A gel preparation injection system for local radiotherapy

Abstract

The present invention relates to a gel preparation injection system for local radiotherapy. The system includes an injection kit, a data detection module, a first data processing module, a second data processing module, and an injection analysis module. The present invention utilizes the injection kit, the data detection module, the first data processing module, the second data processing module, and the injection analysis module to assist in injection. The system regulates the injection of the gel preparation to achieve high-precision injection, reducing pain for the patient and any secondary damage to the patient caused by manual manipulation. During radiotherapy, the system also protects surrounding healthy organs from damage by ionizing radiation, minimizing systemic reactions and local radiation damage caused by radiotherapy, achieving the goal of clearing cancer cells while protecting the patient's healthy organs. Furthermore, the system also prevents various complications caused by implantation and puncture, such as infection and mild hematospermia.

Description

Technical Field

[0001] The present invention relates to the field of injection, and in particular to a gel preparation injection system for local radiotherapy. Background Art

[0002] Prostate cancer, an epithelial malignancy arising in the prostate, is a relatively common malignancy of the reproductive system. It is characterized by high malignancy, insidious onset, rapid progression, and high metastatic potential, resulting in a poor prognosis and a high mortality rate. In recent years, the incidence and mortality of prostate cancer have been rapidly increasing, posing a serious threat to human health. However, traditional chemotherapy drugs have limited efficacy in the treatment of prostate cancer and are associated with significant toxic side effects. Therefore, radiotherapy has become the primary treatment option for patients with advanced prostate cancer.

[0003] Radiation therapy is an important treatment for prostate cancer, but it can often harm and damage surrounding organs and tissues, particularly the rectum. To minimize damage to surrounding tissues and organs, radiation doses are often reduced during radiotherapy, resulting in ineffective cancer cell destruction. Because the prostate and rectum are located in close proximity, radiation therapy for prostate cancer often causes rectal damage, increasing the risk of radiation-induced proctitis.

[0004] Hydrogel is a material containing a large amount of water obtained by cross-linking hydrophilic polymers. Hydrogel has excellent physical and chemical properties and biological characteristics, such as high water content, high elasticity, softness, good biocompatibility, etc., and has important application value in biomedical research fields such as drug transport and tissue engineering. Injectable hydrogel refers to a type of hydrogel with a certain fluidity that can be applied by injection. Before being injected into the human body, it is in liquid state or a semi-solid state with shear-thinning properties. After being injected into the human body, it can gel in situ, so there is no need for invasive surgery, which effectively avoids the risk of infection and reduces the patient's pain. In the existing technology, gel preparations can be used as radiation protection materials.

[0005] For example, CN 109646723B discloses a medical hydrogel formed by in-situ crosslinking of an aldehyde-terminated star-shaped multi-arm polyethylene glycol and a polyamino compound. The aldehyde groups are linked to the star-shaped multi-arm polyethylene glycol via ether, amide, urethane, imine, or urea bonds. The molar ratio of amino groups in the polyamino compound to aldehyde groups in the aldehyde-terminated star-shaped multi-arm polyethylene glycol is 0.4 to 4.4:1. The polyamino compound is polylysine or a mixture of polylysine and polyethyleneimine, with a molar ratio of polylysine to polyethyleneimine of 2 to 30:3. This hydrogel exhibits rapid gelation, long-term stability in aqueous solution, and excellent swelling and stability even after multiple irradiations. It can be used as a medical radiotherapy protective pad for radiation protection.

[0006] In addition, hydrogels used in the field of radiotherapy in the prior art can also form compositions with different properties based on different components.

[0007] For example, CN 113461973A discloses an injectable medical hydrogel composed of a cross-linked aldehyde-terminated star-shaped multi-arm polyethylene glycol, polyethyleneimine, and hydrazide-terminated multi-arm polyethylene glycol. The aldehyde-terminated star-shaped multi-arm polyethylene glycol has 2 to 8 arms and a molecular weight of 1000 to 5000 Da per arm. The hydrogel can be used in radiotherapy spacers, vascular embolization, postoperative tissue sealing and leakage prevention, tissue adhesion prevention, tissue filler, tissue repair, skin dressing, and drug delivery. While degradable upon injection, it struggles to block radiation and protect tissues and organs.

[0008] CN 106215199B relates to an injectable polypeptide hydrogel for local tumor radiotherapy and its preparation method. It is self-assembled from polyethylene glycol and hydrophobic polytyrosine high molecular block polymer, and the radiotherapy agent is injected into the hydrogel by the chloramine T method. 131 I-labeled polytyrosine segments in the hydrogel complete the loading of the radiotherapeutic agent, forming a hydrogel preparation for local radiotherapy. The injectable hydrogel radiotherapy agent of this invention features high radiotherapeutic agent loading efficiency, non-toxicity, stability, biodegradability, and ease of injection. This invention pioneers the use of gels for specific, long-term localized tumor radiotherapy. Compared to other radiotherapy preparations, it offers advantages such as ease of injection, elimination of surgical seed implantation and removal, no radiation damage to non-tumor tissues, and prolonged efficacy.

[0009] However, the existing technology does not conduct specific analysis on different patients with specific cancers (such as prostate cancer) at different stages of radiotherapy. Different radiotherapy sites, different radiotherapy periods, and individual differences among different patients will affect the use of gel preparations. Currently, there is a need for a gel preparation injection system for local radiotherapy to adapt to different usage scenarios.

[0010] In addition, on the one hand, there are differences in understanding among those skilled in the art; on the other hand, the applicant studied a large number of documents and patents when making the present invention, but due to space limitations, not all details and contents are listed in detail. However, this does not mean that the present invention does not have the characteristics of these prior arts. On the contrary, the present invention already has all the characteristics of the prior art, and the applicant reserves the right to add relevant prior art to the background technology. Summary of the Invention

[0011] To address the shortcomings of the prior art, the present invention discloses a gel preparation injection system for localized radiotherapy, comprising at least an injection kit, a data detection module, a first data processing module, a second data processing module, and an injection analysis module. The data detection module is configured to detect at least one position data of the injection kit associated with at least one injection step performed at a location between the patient's radiotherapy site and a healthy organ to establish injection deployment. The first data processing module is configured to process the position data detected by the data detection module and transmit the processed position data to the second data processing module for executing the next injection step via the injection kit. The gel preparation injection system for localized radiotherapy of the present invention further reduces the time required to inject the gel preparation, improves the accuracy of gel preparation injection, reduces patient pain, prevents various secondary injuries to the patient caused by manual operation, and prevents various complications caused by implantation and puncture, such as infection, mild hematospermia, and mild lower urinary tract symptoms.

[0012] According to a preferred embodiment, the injection analysis module is configured to analyze the sagittal and transverse positions of the injection kit within the patient's body based on the position data and to perform a risk analysis for the next injection step. The injection analysis module controls the puncture process of the first injection component to prevent the first injection component from accidentally puncturing the patient's radiation treatment site, adjacent tissues, or organs, thereby avoiding secondary damage to the patient. It also ensures that the gel preparation is accurately injected between the patient's radiation treatment site and adjacent tissues, thereby achieving optimal isolation.

[0013] According to a preferred embodiment, the injection kit includes a first injection component and a second injection component. Before the first injection component punctures the position between the patient's radiotherapy site and the healthy organ, the data detection module is placed at the patient's local radiotherapy site close to the patient's skin to establish the position data of the injection site and transmit it to the first data processing module. The first data processing module processes the data to obtain the puncture depth and puncture angle of the first injection component and transmits it to the second data processing module to adjust the first injection component to advance according to the puncture depth and puncture angle. According to the data processing performed by the first data processing module, the action of the first injection component is adjusted to stably support the patient's radiotherapy site and adjacent tissues and organs. The first injection component is inserted at a uniform speed and physiological saline is injected at a uniform speed based on the internal volume to give full play to the water separation effect, improve the molding effect of the subsequent injection of the gel preparation, and reduce complications.

[0014] According to a preferred embodiment, when the first injection assembly reaches a set puncture position, based on the position data detected by the data detection module and the data processing performed by the first data processing module, the first injection assembly stops puncturing and injects the liquid within the first injection assembly to widen the gap between the patient's radiotherapy site and healthy organs. The liquid used in the first injection assembly is normal saline, which is slowly injected in small amounts to widen the gap, create space for the gel formulation, and improve the molding effect.

[0015] According to a preferred embodiment, after the gap is widened, the first data processing module determines the depth to which the first injection assembly should continue puncturing based on the position data detected by the data detection module. The depth is the distance from the current position of the first injection assembly to the desired position of the first injection assembly needle tip at the end of the procedure. Based on this distance, the first injection assembly is advanced at a uniform speed and liquid is injected at a uniform speed based on the liquid volume within the first injection assembly and the distance. When the first injection assembly needle tip is at the predetermined final position, the remaining liquid is injected, with the total amount of injected liquid being a first volume. The first volume is appropriately selected based on the size of the injection site and the size of the radiotherapy area. For example, if a patient requires isolation of the prostate and rectum, an appropriate amount of saline solution is injected into the anterior rectal wall. The first injection assembly is advanced at a uniform speed and saline solution is injected at a uniform speed based on the internal volume to maximize the hydrodissection effect and allow the saline solution to expand the space. Preferably, the injected liquid may also be a local anesthetic, such as lidocaine, which acts before the saline solution and is injected at multiple locations, such as subcutaneously, mid-stomach, or to the left and right of the injection site.

[0016] According to a preferred embodiment, the injection analysis module derives the sagittal and transverse planes of the first injection component in the patient's body based on the position data detected by the data detection module and / or B-type ultrasound examination, and performs a risk analysis by comparing the position with a preset plan. The risk analysis includes at least whether the position of the first injection component is accurate and whether the gel preparation injected by the second injection component can separate healthy organs and radiotherapy sites based on individual differences of patients and have a safe separation distance, so as to reduce the risk of radiation damage to patients, achieve high-dose radiation on the basis of reducing damage to surrounding organs at risk in the body, and further ensure that the hydrogel isolates the radiotherapy site and adjacent tissues and organs.

[0017] According to a preferred embodiment, when the injection analysis module analyzes that the position of the first injection component is accurate, the first injection component is negatively pressured back to ensure that the needle tip of the first injection component is not in the patient's blood vessel, the syringe of the first injection component is removed, and the needle of the first injection component is retained to complete the injection step of the first injection component.

[0018] According to a preferred embodiment, the second injection assembly comprises at least a frame assembly and a mixing assembly, wherein the frame assembly has a hollow area reserved for accommodating multiple syringes and multiple latches, allowing the syringes to be placed on the frame assembly in a manner that extends through the corresponding hollow area and is fixed in place by the latches on the frame assembly. The nozzle ends of the syringes are connected to the retaining protrusions on the multi-connector end of the mixing assembly, allowing the injection liquid in the syringes to flow into the mixing assembly through the multi-connector end of the mixing assembly. In the case of multiple syringes, different syringes can be connected to multiple different interfaces provided on the mixing assembly on the side facing the frame assembly to achieve communication between the mixing assembly and the multiple syringes, thereby facilitating the loading of different injection liquids into corresponding syringes and pushing them into the mixing assembly in appropriate proportions to complete the mixing of the injection liquids and form a gel preparation. The above-mentioned gel preparation has injectability and rapid gelation properties. After mixing the first component and the second component solution, it can gel in a relatively short time in an aqueous environment and is used to block radiation during radiotherapy.

[0019] According to a preferred embodiment, the second injection assembly is connected to the indwelling needle of the first injection assembly. The second injection assembly continuously and synchronously injects the gel preparation mixed by the framework assembly and the mixing assembly into the patient at a uniform rate within a predetermined time after contact and mixing, with the total amount of gel preparation injected being a second volume. The predetermined time refers to the optimal time for the gel preparation to enter the patient's body. In the case of the gel preparation of the present invention, this time is the time required for the gel preparation to gel rapidly, i.e., the entire mixed gel preparation is injected into the patient within the rapid gelation range.

[0020] According to a preferred embodiment, the gel preparation can at least adjust the amount of the first component and / or the second component and / or the buffer based on the required separation distance of the healthy organ relative to the radiotherapy site and / or based on the different injection sites of the patient through the second injection component, thereby solving the problem of different spacings and reducing the local discomfort caused by stretching the patient's radiotherapy site and adjacent tissues and organs, and even perforation, tenesmus, etc., and the time of injection of the gel preparation and the speed of synchronous injection can also be adjusted through the structural component and the mixing component, and the total injection volume can also be adjusted as needed. The first component and / or the second component are selected from one or more of polyethylene glycol derivatives, polylactic acid, PLGA, and memory materials, and the memory material is preferably memory sponge. The injectable hydrogel for preoperative radiotherapy of the present invention has the functions of filling, blocking the contact between the rectum and the prostate, increasing the distance between the rectum and the prostate, being injectable, and being degradable. Before radiotherapy, the hydrogel is delivered into the abdominal cavity via a catheter, where it forms a hydrogel, blocking contact between the rectum and the prostate, increasing the distance between them, and preventing rectal damage during radiotherapy for prostate cancer. This indirectly increases the target dose during radiotherapy, and the hydrogel degrades within three months after surgery, avoiding secondary wound damage. The present invention also describes a method for preparing the injectable hydrogel for preoperative radiotherapy and its application before radiotherapy.

[0021] The present invention has the following beneficial technical effects:

[0022] (1) The present invention uses an injection kit, a data detection module, a first data processing module, a second data processing module, and an injection analysis module to assist in injection. The gel preparation is regulated by the system to achieve a high-precision injection effect, reducing the patient's pain and various secondary injuries to the patient caused by manual operation. During radiotherapy, it also protects surrounding healthy organs from being damaged by ionizing radiation, reduces systemic reactions and local radiation damage caused by radiotherapy, and achieves the purpose of clearing cancer cells while protecting the patient's healthy organs. At the same time, it also prevents various complications caused by implantation and puncture, such as infection and mild hematospermia.

[0023] (2) The data detection module detects the position data of the first injection component to achieve precise injection of the hydrogel, thereby increasing the distance between the radiotherapy site and adjacent tissues and organs, reducing the incidence of radiation damage, improving the quality of life of patients, and preventing the occurrence of various radiation damage complications such as intestinal damage in the acute phase of patients;

[0024] (3) performing data processing according to the first data processing module to adjust the action of the first injection component, stably expanding the patient's radiotherapy area and adjacent tissues and organs, inserting the first injection component at a uniform speed and injecting normal saline at a uniform speed based on the internal volume to fully exert the hydrodissociation effect, improve the molding effect of the subsequent injection of the gel preparation, and reduce complications;

[0025] (4) Determine through the injection analysis module whether the position of the first injection component is accurate and whether the gel preparation injected by the second injection component can separate the healthy organs from the radiotherapy site based on the individual differences of the patient and have a safe separation distance, so as to reduce the risk of radiation damage to the patient, achieve high-dose radiation on the basis of reducing damage to the surrounding organs at risk, and further ensure that the hydrogel isolates the radiotherapy site from adjacent tissues and organs;

[0026] (5) Through the framework component and the mixing component of the second injection component, the dosage of each first component and / or second component and / or buffer is selected based on the required distance of the healthy organ relative to the radiotherapy site and / or based on the different injection sites of the patient, thereby solving the problem of different intervals and reducing the local pain caused by stretching the patient's radiotherapy site and adjacent tissues and organs, and even perforation, tenesmus, etc., and the framework component and the mixing component can also adjust the injection time of the gel preparation and the speed of synchronous injection, and the total injection volume can also be adjusted as needed;

[0027] (6) The present invention uses n arms-succinimidyl glutarate polyethylene glycol (where n≥4) and m arms-amino polyethylene glycol (where m≥4) to undergo Michael addition reaction to form a hydrogel. Polyethylene glycol is a water-soluble polyether-type polymer compound that is widely used in the fields of medicine, health, food, and chemical industry. Polyethylene glycol has many advantages, such as low toxicity, non-coagulability, and good biocompatibility, so it can be quickly excreted from the body after failure without producing any toxic side effects. When polyethylene glycol is coupled with other molecules, many of its excellent properties will also be transferred to the conjugate;

[0028] (7) The present invention provides an injectable hydrogel that can be directly injected into the location to be isolated with the assistance of an injection system without the need for surgery. It quickly forms a gel and completely degrades within three months after radiotherapy. It does not require surgery, can reduce the patient's pain and damage caused by surgery, control minor bleeding, and reduce the risk of infection. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 is a flow chart of a gel preparation injection system for local radiotherapy in a preferred embodiment of the present invention;

[0030] Figure 2 is the structural formula of eight-arm succinimidyl glutarate polyethylene glycol in a preferred embodiment of the present invention;

[0031] Figure 3 It is the structural formula of four-arm amino polyethylene glycol in a preferred embodiment of the present invention.

[0032] Reference Signs List

[0033] 1: Data detection module; 2: First data processing module; 3: Second data processing module; 401: First injection component; 402: Second injection component. DETAILED DESCRIPTION

[0034] The following is a detailed description with reference to the accompanying drawings.

[0035] The present invention relates to a gel preparation for local radiotherapy, in particular a gel preparation suitable for local radiotherapy of patients with prostate cancer and / or cervical cancer. The gel preparation is injected with a gel preparation having excellent three-dimensional porosity, high water content, amorphous properties, tissue adhesion, biodegradability, and good biocompatibility to separate the rectum from the prostate or vagina, thereby preventing contact between the prostate or vagina and the rectum. This can effectively kill cancer cells by increasing the target dose while avoiding damage to surrounding tissues and organs.

[0036] According to a preferred embodiment, the gel preparation comprises at least multi-arm succinimidyl glutarate polyethylene glycol and multi-arm amino polyethylene glycol, wherein the multi-arm succinimidyl glutarate polyethylene glycol and the multi-arm amino polyethylene glycol are cross-linked to form an injectable hydrogel by a Michael addition reaction. The Michael addition reaction is a conjugate addition reaction between an electrophilic conjugated system (electron acceptor) and a nucleophilic negative carbon ion (electron donor). The reaction mechanism is that the NO covalent bond of the succinimidyl glutarate polyethylene glycol combines with the amino group of the amino polyethylene glycol, and a polymerization reaction occurs to form a hydrogel. The byproduct N-hydroxysuccinimide remains in the hydrogel and is discharged with the degradation of the gel. Furthermore, the multi-arm succinimidyl glutarate polyethylene glycol can be selected from n arms-succinimidyl glutarate polyethylene glycol (where n ≥ 4), and the multi-arm amino polyethylene glycol can be selected from m arms-amino polyethylene glycol (where m ≥ 4). As the number of arms increases, the gelation speed becomes faster. Based on the gelation speed required by the patient, different structures of its components can be selected to adapt to various environments and / or fields with a variety of arm numbers.

[0037] According to a preferred embodiment, the Michael addition reaction must be carried out under the catalysis of a base, and commonly used bases include: sodium ethoxide, sodium hydride, sodium amide and organic bases. A suitable base is selected according to the reactivity of the reactants. If both reactants have high reactivity, a weaker base can also enable the reaction to proceed. A conjugate addition reaction is carried out between an electrophilic conjugated system (electron acceptor) and a nucleophilic negative carbon ion (electron donor). Furthermore, the gel preparation includes a buffer capable of adjusting the pH of the hydrogel, wherein the first component and the second component can be dissolved in their respective buffers and then fully mixed, and injected into the part of the peritoneal cavity where the gel needs to be formed with the assistance of an ultrasonic detector. Preferably, the buffer can be an alkaline buffer so that the pH of the prepared gel preparation is adapted to the pH of the part of the peritoneal cavity in the human body where the gel needs to be formed, for example, the pH of the prepared gel preparation is controlled at 7.0 to 7.5 to adapt to the pH of human tissue fluid.

[0038] Example 1

[0039] This embodiment relates to a gel formulation injection system for localized radiotherapy, the system comprising at least an injection kit, a data detection module, a first data processing module, a second data processing module, and an injection analysis module. The data detection module is configured to detect at least one position data of the injection kit related to at least one injection step performed at a location between the patient's radiotherapy site and a healthy organ to establish injection deployment. The first data processing module is configured to process the position data detected by the data detection module and transmit the processed position data to the second data processing module to adjust the injection kit to perform the next injection step. Preferably, the data detection module can use an ultrasound (TRUS) component, placing the ultrasound probe at the patient's desired injection site and serving as a guide component to ensure that the first injection component slowly penetrates the patient's desired injection site in a manner parallel to the ultrasound probe. Preferably, the data detection module can also use various detection methods such as a computed tomography scanner, magnetic resonance imaging, or positron emission tomography, which will not be described in detail. The gel injection system for localized radiotherapy of the present invention further reduces the time required to inject the gel, improves the accuracy of gel injection, reduces pain for the patient, and mitigates various secondary injuries to the patient caused by manual operation. During radiotherapy, it also protects surrounding healthy organs from damage by ionizing radiation, reduces systemic reactions and localized radiation damage caused by radiotherapy, achieving the goal of clearing cancer cells while protecting the patient's healthy organs. It also prevents various complications caused by implantation and puncture, such as infection and mild hematospermia.

[0040] According to a preferred embodiment, the injection analysis module is configured to perform a position analysis of the sagittal plane and the cross-section of the injection kit in the patient's body based on the position data and to perform a risk analysis on the next injection step. The injection analysis module is used to ensure the puncture process of the first injection component, prevent the first injection component from mistakenly piercing the radiotherapy site, adjacent tissues and organs in the patient's body, so as to avoid secondary damage to the patient, and at the same time ensure that the gel preparation can be accurately injected between the patient's radiotherapy site and adjacent tissues, so as to achieve the best isolation effect. It should be noted that the sagittal plane in the present invention refers to: when the patient is standing upright, the position to be detected is divided into two parts, the left and right sections, namely the sagittal plane. The cross-section refers to: when the patient is standing upright, the section passing through the midline of the position to be detected and perpendicular to the sagittal plane. The sagittal plane and the cross-section change with the change of the patient's posture.

[0041] According to a preferred embodiment, the injection kit includes a first injection component and a second injection component. Before the first injection component punctures the position between the patient's radiotherapy site and the healthy organ, the data detection module is placed at the patient's local radiotherapy site close to the patient's skin to establish the position data of the injection site and transmit it to the first data processing module. The first data processing module processes the data to obtain the puncture depth and puncture angle of the first injection component and transmits it to the second data processing module to adjust the first injection component to advance according to the puncture depth and puncture angle. The first data processing module processes the data to adjust the action of the first injection component to stably support the patient's radiotherapy site and adjacent tissues and organs. The first injection component penetrates at a uniform speed and injects physiological saline at a uniform speed based on the internal volume to give full play to the water separation effect, improve the molding effect of the subsequent injection of the gel preparation, and reduce complications.

[0042] According to a preferred embodiment, when the first injection assembly reaches a set puncture position, based on the position data detected by the data detection module and the data processing performed by the first data processing module, the first injection assembly is adjusted to stop puncturing and inject the liquid within the first injection assembly to expand the gap between the patient's radiotherapy area and healthy organs. Preferably, the liquid used in the first injection assembly is saline, and the first injection assembly slowly injects a small amount of saline to expand the gap, provide injection space for the gel formulation, and improve the molding effect.

[0043] According to a preferred embodiment, after the gap is enlarged, based on the position data detected by the data detection module, the first data processing module determines the depth to which the first injection component needs to continue puncturing. The depth refers to the distance from the current position of the first injection component to the position where the needle tip of the first injection component needs to be at the end. Based on the distance, the first injection component is advanced at a uniform speed and the liquid is injected at a uniform speed based on the liquid capacity in the first injection component and the distance. When the needle tip of the first injection component is at the predetermined final position, the remaining liquid is injected, and the total amount of liquid injected is the first capacity. The first capacity is appropriately selected based on the size of the injection site and the radiotherapy site. For example, if the patient needs to isolate the prostate and rectum, an appropriate amount of saline is injected into the anterior wall of the rectum. The first injection component is inserted at a uniform speed and the saline is injected at a uniform speed based on the internal capacity to give full play to the water separation effect and allow the saline to expand the space.

[0044] According to a preferred embodiment, the injection analysis module derives the sagittal and transverse planes of the first injection component in the patient's body based on the position data detected by the data detection module and / or B-type ultrasound examination, and performs a risk analysis by comparing the position with a preset plan. The risk analysis includes at least whether the position of the first injection component is accurate and whether the gel preparation injected by the second injection component can separate healthy organs and radiotherapy sites based on individual differences of patients and have a safe separation distance, so as to reduce the risk of radiation damage to patients, achieve high-dose radiation on the basis of reducing damage to surrounding organs at risk in the body, and further ensure that the hydrogel isolates the radiotherapy site and adjacent tissues and organs.

[0045] According to a preferred embodiment, when the injection analysis module analyzes that the position of the first injection component is accurate, the first injection component is negatively pressured back to ensure that the needle tip of the first injection component is not in the patient's blood vessel, the syringe of the first injection component is removed, and the needle of the first injection component is retained to complete the injection step of the first injection component.

[0046] According to a preferred embodiment, the second injection assembly comprises at least a frame assembly and a mixing assembly. The frame assembly includes a hollow area for accommodating multiple syringes and a plurality of latches, allowing the syringes to be placed on the frame assembly so as to penetrate the corresponding hollow area and be secured in place by the latches on the frame assembly. The syringe nozzles connect to retaining protrusions on the manifold end of the mixing assembly, allowing the injection solution in the syringes to flow through the manifold end of the mixing assembly into the mixing assembly. If multiple syringes are provided, different syringes can be connected to the mixing assembly via multiple interfaces on a side facing the frame assembly to achieve communication between the mixing assembly and the multiple syringes. This facilitates the loading of different injection solutions into corresponding syringes and their delivery to the mixing assembly in appropriate proportions to complete the mixing of the injection solutions and form a gel preparation. The gel preparation produced by the second injection assembly is injectable and rapidly gels. After mixing the first and second component solutions, the solution can gel in a relatively short time in an aqueous environment, and is therefore useful for blocking radiation during radiotherapy.

[0047] According to a preferred embodiment, the second injection assembly is connected to the needle of the indwelling first injection assembly. The second injection assembly continuously, synchronously, and uniformly injects the gel preparation mixed by the framework assembly and the mixing assembly into the patient within a predetermined time after contact and mixing. The total amount of gel preparation injected is a second volume. The predetermined time refers to the optimal time for the gel preparation to enter the patient's body. In the gel preparation of the present invention, this time is the time required for the gel preparation to gel rapidly, that is, the mixed gel preparation is fully injected into the patient within the rapid gelation range. The first volume is half of the second volume. For example, if a patient needs to isolate the prostate and rectum, 3-15 mL of saline and 6-30 mL of gel preparation are injected into the anterior rectal wall. It should be noted that the above ratios are merely a reference data for a specific embodiment of the present invention and do not exclude other ratios of the first volume and the second volume. Different ratios can be selected for injection according to the present invention.

[0048] According to a preferred embodiment, the injection system is capable of adjusting the dosage and ratio of the first component and / or the second component and / or the buffer of the gel preparation based on at least the required separation distance of the healthy organ relative to the radiotherapy site and / or based on the different injection sites of the patient through the second injection component, thereby solving the problem of different separations and reducing the local discomfort caused by stretching the patient's radiotherapy site and adjacent tissues and organs, and even perforation, tenesmus, etc., and the time of injection of the gel preparation and the speed of synchronous injection can also be adjusted through the structural component and the mixing component, and the total injection volume can also be adjusted as needed. It should be noted that the above-mentioned separation refers to: after injecting an appropriate amount of hydrogel, an isolation area with an average separation of more than 5 mm can be generated. The first component and / or the second component are selected from one or more of polyethylene glycol derivatives, polylactic acid, PLGA, and memory materials, and the memory material is preferably memory foam.

[0049] Example 2

[0050] This embodiment discloses a gel preparation for local radiotherapy, which may be composed of a first component, a second component and an alkaline buffer, wherein the first component is multi-arm succinimidyl glutarate polyethylene glycol, preferably n arms-succinimidyl glutarate polyethylene glycol (wherein, n ≥ 4), the weight percentage of succinimidyl glutarate polyethylene glycol is 5-15%, and the relative molecular mass is 10000-20000 Da; the second component is multi-arm amino polyethylene glycol, preferably marms-amino polyethylene glycol (wherein, m ≥ 4), the weight percentage of amino polyethylene glycol is 5-15%, and the relative molecular mass is 10000-20000 Da; the alkaline buffer is a phosphate buffer, which may include the following components: potassium dihydrogen phosphate and / or sodium chloride and / or sodium hydroxide, preferably, the pH of the alkaline buffer is 7.0-7.5. It should be noted that the present invention lists specific chemical substances for the first component and the second component, but this does not mean that the first component and the second component can only use the substances mentioned in the present invention. For example, the second component can also use trilysine.

[0051] Succinimidyl glutarate polyethylene glycol and amino polyethylene glycol undergo Michael addition reaction in an alkaline buffer to form an injectable gel preparation. The pH of the prepared gel preparation is 7.0-7.5 to adapt to the pH of human tissue fluid.

[0052] According to a preferred embodiment, the preparation method of the gel preparation of the present invention is as follows:

[0053] (1) Preparation of alkaline buffer solution: Take 1.36 g of potassium dihydrogen phosphate, add 79 mL of 0.1 mol / L sodium hydroxide solution, and dilute with water to 200 mL.

[0054] (2) Sterilized succinimidyl glutarate polyethylene glycol powder and alkaline buffer solution are mixed in a mixing bottle; shake the mixing bottle to thoroughly mix the powder and alkaline buffer solution. After mixing, let the mixture stand for at least 1 minute until the bubbles dissipate, thereby preparing an alkaline buffer solution of succinimidyl glutarate polyethylene glycol.

[0055] (3) Mix the sterilized amino polyethylene glycol powder and alkaline buffer solution in a mixing bottle. Shake the mixing bottle to thoroughly mix the powder and alkaline buffer solution. After mixing, let it stand for at least 1 minute until the bubbles dissipate to prepare the amino polyethylene glycol solution.

[0056] According to a preferred embodiment, the method for using the gel preparation of the present invention is as follows:

[0057] (1) Preparation: Place a buffer solution in a syringe, inject the buffer solution into the powder bottle containing succinimidyl glutarate polyethylene glycol solution and / or amino polyethylene glycol solution, mix them, and put them into the syringe. Install the same Y-shaped connector on the needles of the two syringes, and place the two syringes in a double syringe holder. Install a long injection needle at the end of the Y-shaped connector and expel all the air in the Y-shaped connector.

[0058] (2) Water space construction: Inject physiological saline into the area where isolation is required to form a water space.

[0059] (3) Injection of gel: Use a double syringe holder to simultaneously push two syringes containing succinimidyl glutarate polyethylene glycol solution and amino polyethylene glycol solution respectively, so that the two solutions are fully mixed in the Y-type connector. With the assistance of an ultrasound detector, inject the solution into the part of the abdominal cavity where the gel needs to be formed, and adjust the injection range.

[0060] Example 3

[0061] The formula of a gel preparation for local radiotherapy disclosed in this embodiment is: 5% of octa-arm succinimidyl glutarate polyethylene glycol with a molecular weight of 15,000 Da, 5% of octa-arm amino polyethylene glycol with a molecular weight of 10,000 Da, and 90% of alkaline buffer with a pH of 7.2-7.4.

[0062] The preparation method is as in Example 2.

[0063] Example 4

[0064] The formula of a gel preparation for local radiotherapy disclosed in this embodiment is: 5% of octa-arm succinimidyl glutarate polyethylene glycol with a molecular weight of 15,000 Da, 10% of octa-arm amino polyethylene glycol with a molecular weight of 20,000 Da, and 85% of an alkaline buffer solution with a pH of 7.2-7.4.

[0065] The preparation method is as in Example 2.

[0066] Example 5

[0067] The formula of a gel preparation for local radiotherapy disclosed in this embodiment is: 5% of eight-arm succinimidyl glutarate polyethylene glycol with a molecular weight of 10,000 Da, 5% of four-arm amino polyethylene glycol with a molecular weight of 15,000 Da, and 90% of alkaline buffer with a pH of 7.2-7.4.

[0068] The preparation method is as in Example 2.

[0069] Example 6

[0070] The formula of a gel preparation for local radiotherapy disclosed in this embodiment is: 5% of eight-arm succinimidyl glutarate polyethylene glycol with a molecular weight of 20,000 Da, 5% of four-arm amino polyethylene glycol with a molecular weight of 10,000 Da, and 90% of alkaline buffer with a pH of 7.2-7.4.

[0071] The preparation method is as in Example 2.

[0072] Example 7

[0073] The formula of a gel preparation for local radiotherapy disclosed in this embodiment is: 10% of four-arm succinimidyl glutarate polyethylene glycol with a molecular weight of 20,000 Da, 5% of eight-arm amino polyethylene glycol with a molecular weight of 15,000 Da, and 85% of an alkaline buffer solution with a pH of 7.2-7.4.

[0074] The preparation method is as in Example 2.

[0075] Example 8

[0076] The formula of a gel preparation for local radiotherapy disclosed in this embodiment is: 10% of four-arm succinimidyl glutarate polyethylene glycol with a molecular weight of 15,000 Da, 5% of eight-arm amino polyethylene glycol with a molecular weight of 20,000 Da, and 85% of an alkaline buffer solution with a pH of 7.2-7.4.

[0077] The preparation method is as in Example 2.

[0078] Example 9

[0079] The formula of a gel preparation for local radiotherapy disclosed in this embodiment is: 10% four-arm succinimidyl glutarate polyethylene glycol with a molecular weight of 10,000 Da, 10% four-arm amino polyethylene glycol with a molecular weight of 20,000 Da, and 80% alkaline buffer with a pH of 7.2-7.4.

[0080] The preparation method is as in Example 2.

[0081] Example 10

[0082] The formula of a gel preparation for local radiotherapy disclosed in this embodiment is: 5% of four-arm succinimidyl glutarate polyethylene glycol with a molecular weight of 20,000 Da, 10% of four-arm amino polyethylene glycol with a molecular weight of 20,000 Da, and 80% of alkaline buffer with a pH of 7.2-7.4.

[0083] It should be noted that the above formula only shows the proportions of the various components of the gel preparation that may be used for the specific embodiment of the present invention, and does not represent a formula of the gel preparation that does not include the proportions of the remaining components, nor does it mean that it does not contain other components. Preferably, a contrast agent can also be added to the gel preparation. Among them, the contrast agent can be selected from iohexol or an aldehyde-based contrast agent, which is not limited. The present invention relates to a gel preparation for local radiotherapy, and its formula, for example, includes three components: succinimidyl glutarate polyethylene glycol, amino polyethylene glycol and iohexol. The contrast agent is grafted onto the gel molecular chain in the form of chemical reaction or physical blending, so that the gel preparation can be displayed more clearly under the data detection module, realizing multimodal development and tracking the entire radiotherapy process.

[0084] Example 11

[0085] This embodiment is a further improvement of the above embodiments, and repeated contents will not be repeated. This embodiment performs performance testing on gel preparations with different formulations in the above embodiments, wherein the testing parameters and methods may include:

[0086] 1. Determination of gelation time

[0087] Dissolve aminopolyethylene glycol and succinimidyl glutarate polyethylene glycol separately in phosphate buffered saline (pH = 7.4), place the solution in a syringe, and inject equal volumes through a Y-shaped tube into a 37°C insulated glass bottle. During the gelation process, repeatedly invert the glass bottle to observe whether the sample flows. If it does not flow, it can be considered that the solution has turned into a gel. The time from mixing to complete gelation is the gelation time.

[0088] 2. Compression mechanics test

[0089] The hydrogel was compressed at a certain compression rate using a Bose biomaterial mechanical properties testing machine. The compression modulus was calculated using the following formula. The same group of samples were tested three times and the average value was taken.

[0090]

[0091]

[0092]

[0093] σ is stress, ε is strain, Ecompression is compression modulus, F is compression force, L1 is displacement, and L0 is initial length.

[0094] 3. Determination of in vitro degradation performance

[0095] Standard hydrogels were prepared and placed in a PBS buffer (pH = 7.4) environment simulating body fluid at 37°C. Degradation was tested at 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, and 24 weeks (n = 6). After freeze-drying, the dry weight was measured, and the degradation rate of the hydrogel was calculated using the following formula:

[0096]

[0097] Where W0 and W x are the initial dry weight of hydrogel and the sample dry weight, respectively.

[0098] 4. Equilibrium swelling rate test

[0099] The hydrogel was immersed in physiological saline at 37°C, and samples were taken for quality testing at 12h, 24h, 48h, and 72h. The swelling rate of the hydrogel was calculated using the following formula:

[0100]

[0101] Where W0 and W x are the initial mass of the hydrogel and the mass at the time of sampling, respectively.

[0102] It should be noted that the above-mentioned specific embodiments are exemplary, and those skilled in the art can come up with various solutions inspired by the disclosure of the present invention, and these solutions also belong to the disclosure scope of the present invention and fall within the protection scope of the present invention. Those skilled in the art should understand that the present invention specification and its drawings are illustrative and do not constitute a limitation of the claims. The scope of protection of the present invention is defined by the claims and their equivalents. The present invention specification contains multiple inventive concepts, such as "preferably", "according to a preferred embodiment" or "optionally", all of which indicate that the corresponding paragraph discloses an independent concept, and the applicant reserves the right to file a divisional application based on each inventive concept. Throughout the text, the features guided by "preferably" are only an optional method and should not be understood as having to be set, so the applicant reserves the right to abandon or delete the relevant preferred features at any time.

Claims

1. A gel preparation injection system for local radiotherapy, characterized in that: The system at least includes an injection kit, a data detection module, a first data processing module, a second data processing module and an injection analysis module. The data detection module is configured to: when performing at least one injection step at a position between a radiotherapy site and a healthy organ of a patient, detect at least one position data of the injection kit related to the injection step to establish injection deployment; The first data processing module is used to process the position data detected by the data detection module and transmit the processed position data to the second data processing module to adjust the injection kit to perform the next injection step. The injection analysis module is configured to perform a position analysis of the injection kit in the sagittal plane and the transverse plane in the patient's body based on the position data and perform a risk analysis on the next injection step. The injection kit includes a first injection component and a second injection component, Before the first injection component punctures the position between the patient's radiotherapy site and the healthy organ, the data detection module is placed at the patient's local radiotherapy position close to the patient's skin to establish the position data of the injection site and transmit it to the first data processing module. The first data processing module processes the data to obtain the puncture depth and puncture angle of the first injection component and transmits it to the second data processing module to adjust the first injection component to advance according to the puncture depth and puncture angle.

2. The gel preparation injection system for local radiotherapy according to claim 1, characterized in that: When the first injection component punctures to the set position, based on the position data detected by the data detection module and the data processing performed by the first data processing module, the first injection component stops puncturing and injects the liquid in the first injection component to expand the gap between the patient's radiotherapy site and the healthy organ.

3. The gel preparation injection system for local radiotherapy according to claim 2, characterized in that: After the gap is enlarged, based on the position data detected by the data detection module, the first data processing module determines the depth at which the first injection component needs to continue puncturing. The depth refers to the distance from the current position of the first injection component to the position at which the needle tip of the first injection component needs to be at the end. The first injection component is advanced at a uniform speed based on the distance and liquid is injected at a uniform speed based on the liquid capacity in the first injection component and the distance; when the needle tip of the first injection component is located at a predetermined final position, the remaining liquid is injected, and the total amount of liquid injected is the first capacity.

4. The gel preparation injection system for local radiotherapy according to claim 3, characterized in that: The injection analysis module determines the sagittal and transverse planes of the first injection component in the patient's body based on the position data detected by the data detection module and / or B-type ultrasound examination, and performs a risk analysis by comparing it with a preset plan. The risk analysis includes at least whether the position of the first injection component is accurate and whether the gel preparation injected by the second injection component can separate the healthy organs and the radiotherapy site based on the individual differences of the patients and have a safe separation distance.

5. The gel preparation injection system for local radiotherapy according to claim 4, characterized in that: When the injection analysis module analyzes that the position of the first injection component is accurate, the first injection component is negatively pressured to ensure that the needle tip of the first injection component is not in the patient's blood vessel, the syringe of the first injection component is removed, and the needle of the first injection component is retained to complete the injection step of the first injection component.

6. The gel preparation injection system for local radiotherapy according to claim 5, characterized in that: The second injection assembly at least includes a framework assembly and a mixing assembly, wherein the framework assembly is provided with a hollow area for placing a plurality of syringes and a plurality of clips, so that the syringes can be placed on the framework assembly in a manner of passing through the corresponding hollow area and are fixed in position by the clips on the framework assembly, and the nozzle end of the syringe is connected to the limiting protrusion in the multi-joint end of the mixing assembly so that the liquid to be injected in the syringe can flow into the mixing assembly through the multi-joint end of the mixing assembly. In the case where several syringes are provided, different syringes can be connected to several different interfaces provided on the mixing assembly facing the side of the structural assembly to achieve communication between the mixing assembly and the several syringes, thereby facilitating the filling of different injection liquids into the corresponding syringes and pushing them to the mixing assembly based on appropriate proportions to complete the mixing of the injection liquids and form a gel preparation.

7. The gel preparation injection system for local radiotherapy according to claim 6, characterized in that: The second injection component is connected to the retained needle of the first injection component. The second injection component injects the gel preparation mixed by the structural component and the mixing component into the patient's body continuously, synchronously and at a uniform speed within a predetermined time after contact and mixing. The total amount of the injected gel preparation is a second capacity.

8. The gel preparation injection system for local radiotherapy according to claim 7, characterized in that: The gel preparation can adjust the amount and ratio of the first component and / or the second component and / or the buffer at least based on the required distance between the healthy organ and the radiotherapy site and / or based on different injection sites of the patient through the second injection component. The first component and / or the second component are selected from one or more of polyethylene glycol derivatives, polylactic acid, PLGA, and memory materials, and the memory material is memory foam.

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