CN116077817A - A gel formulation injection system for local radiotherapy - Google Patents
A gel formulation injection system for local radiotherapyDownload PDFInfo
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Abstract
Translated fromChinese
Description
Translated fromChinese技术领域technical field
本发明涉及注射领域，尤其涉及一种用于局部放疗的凝胶制剂注射系统。The invention relates to the field of injection, in particular to a gel preparation injection system for local radiotherapy.
背景技术Background technique
前列腺癌是指发生在前列腺的上皮性恶性肿瘤，其是一种比较常见的生殖系统恶性肿瘤，其恶性程度高，起病隐匿，进展迅速，容易转移，预后极差，病死率高。近年来，前列腺癌发病率和死亡率呈快速上升趋势，严重危害人们的生命健康。然而，传统化疗药物在前列腺癌治疗中疗效十分有限，且毒副作用很大，因此放疗成为中晚期前列腺癌患者的主要选择。Prostate cancer refers to epithelial malignant tumors that occur in the prostate. It is a relatively common malignant tumor of the reproductive system. It has a high degree of malignancy, insidious onset, rapid progression, easy metastasis, extremely poor prognosis, and high mortality. In recent years, the morbidity and mortality of prostate cancer have shown a rapid upward trend, seriously endangering people's life and health. However, traditional chemotherapeutic drugs have very limited curative effect in the treatment of prostate cancer, and they have serious side effects. Therefore, radiotherapy has become the main choice for patients with advanced prostate cancer.
放疗是治疗前列腺癌的重要手段，但放疗往往会危及周围其他器官或组织，造成其他器官或组织的损伤，尤以直肠为甚。为了降低对周围组织和器官的伤害，放疗过程中往往会降低射线剂量，导致无法有效杀死癌细胞。由于前列腺和直肠靠得比较近，放疗治疗前列腺癌时通常会造成直肠损伤，增加放疗性直肠炎风险。Radiotherapy is an important means of treating prostate cancer, but radiotherapy often endangers other surrounding organs or tissues, causing damage to other organs or tissues, especially the rectum. In order to reduce the damage to surrounding tissues and organs, the radiation dose is often reduced during radiotherapy, resulting in the inability to effectively kill cancer cells. Due to the close proximity of the prostate and rectum, radiation therapy for prostate cancer often causes damage to the rectum, increasing the risk of radiation-induced proctitis.
水凝胶是一种由亲水性聚合物交联得到的含有大量水分的材料。水凝胶具有优良的理化性能和生物学特性，如高含水量、高弹性、柔软、具有良好的生物相容性等特点，在药物转运、组织工程等生物医学研究领域有着重要的应用价值。可注射水凝胶是指具有一定流动性的、能够通过注射的方法应用的一类水凝胶，在注射入人体之前呈液态或是具有剪切变稀性质的半固态，在注射入人体内之后能原位成胶，因而不需要侵入性手术，这有效地避免了感染的风险，并减轻了病人的痛苦。现有技术中可将凝胶制剂作为辐射防护材料。Hydrogel is a material containing a large amount of water obtained by cross-linking hydrophilic polymers. Hydrogels have excellent physical and chemical properties and biological properties, such as high water content, high elasticity, softness, and good biocompatibility. They have important application values in biomedical research fields such as drug delivery and tissue engineering. Injectable hydrogel refers to a type of hydrogel that has certain fluidity and can be applied by injection. It is liquid or semi-solid with shear thinning properties before being injected into the human body. Afterwards, it can be glued in situ, so invasive surgery is not required, which effectively avoids the risk of infection and reduces the pain of the patient. Gel preparations can be used as radiation protection materials in the prior art.
例如，CN 109646723B公开了一种医用水凝胶，由醛基封端的星形多臂聚乙二醇和多氨基化合物原位交联而成，所述醛基与星形多臂聚乙二醇之间以醚键、酰胺键、氨酯键、亚胺键或脲键化学键连接，所述多氨基化合物中氨基与醛基封端的星形多臂聚乙二醇中醛基的摩尔比为0.4～4.4∶1，所述多氨基化合物为聚赖氨酸或聚赖氨酸与聚乙烯亚胺的混合物，聚赖氨酸与聚乙烯亚胺的摩尔比为2～30∶3。该发明水凝胶成胶快，在水溶液中具有长期稳定性，在多次辐照后仍然具有很好的溶胀性能和稳定性，可以作为医用放疗防护垫片用于辐射防护。For example, CN 109646723B discloses a medical hydrogel, which is formed by in-situ cross-linking of star-shaped multi-arm polyethylene glycol terminated by aldehyde groups and polyamino compounds, and the aldehyde group and star-shaped multi-arm polyethylene glycol They are connected by chemical bonds of ether bond, amide bond, urethane bond, imine bond or urea bond, and the molar ratio of the amino group in the polyamino compound to the aldehyde group in the star-shaped multi-arm polyethylene glycol terminated by the aldehyde group is 0.4～ 4. 4:1, the polyamino compound is polylysine or a mixture of polylysine and polyethyleneimine, and the molar ratio of polylysine to polyethyleneimine is 2-30:3. The hydrogel of the invention gels quickly, has long-term stability in aqueous solution, and still has good swelling performance and stability after multiple irradiations, and can be used as a medical radiotherapy protective gasket for radiation protection.
此外，现有技术中在放射治疗领域使用的水凝胶还可基于不同的组分形成不同性质的组合物。In addition, the hydrogels used in the field of radiotherapy in the prior art can also form compositions with different properties based on different components.
例如，CN 113461973A公开了一种可注射型的医用水凝胶，由醛基封端的星形多臂聚乙二醇、聚乙烯亚胺和酰肼基封端的多臂聚乙二醇交联而成，所述醛基封端的星形多臂聚乙二醇的臂数为2～8，单臂分子量1000～5000Da，能够应用于放疗垫片、血管栓塞、术后组织密封与防渗漏、防组织黏连、组织填充剂、组织修复、皮肤敷料和药物释放等领域。该凝胶能够用于注射降解，但难以格挡射线，保护组织和器官。For example, CN 113461973A discloses an injectable medical hydrogel, which is cross-linked by aldehyde-terminated star-shaped multi-arm polyethylene glycol, polyethyleneimine and hydrazide-terminated multi-arm polyethylene glycol. The number of arms of the aldehyde-terminated star-shaped multi-arm polyethylene glycol is 2-8, and the molecular weight of a single arm is 1000-5000 Da, which can be applied to radiotherapy gaskets, vascular embolism, postoperative tissue sealing and anti-leakage, Anti-tissue adhesion, tissue filler, tissue repair, skin dressing and drug release and other fields. The gel can be used for injection degradation, but it is difficult to block radiation and protect tissues and organs.
CN 106215199B涉及一种用于肿瘤局部放疗的可注射多肽水凝胶及其制备方法。它是由聚乙二醇和疏水性聚酪氨酸高分子嵌段聚合物自组装成，通过氯胺T法将放疗剂131I标记在水凝胶的聚酪氨酸链段，即完成对放疗剂的装载，形成局部放疗用水凝胶制剂。本发明的可注射水凝胶放疗剂具有高放疗剂装载率、无毒、稳定、可降解、易于注射等特点。该发明开创了凝胶对肿瘤的特异性长期局部放疗，与其它放疗用制剂相比，具有易于注射治疗、免于手术开创植入和取出籽源、对非肿瘤组织无放射损伤、药效时间长等优点。CN 106215199B relates to an injectable polypeptide hydrogel for local tumor radiotherapy and a preparation method thereof. It is self-assembled by polyethylene glycol and hydrophobic polytyrosine polymer block polymer, and radiotherapeutic agent131 I is labeled on the polytyrosine segment of the hydrogel by the chloramine T method, that is, complete radiotherapy Agent loading to form a hydrogel preparation for local radiotherapy. The injectable hydrogel radiotherapy agent of the present invention has the characteristics of high radiotherapy agent loading rate, non-toxic, stable, degradable, easy to inject and the like. This invention pioneered the specific long-term local radiotherapy of the gel on tumors. Compared with other preparations for radiotherapy, it has the advantages of easy injection treatment, no need for surgery to create implantation and removal of the seed source, no radiation damage to non-tumor tissues, and long-term drug effect. Long and other advantages.
但是现有技术未针对患有特定癌症(例如前列腺癌)的不同患者在放疗过程中的不同时期进行具体分析，不同放疗部位、不同放疗时期、不同患者个体差异都会对凝胶制剂的使用产生影响，目前，需要一种用于局部放疗的凝胶制剂注射系统来适应于不同的使用场景。However, the prior art does not specifically analyze different patients with specific cancers (such as prostate cancer) at different stages of the radiotherapy process. Different radiotherapy sites, different radiotherapy periods, and individual differences in different patients will have an impact on 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.
此外，一方面由于对本领域技术人员的理解存在差异；另一方面由于申请人做出本发明时研究了大量文献和专利，但篇幅所限并未详细罗列所有的细节与内容，然而这绝非本发明不具备这些现有技术的特征，相反本发明已经具备现有技术的所有特征，而且申请人保留在背景技术中增加相关现有技术之权利。In addition, on the one hand, due to differences in the understanding of those skilled in the art; The present invention does not possess the characteristics of these prior art, on the contrary, the present invention already possesses all the characteristics of the prior art, and the applicant reserves the right to add relevant prior art to the background technology.
发明内容Contents of the invention
针对现有技术之不足，本发明公开了一种用于局部放疗的凝胶制剂注射系统，所述系统至少包括注射套件、数据探测模块、第一数据处理模块、第二数据处理模块和注射分析模块。所述数据探测模块被配置为：在对患者的放疗部位和健康器官之间的位置执行至少一个注射步骤时探测与该注射步骤相关的所述注射套件的至少一个位置数据以确立注射展开。所述第一数据处理模块用于对所述数据探测模块探测到的所述位置数据进行数据处理并将经过数据处理的位置数据传输至所述第二数据处理模块以通过注射套件执行下一注射步骤。本发明的一种用于局部放疗的凝胶制剂注射系统进一步减少了注入凝胶制剂需要的时间，并且提高凝胶制剂注入的精准度，减少了患者的疼痛，防止因人工操作导致的各种对患者的二次伤害，防止因植入、穿刺导致的各类并发症，例如感染、轻度血精、轻度下尿路症状等。Aiming at the deficiencies of the prior art, the present invention discloses a gel preparation injection system for local radiotherapy, 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 module. The data detection module is configured to detect at least one position data of the injection set associated with at least one injection step at a location between a patient's radiation therapy site and a healthy organ to establish injection deployment while the injection step is performed. The first data processing module is used to perform data processing on the position data detected by the data detection module and transmit the processed position data to the second data processing module to perform the next injection through the injection set step. A gel preparation injection system for local radiotherapy of the present invention further reduces the time required for injecting the gel preparation, improves the accuracy of the injection of the gel preparation, reduces the pain of the patient, and prevents various injuries caused by manual operations. Secondary injury to patients, preventing various complications caused by implantation and puncture, such as infection, mild blood semen, mild lower urinary tract symptoms, etc.
根据一种优选实施方式，其中，所述注射分析模块被配置为基于所述位置数据对所述注射套件位于患者体内的矢状面与横断面进行位置分析并对下一注射步骤进行风险分析。注射分析模块把控第一注射组件的穿刺过程，防止第一注射组件误刺入患者体内的放疗部位、领近组织和脏器中，以避免对患者造成二次伤害，同时保证凝胶制剂能够准确注入患者放疗部位和领近组织之间，从而达到最好的隔离效果。According to a preferred embodiment, wherein, the injection analysis module is configured to perform position analysis on the sagittal plane and cross-section of the injection kit in the patient's body based on the position data, and perform risk analysis on 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 piercing into the radiotherapy site, adjacent tissues and organs in the patient, so as to avoid secondary damage to the patient, and at the same time ensure that the gel preparation can Accurately inject between the patient's radiotherapy site and the adjacent tissue, so as to achieve the best isolation effect.
根据一种优选实施方式，所述注射套件包括第一注射组件和第二注射组件，所述第一注射组件在对患者的放疗部位和健康器官之间的位置进行穿刺之前，所述数据探测模块置于患者局部放疗位置贴近患者皮肤以确立需要进行注射部位的位置数据，并传输至所述第一数据处理模块，所述第一数据处理模块进行数据处理得出所述第一注射组件的穿刺深度以及穿刺角度并传输至所述第二数据处理模块以调节所述第一注射组件按照所述穿刺深度以及穿刺角度进行推进。依据第一数据处理模块进行数据处理，以调节第一注射组件的动作，稳定撑开患者放疗部位和邻近组织、脏器，第一注射组件匀速刺入并且基于内部容量同比匀速注入生理盐水以充分发挥水分离效果，提高后续注入凝胶制剂的成型效果，减少并发症。According to a preferred embodiment, the injection set includes a first injection assembly and a second injection assembly, and before the first injection assembly punctures a position between the patient's radiotherapy site and a healthy organ, the data detection module Place 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, and the first data processing module performs data processing to obtain the puncture of the first injection component The depth and puncture angle are transmitted to the second data processing module to adjust the first injection assembly to advance according to the puncture depth and puncture angle. Perform data processing according to the first data processing module to adjust the action of the first injection assembly, stably expand the radiotherapy site and adjacent tissues and organs of the patient, penetrate the first injection assembly at a uniform speed and inject normal saline at a constant speed based on the internal volume to fully Give full play to the effect of water separation, improve the molding effect of subsequent injection gel preparations, and reduce complications.
根据一种优选实施方式，所述第一注射组件在穿刺到设定位置时，基于所述数据探测模块探测的位置数据以及所述第一数据处理模块进行的数据处理，第一注射组件停止进行穿刺并注入所述第一注射组件内的液体以扩大患者放疗部位和健康器官的间隙。第一注射组件所用液体为生理盐水，第一注射组件缓慢注入少量生理盐水以扩开间隙，给出注入凝胶制剂的注入空间以及提高成型效果。According to a preferred embodiment, when the first injection assembly is punctured 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 assembly stops Piercing and injecting the liquid in the first injection assembly to expand the gap between the radiotherapy site of the patient and the healthy organ. The liquid used in the first injection assembly is physiological saline, and the first injection assembly slowly injects a small amount of physiological saline to expand the gap, provide an injection space for injecting the gel preparation and improve the molding effect.
根据一种优选实施方式，所述间隙扩大后，基于所述数据探测模块探测的位置数据，所述第一数据处理模块得出所述第一注射组件需继续穿刺的深度，所述深度是指当前第一注射组件所处位置至结束时第一注射组件针尖需所处位置的距离，基于所述距离匀速推进所述第一注射组件并基于所述第一注射组件内液体容量以及所述距离同比匀速注入液体，当所述第一注射组件针尖位于预定最终位置时，注入剩余液体，注入液体的总量为第一容量。第一容量基于注射部位和放疗部位的大小进行适量选择，例如若患者需隔绝前列腺和直肠，向直肠前壁内注入适量生理盐水。第一注射组件匀速刺入并且基于内部容量同比匀速注入生理盐水，以充分发挥水分离效果，并且使得生理盐水撑开空间。优选地，其注入液体还可为局部麻醉药物例如利多卡因，其作用于生理盐水之前，并注射于多个部位，例如注射部位的皮下、中间、左右。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 obtains the depth that the first injection assembly needs to continue to puncture, and the depth refers to The distance between the current position of the first injection component and the position where the needle tip of the first injection component needs to be at the end, advancing the first injection component at a constant speed based on the distance and based on the liquid volume in the first injection component and the distance The liquid is injected at a uniform speed in the same period, and when the needle point of the first injection assembly is at the predetermined final position, the remaining liquid is injected, and the total amount of injected liquid is the first capacity. The first volume 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 normal saline is injected into the anterior wall of the rectum. The first injection component penetrates at a constant speed and injects the normal saline at a constant speed based on the internal volume, so as to fully exert the water separation effect and make the normal saline expand the space. Preferably, the injection liquid can also be a local anesthetic drug such as lidocaine, which is injected into multiple sites before acting on the saline, such as the subcutaneous, middle, and left sides of the injection site.
根据一种优选实施方式，所述注射分析模块基于所述数据探测模块探测的位置数据和/或B型超声检查得出所述第一注射组件位于患者体内的矢状面与横断面，与预设方案对比进行风险分析，所述风险分析至少包括所述第一注射组件所处位置是否准确以及第二注射组件注入的凝胶制剂是否能够基于患者的个体差异将健康器官和放疗部位分隔开并具有安全隔开距离，以减少患者放射性损伤的风险，实现高剂量放射性的基础上降低对体内周围危及器官的损伤，进一步保障水凝胶隔绝放疗部位和邻近组织、脏器。According to a preferred embodiment, the injection analysis module obtains the sagittal plane and cross section of the first injection component in the patient's body based on the position data detected by the data detection module and/or B-mode ultrasound examination, and the predicted Carrying out risk analysis based on plan comparison, the risk analysis at least includes whether the position of the first injection assembly is accurate and whether the gel preparation injected by the second injection assembly can separate healthy organs from radiotherapy sites based on individual differences of patients And it has a safe separation distance to reduce the risk of radiation injury to patients, and reduce the damage to organs at risk around the body on the basis of high-dose radiation, and further ensure that the hydrogel isolates the radiotherapy site from adjacent tissues and organs.
根据一种优选实施方式，所述注射分析模块分析所述第一注射组件所处位置准确时，第一注射组件负压回抽以确保所述第一注射组件针尖未处于患者血管内，去除所述第一注射组件的注射器，留置所述第一注射组件的针头，以完成所述第一注射组件的注射步骤。According to a preferred embodiment, when the injection analysis module analyzes that the position of the first injection assembly is correct, the first injection assembly is withdrawn with negative pressure to ensure that the needle tip of the first injection assembly is not in the patient's blood vessel, and remove all the syringe of the first injection assembly, and retain the needle of the first injection assembly to complete the injection step of the first injection assembly.
根据一种优选实施方式，所述第二注射组件至少包括架构组件和混合组件，其中，所述架构组件中预留有可放置若干个注射器的中空区域以及若干处卡扣，使注射器能够以贯穿于相应中空区域的方式放置在架构组件上，并通过架构组件上的卡扣进行限位固定，所述注射器喷口端通过与混合组件多联端中的限位凸起进行连接，使得处于注射器中的待注射液能通过混合组件多联端流入混合组件。在设置有若干个注射器的情况下，不同的注射器能够通过与混合组件在朝向于架构组件一侧设置的若干个不同的接口连接，以实现混合组件与若干个注射器的连通，从而便于不同的待注射液装填至相应的注射器内，并基于适当的比例推送至混合组件以完成待注射液的混合并形成凝胶制剂。上述凝胶制剂具有可注射性和快速成胶性，在第一组分与第二组分溶液混合后可在水环境下较短时间内成胶，用于阻隔放疗时射线。According to a preferred embodiment, the second injection assembly includes at least a frame assembly and a mixing assembly, wherein a hollow area where several syringes can be placed and several buckles are reserved in the frame assembly, so that the syringes can pass through It is placed on the frame assembly in the corresponding hollow area, and is fixed by the buckle on the frame assembly. The nozzle end of the syringe is connected with the stop protrusion in the multi-joint end of the mixing assembly, so that it is in the syringe The liquid to be injected can flow into the mixing component through the multi-connected end of the mixing component. In the case where several syringes are provided, different syringes can be connected to several different interfaces of the mixing assembly on the side facing the frame assembly to realize the communication between the mixing assembly and several syringes, thereby facilitating different The injection liquid is filled into the corresponding syringe, and pushed to the mixing component based on the appropriate ratio to complete the mixing of the liquid to be injected and form a gel preparation. The above-mentioned gel preparation has injectability and rapid gelation property, and can be gelled in a short time under water environment after the first component and the second component solution are mixed, and is used for blocking radiation during radiotherapy.
根据一种优选实施方式，所述第二注射组件连接于留置的所述第一注射组件的针头，所述第二注射组件将经过所述架构组件和混合组件混合后的凝胶制剂在接触混合后的预定时间内连续同步并且匀速注入患者体内，注入凝胶制剂的总量为第二容量。预定时间是指凝胶制剂进入患者体内的最佳时间，在本发明的凝胶制剂中，该时间为能使凝胶制剂快速凝胶的时间，即将混合后的凝胶制剂在快速凝胶范围内全部注入患者体内。According to a preferred embodiment, the second injection assembly is connected to the indwelling needle of the first injection assembly, and the second injection assembly mixes the gel preparation mixed by the architecture assembly and the mixing assembly in contact with each other. The gel preparation is injected continuously and at a constant speed into the patient within a predetermined period of time, and the total amount of the injected gel preparation is the second volume. 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 that can make the gel preparation quickly gel, that is, the gel preparation after mixing is within the range of fast gel. injected into the patient's body.
根据一种优选实施方式，所述凝胶制剂至少能够基于健康器官需要相对于放疗部位的隔开距离和/或基于患者不同的注射部位通过所述第二注射组件而调节第一组分和/或第二组分和/或缓冲液的用量，解决的间隔不同的问题，减小因撑开患者放疗部位和邻近组织、脏器带来的局部不适感，甚至穿孔、里急后重感等，并且通过架构组件和混合组件也能够调节注入凝胶制剂的时间和同步注入的速度，同时注入的总容量也能根据需要进行调节。所述第一组分和/或第二组分选自聚乙二醇衍生物、聚乳酸、PLGA、记忆材料中的一种或多种，所述记忆材料优选为记忆海绵。本发明放疗术前用可注射水凝胶具有填充、阻隔直肠与前列腺接触、增加直肠与前列腺距离、可注射、可降解的作用。在放疗术前用导管输送入腹腔内，并在腹腔内形成水凝胶，阻隔直肠与前列腺接触，增大直肠与前列腺距离，防止放疗治疗前列腺癌时损伤直肠，间接增大放疗时靶区剂量，并在术后三个月内降解，避免了二次创面的损伤。因此本发明对该放疗术前用可注射水凝胶的制备方法，以及在放疗术前的应用也进行说明。According to a preferred embodiment, the gel formulation can at least adjust the first component and/or the first component and/or based on the second injection component based on the distance of the healthy organ from the radiotherapy site and/or based on the different injection sites of the patient. Or the amount of the second component and/or buffer solution to solve the problem of different intervals, reduce the local discomfort caused by spreading the patient's radiotherapy site and adjacent tissues and organs, even perforation, tenesmus, etc., and through The architecture component and the mixing component are also able to adjust the timing of injection of the gel formulation and the speed of simultaneous injection, while the total volume injected 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 materials are preferably memory foam. 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, and being injectable and degradable. Before radiotherapy, a catheter is used to transport it into the abdominal cavity, and a hydrogel is formed in the abdominal cavity to block the contact between the rectum and the prostate, increase the distance between the rectum and the prostate, prevent the rectum from being damaged during radiotherapy for prostate cancer, and indirectly increase the dose of the target area during radiotherapy , and degrade within three months after surgery, avoiding secondary wound damage. Therefore, the present invention also describes the preparation method of the injectable hydrogel for radiotherapy and its application before radiotherapy.
本发明具有如下有益技术效果：The present invention has the following beneficial technical effects:
(1)本发明采用注射套件、数据探测模块、第一数据处理模块、第二数据处理模块和注射分析模块协助注射，将凝胶制剂通过系统调控以达到高精度注射的效果，减少了患者的疼痛，减小因人工操作导致的各种对患者的二次伤害，在放疗过程中也保护了周围健康器官，防止其被电离辐射损伤，减小放疗导致的全身反应和局部放射性损伤，达到清除癌细胞同时保护患者健康器官的目的。同时也防止因植入、穿刺导致的各类并发症，例如感染和轻度血精等；(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 injection, and the gel preparation is regulated by the system to achieve the effect of high-precision injection, reducing the patient's Pain, reduce various secondary injuries to patients caused by manual operation, protect surrounding healthy organs during radiotherapy, prevent them from being damaged by ionizing radiation, reduce systemic reactions and local radiation damage caused by radiotherapy, and achieve clearing The purpose of 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 blood semen, etc.;
(2)通过数据探测模块对第一注射组件的位置数据检测，实现水凝胶的精准注入，从而增加放疗部位和邻近组织、脏器之间的距离，降低放射性损伤的发生率，提高患者生活质量，防止患者急性期肠道等多种放射性损伤并发症的出现；(2) Through the data detection module to detect the position data of the first injection component, realize the precise injection of hydrogel, thereby increasing the distance between the radiotherapy site and adjacent tissues and organs, reducing the incidence of radiation damage, and improving the life of patients Quality, to prevent the emergence of multiple radiation injury complications such as intestinal tract in patients in the acute stage;
(3)依据第一数据处理模块进行数据处理，以调节第一注射组件的动作，稳定撑开患者放疗部位和邻近组织、脏器，第一注射组件匀速刺入并且基于内部容量同比匀速注入生理盐水以充分发挥水分离效果，提高后续注入凝胶制剂的成型效果，减少并发症；(3) Perform data processing according to the first data processing module to adjust the action of the first injection assembly, stably expand the patient's radiotherapy site and adjacent tissues and organs, and the first injection assembly penetrates at a uniform speed and injects physiological injections at a uniform rate based on the internal volume. Saline to give full play to the water separation effect, improve the molding effect of subsequent injection gel preparations, and reduce complications;
(4)通过注射分析模块确立第一注射组件所处位置是否准确以及第二注射组件注入的凝胶制剂是否能够基于患者的个体差异将健康器官和放疗部位分隔开并具有安全隔开距离，以减少患者放射性损伤的风险，实现高剂量放射性的基础上降低对体内周围危及器官的损伤，进一步保障水凝胶隔绝放疗部位和邻近组织、脏器；(4) Establish 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 organ from the radiotherapy site based on the individual differences of patients and have a safe separation distance through the injection analysis module, In order to reduce the risk of radiation damage to patients, reduce the damage to the surrounding organs in the body on the basis of high-dose radiation, and further ensure that the hydrogel isolates the radiotherapy site from adjacent tissues and organs;
(5)通过第二注射组件的架构组件和混合组件，将各第一组分和/或第二组分和/或缓冲液基于健康器官需要相对于放疗部位的隔开距离和/或基于患者不同的注射部位进行用量的选择，解决间隔不同的问题，减小因撑开患者放疗部位和邻近组织、脏器带来的局部疼痛感，甚至穿孔、里急后重感等，并且通过架构组件和混合组件也能够调节注入凝胶制剂的时间、同步注入的速度，同时注入的总容量也能根据需要进行调节；(5) Through the framework component and the mixing component of the second injection component, each first component and/or second component and/or buffer solution is separated from the radiotherapy site based on the healthy organ needs and/or based on the patient Choose the dosage at different injection sites, solve the problem of different intervals, reduce the local pain caused by spreading the patient's radiotherapy site and adjacent tissues and organs, and even perforation, tenesmus, etc. It is also possible to adjust the injection time of the gel preparation, the speed of synchronous injection, and the total volume injected can also be adjusted according to needs;
(6)本发明采用n arms-琥珀酰亚胺戊二酸酯聚乙二醇(其中，n≥4)与m arms-氨基聚乙二醇(其中，m≥4)发生迈克尔加成反应形成水凝胶。聚乙二醇是一种水溶性聚醚型高分子化合物，广泛用于医药、卫生、食品、化工等领域。聚乙二醇具有很多优点，如低毒性、不凝血性以及良好的生物相容性，因而能在失效后被机体迅速排出体外而不产生任何毒副作用。聚乙二醇和其他分子偶合时，其许多优良性质也会随之转移到结合物中；(6) The present invention uses n arms-succinimide glutarate polyethylene glycol (where n≥4) and m arms-amino polyethylene glycol (wherein m≥4) to form a Michael addition reaction Hydrogels. Polyethylene glycol is a water-soluble polyether polymer compound widely used in medicine, sanitation, food, chemical industry and other fields. Polyethylene glycol has many advantages, such as low toxicity, non-coagulation and good biocompatibility, so it can be quickly excreted by the body after failure without any toxic side effects. When polyethylene glycol is coupled with other molecules, many of its excellent properties will also be transferred to the conjugate;
(7)本发明提供的一种可注射水凝胶，无需开刀，可直接在注射系统辅助下直接注射到需隔绝位置，并迅速成胶，并在放疗术后三个月内完全降解，无需开刀，能减轻患者的疼痛及开刀造成的损伤，控制少量出血，降低感染风险。(7) An injectable hydrogel provided by the present invention can be directly injected into the location to be isolated with the assistance of the injection system without surgery, and can be gelled rapidly and completely degraded within three months after radiotherapy without the need for Surgery can reduce the patient's pain and damage caused by surgery, control a small amount of bleeding, and reduce the risk of infection.
附图说明Description of drawings
图1是本发明的一种优选实施方式中用于局部放疗的凝胶制剂注射系统的流程图；Fig. 1 is the flow chart of the gel preparation injection system for local radiotherapy in a kind of preferred embodiment of the present invention;
图2是本发明的一种优选实施方式中八臂琥珀酰亚胺戊二酸酯聚乙二醇的结构式；Fig. 2 is the structural formula of eight-arm succinimide glutarate polyethylene glycol in a preferred embodiment of the present invention;
图3是本发明的一种优选实施方式中四臂氨基聚乙二醇的结构式。Fig. 3 is the structural formula of four-arm aminopolyethylene glycol in a preferred embodiment of the present invention.
附图标记列表List of reference signs
1：数据探测模块；2：第一数据处理模块；3：第二数据处理模块；401：第一注射组件；402：第二注射组件。1: data detection module; 2: first data processing module; 3: second data processing module; 401: first injection component; 402: second injection component.
具体实施方式Detailed ways
下面结合附图进行详细说明。A detailed description will be given below in conjunction with the accompanying drawings.
本发明涉及一种用于局部放疗的凝胶制剂，尤其是适用于前列腺癌和/或宫颈癌患者的局部放疗的凝胶制剂，通过注射具有优越的三维多孔性、高含水量性、不定型性、组织粘附性、生物可降解性、良好的生物相容性的凝胶制剂将直肠与前列腺或阴道隔开，以阻隔前列腺或阴道与直肠接触，从而可通过提高靶区剂量的方式有效杀死癌细胞的同时，避免对周围组织和器官的伤害。The invention relates to a gel preparation for local radiotherapy, especially a gel preparation suitable for local radiotherapy of patients with prostate cancer and/or cervical cancer, which has excellent three-dimensional porosity, high water content, and amorphous Gel formulations that are non-toxic, tissue-adhesive, biodegradable, and good biocompatibility separate the rectum from the prostate or vagina to block the contact between the prostate or vagina and the rectum, which can be effective by increasing the dose of the target area While killing cancer cells, avoid damage to surrounding tissues and organs.
根据一种优选实施方式，凝胶制剂至少包括多臂琥珀酰亚胺戊二酸酯聚乙二醇和多臂氨基聚乙二醇，其中，通过多臂琥珀酰亚胺戊二酸酯聚乙二醇和多臂氨基聚乙二醇进行迈克尔加成反应来交联形成可注射水凝胶。迈克尔加成反应是亲电的共轭体系(电子受体)与亲核的负碳离子(电子给体)进行的共轭加成反应，其反应机理为琥珀酰亚胺戊二酸酯聚乙二醇的N-O共价键与氨基聚乙二醇的胺基结合，发生聚合反应以生成水凝胶，副产物N-羟基琥珀酰亚胺残留在水凝胶中，随凝胶的降解排出。进一步地，多臂琥珀酰亚胺戊二酸酯聚乙二醇可选用n arms-琥珀酰亚胺戊二酸酯聚乙二醇(其中，n≥4)，多臂氨基聚乙二醇可选用m arms-氨基聚乙二醇(其中，m≥4)。随着臂数的增长，成胶速度变快，可基于患者需要的成胶速度，选择其成分的不同结构，以多种臂数适应于多种环境和/或领域。According to a preferred embodiment, the gel preparation at least includes multi-arm succinimide glutarate polyethylene glycol and multi-arm amino polyethylene glycol, wherein, through multi-arm succinimide glutarate polyethylene glycol Alcohol and multi-armed aminopolyethylene glycol undergo Michael addition reaction to form injectable hydrogel. The Michael addition reaction is a conjugated addition reaction between an electrophilic conjugated system (electron acceptor) and a nucleophilic carbanion (electron donor). The reaction mechanism is succinimide glutarate polyethylene The N-O covalent bond of the diol is combined with the amine group of aminopolyethylene glycol to undergo a polymerization reaction to form a hydrogel, and the by-product N-hydroxysuccinimide remains in the hydrogel and is discharged with the degradation of the gel. Further, the multi-arm succinimide glutarate polyethylene glycol can be selected from n arms-succinimide glutarate polyethylene glycol (wherein, n≥4), and the multi-arm amino polyethylene glycol can be Use m arms-amino polyethylene glycol (wherein, m≥4). With the increase of the number of arms, the speed of gelation becomes faster. Based on the speed of gelation required by the patient, different structures of its components can be selected to adapt to various environments and/or fields with various numbers of arms.
根据一种优选实施方式，迈克尔加成反应必须在碱的催化下进行，常用的碱有：乙醇钠、氢化钠、氨基钠和有机碱等。根据反应物的反应活性来选择合适的碱，如果反应物双方均有较高的反应活性时，用较弱的碱也能使反应进行。亲电的共轭体系(电子受体)与亲核的负碳离子(电子给体)进行的共轭加成反应。进一步地，凝胶制剂包括有能够对水凝胶的pH进行调节的缓冲液，其中，可先将第一组分和第二组分分别溶于各自的缓冲液中再进行充分混合，并在超声波探测器辅助下注入腹腔需形成凝胶的部位。优选地，缓冲液可选为碱性缓冲液，使得制得的凝胶制剂的pH适应于人体内腹腔需形成凝胶的部位的pH，例如将制得的凝胶制剂pH控制在7.0～7.5，以适应人体组织液的pH。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. Choose the appropriate base according to the reactivity of the reactant. If both reactants have high reactivity, the reaction can also be carried out with a weaker base. Conjugate addition reaction between an electrophilic conjugated system (electron acceptor) and a nucleophilic carbanion (electron donor). Further, the gel preparation includes a buffer that can adjust the pH of the hydrogel, wherein the first component and the second component can be dissolved in their respective buffers and then thoroughly mixed, and With the aid of an ultrasound probe, it is injected into the abdominal cavity where the gel needs to be formed. Preferably, the buffer can be an alkaline buffer, so that the pH of the prepared gel preparation is adapted to the pH of the site where the gel needs to be formed in the peritoneal cavity of the human body, for example, the pH of the prepared gel preparation is controlled at 7.0-7.5 , to adapt to the pH of human tissue fluid.
实施例1Example 1
本实施例涉及一种用于局部放疗的凝胶制剂注射系统，所述系统至少包括注射套件、数据探测模块、第一数据处理模块、第二数据处理模块和注射分析模块。所述数据探测模块被配置为：在对患者的放疗部位和健康器官之间的位置执行至少一个注射步骤时探测与该注射步骤相关的所述注射套件的至少一个位置数据以确立注射展开。所述第一数据处理模块用于对所述数据探测模块探测到的所述位置数据进行数据处理并将经过数据处理的位置数据传输至所述第二数据处理模块以调节注射套件执行下一注射步骤。优选地，数据探测模块可采用超声(TRUS)组件，将超声探头置于患者需要注射部位，并作为引导部件，确保第一注射组件沿平行于超声探头方式缓慢刺入患者需要注射部位。优选地，数据探测模块还可采用计算机断层扫描仪或核磁共振成像或正电子发射断层扫描等多种检测方式，对此不进行赘述。本发明的一种用于局部放疗的凝胶制剂注射系统进一步减少了注入凝胶制剂需要的时间，并且提高凝胶制剂注入的精准度，减少了患者的疼痛，减小因人工操作导致的各种对患者的二次伤害，在放疗过程中也保护了周围健康器官，防止其被电离辐射损伤，减小放疗导致的全身反应和局部放射性损伤，达到清除癌细胞同时保护患者健康器官的目的。同时也防止因植入、穿刺导致的各类并发症，例如感染和轻度血精等。This embodiment relates to a gel preparation injection system for local radiotherapy, 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 detect at least one position data of the injection set associated with at least one injection step at a location between a patient's radiation therapy site and a healthy organ to establish injection deployment while the injection step is performed. The first data processing module is used to perform data processing on 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 ultrasonic (TRUS) component to place the ultrasonic probe at the site where the patient needs injection, and as a guiding component, to ensure that the first injection component slowly penetrates the site where the patient needs injection in parallel to the ultrasonic probe. Preferably, the data detection module can also adopt multiple detection methods such as computer tomography scanner, nuclear magnetic resonance imaging, or positron emission tomography, which will not be described in detail. A gel preparation injection system for local radiotherapy of the present invention further reduces the time required for injecting the gel preparation, improves the accuracy of the gel preparation injection, reduces the pain of the patient, and reduces various problems caused by manual operations. This kind of secondary injury to the patient also protects the surrounding healthy organs during radiotherapy, prevents them from being damaged by ionizing radiation, reduces the systemic reaction and local radiation damage caused by radiotherapy, and achieves the purpose of removing 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 blood semen.
根据一种优选实施方式，其中，所述注射分析模块被配置为基于所述位置数据对所述注射套件位于患者体内的矢状面与横断面进行位置分析并对下一注射步骤进行风险分析。依据注射分析模块保障第一注射组件的穿刺过程，防止第一注射组件误刺入患者体内的放疗部位、领近组织和脏器中，以避免对患者造成二次伤害，同时保证凝胶制剂能够准确注入患者放疗部位和领近组织之间，从而达到最好的隔离效果。需要说明的是，本发明中所述矢状面是指：在患者直立时，将待检测位置分切为左右两部分，左右切面即为矢状面。横断面是指：在患者直立时，过待检测位置中线并与矢状面垂直的断面。矢状面与横断面随着患者姿势的改变而随之改变。According to a preferred embodiment, wherein, the injection analysis module is configured to perform position analysis on the sagittal plane and cross-section of the injection kit in the patient's body based on the position data, and perform risk analysis on the next injection step. Guarantee the puncture process of the first injection component according to the injection analysis module, prevent the first injection component from accidentally piercing into the radiotherapy site, adjacent tissues and organs in the patient, so as to avoid secondary damage to the patient, and at the same time ensure that the gel preparation can Accurately inject between the patient's radiotherapy site and the adjacent tissue, 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 upright, the position to be detected is divided into left and right parts, and the left and right cut planes are the sagittal plane. Transverse section refers to the section that passes through the midline of the position to be tested and is perpendicular to the sagittal plane when the patient is upright. The sagittal and transverse planes change as the patient's posture changes.
根据一种优选实施方式，所述注射套件包括第一注射组件和第二注射组件，所述第一注射组件在对患者的放疗部位和健康器官之间的位置进行穿刺之前，所述数据探测模块置于患者局部放疗位置贴近患者皮肤以确立需要进行注射部位的位置数据，并传输至所述第一数据处理模块，所述第一数据处理模块进行数据处理得出所述第一注射组件的穿刺深度以及穿刺角度并传输至所述第二数据处理模块以调节所述第一注射组件按照所述穿刺深度以及穿刺角度进行推进。通过第一数据处理模块进行数据处理，以调节第一注射组件的动作，稳定撑开患者放疗部位和邻近组织、脏器，第一注射组件匀速刺入并且基于内部容量同比匀速注入生理盐水以充分发挥水分离效果，提高后续注入凝胶制剂的成型效果，减少并发症。According to a preferred embodiment, the injection set includes a first injection assembly and a second injection assembly, and before the first injection assembly punctures a position between the patient's radiotherapy site and a healthy organ, the data detection module Place 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, and the first data processing module performs data processing to obtain the puncture of the first injection component The depth and puncture angle are transmitted to the second data processing module to adjust the first injection assembly to advance according to the puncture depth and puncture angle. Data processing is performed by the first data processing module to adjust the action of the first injection assembly, stably propel the patient's radiotherapy site and adjacent tissues and organs, and the first injection assembly penetrates at a uniform speed and injects normal saline at a constant speed based on the internal volume to fully Give full play to the effect of water separation, improve the molding effect of subsequent injection gel preparations, and reduce complications.
根据一种优选实施方式，所述第一注射组件在穿刺到设定位置时，基于所述数据探测模块探测的位置数据以及所述第一数据处理模块进行的数据处理，调节第一注射组件停止进行穿刺并注入所述第一注射组件内的液体以扩大患者放疗部位和健康器官的间隙。优选地，第一注射组件所用液体为生理盐水，第一注射组件缓慢注入少量生理盐水以扩开间隙，给出注入凝胶制剂的注入空间以及提高成型效果。According to a preferred embodiment, when the first injection assembly is punctured to a set position, the first injection assembly is adjusted to stop based on the position data detected by the data detection module and the data processing performed by the first data processing module. The puncture is performed and the fluid in the first injection assembly is injected to expand the gap between the patient's radiotherapy site and a healthy organ. Preferably, the liquid used in the first injection assembly is physiological saline, and the first injection assembly slowly injects a small amount of physiological saline to expand the gap, provide an injection space for injecting the gel preparation and improve the molding effect.
根据一种优选实施方式，所述间隙扩大后，基于所述数据探测模块探测的位置数据，所述第一数据处理模块得出所述第一注射组件需继续穿刺的深度，所述深度是指当前第一注射组件所处位置至结束时第一注射组件针尖需所处位置的距离，基于所述距离匀速推进所述第一注射组件并基于所述第一注射组件内液体容量以及所述距离同比匀速注入液体，当所述第一注射组件针尖位于预定最终位置时，注入剩余液体，注入液体的总量为第一容量。第一容量基于注射部位和放疗部位的大小进行适量选择，例如若患者需隔绝前列腺和直肠，向直肠前壁内注入适量生理盐水。第一注射组件匀速刺入并且基于内部容量同比匀速注入生理盐水，以充分发挥水分离效果，并且使得生理盐水撑开空间。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 obtains the depth that the first injection assembly needs to continue to puncture, and the depth refers to The distance between the current position of the first injection component and the position where the needle tip of the first injection component needs to be at the end, advancing the first injection component at a constant speed based on the distance and based on the liquid volume in the first injection component and the distance The liquid is injected at a uniform speed in the same period, and when the needle point of the first injection assembly is at the predetermined final position, the remaining liquid is injected, and the total amount of injected liquid is the first capacity. The first volume 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 normal saline is injected into the anterior wall of the rectum. The first injection component penetrates at a constant speed and injects the normal saline at a constant speed based on the internal volume, so as to fully exert the water separation effect and make the normal saline expand the space.
根据一种优选实施方式，所述注射分析模块基于所述数据探测模块探测的位置数据和/或B型超声检查得出所述第一注射组件位于患者体内的矢状面与横断面，与预设方案对比进行风险分析，所述风险分析至少包括所述第一注射组件所处位置是否准确以及第二注射组件注入的凝胶制剂是否能够基于患者的个体差异将健康器官和放疗部位分隔开并具有安全隔开距离，以减少患者放射性损伤的风险，实现高剂量放射性的基础上降低对体内周围危及器官的损伤，进一步保障水凝胶隔绝放疗部位和邻近组织、脏器。According to a preferred embodiment, the injection analysis module obtains the sagittal plane and cross section of the first injection component in the patient's body based on the position data detected by the data detection module and/or B-mode ultrasound examination, and the predicted Carrying out risk analysis based on plan comparison, the risk analysis at least includes whether the position of the first injection assembly is accurate and whether the gel preparation injected by the second injection assembly can separate healthy organs from radiotherapy sites based on individual differences of patients And it has a safe separation distance to reduce the risk of radiation injury to patients, and reduce the damage to organs at risk around the body on the basis of high-dose radiation, and further ensure that the hydrogel isolates the radiotherapy site from adjacent tissues and organs.
根据一种优选实施方式，所述注射分析模块分析所述第一注射组件所处位置准确时，第一注射组件负压回抽以确保所述第一注射组件针尖未处于患者血管内，去除所述第一注射组件的注射器，留置所述第一注射组件的针头，以完成所述第一注射组件的注射步骤。According to a preferred embodiment, when the injection analysis module analyzes that the position of the first injection assembly is correct, the first injection assembly is withdrawn with negative pressure to ensure that the needle tip of the first injection assembly is not in the patient's blood vessel, and remove all the syringe of the first injection assembly, and retain the needle of the first injection assembly to complete the injection step of the first injection assembly.
根据一种优选实施方式，所述第二注射组件至少包括架构组件和混合组件，其中，所述架构组件中预留有可放置若干个注射器的中空区域以及若干处卡扣，使注射器能够以贯穿于相应中空区域的方式放置在架构组件上，并通过架构组件上的卡扣进行限位固定，所述注射器喷口端通过与混合组件多联端中的限位凸起进行连接，使得处于注射器中的待注射液能通过混合组件多联端流入混合组件。在设置有若干个注射器的情况下，不同的注射器能够通过与混合组件在朝向于架构组件一侧设置的若干个不同的接口连接，以实现混合组件与若干个注射器的连通，从而便于不同的待注射液装填至相应的注射器内，并基于适当的比例推送至混合组件以完成待注射液的混合并形成凝胶制剂。通过第二注射组件制得的凝胶制剂具有可注射性和快速成胶性，在第一组分与第二组分溶液混合后可在水环境下较短时间内成胶，用于阻隔放疗时射线。According to a preferred embodiment, the second injection assembly includes at least a frame assembly and a mixing assembly, wherein a hollow area where several syringes can be placed and several buckles are reserved in the frame assembly, so that the syringes can pass through It is placed on the frame assembly in the corresponding hollow area, and is fixed by the buckle on the frame assembly. The nozzle end of the syringe is connected with the stop protrusion in the multi-joint end of the mixing assembly, so that it is in the syringe The liquid to be injected can flow into the mixing component through the multi-connected end of the mixing component. In the case where several syringes are provided, different syringes can be connected to several different interfaces of the mixing assembly on the side facing the frame assembly to realize the communication between the mixing assembly and several syringes, thereby facilitating different The injection liquid is filled into the corresponding syringe, and pushed to the mixing component based on the appropriate ratio to complete the mixing of the liquid to be injected and form a gel preparation. The gel preparation prepared by the second injection component has injectability and rapid gelation, and can be gelled in a water environment in a short time after the first component and the second component solution are mixed, and is used for blocking radiotherapy time rays.
根据一种优选实施方式，所述第二注射组件连接于留置的所述第一注射组件的针头，所述第二注射组件将经过所述架构组件和混合组件混合后的凝胶制剂在接触混合后的预定时间内连续同步并且匀速注入患者体内，注入凝胶制剂的总量为第二容量。预定时间是指凝胶制剂进入患者体内的最佳时间，在本发明的凝胶制剂中，该时间为能使凝胶制剂快速凝胶的时间，即将混合后的凝胶制剂在快速凝胶范围内全部注入患者体内。第一容量为第二容量的一半。例如，若患者需隔绝前列腺和直肠，向直肠前壁内注入3～15mL生理盐水和6～30mL凝胶制剂。需要说明的是，上述配比仅示出针对本发明的具体实施例的可能存在的一种参考数据，并不代表不包括其他第一容量和第二容量的配比，根据本发明能够选择不同配比进行注射。According to a preferred embodiment, the second injection assembly is connected to the indwelling needle of the first injection assembly, and the second injection assembly mixes the gel preparation mixed by the architecture assembly and the mixing assembly in contact with each other. The gel preparation is injected continuously and at a constant speed into the patient within a predetermined period of time, and the total amount of the injected gel preparation is the second volume. 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 that can make the gel preparation quickly gel, that is, the gel preparation after mixing is within the range of fast gel. injected into the patient's body. The first capacity is half of the second capacity. For example, if the patient needs to isolate the prostate and rectum, inject 3-15 mL of normal saline and 6-30 mL of gel preparation into the anterior wall of the rectum. It should be noted that the above ratio only shows a possible reference data for the specific embodiment of the present invention, and does not mean that it does not include other ratios of the first capacity and the second capacity. According to the present invention, different Proportion for injection.
根据一种优选实施方式，所述注射系统至少能够基于健康器官需要相对于放疗部位的隔开距离和/或基于患者不同的注射部位通过所述第二注射组件而调节所述凝胶制剂的第一组分和/或第二组分和/或缓冲液的用量及配比，解决的间隔不同的问题，减小因撑开患者放疗部位和邻近组织、脏器带来的局部不适感，甚至穿孔、里急后重感等，并且通过架构组件和混合组件也能够调节注入凝胶制剂的时间、同步注入的速度，同时注入的总容量也能根据需要进行调节。需要说明的是，上述间隔是指：注入适量水凝胶后能够产生平均间隔达到大于5mm的隔离区域。所述第一组分和/或第二组分选自聚乙二醇衍生物、聚乳酸、PLGA、记忆材料中的一种或多种，所述记忆材料优选为记忆海绵。According to a preferred embodiment, the injection system can at least adjust the second injection component of the gel preparation based on the separation distance of the healthy organ from the radiotherapy site and/or based on the different injection sites of the patient. The amount and ratio of the first component and/or the second component and/or buffer solution can solve the problem of different intervals, reduce the local discomfort caused by spreading the patient's radiotherapy site and adjacent tissues and organs, and even Perforation, tenesmus, etc., and the injection time and synchronous injection speed of the gel formulation can also be adjusted through the framework component and the mixing component, and the total volume injected can also be adjusted as needed. It should be noted that, the above-mentioned interval refers to: after injecting an appropriate amount of hydrogel, an isolated area with an average interval greater than 5 mm can be produced. 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 materials are preferably memory foam.
实施例2Example 2
本实施例公开了一种用于局部放疗的凝胶制剂，其可由第一组分、第二组分和碱性缓冲液组成，其中，第一组分选择多臂琥珀酰亚胺戊二酸酯聚乙二醇，优选为n arms-琥珀酰亚胺戊二酸酯聚乙二醇(其中，n≥4)，琥珀酰亚胺戊二酸酯聚乙二醇的重量百分占比为5～15％，相对分子质量为10000～20000Da；第二组分选择多臂氨基聚乙二醇，优选为marms-氨基聚乙二醇(其中，m≥4)，氨基聚乙二醇的重量百分占比为5～15％，相对分子质量为10000～20000Da；碱性缓冲液为磷酸盐缓冲液，可包括以下组分：磷酸二氢钾和/或氯化钠和/或氢氧化钠，优选地，碱性缓冲液的pH为7.0-7.5。需要说明的是，本发明列举出第一组分和第二组分的具体化学物质，但并不代表第一组分和第二组分仅能使用本发明提及的物质，例如，第二组分还可采用三赖氨酸。This embodiment discloses a gel preparation for local radiotherapy, which can be composed of a first component, a second component and an alkaline buffer, wherein the first component is multi-arm succinimide glutaric acid Ester polyethylene glycol, preferably n arms-succinimide glutarate polyethylene glycol (wherein, n≥4), the weight percentage of succinimide glutarate polyethylene glycol is 5-15%, the relative molecular mass is 10000-20000Da; the second component is multi-arm amino polyethylene glycol, preferably marms-amino polyethylene glycol (wherein, m≥4), the weight of amino polyethylene glycol The percentage is 5-15%, and the relative molecular mass is 10,000-20,000 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 the specific chemical substances of the first component and the second component, but it 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 The composition can also use trilysine.
琥珀酰亚胺戊二酸酯聚乙二醇和氨基聚乙二醇在碱性缓冲液中进行迈克尔加成反应以形成可注射的凝胶制剂。制得的凝胶制剂的pH为7.0-7.5，以适应人体组织液的pH。Succinimide glutarate polyethylene glycol and amino polyethylene glycol undergo Michael addition reaction in alkaline buffer to form an injectable gel formulation. The pH of the prepared gel preparation is 7.0-7.5 to adapt to the pH of human tissue fluid.
根据一种优选实施方式，本发明的凝胶制剂的制备方法如下：According to a preferred embodiment, the preparation method of the gel preparation of the present invention is as follows:
(1)碱性缓冲液配置：取磷酸二氢钾1.36g，加0.1mol/L氢氧化钠溶液79mL，用水稀释至200mL，即得。(1) Alkaline buffer preparation: Take 1.36g of potassium dihydrogen phosphate, add 79mL of 0.1mol/L sodium hydroxide solution, dilute with water to 200mL, and obtain.
(2)将灭好菌的琥珀酰亚胺戊二酸酯聚乙二醇粉末与碱性缓冲溶液在混药瓶中混合；晃动混药瓶，使得粉末与碱性缓冲溶液充分混合。混合后至少静置1分钟，至气泡消散，制成琥珀酰亚胺戊二酸酯聚乙二醇的碱性缓冲溶液。(2) Mix the sterilized succinimide glutarate polyethylene glycol powder and the alkaline buffer solution in the mixing bottle; shake the mixing bottle so that the powder is fully mixed with the alkaline buffer solution. After mixing, let it stand for at least 1 minute until the air bubbles dissipate to prepare an alkaline buffer solution of succinimide glutarate polyethylene glycol.
(3)将灭好菌的氨基聚乙二醇粉末与碱性缓冲溶液在混药瓶内混合，晃动混药瓶，使得粉末与碱性缓冲溶液充分混合。混合后至少静置1分钟，至气泡消散，制成氨基聚乙二醇溶液。(3) Mix the sterilized aminopolyethylene glycol powder and the alkaline buffer solution in the mixing bottle, and shake the mixing bottle so that the powder and the alkaline buffer solution are fully mixed. After mixing, let it stand for at least 1 minute until the air bubbles dissipate to make an aminopolyethylene glycol solution.
根据一种优选实施方式，本发明的凝胶制剂的使用方法如下：According to a preferred embodiment, the use method of the gel preparation of the present invention is as follows:
(1)制剂准备：在注射器中放置缓冲溶液，将缓冲溶液注射入盛有琥珀酰亚胺戊二酸酯聚乙二醇溶液和/或氨基聚乙二醇溶液的粉剂瓶中，混合后放入注射器中，在两个注射器的针头部位安装上同一Y形连接器，并将两个注射器放入双联注射器固定架中，在Y形连接器的末端安装上注射长针头，排尽Y形连接器内的空气。(1) preparation preparation: place the buffer solution in the syringe, inject the buffer solution into the powder bottle filled with succinimide glutarate polyethylene glycol solution and/or amino polyethylene glycol solution, mix and put Insert the syringe into the syringe, install the same Y-shaped connector on the needles of the two syringes, put the two syringes into the double syringe holder, install a long injection needle at the end of the Y-shaped connector, and drain the Y-shaped air inside the connector.
(2)水空间构建：向需要形成隔离的部位注入生理盐水以形成水空间。(2) Water space construction: Inject physiological saline into the parts that need to be isolated to form a water space.
(3)注入凝胶：利用双联注射器固定架同时推动分别两个分别盛有琥珀酰亚胺戊二酸酯聚乙二醇溶液和氨基聚乙二醇溶液的注射器，使两种溶液在Y型连接器内充分混合，在超声波探测器辅助下注入腹腔需形成凝胶的部位，并调整注射的范围。(3) Inject the gel: Use the double syringe holder to simultaneously push two syringes filled with succinimide glutarate polyethylene glycol solution and amino polyethylene glycol solution respectively, so that the two solutions are in Y Fully mixed in the type connector, injected into the abdominal cavity where the gel needs to be formed with the assistance of an ultrasonic probe, and adjusted the scope of injection.
实施例3Example 3
本实施例公开的一种用于局部放疗的凝胶制剂的配方为：分子量为15000Da的八臂琥珀酰亚胺戊二酸酯聚乙二醇5％，分子量为10000Da的八臂氨基聚乙二醇5％，pH为7.2-7.4的碱性缓冲液90％。The formulation of a gel preparation for local radiotherapy disclosed in this example is: eight-arm succinimide glutarate polyethylene glycol with a molecular weight of 15000Da 5%, eight-arm aminopolyethylene glycol with a molecular weight of 10000Da Alcohol 5%, alkaline buffer 90% at pH 7.2-7.4.
制备方法参考实施例2。The preparation method refers to Example 2.
实施例4Example 4
本实施例公开的一种用于局部放疗的凝胶制剂的配方为：分子量为15000Da的八臂琥珀酰亚胺戊二酸酯聚乙二醇5％，分子量为20000Da的八臂氨基聚乙二醇10％，pH为7.2-7.4的碱性缓冲液85％。The formulation of a gel preparation for local radiotherapy disclosed in this example is: eight-arm succinimide glutarate polyethylene glycol with a molecular weight of 15000Da 5%, eight-arm aminopolyethylene glycol with a molecular weight of 20000Da Alcohol 10%, alkaline buffer 85% at pH 7.2-7.4.
制备方法参考实施例2。The preparation method refers to Example 2.
实施例5Example 5
本实施例公开的一种用于局部放疗的凝胶制剂的配方为：分子量为10000Da的八臂琥珀酰亚胺戊二酸酯聚乙二醇5％，分子量为15000Da的四臂氨基聚乙二醇5％，pH为7.2-7.4的碱性缓冲液90％。The formulation of a gel preparation for local radiotherapy disclosed in this example is: eight-arm succinimide 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 Alcohol 5%, alkaline buffer 90% at pH 7.2-7.4.
制备方法参考实施例2。The preparation method refers to Example 2.
实施例6Example 6
本实施例公开的一种用于局部放疗的凝胶制剂的配方为：分子量为20000Da的八臂琥珀酰亚胺戊二酸酯聚乙二醇5％，分子量为10000Da的四臂氨基聚乙二醇5％，pH为7.2-7.4的碱性缓冲液90％。The formulation of a gel preparation for local radiotherapy disclosed in this example is: eight-arm succinimide 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 Alcohol 5%, alkaline buffer 90% at pH 7.2-7.4.
制备方法参考实施例2。The preparation method refers to Example 2.
实施例7Example 7
本实施例公开的一种用于局部放疗的凝胶制剂的配方为：分子量为20000Da的四臂琥珀酰亚胺戊二酸酯聚乙二醇10％，分子量为15000Da的八臂氨基聚乙二醇5％，pH为7.2-7.4的碱性缓冲液85％。The formulation of a gel preparation for local radiotherapy disclosed in this example is: 10% four-arm succinimide glutarate polyethylene glycol with a molecular weight of 20000Da, eight-arm aminopolyethylene glycol with a molecular weight of 15000Da Alcohol 5%, alkaline buffer 85% at pH 7.2-7.4.
制备方法参考实施例2。The preparation method refers to Example 2.
实施例8Example 8
本实施例公开的一种用于局部放疗的凝胶制剂的配方为：分子量为15000Da的四臂琥珀酰亚胺戊二酸酯聚乙二醇10％，分子量为20000Da的八臂氨基聚乙二醇5％，pH为7.2-7.4的碱性缓冲液85％。The formulation of a gel preparation for local radiotherapy disclosed in this example is: 10% four-arm succinimide glutarate polyethylene glycol with a molecular weight of 15000Da, eight-arm aminopolyethylene glycol with a molecular weight of 20000Da Alcohol 5%, alkaline buffer 85% at pH 7.2-7.4.
制备方法参考实施例2。The preparation method refers to Example 2.
实施例9Example 9
本实施例公开的一种用于局部放疗的凝胶制剂的配方为：分子量为10000Da的四臂琥珀酰亚胺戊二酸酯聚乙二醇10％，分子量为20000Da的四臂氨基聚乙二醇10％，pH为7.2-7.4的碱性缓冲液80％。The formulation of a gel preparation for local radiotherapy disclosed in this example is: 10% four-arm succinimide glutarate polyethylene glycol with a molecular weight of 10000Da, four-arm aminopolyethylene glycol with a molecular weight of 20000Da Alcohol 10%, alkaline buffer 80% at pH 7.2-7.4.
制备方法参考实施例2。The preparation method refers to Example 2.
实施例10Example 10
本实施例公开的一种用于局部放疗的凝胶制剂的配方为：分子量为20000Da的四臂琥珀酰亚胺戊二酸酯聚乙二醇5％，分子量为20000Da的四臂氨基聚乙二醇10％，pH为7.2-7.4的碱性缓冲液80％。The formulation of a gel preparation for local radiotherapy disclosed in this example is: 5% four-arm succinimide glutarate polyethylene glycol with a molecular weight of 20000Da, four-arm aminopolyethylene glycol with a molecular weight of 20000Da Alcohol 10%, alkaline buffer 80% at pH 7.2-7.4.
需要说明的是，上述配方仅示出针对本发明的具体实施例所可能用到的凝胶制剂的各成分比例，并不代表不包括其余成分比例的凝胶制剂配方，也不代表不含有其他成分。优选地，所述凝胶制剂内还可加入造影剂。其中，造影剂可选择碘海醇或醛基化造影剂，对此不作限定。本发明涉及一种用于局部放疗的凝胶制剂，其配方例如：琥珀酰亚胺戊二酸酯聚乙二醇、氨基聚乙二醇以及碘海醇三种成分。造影剂以化学反应或物理共混的形式接枝在凝胶分子链上，以使得在数据探测模块下，凝胶制剂能够更清楚地显示出来，实现多模态显影并跟踪整个放疗过程。It should be noted that the above formula only shows the ratio of the ingredients of the gel preparation that may be used in specific embodiments of the present invention, and does not mean that the gel preparation formula does not include the rest of the ingredients, nor does it mean that it does not contain other ingredients. Element. Preferably, a contrast agent can also be added into the gel preparation. Wherein, the contrast agent can be selected from iohexol or aldehyde contrast agent, which is not limited. The invention relates to a gel preparation for local radiotherapy, the formula of which is, for example, three components: succinimide glutarate polyethylene glycol, amino polyethylene glycol and iohexol. The contrast agent is grafted on the gel molecular chain in the form of chemical reaction or physical blending, so that under the data detection module, the gel preparation can be displayed more clearly, realizing multimodal imaging and tracking the entire radiotherapy process.
实施例11Example 11
本实施例是对前述实施例的进一步改进，重复的内容将不再赘述。本实施例是对上述各实施例中不同配方的凝胶制剂进行性能检测，其中，检测参数及方法可包括：This embodiment is a further improvement on the foregoing embodiments, and repeated content will not be repeated. This embodiment is to perform performance testing on the gel preparations of different formulations in the above-mentioned embodiments, wherein the testing parameters and methods may include:
1、成胶时间的测定1. Determination of gelation time
将氨基聚乙二醇和琥珀酰亚胺戊二酸酯聚乙二醇分别溶于磷酸缓冲盐溶液(pH＝7.4)，放入注射器中经Y型管等体积注入37℃保温玻璃瓶中，在凝胶过程中，不断倒置玻璃瓶，观察样品是否流动，如果不流动，可认为此时溶液转变成了凝胶。凝胶自混合后至凝胶完全的时间为凝胶时间。Dissolve aminopolyethylene glycol and succinimide glutarate polyethylene glycol in phosphate buffered saline (pH=7.4), put them into a syringe, and inject equal volumes into a 37°C thermos glass bottle through a Y-shaped tube. During the gel process, keep inverting 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 at this time. The time from the mixing of the gel to the completion of the gel is the gel time.
2、压缩力学测试2. Compression mechanics test
采用bose生物材料力学性能试验机，以一定的压缩速率对水凝胶进行压缩试验，通过下述公式计算得到压缩模量，同组样品测试三次，取平均值。Bose biomaterial mechanical properties testing machine was used to conduct compression test on the hydrogel at a certain compression rate, and the compression modulus was calculated by the following formula. The same group of samples was tested three times, and the average value was taken.
σ为应力，ε为应变，E压缩为压缩模量，F为压缩力，L1为位移，L0为初始长度。σ is the stress, ε is the strain, E is the compression modulus, F is the compression force,L1 is the displacement andL0 is the initial length.
3、体外降解性能的测定3. Determination of in vitro degradation performance
制备水凝胶标准件，37℃下置于PBS缓冲液(pH＝7.4)模拟体液的环境中，测试降解时间为2w，4w，8w，12w，16w，20w，24w(n＝6)，冻干后称干重，通过下述公式计算水凝胶的降解率：Prepare hydrogel standard pieces, place them in PBS buffer (pH=7.4) at 37°C in an environment simulating body fluids, test the degradation time at 2w, 4w, 8w, 12w, 16w, 20w, 24w (n=6), freeze After drying, the dry weight was weighed, and the degradation rate of the hydrogel was calculated by the following formula:
其中W0和Wx分别是水凝胶初始干重和取样干重。whereW0 andWx are the initial dry weight of the hydrogel and the sampled dry weight, respectively.
4、平衡溶胀率测试4. Equilibrium swelling rate test
在37℃下，将水凝胶浸没在生理盐水中，于12h、24h、48h、72h取样测试质量，通过下述公式计算水凝胶的溶胀率：At 37°C, the hydrogel was immersed in physiological saline, and samples were taken at 12h, 24h, 48h, and 72h to test the quality, and the swelling rate of the hydrogel was calculated by the following formula:
其中W0和Wx分别是水凝胶初始质量和取样时质量。where W0 and Wx are the initial mass of the hydrogel and the mass at the time of sampling, respectively.
需要注意的是，上述具体实施例是示例性的，本领域技术人员可以在本发明公开内容的启发下想出各种解决方案，而这些解决方案也都属于本发明的公开范围并落入本发明的保护范围之内。本领域技术人员应该明白，本发明说明书及其附图均为说明性而并非构成对权利要求的限制。本发明的保护范围由权利要求及其等同物限定。本发明说明书包含多项发明构思，诸如“优选地”、“根据一个优选实施方式”或“可选地”均表示相应段落公开了一个独立的构思，申请人保留根据每项发明构思提出分案申请的权利。在全文中，“优选地”所引导的特征仅为一种可选方式，不应理解为必须设置，故此申请人保留随时放弃或删除相关优选特征之权利。It should be noted that the above 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 scope of the disclosure of the present invention and fall within the scope of this disclosure. within the scope of protection of the invention. Those skilled in the art should understand that the description and drawings of the present invention are illustrative rather than limiting to the claims. The protection scope of the present invention is defined by the claims and their equivalents. The description of the present invention contains a number of inventive concepts, such as "preferably", "according to a preferred embodiment" or "optionally" all indicate that the corresponding paragraph discloses an independent concept, and the applicant reserves the right to propose a division based on each inventive concept right to apply. Throughout the text, the features introduced by "preferably" are only optional, and should not be interpreted as having to be set. Therefore, the applicant reserves the right to waive or delete relevant preferred features at any time.
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