An injectable hydrogel for kidney stone removal, its preparation method and application
An injectable hydrogel formed by combining aldehyde-terminated multi-arm polyethylene glycol derivatives and multi-amino polymers with a thickener solves the safety concerns associated with kidney stone fragment removal, achieving a highly efficient and safe kidney stone removal effect.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- SHANGHAI RUINING BIOTECH CO LTD
- Filing Date
- 2023-10-23
- Publication Date
- 2026-05-26
Smart Images
Figure BDA0004508723050000021 
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Abstract
Description
Technical Field
[0001] This invention relates to the field of medical biopolymer materials technology, specifically to an injectable hydrogel for kidney stone removal, its preparation method, and its application. Background Technology
[0002] Kidney stones are a common disease worldwide. Currently, with changes in economic level and dietary structure, the incidence of kidney stones in China is gradually increasing, with one in 20 people potentially developing kidney stones. Dozens of components are known to form in kidney stones. Clinically, stones are generally classified into four main categories: calcium-containing stones, infection stones, uric acid stones, and cystine stones. Treatment typically involves medication or minimally invasive therapies.
[0003] With the continuous development of technology, urologists are increasingly choosing endoscopic surgery. An endoscope is inserted into the kidney through the urinary tract to locate and remove stones. If the kidney stone is larger than 5mm (larger than the natural urinary tract), a laser must be used to break it down into fragments. These fragments vary in size; larger fragments can be removed using grasping tools, but smaller fragments are too small to be grasped. Within a few months, the fragments remaining in the kidney will continue to grow, causing further complications. Current treatment options mostly involve medication to resolve the small fragments, but this cannot guarantee a high rate of removal and carries certain safety risks. After being left in the body, excessive calcium ions in the blood can precipitate and precipitate as they pass through the kidney, causing the small fragments to continue growing, leading to re-examination of the kidney stone and requiring further surgery, causing secondary harm to the patient and increasing the risk of infection. Currently, a Chinese patent application (authorization announcement number CN105491966B) discloses a gel-forming system for removing urethral stones and / or urethral stone fragments. The system involves coating the stones with an acidic solution containing metal ions and polysaccharides combined with an alginate polysaccharide solution, followed by removal based on magnetizable particles in the gel. However, there may still be issues such as insufficient coating effect and tissue damage due to excessive acidity of the system. Summary of the Invention
[0004] To address the aforementioned issues, this invention provides an in-situ solidified hydrogel with strong conformability, good toughness, and viscosity, which effectively encapsulates kidney stones and can be removed from the body using a stone removal device. It possesses significant industrial and clinical value.
[0005] The present invention provides an injectable hydrogel for the removal of kidney stones, the raw materials for which the preparation includes at least a precursor solution 1 and a precursor solution 2, wherein the precursor solution 1 contains at least a polyethylene glycol derivative and a thickener, and the precursor solution 2 contains at least a polyamino polymer.
[0006] As a preferred technical solution, the polyethylene glycol derivative is an aldehyde-terminated multi-arm polyethylene glycol derivative, wherein the number of arms of the aldehyde-terminated multi-arm polyethylene glycol derivative is 2-8, preferably any one of the aldehyde-terminated multi-arm polyethylene glycol derivatives having the structure shown in Formulas 1-3.
[0007]
[0008]
[0009] Preferably, the molecular weight of the aldehyde-terminated multi-arm polyethylene glycol derivative is 10,000-20,000 Da.
[0010] Preferably, the aldehyde-terminated multi-arm polyethylene glycol derivative is the aldehyde-terminated multi-arm polyethylene glycol derivative shown in Formula 1, with a molecular weight of 15000 Da.
[0011] As a preferred technical solution, the thickener is selected from at least one of cellulose, collagen, polysaccharides, and Span. Preferably, the thickener is selected from at least one of sodium carboxymethyl cellulose, dextran, and Span 80; more preferably, the thickener is sodium carboxymethyl cellulose (1500-3100 mPa·s, purchased from Shanghai Aladdin Biochemical Technology Co., Ltd., product number C104979).
[0012] As a preferred technical solution, the concentration of the polyethylene glycol derivative in the precursor solution 1 is 0.05-0.2 g / mL, and the concentration of the thickener is 0.01-0.05 g / mL. Preferably, the concentration of the polyethylene glycol derivative in the precursor solution 1 is 0.1 g / mL, and the concentration of the thickener is 0.01 g / mL.
[0013] As a preferred technical solution, the solvent in the precursor solution 1 is a phosphate buffer solution, and the pH of the phosphate buffer solution is 5.6.
[0014] The purpose of this invention is to use a two-component precursor solution to solidify in situ into a gel in the kidney stone area, encapsulating the kidney stone for easy removal from the body and avoiding the problems of small stone fragments remaining or the safety hazards caused by conventional drug treatment. The inventors prepared precursor solution 1 using aldehyde-terminated polyethylene glycol as a raw material, and then solidified and crosslinked it in situ with a precursor solution 2 containing polyamino polymers to form a hydrogel with low toxicity and high biocompatibility. However, even by adjusting the viscosity of the precursor solution and the content of active groups, the in-situ formed hydrogel still cannot achieve a balance between effectively encapsulating the kidney stone and avoiding the formation of an inextensible, monolithic gel. This inability to effectively encapsulate the kidney stone leads to stone fragments remaining, posing a safety hazard. Furthermore, an inextensible, monolithic gel cannot be removed from the body through the narrow urethra using a stone retrieval device. During development, the inventors unexpectedly discovered that introducing a thickener into precursor solution 1, particularly a polyethylene glycol derivative at a concentration of 0.1 g / mL matched with sodium carboxymethyl cellulose at a concentration of 0.01 g / mL, allows precursor solution 1 and precursor solution 2 to crosslink in situ within the kidney stone region, achieving efficient encapsulation of the kidney stone. The resulting hydrogel-kidney stone conjugate exhibits good stretchability and viscosity, allowing it to be removed from the body using a stone removal device. The hydrogel is stable, biosafety-free, and low-cost, possessing significant industrial and clinical value. In contrast, the introduction of dextran T70, Span 80, etc., cannot simultaneously guarantee the encapsulation and stretchability of the hydrogel.
[0015] As a preferred technical solution, the concentration of the polyamino polymer in the precursor solution 2 is 0.10-0.21 g / mL.
[0016] As a preferred technical solution, the polyamino polymer is selected from at least one of trilysine, polylysine and polyethyleneimine, preferably a combination of polylysine and polyethyleneimine.
[0017] As a preferred technical solution, the concentration ratio of polylysine to polyethyleneimine is (1-8):(2-20). Preferably, the concentration of the polyamino polymer in the precursor solution 2 is 0.21 g / mL, and the concentration ratio of polylysine to polyethyleneimine is 1:20.
[0018] As a preferred technical solution, the solvent in the precursor solution 2 is borax buffer solution, and the pH of the borax buffer solution is 9.2.
[0019] As a preferred technical solution, the volume ratio of precursor solution 1 to precursor solution 2 is 1:(0.8-1.2), preferably 1:1.
[0020] In this invention, based on precursor solution 1, the concentration ratio of polylysine and polyethyleneimine in the precursor solution is matched and optimized. This can effectively reduce the concentration of polylysine in the precursor solution, and effectively encapsulate the kidney stone fragments while avoiding the formation of a gel with high gel strength that is difficult to stretch. This ensures that the gel encapsulating the stone fragments can be easily removed from the body through the narrow urethra to meet clinical needs.
[0021] Another aspect of the present invention provides a method for preparing an injectable hydrogel for kidney stone removal, comprising at least the following steps: mixing and crosslinking precursor solution 1 and precursor solution 2 in a certain proportion to obtain the product.
[0022] The preparation method of the injectable hydrogel for kidney stone removal specifically includes the following steps:
[0023] (1) Dissolve the polyethylene glycol derivative in phosphate buffer, add a thickener, and prepare precursor solution 1;
[0024] (2) Dissolve the polyamino polymer in borate buffer solution to prepare precursor solution 2;
[0025] (3) The precursor solution 1 and the precursor solution 2 are cross-linked according to the ratio to obtain the product.
[0026] A third aspect of the present invention provides the application of an injectable hydrogel for kidney stone removal as a material for implantable medical devices.
[0027] Beneficial effects
[0028] 1. This invention provides an in-situ solidified hydrogel with strong conformability, good toughness and viscosity, which can effectively encapsulate kidney stones and remove them from the body using a stone removal device. It has great industrialization and clinical application value.
[0029] 2. This application prepares a precursor solution 1 using aldehyde-terminated polyethylene glycol as a raw material, and then crosslinks it with a precursor solution 2 containing a polyamino polymer in situ to form a gel, so that the resulting hydrogel has low toxicity and high biocompatibility.
[0030] 3. This application introduces a thickener into the precursor solution 1, particularly a polyethylene glycol derivative with a concentration of 0.1 g / mL matched with sodium carboxymethyl cellulose with a concentration of 0.01 g / mL, as a thickener. This allows the precursor solution 1 and precursor solution 2 to crosslink in situ within the kidney stone region, achieving efficient encapsulation of the kidney stone. The resulting hydrogel-kidney stone complex has good stretchability and viscosity, and can be removed from the body using a stone removal device.
[0031] 4. In this invention, based on precursor solution 1, the concentration ratio of polylysine and polyethyleneimine in the precursor solution is matched and optimized. This can effectively reduce the concentration of polylysine in the precursor solution, and effectively encapsulate the kidney stone fragments while avoiding the formation of a gel with high gel strength that is difficult to stretch. This ensures that the gel encapsulating the stone fragments can be easily removed from the body through the narrow urethra to meet clinical needs.
[0032] 5. The injectable hydrogel provided by this invention is stable, has high biocompatibility, and is low in cost. It can be used as a material for implantable medical devices, which increases the scope of clinical applications and greatly increases clinical benefits. Attached Figure Description
[0033] Figure 1 This diagram illustrates the dosage of lithotripsy and hydrogel products used in an in vitro simulation test of kidney stone removal. In the diagram, A represents a small sand block, simulating kidney stone fragmentation; B represents the state after adding precursor solutions 1 and 2.
[0034] Figure 2 The figures show the results of in vitro simulation tests for kidney stone removal in Examples 1-10 of the present invention, where 1-10 correspond to Examples 1-10 respectively. Detailed Implementation
[0035] Example 1
[0036] In one aspect, Embodiment 1 of the present invention provides an injectable hydrogel for the removal of kidney stones, the raw materials of which are composed of precursor solution 1 and precursor solution 2, wherein precursor solution 1 is composed of polyethylene glycol derivative, thickener and solvent 1, and precursor solution 2 is composed of polyamino polymer and solvent 2.
[0037] The polyethylene glycol derivative is an aldehyde-terminated multi-arm polyethylene glycol derivative with the structure shown in Formula 1 (molecular weight 15000 Da, purchased from Beijing Jiankai Technology Co., Ltd.):
[0038]
[0039] The thickener is sodium carboxymethyl cellulose (1500-3100 mPa.s, purchased from Shanghai Aladdin Biochemical Technology Co., Ltd., product number C104979).
[0040] The concentration of the polyethylene glycol derivative in the precursor solution 1 is 0.1 g / mL, and the concentration of the thickener is 0.01 g / mL.
[0041] The solvent in the precursor solution 1 is a phosphate buffer solution, and the pH of the phosphate buffer solution is 5-6.
[0042] The concentration of the polyamino polymer in the precursor solution 2 is 0.21 g / mL. The polyamino polymer is a combination of polylysine (purchased from Shanghai Maclean Biochemical Co., Ltd., CAS No.: 28211-04-3) and polyethyleneimine (purchased from Shanghai Maclean Biochemical Co., Ltd., CAS No.: 9002-98-6, trade number E808878), with a concentration ratio of polylysine to polyethyleneimine of 1:20.
[0043] The solvent in the precursor solution 2 is borax buffer solution, and the pH of the borax buffer solution is 9.2.
[0044] Example 1 of the present invention provides a method for preparing an injectable hydrogel for kidney stone removal, specifically including the following steps:
[0045] (1) Dissolve the polyethylene glycol derivative in 1 mL of phosphate buffer, add a thickener, and prepare precursor solution 1;
[0046] (2) Dissolve the polyamino polymer in 1 mL of borate buffer to prepare precursor solution 2;
[0047] (3) The precursor solution 1 and the precursor solution are cross-linked to obtain the product.
[0048] Example 2
[0049] Example 2 of the present invention provides an injectable hydrogel for kidney stone removal and its preparation method. The specific implementation method is the same as that of Example 1, except that the concentration of the polyamino polymer in the precursor solution 2 is 0.1 g / mL, and the polyamino polymer is a combination of polylysine and polyethyleneimine, with a concentration ratio of polylysine to polyethyleneimine of 8:2.
[0050] Example 3
[0051] Example 3 of the present invention provides an injectable hydrogel for kidney stone removal and its preparation method. The specific implementation method is the same as that of Example 2, except that the concentration of polyethylene glycol derivative in the precursor solution 1 is 0.05 g / mL.
[0052] Example 4
[0053] Example 4 of the present invention provides an injectable hydrogel for kidney stone removal and its preparation method. The specific implementation method is the same as that of Example 2, except that the concentration of polyethylene glycol derivative in the precursor solution 1 is 0.2 g / mL.
[0054] Example 5
[0055] Example 5 of the present invention provides an injectable hydrogel for kidney stone removal and its preparation method. The specific implementation method is the same as that of Example 2, except that the thickener is replaced with dextran 70 (molecular weight 70000) from Shanghai Maclean Biochemical Co., Ltd., and the concentration of the thickener is 0.05 g / mL.
[0056] Example 6
[0057] Example 6 of the present invention provides an injectable hydrogel for kidney stone removal and its preparation method. The specific implementation method is the same as that of Example 2, except that the thickener is replaced with Span 80 and the concentration of the thickener is 0.05 g / mL.
[0058] Example 7
[0059] Example 7 of the present invention provides an injectable hydrogel for kidney stone removal and its preparation method. The specific implementation method is the same as that in Example 2, except that no thickener is added to the precursor solution 1 (the concentration of the thickener is 0 g / mL).
[0060] Example 8
[0061] Example 8 of the present invention provides an injectable hydrogel for kidney stone removal and its preparation method. The specific implementation method is the same as that of Example 1, except that the concentration of thickener in the precursor solution 1 is 0.0025 g / mL.
[0062] Example 9
[0063] Example 9 of the present invention provides an injectable hydrogel for kidney stone removal and its preparation method. The specific implementation method is the same as that of Example 1, except that the concentration of thickener in the precursor solution 1 is 0.005 g / mL.
[0064] Example 10
[0065] Example 10 of the present invention provides an injectable hydrogel for kidney stone removal and its preparation method. The specific implementation method is the same as that of Example 1, except that the concentration of thickener in the precursor solution 1 is 0.02 g / mL.
[0066] Performance testing methods
[0067] In vitro simulation test for kidney stone clearance: See Figure 1 Prepare a PTFE plate, add 0.05g of small sand to simulate kidney stones (small fragments), and add 100uL of precursor solution 1 and 100uL of precursor solution 2 from Examples 1-10 respectively. Let stand for 2 minutes, then use tweezers to pick up the gel and observe the state of the gel encapsulating the kidney stone and whether the stone can be removed. The results are referenced. Figure 2.pass Figure 2 It can be observed that the gel in Example 1 can fully encapsulate the stones and has stretchability, achieving the effect of removing the stones from the body through the urethra; Examples 2, 4, 6, and 7 can all form a whole gel, which can encapsulate the stones, but the gel strength is high and it is not easy to stretch, making it difficult to remove from the body through the narrow urethra; Examples 8, 9, and 10 have good stretchability, but the stones are not completely encapsulated, and there will be residues; Examples 3 and 5 cannot encapsulate the stones.
Claims
1. An injectable hydrogel for the removal of kidney stones, characterized in that, The preparation materials include at least precursor solution 1 and precursor solution 2, wherein precursor solution 1 contains at least a polyethylene glycol derivative and a thickener, and precursor solution 2 contains at least a polyamine polymer; the polyethylene glycol derivative is an aldehyde-terminated multi-arm polyethylene glycol derivative, and the number of arms of the aldehyde-terminated multi-arm polyethylene glycol derivative is 2-8; the concentration of polyethylene glycol derivative in precursor solution 1 is 0.1 g / mL, the concentration of thickener is 0.01 g / mL, and the thickener is sodium carboxymethyl cellulose; the concentration of polyamine polymer in precursor solution 2 is 0.21 g / mL; the polyamine polymer is a combination of polylysine and polyethyleneimine, and the concentration ratio of polylysine to polyethyleneimine is 1:
20.
2. The injectable hydrogel for kidney stone removal according to claim 1, characterized in that, The volume ratio of precursor solution 1 to precursor solution 2 is 1:(0.8-1.2).
3. A method for preparing an injectable hydrogel for kidney stone removal according to any one of claims 1-2, characterized in that, At least the following steps are included: The precursor solution 1 and the precursor solution 2 are mixed and crosslinked in a certain proportion to obtain the product.