CN105560241B - Application, method and pharmaceutical composition of the quinine dihydrochloride in treatment tumour - Google Patents
Application, method and pharmaceutical composition of the quinine dihydrochloride in treatment tumour Download PDFInfo
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/49—Cinchonan derivatives, e.g. quinine
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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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
Abstract
The present invention relates to application and method of the quinine dihydrochloride in treatment tumour, and the pharmaceutical composition comprising quinine dihydrochloride.
Description
Technical field
The present invention relates to application and method of the quinine dihydrochloride in treatment tumour, and the drug comprising quinine dihydrochloride
Composition.
Background technique
Quinine dihydrochloride is well-known anti-malarial agents.Its application except antimalarial, be much with composition forms into
Capable.This kind of composition is once applied to treat a variety of diseases, such as hemorrhoid, rhinitis, hemangioma, facial paralysis etc..It is generally believed that group
The other components (such as urethane) closed in object not only can also play in the treatment certain drug effects with hydrotropy.Thus, for specific
The pharmaceutical composition comprising quinine dihydrochloride of disease is always among research.For example, Chinese patent 87104056 discloses one
Kind contains six components compositions " injection for whole prolapse haemorrhoids " of a quinin hydrochloride and quinine dihydrochloride, for removing hemorrhoid and closing with hemorrhoid
Anal fissure, rectal polyp and the papilla fiber histioma of connection.However in the composition, quinine dihydrochloride total concentration is greater than
0.4M, and contain urethane.Chinese patent 200910103187.7 provide a kind of nine components compositions to treat hemorrhoid and
Tumour.The concentration very little (being less than 0.01M) of quinine in the composition, and contain urethane.Due to the side effect of urethane
Relatively strong, Chinese Government has limited or even has forbidden this kind of application.Chinese patent 96110932 discloses a kind of comprising a quinin hydrochloride
With the composition of Anodynine, it to be used for Treatment of Hyperthyroidism.However, Anodynine side effect is very strong, in developed country, oneself is eliminated.
Possible application of the quinine derivative in terms of oncotherapy, once by very more concerns.Actually, with swollen
Oncocyte is in the in vitro test of model, several quinine derivatives and conventional antitumor medicine (such as 5-FU, adriamycin, purple
Shirt alcohol etc.) cell 503nhibiting concentration (IC50) all in the level of micromole every liter (μM ol/L).According to common understanding, one
The concentration dependent of the Antineoplastic effect of a drug is in IC50Increase later with concentration and reduces.Conventional antitumor medicine usually with than
IC50When being higher by the concentration (still in every liter of range of micromole) of several times and being injected in knurl, anti-tumor validity is just shown.However,
Even if the injection concentration of quinine dihydrochloride is improved about 500 times (0.025M) by we, effective anti-tumor effect is also not observed
(tumour inhibiting rate is less than 40%) does not show the drug effect more considerably higher than existing antitumor medicine.In the prior art, other quinine class medicines
The tumour inhibiting rate of object is not also high.In recent years, they are just no longer regarded as a kind of competitive antitumor medicine by people, but as
Anti- tumor activity increase agent is studied.For example, No. 201310459568.5 Chinese patent application is exactly that quinine and antitumor medicine is (long
Spring new bases drug) multidrug resistance to reduce cell is combined to make antitumor medicine reach preferable drug effect.
The treatment of tumour at present is mainly performed the operation, the chemotherapy of radiation cure and other medicines.Operation causes to hurt to body
Evil, it is frustrating on certain injuries for influencing beautiful gland (such as mammary gland and thyroid gland), so that it is become a kind of pain
Selection.The side effect of radiation cure is also clearly.Existing chemotherapy is substantially systemic administration, there is very high systemic pair
Act on risk.For example, existing antitumor medicine has also killed a large amount of normal cells, has exempted from while a wide range of interior killing cancer cell
Epidemic disease system is seriously damaged, and curative effect is also and unsatisfactory.
Summary of the invention
Goal of the invention of the invention is to provide that a kind of more effectively the pharmaceutical composition of tumour is treated in smelting compared with prior art
Object and treatment method.
According to an aspect of the present invention, provide a kind of for treating the pharmaceutical composition of tumour, it includes two hydrochloric acid
Quinine and pharmaceutically acceptable excipient, and to be suitable for the dosage form being administered through tumor area, wherein when institute is administered through tumor area
The concentration for stating quinine dihydrochloride in pharmaceutical composition is 0.05-0.5M, preferably 0.15-0.4M, more preferably 0.2-0.3M.
According to another aspect of the present invention, application of the quinine dihydrochloride in treatment tumour is provided, wherein described two
Quinin hydrochloride is included in pharmaceutical composition, and described pharmaceutical composition includes pharmaceutically acceptable excipient or carrier and is suitable
Together in the dosage form being administered through tumor area, wherein the concentration of quinine dihydrochloride is 0.05- in described pharmaceutical composition when tumor area is administered
0.5M, preferably 0.15-0.4M, more preferably 0.2-0.3M.
According to a further aspect of the invention, a kind of method for treating tumour is provided comprising to for having this to need
The area Ti Liu administration pharmaceutical composition of acceptable excipient or carrier comprising quinine dihydrochloride and pharmaceutically, wherein the medicine
Compositions are the dosage form for being suitable for being administered through tumor area, and when the tumor area is administered, two hydrochloric acid Kuis in described pharmaceutical composition
Peaceful concentration is 0.05-0.5M, preferably 0.15-0.4M, more preferably 0.2-0.3M.
Within the scope of the invention, when tumor area is administered, the administered volume of described pharmaceutical composition, which is not less than, to be intended to handle it
70%, preferably not less than the 110% of tumor volume.
Within the scope of the invention, the pharmaceutically acceptable excipient or carrier include water, water is miscible has
Solvent or their mixture, wherein the miscible organic solvent of the water includes following one kind or a variety of: ethyl alcohol, the third two
Alcohol, PEG, isopropanol.Pharmaceutical composition according to the present invention does not include urethane and antipyrine etc. because side effect is stronger
And it is prohibited or limits the drug ingedient used.
Within the scope of the invention, except quinine dihydrochloride and pharmaceutically in addition to acceptable excipient or carrier, described group
Analgesic, other anti-tumor drugs, and/or synergist can also be further included by closing object.
Within the scope of the invention, the tumour includes malignant tumour and benign tumour, the malignant tumour such as mammary gland
The various malignant entity tumors such as cancer, liver cancer, cancer of pancreas, thyroid cancer, prostate cancer, lung cancer, head and neck cancer, colon cancer, nasopharyngeal carcinoma,
And the benign tumour includes various benign entity tumors, such as mastadenoma, hepatoma, thyroid adenoma, prostate tumor etc..
Embodiment according to the present invention has the advantage that compared with prior art to be controlled with existing operation and radioactive ray
Treatment is compared, and shows same efficient more friendly " treatment-patient body " relationship (disturbing to body smaller)；With it is existing
Systemic administration treatment is compared, and can improve curative effect to conspicuousness under the toxic side effect of minimum；With existing local application,
Especially curing agent (such as dehydrated alcohol) treatment is compared, and the compatibility between perilesional tissue is higher, and curative effect is better.
The present invention is described in more detail below with reference to attached drawing.
Detailed description of the invention
Fig. 1 is injection concentration-tumour inhibiting rate relation curve of quinine dihydrochloride injection, and wherein abscissa X is the injection of tumor area
Concentration (4 × 10XμM) index (X), and ordinate Y is the tumour inhibiting rate (Y%) measured in zoopery.
Specific embodiment
Within the scope of this invention, pharmaceutically to can be water, water miscible for acceptable excipient (or solvent)
Organic solvent or vehicle system comprising water and the miscible organic solvent of water.The miscible organic solvent of water includes following
It is one or more: ethyl alcohol, propylene glycol, polyethylene glycol (PEG), isopropanol.Wherein PEG can optionally employ molecular weight less than 600
PEG, such as PEG200, PEG300 and PEG400 etc..
Within the scope of the invention, except quinine dihydrochloride and pharmaceutically in addition to acceptable excipient, the composition is also
Analgesic, other anti-tumor drugs and/or synergist can be further included.
The analgesic can be known to the skilled in the art any appropriate person, to mitigate the feeling of pain of patient, example
Such as benzyl alcohol, procaine hydrochloride, anesin, hydrochloric acid benefit card.
Other described anti-tumor drugs can be known to the skilled in the art any appropriate person, anti-to further enhance
Tumor promotion, for example including adriamycin, 5-FU, gemcitabine, cis-platinum, chloroquine, primaquine, qinghaosu and its derivative
Deng.
Within the scope of the invention, except quinine dihydrochloride and pharmaceutically in addition to acceptable excipient, the composition is also
Synergist can be further included.The synergist can be known to the skilled in the art any appropriate person, with further
Enhancing treatment tumor effect, for example including curing agent and activity increase agent.
The curing agent can be known to the skilled in the art any appropriate person, it is added to promote the bad of tumour
Extremely, diminution and fibrosis, such as can be Lauromacrogol, sodium morrhuate, ethanolamine oleate, polidocanol and bleomycin A5
Deng.
In the present invention, term " activity increase agent " refers to activity compared to smaller or even there is no (such as in animal experiments
Tumour inhibiting rate 40%) but can be to increase the substance of other medicines anti-tumor activity, including immunologic adjuvant less than.The immune assistant
Agent can be known to the skilled in the art any appropriate person, it is added, and to promote, relevant in illness area to be beneficial to treatment swollen
The activity of the antigen of tumor, such as can be inorganic adjuvant, such as aluminium hydroxide, alum；Microorganism and its product such as branch bar
Bacterium (tubercle bacillus, BCG vaccine), bacillus pumilis, Bordetella pertussis, endotoxin, bacterial extract (muramyl dipeptide) etc.；Synthesis
Adjuvant, such as artificial synthesized double stranded polynucleotide (double-strand polyadenylic acid, uridylic acid), levamisol, isoprinosine；Oil
Agent, such as Fei Shi adjuvant, adjuvant 65, mineral oil, vegetable oil；Immunostimulant (BCG vaccine, corynebacteria, endogenous toxic material
Element, trehalose, thymic peptide, OK432 etc.)；Cell factor, such as interferon, interleukins, tumor necrosis factor, conversion growth
The factor, colony stimulating factor, chemotactic factor (CF), thymosin extrasin etc.；Heterogenetic antigen such as inactivates streptococcus, human red blood cells membranous antigen, tumour
Lymphocyte infiltration, tumor vaccine etc..
Term " administration of tumor area ", which refers to, is administered directly to drug including knurl and the area Liu Zhouliu.Tumor area dosing techniques can
To be realized by all multi-methods, such as injection, conduit introducing, arterial perfusion etc..When tumor area is administered, drug according to the present invention
Composition is the dosage form for being suitable for the administration of tumor area, such as can be injection etc., and the medicine that quinine dihydrochloride is administered in the tumor area
Concentration in compositions is 0.05-0.5M (Mol/L), preferably 0.15-0.4M, more preferably 0.2-0.3M.In addition, in tumor
When area is administered, the administered volume of described pharmaceutical composition is not less than the 70% of the tumor mass volume for being intended to handle, is preferably not less than
110%, so that the pharmaceutical composition comprising quinine dihydrochloride can infiltrate knurl and its peripheral region, realize higher antitumor
Effect.If the volume of tumour to be processed is sufficiently small, volume is the above-mentioned volume for being intended to handle.It is larger in gross tumor volume
When, then it needs to be allocated as the medication in batches of multiple parts, then the part volume is the above-mentioned volume for being intended to handle.
The pharmaceutical composition of application and the administration of the area method Zhong Jingliu for the present invention can be according to by taking injection as an example
It is prepared by following methods.
Method one: 0.35M is less than for solid phase quinine dihydrochloride of the required concentration in water-soluble concentration range, such as concentration
Quinine dihydrochloride, and its analgesic, other anti-tumor drugs and/or synergist that the water solubility that is optionally present is strong, by him
Be directly added into water for injection and can be obtained corresponding injection.
Method two: solid phase quinine dihydrochloride of the required concentration except water-soluble concentration range, such as concentration are greater than
The quinine dihydrochloride of 0.35M, and analgesic, other anti-tumor drugs and/or the synergist of the poorly water-soluble that are optionally present, then
Required vehicle system (such as 9% ethanol solution) is first prepared, then above-mentioned solid matter is added in the vehicle system
Obtain the injection of the quinine dihydrochloride comprising required concentration.
Method three: when the analgesic for being insoluble in water, other anti-tumor drugs and/or synergist need to be added, then for example may be used
It prepares by the following method:
A. quinine dihydrochloride aqueous solution is prepared, or prepares the solution of required vehicle system and quinine dihydrochloride；
B. vehicle system needed for preparing and the solution for being insoluble in the analgesic of water, other anti-tumor drugs and/or synergist；
C. a and b solution prepared is mixed.
By these above-mentioned methods, the various injections comprising quinine dihydrochloride can be prepared.For example, the change in different injections
Change includes: the quinine dihydrochloride containing various concentration, and containing the different miscible organic solvents of water, the water containing various concentration is miscible
Property organic solvent, other anti-tumor drugs, analgesic, curing agent, and/or synergist containing different kinds and concentrations, etc..But
Change anyway, concentration of the quinine dihydrochloride in the pharmaceutical composition that tumor area is administered should remain 0.05-0.5M (Mol/
L), preferably 0.15-0.4M, more preferably 0.2-0.3M.Activity increase agent includes.
If it does, the concentration of analgesic is 0-3% (weight)；The concentration of other tumour medicines is 0-0.15M；Synergist
Concentration be 0-3% (weight).
Certainly, the injection concentration of quinine dihydrochloride needed for the present invention can also be infused by diluting high-concentration quinine dihydrochloride
Liquid (such as injection of the quinine dihydrochloride containing 25W/V%) is penetrated to obtain.
Within the scope of the invention, the pharmaceutical composition comprising quinine dihydrochloride is also possible to solid before the administration of tumor area
The form of powder is restored with corresponding solvent before administration.
It within the scope of the invention, is to increase effective acting time of the quinine class compound at administration, improve its biology
Availability, such as can mix as slow-released carrier or the micro particles of matrix, nanoparticle, micella and situ-gel matrix
In.
Embodiment
By following specific embodiments, the present invention is further illustrated, but not as limitation of the present invention.
In the examples below, unless otherwise indicated, subcutaneous transplantation tumor animal experiment carries out as follows.
Animal: SPF grades of nude mices (BALB/C-Nude), all females of gender, about 6~8 week old of animal when grouping, weight
For 17.5-20.5g.
Animal inoculation pvaccination and grouping: the tested tumour cell of in vitro culture collects the tumour cell of logarithmic growth phase, by required number
Purpose tumor cell inoculation is in the subcutaneous of nude mice.Tested tumour cell includes: human liver cancer cell (HepG2), human breast cancer cell
(MDA-MB231), human lung carcinoma cell (A549), human thyroid cancer cell (SW579), Human Prostate Cancer Cells (LNCaP/AR),
Human pancreatic cancer cell (PANC-1), human colon cancer cell (COLO205), people's head & neck cancer cell (Fuda), KB cell
(CNE1), human gastric cancer (BGC823), oophoroma (PA1) etc..Research method and result in the embodiment of the present invention are also applied for
Quinine dihydrochloride has other tumour cells of anti-tumor activity to it.It is long to 50-100mm to tumour3When, using PEMS3.2 software
(establishment of Sichuan University's West China School of Public Health) carries out random district's groups to animal subject, and respectively negative control group, the positive is right
According to group and several drug research groups, every group 8.
Administration: the grouping same day starts to be administered, and injection volume is determined by dosage and concentration.Administration number of times is 6 times, and administration frequency is
Once every two days.The injected material of negative control group is corresponding solvent.The positive control of positive controls injection is selected from above-mentioned
The convention that existing antitumor medicine, administration mode and dosage press selected drug carries out (such as tail vein injection).Drug research group
The research drug for needing to inject different kinds and concentrations according to experiment is the injection of tumor area unless otherwise indicated.
Observation, measurement and analysis:
1) general state: observation 1 time daily, self administration of medication start to test the 28th day, and observation index or content include but not
Situations such as being limited to animal administration part, appearance sign, general behavior activity, the state of mind, death and other Novel presentations.
2) weight: quarantine measures 1 time, measures 1 time before being administered and the administration phase measures weekly 2 times.
3) food ration: the administration phase measures weekly 1 time.
4) relative tumor growth inhibiting rate: the 1st, 3,5,7,11,16,21,27 day measurement transplantable tumor size after administration.
Gross tumor volume calculation formula is as follows: TV=l/2 × a × b2, a indicates length of tumor in formula, and b indicates tumor width.
Relative tumour volume calculation formula is as follows: RTV=Vt/V0, V in formula0The same day (i.e. first day) measurement is administered for grouping
Resulting gross tumor volume, VtGross tumor volume when to measure each time.
Relative tumor proliferation rate calculation formula is as follows: T/C (%)=TRTV/CRTV× 100, T in formulaRTVFor positive controls
Or the RTV of drug research group, CRTVFor the RTV of negative control group.
The evaluating drug effect standard of drug research group are as follows: T/C (%) > 40 is inactive, T/C (%)≤40 (still > 15%)
And P < 0.05 is active (no preferred agents activity) to Analysis of variance compared with negative control group, T/C (%)≤15 is simultaneously passed through
P < 0.05 is to have preferred agents active compared with negative control group for variance analysis.
5) inhibition rate of tumor growth (tumour inhibiting rate) measures: the 28th day carry out system becomes celestial after being administered in first time, carries out tumor
Body weighing.Tumour inhibiting rate calculation formula is as follows: tumour inhibiting rate %=(TW-CW)/CW × 100%, and TW is positive controls or medicine in formula
The average knurl weight of object study group；CW is the average knurl weight of negative control group.
The evaluating drug effect standard of drug research group are as follows: tumour inhibiting rate<40% be it is inactive, tumour inhibiting rate>=40% (still<
85%) and Analysis of variance P<0.05 is active, tumour inhibiting rate>=85% and Analysis of variance and yin compared with negative control group
Property control group compared to P < 0.05 be have preferred agents activity.
In the examples below, zoopery is all made of duplicate measurements variance analysis (Repeated Measures
ANOVA statistical test) is carried out to the group differences of index mean respectively.When group differences are statistically significant (P≤0.05),
Each group is compared with negative control group difference using least significant difference method.Quantitative target uses mean ± standard error (X
± SEM) description.When LEVENE homogeneity test of variance prompts heterogeneity of variance (P≤0.05), using Mann-Whitney U sum of ranks
(M-W method) is examined to compare group difference.All statistical analysis are completed under 13.0 software of SPSS for Windows.
Embodiment 1: the preparation of quinine dihydrochloride injection
Table 1
Remarks :+refer to that remaining is water for injection entirely in addition to the composition in table；
It refers to being free of.
In table 1, A2's the preparation method is as follows: at room temperature, and 0.2ml benzyl alcohol is added in 8.5ml water for injection and is dissolved,
Then 758mg quinine dihydrochloride dry powder is added in the solution and is dissolved, adding water for injection makes total volume reach 10ml, mixing
2ml/ bottle spare, just obtained injection A2 are packed as after uniformly.
A3's in 0.2ml benzyl alcohol addition 8.0ml water for injection the preparation method is as follows: at room temperature, dissolving, then
758mg quinine dihydrochloride dry powder, which is added in the solution, to be dissolved, and is added the dissolution of 1000mg polidocanol, is eventually adding water for injection
So that total volume is reached 10ml, be packed as after mixing 2ml/ bottles it is spare, just be made injection A3.
A4's in 0.2ml benzyl alcohol addition 8.0ml water for injection the preparation method is as follows: at room temperature, dissolving, then
379mg quinine dihydrochloride dry powder, which is added in the solution, to be dissolved, and is added the dissolution of 516mg chloroquine diphosphate, is eventually adding water for injection
So that total volume is reached 10ml, be packed as after mixing 2ml/ bottles it is spare, just be made injection A4.
Unmentioned A1, A5 and A6 are prepared according to method similar to the above.
The injection concentration of required quinine dihydrochloride (such as quinine dihydrochloride) in the present invention, can also be highly concentrated by diluting
Quinine dihydrochloride (such as quinine dihydrochloride of W/V percentage 25%) injection is spent to obtain.
Embodiment 2: the optimum condition research of application
In the experiment of anti-tumor, positive control is usually existing clinical medicine (such as cis-platinum, adriamycin, mitomycin, Ji
Western his shore, 5-FU etc.).Their clinical meaning is hypotoxicity high activity, such as shows low toxicity in animal experiments
Property and up to 75% tumour inhibiting rate.Term " anti-tumor activity ", sometimes again referred to as active, referring to has compared with existing clinical medicine
Certain anti-homophylic property of tumor.A kind of substance is as in vitro experiment there is lower 503nhibiting concentration (to be abbreviated as IC50, lead to
Often less than 50 μM in the reaction of inhibition in 72 hours) or show that higher inhibition rate of tumor growth (referred to as presses down in animal experiments
Ratio of outflow, typically larger than 40% but less than 75%), being just considered having similarity with existing clinical medicine, to show anti-
Tumor activity, the substance are also just referred to as active material.Term " reactive conditions " refer to researcher provide show something
The condition of its anti-tumor activity.For example, make the tumour inhibiting rate of quinine dihydrochloride from 35% or so be increased to 75% or so condition (medication
Mode, dosage etc.).
Term " preferably anti-tumor activity ", it is sometimes again referred to as preferred active, refer to compared with existing clinical medicine with lower
The property of toxicity and considerably higher anti-tumor activity.For example, it is preferable to which activity can refer in zoopery with lesser side reaction generation
Valence (non-toxic only slight side effect) shows significantly greater tumour inhibiting rate (such as 85% or more).Term " optimum condition " refers to
What researcher provided can make something show the condition of its preferred anti-tumor activity.Term " preferred substance ", which refers to, not only to be provided
Anti-tumor activity condition and give the substance of optimum condition.
The optimum condition of the application of quinine dihydrochloride of the invention in oncotherapy, anti-tumor activity is tested in vitro first
It is studied on transplantable tumor animal model.
1) anti-tumor activity
In the present invention, medium effective concentration (is abbreviated as IC50) medicine when cell survival rate reduces 50% i.e. in experiment in vitro
Object concentration.11 plants of man―machine systems are selected in this experiment, use the antitumor action of tetrazolium MTT reduction method measurement drug.Examination
It tests and sets positive and negative control group and study group.Negative control group adds isometric physiological saline, and positive controls are different dense
Spend the conventional chemotherapeutic drugs 5-FU of (in μM ol/l level).Study group is to dilute by mother liquor of A2 prepared by embodiment 1
Made of various concentration quinine dihydrochloride solution (in μM ol/l level).
In experiment, the attached tumor cells of logarithmic growth phase are selected, after being digested with pancreatin, with containing 10% calf serum
RPMI l640 culture medium is made into the suspension of required cell concentration, is seeded in 96 well culture plates, and every hole is inoculated with 200 μ l, then exists
37 DEG C and 5%CO2Middle culture is for 24 hours.The culture medium for the sample containing various concentration that study group and positive controls renew, it is negative
Control group then changes the culture medium containing isometric physiological saline, and every group sets 5 parallel holes, makes the hole final volume 200ul/, culture 48
Hour.Then liquid is discarded supernatant .37 DEG C of serum free medium of the MTT containing 0.2mg/ml of 200 μ l Fresh is added in every hole
Continue to cultivate 4h.It is careful to abandon supernatant, and 200 μ l DMSO are added, after being mixed with miniature ultrasonic oscillator, with examination in microplate reader
Testing wavelength is 570nm, and reference wavelength is that 450nm measures OD value.Inhibition of the drug to growth of tumour cell is calculated as follows
Rate: growth of tumour cell inhibiting rate %=(1-OD experiment/OD control) × 100%
Dose-effect curve can be obtained to inhibition rate of tumor cell mapping with same sample various concentration, then use
Logit method calculates medium effective concentration (IC50Value).Usual IC50Concentration less than 100 μM when, then judgement sample is in vitro to swollen
Oncocyte has lethal effect.Table 2 is IC of the test composition to test tumour cell50, concentration value is with two hydrochloric acid in composition
Quinine densimeter.Generally speaking, they all μM concentration level, do not see significant difference statistically.And positive control
IC50Then between 0.01-0.5 μM.
Table 2
| Tested tumour cell | C group IC50(μM) |
| Human breast carcinoma MDA-MB231 | 56.5 |
| Human lung adenocarcinoma A549 | 51.4 |
| Oophoroma PA1 | 13.4 |
| Gastric cancer BGC823 | 66.8 |
| Colorectal cancer LOVO | 103 |
| Human liver cancer HepG2 | 32.6 |
| Human colon carcinoma LS174T | 62.9 |
| Human prostata cancer LNCaP/AR | 28.9 |
| Number of people neck cancer Fuda | 51.6 |
| Human thyroid cancer cell SW579 | 46.8 |
| Human pancreatic cancer cell PANC-1 | 31.7 |
Further test also demonstrates, the organic solvent and analgesic pair in concentration range introduced in the present composition
The anti-tumor activity of quinine dihydrochloride has no negative effect.
2) application method
Experimental animal is lotus liver cancer cells nude mice, is divided into negative control group, positive controls and drug research group.It is negative right
According to a group injecting normal saline, positive controls inject conventional antitumor medicine 5-FU, and drug research group injects quinine dihydrochloride
Solution.When tail vein injection is small, in, large dosage concentration be 0.025M quinine dihydrochloride aqueous solution when, although we also make
Some technical improvement, eligible result is still consistent with the result of the prior art, and tumour inhibiting rate is less than 30%.And as positive right
According to the tumour inhibiting rate of 5-FU but reach 75%.
When we a kind of preparation is diluted spare 0.25M quinine dihydrochloride (containing 2% analgesic) be injected directly into it is dynamic
When in object knurl, but there is unexpected result.Although target area administration may improve the effect of systemic administration as you know
Rate (such as makes tumour inhibiting rate increase, usually raising 10-30%), and drug effect has been increased to can not for our research achievement
The height (can be improved 90% or more) conceived.On the contrary, when the composition passes through tail vein injection, tumour inhibiting rate again below
30%.
The administration of tumor area depends not only on drug effect, also depends on its safety.For this purpose, we compare bis- hydrochloric acid Kui of 0.25M
The peaceful animal tail vein injection of injection and the maximum tolerated dose (Maximum tolerated dose, MTO) of Lump body injection,
Method is as follows:
Experimental animal is lotus liver cancer cells nude mice, is grouped into tail vein injection various dose group (four groups) and knurl at random
It injects various dose group (four groups), 5 nude mices of each dosage group, injection dosage respectively 250mg/kg, 300mg/kg,
350mg/kg and 400mg/kg.It is administered every other day, is five times continuous.
Naked mouse changes of weight and Survival are observed in test, while recording the toxicity with obvious physiological significance, such as chaff
It Blighted scurf, dehydration, drowsiness, incoordination and is short of breath.If occur mouse weight decline > 30% continue 3 days or more or
Increase because toxic death then stops trial drug dosage, determines that previous group dosage is maximum tolerated dose, 21 days are experimental observation
Period, the 22nd day execution animal, autopsy visually observe that whether there is or not lesions.MTO in tail vein injection is less than 250mg/kg,
And the MTO in Lump body injection may be up to 300mg/kg.Using same dosage, the injection of tumor area seems the toxicity than intravenous injection
It is also smaller.
Further investigation revealed that also having similar performance in the animal experiment of some other tumours.It is prepared by embodiment 1
Some other quinine dihydrochloride injections also have similar performance.Therefore, application of the invention has selected based on the administration of target area
Want application mode.
3) administration concentration range
Experimental animal is lotus liver cancer cells nude mice, is divided into negative control group, positive controls and drug research group.It is positive right
Conventional antitumor medicine 5-FU is injected according to group, drug research group injects quinine dihydrochloride aqueous solution.Positive controls prescription
Formula is still tail vein injection, and negative control group and drug research group are Lump body injection.Positive controls application method is still that tail is quiet
Arteries and veins injection, negative control group and drug research group are Lump body injection.The injection of each drug research group (B, C, D, E, F, G group)
Preparation method is identical as the preparation method of A2 in table 1, includes 2% benzyl alcohol but contains required various concentration quinine dihydrochloride.
Quinine dihydrochloride Drug level designs anomaly gradient design, and uses logarithm gradient design, that is, refers to its IC50It is arranged without work
The negative control group (A group) of property concentration (5 μM), with its 102、103、5×103、104、8×104、105Setting experimental concentration again, two
The injection concentration of quinin hydrochloride is respectively 0.0005M, 0.005M, 0.025M, 0.05M, 0.4M, 0.5M.The area drug research Zu Liu
Injection dosage is less than 300mg quinine dihydrochloride/kg, and volume injected is determined by injection dosage and concentration, and administration number of times is 5 times, gives
Medicine frequency is once every two days.Fig. 1 shows injection concentration-tumour inhibiting rate relation curve of quinine dihydrochloride injection.
In Fig. 1, abscissa X is tumor area injection concentration (4 × 10XμM) index (X), ordinate Y be zoopery in
The tumour inhibiting rate (Y%) measured.It is in very big concentration range (difference of X is greater than 3), i.e., foreseeable greater than IC in common sense50Tens
Again, within the scope of even thousands of times of Drug level, pharmacodynamic change corresponding with the variation of this concentration is not observed, tumour inhibiting rate is small always
In 25%.Compared with negative control group, tumour inhibiting rate no significant difference (P < 0.05).And at 50mM (X=4), tumor suppression
Rate mutation rises to 55%, and then (difference of X is equal to 1) is rapidly reached 92% within the scope of a relatively narrow Drug level,
Occur breaking through.At 0.5M, tumour inhibiting rate declines again.
Within entire experimental period, negative control group gross tumor volume shows a increasing trend.In 0.05M-0.5M quinine dihydrochloride
Compared with negative control group, tumour inhibiting rate difference is statistically significant (P < 0.05) for drug research group within the scope of injection concentration.Sun
Property reference material tumour inhibiting rate be 75%, difference is statistically significant (P < 0.05) compared with negative control group.
To sum up, quinine dihydrochloride injection is just shown when having its Lump body injection concentration only more than a certain critical value
Then drug effect becomes less sensitive, even tumour inhibiting rate is likely to occur decline to the highly sensitive of concentration again.
We have also observed general status, changes of weight, the death rate and the partial denaturization after the injection of animal subject tumor area.?
During experiment, each study group of quinine dihydrochloride injection has no nude mice death, average weight and negative control group changes of weight
Close to (being dropped by less than 10%), indicate drug under experimental conditions without apparent toxic reaction.Study group and positive controls phase
Compare, general status is similar.But the decline of positive controls average weight is bigger (being greater than 20%), prompts a stronger toxicity anti-
It answers.
During the medication of tumor area, compared with negative control group compared with big in study group, especially in high concentration (> 0.4M) group
There is apparent color variation at partial syringe position, even with myodegeneration, and range is mostly within 10mm.This prompts the application
Condition causes the partial injury of myocyte really, and there is inflammatory cell infiltration in injection site, but does not influence normal function.It is being administered
After stopping, normalization is done step-by-step in the musculature appearance of study group nude mice injection site.It cuts open within 30 days and kills after stopping to administration
The injection site of nude mice has carried out check pathological section, and the difference of study group and negative control group is obviously reduced as the result is shown, becomes
In normal.
In addition, we also utilize identical technique study quinine dihydrochloride injection it is different for inoculation time, thus
The effect of the knurl of the development different from of cancer cell.Drug research group is B group and C group.Late 10 days inoculation people livers of B group ratio C group
The animal of cancer cell.10 days after last group inoculation, each group selects knurl average external volume to respectively may be about 28mm respectively3(B group)
And 126mm38 tumor bearing nude mices of (C group) are injected.Lump body injection 0.25M quinine dihydrochloride, injection dosage are 300mg/kg,
Volume injected is determined by injection dosage and concentration.It is administered every other day, is 6 times continuous.
From test the 5th day, each drug research group tumor-bearing mice tumour relative tumour volume was substantially reduced；Tumour at 17 days
Relative volume reaches minimum；From 32 days, C group relative tumour volume rises, and has the tendency that recurrence；Then effect is always for B group
Clearly, temporarily without the trend of recurrence.At 38 days, the knurl weight of C group ratio B group is significantly greater, and the average knurl weight of B group is close to 0.
This is the experiment results show that quinine dihydrochloride is injected under the optimum condition in anti-tumor application provided by the invention
Agent can be applied to treating malignant tumor, even can be used for completely removing the tumour of certain carcinogenic risk, to prevent its development
For malignant tumour.
In some documents, quinine dihydrochloride is also considered curing agent.We have selected it has been generally acknowledged that more effectively a kind of
Curing agent (polidocanol) has carried out comparative study.At identical conditions, the concentration of polidocanol be from 1.5w/v% until
6w/v% (concentration causes the obvious bubble in tumor area and poisoning symptom occurs), tumour inhibiting rate 30% or so, is found no always
Similar concentration-tumour inhibiting rate relationship trend.The result of this control experiment illustrates that composition of the invention is clearly distinguished from base
In the application of curing agent mechanism.
Similar results are also obtained with other quinine dihydrochloride injections prepared by embodiment 1.
According to these pharmacodynamic results and local side reaction as a result, quinine dihydrochloride provided by the invention is answered in oncotherapy
Optimum condition in is as follows: the administration of tumor area, and quinine dihydrochloride injection concentration is 0.05-0.50M, preferably 0.15-0.4M, more excellent
Select 0.2-0.3M.
In addition, another battery of tests is shown, for pharmaceutical composition of the invention under same concentration, a biggish injection volume is aobvious
Better pharmacological effect is shown.If tumor area volume is too big, to control dosage, branch's processing can be carried out to tumor area.
Each administered volume of injection is necessary for 70% or more of part volume to be handled, preferably 110% or more.When tumour individual foot
Enough hours, part volume to be handled is single tumor volume.
Embodiment 3: the application in tumor of breast treatment
Experimental animal is lotus breast cancer cell nude mice, is divided into negative control group, positive controls and drug research group.It is positive
Control group tail vein injection routine antitumor medicine adriamycin (7mg/kg), negative control group Lump body injection physiological saline.Each drug
The preparation method of the injection of study group's (B, C, D, E, F group) is identical as the preparation method of A2 in table 1, include 2% benzyl alcohol but
Containing required various concentration quinine dihydrochloride, injection concentration is respectively 0.025M, 0.05M, 0.15M, 0.25M, 0.4M.Drug
Study group's tumor area injection dosage is less than 300mg quinine dihydrochloride/kg, and volume injected is determined by injection dosage and concentration, administration time
Number is 5 times, and administration frequency is once every two days.
Within entire experimental period, negative control group gross tumor volume shows a increasing trend；From test the 5th day, positive controls
It is reduced compared with negative control group with each drug research group tumor-bearing mice gross tumor volume, difference is statistically significant (P < 0.05).
Until the 17th day from test the 7th day, the Relative tumor proliferation rate (T/C) of each drug research group tumor-bearing mice is small
In 40%；From testing the 17th day, B group Relative tumor proliferation rate rises, and has the tendency that recurrence；C, the Relative tumor of D, E, F, G group
Proliferation rate (T/C) is still reducing, and illustrates that this four groups still have apparent tumor growth inhibitory effect after drug withdrawal.It tests the 22nd day
It rises, C, F group Relative tumor proliferation rate rise, and have recurrence trend；And D, E group Relative tumor proliferation rate remain close to 0%, effect one
Directly clearly, temporarily without recurrence trend.During test, suppression ratio D, the E group of positive controls Relative tumor proliferation rate when
Between upper evening, it is significantly larger in data (40% or so).
The 28th day after administration, the knurl weight of each drug research group tumor-bearing mice significantly reduces compared with negative control group, and has
There is statistical difference (P < 0.05), wherein with D, E group tumour inhibiting rate highest (95% or more)；F group tumour inhibiting rate 90.11 ±
2.76%, other groups of tumour inhibiting rates are lower than 85%.Positive controls tumour inhibiting rate is 53%.
In addition, under the optimum condition in anti-tumor application provided by the invention, when quinine dihydrochloride injection is for inoculation
Between it is different, thus tumour cell development different froms knurl effect and the shorter tumour tumor killing effect of inoculation time
It is better, in addition to can be applied to treatment of cancer, it even can be used for having completely removing for the more substantially nonmalignant tumor of tumor risk,
To prevent its development as malignant tumor.
During the experiment, each study group has no nude mice death, average weight and negative control group changes of weight close to (decline
Less than 10%), expression drug is under experimental conditions without apparent toxic reaction.Study group is compared with positive controls, generally
Situation is similar.But the decline of positive controls average weight is bigger (being greater than 20%), prompts a stronger toxic reaction.
During the medication of target area, compared with negative control group compared with most of injection site in study group, especially in F group
There is apparent color variation, even with myodegeneration, range is mostly within 10mm.Further research explanation, these changes
Property be quinine dihydrochloride effect caused by.After administration stops, the musculature appearance of experimental group nude mice injection site is gradually real
Existing normalization.The injection site for cuing open the nude mice killed after stopping to administration for 30 days has carried out check pathological section, tests as the result is shown
The difference of group and negative control group is obviously reduced, and tends to be normal.
Similar results can also be obtained with other quinine dihydrochloride injections.It is secondary anti-according to these pharmacodynamic results and part
It answers as a result, optimum condition of the quinine dihydrochloride provided by the invention in tumor of breast treatment use is as follows: the administration of tumor area, disalt
Sour quinine injection concentration is 0.05-0.50M, preferably 0.15-0.4M or 0.2-0.3M.
In addition, another battery of tests shows that under same concentration, a biggish injection volume shows more preferable drug effect.If
Knurl product is too big, to control dosage, can carry out branch's processing.Each administered volume of injection is necessary for being intended to handle it
70% or more, preferably 110% or more of knurl product (being tumor volume in smaller knurl).
Embodiment 4: the application in liver tumour prevention and treatment
Experimental animal is lotus liver cancer cells nude mice, positive controls tail vein injection routine antitumor medicine 5-FU.Respectively
Drug research group (B, C, D, E, F group) and other experiment conditions are identical as method described in embodiment 3.Its experimental result is such as
Under.
From test the 5th day, each drug research group tumor-bearing mice gross tumor volume reduced compared with negative control group, and difference has
Statistical significance (P < 0.05).Until the 17th day from test the 7th day, the Relative tumor of each drug research group tumor-bearing mice is proliferated
Rate (T/C) is respectively less than 40%.From testing the 17th day, the Relative tumor proliferation rate (T/C) of higher concentration (0.2M or more) group is equal
Less than 15%, illustrate that they still have apparent tumor growth inhibitory effect after drug withdrawal.
The 28th day after administration, the knurl weight of each drug research group tumor-bearing mice significantly reduces compared with negative control group, and has
There is statistical difference (P < 0.05).The tumour inhibiting rate of each drug research group tumor-bearing mice is all larger than > 40%, wherein the tumor suppression of D, E group
Rate may be up to 95% or more, and other groups of tumour inhibiting rates are lower than 85%.During test, under positive controls Relative tumor proliferation rate
It drops more late in time than D, E, E, F group, significantly larger in data (35% or so), tumour inhibiting rate is then significantly smaller (72%).
In addition, also illustrating with similar model in embodiment 2, the optimum condition in anti-tumor application provided by the invention
Under, effect of the quinine dihydrochloride injection for the knurl of the development different from of inoculation time difference thus tumour cell,
Being that the shorter tumour tumor killing effect of inoculation time is better, in addition to can be applied to treatment of cancer, even can be used for having more substantially
The nonmalignant tumor of cancer risk completely removes, to prevent its development as malignant tumor.
During the above experiment, each study group has no animal dead, and average weight and negative control group changes of weight are close
(being dropped by less than 10%) indicates drug under experimental conditions without apparent toxic reaction.Study group compared with positive controls,
General status is similar.But the decline of positive controls average weight is bigger in transplantable tumor test (being greater than 20%), prompts one relatively strong
Toxic reaction.
During the medication of target area, compared with negative control group compared with most of injection site in study group, especially in F group
There is apparent color variation, even with myodegeneration, range is mostly within 10mm.Further research explanation, these changes
Property be quinine dihydrochloride effect caused by.After administration stops, the musculature appearance of experimental group nude mice injection site is gradually real
Existing normalization.The injection site for cuing open the nude mice killed after stopping to administration for 30 days has carried out check pathological section, tests as the result is shown
The difference of group and negative control group is obviously reduced, and tends to be normal.
Similar results are also obtained with other quinine dihydrochloride injections.According to these pharmacodynamic results and local side reaction knot
Fruit, optimum condition of the quinine dihydrochloride provided by the invention in liver tumour treatment use are as follows: the administration of tumor area, quinine dihydrochloride
Injection concentration is 0.05-0.50M, preferably 0.15-0.4M or 0.2-0.3M.
In addition, another battery of tests shows that under same concentration, a biggish injection volume shows more preferable drug effect.If
Knurl product is too big, to control dosage, can carry out branch's processing.Each administered volume of injection is necessary for being intended to processing unit
70% or more, preferably 110% or more of part knurl product (being tumor volume in smaller knurl).
Embodiment 5: the application in pancreatic neoplasm prevention and treatment
Experimental animal is pancreatic tumor borne cell nude mice.Positive controls tail vein injection routine antitumor medicine gemcitabine
(100mg/kg).Tumor of breast treatment is real in each drug research group (B, C, D, E, F group) and other experiment conditions and embodiment 3
The method tested is identical.Its experimental result is as follows.
From test the 5th day, each drug research group tumor-bearing mice gross tumor volume reduced compared with negative control group, and difference has
Statistical significance (P < 0.05).Until the 17th day from test the 7th day, the Relative tumor of each drug research group tumor-bearing mice is proliferated
Rate (T/C) is respectively less than 40%.From testing the 17th day, the Relative tumor proliferation rate (T/C) of C, D, E group is respectively less than 15%, illustrates it
Still have apparent tumor growth inhibitory effect after drug withdrawal.
The 28th day after administration, the knurl weight of each drug research group tumor-bearing mice significantly reduces compared with negative control group, and has
There is statistical difference (P < 0.05).The tumour inhibiting rate of each drug research group tumor-bearing mice is all larger than > 40%, wherein the tumor suppression of D, E group
Rate may be up to 90% or more.Other groups of tumour inhibiting rates are lower than 85%.During test, under positive controls Relative tumor proliferation rate
It drops more late in time than D, E, E, F group, significantly larger in data (35% or so), tumour inhibiting rate is then significantly smaller (62%).
In addition, also illustrating with similar model in embodiment 2, the optimum condition in anti-tumor application provided by the invention
Under, effect of the quinine dihydrochloride injection for the knurl of the development different from of inoculation time difference thus cancer cell, and
The shorter tumour tumor killing effect of inoculation time is better, in addition to can be applied to treatment of cancer, even can be used for having larger carcinogenic
The nonmalignant tumor of risk completely removes, to prevent its development as malignant tumor.
During the above experiment, each study group has no animal dead, and average weight and negative control group changes of weight are close
(being dropped by less than 10%) indicates drug under experimental conditions without apparent toxic reaction.Study group compared with positive controls,
General status is similar.But the decline of positive controls average weight is bigger in transplantable tumor test (being greater than 20%), prompts one relatively strong
Toxic reaction.
During the medication of target area, compared with negative control group compared with most of injection site in study group, especially in F group
There is apparent color variation, even with myodegeneration, range is mostly within 10mm.Further research explanation, these changes
Property be quinine dihydrochloride effect caused by.After administration stops, the musculature appearance of experimental group nude mice injection site is gradually real
Existing normalization.The injection site for cuing open the nude mice killed after stopping to administration for 30 days has carried out check pathological section, tests as the result is shown
The difference of group and negative control group is obviously reduced, and tends to be normal.
The some other quinine dihydrochloride injections prepared using embodiment 1, it is also possible to obtain similar results.According to these
Pharmacodynamic result and local side reaction are as a result, preferred stripe of the quinine dihydrochloride provided by the invention in pancreatic neoplasm treatment use
Part is as follows: the administration of tumor area；Quinine dihydrochloride injection concentration is 0.05-0.50M, preferably 0.15-0.4M or 0.2-0.3M.
In addition, another battery of tests shows that under same concentration, a biggish injection volume shows more preferable drug effect.If
Knurl product is too big, to control dosage, can carry out branch's processing.Each administered volume of injection is necessary for being intended to processing unit
70% or more, preferably 110% or more of part knurl product (being tumor volume in smaller knurl).
Embodiment 6: the application in thyroid tumors prevention and treatment
Experimental animal is lotus thyroid carcinoma cell nude mice, positive controls tail vein injection routine antitumor medicine adriamycin
(4mg/kg), negative control group Lump body injection physiological saline.Each drug research group (B, C, D, E, F group) and other experiment conditions
It is identical as the method for tumor of breast Experiment on therapy in embodiment 3.Its experimental result is as follows.
From test the 5th day, each drug research group tumor-bearing mice gross tumor volume reduced compared with negative control group, and difference has
Statistical significance (P < 0.05).Until the 17th day from test the 7th day, the Relative tumor of each drug research group tumor-bearing mice is proliferated
Rate (T/C) is respectively less than 40%.From testing the 17th day, the Relative tumor proliferation rate (T/C) of C, D, E group is respectively less than 15%, illustrates it
Still have apparent tumor growth inhibitory effect after drug withdrawal.
The 28th day after administration, the knurl weight of each drug research group tumor-bearing mice significantly reduces compared with negative control group, and has
There is statistical difference (P < 0.05).The tumour inhibiting rate of each drug research group tumor-bearing mice is all larger than > 40%, wherein the tumor suppression of D, E group
Rate may be up to 92% or more, and other groups of tumour inhibiting rates are lower than 85%.During test, under positive controls Relative tumor proliferation rate
It drops more late in time than D, E, E, F group, significantly larger in data (35% or so), tumour inhibiting rate is then significantly smaller (61%).
In addition, effect of the injection for the knurl of the development different from of inoculation time difference thus cancer cell,
Being that the shorter tumour tumor killing effect of inoculation time is better, in addition to can be applied to treatment of cancer, even can be used for having more substantially
The non-malignant tumors of cancer risk completely remove, to prevent its development as malignant tumor.
The some other quinine dihydrochloride injections prepared using embodiment 1, it is also possible to obtain similar results.According to these
Pharmacodynamic result and local side reaction are as a result, quinine dihydrochloride provided by the invention is preferred in thyroid tumors treatment use
Condition is as follows: the administration of tumor area；Quinine dihydrochloride injection concentration is 0.05-0.50M, preferably 0.15-0.4M or 0.2-0.3M.
In addition, another battery of tests shows that under same concentration, a biggish injection volume shows more preferable drug effect.If
Knurl product is too big, to control dosage, can carry out branch's processing.Each administered volume of injection is necessary for being intended to processing unit
70% or more, preferably 110% or more of part knurl product (being tumor volume in smaller knurl).
Embodiment 7: the application in tumor of prostate prevention and treatment
Experimental animal is lotus prostate gland cancer cell nude mice, positive controls tail vein injection routine antitumor medicine adriamycin
(4mg/kg), negative control group Lump body injection physiological saline.Each drug research group (B, C, D, E, F group) and other experiment conditions
It is identical as the method for tumor of breast Experiment on therapy in embodiment 3.Its experimental result is as follows.
Within entire experimental period, negative control group gross tumor volume shows a increasing trend；From test the 5th day, positive controls
It is reduced compared with negative control group with each drug research group tumor-bearing mice gross tumor volume other than B group, difference is statistically significant
(P<0.05)。
In the administration phase, the Relative tumor proliferation rate of each drug research group tumor-bearing mice declines；From testing the 17th day, B group with
Outer each drug research group Relative tumor proliferation rate is in very low level (< 40%).From testing the 22nd day, C, D group are relatively swollen
Tumor proliferation rate is lower than 15%, effect always clearly, temporarily without recurrence trend.During test, positive controls Relative tumor
Each drug research group other than the suppression ratio B group of proliferation rate is late in time, significantly larger in data (being greater than 35%).
The 28th day after administration, the knurl weight of each drug research group tumor-bearing mice other than B group is significant compared with negative control group
It reduces, and there is statistical difference (P < 0.05), wherein other groups of tumour inhibiting rates are low with C, D group tumour inhibiting rate highest (90% or more)
In 80%.Positive controls tumour inhibiting rate is 63%.
In addition, effect of the injection for the knurl of the development different from of inoculation time difference thus tumour cell,
It is also that the shorter tumour tumor killing effect of inoculation time is better, in addition to can be applied to relatively late period prostate cancer and early prostate cancer,
The nonmalignant tumor that even can be used for having larger carcinogenic risk completely removes, to prevent its development as malignant tumor.
The some other quinine dihydrochloride injections prepared using embodiment 1, can also obtain similar results.According to these
Pharmacodynamic result and local side reaction result, quinine dihydrochloride provided by the invention are preferred in tumor of prostate treatment use
Condition is as follows: the administration of tumor area；Quinine dihydrochloride injection concentration is 0.05-0.50M, preferably 0.15-0.4M or 0.2-0.3M.
In addition, another battery of tests shows that under same concentration, a biggish injection volume shows more preferable drug effect.If
Knurl product is too big, to control dosage, can carry out branch's processing.Each administered volume of injection is necessary for being intended to processing unit
70% or more, preferably 110% or more of part knurl product (being tumor volume in smaller knurl).
Embodiment 8: the application in rhinopharyngeal neoplasm treatment
Experimental animal is lotus nasopharyngeal carcinoma cell nude mice, positive controls tail vein injection routine antitumor medicine 5-FU.
The method phase of each drug research group (B, C, D, E, F group) and other experiment conditions and tumor of breast Experiment on therapy in embodiment 3
Together.Its experimental result is as follows.
From test the 5th day, each drug research group tumor-bearing mice gross tumor volume reduced compared with negative control group, and difference has
Statistical significance (P < 0.05).Until the 17th day from test the 7th day, the Relative tumor of each drug research group tumor-bearing mice is proliferated
Rate (T/C) is respectively less than 40%.From testing the 17th day, the Relative tumor proliferation rate (T/C) of higher concentration (0.2M or more) group is equal
Less than 15%, illustrate that they still have apparent tumor growth inhibitory effect after drug withdrawal.
The 28th day after administration, the knurl weight of each drug research group tumor-bearing mice significantly reduces compared with negative control group, and has
There is statistical difference (P < 0.05).The Relative tumor tumour inhibiting rate of each drug research group tumor-bearing mice is all larger than > 40%, wherein higher
The tumour inhibiting rate of concentration (0.2M or more) group may be up to 95% or more, and other groups of tumour inhibiting rates are lower than 85%.It is positive during test
Suppression ratio D, E, E, F group of control group Relative tumor proliferation rate are late in time, significantly larger in data (30% or so)；Suppression
Ratio of outflow average value is 68%.
The some other quinine dihydrochloride injections prepared using embodiment 1, it is also possible to obtain similar results.According to these
Pharmacodynamic result and local side reaction are as a result, preferred stripe of the quinine dihydrochloride provided by the invention in rhinopharyngeal neoplasm treatment use
Part is as follows: the administration of tumor area；Quinine dihydrochloride injection concentration is 0.05-0.50M, preferably 0.15-0.4M or 0.2-0.3M.
In addition, another battery of tests shows that under same concentration, a biggish injection volume shows more preferable drug effect.If
Knurl product is too big, to control dosage, can carry out branch's processing.Each administered volume of injection is necessary for being intended to processing unit
70% or more, preferably 110% or more of part knurl product (being tumor volume in smaller knurl).
Application of the embodiment 9 in lung neoplasm treatment
Experimental animal is lotus lung carcinoma cell nude mice, positive controls tail vein injection routine antitumor medicine 5-FU.It is right
The research of quinine dihydrochloride is carried out using quinine dihydrochloride first.Each drug research group (B, C, D, E, F group) and other experiments
Condition is identical as the method for tumor of breast Experiment on therapy in embodiment 3.Its experimental result is as follows.
From test the 5th day, each drug research group tumor-bearing mice gross tumor volume reduced compared with negative control group, and difference has
Statistical significance (P < 0.05).Until the 17th day from test the 7th day, the Relative tumor of each drug research group tumor-bearing mice is proliferated
Rate is obviously reduced.From testing the 17th day, the Relative tumor proliferation rate (T/C) of higher concentration (0.2M or more) group is respectively less than
15%, illustrate that they still have apparent tumor growth inhibitory effect after drug withdrawal.
The 28th day after administration, the knurl weight of each drug research group tumor-bearing mice significantly reduces compared with negative control group, and has
There is statistical difference (P < 0.05).The Relative tumor tumour inhibiting rate of each drug research group tumor-bearing mice is all larger than > 40%, wherein higher
The tumour inhibiting rate of concentration (0.2M or more) group may be up to 95% or more, and other groups of tumour inhibiting rates are lower than 85%.It is positive during test
Suppression ratio D, E, E, F group of control group Relative tumor proliferation rate are late in time, significantly larger in data (30% or so)；Sun
Property control group tumour inhibiting rate be 54%.
The some other quinine dihydrochloride injections prepared using embodiment 1, can also obtain similar results.According to these
Pharmacodynamic result and local side reaction are as a result, optimum condition of the quinine dihydrochloride provided by the invention in lung neoplasm treatment use
It is as follows: the administration of tumor area；Quinine dihydrochloride injection concentration is 0.05-0.50M, preferably 0.15-0.4M or 0.2-0.3M.
In addition, another battery of tests shows that under same concentration, a biggish injection volume shows more preferable drug effect.If
Knurl product is too big, to control dosage, can carry out branch's processing.Each administered volume of injection is necessary for being intended to processing unit
70% or more, preferably 110% or more of part knurl product (being tumor volume in smaller knurl).
Embodiment 10: the application in colon tumor treatment
Experimental animal is lotus colon cancer cell nude mice.Positive controls tail vein injection routine antitumor medicine cis-platinum.To two
The research of quinin hydrochloride is carried out using quinine dihydrochloride first.Each drug research group (B, C, D, E, F group) and other experiment items
Part is identical as the method for tumor of breast Experiment on therapy in embodiment 3.Its experimental result is as follows.
From test the 5th day, each drug research group tumor-bearing mice gross tumor volume reduced compared with negative control group, and difference has
Statistical significance (P < 0.05).Until the 17th day from test the 7th day, the Relative tumor of each drug research group tumor-bearing mice is proliferated
Rate is obviously reduced.From testing the 17th day, the Relative tumor proliferation rate (T/C) of higher concentration (0.2M or more) group is respectively less than
15%, illustrate that they still have apparent tumor growth inhibitory effect after drug withdrawal.
The 28th day after administration, the knurl weight of each drug research group tumor-bearing mice significantly reduces compared with negative control group, and has
There is statistical difference (P < 0.05).The Relative tumor tumour inhibiting rate of each drug research group tumor-bearing mice is all larger than > 40%, wherein higher
The tumour inhibiting rate of concentration (0.2M or more) group may be up to 95% or more, and other groups of tumour inhibiting rates are lower than 85%.It is positive during test
Suppression ratio D, E, E, F group of control group Relative tumor proliferation rate are late in time, significantly larger in data (30% or so)；Suppression
Ratio of outflow average value is 75%.
The some other quinine dihydrochloride injections prepared using embodiment 1, it is also possible to obtain similar results.According to these
Pharmacodynamic result and local side reaction are as a result, preferred stripe of the quinine dihydrochloride provided by the invention in colon tumor treatment use
Part is as follows: the administration of tumor area；Quinine dihydrochloride injection concentration is 0.05-0.50M, preferably 0.15-0.4M or 0.2-0.3M.
In addition, another battery of tests shows that under same concentration, a biggish injection volume shows more preferable drug effect.If
Knurl product is too big, to control dosage, can carry out branch's processing.Each administered volume of injection is necessary for being intended to processing unit
70% or more, preferably 110% or more of part knurl product (being tumor volume in smaller knurl).
Claims (9)
1. quinine dihydrochloride is preparing the application in drug for treating tumour, wherein the drug include quinine dihydrochloride with
And pharmaceutically acceptable excipient or carrier and to be suitable for the dosage form being administered through tumor area, quinine dihydrochloride in the drug
Concentration is 0.15-0.4M, and the drug is administered with the quinine dihydrochloride of this concentration through tumor area, wherein the tumour is selected from pancreas
Cancer, thyroid cancer and head and neck cancer.
2. application described in claim 1, wherein the concentration of the quinine dihydrochloride is 0.2-0.3M.
3. application described in claim 1, wherein when tumor area is administered, the dosage form is injection and its volume not less than being intended to locate
The 70% of the tumor mass volume of reason.
4. application as claimed in claim 3, wherein when tumor area is administered, the dosage form is injection and its volume not less than being intended to locate
The 110% of the tumor mass volume of reason.
5. application described in one of claim 1-4, wherein the pharmaceutically acceptable excipient or carrier are that water, water can
Misci-ble organic solvents or their mixture.
6. application described in claim 5, wherein the miscible organic solvent of the water is one of the following kind or a variety of: ethyl alcohol,
Propylene glycol, PEG, isopropanol.
7. application described in one of claim 1-4, wherein the drug also includes analgesic and/or curing agent.
8. application as claimed in claim 7, wherein the analgesic is one of the following kind or a variety of: benzyl alcohol, hydrochloric acid Proca
Cause, anesin, hydrochloric acid benefit card.
9. application as claimed in claim 7, wherein the curing agent is one of the following kind or a variety of: Lauromacrogol, sodium morrhuate,
Ethanolamine oleate, polidocanol, bleomycin A5.
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