APPLICATION OF MITOXANTRONE PREPARATION IN PREPARATION OF DRUG FOR DIAGNOSING AND TREATING DISEASE RELATED TO THYROIDECTOMY

Abstract

An application of a mitoxantrone preparation in preparation of a drug for diagnosing and treating a disease related to thyroidectomy, and use of mitoxantrone and/or a pharmaceutically acceptable salt thereof in preparation of a lymph tracer for preventing parathyroid gland staining in error, preventing parathyroid gland cutting in error, or reducing the rate of parathyroid gland cutting in error. Local injection of a mitoxantrone hydrochloride injection fluid would not cause parathyroid gland staining in error, and can reduce the rate of parathyroid gland cutting in error, thus protecting parathyroid glands well; moreover, no local or systemic toxic side effect is found after the local injection. The present invention has good tolerability, efficacy, and safety, and provides a new treatment idea in radically curing thyroid diseases thoroughly for patients suffering from diseases related to thyroidectomy.

Claims

1. Use of mitoxantrone and/or a pharmaceutically acceptable salt thereof in preparation of a lymphatic tracer for preventing parathyroid gland staining in error, preventing parathyroid gland cutting in error or reducing the rate of parathyroid gland cutting in error for a disease related to thyroidectomy, preferably, the disease related to thyroidectomy being selected from thyroid tumor or hyperthyroidism; preferably, the thyroid tumor comprising benign thyroid tumor and malignant thyroid tumor; preferably, the benign thyroid tumor being selected from thyroid adenoma or cyst; and preferably, the malignant thyroid tumor being selected from thyroid carcinoma or malignant thyroid lymphoma.

2. A method for preventing parathyroid gland staining in error, preventing parathyroid gland cutting in error or reducing the rate of parathyroid gland cutting in error for a disease related to thyroidectomy, comprising: administering mitoxantrone and/or a pharmaceutically acceptable salt thereof to a patient, preferably, the disease related to thyroidectomy being selected from thyroid tumor or hyperthyroidism; preferably, the thyroid tumor comprising benign thyroid tumor and malignant thyroid tumor; preferably, the benign thyroid tumor being selected from thyroid adenoma or cyst; and preferably, the malignant thyroid tumor being selected from thyroid carcinoma or malignant thyroid lymphoma.

3. The use according to claim 1 or the method according to claim 2, wherein the parathyroid gland cutting in error is parathyroid gland cutting in error in thyroidectomy.

4. The use or the method according to the preceding claims, wherein the thyroidectomy is selected from total thyroidectomy, near total thyroidectomy, lobectomy+isthmectomy for thyroid, partial lobectomy for thyroid, thyroid adenoma enucleation, unilateral total lobectomy for thyroid, and radical thyroidectomy; and preferably, the lymphatic tracer is used for lymphatic tracing in thyroid carcinoma.

5. The use or the method according to the preceding claims, wherein the lymphatic tracer contains the mitoxantrone and/or the pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient; preferably, the pharmaceutically acceptable excipient comprises, but is not limited to, a buffer, a carrier, a stabilizer, or a preservative; preferably, the lymphatic tracer is an injection; preferably, the injection is in a form of solution, lyophilized powder, emulsion, liposome, nanoparticles, nanocrystals, microcrystals, microspheres or gel; and preferably, the injection in the form of solution is a sodium chloride injection or a glucose injection.

6. The use or the method according to the preceding claims, wherein the injection is administered subcutaneously or intramuscularly, and preferably, subcutaneously; preferably, the injection is administered locally; preferably, injecting sites are on thyroid glands and/or tissues and organs around the thyroid; preferably, 0.2-1.2 mL of the injection at a concentration of 5 mg/mL is administered; preferably, the injection is administered at multiple sites spaced by about 1 cm; preferably, about 0.1 mL of the injection is administered at each site; preferably, a total dosage of the injection administered to two sides does not exceed 0.6 mL; and preferably, an operation is performed about 5 min after the administration for the injection.

7. The use or the method according to the preceding claims, wherein the pharmaceutically acceptable salt is a pharmaceutically acceptable salt formed by the mitoxantrone and an inorganic acid or an organic acid; preferably, the inorganic acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, and phosphoric acid; preferably, the organic acid is selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, pamoic acid, phenylacetic acid, methanesulfonic acid (methanesulfonate), ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid; and preferably, the pharmaceutically acceptable salt is selected from mitoxantrone hydrochloride, mitoxantrone oxalate, mitoxantrone sulfate, mitoxantrone phosphate, mitoxantrone acetate, and mitoxantrone citrate, and more preferably, the pharmaceutically acceptable salt is mitoxantrone hydrochloride.

8. The use or the method according to the preceding claims, wherein the lymphatic tracer contains a pH regulator; and preferably, the pH regulator is one or more selected from the group consisting of hydrochloric acid, phosphoric acid, sulfuric acid, oxalic acid, acetic acid, and citric acid.

9. The use or the method according to the preceding claims, wherein the lymphatic tracer contains an antioxidant; preferably, the antioxidant is one or more selected from the group consisting of sodium sulfite, sodium bisulfite, sodium pyrosulfite, sodium thiosulfate, and disodium edetate, and preferably, the antioxidant is sodium pyrosulfite or disodium edetate; preferably, the lymphatic tracer contains mitoxantrone or a salt thereof, sodium chloride, acetic acid, sodium acetate, and sodium pyrosulfite, and more preferably, the lymphatic tracer further contains sodium sulfate; preferably, the lymphatic tracer contains mitoxantrone or a salt thereof, sodium chloride, acetic acid, sodium acetate, and disodium edetate; preferably, a pH value of the injection is in a range of in a range of 2.8-4.3; preferably, the content of the mitoxantrone or mitoxantrone in the salt thereof is 1-15 mg/mL, preferably, 2-10 mg/mL, and more preferably, 2 mg/mL, 5 mg/mL or 10 mg/mL, in terms of weight by volume; preferably, the content of the sodium chloride is 3-18 mg/mL, preferably, 4-16 mg/mL, and more preferably, 4 mg/mL, 8 mg/mL or 16 mg/mL, in terms of weight by volume; preferably, the content of the acetic acid is 0.15-1 mg/mL, preferably, 0.23-0.92 mg/mL, and more preferably, 0.23 mg/mL, 0.46 mg/mL or 0.92 mg/mL, in terms of weight by volume; preferably, the content of the sodium acetate is 0.03-0.15 mg/mL, preferably, 0.05-0.1 mg/mL, and more preferably, 0.05 mg/mL or 0.1 mg/mL, in terms of weight by volume; preferably, the content of the antioxidant is 0.05-0.5 mg/mL, preferably, 0.08-0.4 mg/mL, and more preferably, 0.1 mg/mL, 0.2 mg/mL or 0.3 mg/mL, in terms of weight by volume; and preferably, the content of the sodium sulfate is 0.05-0.6 mg/mL, preferably, 0.15-0.45 mg/mL, and more preferably, 0.15 mg/mL, 0.3 mg/mL or 0.45 mg/mL, in terms of weight by volume.

10. The use or the method according to the preceding claims, wherein the injection is prepared by the following method: (1) weighing prescribed amounts of acetic acid, sodium acetate, sodium chloride, and disodium edetate, or weighing prescribed amounts of acetic acid, sodium acetate, sodium chloride, and sodium pyrosulfite, or weighing prescribed amounts of acetic acid, sodium acetate, sodium chloride, sodium pyrosulfite, and sodium sulfate, mixing them with a solvent, and dissolving them to obtain a mixed solution of excipients, preferably, the solvent being water for injecting, preferably, the excipients being dissolved by stirring; and (2) mixing the mixed solution of excipients obtained in the step (1) with prescribed amounts of mitoxantrone and/or a pharmaceutically acceptable salt thereof, preferably, the mitoxantrone and/or the pharmaceutically acceptable salt thereof being dissolved by stirring, preferably, the mitoxantrone and/or the pharmaceutically acceptable salt thereof being dissolved by stirring for 10-30 min; preferably, the method further comprises the following step: (3) filtering, preferably, filtering with 0.45 μm and/or 0.22 μm of filter membranes; preferably, the method further comprises the following step: (4) bottling and filling with nitrogen gas, preferably, sterilization being performed at 121° C. for 15 min after filling with nitrogen gas; preferably, a pH value of the injection is in a range of 2.8-4.3; and preferably, the injection is prepared into a specification of 2 mL:10 mg.

Description

DETAILED DESCRIPTION OF EMBODIMENTS

[0076] For purposes of clarity and conciseness of description, features are described herein as part of the same or separate embodiments. However, it is to be understood that the scope of the present disclosure may include some embodiments having combinations of all or some of the described features.

EXAMPLE 1 PREPARATION OF A MITOXANTRONE HYDROCHLORIDE INJECTION ACCORDING TO FORMULA 1

[0077]

TABLE-US-00001 Usage amount Raw materials and excipients g % mitoxantrone hydrochloride 11.64 0.582 sodium chloride 16.0 0.8 acetic acid 0.92 0.046 sodium acetate 0.10 0.005 disodium edetate 0.40 0.02 water for injecting (made up to) 2,000 mL —

[0078] Prescribed amounts of sodium chloride, acetic acid, sodium acetate, and disodium edetate were weighed, added into a prescribed amount of water for injecting, and dissolved by stirring; a prescribed amount of mitoxantrone hydrochloride was added after the excipients were dissolved, and dissolved by stirring for 30 min; and the mixed solution was finely filtered with 0.45 μm and 0.22 μm of filter membranes, bottled and filled with nitrogen gas, capped, and sterilized at 121° C. for 15 min. A pH value of the mitoxantrone hydrochloride injection was detected to be 3.5.

EXAMPLE 2 PREPARATION OF A MITOXANTRONE HYDROCHLORIDE INJECTION ACCORDING TO FORMULA 2

[0079]

TABLE-US-00002 Usage amount Raw materials and excipients g % mitoxantrone hydrochloride 23.28 1.164 sodium chloride 32.0 1.6 acetic acid 1.84 0.092 sodium acetate 0.20 0.01 sodium pyrosulfite 0.40 0.02 sodium sulfate 0.60 0.03 water for injecting (made up to) 2,000 mL —

[0080] Prescribed amounts of sodium chloride, acetic acid, sodium acetate, sodium pyrosulfite, and sodium sulfate were weighed, added into a prescribed amount of water for injecting, and dissolved by stirring; a prescribed amount of mitoxantrone hydrochloride was added after the excipients were dissolved, and dissolved by stirring for 30 min; and the mixed solution was finely filtered with 0.45 μm and 0.22 μm of filter membranes, bottled and filled with nitrogen gas, capped, and sterilized at 121° C. for 15 min. A pH value of the mitoxantrone hydrochloride injection was detected to be 3.4.

EXAMPLE 3 PREPARATION OF A MITOXANTRONE HYDROCHLORIDE INJECTION ACCORDING TO FORMULA 3

[0081]

TABLE-US-00003 Usage amount Raw materials and excipients g % mitoxantrone hydrochloride 2.91 0.1455 sodium chloride 16.0 0.8 acetic acid 0.92 0.046 sodium acetate 0.10 0.005 disodium edetate 0.40 0.02 water for injecting (made up to) 2,000 mL —

[0082] Prescribed amounts of sodium chloride, acetic acid, sodium acetate, and disodium edetate were weighed, added into a prescribed amount of water for injecting, and dissolved by stirring; a prescribed amount of mitoxantrone hydrochloride was added after the excipients were dissolved, and dissolved by stirring for 30 min; and the mixed solution was finely filtered with 0.45 μm and 0.22 μm of filter membranes, bottled and filled with nitrogen gas, capped, and sterilized at 121° C. for 15 min. A pH value of the mitoxantrone hydrochloride injection was detected to be 3.6.

EXAMPLE 4 PREPARATION OF A MITOXANTRONE HYDROCHLORIDE INJECTION ACCORDING TO FORMULA 4

[0083]

TABLE-US-00004 Usage amount Raw materials and excipients g % mitoxantrone hydrochloride 11.64 0.582 sodium chloride 16.0 0.8 acetic acid 0.92 0.046 sodium acetate 0.10 0.005 sodium pyrosulfite 0.20 0.01 sodium sulfate 0.30 0.015 water for injecting (made up to) 2,000 mL —

[0084] Prescribed amounts of sodium chloride, acetic acid, sodium acetate, sodium pyrosulfite, and sodium sulfate were weighed, added into a prescribed amount of water for injecting, and dissolved by stirring; a prescribed amount of mitoxantrone hydrochloride was added after the excipients were dissolved, and dissolved by stirring for 30 min; and the mixed solution was finely filtered with 0.45 μm and 0.22 μm of filter membranes, bottled and filled with nitrogen gas, capped, and sterilized at 121° C. for 15 min. A pH value of the mitoxantrone hydrochloride injection was detected to be 3.7.

EXAMPLE 5 PREPARATION OF A MITOXANTRONE HYDROCHLORIDE INJECTION ACCORDING TO FORMULA 5

[0085]

TABLE-US-00005 Usage amount Raw materials and excipients g % mitoxantrone hydrochloride 23.28 1.164 sodium chloride 16.0 0.8 acetic acid 0.92 0.046 sodium acetate 0.10 0.005 sodium pyrosulfite 0.40 0.020 sodium sulfate 0.90 0.045 water for injecting (made up to) 2,000 mL —

[0086] Prescribed amounts of sodium chloride, acetic acid, sodium acetate, sodium pyrosulfite, and sodium sulfate were weighed, added into a prescribed amount of water for injecting, and dissolved by stirring; a prescribed amount of mitoxantrone hydrochloride was added after the excipients were dissolved, and dissolved by stirring for 30 min; and the mixed solution was finely filtered with 0.45 μm and 0.22 μm of filter membranes, bottled and filled with nitrogen gas, capped, and sterilized at 121° C. for 15 min. A pH value of the mitoxantrone hydrochloride injection was detected to be 3.6.

EXAMPLE 6 PREPARATION OF A MITOXANTRONE HYDROCHLORIDE INJECTION ACCORDING TO FORMULA 6

[0087]

TABLE-US-00006 Usage amount Raw materials and excipients g % mitoxantrone hydrochloride 23.28 1.164 sodium chloride 16.0 0.8 acetic acid 0.92 0.046 sodium acetate 0.10 0.005 disodium edetate 0.60 0.03 water for injecting (made up to) 2,000 mL —

[0088] Prescribed amounts of sodium chloride, acetic acid, sodium acetate, and disodium edetate were weighed, added into a prescribed amount of water for injecting, and dissolved by stirring; a prescribed amount of mitoxantrone hydrochloride was added after the excipients were dissolved, and dissolved by stirring for 30 min; and the mixed solution was finely filtered with 0.45 μm and 0.22 μm of filter membranes, bottled and filled with nitrogen gas, capped, and sterilized at 121° C. for 15 min. A pH value of the mitoxantrone hydrochloride injection was detected to be 3.7.

EXAMPLE 7 PREPARATION OF A MITOXANTRONE HYDROCHLORIDE INJECTION ACCORDING TO FORMULA 7

[0089]

TABLE-US-00007 Usage amount Raw materials and excipients g % mitoxantrone hydrochloride 11.64 0.582 sodium chloride 8.0 0.4 acetic acid 0.46 0.023 sodium acetate 0.10 0.005 sodium pyrosulfite 0.40 0.020 water for injecting (made up to) 2,000 mL —

[0090] Prescribed amounts of sodium chloride, acetic acid, sodium acetate, and sodium pyrosulfite were weighed, added into a prescribed amount of water for injecting, and dissolved by stirring; a prescribed amount of mitoxantrone hydrochloride was added after the excipients were dissolved, and dissolved by stirring for 30 min; and the mixed solution was finely filtered with 0.45 μm and 0.22 μm of filter membranes, bottled and filled with nitrogen gas, capped, and sterilized at 121° C. for 15 min. A pH value of the mitoxantrone hydrochloride injection was detected to be 3.9.

EXAMPLE 8 PREPARATION OF A MITOXANTRONE HYDROCHLORIDE INJECTION ACCORDING TO FORMULA 8

[0091]

TABLE-US-00008 Usage amount Raw materials and excipients g % mitoxantrone hydrochloride 5.82 0.291 sodium chloride 8.0 0.4 acetic acid 0.46 0.023 sodium acetate 0.10 0.005 sodium pyrosulfite 0.40 0.020 sodium sulfate 0.60 0.03 water for injecting (made up to) 2,000 mL —

[0092] Prescribed amounts of sodium chloride, acetic acid, sodium acetate, sodium pyrosulfite, and sodium sulfate were weighed, added into a prescribed amount of water for injecting, and dissolved by stirring; a prescribed amount of mitoxantrone hydrochloride was added after the excipients were dissolved, and dissolved by stirring for 30 min; and the mixed solution was finely filtered with 0.45 μm and 0.22 μm of filter membranes, bottled and filled with nitrogen gas, capped, and sterilized at 121° C. for 15 min. A pH value of the mitoxantrone hydrochloride injection was detected to be 3.5.

EXAMPLE 9 STUDIES ON PHARMACOKINETIC AND PHARMACODYNAMIC OF A MITOXANTRONE HYDROCHLORIDE INJECTION

[0093] A target organ of a mitoxantrone hydrochloride injection for lymphatic tracing is a lymph node in the thyroid drainage area. When mitoxantrone hydrochloride is compounded with hydrochloric acid, a uniform acidic solution can be formed. After a mitoxantrone hydrochloride injection is administered to the tissue space, the pH of the microenvironment changes, and mitoxantrone hydrochloride will gradually precipitate into nanocrystals. The crystals prevent mitoxantrone hydrochloride from entering the blood circulation through capillaries. Due to high permeability of lymphatic capillaries, mitoxantrone hydrochloride can enter the lymphatic capillaries through endothelial cell space as well as pinocytosis and phagocytosis of endothelial cells, reach regional lymph nodes through lymphatic drainage and enrich in regional lymph nodes, and stay in the lymph nodes for a period of time, thereby achieving effects of staining and tracing of the lymph nodes.

[0094] In order to test the safety and efficacy of a mitoxantrone hydrochloride injection for lymphatic tracing in tracing of lesion-draining lymph nodes in a patient with thyroid carcinoma, and to test the tolerance and in vivo pharmacokinetics of the mitoxantrone hydrochloride injection for lymphatic tracing in the subject with thyroid carcinoma, so as to determine a safe dose range, this example adopted a single-center, randomized, open, and blank-controlled trial design. After the thyroid was fully exposed, a mitoxantrone hydrochloride injection for lymphatic tracing was administered at multiple sites on the thyroid gland. According to the size of the thyroid, a total dose of the injection did not exceed 0.6 mL. The tolerance in human being and pharmacokinetics in subjects were tested group by group, and the efficacy of the investigational drug was observed at the same time.

[0095] Pharmacokinetic results: the mitoxantrone hydrochloride injection is rapidly absorbed after being peritumorally administered, and the peak is basically reached 10 min after injecting. Moreover, the drug is metabolized rapidly after entering the blood, and the drug in the plasma is almost completely metabolized 30 min after the administration. In addition, the plasma concentration after the administration generally shows a dose-dependent trend, plasma concentrations in different subjects in a low-dose group are all lower than the lower limit of quantification at various time points; plasma concentrations in various patients in medium- and high-dose groups are equal to and higher than the lower limit of quantification at 3 time points at most; and the detected maximum concentration is 13.10 ng/mL only. In the prior art document (Zhu Jianming et al., “Cutting in error of Parathyroid Glands in Thyroid Operation and Postoperative Hypocalcemia”, Chinese Journal of Modern Operative Surgery, April 2010, Volume 14, Issue 2, p. 112-114), high-dose mitoxantrone is used for chemotherapeutically treating ovarian cancer. The maximum tolerated total dosage of mitoxantrone administered by intravenous bolus injecting is 75 mg/m.sup.2, and AUC at this dose is 560-1700 ng.Math.h/mL, which is 135.4-411.0 times the maximum AUC (248.15 ng.Math.min/ml) in the present trial. It can be seen that the mitoxantrone hydrochloride injection does not cause toxic side effects after being peritumorally administered, and there is no security risk after local administration.

[0096] Pharmacodynamic results: after the tracer is injected into the subject, the stained lymph nodes do not fade until the lymph node dissection is completed. Therefore, the success rate of sustained tracing is 100%.

EXAMPLE 10 APPLICATION OF A MITOXANTRONE HYDROCHLORIDE INJECTION FOR LYMPHATIC TRACING IN AN OPERATION FOR A PATIENT WITH THYROID CARCINOMA

1. Clinical Trial Design

[0097] The present example adopted a multi-center and randomized clinical trial design. Subjects meeting scheme requirements were randomly grouped in a ratio of 1:1 for comparison of the efficacy and safety of the mitoxantrone hydrochloride injection for lymphatic tracing in treatment for patients with thyroid carcinoma. The scheme requirements were specifically as follows:

[0098] Aged 18-70 (including 18 and 70), no gender preference

[0099] Preoperative clinical diagnosis of thyroid carcinoma, planning to undergo a radical operation for thyroid carcinoma

[0100] Planning to undergo total thyroidectomy and total central lymph node dissection according to preoperative evaluation

[0101] No obvious operative contraindications in routine preoperative examination

[0102] Able to well communicate with researchers and complete the study in accordance with study regulations

[0103] Voluntarily participating in the study and sign informed consent

[0104] An experiment group (each patient was administered with the mitoxantrone hydrochloride injection in which the content of an active ingredient was 5 mg/mL at multiple sites on the thyroid gland, the injecting sites were spaced by about 1 cm according to the size of the thyroid, about 0.1 mL of the injection was administered at each site, a total dosage of the injection administered to two sides did not exceed 0.6 mL, and an operation was performed about 5 min after the administration) and a control group (each patient underwent a conventional operation without administration of the mitoxantrone hydrochloride injection) were checked, and the number of parathyroid glands cut in error, the total number of dissected lymph nodes, and the number of metastatic lymph nodes were recorded.

Safety Evaluation Indicators

[0105] Safety evaluations were conducted throughout the study. Subjects with early withdrawal underwent the safety evaluation before withdrawal. The safety evaluation included changes in vital signs, physical examination, electrocardiogram, clinical laboratory test indicators (blood routine, urine routine, blood biochemistry, coagulation function, pregnancy test, etc.), adverse events and serious adverse events, and early withdrawal due to safety or tolerance.

2. Efficacy Results of the Clinical Trial

[0106] Results of the clinical trial show that the rate of parathyroid gland cutting in error in the conventional operations is about 27%, the rate of parathyroid gland cutting in error in the operations using the product of the present disclosure is 7% or less, and the rate of parathyroid gland cutting in error and the number of parathyroid glands cut in error in the individuals undergoing the operations using the product of the present disclosure are both less than those in the individuals undergoing the conventional operations. In this study, for the evaluation of the main therapeutic effect indicators, statistical analysis is performed by means of a PPS data set and an FAS data set, respectively, and the conclusions are consistent. Furthermore, sensitivity analysis results are also consistent. There is a significant difference (P<0.001) between the experiment group and the control group in the main therapeutic effect indicators, and no obvious adverse effects are found.

3. Safety Evaluation Results of the Clinical Trial

[0107] Phase I clinical trial shows that the mitoxantrone hydrochloride injection for lymphatic tracing enters the blood circulation in a very small amount after being administered locally, does not cause systemic toxic side effects, and has good safety. Phase II and Phase III clinical trials show that when the mitoxantrone hydrochloride injection for lymphatic tracing is used for lymphatic tracing in the operations for the patients with thyroid carcinoma in the experiment group and the blank control group, the percentage of adverse events (AE), the percentage of serious adverse events (SAE), and the percentage of AE of grade 3 or more in the subjects are all similar, and no AE and SAE related to the investigational drug occur. A chi-square test is used for comparison of the groups, and there is no statistically significant difference between the two groups in occurrence rates of AE, SAE, and AE of grade 3 or more. Therefore, it can be concluded that the safety results of the experimental group are similar to those of the blank control group, and are good.

[0108] The results of the above clinical trials show that:

[0109] (1) the mitoxantrone hydrochloride injection can well protect the parathyroid glands;

[0110] (2) the mitoxantrone hydrochloride injection can well stain lymph nodes and can accurately trace the lymph nodes;

[0111] (3) the investigational drug does not stain the parathyroid glands in error;

[0112] (4) the investigational drug can dissect more lymph nodes while applied in a thyroid operation;

[0113] (5) the lymph nodes with a size of ≤2 mm, >2 mm and ≤5 mm, and >5 mm and ≤10 mm are detected and dissected, wherein there is a significant difference between the experimental group and the control group, and there is no statistically significant difference between the experimental group and the control group in the lymph nodes with a size of >10 mm; and

[0114] (6) after the investigational drug is administered locally, no local or systemic toxic side effect is found, and no adverse event or adverse effect related to the investigational drug occurs, indicating that the investigational drug has good tolerance and safety.

[0115] It can be known from the above results that the study of these clinical trials has good efficacy and safety. By using the mitoxantrone hydrochloride injection for tracing to position and dissect lymph nodes on the basis of its staining function for lymph nodes, lymph nodes can be accurately traced, and more lymph nodes can be dissected, thereby preventing parathyroid gland cutting in error, reducing the rate of parathyroid gland cutting in error, and providing a new treatment idea in complete eradication of thyroid carcinoma for patients with thyroid carcinoma.

EXAMPLE 11 APPLICATION OF A MITOXANTRONE HYDROCHLORIDE INJECTION FOR LYMPHATIC TRACING IN A RADICAL OPERATION FOR A PATIENT WITH THYROID CARCINOMA

[0116] Preoperative diagnosis: thyroid carcinoma

[0117] Postoperative diagnosis: thyroid carcinoma

[0118] Operation name: a radical operation for thyroid carcinoma (bilateral total lobectomy for thyroid+bilateral VI- and VII-level lymph node dissection)

[0119] Anesthesia method: general anesthesia

[0120] Operative procedures are as follows. The patient was checked. After the patient was anesthetized successfully, the patient's shoulders were supported by a pillow, the neck was tilted back, and the conventional surgical field was disinfected with iodine complex and draped. An arc-shaped incision with a length of about 7 cm was formed below the neck and anastomosed with the dermatoglyph, the skin, the subcutaneous tissue, and the platysma to the anterior cervical fascia were cut open layer by layer, and flaps were dissociated upwards and downwards along the space between the platysma and the anterior cervical fascia: the anterior cervical fascia was cut open at the midline of the neck, and the anterior cervical muscles were dissociated to both sides to reach the surface of the thyroid. It was found by exploration that the thyroid was softer in texture, with multiple tough nodules in two lobes, of which the right lobe was accessible with a hard nodules having a size of about 1 cm. 0.1 mL of the mitoxantrone hydrochloride injection for lymphatic tracing was administered under the thyroid capsule at upper and lower portions, spaced by 1 cm, of the left thyroid lobe as well as upper and lower portions, spaced by 1 cm, of the right thyroid lobe, respectively (total 0.4 mL), and the drug was withdrawn. After the puncture sites were pressed for 5 min, the thyroid and lymph nodes were gradually stained blue. First, right lobectomy was performed, the lateral of the right thyroid lobe was dissociated, the middle thyroid veins in the right lobe were severed, and anterior laryngeal lymph nodes and the thyroid conical lobe were cut and removed. The isthmus close to the right lobe was dissociated, the right thyroid lobe was pulled to the left, and upper and lower polar vessels in the right thyroid lobe were severed. The thyroid gland was pulled upwards, and the recurrent laryngeal nerve was carefully separated from the dorsal part of the thyroid and protected carefully: the right thyroid lobe was dissociated from the inside out to completely cut and remove the right thyroid lobe. Left lobectomy was performed in a similar way. The bilateral recurrent laryngeal nerves were dissociated throughout the lobectomy, VI- and VII-level regional lymphatic adipose tissues (up to the level of the hyoid bone, from the external carotid artery to the medial border, down to the superior border of the innominate artery) were dissected under the guidance of the lymphatic tracer, and visible parathyroid glands were reserved in situ throughout the lobectomy. The bleeding in the wound was carefully stopped; after no obvious active bleeding was observed, the numbers of gauzes and instruments were checked; and after confirmation, the layers from the anterior cervical fascia to the subcutaneous tissue were closed layer by layer by using absorbable sutures to suture the wound. The operation was performed smoothly, with little bleeding, and no blood transfusion was required. After the operation, the tracheal intubation was successfully removed, and the patient returned to the ward safely without hoarseness. The removed tissues were examined pathologically.

[0121] Pathological examination results: metastatic carcinoma of lymph nodes (the right paratracheal area: 0/0; the pretracheal area: 1/1; the left paratracheal area: 1/6; and the prelaryngeal area: 0/0), with a small amount of visible thyroid tissues (the right paratracheal area and the prelaryngeal area).

[0122] No parathyroid gland is cut in error, and a total of 7 lymph nodes are detected, which include 2 lymph nodes with a size of ≤2 mm, 5 lymph nodes with a size of >2 mm and ≤5 mm, and 0 lymph node with a size of >5 mm and ≤10 mm. The above detected lymph nodes are all stained with the staining rate of 100%.