CN109718228A - The antitumor Lymph Node Metastasis of mitoxantrone acts on and its pharmaceutical preparation - Google Patents
The antitumor Lymph Node Metastasis of mitoxantrone acts on and its pharmaceutical preparation Download PDFInfo
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- CN109718228A CN109718228A CN201711031983.5A CN201711031983A CN109718228A CN 109718228 A CN109718228 A CN 109718228A CN 201711031983 A CN201711031983 A CN 201711031983A CN 109718228 A CN109718228 A CN 109718228A
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Abstract
The present invention relates to the effect of the antitumor Lymph Node Metastasis of pharmaceutical technology field more particularly to mitoxantrone and its pharmaceutical preparations.Mitoxantrone of the present invention uses local administration, such as administration, tumour tumor week subcutaneous administration in tumour tumor.The mitoxantrone can be prepared into clinically acceptable pharmaceutical preparation with pharmaceutically acceptable carrier.The pharmaceutical preparation is non-intestinal drug delivery agent.The non-intestinal drug delivery agent is selected from solution, liposome, dendrimer, nanoparticle, nanocrystalline, crystallite, microballoon, gelling agent.In the present invention, mitoxantrone can be improved its anti-tumor activity for local chemotherapy, reduce toxic side effect, target lymphatic system, inhibit lymph metastases.Mitoxantrone, which is used for new adjuvant chemotherapy, can not only reduce gross tumor volume convenient for subsequent procedures excision, moreover it is possible to kill tumour cell transferred in lymphatic vessel, reduce the risk of had postoperative recurrent tumor, improve the quality of life of patient.
Description
Technical field
The present invention relates to the effect of the antitumor Lymph Node Metastasis of pharmaceutical technology field more particularly to mitoxantrone and its drug systems
Agent.
Background technique
Metastases are the key factors of certain solid tumor patient death, and the probability of mammary gland carcinogenesis transfer is higher.It is logical
The initial position often shifted is tumor week lymph node.For most of tumour, lymphatic system is the main of metastases
And unique channel.Lymph node can focus on all tumour cells to fall off in the reticular fibre of marginal sinus and then in situ
Proliferation.More and more clinical and experimental datas show that the transfer ratio sarcoma of tumour is more common.First finger of cancer cell diffusion
Mark is the presence of tumour cell in lymph node.It is therefore prevented that the Lymph Node Metastasis of tumour cell is very important.On Present clinical
For treating the method for lymph metastases as using traditional small-molecule drug progress systemic chemotherapy.These small-molecule drug lymphs
Compatibility is poor, causes strong toxic side effect after Formulations for systemic administration, and therapeutic effect is unsatisfactory.Clinically by tumour sentinel lymph node
Excision is another conventional treatment method, but as lymphangiogenesis generates the appearance with cancer immunity theory, it is this
The validity of sentinel lymph node resection is queried again.So far, for lymph metastases, we are not yet developed
Satisfied treatment method.
New adjuvant chemotherapy, also known as staging tomography, induction chemother, initial chemotherapy etc., refer to the change for giving whole body before surgery
Treat drug therapy.New adjuvant chemotherapy can reduce tumour convenient for operation, improve the resection rate for the Locally Advanced tumour that can not perform the operation.Newly
Adjuvant chemotherapy is not a kind of new treatment method, and is referred to different from adjuvant chemotherapy on the time point of systemic therapy.
Mitoxantrone is a kind of successful antineoplastic, is able to suppress the activity of tumor topoisomerase, is chiefly used at present
Formulations for systemic administration.As many other anti-tumor drugs, mitoxantrone can generate serious toxic side effect for Formulations for systemic administration.
Summary of the invention
The purpose of the present invention is to provide the effects of the antitumor Lymph Node Metastasis of mitoxantrone.
The present invention is achieved through the following technical solutions:
Wherein, mitoxantrone of the present invention uses local administration, as administration, tumour tumor week are subcutaneously given in tumour tumor
Medicine.
Further, the mitoxantrone in the present invention can be prepared into pharmaceutically acceptable carrier is clinically subjected to
Pharmaceutical preparation.
The pharmaceutical preparation is non-intestinal drug delivery agent.
The non-intestinal drug delivery agent be selected from solution, liposome, dendrimer, nanoparticle, nanocrystalline, crystallite,
Microballoon, gelling agent.
Wherein, the gelling agent be selected from contain the gelling agent of liposome, the gelling agent for containing nanoparticle, contain it is tree-shaped big
The gelling agent of molecule one of contains nanocrystalline gelling agent, the gelling agent for containing crystallite and the gelling agent for containing microballoon.
Pharmaceutical preparation provided by the invention contains the mitoxantrone of 99%-1% and the pharmaceutical excipient of 1%-99%, preferably
The pharmaceutical excipient of mitoxantrone and 60%-40% containing 40%-60%, the preferably mitoxantrone containing 10%-20% and
The pharmaceutical excipient of 90%-80%.
The auxiliary material in antitumor Lymph Node Metastasis drug in the present invention is conventional excipient, as solvent, phosphatide, gallbladder are solid
Alcohol, dendrimer, human serum albumin, poloxamer, chitosan etc..
Further, crystallite gelling agent is made in mitoxantrone of the present invention and pharmaceutically acceptable excipient.
The crystallite gel includes the ingredient of following weight composition: mitoxantrone 0.1mg-1000mg, mitoxantrone salt
Hydrochlorate 0.1mg-1000mg, poloxamer188 1.5g-25g, PLURONICS F87 0.1g-8g, distilled water 10mL-100mL.Its
Middle difference mitoxantrone and excipient ratios will generate different formulation properties, and formulation properties are mainly shown as that gel gelling is special
Property, the suitable prescription of selection can be carried out according to the actual situation.
Mitoxantrone is used for local chemotherapy by the present invention can be improved its anti-tumor activity, reduce toxic side effect, targeting leaching
Bar system inhibits lymph metastases.Mitoxantrone, which is used for new adjuvant chemotherapy, can not only reduce gross tumor volume convenient for subsequent
Operation excision, moreover it is possible to kill tumour cell transferred in lymphatic vessel, reduce the risk of had postoperative recurrent tumor, improve patient's
Quality of life.
Detailed description of the invention
Fig. 1 is drug entities distribution situation after the mice with tumor vein or local administration of the embodiment of the present invention 1.
Fig. 2 is that Hou lymphonodi poplitei relative weight situation of change is administered in the mice with tumor of the embodiment of the present invention 1.
Fig. 3 is lumbar vertebrae lymph node relative weight situation of change after the mice with tumor of the embodiment of the present invention 1 is administered.
Fig. 4 is lymph node drug concentration after the mice with tumor tumor by local or intravenously administrable of the embodiment of the present invention 1.
Fig. 5 is drug in lymph node after office's chemotherapy before the mice with tumor Tumor Resection of the embodiment of the present invention 1 or postoperative systemic chemotherapy
Concentration.
Fig. 6 be the embodiment of the present invention 1 mice with tumor Tumor Resection before mouse amount of drinking water after office's chemotherapy or postoperative systemic chemotherapy, take the photograph
The situation of change of appetite and weight.
Specific embodiment
To make the purpose of the present invention, technical solution and effect clearer, clear and definite, right as follows in conjunction with drawings and embodiments
The present invention is further described.It should be appreciated that described herein, specific examples are only used to explain the present invention, is not used to limit
The fixed present invention.
The preparation of embodiment 1, solution
The present embodiment provides a kind of mitoxantron solutions agent, each raw material proportioning of the drug of every 100ml is as follows: mitoxantrone
0.5%, sodium acetate 0.01%, sodium pyrosulfite 0.02%, acetic acid 0.092%, sodium chloride 0.8%.Preparation process is as follows: will
0.01% sodium acetate, 0.02% sodium pyrosulfite, 0.092% acetic acid, 0.8% sodium chloride are dissolved in 100ml pure water, are obtained
Injection solution.0.5% mitoxantrone is added into injection solution, at room temperature 50rpm magnetic agitation, stirs 25min, then
Medical charcoal is added and obtains mitoxantron solutions agent in 50 DEG C, 50rpm magnetic agitation 20min.Mitoxantron solutions agent is used
0.22 μm of filtering with microporous membrane, 121 DEG C of sterilizing 15min, the mitoxantron solutions agent after being sterilized.
In the present embodiment 1, in order to further verify beneficial effects of the present invention, following tests example is provided.
1, the lymph node pharmacokinetics of mitoxantron solutions agent tumor by local administration and Tissue distribution are investigated.
The foundation of lymph metastases type animal model: male mouse of kunming (18-22g) left foot subcutaneous lotus knurl (S180 abdomen
Hydatoncus suspension).After 7 days, mice with tumor lymphonodi poplitei (popliteal lymph node, PLN), lumbar vertebrae lymph node are taken out
(lumbar aortic lymph node, ILN) and lymphonodi renales (renal lymph node, RLN) are simultaneously dipped into rapidly
It in 10% formalin, embeds into paraffin mass, is cut into 5mm slab, HE dyeing carries out pathological analysis, observation tumour leaching
Whether bar metastasis model constructs success.
The internal lympha targeted ability of mitoxantron solutions agent: to mice with tumor locally injected into tumor rice support anthracene described above
Quinone solution, dosage 5mg/kg.The mitoxantron solutions agent of control group mice tail vein injection same dose.After administration
In the tissue such as specific time point Shou art Zhai Chu lymphonodi poplitei, lumbar vertebrae lymph node and lymphonodi renales, the heart, liver, spleen, lung, kidney.Biology
Sample after processing, the content of tissue sample Chinese medicine object is analyzed using high-efficient liquid phase technique.
Measurement result are as follows: by pathology slice result it is found that this test example 1 successfully constructs lymph metastases model.
Lymph node Pharmacokinetic Results are shown in Table 1 after being administered in mitoxantron solutions tumor made from the present embodiment.
Table 1
As shown in Table 1, mitoxantron solutions in tumor after being administered, Neng Gou lymphonodi poplitei, lumbar vertebrae lymph node and kidney lymph
Drug is detected in knot, that is to say, that mitoxantron solutions can target lymph node after being administered in tumor.
For mitoxantron solutions after vein or intratumor injection, the concentration that drug is accumulated in the heart, liver, spleen, lung, kidney is shown in Fig. 1.
As can be seen from the results, drug concentration of the mitoxantrone in the heart and liver is lower than detection limit after local administration, in spleen, lung and kidney
Drug concentration is also below through vein mitoxantrone group.It, can after mitoxantrone local administration compared with traditional intravenous systemic administration
The general toxicity for reducing drug accumulation in the normal tissue, reducing drug.
2, mitoxantron solutions agent applies the validity in new adjuvant chemotherapy to investigate.
The foundation of lymph metastases type animal model: male mouse of kunming (18-22g) left foot subcutaneous lotus knurl (S180 abdomen
Hydatoncus suspension).After 7 days, mice with tumor lymphonodi poplitei (popliteal lymph node, PLN), lumbar vertebrae lymph node are taken out
(lumbar aortic lymph node, ILN) and lymphonodi renales (renal lymph node, RLN) are simultaneously dipped into rapidly
It in 10% formalin, embeds into paraffin mass, is cut into 5mm slab, HE dyeing carries out pathological analysis, observation tumour leaching
Whether bar metastasis model constructs success.
Animal dosage regimen: the above-mentioned lymph metastases mouse model being successfully established is divided into 6 groups, every group 24.(1)
C-sc group: mice with tumor bound feet locally injected into tumor mitoxantron solutions, dosage 5mg/kg give a medicine in every seven days.(2)
C-iv group: mice with tumor bound feet tumour is injected intravenously mitoxantron solutions, and dosage 5mg/kg gives a medicine in every seven days.(3)
S group: Shou art Qie Chu lymphonodi poplitei is not administered.(4) S+C group: postoperative systemic chemotherapy holds in the palm rice after Shou art Zhai Chu lymphonodi poplitei
Anthraquinone intravenously administrable, dosage 5mg/kg, gives a medicine in every seven days.(5) C+S group: preoperative local chemotherapy first holds in the palm rice
Anthraquinone solution carries out the administration of bound feet tumor by local, and dosage 5mg/kg gives a medicine in every seven days, in the 14th after being administered twice
It extracts lymph node, is no longer administered.(6) Control group: control group, the isodose physiological saline of bound feet locally injected into tumor.Note
Record amount of drinking water, food ration and the body weights of all mouse.All groups select 8 on the 7th, 14,21,28 day after administration at random
Mouse is put to death, and is taken out C-sc group, C-iv group and Control group Qu Chu lymphonodi poplitei and lumbar vertebrae lymph node remaining group and is only taken out waist
Vertebra lymph node.Each time point lymph node is weighed, calculating opposite lymph node weights WR, (WR=Wi/Wc, Wi are the ipsilateral lymph of tumour
Weight is tied, Wc is tumour contralateral lymph knot weight), then lymph node is handled, Syrups by HPLC drug therein
Concentration.
As shown in Figure 2, C-sc Zu lymphonodi poplitei relative weight is significantly lower than C-iv group and Control group, as a result table
Therapeutic effect after bright mitoxantron solutions tumor by local administration is substantially better than Formulations for systemic administration.
From the figure 3, it may be seen that lumbar vertebrae lymph node relative weight sequence are as follows: Control group > S group > S+C group > C-iv group > C-
Sc group > C+S group, in different administration modes and in the different surgical removal time, preoperative local chemotherapy is substantially better than postoperative complete
Body chemotherapy can obviously inhibit metastases.
As shown in Figure 4, concentration of the mitoxantron solutions Hou tumor by local administration in lymphonodi poplitei and lumbar vertebrae lymph node
It is above intravenously administrable group.The result shows that there is certain lympha targeted property after the administration of mitoxantron solutions tumor by local.
As shown in Figure 5, its lumbar vertebrae lymph node concentration is obvious after preoperative application mitoxantron solutions carry out tumor by local chemotherapy
Higher than postoperative systemic chemotherapy.The result shows that mitoxantron solutions have good effect using preoperative local chemotherapy.
It will be appreciated from fig. 6 that the amount of drinking water of C+S group mouse, food ration do not reduce equally with Control group and S group, and should
The mouse weight of group does not decline.For synthesis, the mouse after receiving mitoxantron solutions local administration is serious there is no generating
Adverse reaction.Its small toxicity after mitoxantron solutions local administration is a kind of safe drugs.
In the present embodiment, we can after demonstrating the administration of mitoxantron solutions agent tumor by local by two test examples
Targeted to lymphatic system, the therapeutic effect of preoperative local chemotherapy is better than the therapeutic effect of postoperative systemic chemotherapy, additionally it is possible to reduce rice
The system toxicity of anthraquinone Formulations for systemic administration is held in the palm, animal subject does not generate serious adverse reaction, therefore mitoxantrone local administration
The advantage of synergy toxicity reduction is shown afterwards.In recent years, people are more and more to the research of new adjuvant chemotherapy, accelerate people to new auxiliary
The applicable drug of chemotherapy institute is helped to be studied.Embodiment provided by the invention can be applied to new adjuvant chemotherapy and reach beneficial
Effect, and the clinical application range of the drug of mitoxantrone class has also been enlarged, there is very high practical value, will suffer from for cancer
Person brings glad tidings.
The preparation of embodiment 2, crystallite gel
The present embodiment provides a kind of mitoxantrone crystallite gel, each raw material proportioning of the drug of every 10g is as follows: mitoxantrone
10mg, mitoxantrone hydrochloride 5mg, poloxamer188 2g, PLURONICS F87 0.5g, 7.49ml distilled water.Preparation process
As follows: precision weighs mitoxantrone 10mg, the mitoxantrone hydrochloride 5mg for being ground up, sieved rear (200 mesh), and poloxamer is added
407 2g, PLURONICS F87 0.5g, distilled water 7.49ml, 30rpm magnetic agitation 6h is all dissolved to particle under ice-water bath, and 4
It is placed at DEG C for 24 hours to get mitoxantrone crystallite gel.
It can reduce the drug poison of mitoxantrone Formulations for systemic administration after local administration to verify the crystallite gel of the present embodiment 2
Property, the present embodiment has investigated the mouse tissue distribution situation after intratumor injection crystallite gel.With the test example 1 under embodiment 1
Test method is similar, chooses intravenous injection mitoxantron solutions as a control group, intratumor injection mitoxantrone crystallite gel conduct
Experimental group.The drug accumulation concentration that experimental result shows that experimental group is respectively organized is below control group, the results showed that mitoxantrone is micro-
Brilliant gel can reduce drug toxicity after tumor by local is administered.
The preparation of embodiment 3, liposome
The present embodiment provides a kind of mitoxantrone liposome, each raw material proportioning of the drug of every 10ml is as follows: mitoxantrone
10mg, soybean lecithin 0.4g, cholesterol 0.04g, glucose 1.5g.Preparation process is as follows: by 10mg mitoxantrone, 0.4g soybean
Phosphatide, the suitable dehydrated alcohol of 0.04g cholesterol solution, obtain clear solution.1.5g glucose is added into clear solution
Powder shakes up, ultrasound to milky suspension.Milky suspension is removed into ethyl alcohol in 50 DEG C of rotary evaporations, obtains liposome
Film.10ml distilled water aquation at 50 DEG C is added into liposome membrane, until solid all dissolves, Probe Ultrasonic Searching 10min, mistake
0.45 μm of filter membrane is up to mitoxantrone liposome.
It can reduce the drug poison of mitoxantrone Formulations for systemic administration after local administration to verify the liposome of the present embodiment 3
Property, the present embodiment has investigated the mouse tissue distribution situation after intratumor injection liposome.It is tried with the test example 1 under embodiment 1
Proved recipe method is similar, chooses intravenous injection mitoxantron solutions as a control group, intratumor injection mitoxantrone liposome is as experiment
Group.The experimental results showed that the drug concentration that experimental group is accumulated in each health tissues (heart, liver, spleen, lung, kidney) is below control
Group, the results showed that mitoxantrone liposome can reduce drug toxicity after tumor by local is administered.
Embodiment 4, microballoon preparation
The present embodiment provides a kind of mitoxantrone microballoon, each raw material proportioning of the drug of every 110mg is as follows: mitoxantrone
10mg,PLGA100mg.Preparation process is as follows: precision weighs PLGA100mg, is dissolved in 2ml methylene chloride, and 10mg meters of supports are added
Anthraquinone, ultrasonic dissolution obtain organic phase.Water phase is the aqueous solution of 5%PVA, and water phase is held in ice-water bath.At 800 rpm,
Organic phase is slowly injected into water phase and obtains mixed liquor, continues to be stirred liquid and volatilize completely to organic phase, mixed liquor is crossed into 0.45 μ
M filter membrane collects microballoon, and the microballoon being collected into 200ml is distilled water washing, until dry 48h is in drier to get mitoxantrone
Microballoon.
It can reduce the drug toxicity of mitoxantrone Formulations for systemic administration after local administration to verify the microballoon of the present embodiment 4,
The present embodiment has investigated the mouse tissue distribution situation after intratumor injection microballoon.With 1 test method of test example under embodiment 1
It is similar, choose intravenous injection mitoxantron solutions as a control group, intratumor injection mitoxantrone microballoon is as experimental group.Experiment knot
The drug accumulation concentration that fruit shows that experimental group is respectively organized is below control group, the results showed that mitoxantrone microballoon is given through tumor by local
It can reduce drug toxicity, the safety for improving mitoxantrone medication after medicine.
It, can according to the technique and scheme of the present invention and its hair it is understood that for those of ordinary skills
Bright design is subject to equivalent substitution or change, and all these changes or replacement all should belong to the guarantor of appended claims of the invention
Protect range.
Claims (8)
1. mitoxantrone is preparing the application in antitumor Lymph Node Metastasis drug.
2. application as described in claim 1, which is characterized in that the mitoxantrone uses local administration.
3. application as claimed in claim 1 or 2, which is characterized in that the mitoxantrone uses administration or swollen in tumour tumor
Tumor tumor week subcutaneous administration.
4. the application as described in claim 1-3 any one, which is characterized in that the mitoxantrone with it is pharmaceutically acceptable
Carrier be prepared into clinically acceptable pharmaceutical preparation.
5. application as claimed in claim 4, which is characterized in that the pharmaceutical preparation is non-intestinal drug delivery agent.
6. application as described in claim 4 or 5, which is characterized in that the pharmaceutical preparation is solution, liposome, tree-shaped
Macromolecular, nanoparticle, nanocrystalline, crystallite, microballoon or gelling agent.
7. application as claimed in claim 4, which is characterized in that the pharmaceutical preparation contain 99%-1% mitoxantrone and
The pharmaceutical excipient of 1%-99% preferably comprises the mitoxantrone of 40%-60% and the pharmaceutical excipient of 60%-40%, best
The pharmaceutical excipient of mitoxantrone and 90%-80% containing 10%-20%.
8. application as claimed in claim 6, which is characterized in that the gelling agent includes the ingredient of following weight composition: rice
Hold in the palm anthraquinone 0.1mg-1000mg, mitoxantrone hydrochloride 0.1mg-1000mg, poloxamer188 1.5g-25g, poloxamer
188 0.1g-8g, distilled water 10mL-100mL.
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| CN113730603A (en) * | 2020-05-27 | 2021-12-03 | 深圳华润九创医药有限公司 | Application of mitoxantrone preparation in preparation of medicine for treating thyroidectomy-related diseases |
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| CN114469953A (en) * | 2022-02-14 | 2022-05-13 | 沈阳药科大学 | Antitumor drug composition with synergistic effect, nano preparation, preparation method and application thereof |
| WO2023242097A1 (en) | 2022-06-13 | 2023-12-21 | KHR Biotec GmbH | Mitoxanthrone derivatives as ras inhibitors |
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| WO2023242097A1 (en) | 2022-06-13 | 2023-12-21 | KHR Biotec GmbH | Mitoxanthrone derivatives as ras inhibitors |
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