CN110279696A - Itraconazole inhibits the application in tumor metastasis medicine in preparation - Google Patents
Itraconazole inhibits the application in tumor metastasis medicine in preparation Download PDFInfo
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- CN110279696A CN110279696A CN201910702922.XA CN201910702922A CN110279696A CN 110279696 A CN110279696 A CN 110279696A CN 201910702922 A CN201910702922 A CN 201910702922A CN 110279696 A CN110279696 A CN 110279696A
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- Prior art keywords
- cancer
- monoclonal antibody
- itraconazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
Abstract
The embodiment of the invention discloses a kind of Itraconazoles to inhibit the application in tumor metastasis medicine in preparation；Itraconazole is used to prepare by the present invention to be inhibited effectively inhibit the transfer of tumour cell in tumor metastasis medicine, and to human body is without side-effects or smaller side effect.
Description
Technical field
The present embodiments relate to pharmaceutical technology fields, and in particular to a kind of Itraconazole inhibits metastases medicine in preparation
Application in object.
Background technique
Transfer is the main reason for tumor patient is dead, and malignant tumour dies of DISTANT METASTASES IN.Nasopharyngeal neoplasms are related to more
Step and complicated molecular events, specifically include that tumor cell adhesion characteristic changing, matrix degradation protein molecular, tumour cell
It is detached from from original site, cell migration enters circulation or lymphatic system, and escape is immune, is adhered to blood vessel or lymphatic endothelial cells
Wall and to vascular external migration, into surrounding substrate infiltration to metastasis site, the chemotactic of tumour cell target organ transfer and field planting, shape
Transfer stove and metastatic tumor growth of Cheng Xin etc..The committed step of the transfer process of effective prevention tumour can successfully inhibit its progress,
This is of great significance to the treatment of tumour.
Melanoma is a kind of tumour of high malignancy, seriously threatens crowd's life and health.Transfer is melanoma patient death
The main reason for, 90% malignant tumour dies of DISTANT METASTASES IN.After lymph node and DISTANT METASTASES IN occur for melanoma, poor prognosis is died of illness
Rate is high, and five year survival rate about 5-15%, though treatment means are more, how undesirable effect is.In recent years, melanoma targeted therapy is trend
Place, drug mainly divide two classes: one kind is immune tumour medicine, using anti-PD-1/L1 and CTLA-4 antibody as representative；One kind is mutation
Gene inhibitor, with BRAF inhibition from mutation agent vemurafenib etc. for representative；However these drug prices are expensive and side effect compared with
Greatly.
Summary of the invention
For this purpose, the embodiment of the present invention, which provides a kind of Itraconazole, inhibits the application in tumor metastasis medicine in preparation, with solution
The problem expensive existing for certainly existing drug, side effect is larger.
To achieve the goals above, the embodiment of the present invention provides the following technical solutions:
A kind of Itraconazole is provided according to a first aspect of the embodiments of the present invention to inhibit in tumor metastasis medicine in preparation
Application.
Further, the tumour includes melanoma, non-small cell lung cancer, basal-cell carcinoma, choriocarcinoma, ovary
Cancer, colon cancer, prostate cancer, breast cancer, gastric cancer, cancer of pancreas, carcinoma of endometrium, bladder cancer, kidney and thyroid cancer.
Further, shown Itraconazole can be Itraconazole isomers.
A kind of drug for inhibiting metastases is provided according to a second aspect of the embodiments of the present invention, and the drug includes effective
The Itraconazole of dosage and pharmaceutically acceptable auxiliary material.
Further, the drug further include receive Wu Liyou monoclonal antibody, Pa Boli pearl monoclonal antibody, Aunar pearl monoclonal antibody, degree cut down Shandong list
Anti-, AVM hereinafter monoclonal antibody, her monoclonal antibody, Torr pearl monoclonal antibody, mustargen, cyclophosphamide, methotrexate (MTX), cis-platinum, carboplatin, oxaliplatin, card training
It is his shore, 5 FU 5 fluorouracil, Raltitrexed, cytarabine, gemcitabine, pemetrexed, hydroxycarbamide, 6- sulphur purine, adriamycin, soft
Erythromycin, Hydroxycamptothecin, Irinotecan, topotecan, vincristine, eldisine, vinorelbine, taxol, Taxotere
Alcohol, Toremifene, Exemestane, Letrozole, Bicalutamide, bleomycin, mitomycin C, everolimus, pazopanib, song
Trastuzumab, Sutent, bevacizumab, VEGF Trap, endostatin research, Gefitinib, Herceptin, western appropriate former times are single
In anti-, Rituximab, Imatinib, Avastin, Gefitinib, Tarceva and small molecule tyrosine kinase inhibitors
Any one or more.
Further, the small molecule tyrosine kinase inhibitors are Wei Luofeini, Imatinib, darafinib, Sibutramine Hydrochloride
For Buddhist nun, Afatinib or Gefitinib.
The present invention can preferably inhibit tumour thin by the way that Itraconazole can be treated tumor metastasis medicine combination with other
The transfer of born of the same parents improves drug entirety curative effect.
Further, the pharmaceutical dosage form is tablet, capsule, granule, oral solution or injection.
Further, the auxiliary material be selected from diluent, excipient, filler, absorption carrier, disintegrating agent, sorbefacient,
Any one or more in surfactant and lubricant.
In the present invention stringent limitation is not done to above-mentioned auxiliary material, such as above-mentioned auxiliary material is the customary adjuvant of this field, leads to
Corresponding dosage form can be made in drug by the selection for crossing above-mentioned auxiliary material, and improves the absorption of effective component in drug, and then reach
Improve the effect for inhibiting metastases；Preferably, the diluent can for alcohols, benzene class, ketone, esters, dimethyl sulfoxide,
Water, finish (mineral oil, vegetable oil, animal oil, any one or more in synthetic oil；
The excipient can for water, stearic broken magnesium, starch, lactose, microcrystalline cellulose, sucrose, talcum, two formula SiClxs,
Gelatin, Arabic gum, Dicalcium Phosphate, glucose, molasses, dextrose be liquor-saturated, lactose, magnesium carbonate, mineral oil, boric acid, vegetable oil, hard
Any one or more in resin acid (salt), liposome and nano particle；
The filler can be starch, Icing Sugar, dextrin, lactose, amylum pregelatinisatum, microcrystalline cellulose (MCC), inorganic salts
Any one or more in class and mannitol；
The absorption carrier can be active carbon, nano meter biomaterial, polyacrylamide microsphere, latex, the compound magnetic of iron carbon
Property carrier, agar gel ball, nano particle, resin, black alkene and polysaccharide carrier in any one or more；
The disintegrating agent can for carboxyrnethyl starch sodium (CMS-Na), sodium carboxymethylcellulose, microcrystalline cellulose, dried starch,
Low-substituted hydroxypropyl cellulose (L-HPC), pregelatinized starch, crospovidone, cross linked polyvinyl pyrrolidone (are also known as crosslinked
PVP), any one in croscarmellose sodium (CCNa) and gas-producing disintegrant (sodium bicarbonate and citric acid) or more
Kind；
The sorbefacient can be ethyl alcohol, propylene glycol, isopropyl myristate, nonyl for penta bis ether of ring, N- trimethyl
Chitosan, oleic acid dendrimer, 6-aminocaprolc acid derivative, menthol, eucalyptus oil, borneol, propylene glycol, azone, dimethyl
Any one or more in sulfoxide (DMSO), chitosan, carbomer and fatty acid and fatty acid salt；
The surfactant can be high molecular surfactant, cationic and anionic surfactant, element surface-active
Agent, Gemini surfactant, green surfactant, mild surfactants, Bola type surfactant, chelating type table
Face activating agent, Chiral surfactant, surfactant, response type surfactant active, including TWEEN Series, Bo Luosha
Nurse, Emulsifier EL-60, docusate sodium, lauryl sodium sulfate, sodium ethylene diamine tetracetate and vitamin E polyethylene glycol 1000
Any one or more in succinate；
The lubricant can be mineral lubricant (such as machinery oil), vegetable lubricant (such as castor oil) and animality
Lubricant (such as tallow), syntholube, as any one in silicone oil, fatty acid amide, oleic acid, polyester, synthetic ester and carboxylic acid
Kind is a variety of.
Further, the dosage of the Itraconazole is 0.1-50mg/kg.
The embodiment of the present invention has the advantages that
(1) Itraconazole is used to prepare by the present invention inhibits effectively inhibit tumour cell in tumor metastasis medicine
Transfer, and it is without side-effects to human body.
(2) present invention can preferably inhibit swollen by the way that Itraconazole can be treated tumor metastasis medicine combination with other
The transfer of oncocyte improves drug entirety curative effect.
(3) present invention can be improved preferably common between each component by the restriction in drug to each component content
Effect, and then drug is improved to the inhibiting effect of tumour cell.
Detailed description of the invention
It, below will be to embodiment party in order to illustrate more clearly of embodiments of the present invention or technical solution in the prior art
Formula or attached drawing needed to be used in the description of the prior art are briefly described.It should be evident that the accompanying drawings in the following description is only
It is merely exemplary, it for those of ordinary skill in the art, without creative efforts, can also basis
The attached drawing of offer, which is extended, obtains other implementation attached drawings.
Fig. 1 is the transfer case for each group mouse lung melanoma that experimental example 1 of the present invention provides；
Fig. 2 is each group mouse lung tissue pathological slice HE colored graph that experimental example 1 of the present invention provides；
Fig. 3 is each group mouse survival curve that experimental example 2 of the present invention provides.
Specific embodiment
Embodiments of the present invention are illustrated by particular specific embodiment below, those skilled in the art can be by this explanation
Content disclosed by book is understood other advantages and efficacy of the present invention easily, it is clear that described embodiment is the present invention one
Section Example, instead of all the embodiments.Based on the embodiments of the present invention, those of ordinary skill in the art are not doing
Every other embodiment obtained under the premise of creative work out, shall fall within the protection scope of the present invention.
Embodiment 1
The present embodiment is that Itraconazole oral solution (purchase is in Xian-Janssen Pharmaceutical Ltd.) inhibits melanoma Lung metastases
Zoopery:
The building of C57/BL mouse black-in lymphoma Lung metastases model:
Zoopery follows ethical standard, and experiment mice is 20-22g female C57/BL mouse, 7-8 weeks size；It takes pair
Number phase B16F10 cell, pancreatin digestion, counts, and PBS makes single cell suspension, and adjustment cell concentration to 0.2mL contains 1 × 106It is a
Cell；With 1ml syringe, tail vein injection 0.2ml contains cellular liquid, and mouse totally 18；
Each group model mice stomach-filling Itraconazole oral solution 0,25,50mg/kg/qd, wherein control group gives 40%
HPCD2- hydroxypropyl cellulose-beta-cyclodextrin 0.2ml；Every day entry mouse state, measures weight, and raising continues 14 days.
1, mouse state and weight result:
It is compared during experiment with control group, medication group mouse movement, hair color, diet are shown no obvious abnormalities；It ties within medication 14 days
Beam experiment, each group mouse weight are 18.2 ± 1.0g of control group, 18.1 ± 1.2g of 25mg/kg/qd group, 50mg/kg/qd group 18.4
± 1.3g, statistical analysis is without significant difference, it can be seen that, test dose Itraconazole non-evident effect.
2, dissection mouse takes lungs etc. to organize after experiment terminates, and observes and records each organ melanoma transfer case, observation knot
Fruit is as shown in Figure 1:
As shown in Figure 1, control group surface black tumor stove is intensive, fusion is blocking, covers entire lungs surface, normal lungs group
It knits and almost disappears；25mg/kg/qd medication group, lungs surface tumor stove are significantly reduced compared with control group, have no that tumor stove merges；50mg/
Kg/qd medication group lungs surface tumor stove is minimum, fragmentary denumerable, and part lungs any surface finish has no obvious transfer stove, the fresh profit of color,
Perception is close to normal lungs.
3, tissue pathology checking's observing and nursing mouse black-in lymphoma lung shifts:
It is fixed using 10% formaldehyde lungs sample, (from low to high, dehydration, paraffin embedding and film-making, graded ethanol are dehydrated
50%, 70%, 95%, 100%)) sufficiently dehydration；Complete waxdip is organized, is sliced 5 μm；Dewaxing and aquation: 60 degree of 20min, then
Dimethylbenzene 1-3 distinguishes 10min immediately；Aquation is with graded ethanol (from high to low)；It is redyed (karyon dyestuff) with haematoxylin, the several seconds,
It is subsequently placed in hydrochloride alcohol after the several seconds and takes out flowing water vibration washing, orchid is returned in being put into ammonium hydroxide；Mounting: the mountings such as neutral gum are kept away
Exempt to generate bubble；Optical microphotograph under the microscope, is taken pictures and is analyzed to be saved using 10% formaldehyde and dissect mouse lung, and tissue disease is carried out
Reason checks HE dyeing, and microscopically observation melanoma Lung metastases situation observes result as shown in Figure 2 (in Fig. 2 from left to right successively
For the observation result figure of control group, 25mg/kg/qd, 50mg/kg/qd):
As shown in Figure 2, control group mice lungs are obviously full of Melanoma Tissue, and the larger and tumor mass of tumour stove product diffuses point
Cloth；25mg/kg/qd medication group melanoma agglomerate quantity and size are small compared with control group, and melanoma area reduces；And 50mg/kg/qd
The invasion of medication group lungs melanoma are most light, only have smaller tumor mass in partial region；Then soft using Image-pro plus 6.0
Part software calculates lungs melanoma area, and tumor area is as follows: control group (59.10 ± 8.78) %, 25mg/kg/
Qd medication group (38.67 ± 9.12) %, 50mg/kg/qd medication group (12.00 ± 7.16) %；It can be seen that Itraconazole is to melanoma
The influence of transfer, microscopic observation result are consistent with gross findings trend；Through statistical analysis, Itraconazole medication group and right
(P < 0.05) is had differences according to group.
Researcher has found that therapeutic effect can not be improved by improving Itraconazole dosage (100mg/kg/qd), and data are herein not
It presents, what this patent was mainly inquired into is the optimal dosage (≤50mg/kg/qd) of Itraconazole, this dosage more clinic is answered
Use promotion potential.
Embodiment 2
The present embodiment is the observation of B16F10 cell melanoma Lung metastases model mice life cycle:
30, C57/BL mouse black-in lymphoma Lung metastases model is constructed according to the method in embodiment 1；
3 groups are randomly divided into, every group of 10 mouse, each group model mice stomach-filling Itraconazole oral solution (derives from Xi'an poplar
Gloomy pharmaceutical Co. Ltd) 0,25,50mg/kg/qd, wherein control group gives PBS0.2ml, successive administration 14 days, continuous to see
It examines 30 days or more, records dead mouse situation, it is as shown in Figure 3 to obtain survivorship curve:
From the figure 3, it may be seen that Itraconazole can be with the median survival interval of lengthening model mouse；Control group median survival interval is 27
It, 25mg/kg/qd group median survival interval is 28 days (P=0.105), and 50mg/kg qd group median survival interval significantly extends, so that
Specific number of days (P=0.0138) is not can determine that；Mouse survival rate analyzes (30 and 45 days) the results show that control group mice is the 30th
It is i.e. all dead, and 25mg/kg qd group survival rate is 0.369, its life cycle is obviously prolonged after declaratives mouse medication；
50mg/kg qd group mouse 30 days and 45 days survival rates are 0.746, illustrate that most of survival time of mice significantly extends.
Although above having used general explanation and specific embodiment, the present invention is described in detail, at this
On the basis of invention, it can be made some modifications or improvements, this will be apparent to those skilled in the art.Therefore,
These modifications or improvements without departing from theon the basis of the spirit of the present invention are fallen within the scope of the claimed invention.
Claims (8)
1. Itraconazole inhibits the application in tumor metastasis medicine in preparation.
2. application according to claim 1, which is characterized in that the tumour includes melanoma, non-small cell lung cancer, base
Floor cells cancer, choriocarcinoma, oophoroma, colon cancer, prostate cancer, breast cancer, gastric cancer, cancer of pancreas, carcinoma of endometrium, bladder
Cancer, kidney and thyroid cancer.
3. application according to claim 1, which is characterized in that the drug includes the Itraconazole of effective dose, and
Pharmaceutically acceptable auxiliary material.
4. application according to claim 1, which is characterized in that the drug further includes receiving Wu Liyou monoclonal antibody, Pa Boli pearl
Monoclonal antibody, Aunar pearl monoclonal antibody, degree cut down Shandong monoclonal antibody, AVM hereinafter monoclonal antibody, her monoclonal antibody, Torr pearl monoclonal antibody, mustargen, cyclophosphamide, methotrexate (MTX),
Cis-platinum, carboplatin, oxaliplatin, capecitabine, 5 FU 5 fluorouracil, Raltitrexed, cytarabine, gemcitabine, pemetrexed, hydroxyl
Base urea, 6- sulphur purine, adriamycin, daunorubicin, Hydroxycamptothecin, Irinotecan, topotecan, vincristine, eldisine, length
Spring Rui Bin, taxol, Docetaxel, Toremifene, Exemestane, Letrozole, Bicalutamide, bleomycin, mitomycin
C, everolimus, pazopanib, Herceptin, Sutent, bevacizumab, VEGF Trap, endostatin research, Ji Fei are replaced
Buddhist nun, Herceptin, Cetuximab, Rituximab, Imatinib, Avastin, Gefitinib, Tarceva and small
Any one or more in molecule tyrosine kinase inhibitor.
5. application according to claim 4, which is characterized in that the small molecule tyrosine kinase inhibitors are dimension Rofe
Buddhist nun, Imatinib, darafinib, Trimetinib, Afatinib or Gefitinib.
6. application according to claim 1, which is characterized in that the pharmaceutical dosage form is tablet, capsule, granule, mouth
Take liquid or injection.
7. application according to claim 1, which is characterized in that the auxiliary material is selected from diluent, excipient, filler, suction
Any one or more in appendix body, disintegrating agent, sorbefacient, surfactant and lubricant.
8. application according to claim 1, which is characterized in that the dosage of the Itraconazole is 0.1-50mg/kg.
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Citations (5)
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|---|---|---|---|---|
| US20090203713A1 (en) * | 2005-08-22 | 2009-08-13 | Beachy Philip A | Hedgehog pathway antagonists to treat disease |
| CN103044408A (en) * | 2013-01-21 | 2013-04-17 | 万礼 | Itraconazole applied to treatment of malignant tumor or salt thereof and composition thereof |
| US20160045598A1 (en) * | 2013-04-04 | 2016-02-18 | The General Hospital Corporation | Combination Treatments with Sonic Hedgehog Inhibitors |
| CN105640957A (en) * | 2014-11-28 | 2016-06-08 | 四川大学华西医院 | Novel application of itraconazole |
| WO2019100003A1 (en) * | 2017-11-17 | 2019-05-23 | Yoon Jaeyoung | Combination therapy targeting cancer associated with the hedgehog pathway |
-
2019
- 2019-07-31 CN CN201910702922.XA patent/CN110279696A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090203713A1 (en) * | 2005-08-22 | 2009-08-13 | Beachy Philip A | Hedgehog pathway antagonists to treat disease |
| CN103044408A (en) * | 2013-01-21 | 2013-04-17 | 万礼 | Itraconazole applied to treatment of malignant tumor or salt thereof and composition thereof |
| US20160045598A1 (en) * | 2013-04-04 | 2016-02-18 | The General Hospital Corporation | Combination Treatments with Sonic Hedgehog Inhibitors |
| CN105640957A (en) * | 2014-11-28 | 2016-06-08 | 四川大学华西医院 | Novel application of itraconazole |
| WO2019100003A1 (en) * | 2017-11-17 | 2019-05-23 | Yoon Jaeyoung | Combination therapy targeting cancer associated with the hedgehog pathway |
Non-Patent Citations (3)
| Title |
|---|
| GUANZHAO LIANG等: "Itraconazole exerts its anti-melanoma effect by suppressing Hedgehog, Wnt, and PI3K/mTOR signaling pathways", 《ONCOTARGET》 * |
| 王娟等: "索拉非尼合并伊曲康唑的抗肿瘤作用", 《中国医药工业杂志》 * |
| 黄桃源等: "伊曲康唑治疗皮肤肿瘤的研究进展", 《皮肤性病诊疗学杂志》 * |
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