Application of indigo carmine in preparation of surgical lymph node tracing medicine for treating malignant tumors

Abstract

The invention discloses a novel application of indigo carmine in preparation of a medicine for draining lymph nodes in a tracing area during a malignant tumor treatment operation, and belongs to the technical field of medicines. Aiming at the technical problems of pigmentation, tissue corrosivity and other side injuries of an existing lymph node tracer, animal experiments prove for the first time that indigo carmine with a specific dosage is adopted to trace a tumor area to drain lymph nodes, so that the side effects of the existing tracer can be remarkably reduced, and the curative effect of the tracer is improved. Meanwhile, the detection effect on target lymph nodes is similar to that of the existing common tracer agent methylene blue. The invention provides clear experimental evidence, the known safe drug indigo carmine injection is repositioned to be used for accurately tracing the regional lymph node in the malignant tumor operation, the sentinel lymph node biopsy is guided, the side injury caused by blind enlargement of the operation cleaning range is avoided, and the method has the advantages of short development period, definite tracing effect, low cost and the like. The invention provides a drug choice with clinical application potential for precise and minimally invasive surgery of various malignant tumors.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a new medical use of a known drug, indigo carmine injection, and particularly to its use in the preparation of a drug for tracing regional lymph node drainage during surgery for the treatment of malignant tumors. Background Technology

[0002] Improving the treatment efficacy of malignant tumors, reducing complications and side effects during treatment, and enhancing the quality of life for patients with malignant tumors are important issues in the medical field. Early-stage malignant tumors are primarily treated with radical surgical resection. Radical resection does not mean removing as much tissue as possible, but rather aims to completely remove the tumor and surrounding draining lymph nodes with clear evidence of metastasis. This avoids complications and damage to the patient's normal physiological functions caused by indiscriminately dissecting lymph nodes beyond the intended area. Sentinel lymph node biopsy is currently the universally recognized and perfectly feasible standard answer for accurately removing draining lymph nodes around a malignant tumor. The sentinel lymph node is the first-line lymph node for regional drainage at the location of the malignant tumor. Currently, there are three main methods for sentinel lymph node tracing used in clinical medicine: 1. radionuclide method; 2. fluorescence method; 3. dye method.

[0003] However, among commonly used lymph node tracing methods, the radionuclide method is not widely used clinically due to its radioactive radiation; the fluorescence method requires the assistance of a fluorescence detector, and its effectiveness is not ideal when used alone due to the limited tissue penetration of fluorescence; the dye method is currently the most commonly used sentinel lymph node tracing method in oncological surgery. Commonly used tracers for the dye method in China are methylene blue, nano-carbon, and mitoxantrone, which has begun to be used in recent years. Methylene blue is corrosive to soft tissue; intradermal, subcutaneous, or intra-soft tissue injection can cause soft tissue ischemia and necrosis. Nano-carbon is expensive, and because its lymph node tracing principle relies on the physical deposition of nano-carbon particles in lymph nodes, it can also cause pigmentation at the injection site that is difficult to fade. Mitoxantrone itself is a chemotherapy drug, and its corrosiveness to soft tissue at the injection site is even greater than that of methylene blue. During surgery, the soft tissue at the injection site needs to be removed as much as possible, which unnecessarily expands the surgical area and may cause unnecessary collateral damage. Therefore, there is an urgent clinical need for a sentinel lymph node tracer that can effectively trace sentinel lymph nodes while avoiding the aforementioned adverse reactions. Thus, exploring the mechanism of action of the compound indigo carmine in tracing draining lymph nodes in malignant tumor regions and developing its application in sentinel lymph node biopsy surgery for malignant tumors has significant clinical value and application prospects.

[0004] Indigo carmine is commonly used clinically to measure kidney function or to stain mucosa during gastrointestinal and respiratory tract endoscopy. Currently, there are no reports on the use of indigo carmine for tracing sentinel lymph nodes during surgery for malignant tumors. Summary of the Invention

[0005] I. Purpose of the Invention The purpose of this invention is to provide a new use for indigo carmine, namely its application in the preparation of drugs for tracing regional drainage lymph nodes during surgery for treating malignant tumors, to clarify its mechanism of action in sentinel lymph node tracing, and to provide new drug options and treatment plans for the precise clearing of regional metastatic lymph nodes of malignant tumors and the avoidance of unnecessary damage to surrounding normal tissues. This is also in line with the modern medical concept of precision and minimally invasive surgery.

[0006] II. Technical Solution This invention discloses the application of indigo carmine in the preparation of a drug for tracing regional drainage lymph nodes during surgery for treating malignant tumors. The indigo carmine is absorbed by the capillary lymphatic system at the injection site, drained by lymphatic vessels, and enriched by regional lymph nodes, thereby staining the regional drainage sentinel lymph nodes at the tumor site, and thus guiding the sentinel lymph node biopsy procedure.

[0007] Furthermore, the dosage form of the drug described in this invention is an injectable preparation, and its administration method when tracing sentinel lymph nodes is intradermal injection, subcutaneous injection, intramuscular injection, intratumoral injection, or other soft tissue injection methods.

[0008] Furthermore, the concentration of the drug described in this invention is 0.2%-2%, the indigo carmine solute content in each vial is 5-40mg within the safe dosage range, the dosage for each soft tissue injection is no more than 40mg, and the soft tissue at the injection site needs to be removed during surgery to ensure no residue remains.

[0009] Furthermore, the drug of the present invention may also contain pharmaceutically acceptable excipients, including solubilizers, isotonic adjusters, pH adjusters, antibacterial agents, antioxidants, etc., such as glucose, sodium chloride, sodium hydroxide, hydrochloric acid, sodium bisulfite, sodium metabisulfite, etc.

[0010] III. Specific Mechanism of Action The core mechanism of indigo carmine as a sentinel lymph node staining agent is to utilize its macromolecular colloidal properties and differences in tissue permeability. After local injection, it diffuses through the interstitial space, is taken up by lymphatic endothelial cells, and transported to the first-stop lymph nodes (sentinel lymph nodes) draining from the malignant tumor area, thus staining them for intraoperative localization and identification. The specific process can be divided into two steps: 1. When indigo carmine is injected around a tumor or into the skin or subcutaneous tissue, it does not easily enter capillaries due to its molecular size and colloidal osmotic pressure characteristics. Instead, it mainly penetrates into the interstitial lymphatic capillaries.

[0011] 2. The valve structure of capillary lymphatic endothelial cells and the flow of lymph will drain lymph carrying indigo carmine to the first station lymph node in the region (sentinel lymph node). Indigo carmine accumulates in the medullary sinus of the lymph node, making the lymph node appear blue, thus distinguishing it from the surrounding unstained lymph nodes and tissues, and thus guiding the sentinel lymph node biopsy procedure.

[0012] The malignant tumors described in this invention include, but are not limited to, the following types: head and neck malignant tumors such as oral cancer, nasopharyngeal cancer, tongue cancer, laryngeal cancer, and thyroid cancer; thoracic malignant tumors such as breast cancer, lung cancer, and esophageal cancer; abdominal malignant tumors such as stomach cancer, colon cancer, rectal cancer, liver cancer, bile duct cancer, gallbladder cancer, and pancreatic cancer; gynecological malignant tumors such as vulvar cancer, cervical cancer, endometrial cancer, and ovarian cancer; urinary system malignant tumors such as kidney cancer, bladder cancer, and urinary tract cancer; and andrological malignant tumors such as testicular cancer and prostate cancer; soft tissue malignant tumors such as skin cancer, malignant melanoma, and sarcoma; and malignant tumors in other parts of the body. Beneficial effects

[0013] 1. It expands the clinical application scope of indigo carmine, extending its use from clinical applications in measuring renal function or staining mucosa in gastrointestinal and respiratory tract endoscopy to sentinel lymph node biopsy for surgical tracing of malignant tumors, providing a new, safe and effective treatment option for precise and minimally invasive surgical removal of regional metastatic lymph nodes for various malignant tumors. 2. The mechanism of action of indigo carmine in the enrichment and staining of lymph nodes in the injection site has been clarified, providing a theoretical basis for precise and minimally invasive treatment in tumor surgery, thereby helping to improve the targeting and effectiveness of treatment; 3. Indigo carmine injection is currently routinely used in clinical practice to measure kidney function. Its clinical application has been carried out for many years, and its safety has been fully verified. The incidence of adverse reactions is low. It avoids the drawbacks of commonly used lymph node tracers, such as local tissue corrosion, pigment deposition, and radionuclide radioactivity at the injection site. Patients tolerate it well, and the price is low. It can significantly reduce the medical cost of surgical treatment for malignant tumors and has broad clinical application prospects and market value. Detailed Implementation

[0014] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are for illustrative purposes only and are not intended to limit the scope of the invention.

[0015] Example 1: Comparison of the tracing effect of indigo carmine on mouse inguinal sentinel lymph nodes with methylene blue. 1. Experimental materials: 20 healthy mice, 0.2% indigo carmine, and 1% methylene blue injection were selected for the experiment.

[0016] 2. Experimental Methods: (1) The experimental mice were randomly divided into two groups. 0.2 ml of each of the two lymph node tracers, namely 0.2% indigo carmine and 0.2% methylene blue, were injected intradermally into the middle section of the medial thigh of both lower limbs. Each group was divided into two subgroups according to the time interval between injection and dissection. The experimental mice were sacrificed 10 minutes and 20 minutes after injection. The lymph node staining effect of the indigo carmine experimental group and the methylene blue control group and the staining effect between different subgroups within the group were compared. (2) Dissect the groin, locate the blue-stained sentinel lymph node, and collect the specimen. Remove the adipose tissue on the surface of the blue-stained lymph node, cut it longitudinally along the long axis of the lymph node, and use the Color Meter-Light Meter color measurement tool to measure and record the L value (color brightness value, the lower the L value, the darker the color and the better the staining effect) of the blue-stained lymph node. (3) Statistical analysis was performed to compare the difference in the detection rate of blue-stained sentinel lymph nodes in the groin between the experimental group and the control group; the difference in L value of blue-stained lymph nodes in different subgroups of injection-to-anatomical interval within each group was compared; and the difference in L value of blue-stained lymph nodes in the experimental group and the control group was compared. 3. Experimental Results: There was no statistically significant difference in the detection rate of inguinal blue-stained sentinel lymph nodes between the experimental and control groups. Within the experimental group, there was no statistically significant difference in the L values ​​of blue-stained lymph nodes from different injection-to-dissection intervals (comparing 10 minutes and 20 minutes), indicating that sentinel lymph nodes could be dissected and removed 10 minutes after injection, thus shortening the waiting time between injection and surgery. Comparing the L values ​​of blue-stained lymph nodes between the experimental and control groups, the control group showed a slightly better staining effect, but there was no statistically significant difference. This is likely related to the intensity of the blue color exhibited by the chemical structure of indigo carmine itself (indigo carmine of the same concentration is lighter in color than methylene blue). In practical applications, this can be addressed by appropriately increasing the concentration of the indigo carmine injection solution, while ensuring the safety of the drug dosage.

[0017] Example 2: Comparative experiment of skin damage at the injection site of indigo carmine and methylene blue in mice. 1. Experimental materials: 20 healthy mice, 0.2% indigo carmine, and 1% methylene blue injection were selected for the experiment.

[0018] 2. Experimental Methods: (1) The experimental mice were randomly divided into two groups, and 0.2 ml of each of the two drugs, 0.2% indigo carmine and 0.2% methylene blue, were injected intradermally into the back of the mice near the waist and buttocks. (2) The daily physiological activities of the two groups of mice were observed for three consecutive days. (3) Three days later, the mice in both groups were sacrificed, and the skin at the injection site was excised, fixed with 10% medical formalin, embedded in paraffin, stained, and pathologically analyzed to determine the damage to the skin at the injection site of the mice caused by the two drugs.

[0019] 3. Experimental results: Compared with the methylene blue control group, the indigo carmine experimental group showed significantly milder skin inflammatory reactions at the injection site.

[0020] Description of Detailed Implementation The above embodiments are only used to illustrate specific implementations of the technical solutions of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solutions and inventive concepts of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. The use of a compound, indigo carmine (English name: Indigo Carmine; Indicarminum; Indicarmine), in the preparation of a drug for tracing regional lymph node drainage during surgery for the treatment of malignant tumors.

2. The application as described in claim 1, characterized in that, The malignant tumors mentioned include, but are not limited to, the following types: head and neck malignant tumors such as oral cancer, nasopharyngeal cancer, tongue cancer, laryngeal cancer, and thyroid cancer; thoracic malignant tumors such as breast cancer, lung cancer, and esophageal cancer; abdominal malignant tumors such as stomach cancer, colon cancer, rectal cancer, liver cancer, bile duct cancer, gallbladder cancer, and pancreatic cancer; gynecological malignant tumors such as vulvar cancer, cervical cancer, endometrial cancer, and ovarian cancer; urinary system malignant tumors such as kidney cancer, bladder cancer, and urinary tract cancer; and andrological malignant tumors such as testicular cancer and prostate cancer; soft tissue malignant tumors such as skin cancer, malignant melanoma, and sarcoma; and malignant tumors in other parts of the body.

3. The application as described in claim 1 or 2, characterized in that, The drug is used to accurately locate the drainage lymph nodes in the tumor area during various malignant tumor surgeries, guide sentinel lymph node biopsy, and guide surgical clearance of lymph nodes around the tumor.

4. The application as described in any one of claims 1-3, characterized in that, The drug is used to trace the location of the sentinel lymph node, the first site where malignant tumor cells may metastasize, and guides the intraoperative removal of the sentinel lymph node and intraoperative frozen section pathological examination. If there is no cancer cell metastasis in the sentinel lymph node, it can avoid extensive lymph node dissection in the surrounding area, thereby reducing the incidence of surgical complications and protecting the normal physiological functions of the human body from damage.

5. The application as described in any one of claims 1-4, characterized in that, The drug is an injectable preparation, and when used to trace sentinel lymph nodes, it can be administered via intradermal injection, subcutaneous injection, intramuscular injection, intratumoral injection, or other soft tissue injection methods.

6. The application as described in any one of claims 1-5, characterized in that, The concentration of the drug is 0.2%-2%, and the indigo carmine solute content in each vial is 5-40mg within the safe dosage range. The dosage for each soft tissue injection shall not exceed 40mg, and the soft tissue at the injection site must be surgically removed to ensure no residue remains.

7. The application as described in any one of claims 1-6, characterized in that, The patient in question is a malignant tumor who requires surgical removal of the lesion.

8. The application as described in any one of claims 1-6, characterized in that, The patients in question are those who are not allergic to indigo carmine preparations, their excipients, or other combined ingredients.

9. The application as described in any one of claims 1-6, characterized in that, The drug comprises a pharmaceutical composition consisting of indigo carmine within a safe and effective dosage range and at least one pharmaceutically acceptable carrier or excipient.

10. The pharmaceutical composition according to claim 9, characterized in that, The composition also contains one or more other drugs that can synergistically trace lymph nodes with indigo carmine, or whose addition can improve the efficiency of indigo carmine in tracing lymph nodes, with the aim of improving the lymph node tracing effect, thereby improving the diagnostic or therapeutic effect. Such combination components include one or more of the following types: carrier materials, surfactants, pH adjusters, isotonic adjusters, isotonic adjusters, solubilizers, stabilizers, antioxidants, penetration enhancers, absorption enhancers, buffers, adhesives, tumor-targeting modifiers, sustained-release agents, local anesthetics, antibacterial agents, antiirritants, anti-inflammatory components, etc., such as liposomes, nanoparticles, microspheres, polysorbates, polyoxyethylene fatty acid esters, polyethylene glycol, propylene glycol, azone, chitosan, carbomer, hyaluronidase, etc., as well as other drugs with the above-mentioned effects.