Developable hydrogel and method of making the same

Abstract

The present application relates to a kind of visible hydrogel, the iodine-containing polyethylene glycol in the first phase solution is 4 arm-polyethylene glycol-2,3,5-triiodo-benzamide-succinimidyl glutarate or 4 arm-polyethylene glycol-2,4,6 triiodo-benzamide-succinimidyl glutarate or 8 arm-polyethylene glycol-2,3,5-triiodo-benzamide-succinimidyl glutarate or 8 arm-polyethylene glycol-2,4,6-triiodo-benzamide-succinimidyl glutarate, the amino compound in the second phase solution is tri-l-lysine, polyethyleneimine, four arm amino polyethylene glycol or eight arm amino polyethylene glycol.The present application also relates to the preparation method of the above-mentioned visible hydrogel.The visible hydrogel according to the present application is two different liquids, i.e.the first phase solution and the second phase solution, before polymerization, after mixing two liquids, polymerization into hydrogel when using, can be closely fitted with tissue and can be developed under X-ray.

Description

TECHNICAL FIELD

[0001] The present application relates to biomaterials, and more particularly to a visualizable hydrogel and a preparation method thereof. BACKGROUND

[0002] A hydrogel is a kind of polymer with a three-dimensional network structure of hydrophilic groups. Due to the physical cross-linking and chemical cross-linking between polymers, the hydrogel can be swollen, but is not soluble in water, and can maintain a certain shape. At the same time, the hydrogel has excellent physicochemical properties and biological characteristics, such as biocompatibility, high elasticity, swelling, etc., and is widely used in the fields of medicine, tissue engineering and medical devices.

[0003] Materials that can be used to prepare hydrogels include chitosan, alginate, polyethylene glycol, etc. Polyethylene glycol is a high molecular polymer, which has good biocompatibility and safety and can be used as a pharmaceutical excipient. Modification of the end groups of polyethylene glycol increases its performance of forming a hydrogel and retains the original safety properties of polyethylene glycol, making it an ideal hydrogel material.

[0004] There are reports of using polyethylene glycol succinimidyl ester and polylysine and polyethyleneimine to form a hydrogel, and there are also methods of using aldehyde-terminated polyethylene glycol and amino polyethylene glycol to polymerize into a hydrogel. However, the above hydrogels do not have the function and characteristics of being visualizable under X-rays. When doctors use them, they cannot observe the implantation position of the hydrogel in real time, which puts high requirements on the operation level of the doctors, and the patients also bear greater risks of ectopic implantation. SUMMARY

[0005] In order to solve the problem of the hydrogel in the prior art not being visualizable under X-rays, the present application provides a visualizable hydrogel and a preparation method thereof.

[0006] The developable hydrogel according to the present invention is polymerized from a first phase solution and a second phase solution. The first phase solution is formed by dissolving iodinated polyethylene glycol (PEG-TIBSG) in a first buffer solution. The iodinated polyethylene glycol (PEG-TIBSG) is either a four-armed iodinated polyethylene glycol (4-arm-PEG-TIBSG) or an eight-armed iodinated polyethylene glycol (8-arm-PEG-TIBSG). The four-armed iodinated polyethylene glycol (4-arm-PEG-TIBSG) is either 4-arm-polyethylene glycol-2,3,5-triiodobenzamide-succinimide glutarate or 4-arm-polyethylene glycol-2,4,6-triiodobenzamide-succinimide glutarate. The octyl-2,3,5-triiodobenzamide-succinimide glutarate or octyl-2,4,6-triiodobenzamide-succinimide glutarate is formed by dissolving an amino compound in a second buffer solution. The amino compound is trilysine, polyethyleneimine, or amino polyethylene glycol (PEG-NH2), wherein the amino polyethylene glycol (PEG-NH2) is a tetra-arm amino polyethylene glycol (4-arm-PEG-NH2) or an octyl-arm amino polyethylene glycol (8-arm-PEG-NH2).

[0007] Through extensive inventive effort, the inventors of this application ultimately selected 4-arm polyethylene glycol-2,3,5-triiodobenzamide-succinimide glutarate or 4-arm polyethylene glycol-2,4,6-triiodobenzamide-succinimide glutarate or 8-arm polyethylene glycol-2,3,5-triiodobenzamide-succinimide glutarate or 8-arm polyethylene glycol-2,4,6-triiodobenzamide-succinimide glutarate in the first phase solution and trilysine, polyethyleneimine, tetra-arm amino polyethylene glycol (4-arm-PEG-NH2) or octa-arm amino polyethylene glycol (8-arm-PEG-NH2) in the second phase solution to polymerize a hydrogel that can be visualized under X-rays.

[0008] Preferably, the molar ratio of the iodine-containing group in the iodine-containing polyethylene glycol to the amino group in the amino compound is between 1:1 and 3.

[0009] Preferably, iodine-containing groups are grafted onto 1-2 arms of the four-arm iodine-containing polyethylene glycol (4-arm-PEG-TIBSG), and iodine-containing groups are grafted onto 1-4 arms of the eight-arm iodine-containing polyethylene glycol (8-arm-PEG-TIBSG).

[0010] Preferably, the mass percentage concentration of the first phase solution is between 1.0% and 20%.

[0011] Preferably, the pH of the first buffer solution is 5.0-7.0.

[0012] Preferably, the second phase solution has a mass percentage concentration of 1.0% to 20%.

[0013] Preferably, the second buffer solution has a pH of 7.5 to 10.0.

[0014] Preferably, the iodine-containing polyethylene glycol (PEG-TIBSG) has a molecular weight of 5K to 20K.

[0015] Preferably, the amino polyethylene glycol (PEG-NH2) has a molecular weight of 5K to 20K.

[0016] The preparation method of the visualizable hydrogel according to the present application comprises transporting the first phase solution and the second phase solution to a position to be polymerized through a double-cavity microcatheter respectively, and the first phase solution and the second phase solution are polymerized into a hydrogel after mixing at the position.

[0017] Preferably, the polymerization time is 3 to 20 seconds.

[0018] The visualizable hydrogel according to the present application can be used for isolation protection during radiotherapy of prostate cancer. During radiotherapy, rays will pass through cancer tissues, and there will be inevitable radiation damage to adjacent normal tissues, such as rectum. However, a hydrogel spacer formed between the prostate and the rectum can effectively block excess rays and prevent normal tissues from being damaged by radiation. It should be understood that the visualizable hydrogel according to the present application can also be used for isolation protection during radiotherapy of cervical cancer, etc., by setting the position to be polymerized as the position to be isolated.

[0019] The visualizable hydrogel according to the present application is two different liquids, i.e. the first phase solution and the second phase solution, before polymerization. After mixing the two liquids during use, the visualizable hydrogel is cross-linked and polymerized into a hydrogel. The polymerized hydrogel has high elasticity and can closely adhere to tissues. The polymerized hydrogel can be developed under X-rays. When used under X-rays, doctors can observe the implantation rate and implantation site of the hydrogel in real time, greatly reducing the risk of ectopic implantation. DETAILED DESCRIPTION

[0020] The preferred embodiments of the present application are described below and in detail.

[0021] Example 1

[0022] configuring a first phase solution

[0023] First, a first buffer solution having a pH of 5.0-7.0 is prepared using sodium dihydrogen phosphate, 10% phosphoric acid, and purified water. Then, the iodine-containing polyethylene glycol (PEG-TIBSG) is weighed in the amounts shown in Table 1 below, dissolved in the first buffer solution, and a first phase solution having a mass percentage concentration of 1.0-20% is prepared.

[0024] In Examples 1-13, the iodine-containing polyethylene glycol (PEG-TIBSG) is a four-armed iodine-containing polyethylene glycol (4-arm-PEG-TIBSG) having 1-2 arms to which an iodine-containing group (2,3,5-triiodo-benzamide or 2,4,6-triiodo-benzamide) is attached, such as 4-arm-polyethylene glycol-2,3,5-triiodo-benzamide-succinimidyl glutarate or 4-arm-polyethylene glycol-2,4,6-triiodo-benzamide-succinimidyl glutarate, having the following formula:

[0025]

[0026] wherein R1 is pentaerythritol, n = 1-250, m1 = 2-3, and m2 = 1-2.

[0027] In Examples 14-25, the iodine-containing polyethylene glycol (PEG-TIBSG) is an eight-armed iodine-containing polyethylene glycol (8-arm-PEG-TIBSG) having 1-4 arms to which an iodine-containing group (2,3,5-triiodo-benzamide or 2,4,6-triiodo-benzamide) is attached, such as 8-arm-polyethylene glycol-2,3,5-triiodo-benzamide-succinimidyl glutarate or 8-arm-polyethylene glycol-2,4,6-triiodo-benzamide-succinimidyl glutarate, having the following formula:

[0028]

[0029]

[0030] wherein R2 is tri-pentaerythritol, n = 1-250, m3 = 4-5, and m4 = 3-4.

[0031] configuring a second phase solution

[0032] First, a second buffer solution having a pH of 7.5-10.0 is prepared using sodium tetraborate and 10% phosphoric acid or 20% sodium hydroxide. Then, an amino compound is weighed in the amounts shown in Table 1 below, dissolved in the second buffer solution, and a second phase solution having a mass percentage concentration of 1.0-20% is prepared.

[0033] In Examples 1-4 and Examples 14-17, the amino compound is trilysine.

[0034] In Examples 5-8 and 18-21, the amino compound is polyethyleneimine.

[0035] In Examples 9-13 and 22-25, the amino compound is amino polyethylene glycol (PEG-NH2), such as tetra-armed amino polyethylene glycol (4-arm-PEG-NH2) or octa-armed amino polyethylene glycol (8-arm-PEG-NH2).

[0036] preparing a hydrogel

[0037] The 2.0 ml of the first phase solution was drawn into a 3 ml first syringe, and the 2.0 ml of the second phase solution was drawn into a 3 ml second syringe. The first and second syringes were connected to the double-lumen microcatheter, respectively, and the plunger of the syringes was pushed to make the solution flow out of the distal end of the double-lumen microcatheter and then polymerize into a hydrogel. The hydrogel was observed under X-ray and developed, respectively, and the results are shown in Table 1 below:

[0038] Table 1

[0039]

[0040]

[0041] Comparative Example 1

[0042] configuring a first phase solution

[0043] First, a first buffer solution having a pH of 5.0-7.0 was prepared using sodium dihydrogen phosphate, 10% phosphoric acid, and purified water. Then, polyethylene glycol succinimidyl glutarate (PEG-SG) was weighed according to the amounts in Table 2, dissolved in the first buffer solution, and prepared into a first phase solution having a mass percentage concentration of 1.0%-20%.

[0044] In Examples 26-30, the polyethylene glycol succinimidyl glutarate (PEG-SG) is tetra-armed polyethylene glycol (4-arm-PEG-SG).

[0045] In Examples 31-36, the polyethylene glycol succinimidyl glutarate (PEG-SG) is octa-armed polyethylene glycol (8-arm-PEG-SG).

[0046] configuring a second phase solution

[0047] First, a second buffer solution having a pH of 7.5-10.0 was prepared using sodium tetraborate and 10% phosphoric acid or 20% sodium hydroxide. Then, an amino compound was weighed according to the amounts in Table 2, dissolved in the second buffer solution, and prepared into a second phase solution having a mass percentage concentration of 1.0%-20%.

[0048] In Example 26 and Example 31, the amino compound is trilysine.

[0049] In Example 27 and Example 32, the amino compound is polyethyleneimine.

[0050] In Example 28-Example 30 and Example 33, the amino compound is aminopolyethylene glycol (PEG-NH2), such as tetra-armed aminopolyethylene glycol (4-arm-PEG-NH2) or octa-armed aminopolyethylene glycol (8-arm-PEG-NH2).

[0051] preparing a hydrogel

[0052] The 2.0 ml of the first phase solution was drawn into a 3 ml first syringe, and the 2.0 ml of the second phase solution was drawn into a 3 ml second syringe. The first and second syringes were connected to a double-lumen microcatheter, respectively, and the plunger of the syringes was pushed, so that the solution flowed out of the distal end of the double-lumen microcatheter and then polymerized into a hydrogel. The hydrogel was observed under X-ray and developed, respectively, and the results are shown in Table 2 below:

[0053] Table 2

[0054]

[0055] Comparative Example 2

[0056] configuring a first phase solution

[0057] First, a first buffer solution having a pH of 5.0-7.0 was prepared using sodium dihydrogen phosphate, 10% phosphoric acid, and purified water. Then, iodine-containing polyethylene glycol (PEG-I-SG) was weighed according to the amounts in Table 3 below, dissolved in the first buffer solution, and prepared into a first phase solution having a mass percentage concentration of 1.0%-20%.

[0058] In Example 37-Example 41, the iodine-containing polyethylene glycol (PEG-I-SG) is tetra-armed iodine-containing polyethylene glycol (4-arm-PEG-I-SG), which is 4-arm-polyethylene glycol-iodo-succinimidyl glutarate, and has the following formula:

[0059]

[0060] wherein R1 is pentaerythritol, n = 1-250, m1 = 2-3, and m2 = 1-2.

[0061] In Example 42-Example 47, the iodine-containing polyethylene glycol (PEG-I-SG) is octa-armed iodine-containing polyethylene glycol (8-arm-PEG-I-SG), which is 8-arm-polyethylene glycol-iodo-succinimidyl glutarate, and has the following formula:

[0062]

[0063] wherein R2 is tripentaerythritol, n = 1-250, m3 = 4-5, m4 = 3-4.

[0064] configuring a second phase solution

[0065] First, sodium tetraborate is prepared with 10% phosphoric acid or 20% sodium hydroxide to make a second buffer solution with pH = 7.5-10.0. Then, the amino compound is weighed according to the following Table 3, dissolved in the second buffer solution, and prepared into a second phase solution with a mass percentage concentration of 1.0%-20%.

[0066] In Example 37 and Example 42, the amino compound is trilysine.

[0067] In Example 38 and Example 43, the amino compound is polyethyleneimine.

[0068] In Example 39-Example 41 and Example 44-Example 47, the amino compound is amino polyethylene glycol (PEG-NH2), such as four-arm amino polyethylene glycol (4-arm-PEG-NH2) or eight-arm amino polyethylene glycol (8-arm-PEG-NH2).

[0069] preparing a hydrogel

[0070] 2.0 ml of the first phase solution is extracted into a 3 ml first syringe, 2.0 ml of the second phase solution is extracted into a 3 ml second syringe, the first and second syringes are respectively connected with a double-lumen microcatheter, and the syringe plunger is pushed to make the solution flow out of the distal end of the double-lumen microcatheter, and then polymerize into a hydrogel. The hydrogel is respectively placed under X-ray observation, developed, and the results are shown in the following Table 3:

[0071] Table 3

[0072]

[0073] The above description is only a preferred embodiment of the present application, and is not intended to limit the scope of the present application. The above-described embodiments of the present application can be variously changed. Any simple, equivalent changes and modifications made in accordance with the content of the claims and the specification of the present application are within the scope of the present application. The present application is not described in detail, and is a routine technical content.

Claims

1. A developable hydrogel, characterized in that, The developable hydrogel is polymerized from a first phase solution and a second phase solution. The first phase solution is formed by dissolving iodine-containing polyethylene glycol in a first buffer solution. The iodine-containing polyethylene glycol is either 4-arm polyethylene glycol-2,4,6-triiodobenzamide-succinimide glutarate or 8-arm polyethylene glycol-2,4,6-triiodobenzamide-succinimide glutarate. The second phase solution is formed by dissolving an amino compound in a second buffer solution. The amino compound is either trilysine, polyethyleneimine, or amino polyethylene glycol. The amino polyethylene glycol is either 4-arm amino polyethylene glycol or 8-arm amino polyethylene glycol.

2. The developable hydrogel according to claim 1, characterized in that, The molar ratio of the iodine-containing group in the iodine-containing polyethylene glycol to the amino group in the amino compound is between 1:1 and 3.

3. The developable hydrogel according to claim 1, characterized in that, For four-arm iodine-containing polyethylene glycol, 1-2 arms are grafted with iodine-containing groups; for eight-arm iodine-containing polyethylene glycol, 1-4 arms are grafted with iodine-containing groups.

4. The developable hydrogel according to claim 1, characterized in that, The mass percentage concentration of the first phase solution is between 1.0% and 20%.

5. The developable hydrogel according to claim 1, characterized in that, The pH of the first buffer solution is 5.0-7.

0.

6. The developable hydrogel according to claim 1, characterized in that, The mass percentage concentration of the second phase solution is between 1.0% and 20%.

7. The developable hydrogel according to claim 1, characterized in that, The pH of the second buffer solution is 7.5-10.

0.

8. A method for preparing a developable hydrogel according to any one of claims 1-7, characterized in that, The preparation method involves delivering a first-phase solution and a second-phase solution to the polymerization site via a dual-lumen microcatheter, where the first-phase solution and the second-phase solution are mixed and polymerized into a hydrogel.

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