CN101429201A - Lemon acid berbamine salt, preparation method and application thereof - Google Patents
Lemon acid berbamine salt, preparation method and application thereof Download PDFInfo
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- CN101429201A CN101429201A CNA2008101634386A CN200810163438A CN101429201A CN 101429201 A CN101429201 A CN 101429201A CN A2008101634386 A CNA2008101634386 A CN A2008101634386A CN 200810163438 A CN200810163438 A CN 200810163438A CN 101429201 A CN101429201 A CN 101429201A
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Abstract
The invention provides berbamine citrate. Berbamine free alkali is taken as a raw material, and edible strong organic acid is applied to substitute the prior commonly-used inorganic acid to perform a salt-forming reaction according to certain proportion at room temperature to obtain the berbamine citrate. The berbamine citrate has remarkable killing effect on various hematological tumor cells cultured in vitro such as human leukemia, multiple myeloma, lymphoma and so on, and also has remarkable inhibition effect on the growth of human hematological tumor cells in the bodies of nude mice, but the berbamine citrate with the same concentration has no remarkable effect on the cell growth of normal persons and has no remarkable toxic side effect on the nude rice; and the berbamine citrate can form a pharmaceutical composition with other optional known anti-tumor medicines with one or more therapeutically effective amounts to achieve the synergistic effect. Therefore, the berbamine citrate can be applied to the preparation of medicines for treating hematological tumor diseases.
Description
Technical field
The invention belongs to chemical field, relate to lemon acid berbamine (Shengbaian Pian citrate) and preparation thereof, and the drug regimen and their application in preparation treatment neoplastic hematologic disorder disease that contain them.
Background technology
Report according to the World Health Organization: about 2,500 ten thousand people in the whole world suffered from various cancers in 2007, and 7,900,000 people die from these cancers (account for all death tolls 13%).Estimate that whole world cancer mortality will continue to increase, the year two thousand thirty estimation will have 1,200 ten thousand people to die from cancer.2006, cancer was seized nearly 1,800,000 people's life in China, and the numeral than 2005 has had more about 300,000." the Chinese Development of Health Service situation statistical communique in 2006 " made by Ministry of Health health statistics center shows, cancer is the first time " citing for the first " in the cause of the death of urban and rural residents in 2006.Wherein, cities and towns and urban residents' cancer mortality has risen 14.76% and 21.57% than 2005 respectively.That is to say had last year 83.4 ten thousand town dweller and 960,000 urban residents to die from cancer, this has almost accounted for 1/4th of annual total death toll, and cancer has become first killer of human health.Yet regrettably, these cancers can not effectively be controlled and treat to medicine commonly used at present, and therefore studying new better medicament prevents and treat these cancers that crucial meaning is arranged.
Berbamine is a kind of bisbenzylisoquinoline alkaloid.More existing bibliographical informations, Berbamine has the effect of inducing some leukemia cells and other apoptosis of tumor cells.As the present inventor's early-stage Study bibliographical information, in the vitro culture system, Berbamine hydrochloride can be induced people K562, Jurkat, HL-60, NB-4 apoptosis of leukemia, suppresses leukemia cell's growth [Xu R, et al.Leukemia Research.2006,30:17-23; Sun JR, et al.Zhonghua Yi Xue Za Zhi.2006; 86:2246-51; Zhao XY, et al.Chin Med J (Engl) .2007; 120:802-6].Bibliographical information is also arranged, Berbamine can induce the Bel7402 SMMC7721 of vitro culture and prostate cancer cell PC-3 apoptosis [Wang GY, et al.J ZhejiangUniv Sci B.2007; 8:248-55; China's experimental surgery magazine, 2007; 24 volumes, 8 phase 957-959 pages or leaves].Bibliographical information effect of berbamine derivative 4 ethoxy butyl Berbamine [0-4-ethoxy-butyl-berbamine are also arranged, be called for short EBB] have the rat liver cancer of an inhibition growth [Fang BJ, et al.World J Gastroenterol2004,10:950-953] and induce the human lung carcinoma cell apoptosis [Shanxi Normal University's journal (natural science edition) 04 phase of calendar year 2001 55-58 page or leaf] of vitro culture.But these bibliographical informations result shows, although Berbamine hydrochloride or effect of berbamine derivative EBB have lethal effect to the tumour cell of vitro culture, and, their anti-tumor in vivo effects are unsatisfactory.
Known, compound water-soluble is one of key factor of its bioavailability of decision and drug effect.Most of alkaloids are normal in plant materials to be combined into the salt of highly water-soluble with organic acid (citric acid, tartaric acid, oxalic acid, succsinic acid, acetic acid, propionic acid etc.) and to play a role, and Berbamine or the effect of berbamine derivative of using always is hydrophobic alkaloid at present, and be water insoluble.Use the Berbamine hydrochloride of mineral acid hydrochloric acid preparation, water-soluble not high yet, less than 30mg/ml.The hydrophobicity of Berbamine and the low water solubility of Berbamine hydrochloride can influence its antitumous effect undoubtedly.Therefore, develop new Berbamine salt, to improve its water-soluble and bioavailability, it is antitumor to improve Berbamine.
Summary of the invention
The purpose of this invention is to provide a kind of novel Berbamine organic acid salt (Shengbaian Pian citrate), the formula of described Berbamine organic acid salt lemon acid berbamine salt with following formula:
Wherein: R is Citric acid monohydrate Food grade (C
6H
5O
7.H
2O), also can be Citric Acid, usp, Anhydrous Powder (C
6H
5O
7).
Another object of the present invention provides the preparation method of above-mentioned lemon acid berbamine organic acid salt, realizes by following steps:
(1) under the room temperature, Berbamine is added R (Citric acid monohydrate Food grade or Citric Acid, usp, Anhydrous Powder) solution be carried out to reactant salt, the preferred weight ratio of Berbamine and citric acid but be not limited to 4～20:1.
(2), get little Huang or white lemon acid berbamine salt powder with above-mentioned lemon acid berbamine salt solution drying.Reaction formula:
The Berbamine lemon acid berbamine salt
The method for preparing lemon acid berbamine salt that the present invention is used, the success ratio height, simple, cost is low, is fit to large-scale production (embodiment 1-2).
A further object of the present invention provides the application of above-mentioned lemon acid berbamine salt in the anti-neoplastic hematologic disorder disease medicament of preparation.Relate to but be not limited to administer application in the medicines such as leukemia, multiple myeloma, lymphoma in preparation.
Drug prepared is formed by containing the lemon acid berbamine salt and the pharmaceutically acceptable assistant agent for the treatment of significant quantity.
Drug prepared also contains other antitumor drugs.The anti-neoplastic hematologic disorder disease medicament combination of described lemon acid berbamine salt is such as but not limited to anti-leukemia medicine combination, anti-multiple myeloma drug regimen, lymphoma drug regimen etc.
The present invention is main according to being: Berbamine commonly used at present is a kind of not salifiable free alkaloid, water insoluble, or a kind of Berbamine hydrochloride of using the low water solubility of mineral acid hydrochloric acid preparation, and in fact, most of alkaloids normal and organic acid (citric acid, tartaric acid in plant materials, oxalic acid, succsinic acid, acetic acid, propionic acid etc.) be combined into the organic acid salt of highly water-soluble and play a role.Therefore, the present inventor uses edible strong organic acid citric acid design and prepares water-soluble (Water-solubility) better Berbamine organic acid salt, by antitumor activity screening in external and the animal body, in the hope of obtaining the novel berbamine salt that anti-tumor activity is higher, toxicity is lower, for being developed further into new medicine.The discovery that the inventor is surprised, lemon acid berbamine not only have well water-soluble, and in animal body multiple neoplastic hematologic disorder disease are had good therapeutic action.
The characteristics of Zhi Bei lemon acid berbamine salt are as stated above: use edible strong organic acid citric acid and replace and commonly used at present prepare berbamine salt with mineral acid hydrochloric acid, the lemon acid berbamine salt that obtains is its water-soluble height not only, be about 500mg/ml (seeing embodiment 3), be more than 16.6 times of Berbamine hydrochloride (30mg/ml) commonly used at present, and with the pH value of the solution of above-mentioned lemon acid berbamine salt preparation between 4-5, apparently higher than Berbamine hydrochloride salts solution (the pH value is about 2) (seeing embodiment 4).
Death of neoplastic cells (seeing embodiment 5-10) such as Berbamine Citrate trianion energy multiple neoplastic hematologic disorder of selective induction of the present invention such as leukemia, multiple myeloma, lymphoma.Experimentation on animals confirms that oral Berbamine Citrate trianion can significantly suppress people's xenotransplantation knurl growth in the animal body, to some tumours wherein, demonstrate removing fully as leukemia, reach the radical cure tumor effect, the anti-tumor in vivo activity is apparently higher than Berbamine hydrochloride salt (seeing embodiment 11).More meaningfully, the experimentation on animals result shows that lemon acid berbamine of the present invention does not have overt toxicity reaction (seeing embodiment 11) to laboratory animal under antitumor effective dose.
Forming of described medicine by general formula of the present invention (I) compound and optional preparation allowable pharmaceutical excipients or carrier.
Compound of the present invention can be with oral form administration, such as but not limited to conventional tablet and enteric coated tablet, capsule, pill, pulvis, granula, tincture, solution, suspension and syrup.They also can be with parenteral form administration, in the intravenously of knowing such as but not limited to the general population of pharmaceutical field, the peritoneal cavity, form such as subcutaneous and muscle.
Use the dosage of compound of the present invention to select described factor to include but not limited to according to various factors: the dosage form of the approach of age, body weight, sex and recipient's physical state, the severity that needs the disease of treatment, administration, recipient's metaboilic level and excretory function, employing by those of ordinary skill in the art.
Drug regimen of the present invention can further comprise another or multiple cancer therapy drug, the existing cancer therapy drug of for example supplying on the market.
Cancer therapy drug is more effective when uniting use usually.In addition, preferably with the maximum tolerated dose of most drug, the timed interval minimum between twice administration is carried out administration.
Compound of the present invention preferably before administration with one or more pharmaceutically the acceptable excipient prepare.Excipient is an inert substance, such as but not limited to carrier, diluent, seasonings, sweeting agent, lubricant, solubilizing agent, suspension agent, tackiness agent, medicine disintegrating agent and capsule material.
Another specific embodiments of the present invention is a pharmaceutical preparation, and said preparation comprises pharmaceutically acceptable excipient of compound of the present invention and one or more, and this excipient can be compatible with other composition in the said preparation and harmless to its recipient.Pharmaceutical preparation of the present invention by will treating significant quantity compound of the present invention and one or more pharmaceutically the acceptable excipient make up and prepare.In preparation composition process of the present invention, described activeconstituents can or be closed in the carrier with mixing diluents, and this carrier can be capsule, pouch, wrapping paper or other container.This carrier can be used as thinner, can be solid, semisolid or fluent material as vehicle; Or tablet, pill, pulvis, lozenge, suspension, emulsion, solution, syrup, soft hard gel capsule, suppository, aseptic injection solution and aseptic packing pulvis.
For oral administration, described activeconstituents can with oral, atoxic pharmaceutically acceptable carrier combinations, this carrier is such as but not limited to sugar alcohol, lime carbonate, calcium phosphate, calcium sulfate, methylcellulose gum etc. in lactose, starch, sucrose, glucose, yellow soda ash, N.F,USP MANNITOL, the mountain; Randomly can also with disintegrating agent, wedding agent, lubricant combination, this disintegrating agent is such as but not limited to corn, starch, methylcellulose gum, agar profit soil, xanthan gum, alginic acid etc.; Wedding agent is such as but not limited to gel, natural sugar, beta lactose, corn sweetener, natural and synthetic rubber, Sudan Gum-arabic, carboxymethyl cellulose, polyoxyethylene glycol, paraffin etc.; Lubricant is such as but not limited to Magnesium Stearate, sodium stearate, stearic acid, sodium oleate, Sodium Benzoate, sodium acetate etc.
In powder form, described carrier can be the solid in small, broken bits with activeconstituents blended in small, broken bits.This activeconstituents can with suitable ratio with have the carrier that combines attribute and mix, and be pressed into desirable shape and size, thereby form tablet.Described pulvis and tablet preferably contain the activeconstituents of 1% to 99% weight, and this activeconstituents is a novel composition of the present invention.Suitable solid carrier is carboxymethyl cellulose magnesium, the cured and theobroma oil of low-melting honeybee.
Aseptic liquid preparation comprises suspension, milk sap and syrup.Described activeconstituents can be dissolved or suspended in the pharmaceutically acceptable carrier, for example the mixture of sterilized water, aseptic organic solvent or sterilized water and aseptic organic solvent.
Above-mentioned preparation can exist with unit dosage, and this unit dosage is the physics dispersal unit that contains unitary dose, is suitable for to human body and other mammalian body administration.Unit dosage can be capsule or tablet, or a lot of capsule or tablet." unitary dose " is the predetermined amount of active compound of the present invention, makes itself and one or more excipient combination can produce the ideal result of treatment through calculating.According to related concrete treatment, the amount of the unitary dose of activeconstituents can about 0.1 to about 1000 milligrams or more between change or adjust.
Lemon acid berbamine salt of the present invention is compared with Berbamine hydrochloride with Berbamine commonly used at present, have following advantages and characteristic: (1) has better water-solubility and near blood of human body physiological status pH value, helps improving its bioavailability (embodiment 3-4); (2) preparation is simple, and cost is low, is fit to scale operation (embodiment 1-2); (3), has the higher security of Berbamine hydrochloride salt than the preparation of mineral acid hydrochloric acid because of adopting edible organic acid citric acid to prepare berbamine salt; (4) have wider and stronger anti-tumor activity, confirmed responsive neoplastic hematologic disorder have leukemia, multiple myeloma, lymphoma, etc. (seeing embodiment 5-11); (5) it is lower that poison is paid effect, and cell in vitro culture system and experimentation on animals confirm that lemon acid berbamine does not have obvious toxic-side effects (seeing embodiment 11) to normal cell growth and laboratory animal under effective antitumor amount.
Embodiment:
The present invention is further described in conjunction with the embodiments.Should be understood that the following example to be intended to the present invention is described and scope of the present invention is not constituted any restriction
Embodiment 1: the preparation of Citric acid monohydrate Food grade berbamine salt
At room temperature, take by weighing 20 gram Berbamines, put into glass beaker, add 200 milliliter 2.5% Citric acid monohydrate Food grade (C then
6H
5O
7.H
2O) solution stirs, and treats that Berbamine dissolves fully, and solution is transparent fully, then lemon acid berbamine salt solution is carried out drying, gets little yellow or white lemon acid berbamine salt crystallization.
Reaction formula:
Berbamine Citric acid monohydrate Food grade berbamine salt
Experimental result shows: the Citric acid monohydrate Food grade berbamine salt of using this method preparation is success ratio height (100%) not only; And required reagent is few, only needs citric acid and water, and operation steps is few and simple, and common lab can be operated.
Embodiment 2: the preparation of Citric Acid, usp, Anhydrous Powder Berbamine
At room temperature, take by weighing 20 gram Berbamines, put into glass beaker, add 200 milliliter 2.5% Citric Acid, usp, Anhydrous Powder (C then
6H
5O
7) solution, stir, treat that Berbamine dissolves fully, solution is transparent fully, then the Berbamine citrate solution is carried out drying, gets little yellow or the crystallization of white Berbamine Citrate trianion.
Berbamine Citric Acid, usp, Anhydrous Powder berbamine salt
Experimental result shows: the Citric Acid, usp, Anhydrous Powder berbamine salt of using this method preparation is success ratio height (100%) not only; And required reagent is few, only needs citric acid and water, and operation steps is few and simple, and common lab can be operated.
Embodiment 3: lemon acid berbamine salt and the water-soluble comparison of Berbamine hydrochloride salt
At room temperature take by weighing 0.1 gram lemon acid berbamine and Berbamine hydrochloride respectively, put into 10ml respectively in vitro, slowly add deionized water then, the limit edged shakes up, fully dissolve until the berbamine salt that makes adding, solution present transparent fully till.Then, measure and dissolve the required water of berbamine salt fully, calculate the solubleness of berbamine salt in water-soluble.
Experimental result shows: the solubleness of lemon acid berbamine salt in water is about 500mg/ml, and the solubleness of Berbamine hydrochloride in water is about 30mg/ml.Lemon acid berbamine salt water-soluble is 16.6 times of Berbamine hydrochloride.
Embodiment 4: the water-soluble pH value of lemon acid berbamine salt and Berbamine hydrochloride salt relatively
At room temperature take by weighing 0.1 gram lemon acid berbamine and Berbamine hydrochloride respectively, put into 10ml respectively in vitro, slowly add deionized water then, the limit edged shakes up, fully dissolve until the berbamine salt that makes adding, solution present transparent fully till (2ml water).Then, measure the pH value of solution value with accurate pH test paper.
Experimental result shows: the lemon acid berbamine salt pH value of aqueous solution is about about 4.5, and the pH value of Berbamine hydrochloride salt brine solution is about 2.0.Compare with Berbamine hydrochloride salt brine solution pH value, the lemon acid berbamine salt pH value of water solution is more near normal human blood physiological pH value (7.3-7.4).
Embodiment 5: the anti-people's chronic myelogenous leukemia cell of lemon acid berbamine salt K562 determination of activity
(1) experiment material
Leukemia cell line: people K562 leukemia cell is available from Chinese Academy of Sciences's Shanghai cell bank.
Main agents: lemon acid berbamine oneself synthesizes for us.
Key instrument: cell culture incubator, microplate reader
(2) experimental technique
Get 8000 of well-grown leukemia cells, be inoculated into 96 porocytes and cultivate in the plate hole.Nutrient solution is 1640 cell culture fluids that contain 10% foetal calf serum.The medicine that adds different concns behind the mixing, is put carbonic acid gas (5%CO2) cell culture incubator and was cultivated 48 hours for 37 ℃.Measure viable cell concentrations with mtt assay then.Control group (do not add medicine handle) cell viability is made as 100% in this experiment, and calculates cell viability (%) and 48 hours leukemia cell's half growth inhibitory concentrations (48 hours IC50 values) behind the drug effect.
(3) experimental result
Experimental result proof lemon acid berbamine can rapid induction human leukemia cell line K562 necrocytosis and is suppressed leukemia cell's growth, its 48 hours leukemia cell's half growth inhibitory concentration (48 hours IC50) be about about 4.0 μ g/ml.
Embodiment 6: the anti-human acute myeloid leukemia cell of lemon acid berbamine salt NB4 determination of activity
(1) experiment material
Leukemia cell line: people NB4 leukemia cell is available from Chinese Academy of Sciences's Shanghai cell bank.
Main agents: lemon acid berbamine oneself synthesizes for us.
Key instrument: cell culture incubator, microplate reader
(2) experimental technique
Get 8000 of well-grown leukemia cells, be inoculated into 96 porocytes and cultivate in the plate hole.Nutrient solution is 1640 cell culture fluids that contain 10% foetal calf serum.The lemon acid berbamine that adds different concns behind the mixing, is put carbonic acid gas (5%CO2) cell culture incubator and was cultivated 48 hours for 37 ℃.Measure viable cell concentrations with mtt assay then.Control group (do not add medicine handle) cell viability is made as 100% in this experiment, and calculates cell viability (%) and 48 hours leukemia cell's half growth inhibitory concentrations (48 hours IC50 values) behind the drug effect.
(3) experimental result
Experimental result proof lemon acid berbamine can be induced human acute myeloid leukemia clone NB4 necrocytosis and be suppressed leukemia cell's growth, its 48 hours leukemia cell's half growth inhibitory concentration (48 hours IC50) be about 4.5 μ g/ml respectively.
Embodiment 7: lemon acid berbamine salt overriding resistance people chronic myelogenous leukemia cell K562/ADR determination of activity
(1) experiment material
Leukemia cell line: multidrug resistance people K562/ADR leukemia cell system is provided by the Zhejiang University institute of oncology.
Main agents: lemon acid berbamine oneself synthesizes for us.
Key instrument: cell culture incubator, microplate reader
(2) experimental technique
Get 8000 of well-grown leukemia cells, be inoculated into 96 porocytes and cultivate in the plate hole.Nutrient solution is 1640 cell culture fluids that contain 10% foetal calf serum.The medicine that adds different concns behind the mixing, is put carbonic acid gas (5%CO2) cell culture incubator and was cultivated 48 hours for 37 ℃.Measure viable cell concentrations with mtt assay then.Control group (do not add medicine handle) cell viability is made as 100% in this experiment, and calculates cell viability (%) and 48 hours leukemia cell's half growth inhibitory concentrations (48 hours IC50 values) behind the drug effect.
(3) experimental result
Experimental result proof lemon acid berbamine can inducible resistance human leukemia cell line K562 necrocytosis and is suppressed leukemia cell's growth, its 48 hours leukemia cell's half growth inhibitory concentration (48 hours IC50) be about 8.0 μ g/ml.
Embodiment 8: it is leukemia cell Jurkat determination of activity that the anti-people of lemon acid berbamine salt is drenched
(1) experiment material
Human leukemia cell line: the human lymphocyte leukemia cell is that Jurkat is available from Chinese Academy of Sciences's Shanghai cell bank.
Main agents: lemon acid berbamine oneself synthesizes for us.
Key instrument: cell culture incubator, microplate reader
(2) experimental technique
Get 8000 of well-grown leukemia cells, be inoculated into 96 porocytes and cultivate in the plate hole.Nutrient solution is 1640 cell culture fluids that contain 10% foetal calf serum.The medicine that adds different concns behind the mixing, is put carbonic acid gas (5%CO2) cell culture incubator and was cultivated 48 hours for 37 ℃.Measure viable cell concentrations with mtt assay then.Control group (do not add medicine handle) cell viability is made as 100% in this experiment, and calculates cell viability (%) and 48 hours leukemia cell's half growth inhibitory concentrations (48 hours IC50 values) behind the drug effect.
(3) experimental result
Experimental result proof lemon acid berbamine can be induced the human lymphocyte leukemia cell to be the Jurkat necrocytosis and to suppress leukemia cell's growth, its 48 hours leukemia cell's half growth inhibitory concentration (48 hours IC50) be about 3.32 μ g/ml.
Embodiment 9: the anti-people's multiple myeloma cells of lemon acid berbamine salt RPM18226 determination of activity
(1) experiment material
People's multiple myeloma cell line: people's multiple myeloma cell line is that RPM18226 is provided by hemopathy institute of Zhejiang University.
Main agents: lemon acid berbamine oneself synthesizes for us.
Key instrument: cell culture incubator, microplate reader
(2) experimental technique
Getting well-grown people's multiple myeloma cells is 8000 in RPM18226 cell, is inoculated into 96 porocytes and cultivates in the plate hole.Nutrient solution is 1640 cell culture fluids that contain 10% foetal calf serum.The medicine that adds different concns behind the mixing, is put carbonic acid gas (5%CO2) cell culture incubator and was cultivated 48 hours for 37 ℃.Measure viable cell concentrations with mtt assay then.Control group (do not add medicine handle) cell viability is made as 100% in this experiment, and calculates cell viability (%) and 48 hours leukemia cell's half growth inhibitory concentrations (48 hours IC50 values) behind the drug effect.
(3) experimental result
It is the RPM18226 necrocytosis that experimental result proof lemon acid berbamine can be induced people's multiple myeloma cells, its 48 hours the half growth inhibitory concentration (48 hours IC50) be about 8.0 μ g/ml, show that lemon acid berbamine has anti-people's multiple myeloma activity.
The anti-human lymphoma oncocyte of embodiment 10 lemon acid berbamine salts DOHH2 determination of activity
(1) experiment material
Human lymphoma cell's strain: human lymphoma cell's strain is provided by doctor Wu Dong of 2nd Affiliated Hospital Zhejiang University School of Medicine hematology.
Main agents: lemon acid berbamine oneself synthesizes for us.
Key instrument: cell culture incubator, microplate reader
(2) experimental technique
Get 8000 of well-grown leukemia cells, be inoculated into 96 porocytes and cultivate in the plate hole.Nutrient solution is 1640 cell culture fluids that contain 10% foetal calf serum.The medicine that adds different concns behind the mixing, is put carbonic acid gas (5%CO2) cell culture incubator and was cultivated 48 hours for 37 ℃.Measure viable cell concentrations with mtt assay then.Control group (do not add medicine handle) cell viability is made as 100% in this experiment, and calculates cell viability (%) and 48 hours leukemia cell's half growth inhibitory concentrations (48 hours IC50 values) behind the drug effect.
Experimental result proof lemon acid berbamine can be induced human lymphoma cell's death, its 48 hours the half growth inhibitory concentration (48 hours IC50) be about 2.0 μ g/ml, show that lemon acid berbamine has anti-human lymphoma cell's activity.
Embodiment 11: lemon acid berbamine and Berbamine hydrochloride compare xenotransplantation knurl growth in the human leukemia K562/ADR nude mouse and animal toxicity influence
(1) experiment material
Laboratory animal: nude mice is purchased the Shanghai animal center in the Chinese Academy of Sciences
Reagent: lemon acid berbamine is that oneself is synthetic, and Berbamine hydrochloride is available from the imperial natural medicine company life of Chengdu hard iron Science and Technology Ltd..
Instrument: cell culture incubator
(2) experimental technique
Get 7 the week age nude mice, at its back subcutaneous vaccination human leukemia cell K562 5 x 10
7/ every mouse.After 24 hours, divide 3 groups at random.The medication group: lemon acid berbamine and Berbamine hydrochloride group adopt oral administration route, carry out every day 3 times (filling Weihe) by per kilogram of body weight 100mg dosage.Control group: use physiologic saline for substitute, logotype 10 days.Observed altogether 30 days, during measure that the nude mice knurl is heavy, body weight and situations such as movable and diet.When experiment finishes, put to death mouse, get tumor tissues, survey actual weight.
(3) experimental result
Experimental result proof lemon acid berbamine has obvious restraining effect to xenotransplantation knurl growth in the human leukemia nude mouse, in 45 day experimental period, 6 inoculated tumour cell nude mices are treated through lemon acid berbamine, there is not 1 long knurl, no ratio of outflow reaches 100% (6/6), and the Berbamine hydrochloride group has 3 tumor growth to occur in 6 nude mices, knurl body weight in average reaches 4.67 grams, no ratio of outflow 50% (3/6).Obvious tumor growth all appears in 7 nude mices of control group, tumor formation rate 100% (7/7), and knurl body weight in average reaches 7.22 grams.Lemon acid berbamine group nude mice mean body weight is 19.81 grams, and Berbamine hydrochloride group nude mice mean body weight is 16.87 grams.These experimental results show, anti-tumor activity is significantly better than Berbamine hydrochloride in animal body for lemon acid berbamine, and toxicity also is starkly lower than Berbamine hydrochloride.
Claims (8)
1. lemon acid berbamine salt, the general formula of described lemon acid berbamine salt is (I):
Wherein
R is water citric acid or Citric Acid, usp, Anhydrous Powder.
2. preparation method who prepares the described lemon acid berbamine salt of claim 1 is characterized in that realizing by following steps:
(1) under the room temperature, Berbamine is added water citric acid or Citric Acid, usp, Anhydrous Powder solution is carried out to reactant salt, the weight ratio of Berbamine and citric acid is 4～20:1;
(2), get little yellow or white lemon acid berbamine salt powder with above-mentioned lemon acid berbamine salt solution drying;
Reaction formula:
3. the application of formula according to claim 1 (I) lemon acid berbamine salt in preparation treatment neoplastic hematologic disorder disease medicament.
4. application according to claim 3 is characterized in that: the application in the leukemic medicine of preparation treatment.
5. application according to claim 3 is characterized in that: the application in the medicine of preparation treatment multiple myeloma.
6. application according to claim 3 is characterized in that: the application in the lymphadenomatous medicine of preparation treatment.
7. application according to claim 3 is characterized in that: described medicine is formed by containing the lemon acid berbamine salt for the treatment of significant quantity and preparation allowable pharmaceutical excipients or carrier.
8. application according to claim 3 is characterized in that: drug prepared also contains other antitumor drugs.
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| US9233976B2 (en) | 2009-05-19 | 2016-01-12 | City Of Hope | Berbamine derivatives |
| US8722698B2 (en) | 2009-05-19 | 2014-05-13 | City Of Hope | Berbamine derivatives |
| CN102712655A (en) * | 2010-08-27 | 2012-10-03 | 杭州本生药业有限公司 | Diimidated derivative of berbamine, and preparation method therefor and use thereof |
| CN102712655B (en) * | 2010-08-27 | 2014-07-30 | 杭州本生药业有限公司 | Diimidated derivative of berbamine, and preparation method therefor and use thereof |
| CN102078302B (en) * | 2010-12-17 | 2012-12-26 | 广东海洋大学 | Method for preparing berbamine chitosan-agar nano particles |
| CN102078302A (en) * | 2010-12-17 | 2011-06-01 | 广东海洋大学 | Method for preparing berbamine chitosan-agar nano particles |
| WO2013026373A1 (en) * | 2011-08-19 | 2013-02-28 | 杭州本生药业有限公司 | Use of berbamine for treating chronic myeloid leukemia |
| CN109125323A (en) * | 2018-08-01 | 2019-01-04 | 中国医学科学院医药生物技术研究所 | Application of two Berbamine hydrochlorides in preparation Ebola virus inhibitor |
| WO2020024719A1 (en) * | 2018-08-01 | 2020-02-06 | 中国医学科学院医药生物技术研究所 | Use of berbamine dihydrochloride in preparation of ebola virus inhibitor |
| CN109125323B (en) * | 2018-08-01 | 2020-07-03 | 中国医学科学院医药生物技术研究所 | Application of berbamine dihydrochloride in preparation of Ebola virus inhibitor |
| US11654141B2 (en) | 2018-08-01 | 2023-05-23 | Institute Of Medicinal Biotechnology, Chinese Academy Of Medical Sciences | Use of berbamine dihydrochloride in preparation of Ebola virus inhibitor |
| CN113195710A (en) * | 2018-12-06 | 2021-07-30 | 麒麟控股株式会社 | Method for producing T cell or NK cell, culture medium for T cell or NK cell, method for culturing T cell or NK cell, method for maintaining undifferentiated state of undifferentiated T cell, and agent for promoting proliferation of T cell or NK cell |
| CN110314160A (en) * | 2019-08-22 | 2019-10-11 | 辽宁大学 | Berbamine prevents and treats the application in medicine for treating diabetic nephropathy in preparation |
| CN110314160B (en) * | 2019-08-22 | 2023-05-26 | 辽宁大学 | Application of berbamine in preparing medicament for preventing and treating diabetic nephropathy |
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