MEDICAL HYDROGEL HAVING RADIATION PROTECTION FUNCTION

Abstract

A medical hydrogel is formed by in-situ crosslinking an aldehyde-terminated multi-arm star polyethylene glycol and a polyamino compound. The aldehyde group and the multi-arm star polyethylene glycol are linked by a chemical bond such as an ether bond, an amide bond, an ester bond, a urethane bond, an imine bond, or a urea bond. The molar ratio of the amino in the polyamino compound to the aldehyde group in the aldehyde-terminated multi-arm star polyethylene glycol is 0.4-4.4:1. The polyamino compound is polylysine or a mixture of polylysine and polyethylenimine in a molar ratio of 2-30:3.

Claims

1. A medical hydrogel, formed by in-situ crosslinking an aldehyde-terminated multi-arm star polyethylene glycol and a polyamino compound, wherein the aldehyde group and the multi-arm star polyethylene glycol are linked by a chemical bond such as an ether bond, an amide bond, an ester bond, a urethane bond, an imine bond, or a urea bond, and the molar ratio of the amino in the polyamino compound to the aldehyde group in the aldehyde-terminated multi-arm star polyethylene glycol is 0.4-4.4:1, and the polyamino compound is polylysine or a mixture of polylysine and polyethylenimine in a molar ratio of 2-30:3.

2. The medical hydrogel according to claim 1, wherein the aldehyde-terminated multi-arm star polyethylene glycol is a multi-arm polyethylene glycol with more than 2 arms and a molecular weight of greater than 2000.

3. The medical hydrogel according to claim 1, wherein the aldehyde-terminated multi-arm star polyethylene glycol has 2-8 arms.

4. The medical hydrogel according to claim 1, wherein the aldehyde group is selected from one or more of aromatic aldehydes and alkyl aldehydes.

5. Use of the medical hydrogel according to claim 1 in the preparation of a radiation protection material.

6. A method for preparing the medical hydrogel according to claim 1, comprising: dissolving the aldehyde-terminated multi-arm star polyethylene glycol in a pH 4-10 buffer to prepare an aldehyde-terminated multi-arm star polyethylene glycol solution; dissolving the polyamino compound in a pH 4-10 buffer to prepare a polyamino compound solution; and mixing the two solutions to obtain the medical hydrogel.

7. The method for preparing the medical hydrogel according to claim 6, wherein the aldehyde-terminated multi-arm star polyethylene glycol solution has a final concentration of 2-30%, and the polyamino compound solution has a concentration of 0.5-20%.

8. The method for preparing the medical hydrogel according to claim 6, wherein the aldehyde-terminated multi-arm star polyethylene glycol solution has a final concentration of 10-20%, and the polyamino compound solution has a concentration of 1-5%.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0029] FIG. 1 is the observation results of the radiation stability of the hydrogel of the present invention; and

[0030] FIG. 2 shows the hydrogel used as a spacer between uterus and surrounding tissues.

DETAILED DESCRIPTION

[0031] The specific steps of the present invention are described by the following examples, but are not limited to the examples.

[0032] The terms used in the present invention, unless otherwise stated, generally have the meanings commonly understood by those of ordinary skill in the art.

[0033] The present invention is further described below in detail with reference to specific examples and relevant data. It should be understood that the examples are only used to exemplify the present invention, but do not limit the scope of the present invention in any manner.

[0034] In the following examples, various processes and methods that are not described in detail are conventional methods known in the art.

[0035] The present invention is further described below with reference to specific examples, but the protection scope of the present invention is not limited to this.

Example 1. Gelling Time and Stability in an Aqueous Solution of the Hydrogels with Different Compositions

[0036] 600 mg of an amide bond-linked benzaldehyde-terminated eight-arm polyethylene glycol (8-PEG-amide-BA, M.W. 13.5K) was dissolved in 2 mL of phosphate buffer (pH 7.4) to afford solution A. A solution of polylysine and polyethylenimine (M.W. 1.8K) with different contents in phosphate buffer was prepared as solution B. The solution A and the solution B were mixed in equal volume to obtain a viscous hydrogel. The ratios of the amounts of polyethylenimine and polylysine in Table 1 are expressed as the molar ratios of their respective amino groups to the aldehyde group in the aldehyde-terminated multi-arm star polyethylene glycol.

TABLE-US-00001 TABLE 1 Molar Molar ratios ratios of amino in of amino in polylysine polyethylenimine to aldehyde to aldehyde group in Gelling group in 8-PEG- 8-PEG-amide- time Degradation Formulation amide-BA BA (s) time 1 1 0 2 less than 48 h 2 0.8 0.2 2 less than 24 h 3 0.6 0.4 3 more than 1 month 4 0.4 0.4 6 more than 1 month 5 0.4 0.6 5 more than 1 month 6 0.4 1 5 more than 1 month 7 0.4 2 5 more than 1 month 8 0.4 3 5 more than 1 month 9 0.4 4 5 more than 1 month 10 0.2 1 20 more than 1 month 11 0 0.4 35 more than 1 month 12 0 1 25 more than 1 month

[0037] The results show that the content of polylysine significantly affects the stability of the hydrogel in an aqueous solution, and when the molar ratio of the amino of polylysine to the aldehyde group of 8-PEG-amide-BA is greater than or equal to 0.4, the hydrogel can remain stable for more than one month. In addition, the content of polyethylenimine significantly affects the gelling speed, and when the molar ratio of the amino of polyethylenimine to the aldehyde group of 8-PEG-amide-BA is greater than or equal to 0.4, the gelling time is relatively short.

[0038] 400 mg of an ester bond-linked benzaldehyde-terminated eight-arm polyethylene glycol (8-PEG-ester-BA, M.W. 10K) was dissolved in 2 mL of phosphate buffer (pH 7.4) to afford solution A. A solution of polylysine and polyethylenimine (M.W. 1.8K) with different contents in phosphate buffer was prepared as solution B. The solution A and the solution B were mixed in equal volume to obtain a viscous hydrogel. The ratios of the amounts of polyethylenimine and polylysine in Table 2 are expressed as the molar ratios of their respective amino groups to the aldehyde group of the aldehyde-terminated multi-arm star polyethylene glycol.

TABLE-US-00002 TABLE 2 Molar ratios Molar ratios of amino in of amino in polyethylenimine polylysine to aldehyde to aldehyde Gelling group in 8-PEG- group in 8-PEG- time Degradation Formulation ester-BA ester-BA (s) time 1 1 0 3 less than 48 h 2 0.8 0.2 5 less than 24 h 3 0.6 0.4 10 more than 1 month 4 0.4 0.6 14 more than 1 month 5 0.4 1 14 more than 1 month 6 0.4 2 13 more than 1 month 7 0.4 3 15 more than 1 month

[0039] The results show that the content of polylysine significantly affects the stability of the hydrogel in an aqueous solution, and when the molar ratio of the amino of polylysine to the aldehyde group of 8-PEG-ester-BA is greater than or equal to 0.4, the hydrogel can remain stable for more than one month.

Example 2

[0040] 400 mg of an amide bond-linked benzaldehyde-terminated eight-arm polyethylene glycol (8-PEG-amide-BA, M.W. 10K) was dissolved in 2 mL of phosphate buffer (pH 7.4) to afford solution A. A solution of 2.44% (w/v) of polylysine (the ratio of amino to aldehyde group is 1:1) in borate buffer was prepared as solution B. The solution A and the solution B were mixed in equal volume to obtain a viscous hydrogel, which has a gelling time of 25 seconds, and can remain stable in vitro for more than 1 month.

Example 3

[0041] 600 mg of an amide bond-linked benzaldehyde-terminated eight-arm polyethylene glycol (8-PEG-amide-BA, M.W. 13.5K) was dissolved in 2 mL of phosphate buffer (pH 7.4) to afford solution A. A solution of 1.1% (w/v) of polylysine (the ratio of amino to aldehyde group is 0.4:1) in phosphate buffer was prepared as solution B. The solution A and the solution B were mixed in equal volume to obtain a viscous hydrogel, which has a gelling time of 35 seconds, and can remain stable in vitro for more than 1 month.

Example 4

[0042] 600 mg of an amide bond-linked benzaldehyde-terminated eight-arm polyethylene glycol (8-PEG-amide-BA, M.W. 13.5K) was dissolved in 2 mL of phosphate buffer (pH 7.4) to afford solution A. A solution of 2.71% (w/v) of polylysine (the ratio of amino to aldehyde group is 1:1) in phosphate buffer was prepared as solution B. The solution A and the solution B were mixed in equal volume to obtain a viscous hydrogel, which has a gelling time of 22 seconds, and can remain stable in vitro for more than 1 month.

Example 5

[0043] 600 mg of an ether bond-linked benzaldehyde-terminated eight-arm polyethylene glycol (8-PEG-amide-BA, M.W. 13.5K) was dissolved in 2 mL of phosphate buffer (pH 7.4) to afford solution A. A solution containing 2.75% (w/v) of polylysine (the ratio of amino to aldehyde group is 1:1) and 0.67% (w/v) of polyethylenimine (M.W. 1.8K) (the ratio of amino to aldehyde group is 0.4:1) in phosphate buffer was prepared as solution B. The solution A and the solution B were mixed in equal volume to obtain a viscous hydrogel, which has a gelling time of 5 seconds, and can remain stable in vitro for more than 1 month.

Example 6

[0044] 600 mg of an ether bond-linked benzaldehyde-terminated eight-arm polyethylene glycol (8-PEG-amide-BA, M.W. 13.5K) was dissolved in 2 mL of phosphate buffer (pH 7.4) to afford solution A. A solution containing 8.25% (w/v) of polylysine (the ratio of amino to aldehyde group is 3:1) and 0.67% (w/v) of polyethylenimine (M.W. 1.8K) (the ratio of amino to aldehyde group is 0.4:1) in phosphate buffer was prepared as solution B. The solution A and the solution B were mixed in equal volume to obtain a viscous hydrogel, which has a gelling time of 5 seconds, and can remain stable in vitro for more than 1 month.

Example 7

[0045] 400 mg of an ester bond-linked benzaldehyde-terminated eight-arm polyethylene glycol (8-PEG-ester-BA, M.W. 10K) was dissolved in 2 mL of phosphate buffer (pH 7.4) to afford solution A. A solution containing 2.44% (w/v) of polylysine and 0.59% (w/v) of polyethylenimine (M.W. 1.8K) in borate buffer was prepared as solution B. The solution A and the solution B were mixed in equal volume to obtain a viscous hydrogel, which has a gelling time of 15 seconds, and can remain stable in vitro for more than 1 month.

Example 8. Radiation Stability of Hydrogel

[0046] 600 mg of an amide bond/ether bond-linked benzaldehyde-terminated eight-arm polyethylene glycol (8-PEG-amide-BA, M.W. 13.5K) was dissolved in 2 mL of phosphate buffer (pH 7.4) to afford solution A. A solution containing 2.75% (w/v) of polylysine and 1.1% (w/v) of polyethylenimine (M.W. 1.8K) in borate buffer was prepared as solution B. 400 mg of an ester bond-linked benzaldehyde-terminated eight-arm polyethylene glycol (8-PEG-ester-BA, M.W. 10K) was dissolved in 2 mL of phosphate buffer (pH 7.4) to afford solution A. A solution containing 2.44% (w/v) of polylysine and 0.59% (w/v) of polyethylenimine (M.W. 1.8K) in borate buffer was prepared as solution B. The solution A and the solution B were mixed in equal volume to obtain a viscous hydrogel. The samples were prepared in triplicate, wherein sample 1 was not radiated, and the sample 1 and sample 2 were parallel samples. The sample 1 and sample 2 hydrogels were placed in PBS solution at 37 C. for 16 days. On the 16.sup.th day, the hydrogels were subject to three 8Gy radiations, and then were placed in PBS solution at 37 C. again. The experiment results are shown in FIG. 1 (FIG. 1A, FIG. 1B, and FIG. 1C respectively correspond to the observation results of the radiation stabilities of the hydrogels having an aldehyde group and a multi-arm star polyethylene glycol linked through an ether bond, an amide bond, and an ester bond). The results indicate that the hydrogel of the present invention has good radiation stability.

Example 9. Use of Hydrogel as a Spacer Between Uterus and Surrounding Tissues

[0047] The hydrogel solution A and hydrogel solution B of the present invention were mixed and injected around the uterus of a female rabbit with a mixed syringe. Once the mixed solution reached the outer wall of the uterus, it underwent a gelling reaction, and adhered to the outer wall of the uterus. Results are shown in FIG. 2. The results show that the hydrogel forms a physical barrier between the uterus and other organs (e.g., rectum and bladder), which can decrease the injuries to adjacent tissues during radiotherapy of uterus tumors.