CN102178676A - Medicinal composite for treating brain glioma - Google Patents
Medicinal composite for treating brain glioma Download PDFInfo
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- CN102178676A CN102178676A CN 201110111431 CN201110111431A CN102178676A CN 102178676 A CN102178676 A CN 102178676A CN 201110111431 CN201110111431 CN 201110111431 CN 201110111431 A CN201110111431 A CN 201110111431A CN 102178676 A CN102178676 A CN 102178676A
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- temozolomide
- tetrahydropyrimidine
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- cerebral glioma
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Abstract
The invention discloses a medicinal composite for treating brain glioma. The medicinal composite comprises the following active pharmaceutical ingredients: temozolomide and ectoine (1,4,5,6-tetrahydro-2-methyl-4-pyrimidinecarboxylic acid) or a derivative of ectoine, wherein the derivative of the ectoine is 1,4,5,6-tetrahydro-2-methyl-5-hydroxy-4-pyrimidinecarboxylic acid, and the mass ratio of temozolomide to ectoine or a derivative of ectoine is (2-4): 1. Research shows that, in the case of combined administration of the ectoine, the derivative of the ectoine and the temozolomide in a certain proportion, the1,4,5,6-tetrahydro-2-methyl-4-pyrimidinecarboxylic acid and the derivative thereof can obviously improve treatment effect of the temozolomide and reduce adverse effect of the temozolomide.
Description
Technical field
The present invention relates to a kind of antineoplastic pharmaceutical compositions, particularly a kind of pharmaceutical composition for the treatment of cerebral glioma.
Background technology
Tumor is one of common disease that threatens human health, be only second to cardiovascular disease, research about tumor has obtained bigger progress, developed the method such as various radiotherapies, chemotherapy of multiple treatment tumor, but all there are limitation in various medicines and therapy, be difficult to reach the effect of radical cure, and be prone to drug resistance and side effect.The tumor mortality rate still occupy first of the various diseases.The tool data show, China had 3,000,000 people to die from cancer in 2006, and tumor incidence still is in ascendant trend, and rejuvenation trend is arranged.In less than the time in 20 years, China's tumor incidence has risen 69% according to statistics, and mortality rate has risen 29.4%.Therefore, the new developing effective tumor treating medicaments of research is still the main direction of present oncotherapy.
46% sickness rate that cerebral glioma (cerebral glioma) accounts for intracranial tumor is 3～10,/10 ten thousand, accounts for 1%～3% of whole body malignant tumor, and the mean survival time (MST) that operative treatment adds chemicotherapy only is 8～11 months.
The temozolomide is a kind of medicine for the treatment of cerebral glioma, changes reactive compound into through quick non-enzymatic catalysis under physiology PH condition, brings into play cytotoxicity by the alkylation (methylating) of DNA guanine then.
But the temozolomide has pronounced side effects to bone marrow, lymphsystem, testis and gastrointestinal tract, can cause nausea and vomiting, weak and haematics toxicity.
1,4,5,6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic, be commonly called as tetrahydropyrimidine, English ectoine by name, CAS number is 96702-03-3, chemistry 2-Methyl-1 by name, 4,5,6-tetrahydropyrimidine-4-carboxylic acid or (S)-2-methyl-1,4,5,6-tetra-hydro pyrimidine-4-carboxylic acid or 1,4,5,6-tetrahydro-2-methyl-4-pyrimidine carbonic acid, be the amino acid derivativges of finding in 1985, discovered in recent years has certain mitigation to allergic disease, may be relevant with its moisture-keeping function.In addition 1,4,5,6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic has been used to cosmetics, as preserving moisture or suntan lotion.
Summary of the invention
At above-mentioned prior art, the purpose of this invention is to provide a kind of antineoplastic pharmaceutical compositions for the treatment of cerebral glioma, a kind of specifically temozolomide and 1 contained, 4,5,6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic or 1,4,5, the antineoplastic pharmaceutical compositions of the treatment cerebral glioma of 6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic acid derivatives.
For achieving the above object, the technical solution used in the present invention is:
A kind of pharmaceutical composition for the treatment of cerebral glioma, its active drug composition is: temozolomide, tetrahydropyrimidine or derivatives thereof.
The derivant of described tetrahydropyrimidine is 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic.
The mass ratio of described temozolomide and tetrahydropyrimidine or derivatives thereof is (2-4): 1.
Further, be by following active drug composition: temozolomide, tetrahydropyrimidine or derivatives thereof, and pharmaceutically acceptable carrier composition.
The medicine composition dosage form of described treatment cerebral glioma is an injection, is made up of following active drug composition and pharmaceutic adjuvant: in 1000ml, and tetrahydropyrimidine or derivatives thereof 40g, temozolomide 80g, Polyethylene Glycol 150ml, surplus is a water for injection.
The medicine composition dosage form of described treatment cerebral glioma is a tablet, form by following active drug composition and pharmaceutic adjuvant: tetrahydropyrimidine or derivatives thereof, temozolomide, microcrystalline Cellulose, lactose, Sodium Hydroxymethyl Stalcs, magnesium stearate and polyvinylpyrrolidone, wherein, the weight ratio of tetrahydropyrimidine or derivatives thereof, temozolomide, microcrystalline Cellulose, lactose, Sodium Hydroxymethyl Stalcs, magnesium stearate and polyvinylpyrrolidone is 20: 60: 50: 100: 37.5: 12: 30.
The medicine composition dosage form of described treatment cerebral glioma is a tablet, form by following active drug composition and pharmaceutic adjuvant: tetrahydropyrimidine or derivatives thereof, temozolomide, microcrystalline Cellulose, Sodium Hydroxymethyl Stalcs, differential silica gel, polyvinylpyrrolidone and sodium lauryl sulphate, wherein, the weight ratio of tetrahydropyrimidine or derivatives thereof, temozolomide, microcrystalline Cellulose, Sodium Hydroxymethyl Stalcs, differential silica gel, polyvinylpyrrolidone and sodium lauryl sulphate is 10: 40: 10: 12: 20: 30: 5.
The discovery that the present inventor is surprised under study for action, 1,4,5,6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic and derivant thereof and temozolomide be during according to a definite proportion administering drug combinations, and 1,4,5,6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic and derivant thereof can significantly improve temozolomide's drug effect, and reduce its untoward reaction.
Described in the technical scheme of the present invention 1,4,5,6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic is commonly called as tetrahydropyrimidine, English ectoine by name, CAS number is 96702-03-3, chemistry 2-Methyl-1 by name, 4,5,6-tetrahydropyrimidine-4-carboxylic acid or (S)-2-methyl-1,4,5,6-tetra-hydro pyrimidine-4-carboxylic acid or 1,4,5,6-tetrahydro-2-methyl-4-pyrimidine carbonic acid; 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic is commonly called as the hydroxy tetrahydro pyrimidine, and this is well-known to those skilled in the art.
The specific embodiment
Below in conjunction with embodiment the present invention is further explained.Should be understood that following examples only are used to explain the present invention, rather than restriction protection scope of the present invention.
Embodiment 11, and 4,5,6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic and temozolomide's compound injection and preparation
The Mo Siting compound injection
Preparation technology:
Cillin bottle, plug are slightly washed earlier, after use through the filterable water for injection fine purifiation of 0.45 μ m microporous filter membrane qualified to visible foreign matters, dry for standby then.
In irritating, dosing adds 1,4,5 of recipe quantity, 6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic, and Polyethylene Glycol 50ml dissolves it fully, as solution 1.
Add the temozolomide of recipe quantity in another dosing is irritated, Polyethylene Glycol 100ml dissolves it fully, as solution 2.
Solution 2 is merged in the adding solution 1, and 80 ℃ were heated 10 minutes, and cooling adds to the full amount of water for injection, mixing.
Embodiment 21, and 4,5, the preparation of 6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic and temozolomide's composition tablet
It is as follows to fill a prescription:
With 1,4,5 of prescription, 6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic and temozolomide cross 150 μ m sieve, and it is standby that adjuvant is crossed 180 μ m sieve; Now with 1,4,5,6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic mixes with microcrystalline Cellulose, successively mixes with lactose, carboxymethyl starch sodium, polyvinylpyrrolidone, magnesium stearate again, and tabletting gets final product behind the mix homogeneously.
Embodiment 31, and 4,5, the preparation of 6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic and temozolomide's composition tablet
With 1,4,5 of prescription, it is standby that 6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic and temozolomide cross 180 μ m sieve; With sieve 1,4,5, press large stretch of behind 6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic and microcrystalline Cellulose, carboxymethyl starch sodium and the polyvinylpyrrolidone mixing, to obtain smaller particles behind large stretch of crushing and pelletizing, add sodium lauryl sulphate and differential silica gel, the mixing tabletting gets final product.
Embodiment 41, and 4,5,6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic and temozolomide's antineoplastic pharmaceutical compositions are to the therapeutical effect evaluation of rat pulmonary carcinoma
People's lung cancer A549 cell suspension is adjusted to every milliliter 15 * 10
6Individual cell is got 0.2ml (3 * 10
6Individual cell) left fore axillary fossa inoculated with subcutaneous injections is in male adult nude rat, is divided into three groups at random, matched group (NS) tail vein injection saline every day 0.2ml after inoculating for two weeks.The administration group is pressed following scheme administration:
A group cyclophosphamide group, the cyclophosphamide tail vein injection gives rat (10mg/kg)
B group ifosfamide group, the ifosfamide tail vein injection gives rat (10mg/kg)
2 groups of C group embodiment irritate the medicine that stomach gives embodiment, calculate by the temozolomide, and dosage is 2mg/kg
3 groups of D group embodiment irritate the medicine that stomach gives embodiment, calculate by the temozolomide, and dosage is 2mg/kg
Each organizes administration every day 1 time, gives for 3 weeks continuously.Weekly with the maximum gauge of each treated animal tumor of vernier caliper measurement 3 weeks to the administration, and calculate and respectively organize mortality rate, rat is put to death in the back.Each organizes the tumor footpath as table 1.
Table 1
Each is organized in the mortality rate, and 3 groups of mortality rates of 2 groups of embodiment and embodiment are 4% and 0%, and cyclophosphamide group and ifosfamide group mortality rate are 35% and 51%, and NS group group mortality rate is 94%.
As seen, 1,4,5, used cyclophosphamide and the ifosfamide of being significantly higher than of the antitumor of 6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic and derivant and temozolomide's compositions.
Embodiment 51, and 4,5,6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic and temozolomide's combination medicine are to the therapeutical effect evaluation of cerebral glioma
Cultivate the C6 glioma cell with the DMEM liquid that contains 10% calf serum.Determine otch and bore position according to the Barker method, choosing caudatum district, rat brain left side on the rat brain stereotaxic instrument is target spot, and the sagittal suture right side is other opens 3.5mm, 5.0mm under the dura mater.Stereotaxis is implanted logarithmic (log) phase growth C6 tumor cell 2 * 10
6Individual.Lumbar injection gives the rat penicillin 100,000 units in the postoperative 5 days.Postoperative wardrobe cranium scanning in the 5th day proves the rat intracranial tumor.
Get modeling success rat, be divided into 4 groups at random, the A group is irritated the stomach normal saline; The B group is irritated the compositions that stomach gives embodiment 2, and calculating dosage by the temozolomide is 2mg/kg; The C group is irritated the compositions that stomach gives embodiment 3, and calculating dosage by the temozolomide is 2mg/kg; The D group is irritated stomach and is given the temozolomide 5mg/kg.
Each treated animal, be administered once every day, and successive administration was added up each treated animal mortality rate after 7 days, and measured the tumor footpath of each treated animal.
The results are shown in Table 2.
Table 2
Visible 1,4,5 by table 2, the antitumor of 6-tetrahydrochysene-2-methyl-4-pyrimidine carboxylic and derivant and temozolomide's compositions is used to be significantly higher than the temozolomide, and mortality rate is lower than the temozolomide.
Claims (7)
1. pharmaceutical composition for the treatment of cerebral glioma, it is characterized in that: its active drug composition is: temozolomide, tetrahydropyrimidine or derivatives thereof.
2. the pharmaceutical composition of treatment cerebral glioma according to claim 1 is characterized in that: the derivant of described tetrahydropyrimidine is 1,4,5,6-tetrahydrochysene-2-methyl-5-hydroxyl-4-pyrimidine carboxylic.
3. the pharmaceutical composition of treatment cerebral glioma according to claim 1 is characterized in that: the mass ratio of described temozolomide and tetrahydropyrimidine or derivatives thereof is (2-4): 1.
4. the pharmaceutical composition of treatment cerebral glioma according to claim 1 is characterized in that: be by following active drug composition: temozolomide, tetrahydropyrimidine or derivatives thereof, and pharmaceutically acceptable carrier composition.
5. the pharmaceutical composition of treatment cerebral glioma according to claim 1, it is characterized in that: dosage form is an injection, form by following active drug composition and pharmaceutic adjuvant: in 1000ml, tetrahydropyrimidine or derivatives thereof 40g, temozolomide 80g, Polyethylene Glycol 150ml, surplus is a water for injection.
6. the pharmaceutical composition of treatment cerebral glioma according to claim 1, it is characterized in that: dosage form is a tablet, form by following active drug composition and pharmaceutic adjuvant: tetrahydropyrimidine or derivatives thereof, temozolomide, microcrystalline Cellulose, lactose, Sodium Hydroxymethyl Stalcs, magnesium stearate and polyvinylpyrrolidone, wherein, the weight ratio of tetrahydropyrimidine or derivatives thereof, temozolomide, microcrystalline Cellulose, lactose, Sodium Hydroxymethyl Stalcs, magnesium stearate and polyvinylpyrrolidone is 20: 60: 50: 100: 37.5: 12: 30.
7. the pharmaceutical composition of treatment cerebral glioma according to claim 1, it is characterized in that: dosage form is a tablet, form by following active drug composition and pharmaceutic adjuvant: tetrahydropyrimidine or derivatives thereof, temozolomide, microcrystalline Cellulose, Sodium Hydroxymethyl Stalcs, differential silica gel, polyvinylpyrrolidone and sodium lauryl sulphate, wherein, the weight ratio of tetrahydropyrimidine or derivatives thereof, temozolomide, microcrystalline Cellulose, Sodium Hydroxymethyl Stalcs, differential silica gel, polyvinylpyrrolidone and sodium lauryl sulphate is 10: 40: 10: 12: 20: 30: 5.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2011101114311A CN102178676B (en) | 2011-04-29 | 2011-04-29 | Medicinal composite for treating brain glioma |
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| CN2011101114311A CN102178676B (en) | 2011-04-29 | 2011-04-29 | Medicinal composite for treating brain glioma |
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| CN102178676B CN102178676B (en) | 2012-07-25 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111132672A (en) * | 2017-09-20 | 2020-05-08 | 俄克拉荷马医学研究基金会 | Treatment of drug resistant glioma |
| RU2726996C1 (en) * | 2014-12-16 | 2020-07-17 | Бристол-Маерс Сквибб Компани | Use of inhibitors of immune control points in new growths of central nervous system |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1486319A (en) * | 2001-01-18 | 2004-03-31 | ���鹫˾ | Synthesis of temozolomide and analogs |
| CN1615855A (en) * | 2004-09-29 | 2005-05-18 | 赵世光 | Temozolomide-polymer local slow release chemotherapy medicine for treating malignant brain tumor |
| CN1622814A (en) * | 2002-03-26 | 2005-06-01 | 万有制药株式会社 | Use of antitumor indolopyrrolocarbazole derivative and other anticancer agent in combination |
| CN1665507A (en) * | 2002-05-02 | 2005-09-07 | 克拉蒙特药品有限公司 | Therapeutic 1,2,3,6-tetrahydropyrimidine-2-one compositions and methods therewith |
| CN101172104A (en) * | 2002-02-22 | 2008-05-07 | 先灵公司 | Processes of making and using pharmaceutical formulations of antineoplastic agents |
-
2011
- 2011-04-29 CN CN2011101114311A patent/CN102178676B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1486319A (en) * | 2001-01-18 | 2004-03-31 | ���鹫˾ | Synthesis of temozolomide and analogs |
| CN101172104A (en) * | 2002-02-22 | 2008-05-07 | 先灵公司 | Processes of making and using pharmaceutical formulations of antineoplastic agents |
| CN1622814A (en) * | 2002-03-26 | 2005-06-01 | 万有制药株式会社 | Use of antitumor indolopyrrolocarbazole derivative and other anticancer agent in combination |
| CN1665507A (en) * | 2002-05-02 | 2005-09-07 | 克拉蒙特药品有限公司 | Therapeutic 1,2,3,6-tetrahydropyrimidine-2-one compositions and methods therewith |
| CN1615855A (en) * | 2004-09-29 | 2005-05-18 | 赵世光 | Temozolomide-polymer local slow release chemotherapy medicine for treating malignant brain tumor |
Non-Patent Citations (1)
| Title |
|---|
| 《肿瘤防治研究》 20100131 晏怡等 替莫唑胺治疗复发性胶质瘤的疗效分析 91-94 第37卷, 第01期 2 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2726996C1 (en) * | 2014-12-16 | 2020-07-17 | Бристол-Маерс Сквибб Компани | Use of inhibitors of immune control points in new growths of central nervous system |
| CN111132672A (en) * | 2017-09-20 | 2020-05-08 | 俄克拉荷马医学研究基金会 | Treatment of drug resistant glioma |
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| CN102178676B (en) | 2012-07-25 |
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