In-situ cross-linked hydrogel and kit special for radioprotection between rectum and lesion prostate or lesion cervix uteri

Abstract

The invention relates to an in-situ cross-linked hydrogel and a kit specially used for radioprotection between rectum and lesion prostate or lesion cervix uteri, the hydrogel comprises the following raw materials: a first component composed of sodium alginate, polyvinyl alcohol, calcium carbonate and water, and a second component composed of sodium alginate, polyvinyl alcohol, calcium carbonate and water, the total mass concentration of the polyvinyl alcohol, the sodium alginate and the calcium carbonate in the first component is 2%-5%, and the mass ratio of the sodium alginate to the polyvinyl alcohol to the calcium carbonate in the first component is 3: (3-17): (0.06-9); the second component is an aqueous solution of gluconolactone with the mass concentration of 3%-10%; when the first component and the second component are mixed according to the volume ratio of (1-3): 1, the first component and the second component can be cross-linked and cured within 5-30 seconds to form a hydrogel protection body with a fixed form and an elastic modulus of 15-40KPa.

Description

Technical Field

[0001] The invention relates to the field of biomedical materials, and in particular to an in-situ cross-linked hydrogel and a kit specially used for radiation protection between a rectum and a diseased prostate or a diseased cervix. Background Art

[0002] Radiotherapy is a common treatment for cancer, but it may cause radiation damage to tissues around cancer lesions, affecting the patient's quality of life. In order to avoid this situation, hydrogels are used as protective agents in the prior art. Hydrogels have good biocompatibility and human adaptability, and can be degraded and absorbed within a certain period of time. They can isolate cancer lesions from normal tissues and provide buffering and protection for the human body.

[0003] Prostate cancer is a common cancer. The main treatments for this type of cancer include radiotherapy and resection. When using radiotherapy, placing a hydrogel spacer between the prostate and the rectum can reduce the volume of the rectum exposed to higher radiation and reduce rectal damage. This type of hydrogel is also used in radiotherapy scenarios such as cervical cancer. However, the hydrogel used between the rectum and the diseased prostate or diseased cervix in the prior art has no fixed shape and is easily displaced after placement, resulting in the rectum that should be covered with hydrogel being partially covered and partially uncovered, and the protection of the rectum is not comprehensive. Summary of the invention

[0004] The technical problem to be solved by the present invention is to provide a novel in-situ cross-linked hydrogel and a kit specially used for radiation protection between the rectum and the diseased prostate or the diseased cervix.

[0005] In order to solve the above technical problems, the technical solution adopted by the present invention is:

[0006] The first aspect of the present invention provides an in situ cross-linked hydrogel specifically used for radiation protection between the rectum and a diseased prostate or a diseased cervix, wherein the raw materials of the hydrogel include:

[0007] The first component is composed of sodium alginate, polyvinyl alcohol, calcium carbonate and water, wherein the total mass concentration of the polyvinyl alcohol, the sodium alginate and the calcium carbonate in the first component is 2% to 5%, wherein the mass ratio of the polyvinyl alcohol, the sodium alginate and the calcium carbonate in the first component is 3:3 to 17:0.06 to 9;

[0008] A second component, wherein the second component is an aqueous solution of gluconolactone with a mass concentration of 3% to 10%;

[0009] When the first component and the second component are mixed at a volume ratio of 1 to 3:1, the two will undergo cross-linking and curing within 5 to 30 seconds to form a hydrogel protective body with a fixed shape and an elastic modulus between 15 KPa and 40 KPa.

[0010] In one embodiment, the first component is prepared by the following method: firstly, the sodium alginate and the polyvinyl alcohol are added into water, stirred at 70° C. to 95° C. for 1 h to 2 h to form a mixed solution of sodium alginate and polyvinyl alcohol, and then mixed with the calcium carbonate after the sodium alginate and polyvinyl alcohol are fully dissolved.

[0011] In one embodiment, the calcium carbonate is placed in water, ultrasonically dispersed, and then added to the mixed solution of sodium alginate and polyvinyl alcohol, and stirred for 30 minutes to form a uniformly dispersed suspension, which is the first component.

[0012] In one embodiment, the sodium alginate in the first component has a M / G ratio of 2:1 and a molecular weight of 80K-120K, the molecular weight of the polyvinyl alcohol has a molecular weight of 50K-80K, and a degree of alcoholysis of 88%.

[0013] In one embodiment, the first component and the second component are cross-linked and cured within 8 to 12 seconds to form the hydrogel protective body. This curing time allows the first component and the second component to be fully mixed and then cross-linked and cured at the desired protective position, ensuring that the formed hydrogel protective body can completely fit the desired protective position.

[0014] In one embodiment, in the first component, the mass ratio of the polyvinyl alcohol, the sodium alginate and the calcium carbonate is 3:3-7:0.5-2.5.

[0015] In one embodiment, the elastic modulus of the hydrogel protective body is between 15 KPa and 32 KPa.

[0016] In one embodiment, the mass concentration of the calcium carbonate in the first component is 0.05% to 1%.

[0017] The second aspect of the present invention provides a kit specifically for radiation protection between the rectum and a diseased prostate or diseased cervix, characterized in that it includes the first component and the second component as described above, and a mixer for mixing the first component and the second component.

[0018] In one embodiment, the mixer includes a first tube for introducing the first component and a second tube for introducing the second component, the first tube and the second tube are respectively connected to a mixing tube, and the first tube, the second tube and the mixing tube together form a Y-shaped mixer.

[0019] In one embodiment, an injection portion for injection is provided at the end of the mixing tube.

[0020] In one embodiment, a first pusher is slidably disposed in the first tube, a second pusher is slidably disposed in the second tube, and the first pusher and the second pusher are fixedly connected to the pusher plate respectively.

[0021] Due to the application of the above technical solution, the present invention has the following advantages compared with the prior art:

[0022] 1. The in-situ cross-linked hydrogel of the present invention is conformally cured and has a specific elastic modulus. It has good shape adaptability while maintaining morphological stability. The shape after curing conforms to the structure of tissues, always fits the protected part, and is not easy to move;

[0023] 2. The in-situ cross-linked hydrogel of the present invention can be instantly gelled and solidified by setting its specific component ratio. When it is applied by injection, it can quickly form filling according to the injection site, with high efficiency and good reliability;

[0024] 3. The in-situ cross-linked hydrogel of the present invention is configured to have a specific elastic modulus, which can reduce the user's foreign body sensation while providing radiation protection;

[0025] 4. The in-situ cross-linked hydrogel of the present invention has a stable morphology and can maintain a stable volume and a good elastic modulus even when immersed in an environment with a high water content after solidification, thereby ensuring the stability of its function during the entire radiation protection period. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 This is a photo of the cured in-situ cross-linked hydrogel in Example 1 of the present invention;

[0027] Figure 2 This is a photo of the cured in-situ cross-linked hydrogel in Example 2 of the present invention;

[0028] Figure 3 This is a photo of the cured in-situ cross-linked hydrogel in Comparative Example 1 of the present invention;

[0029] Figure 4 This is a photograph of the stability test of the in situ cross-linked hydrogel in Example 4 of the present invention, wherein the sample is on day 0.

[0030] Figure 5 This is a photograph of the stability test of the in-situ cross-linked hydrogel in Example 4 of the present invention, wherein the sample is on the 7th day;

[0031] Figure 6 A three-dimensional schematic diagram of a conformal curing test of the in-situ cross-linked hydrogel of the present invention;

[0032] Figure 7 A cross-sectional view of the in-situ cross-linked hydrogel of the present invention undergoing a conformal curing test;

[0033] Figure 8 Photo 1 of the hydrogel protective body after curing, which is a conformal curing test of the in-situ cross-linked hydrogel of the present invention;

[0034] Fig. 9 Photo 2 of the hydrogel protective body after curing, which is a conformal curing test of the in-situ cross-linked hydrogel of the present invention;

[0035] In the figure:

[0036] 1-first tube; 11-first push-injection piece; 2-second tube; 21-second push-injection piece; 22-push-injection plate; 3-mixing tube; 4-mold; 5-rubber ball; 51-groove. DETAILED DESCRIPTION

[0037] The present invention is further described below in conjunction with examples. However, the present invention is not limited to the following examples. The implementation conditions used in the examples can be further adjusted according to the different requirements of specific use, and the implementation conditions not specified are conventional conditions in the industry. The technical features involved in each embodiment of the present invention can be combined with each other as long as they do not conflict with each other. Unless otherwise specified, the reagents in this application can be commercially available or prepared by methods known in the art.

[0038] The in situ cross-linked hydrogel of the present invention is specifically used between the rectum and the diseased prostate or diseased cervix. It can push the rectum away from the cervix / prostate as much as possible, and protect the rectum from radiation damage during radiotherapy for cervical cancer or prostate cancer. The present invention is further described below with specific embodiments and comparative examples.

[0039] Example 1

[0040] The in situ cross-linked hydrogel specifically used for radiation protection between the rectum and the diseased prostate or diseased cervix in Example 1 is prepared by the following method:

[0041] S1 Prepare the first component: 0.5g sodium alginate (M / G = 2:1, molecular weight Mw = 100k) and 0.5g polyvinyl alcohol PVA (molecular weight Mw = 70K, alcoholysis degree 88%), add 50mL water, heat and stir at 70℃ for 1h to fully dissolve. 3Dissolve in 5 mL of water, disperse by ultrasonic, add to the above solution, continue stirring for 30 minutes to form a uniformly dispersed suspension, which is the first component. Wherein M / G = 2:1 means that the sodium alginate molecule is formed by β-D-mannuronic acid (β-D-mannuronic, M) and α-L-guluronic acid (α-L-guluronic, G) connected by a 2:1 bond.

[0042] S2: Prepare the second component: dissolve 0.1 g of gluconolactone GDL in 10 ml of water to prepare a B solution with a concentration of 3%.

[0043] S3 In-situ cross-linking reaction: Add 10mL of the first component to the first tube, and 10mL of the second component to the second tube. Mix the first component and the second component in a volume ratio of 1:1. Connect the first tube and the second tube through a mixing tube. Push the first component and the second component into the first tube and the second tube at the same time. Tilt the mixing tube every 10 seconds to check the fluidity of the mixed solution. After 30 seconds, the in-situ cross-linked hydrogel solidifies. For specific solidification photos, see Figure 1 .

[0044] Example 2

[0045] The main difference between this embodiment and embodiment 1 is that in step S2, the concentration of the second component in this embodiment is 5%, and in step S3, the curing time in this embodiment is 10S. For specific curing photos, please see Figure 2 .

[0046] Comparative Example 1

[0047] The main difference between this comparative example and Example 1 is that in step S2, the concentration of the second component in this comparative example is 1%, and in step S3, the curing time of this comparative example is 5 minutes. For specific curing photos, please see Figure 3 .

[0048] Example 3-4, Comparative Example 2-3

[0049] The in situ cross-linked hydrogel for radiation protection in Examples 3-4 and Comparative Examples 2-3 was prepared by the following method:

[0050] S1 Prepare the first component: Add 10 mL of water to sodium alginate (M / G = 2:1, molecular weight Mw = 100k) and polyvinyl alcohol PVA (molecular weight Mw = 70K, alcoholysis degree 88%), heat and stir at 95 °C for 2 h to fully dissolve, and the solution concentration is 0.02 g / ml. Add 0.05 g of CaCO 3 Dissolve in the above solution, continue stirring for 30 minutes to form a uniformly dispersed suspension, which is the first component. Specific mass ratios of sodium alginate and PVA in Examples 3-4 and Comparative Examples 2-3 are shown in Table 1.

[0051] S2: Prepare the second component: dissolve 0.05 g of gluconolactone GDL in 10 mL of water to prepare a B solution with a concentration of 5%.

[0052] S3 in situ cross-linking reaction: add 10 mL of the first component to the first tube, add 10 mL of the second component to the second tube, mix the first component and the second component in a volume ratio of 1:1, connect the first tube and the second tube through a mixing tube, push the first component and the second component into the first tube and the second tube at the same time, and the in situ cross-linked hydrogel solidifies after 10S.

[0053] The elastic modulus of the in-situ cross-linked hydrogels of Examples 3-4 and Comparative Examples 2-3 obtained by the above steps was tested using a TA.XTC-20 texture analyzer produced by Shanghai BosinTech. Parameter settings: test type, pressure; target mode, deformation; target value, 30%; pre-test speed, 2 mm / s; test speed, 0.2 mm / s; post-test speed, 2 mm / s; trigger point type, force; trigger point value, 2 gf.

[0054] The specific values ​​are shown in Table 1.

[0055] Table 1

[0056] serial number Sodium Alginate / PVA Elastic modulus Example 3 1：1 16.2KPa Example 4 7：3 30.4KPa Comparative Example 2 9：1 47.05KPa Comparative Example 3 1：0 52.83KPa

[0057] Example 5

[0058] S1 Prepare the first component: add 0.7g sodium alginate (M / G=2:1, molecular weight Mw=100k) and 0.3g polyvinyl alcohol PVA (molecular weight Mw=70K, alcoholysis degree 88%), add 50mL water, heat and stir at 95℃ for 2h to fully dissolve, and obtain a mixed solution of sodium alginate and PVA. 3 5 mL of water was added and ultrasonically dispersed to form a uniformly dispersed suspension. 1 mL of the suspension was taken and mixed with a mixed solution of sodium alginate and PVA to obtain a first component.

[0059] S2: Prepare the second component: dissolve 0.05 g of gluconolactone GDL in 10 mL of water to prepare a B solution with a concentration of 5%.

[0060] S3 in situ cross-linking reaction: add 10 mL of the first component to the first tube, add 10 mL of the second component to the second tube, mix the first component and the second component in a volume ratio of 1:1, connect the first tube and the second tube through a mixing tube, push the first component and the second component into the first tube and the second tube at the same time, and the in situ cross-linked hydrogel solidifies after 10S.

[0061] Performance Testing

[0062] 1. Stability test

[0063] The stability test of the in-situ cross-linked hydrogel for radiation protection prepared by the method in Example 4 was performed, and the specific steps and results are as follows:

[0064] Take a sample of 10mm×10mm×5mm (length×width×thickness), immerse it in sterile saline, and incubate it at 37℃ for 7 days. For the specific sample photo on day 0, see Figure 4 , see the sample photos on the 7th day Figure 5 , it was observed that the sample volume was basically unchanged, that is, the sample could maintain a stable volume and a stable elastic modulus.

[0065] 2. Conformal curing test

[0066] The conformability curing test was conducted on the in situ cross-linked hydrogel prepared by the method in Example 5 for radiation protection between the rectum and the diseased prostate or diseased cervix. The specific steps and results are as follows:

[0067] like Figure 6-7 As shown, the method in Example 5 is used to configure the first component and the second component. 10 mL of the first component is sucked into the first tube 1, and 10 mL of the second component is sucked into the second tube 2. The first tube 1 and the second tube 2 are connected through the mixing tube 3. The first tube 1, the second tube 2 and the mixing tube 3 together form a Y-shaped mixer. The end of the mixing tube 3 is provided with an injection portion for injection (not shown in the figure). A first push piece 11 is slidably provided in the first tube 1, and a second push piece 21 is slidably provided in the second tube 2. The first push piece 11 and the second push piece 21 are fixedly connected to the push plate 22 respectively. The mixing tube 3 is inserted into the bottom of the model 4. By pushing the push plate 22, the mixed liquid of the first component and the second component is simultaneously pushed out at the bottom of the rubber ball 5. After 10S, a hydrogel spacer can be formed. The rubber ball 5 is lifted up by the hydrogel. The rubber ball 5 weighs about 25g. Figure 8-9 It can be seen that the shape of the hydrogel after curing is conformal to the shape of the filling position. Specifically, the hydrogel is bowl-shaped with a protrusion in the middle, and the shape of the groove 51 at the bottom of the protrusion rubber ball 5 is adapted. It can be seen that the hydrogel of the present invention can push the lesion away from the normal tissue and isolate the two, and the shape can completely fit the injection site and is not easy to shift.

[0068] In actual application, before the doctor performs radiotherapy on the patient, he first takes out the kit for radiological protection between the rectum and the diseased prostate or the diseased cervix of the present invention, and after determining the injection site, pushes the first tube with the first component and the second tube with the second component into the mixing tube and into the patient's body through the injection part at the same time, and forms an in situ cross-linked hydrogel after 5 to 30 seconds to protect the rectum. The in situ cross-linked hydrogel can provide continuous protection within 3 months and completely degrade within 12 months without being taken out. It can provide protection multiple times during the entire chemotherapy course without multiple injections, thereby improving the patient's experience.

[0069] The above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with the technology to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims

1. An in situ cross-linked hydrogel specifically used for radiation protection between the rectum and a diseased prostate or a diseased cervix, characterized in that: The raw materials of the hydrogel include: The first component is composed of sodium alginate, polyvinyl alcohol, calcium carbonate and water, wherein the total mass concentration of the polyvinyl alcohol, the sodium alginate and the calcium carbonate in the first component is 2% to 5%, wherein the mass ratio of the polyvinyl alcohol, the sodium alginate and the calcium carbonate in the first component is 3:3 to 17:0.06 to 9; A second component, wherein the second component is an aqueous solution of gluconolactone with a mass concentration of 3% to 10%; When the first component and the second component are mixed at a volume ratio of 1 to 3:1, the two will undergo cross-linking and curing within 5 to 30 seconds to form a hydrogel protective body with a fixed shape and an elastic modulus between 15 KPa and 40 KPa.

2. The in situ cross-linked hydrogel for radiation protection between the rectum and the diseased prostate or diseased cervix according to claim 1, characterized in that: The first component is prepared by the following method: firstly, the sodium alginate and the polyvinyl alcohol are added into water, stirred at 70° C. to 95° C. for 1 h to 2 h to form a mixed solution of sodium alginate and polyvinyl alcohol, and then mixed with the calcium carbonate after the sodium alginate and polyvinyl alcohol are fully dissolved.

3. The in situ cross-linked hydrogel for radiation protection between the rectum and the diseased prostate or diseased cervix according to claim 1, characterized in that: The first component and the second component will be cross-linked and cured within 8 to 12 seconds to form the hydrogel protective body.

4. The in situ cross-linked hydrogel for radiation protection between the rectum and the diseased prostate or diseased cervix according to claim 1, characterized in that: Among the first component, the mass ratio of the polyvinyl alcohol, the sodium alginate and the calcium carbonate is 3:3-7:0.5-2.

5.

5. The in situ cross-linked hydrogel for radiation protection between the rectum and the diseased prostate or diseased cervix according to claim 1, characterized in that: The elastic modulus of the hydrogel protective body is between 15KPa and 32KPa.

6. The in situ cross-linked hydrogel for radiation protection between the rectum and the diseased prostate or diseased cervix according to claim 1, characterized in that: The mass concentration of the calcium carbonate in the first component is 0.05% to 1%.

7. A kit for radiation protection between the rectum and a diseased prostate or diseased cervix, characterized in that: The invention comprises the first component and the second component according to any one of claims 1 to 6, and a mixer for mixing the first component and the second component.

8. A kit for radiation protection between the rectum and the diseased prostate or diseased cervix according to claim 7, characterized in that: The mixer includes a first tube for introducing the first component and a second tube for introducing the second component. The first tube and the second tube are respectively connected to a mixing tube. The first tube, the second tube and the mixing tube together form a Y-shaped mixer.

9. A kit for radiation protection between the rectum and the diseased prostate or diseased cervix according to claim 8, characterized in that: The end of the mixing tube is provided with an injection portion for injection.

10. A kit for radiation protection between the rectum and the diseased prostate or diseased cervix according to claim 8, characterized in that: A first pusher is slidably disposed in the first tube, and a second pusher is slidably disposed in the second tube. The first pusher and the second pusher are fixedly connected to the pusher plate respectively.

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