aldehyde group is selected from one or a combination of aromatic aldehyde groups and alkyl aldehyde groups. More preferably, the aldehyde group is a benzaldehyde group.

[0012] As a preferred embodiment, the aldehyde group is combined with the star-shaped multi-arm polyethylene glycol using one or a combination of ether bonds, amide bonds, urethane bonds, imine bonds, and urea bonds.

[0013] As a preferred embodiment, the mass fraction of the polyethylene glycol aldehyde derivative aqueous solution is 5-50%; the mass fraction of the polyamine aqueous solution is 0.5-30%.

[0014] As a preferred embodiment, the mass fraction of the polyethylene glycol benzaldehyde derivative aqueous solution is 15-30%; the mass fraction of the polyamine aqueous solution is 1-6%.

[0015] As a preferred embodiment, the mass fraction of the polyethylene glycol benzaldehyde derivative aqueous solution is 20-25%; the mass fraction of the polyamine aqueous solution is 1-5%.

[0016] As a preferred embodiment, the mass fraction of the polyethylene glycol benzaldehyde derivative aqueous solution is 20%; the mass fraction of the polyamine aqueous solution is 1-5%.

[0017] As a preferred embodiment, the polyamino aqueous solution is selected from one or a combination of polyethyleneimine aqueous solution and polylysine aqueous solution.

[0018] As a preferred embodiment, the mass fraction of the polyethyleneimine aqueous solution is 0.5-10%, and the mass fraction of the polylysine aqueous solution is 1-30%.

[0019] As a preferred embodiment, the mass fraction of the polyethyleneimine aqueous solution is 1-6%, and the mass fraction of the polylysine aqueous solution is 1.5-4.5%.

[0020] As a preferred embodiment, the mass fraction of the polyethyleneimine aqueous solution is 1-5%, and the mass fraction of the polylysine aqueous solution is 2-3%.

[0021] As a preferred embodiment, when the polyamino aqueous solution comprises only the polyethyleneimine aqueous solution, the mass fraction of the polyethyleneimine aqueous solution is 5%. The volume ratio of the polyethylene glycol aldehyde derivative aqueous solution to the polyethyleneimine aqueous solution in the gel system is 1:1.

[0022] In a preferred embodiment, when the polyamino aqueous solution comprises a combination of a polyethyleneimine aqueous solution and a polylysine aqueous solution, the mass fraction of the polyethyleneimine aqueous solution is 1.2%, and the mass fraction of the polylysine aqueous solution is 2.6%. In the gel system, the volume ratio of the polyethylene glycol aldehyde derivative aqueous solution, the polyethyleneimine aqueous solution, and the polylysine aqueous solution is 1:1:1.

[0023] During their experiments, the applicant discovered that combining a gel system with a solution of a water-soluble amino compound, under certain acidic and alkaline conditions, can rapidly degrade the gel, achieving gel degradation within half an hour. This prevents the gel from causing inflammation and other issues even after fulfilling its functional requirements. The possible cause is speculated to be that the aldehyde-terminated multi-arm polyethylene glycol derivatives react with the polyamino compound through a Schiff base reaction to form a gel network cross-linked by amide bonds. The crosslinking points in the gel network are dynamic amide bonds. By introducing a solution of a water-soluble amino compound under appropriate acidic and alkaline conditions, single amino molecules can disrupt the dynamic amide bonds, breaking the cross-linked network structure and dissolving it in the solution for excretion.

[0024] As a preferred embodiment, the dissolving liquid is selected from one or a combination of hydroxylamine hydrochloride aqueous solution, amino acid aqueous solution, and short peptide aqueous solution.

[0025] As a preferred embodiment, the dissolving liquid is selected from one of a hydroxylamine hydrochloride aqueous solution, a glycine aqueous solution, and a lysine aqueous solution.

[0026] As a preferred embodiment, the dissolving liquid is a hydroxylamine hydrochloride aqueous solution; preferably, the dissolving liquid is a glycine aqueous solution; preferably, the dissolving liquid is a lysine aqueous solution.

[0027] As a preferred embodiment, the concentration of the dissolving solution is 0.1-5wt%. Preferably, the concentration of the dissolving solution is one of 0.1wt%, 0.5wt%, 2wt% and 5wt%.

[0028] As a preferred embodiment, the pH of the dissolving solution before dissolution is 1-7.5, and the pH of the dissolving solution after dissolution is 3-8.

[0029] Preferably, the pH of the dissolving solution before dissolution is 3-7.5, and the pH of the dissolving solution after dissolution is 3-8.

[0030] The applicant further discovered that the multi-arm polyethylene glycol derivative carries negatively charged groups, and the ionic bonds with the polyamino compounds have different bonding strengths under different pH conditions. At a pH of 3-7.5, the water-soluble amino compounds can achieve rapid degradation of the gel system.

[0031] As a preferred embodiment, the dissolution time of the gel system in the hydrogel kit is 2-210 min.

[0032] As a preferred embodiment, the dissolution time of the gel system in the hydrogel kit is 2-30 min.

[0033] As a preferred embodiment, the dissolution temperature of the gel system in the hydrogel kit is 20-37°C.

[0034] As a preferred embodiment, the hydrogel kit that can be quickly dissolved on demand can be used to prepare one of tissue fillers, tissue anti-adhesion agents, tissue engineering scaffolds, sealants, embolic agents, drug carrier materials, skin dressings, radiotherapy gaskets, postoperative tissue sealing and anti-leakage agents, etc.

[0035] A second aspect of the present invention provides a method for using a hydrogel kit that can be rapidly dissolved on demand, comprising the following steps:

[0036] (1) mixing an aqueous solution of a polyethylene glycol aldehyde derivative and an aqueous solution of a polyamine in a corresponding volume ratio to form a gel system;

[0037] (2) mixing the gel system and the dissolving solution according to the volume ratio and adjusting the pH of the system;

[0038] (3) Test the degradation time.

[0039] Compared with the prior art, the present invention has the following beneficial effects:

[0040] (1) The hydrogel kit that can be quickly dissolved on demand described in the present invention combines an aldehyde-terminated star-shaped multi-arm polyethylene glycol gel system with a water-soluble amino compound dissolving solution to achieve rapid degradation of the gel within half an hour, thereby avoiding problems such as inflammation in the body after the gel has completed its functional requirements.

[0041] (2) The hydrogel kit capable of rapid dissolution on demand of the present invention controls the pH of the water-soluble amino compound solution to be 1-7.5, thereby achieving rapid degradation of the gel system at low temperature, and controlling the degradation time to be less than 30 min.

[0042] (3) The hydrogel kit of the present invention that can be quickly dissolved on demand can achieve rapid degradation within half an hour under mild temperature and mild acid-base environment, greatly broadening the application range of the gel and reducing the long-term foreign body irritation side effects on patients. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] FIG1 is a picture of the gel system of Example 17 before dissolution;

[0044] FIG2 is a picture of the gel system of Example 17 during dissolution;

[0045] FIG3 is a picture of the gel system of Example 17 after dissolution. DETAILED DESCRIPTION

[0046] Example

[0047] A hydrogel kit capable of rapid dissolution on demand and a method for using the kit comprise a gel system and a dissolving solution, wherein the volume ratio of the gel system to the dissolving solution is 1:5.

[0048] The gel system I comprises: 20 wt% polyethylene glycol benzaldehyde derivative solution and 5 wt% polyethyleneimine aqueous solution, with a volume ratio of 1:1.

[0049] The gel system II comprises: 20 wt% polyethylene glycol benzaldehyde derivative solution, 1.2 wt% polyethyleneimine aqueous solution and 2.6 wt% polylysine aqueous solution, with a volume ratio of 1:1:1.

[0050] The gel system III comprises: 20 wt% aldehyde oxidized dextran aqueous solution and 10 wt% polyethyleneimine aqueous solution, with a volume ratio of 1:1.

[0051] The gel system IV is composed of a mixed solution of 20 wt% aldehyde-oxidized dextran aqueous solution, 1.2 wt% polyethyleneimine and 2.6 wt% polylysine, with a volume ratio of 1:1:1.

[0052] The polyethylene glycol benzaldehyde derivative solution is a benzaldehyde-terminated, star-shaped, multi-arm polyethylene glycol solution with four arms and a weight-average molecular weight of 2000-5000 Da, purchased from Beijing Jiankai Technology Co., Ltd. The aldehyde-oxidized dextran was purchased from Shanghai Ruining Biotechnology Co., Ltd.; the polyethyleneimine was purchased from Shanghai Maclean Biochemical Co., Ltd.; and the polylysine was purchased from Shanghai Maclean Biochemical Co., Ltd.

[0053] The preparation of raw materials, process conditions used, and degradation time are shown in Table 1.

[0054] Table 1

[0055] PBS is a buffer solution of sodium dihydrogen phosphate and disodium hydrogen phosphate.

[0056] The gel of Gel System II degrades in PBS buffer at pH 7.4 for 90 days, maintaining its gel morphology and exhibiting a long degradation cycle. Adding an amino-containing acidic solution allows the gel to dissolve within 2-3 minutes, significantly expanding its application and mitigating long-term foreign body irritation side effects on patients.

[0057] The dissolution process of the gel system of Example 17 is shown in Figures 1-3.

Claims

1. A hydrogel kit that can be quickly dissolved on demand, characterized in that: It comprises a gel system and a dissolving solution, wherein the volume ratio of the gel system to the dissolving solution is 1:(2-10).

2. The hydrogel kit that can be quickly dissolved on demand according to claim 1, characterized in that: The gel system comprises an aldehyde derivative aqueous solution and a polyamine aqueous solution, and the volume ratio of the aldehyde derivative aqueous solution to the polyamine aqueous solution is 1:(0-10).

3. The hydrogel kit that can be quickly dissolved on demand according to claim 2, characterized in that: The aldehyde derivative aqueous solution is selected from a combination of one or more of a polyethylene glycol aldehyde derivative aqueous solution, an aldehyde-oxidized sodium carboxymethyl cellulose aqueous solution, an aldehyde-oxidized sodium alginate aqueous solution, and an aldehyde-oxidized dextran aqueous solution. The polyethylene glycol aldehyde derivative aqueous solution is an aldehyde-terminated star-shaped multi-arm polyethylene glycol, and the number of arms of the aldehyde-terminated star-shaped multi-arm polyethylene glycol is 4-8.

4. The hydrogel kit that can be quickly dissolved on demand according to claim 2, characterized in that: The mass fraction of the polyethylene glycol aldehyde derivative aqueous solution is 5-50%; the mass fraction of the polyamine aqueous solution is 0.5-30%.

5. The hydrogel kit capable of rapid dissolution on demand according to claim 2, characterized in that: The polyamino aqueous solution is selected from a polyethyleneimine aqueous solution, a polylysine aqueous solution, or a combination of the two.

6. The hydrogel kit capable of rapid dissolution on demand according to claim 5, characterized in that: The mass fraction of the polyethyleneimine aqueous solution is 0.5-10%, and the mass fraction of the polylysine aqueous solution is 1-30%.

7. The hydrogel kit capable of rapid dissolution on demand according to claim 5, characterized in that: The dissolving liquid is selected from one or a combination of hydroxylamine hydrochloride aqueous solution, amino acid aqueous solution, and short peptide aqueous solution.

8. The hydrogel kit capable of rapid dissolution on demand according to claim 5, characterized in that: The pH of the dissolving solution before dissolution is 1-7.5, and the pH of the dissolving solution after dissolution is 3-8.

9. The hydrogel kit capable of rapid dissolution on demand according to claim 5, characterized in that: The dissolution time of the gel system in the hydrogel kit is 2-210 min.

10. A method for using the hydrogel kit that can be quickly dissolved on demand according to any one of claims 2 to 9, characterized in that: The following steps are involved: (1) mixing an aqueous solution of a polyethylene glycol aldehyde derivative and an aqueous solution of a polyamine in a corresponding volume ratio to form a gel system; (2) mixing the gel system and the dissolving solution according to a volume ratio and adjusting the pH of the system; (3) Test the degradation time.

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