CN108670963A - Adapalene is preparing the application in preventing or treating people's cell abnormal proliferative conditions drug - Google Patents
Adapalene is preparing the application in preventing or treating people's cell abnormal proliferative conditions drug Download PDFInfo
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Abstract
Adapalene is preparing the application in preventing or treating people's cell abnormal proliferative conditions drug.The Adapalene is：6 [3 (1 adamantyl) 4 methoxyphenyls] 2 naphthalene-carboxylic acids or its salt list medicine combine the drug for being used to prepare prevention or treating human cell's abnormal proliferative conditions；Wherein Adapalene has following structural：
Description
Technical field
The present invention relates to field of medicaments, and in particular to Adapalene is preparing prevention or treatment abnormal cell proliferation disease
The new of integumentary system tumour, hematological system tumor and fibrotic skin diseases is treated in application in drug, especially Adapalene
Clever purposes.
Background technology
Abnormal cell proliferation disease is worldwide public health problem, and China is as populous nation, including cancer
Increased development trend year by year is presented in abnormal cell proliferation Disease including disease.Although at present both at home and abroad in related new drug
The input in research and development field is more and more, and the selection of drug therapy is also in diversified development, but clinically cytotoxic drug at present
Object is still the main force for treating abnormal cell proliferation disease.Tretinoin medicines are applied to clinic for many years, such drug is main
By activating Retinoic acid receptor（Retinoid acid receptor, RAR）And Tretinoin X receptors（retinoid X
Receptor, RXR）And play a role, the work with external inhibition multiple types cell Proliferation, Cell differentiation inducing activity and apoptosis
With, while certain achievement in research is also achieved in terms of clinical treatment disease in the blood system and solid tumor, such as total trans dimension first
Acid is widely used in the clinical treatment of acute promyelocytic leukemic, and remission rate is high, and ill-effect is few；Bei Zhaluoting is the U.S.
FDA ratifies the first tretinoin medicines for treating skin T cell lymphoma.
Adapalene is the tretinoin medicines of third generation synthesis, and clinically it is mainly used for the part of homeliness type acne and controls
It treats（United States Patent (USP) US07642288B2）.In addition, Chinese patent（CN 1642538A）Adapalene is authorized to can be used for treating Cuo
Sore, psoriasis and seborrheic keratosis etc..In the antitumor drug effect activity research of Adapalene, there are document report discovery, Adapalene can
The effect of anti-colorectal carcinoma is played by inducing cell G1 phases Cycle Arrest and apoptosis（Adapalene inhibits the
activity of cyclin-dependent kinase 2 in colorectal carcinoma. Mol Med Rep.
2015,12(5):6501-650）.In addition, related patents declare the treatment that Adapalene can be used for part entity tumor, including lung
Cancer, head and neck cancer, cancer of pancreas, the cancer of the esophagus, gastric cancer, carcinoma of urinary bladder, colorectal cancer and glioma etc.（CN 103961342 A、
US20160113895A1 and US20170181988A1）.
Adapalene is as dept. of dermatology's common drug, early-stage study or patent only for the skin disease based on acne
With the treatment of part entity tumour.There is document to show that most tretinoin medicines are by inducing hinder G1 cell cycles phase at present
Stagnant performance antitumor action.The study found that Adapalene is different from other tretinoin medicines, which specific can induce thin
Born of the same parents' Cycle Arrest causes Cellular DNA Fragmentation to damage in the S phases, promotes Apoptosis.Therefore, Adapalene is in treatment integumentary system
There is greatly treatment advantage in terms of the abnormal cell proliferations such as tumour, hematological system tumor and fibrosis of skin disease.Therefore,
Based on the mechanism of action of S phase Cycle Arrests, Adapalene equally has the treatment of abnormal cell proliferation disease very heavy
The clinical meaning wanted.
Invention content
The present invention be directed to Adapalene based on S phase blocking agent effectiveness in a kind of novel doctor of abnormal cell proliferation disease
Medicinal way, has treatment integumentary system tumour, the activity of hematological system tumor and fibrotic skin diseases, includes mainly melanocyte
Tumor, squamous cell carcinoma, leukaemia, Huppert's disease, lymthoma, keloid and chorionitis etc..Pass through Adapalene
Specific S phases Cycle Arrest and apoptosis-induced effect and play response to treatment.
Completing the technical solution of foregoing invention task is：A kind of Adapalene is preventing or treatment people's cell is abnormal preparing
Application in proliferative diseases drug.
The Adapalene is：6- [3- (1- adamantyls) -4- methoxyphenyls] -2- naphthalene-carboxylic acids or its salt list medicine
Or combine the new application for the drug for being used to prepare prevention or treatment human cell's abnormal proliferative conditions.
Wherein Adapalene has following structural：
The salt of the Adapalene includes hydrochloride, sulfate, phosphate, tartrate, tetrafluoroborate, bromate, oxalic acid
Salt, hydrofluoride, sulfonate, perchlorate, rhodanate and acetate etc..
Adapalene, which plays prevention or therapeutic effect, to be sent out based on drug-induced cell S phase Cycle Arrests effect
It waves.
Wherein, refer to the relevant disease of abnormal cell proliferation disease：Integumentary system tumour, hematological system tumor and skin
Skin fibrotic disease etc.；Integumentary system tumour is selected from melanoma and squamous cell carcinoma；Hematological system tumor is selected from leukaemia, multiple
Property myeloma and lymthoma；Fibrotic skin diseases are selected from keloid and chorionitis.
Adapalene production treat people's cell abnormal proliferative conditions drug in application in, dosage can according to
Medicine approach, patient age, weight, body surface area, disease type and severity etc. change and select, and injection recommended dose is
100mg/m2, oral recommended dose 10mg/Kg, it is 0.1% that external preparation, which recommends specification, once a day.
The anti-proliferative drugs that antagonism can not also occur with other with the drug for Adapalene are combined for treating carefully
Born of the same parents' abnormal proliferative conditions.
Adapalene for treating melanoma, other drugs include mainly carboplatin, taxol, Dacarbazine, Temozolomide,
Fotemustine, Wei Luofeini, darafinib, Imatinib, easy Puli's monoclonal antibody, training cloth pearl monoclonal antibody and Ni Wo monoclonal antibodies etc..
Adapalene includes mainly 5 FU 5 fluorouracil and imiquimod etc. for treating squamous cell carcinoma, other drugs.
Adapalene includes mainly methotrexate (MTX), Bei Zhaluoting, shellfish for treating skin T cell lymphoma, other drugs
The appropriate monoclonal antibody of human relations, interferon, Vorinostat and alemtuzumab etc..
Adapalene includes mainly daunorubicin, methotrexate (MTX), cyclophosphamide, rice for treating leukaemia, other drugs
Hold in the palm anthraquinone, Etoposide, cytarabine, vincristine, Rituximab and bortezomib etc..
Adapalene includes mainly lenalidomide, pomalidomide, Sha Lidu for treating Huppert's disease, other drugs
Amine, Carfilzomib, reaches thunder wood monoclonal antibody, angstrom sieve trastuzumab, pabishta etc. at bortezomib.
Adapalene for treating lymthoma, other drugs include mainly mustargen, vincaleukoblastinum, Etoposide, Doxorubicin,
Bleomycin, vincaleukoblastinum and Dacarbazine, procarbazine and prednisone etc..
Adapalene includes mainly 5 FU 5 fluorouracil, imiquimod, Wella pa for treating keloid, other drugs
Rice, bleomycin and mitomycin etc..
Adapalene includes mainly methotrexate (MTX), mycophenolate mofetil, cyclophosphamide for treating chorionitis, other drugs
With Rituximab etc..
Pharmacodynamic experiment shows compared with other tretinoin medicines drugs, growth inhibition of the Adapalene to tumour cell
Effect is most strong, and the effect has concentration dependent；In addition, Adapalene acts on a variety of different cell IC50It is relatively low, including
Melanoma A375 and M14 cell, phosphorus shape cell cancer SCC-9 cells, skin T cell lymphoma Hut78 cells, leukaemia U937 are thin
Born of the same parents and people's fibroblasts in keloid show that the drug has stronger antitumor activity；Increase with drug concentration, A Dapa
Woods obviously induces the reduction of melanoma cells quantity and morphologic change；Adapalene significantly inhibits the Clone formation of melanoma cells；
Adapalene inducing cell cycle arrest is in the S phases, and apparent inducing cell apoptosis occurs.Result above proves that Adapalene is logical
The specific induced cell cycle S phases are spent to block and the effects that apoptosis, melanoma, squamous cell carcinoma, skin T cell lymphoma,
Therapeutic effect is played in the diseases such as leukaemia, keloid and chorionitis.
Pharmaceutical preparation can be made with any one auxiliary material pharmaceutically allowed in Adapalene, these preparations can be pharmacy
Any one dosage form of upper permission, including but not limited to tablet, granule, pill, oral solution, injection, capsule and lipid
Body etc..The anti-proliferative drugs that antagonism can not also occur with Adapalene with other are combined for treating abnormal cell proliferation
Property disease.The dosage of Adapalene can be according to route of administration, patient age, weight, body surface area, disease type and severity
It selects, one or many can apply Deng variation.
Adapalene is made into tablet or capsule, and auxiliary material is selected from starch, dextrin, tartaric acid and magnesium stearate, wherein tablet
With coating, coating solution is the ethanol solution of Opadry；Adapalene is made into granule, and auxiliary material is selected from microcrystalline cellulose, sugarcane
30% ethyl alcohol of Icing Sugar, sodium carboxymethyl starch, lactose, Aspartame, orange essence, lauryl sodium sulfate and 3% povidone
Liquid etc.；Adapalene is made into soft capsule, and liquid auxiliary material is soybean oil, and capsule shells auxiliary material is selected from gelatin, glycerine and distilled water etc.；
Adapalene is made into cream preparation, and auxiliary material is selected from vitamin E, dimethyl sulfoxide (DMSO), beta-cyclodextrin, lauryl sodium sulfate, and ten
Eight alcohol, albolene, liquid paraffin, ethylparaben, glycerine, glycerin monostearate, to chlorine m-cresol, hexadecanol, ten
Eight alcohol, glycerin monostearate, paregal O -20, Arlacel-60, propylene glycol, benzyl alcohol and distilled water；Adapalene is made into solidifying
Glue preparation, auxiliary material be selected from dimethyl sulfoxide (DMSO), propylene glycol, ethyl alcohol, carbomer, triethanolamine, ethyl hydroxy benzoate, PEG400, hexylene glycol,
Tween-80, benzyl alcohol and distilled water etc.；Adapalene is made into pharmaceutical solutions, and auxiliary material is selected from dimethyl sulfoxide (DMSO), propylene glycol, second
Alcohol, n,N-Dimethylformamide, 2,6-di-tert-butyl p-cresol, butylated hydroxy anisole, ethyl hydroxy benzoate and distilled water etc.；A Da
Pa Lin is made into injection, and auxiliary material is selected from sodium chloride, glucose, hydrochloric acid, citric acid, sodium bicarbonate, disodium hydrogen phosphate, di(2-ethylhexyl)phosphate
Hydrogen sodium, sodium sulfite, sodium hydrogensulfite, sodium pyrosulfite and sodium thiosulfate, anesin, phenol, such as benzyl alcohol, sweet dew
Alcohol, sorbierite etc..
Beneficial effects of the present invention：
Present invention research finds that Adapalene obviously inhibits integumentary system tumour, hematological system tumor and fibrotic skin diseases phase
The proliferation of cell is closed, and the inducing cell S phases block and cells apoptosis, being one has apparent anti-cell abnormal proliferative disease
The active drug of disease, and provide new use for the treatment of the diseases such as integumentary system tumour, hematological system tumor and fibrosis of skin
Medicine selects.
1 Adapalene of table to melanoma, phosphorus shape cell cancer, skin T cell lymphoma, leukaemia and people's keloid at
The when IC of the cytosiies such as fibrocyte 72h50Value：
Table 1.
Description of the drawings
Fig. 1-A, Fig. 1-B are five kinds of tretinoin medicines all-trans retinoic acids, isotretinoin, Acitretin, Bei Zhaluoting and A Da
Comparisons of the Pa Lin to the inhibited proliferation of melanoma A375 and M14 cytosis 72h.
Fig. 2-A, Fig. 2-B, Fig. 2-C, Fig. 2-D, Fig. 2-E, Fig. 2-F be Adapalene respectively to melanoma, phosphorus shape cell cancer,
The inhibited proliferation of the cytosiies 72h such as skin T cell lymphoma, leukaemia and people's fibroblasts in keloid.
Fig. 3 is that Adapalene acts on cell growth and metamorphosis situation after melanoma A375 and M14 cell 48h.
Fig. 4 is influence of the Adapalene to the Clone formation of melanoma A375 and M14 cell.
Fig. 5-A, Fig. 5-B, Fig. 5-C are influence of the Adapalene to the cell cycle of melanoma A375 and M14 cell respectively.
Fig. 6 is influence of the Adapalene to the Apoptosis of melanoma A375 and M14 cell.
Specific implementation mode
The invention will be further elaborated by the following examples：
The effect of 1 tretinoin medicines suppressing cell reproduction of embodiment is compared.
Use mtt assay, concrete operations as follows in this experiment：1. well and being located using EDTA pancreatin digestion process growth conditions
In the tumour cell of logarithmic phase growth, mixing after digestion is terminated, cell suspension is made.2. take the cell suspensions of 20 μ l volumes into
Row counts, and is diluted to（1-2）×104A/ml.3. ready cell suspension is transferred in 96 orifice plates, 180 holes μ l/,
It is placed in cell incubator and cultivates.4. by reagent is added with the volume of 20 μ l of every hole overnight to after completely adherent after cell incubation
Object, every group of concentration set 3 parallel holes, then proceed to culture 72 hours.5. 5 mg/ml MTT solution are added in 96 orifice plates,
20 holes μ l/ are reacted 4 hours in 37 DEG C of incubators.6. abandoning the solution in most culture plate, the DMSO of proper volume is added into every hole
Solution is placed on oscillator and shakes 5 minutes, after Jia Za is completely dissolved, is detected respectively at 570 nm wavelength using microplate reader
The absorbance value in hole.7. being control with solvent hole, the inhibitory rate of cell growth under the conditions of each administration concentration is calculated, drug is to cell
Growth inhibition ratio calculation formula it is as follows：Cell inhibitory rate（%）=（1- susceptibility group OD/ control groups OD）×100%.
Analysis：According to Fig. 1-A and Fig. 1-B, in five kinds of tretinoin medicines, all-trans retinoic acid, the isotretinoin of various concentration
Weaker to the inhibited proliferation of melanoma cells A375 and M14 with Bei Zhaluoting, the inhibited proliferation of Acitretin is stronger, but
It is not in concentration dependent trend, the cell inhibitory effect effect of wherein Adapalene is most strong, and is in concentration dependent trend.Therefore
It proves, Adapalene can play antitumor action in melanoma cells.
IC of 2 Adapalene of embodiment in a variety of different tumour cells50：
This experiment investigates A Dapa in attached cell A375, M14, SCC-9 and people's fibroblasts in keloid using mtt assay
The suppressing cell reproduction of woods acts on, and the suppressing cell reproduction that suspension cell HuT-78 and U937 investigate Adapalene using CCK8 methods is made
With CCK8 method concrete operations are as follows：1. cell count prepares a concentration of 2 × 104The cell suspension of a/ml.2. with 180 μ l/
Pore volume is transferred in 96 orifice plates, is placed in cell incubator and is cultivated.3. after overnight, being added with the volume of 20 μ l of every hole tested
Drug, every group of concentration set 3 parallel holes, then proceed to culture 72 hours.4. CCK8 solution is added in 96 orifice plates, 20 μ l/
Hole is reacted 2 hours in 37 DEG C of incubators.5. the absorbance value in each hole is detected at 450 nm wavelength using microplate reader.6. with solvent
Hole is control, calculates the inhibitory rate of cell growth under the conditions of each administration concentration, growth inhibition ratio calculation formula of the drug to cell
It is as follows：Cell inhibitory rate（%）=（1- susceptibility group OD/ control groups OD）×100%.
Analysis：- A arrives Fig. 2-F and table 1 according to fig. 2, and Adapalene acts on the IC of melanoma cells A37550For 3.95 ±
0.19 μM, act on the IC of melanoma cells M1450It is 1.89 ± 0.22 μM, acts on oral cavity phosphorus columnar epithelium tumour SCC-9 cells
IC50It is 7.62 ± 0.72 μM, acts on the IC of skin T cell lymphoma HuT-78 cells50It is 0.72 ± 0.26 μM, effect
In the IC of human tissue cell lymphoma cell U93750It is 7.17 ± 1.37 μM, acts on people's fibroblasts in keloid
IC50It is 21.14 ± 10.24 μM.In short, IC of the Adapalene in above-mentioned cell50Relatively low, Adapalene is in melanoma, phosphorus shape
Stronger antitumor action can be played in the cells of types such as cell cancer, application on human skin t cell lymphoma and leukaemia, and to people
Keloid plays therapeutic effect by inhibiting fibroblastic proliferation.
Influence of 3 Adapalene of embodiment to melanoma cells quantity and form：
This experiment investigates influence of the Adapalene to cell number and form using inverted phase contrast microscope.Logarithmic growth phase
A375 and M14 cells, after cell count, with every hole 30 × 104The even density of a cell is inoculated into six orifice plates, adherent overnight
After culture, final concentration of 2.5 μM, 5 μM and 10 μM of Adapalene is added, using the cell of non-dosing object as negative control
Group.After cultivating 48h after administration, cell density and morphological change are observed under inverted phase contrast microscope and is taken a picture.
Analysis：According to Fig.3, compared with the control group, with the raising of Adapalene drug concentration, the space between cells A375
Become larger, quantity is reduced, and cellular morphology is stretched to fusiformis, and dead cell showed increased；M14 cells are after Adapalene is handled, carefully
Born of the same parents' density is decreased obviously, and apparent wire drawing is presented in cellular morphology.Therefore Adapalene has stronger cell inhibitory effect effect, and
Inducing cell damages and apoptosis occurs.
The influence that 4 Adapalene of embodiment forms melanoma cell clone：
This experiment has investigated the influence that Adapalene forms melanoma cell clone using clone forming method, and operation is as follows：①
It takes growth conditions good and the tumour cell in exponential phase is made after 0.25% EDTA trypsin digestion cells
Cell suspension.2. the cell suspension of 20 μ l volumes is taken to count, and it is diluted to 5000/ml.3. by the cell suspension after dilution with
200 μ l volumes shift in six orifice plates, and about 1000 cells are inoculated with per hole, fully shake it is even after be placed in cell incubator train again
It supports.4. waiting for that cell incubation overnight to completely adherent, change liquid processing with fresh complete medium, and test medicine is added, waits for medicine
After object acts on 48h, the culture medium containing test medicine to the greatest extent is abandoned.5. replacing fresh complete medium, continue to cultivate cell 7 days.Phase
Between close observation Clone formation situation, when cell forms macroscopic clone（It typically contains cell number and is no less than 50）,
Terminate cell culture.6. 4% paraformaldehyde solution is added after twice of the PBS solution rinse cell of precooling in reject culture medium
Fixed cell 15 minutes.7. discarding fixer, then with twice of PBS solution rinse cell, and 0.1% violet staining liquid is added
Processing 15 minutes slowly cleans dyeing liquor with flowing water, and by culture plate back-off on blotting paper to blot moisture in plate.8. will
Culture plate is positioned in gel imaging system, is shot using visible light, and the image of scanning is preserved, and finally and uses IPP
6.0 softwares are counted.
Analysis：According to Fig. 4, compared with the control group, A375 and M14 cells are respectively after Adapalene is handled, cell clone
It forms number to substantially reduce, and concentration dependent trend is presented.Hence it is demonstrated that Adapalene can be by inhibiting melanoma cells
Clone formation and play inhibit Melanoma Cell Proliferation effect.
Influence of 5 Adapalene of embodiment to melanoma cells period profile：
This experiment investigates influence of the Adapalene to melanoma cells period profile using the mono- dye methods of PI.Steps are as follows：1. taking life
The good melanoma cells of long status, with every hole 3 × 105Cell is transferred in six well culture plates by the density of a cell, is waited for thin
Born of the same parents be incubated overnight and completely it is adherent after, be added Adapalene continue cultivate 48h.2. after acting on the corresponding time, most culture medium is abandoned, and
With the PBS solution rinse cell of precooling, EDTA trypsin solution vitellophags terminate digestion gained cell suspension with 1000 rpm/
The pelleted by centrifugation of min 5 minutes.3. gained cell precipitation is resuspended with PBS, and is centrifuged under the same conditions, liquid is discarded supernatant.④
200 μ l tri-distilled waters are firstly added quickly after suspension cell, add the 90% ethyl alcohol piping and druming mixing of 800 μ l ice baths precooling, and
It is fixed overnight in 4 DEG C.5. being centrifuged 5 minutes under the conditions of 1000 rpm/min, reject fixer, the PBS solution of 1 ml precoolings is added
It is resuspended and is cleaned cell, is discarded supernatant after centrifugation.6. 0.5 ml PI dyeing liquors are added in each sample is resuspended cell, 37 DEG C are kept away
Light is incubated 30 minutes.After the completion of dyeing, period profile detection is directly carried out using flow cytometer.
Analysis：Fig. 5-C are arrived according to Fig. 5-A, after Adapalene acts on A375 cells 48h, 2.5 μM, 5 μM and 10 μM Ahs
Treated that S phase cell proportions are respectively 27.22%, 51.26% and 100% by Da Palin, after Adapalene acts on M14 cells 48h,
Treated that S phase cell proportions are respectively 25.48%, 59.05% and 100% for 2.5 μM, 5 μM and 10 μM Adapalenes.Therefore it demonstrate,proves
Bright, Adapalene can be by inducing melanoma cells retardance to play antitumor action in the S phases.
Inducing action of 6 Adapalene of embodiment to melanoma cells apoptosis：
This experiment investigates inducing action of the Adapalene to Apoptosis using AnnexinV/PI methods.Operation is as follows：1. taking growth
Melanoma cells in good condition, with every hole 3 × 10 after counting5Cell is transferred in six well culture plates by a density, is waited for thin
Born of the same parents be incubated overnight and completely it is adherent after, be added Adapalene act on 48 hours.2. abandon most culture medium, then with precooling PBS rinses
Cell, the vitellophag under the action of pancreatin of no EDTA, gained suspension is divided with the pelleted by centrifugation 5 of 1000 rpm/min after termination
Then clock abandons most supernatant, then cell is resuspended with PBS.3. being centrifuged under the same terms, take cell precipitation, with 500 μ l 1 ×
Binding Buffer dispel cell, are separately added into 5 μ l Annexin V and 5 μ l PI dyeing liquors in every group of sample again.4. mixing
After even, it is protected from light standing 15 minutes, and completes all detections in 1 hour.
Analysis：According to Fig.6, after Adapalene effect A375 cells 48h, 2.5 μM, 5 μM and 10 μM Adapalenes
Apoptosis ratio that treated is respectively 2.98%, 19.33% and 53.33%, after Adapalene acts on M14 cells 48h, 2.5 μ
M, treated that Apoptosis ratio is respectively 22.06%, 51.86% and 53.50% for 5 μM and 10 μM of Adapalenes.Therefore it demonstrate,proves
Bright, Adapalene can play antitumor action by inducing melanoma cells apoptosis.
Claims (9)
1. a kind of Adapalene is preparing the application in preventing or treating people's cell abnormal proliferative conditions drug.
2. Adapalene according to claim 1 is in preparing prevention or treatment people's cell abnormal proliferative conditions drug
It is using, which is characterized in that the Adapalene：6- [3- (1- adamantyls) -4- methoxyphenyls] -2- naphthalene-carboxylic acids, or
Its salt list medicine combines the drug for being used to prepare prevention or treating human cell's abnormal proliferative conditions；Wherein Adapalene has
Following structural：
。
3. the salt of Adapalene according to claim 2 includes hydrochloride, sulfate, phosphate, tartrate, tetrafluoro boron
Hydrochlorate, bromate, oxalates, hydrofluoride, sulfonate, perchlorate, rhodanate and acetate etc..
4. Adapalene according to claim 1 is in preparing prevention or treatment people's cell abnormal proliferative conditions drug
Using, which is characterized in that wherein, refer to the relevant disease of abnormal cell proliferation disease：Integumentary system tumour, hematological system
Tumour and fibrotic skin diseases；Integumentary system tumour is selected from melanoma and squamous cell carcinoma；Hematological system tumor is selected from white blood
Disease, Huppert's disease and lymthoma；Fibrotic skin diseases are selected from keloid and chorionitis.
5. Adapalene according to claim 1 is in preparing prevention or treatment people's cell abnormal proliferative conditions drug
Using, which is characterized in that Adapalene and other anti-proliferative drugs that antagonism does not occur with the drug are combined for treating
Abnormal cell proliferation disease.
6. the Adapalene stated according to claim 5 is preparing answering in preventing or treating people's cell abnormal proliferative conditions drug
With, which is characterized in that the Adapalene and other anti-proliferative drugs that antagonism does not occur with the drug are combined for controlling
Treating abnormal cell proliferation disease refers to：
For treating melanoma, other drugs include Adapalene：Taxol, Dacarbazine, Temozolomide, Fotemustine, prestige
Rofe Buddhist nun, darafinib, Imatinib, easy Puli's monoclonal antibody, training cloth pearl monoclonal antibody and Ni Wo monoclonal antibodies；
For Adapalene for treating squamous cell carcinoma, other drugs include 5 FU 5 fluorouracil and imiquimod；
For treating skin T cell lymphoma, other drugs include Adapalene：Aminopterin, Bei Zhaluoting, the appropriate monoclonal antibody in Belém,
Interferon, Vorinostat and alemtuzumab；
For treating leukaemia, other drugs include Adapalene：Erythromycin, methotrexate (MTX), cyclophosphamide, mitoxantrone, according to
Support pool glycosides, cytarabine, vincristine, Rituximab and bortezomib；
For treating Huppert's disease, other drugs include Adapalene：That degree amine, pomalidomide, Thalidomide, boron are for assistant
Rice, reaches thunder wood monoclonal antibody, angstrom sieve trastuzumab, pabishta at Carfilzomib；
For treating lymthoma, other drugs include Adapalene：Mustargen, vincaleukoblastinum, Etoposide, Doxorubicin, it is rich come it is mould
Element, vincaleukoblastinum and Dacarbazine, procarbazine and prednisone；
For treating keloid, other drugs include Adapalene：5 FU 5 fluorouracil, imiquimod, Verapamil, it is rich come it is mould
Element and mitomycin；
For treating chorionitis, other drugs include Adapalene：Methotrexate (MTX), mycophenolate mofetil, cyclophosphamide and profit are appropriate
Former times monoclonal antibody.
7. the Adapalene stated according to claim 1 is preparing answering in preventing or treating people's cell abnormal proliferative conditions drug
With, which is characterized in that for Adapalene in the application in people's cell abnormal proliferative conditions drug is treated in production, dosage can
Changed according to route of administration, patient age, weight, body surface area, disease type and severity etc. and selected, injection is recommended
Dosage is 100mg/m2, oral recommended dose 10mg/Kg, it is 0.1% that external preparation, which recommends specification, once a day.
8. the Adapalene according to claim 1-7 is preparing prevention or treatment people's cell abnormal proliferative conditions drug
In application, which is characterized in that pharmaceutical preparation is made in Adapalene and any one auxiliary material pharmaceutically allowed, these preparations are
Any one dosage form pharmaceutically allowed, including but not limited to tablet, granule, pill, oral solution, injection, capsule and
Liposome.
9. the Adapalene stated according to claim 8 is in preparing prevention or treatment people's cell abnormal proliferative conditions drug
Using, which is characterized in that Adapalene is made into tablet or capsule, and auxiliary material is selected from starch, dextrin, tartaric acid and magnesium stearate,
For wherein tablet with coating, coating solution is the ethanol solution of Opadry；Adapalene is made into granule, and it is fine that auxiliary material is selected from crystallite
Dimension element, cane sugar powder, sodium carboxymethyl starch, lactose, Aspartame, orange essence, lauryl sodium sulfate and 3% povidone
30% ethanol；Adapalene is made into soft capsule, and liquid auxiliary material is soybean oil, and capsule shells auxiliary material is selected from gelatin, glycerine and steaming
Distilled water etc.；Adapalene is made into cream preparation, and auxiliary material is selected from vitamin E, dimethyl sulfoxide (DMSO), beta-cyclodextrin, dodecyl sulphur
Sour sodium, octadecyl alcolol, albolene, liquid paraffin, ethylparaben, glycerine, glycerin monostearate, to chlorine m-cresol, ten
Six alcohol, octadecyl alcolol, glycerin monostearate, paregal O -20, Arlacel-60, propylene glycol, benzyl alcohol and distilled water；Adapalene
It is made into gel preparation, auxiliary material is selected from dimethyl sulfoxide (DMSO), propylene glycol, ethyl alcohol, carbomer, triethanolamine, ethyl hydroxy benzoate,
PEG400, hexylene glycol, Tween-80, benzyl alcohol and distilled water；Adapalene is made into pharmaceutical solutions, and it is sub- that auxiliary material is selected from dimethyl
Sulfone, propylene glycol, ethyl alcohol, n,N-Dimethylformamide, 2,6-di-tert-butyl p-cresol, butylated hydroxy anisole, ethyl hydroxy benzoate and
Distilled water；Adapalene is made into injection, and auxiliary material is selected from sodium chloride, glucose, hydrochloric acid, citric acid, sodium bicarbonate, phosphoric acid hydrogen
Disodium, sodium dihydrogen phosphate, sodium sulfite, sodium hydrogensulfite, sodium pyrosulfite and sodium thiosulfate, anesin, phenol, such as
Benzyl alcohol, mannitol, sorbierite.
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| CN202010210820.9A CN111329851A (en) | 2018-06-08 | 2018-07-11 | Application of adapalene and antiproliferative drug combination in preparation of drugs for preventing or treating tumors in blood system |
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| CN201810585479 | 2018-06-08 | ||
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| CN202010210820.9A Division CN111329851A (en) | 2018-06-08 | 2018-07-11 | Application of adapalene and antiproliferative drug combination in preparation of drugs for preventing or treating tumors in blood system |
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| CN201810754315.3A Pending CN108670963A (en) | 2018-06-08 | 2018-07-11 | Adapalene is preparing the application in preventing or treating people's cell abnormal proliferative conditions drug |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115089568A (en) * | 2022-03-28 | 2022-09-23 | 中国人民解放军海军军医大学 | Application of adapalene in preparing medicine for resisting infection of tick-borne encephalitis virus West Nile virus yellow fever virus and chikungunya virus |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| FR3112684B1 (en) * | 2020-07-24 | 2022-08-12 | Univ Grenoble Alpes | COMPOUNDS FOR THE TREATMENT OF HEMOPHILIA |
| CN112023022A (en) * | 2020-10-20 | 2020-12-04 | 澳门大学 | New application of carfilzomib in preparation of drug for treating drug-resistant tumor |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011135090A1 (en) * | 2010-04-29 | 2011-11-03 | Galderma Research & Development | Method for treating scars with adapalene 0.3% |
| CN103961342A (en) * | 2013-01-31 | 2014-08-06 | 易大生物科技股份有限公司 | Novel use of adapalene in treating cancer |
| CN104661656A (en) * | 2012-06-01 | 2015-05-27 | 盖尔德马研究及发展公司 | Microcapsules containing retinoids, method for preparing same, and pharmaceutical compositions containing same |
| US20160113895A1 (en) * | 2013-01-31 | 2016-04-28 | Biodelight Biotech Inc. | Novel Use of Adapalene in Treating Esophageal Cancer and Gastrointestinal Stromal Tumor |
| US20170181988A1 (en) * | 2015-12-23 | 2017-06-29 | Cipla Limited | Methods for the treatment of bladder cancer |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101569617A (en) * | 2009-06-11 | 2009-11-04 | 辽宁利锋科技开发有限公司 | Application of drug with adamantane structure, derivative and analogue thereof to preventing new tumor indication |
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2018
- 2018-07-11 CN CN202010210820.9A patent/CN111329851A/en active Pending
- 2018-07-11 CN CN201810754315.3A patent/CN108670963A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011135090A1 (en) * | 2010-04-29 | 2011-11-03 | Galderma Research & Development | Method for treating scars with adapalene 0.3% |
| CN104661656A (en) * | 2012-06-01 | 2015-05-27 | 盖尔德马研究及发展公司 | Microcapsules containing retinoids, method for preparing same, and pharmaceutical compositions containing same |
| CN103961342A (en) * | 2013-01-31 | 2014-08-06 | 易大生物科技股份有限公司 | Novel use of adapalene in treating cancer |
| US20160113895A1 (en) * | 2013-01-31 | 2016-04-28 | Biodelight Biotech Inc. | Novel Use of Adapalene in Treating Esophageal Cancer and Gastrointestinal Stromal Tumor |
| US20170181988A1 (en) * | 2015-12-23 | 2017-06-29 | Cipla Limited | Methods for the treatment of bladder cancer |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115089568A (en) * | 2022-03-28 | 2022-09-23 | 中国人民解放军海军军医大学 | Application of adapalene in preparing medicine for resisting infection of tick-borne encephalitis virus West Nile virus yellow fever virus and chikungunya virus |
| CN115089568B (en) * | 2022-03-28 | 2023-10-31 | 中国人民解放军海军军医大学 | Application of adapalene in preparation of medicines for resisting tick-borne encephalitis virus west nile virus yellow fever virus and chikungunya fever virus infection |
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| CN111329851A (en) | 2020-06-26 |
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