A rapid-dissolve-on-demand hydrogel kit and methods of use thereof

Abstract

The application discloses a hydrogel kit capable of quick dissolution on demand, comprising a gel system and a dissolving solution, and the volume ratio of the gel system to the dissolving solution is 1:(2-10). The aldehyde group-terminated star-shaped multi-arm polyethylene glycol gel system and the dissolving solution of the water-soluble amino compound jointly act, so that the gel can be quickly degraded, the gel degradation is realized within half an hour, and the problem that inflammation is caused to the body after the gel is completed is avoided. Moreover, the pH of the water-soluble amino compound dissolving solution is controlled to be 3-7.5, the low-temperature quick degradation of the gel system can be realized, and the degradation time is controlled to be less than 30 min. The application range of the gel is greatly widened, and the long-term foreign body stimulation side effect on patients is reduced.

Description

TECHNICAL FIELD

[0001] The present application relates to a water gel kit that can be quickly dissolved on demand and a method for using the same, relates to A61L, and in particular to the field of medical formulations. BACKGROUND

[0002] Water gel is a high-molecular-weight material with high water content and good biocompatibility. In recent years, it has been gradually applied in the medical field. Due to its good biocompatibility, water gel is widely used in tissue isolation, tissue repair, drug release, wound auxiliary materials, medical aesthetics, and scar repair. Due to the gel properties of water gel, its degradation rate in the body is relatively slow. If the gel cannot be quickly removed after completing the functional task, it will exist in the body for a long time, which may cause inflammation caused by foreign bodies in the body. In addition, in the fields of tissue isolation, wound auxiliary materials, and scar repair, the gel needs to be quickly removed after completing the functional task, otherwise it will affect the further repair and growth of the body tissue. When water gel is applied in vivo and in vitro, it may also deviate from the implanted position and need to be removed. However, due to the reasons such as the minimally invasive in-situ injection method used when most water gels are implanted or the strong adhesion between the gel and the tissue at the implantation site, the resistance of the water gel is relatively large when it is removed. Therefore, how to quickly and non-destructively remove the water gel is a technical problem that needs to be solved in clinical applications.

[0003] Chinese invention patent CN115737535A discloses a controllable degradable nano composite gel and its preparation method and application. The amino phenyl boronic acid modified hyaluronic acid cross-linked polyvinyl alcohol / water gel-liposome realizes automatic degradation after completing the release of nano drugs by dynamically adjusting the internal configuration change through the amino phenyl borate covalent bond and the hyaluronic acid skeleton under the action of hydrolysis, and realizes precise treatment in clinical practice. However, the nano composite gel needs a long degradation time and has the risk of foreign body inflammation. Chinese invention patent CN202011119562.X discloses a degradable medical water gel. By using an aldehyde-terminated star-shaped multi-arm polyethylene glycol, the number of arms and the molecular weight range of the star-shaped multi-arm polyethylene glycol are optimized to obtain a water gel that can be degraded in a short period of time. However, the degradation still needs several days to one year, and the degradation speed is slow. SUMMARY

[0004] In order to improve the degradation speed of the water gel and realize quick and non-destructive dissolution, the first aspect of the present application provides a water gel kit that can be quickly dissolved on demand, which comprises a gel system and a dissolving solution, and the volume ratio of the gel system to the dissolving solution is 1:(2-10).

[0005] As a preferred embodiment, the gel system comprises an aldehyde derivative aqueous solution and a multi-amino aqueous solution, and the volume ratio of the aldehyde derivative aqueous solution to the multi-amino aqueous solution is 1:(0-10).

[0006] As a preferred embodiment, the volume ratio of the aldehyde derivative aqueous solution and the polyamino aqueous solution is 1:(0.5-2).

[0007] As a preferred embodiment, the aldehyde derivative aqueous solution is selected from the group consisting of one or more of a combination of polyethylene glycol aldehyde derivative aqueous solution, oxidized sodium carboxymethyl cellulose aqueous solution, oxidized sodium alginate aqueous solution, and oxidized sodium dextran sulfate aqueous solution.

[0008] As a preferred embodiment, 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.

[0009] As a preferred embodiment, the weight average molecular weight of the aldehyde-terminated star-shaped multi-arm polyethylene glycol is 2000-5000 Da.

[0010] As a preferred embodiment, the aldehyde group is selected from the group consisting of one or a combination of aromatic aldehyde group and alkyl aldehyde group. Further preferably, the aldehyde group is a benzaldehyde group.

[0011] As a preferred embodiment, the aldehyde group is combined with the star-shaped multi-arm polyethylene glycol by using one or a combination of ether bond, amide bond, urethane bond, imine bond, and urea bond.

[0012] As a preferred embodiment, the mass fraction of the polyethylene glycol aldehyde derivative aqueous solution is 5-50%, and the mass fraction of the polyamino aqueous solution is 0.5-30%.

[0013] As a preferred embodiment, the mass fraction of the polyethylene glycol benzaldehyde derivative aqueous solution is 15-30%, and the mass fraction of the polyamino aqueous solution is 1-6%.

[0014] As a preferred embodiment, the mass fraction of the polyethylene glycol benzaldehyde derivative aqueous solution is 20-25%, and the mass fraction of the polyamino aqueous solution is 1-5%.

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

[0016] As a preferred embodiment, the polyamino aqueous solution is selected from the group consisting of one or a combination of polyethyleneimine aqueous solution and polylysine aqueous solution.

[0017] 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%.

[0018] 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%.

[0019] 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%.

[0020] As a preferred embodiment, when the polyamino aqueous solution only contains 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.

[0021] As a preferred embodiment, when the polyamino aqueous solution contains a combination of the polyethyleneimine aqueous solution and the 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%. The volume ratio of the polyethylene glycol aldehyde derivative aqueous solution to the polyethyleneimine aqueous solution to the polylysine aqueous solution in the gel system is 1:1:1.

[0022] The applicant found in the experiment that the gel system and the dissolving solution of the water-soluble amino compound are jointly used, and in a certain acid-base environment, the gel can be quickly degraded within half an hour, thereby avoiding the problem that after the gel is completed, inflammation to the body still exists. It is speculated that the possible reason is that after the aldehyde-terminated multi-arm polyethylene glycol derivative and the polyamino compound form a Schiff base reaction to form an amide bond cross-linked gel network, the cross-linking point in the gel network is a dynamic amide bond, by introducing the dissolving solution of the water-soluble amino compound, in a suitable acid-base environment, a single molecule of amino can break the dynamic amide bond, so that the cross-linked network structure is disconnected and dissolved in the dissolving solution and discharged out of the body.

[0023] As a preferred embodiment, the dissolving solution is selected from one or a combination of several of hydroxylamine hydrochloride aqueous solution, amino acid aqueous solution, and short peptide aqueous solution.

[0024] As a preferred embodiment, the dissolving solution is selected from one of hydroxylamine hydrochloride aqueous solution, glycine aqueous solution, and lysine aqueous solution.

[0025] As a preferred embodiment, the dissolving solution is hydroxylamine hydrochloride aqueous solution; preferably, the dissolving solution is glycine aqueous solution, and preferably, the dissolving solution is lysine aqueous solution.

[0026] As a preferred embodiment, the concentration of the dissolving solution is 0.1-5wt%, and preferably, the concentration of the dissolving solution is one of 0.1wt%, 0.5wt%, 2wt%, and 5wt%.

[0027] As a preferred embodiment, the pH of the dissolving solution before dissolving is 1-7.5, and the pH of the dissolving solution after dissolving is 3-8.

[0028] Preferably, the pH of the dissolving solution before dissolving is 3-7.5, and the pH of the dissolving solution after dissolving is 3-8.

[0029] The applicant further found that the multi-arm polyethylene glycol derivative has a negative group, and the ionic bond with the polyamino compound has different bond strengths under different pH conditions. Under the pH of 3-7.5, the water-soluble amino compound can achieve rapid degradation of the gel system.

[0030] As a preferred embodiment, the dissolving time of the gel system in the hydrogel kit is 2-210 min.

[0031] As a preferred embodiment, the dissolving time of the gel system in the hydrogel kit is 2-30 min.

[0032] As a preferred embodiment, the dissolving temperature of the gel system in the hydrogel kit is 20-37℃.

[0033] As a preferred embodiment, the on-demand fast-dissolving hydrogel kit can be applied to one of the following: tissue filler, tissue anti-adhesion agent, tissue engineering scaffold, sealing agent, embolization agent, drug carrier material, skin dressing, radiotherapy pad, postoperative tissue sealing and anti-leakage agent, etc.

[0034] The second aspect of the present application provides a use method of the on-demand fast-dissolving hydrogel kit, comprising the following steps:

[0035] (1) mixing the polyethylene glycol aldehyde derivative aqueous solution and the polyamino aqueous solution according to the corresponding volume ratio to form a gel system;

[0036] (2) mixing the gel system with the dissolving solution according to the volume ratio to adjust the pH of the system;

[0037] (3) testing the degradation time, and it is ready.

[0038] Compared with the prior art, the present application has the following beneficial effects:

[0039] (1) The on-demand fast-dissolving hydrogel kit can realize rapid degradation of the gel by the combined action of the aldehyde-terminated star-shaped multi-arm polyethylene glycol gel system and the dissolving solution of the water-soluble amino compound, and the gel degradation is realized within half an hour, avoiding the problem that the gel still exists after the functional requirement is met, causing inflammation to the body, etc.

[0040] (2) The on-demand fast-dissolving hydrogel kit can control the pH of the water-soluble amino compound solution to be 1-7.5, so that the gel system can be degraded at low temperature in a short time, and the degradation time is less than 30 min.

[0041] (3) The on-demand fast-dissolving hydrogel kit can be degraded in a short time under mild temperature and mild acid-base environment within half an hour, which greatly expands the application range of the gel and reduces the long-term foreign body stimulation side effects on patients. BRIEF DESCRIPTION OF DRAWINGS

[0042] Fig. 1 Picture before the dissolution of the gel system of Example 17;

[0043] Fig. 2 Picture during the dissolution of the gel system of Example 17;

[0044] Fig. 3 Picture after the dissolution of the gel system of Example 17. DETAILED DESCRIPTION

[0045] EMBODIMENT

[0046] An on-demand fast-dissolving hydrogel kit and a method for using the same, comprising a gel system and a dissolving solution, wherein the volume ratio of the gel system to the dissolving solution is 1:5.

[0047] The gel system I is 20wt% polyethylene glycol benzaldehyde derivative solution and 5wt% polyethyleneimine aqueous solution, with a volume ratio of 1:1.

[0048] The gel system II is 20wt% polyethylene glycol benzaldehyde derivative solution, 1.2wt% polyethyleneimine aqueous solution and 2.6wt% polylysine aqueous solution, with a volume ratio of 1:1:1.

[0049] The gel system III is 20wt% aldehyde-based oxidized dextran aqueous solution and 10wt% polyethyleneimine aqueous solution, with a volume ratio of 1:1.

[0050] The gel system IV is 20wt% aldehyde-based oxidized dextran aqueous solution, 1.2wt% polyethyleneimine and 2.6wt% polylysine mixed solution, with a volume ratio of 1:1:1.

[0051] The polyethylene glycol benzaldehyde derivative solution is a star-shaped multi-arm polyethylene glycol solution capped with a benzaldehyde group, with an arm number of 4 and a weight average molecular weight of 2000-5000 Da, which is purchased from Beijing Keygen Technology Co., Ltd. The aldehyde-based oxidized dextran is purchased from Shanghai Ruining Biological Technology Co., Ltd.; the polyethyleneimine is purchased from Shanghai Maikelin Biochemical Co., Ltd. The polylysine is purchased from Shanghai Maikelin Biochemical Co., Ltd.

[0052] The raw materials, process conditions and degradation time are shown in Table 1.

[0053] Table 1

[0054]

[0055]

[0056]

[0057] PBS is a buffer solution of sodium dihydrogen phosphate and disodium hydrogen phosphate.

[0058] The gel of the gel system II can maintain the gel form for 90 days in PBS buffer solution at pH 7.4, and has a long degradation period. After adding an acidic solution containing amino groups, the gel can be dissolved within 2-3 minutes, greatly expanding the application range of the gel and reducing the long-term foreign body irritation side effects on patients.

[0059] The dissolution process of the gel system of Example 17 is shown in the attached Figs. 1-3 .

Claims

1. A hydrogel kit that can be rapidly dissolved on demand, characterized in that, It includes a gel system and a solution, wherein the volume ratio of the gel system to the solution is 1:(2-10). The gel system comprises an aqueous solution of an aldehyde derivative and an aqueous solution of a polyamino group, wherein the volume ratio of the aqueous solution of the aldehyde derivative to the aqueous solution of the polyamino group is 1:(0.5-2). The aldehyde derivative aqueous solution is selected from one or more of the following: polyethylene glycol aldehyde derivative aqueous solution, aldehyde-oxidized sodium carboxymethyl cellulose aqueous solution, aldehyde-oxidized sodium alginate aqueous solution, and aldehyde-oxidized dextran aqueous solution. 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. The solution is selected from one of the following: hydroxylamine hydrochloride aqueous solution, glycine aqueous solution, and lysine aqueous solution; The pH of the solution before dissolution is 1-7.5, and the pH of the solution after dissolution is 3-8.

2. The on-demand, rapidly dissolving hydrogel kit according to claim 1, characterized in that, The mass fraction of the polyethylene glycol aldehyde derivative aqueous solution is 5-50%; the mass fraction of the polyamino aqueous solution is 0.5-30%.

3. The on-demand, rapidly dissolving hydrogel kit according to claim 1, characterized in that, The polyamino aqueous solution is selected from one or a combination of two of polyethyleneimine aqueous solution and polylysine aqueous solution.

4. The on-demand, rapidly dissolving hydrogel kit according to claim 3, characterized in that, The polyethyleneimine aqueous solution has a mass fraction of 0.5-10%, and the polylysine aqueous solution has a mass fraction of 1-30%.

5. A method of using a hydrogel kit that can be rapidly dissolved on demand according to any one of claims 1-4, characterized in that, Includes the following steps: (1) Mix the aqueous solution of polyethylene glycol aldehyde derivative and the aqueous solution of polyamino group in the corresponding volume ratio to form a gel system; (2) Mix the gel system and the dissolving solution at the volume ratio and adjust the pH of the system; (3) Test the degradation time.

Images