CN102120026A - 21(S) argatroban intravenous injection with alcohol as solubilizer - Google Patents
21(S) argatroban intravenous injection with alcohol as solubilizer Download PDFInfo
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- CN102120026A CN102120026A CN2011100514779A CN201110051477A CN102120026A CN 102120026 A CN102120026 A CN 102120026A CN 2011100514779 A CN2011100514779 A CN 2011100514779A CN 201110051477 A CN201110051477 A CN 201110051477A CN 102120026 A CN102120026 A CN 102120026A
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- argatroban
- alcohol
- intravenous fluid
- solubilizing agent
- intravenous injection
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Abstract
The invention discloses a 21(S) argatroban intravenous injection with alcohol as a solubilizer. In the intravenous injection, the alcohol is used for increasing the solubility of 21(S) argatroban, and an infusion property is enhanced by utilizing an osmosis regulator at the same time. Tests show that the intravenous injection can be effectively prevented from hydrolytic degradation and other chemical reactions, is stored stably under optical and thermal conditions, and can be preserved for at least 24 months at room temperature.
Description
Technical field
The invention belongs to field of medicaments, particularly relate to a kind of with the thrombin inhibitor of alcohol as solubilizing agent.
Background technology
Argatroban has been widely used in clinical as a kind of thrombin inhibitor, its chemical name be (2R, 4R)-4-methyl isophthalic acid-[N2-((R; S)-the 3-methyl isophthalic acid; 2,3,4-tetrahydrochysene-8-quinoline sulfonyl)-the L-arginyl-]-Pipecolic Acid-hydrate [141396-28-3].The argatroban of Shi Yonging is the mixture of 21 (S) and two diastereomers of 21 (R) clinically, and drug standard stipulates that both ratios are 65: 35 ± 2, and the chemical structural formula of this medicine is as follows:
X=CH
3, Y=H, 21 (S) argatroban
X=H, Y=CH
3, 21 (R) argatroban
Wherein the chemical name of 21 (S) argatroban be (2R, 4R)-4-methyl isophthalic acid-[N
2-[(S)-and the 3-methyl isophthalic acid, 2,3,4-tetrahydrochysene-8-quinoline sulfonyl]-the L-arginyl-]-Pipecolic Acid [121785-72-6].Prove that through preliminary zoopery the activity of 21 (S) argatroban Trombin inhibiting is 3-5 times of 21 (R) argatroban, and be higher than clinical activity with argatroban [CN101032485].Substitute the mixture of raceme or diastereomer as medicine with high activity single component optics live body, can improve curative effect, reduce consumption, to alleviate side effect to human body, this is a development trend of new drug development, and therefore 21 (S) argatroban is expected to be applied to clinical as a kind of new thrombin inhibitor.
Because the dissolubility of 21 (S) argatroban in water is less than 0.04mg/mL, therefore the solute classification according to American Pharmacopeia belongs to soluble,very slightly, and to illumination and thermoae instability, therefore, study the preparation of 21 (S) argatroban, and it successfully is used for clinical having very important significance.
Summary of the invention
In order to address the above problem, the object of the present invention is to provide a kind of dissolubility good, and under the light and heat condition stable storing with 21 (S) argatroban intravenous fluid of alcohol as solubilizing agent.
In order to achieve the above object, provided by the inventionly comprise 21 (S) argatroban and alcohols as 21 (S) argatroban intravenous fluid of solubilizing agent with alcohol; The amount ratio of argatroban and alcohols is 1-10mg: 0.5-1.0g; Alcohols is selected from least a in dehydrated alcohol, propylene glycol, glycerol and the D-sorbitol.
Describedly also comprise Osmolyte regulator as 21 (S) argatroban intravenous fluid of solubilizing agent with alcohol; The amount ratio of 21 (S) argatrobans and Osmolyte regulator is 1-10mg: 1-100g; Osmolyte regulator is selected from least a in sodium chloride, calcium chloride, potassium chloride, glucose and the lactose sodium.
Describedly also comprise sodium hydroxide or the phosphoric acid that is used to regulate pH as 21 (S) argatroban intravenous fluid of solubilizing agent with alcohol.
Provided by the invention is to utilize alcohol to increase the dissolubility of 21 (S) argatroban with alcohol as 21 (S) argatroban intravenous fluid of solubilizing agent, utilizes Osmolyte regulator to strengthen the infusion characteristic simultaneously.After tested, this intravenous fluid can be avoided hydrolytic degradation and other chemical reaction effectively, and under the light and heat condition stable storing, preserved under the room temperature at least 24 months.
The specific embodiment
Be elaborated with 21 (S) argatroban intravenous fluid of alcohol to provided by the invention below in conjunction with embodiment as solubilizing agent.
Embodiment 1
Embodiment 2
Embodiment 3
Embodiment 4
21 (s) argatroban 10mg
D-sorbitol 1.08g
Water for injection 20ml
To mix, filter and fill the equipment of usefulness and glass drying oven thoroughly washing and depyrogenation, with filter assemblies, fill pipe assembly and miscellaneous part and equipment sterilization.
The cold water for injection that in the scale mixing channel, adds final volume 80%.Add Osmolyte regulator in groove, agitating solution dissolves until Osmolyte regulator.Add the injection water to 90% of groove final volume, mix.After in another container, adding the required alcohol of 21 (s) argatroban and dissolving, add the water of 2L, to prepare the slurry solution of 21 (S) argatroban.Then this serosity is added in the above-mentioned mixing channel, and mix homogeneously.Then, if necessary,, in solution, add the injection water, mix to final volume with sodium hydroxide or the phosphoric acid regulator solution pH value to 5.5 of 1N.
The non-PVC flexible pouch of 250ml of then solution being packed into (Intra Via flexible plastic container; PL2408-3 non-PVC multi-layer plastic sheeting); have the blue top closure device (blue-tip closure) (drug delivery port protector) of a standard P L141PVC, these bags are sealed in the aluminium foil bag.The autoclave of then product being packed into, 20min sterilizes under 121 ℃ temperature.
Now 21 (s) argatroban injection of preparing in the foregoing description is carried out the accelerated degradation experiment, with the stability of prediction product in aqueous medium.This injection liquid samples placed respectively under 25 ℃, 40 ℃ and 55 ℃ of (lucifuge) temperature stored 6 months, measure its appearance character, pH, particulate matter and content then.Wherein the content of 21 (s) argatroban injection uses high phase liquid phase (HPLC) method to measure.Stability was best when by measurement result as can be known, the pH of this injection was in 5.0 ± 0.5 scope; In the time of 40 ℃, the total degradation product is less than 1% in the lay up period.Period of storage is no less than 24 months under 25 ℃ temperature.
In order further to verify the drug effect of 21 (S) provided by the invention argatroban intravenous fluid, the present patent application people adopts beasle dog to carry out pharmacodynamics test, to observe after 21 (s) argatroban intravenous fluid (S body) intravenous injection of preparing influence to dog blood coagulation index of correlation by the foregoing description, simultaneously with 21 (R) argatroban intravenous fluid (R body) of preparing under the same terms with blank sample as a comparison case, in the hope of screening effective ingredient, for clinical application provides reference.Experimentation is as follows:
Getting indexs such as hematometry whole blood clotting time (CT), recalcification time (RT), KPTT (APTT), prothrombin time (PT), thrombin time (TT), platelet adhesion rate, platelet aggregation rate before every animals administer is worth before as medicine, mensuration finishes, every treated animal gives corresponding drug solution by the 10ml/kg volume, once a day, for three days on end, get blood in 15 minutes after the administration in the 3rd day and survey above blood coagulation index of correlation.
The assay method of whole blood clotting time: get 3 in test tube, label is 1,2, No. 3.Successfully extract dog venous blood 3ml with disposable sterilized injector, flow into syringe needle from blood and pick up counting, go the every pipe of syringe needle tailing edge tube wall slowly to inject blood 1ml, put in 37 ℃ of water-baths.At regular intervals first pipe is tilted 1 time, till test tube being inverted blood and not being flowed; Observe second pipe more successively, after second pipe solidifies, observe tee pipe again.With the tee pipe setting time is clotting time.
The recalcification time method: get sodium citrate anticoagulation 1ml, centrifuging and taking blood plasma 0.2ml, the calcium chloride solution 0.2ml of adding 0.025mol/L, mixing is placed on 37 ℃ of water-baths, from adding the calcium timing, is recalcification time until the time of solidifying.
Instrument measuring is adopted in other test.
Data statistics and result judge:
Each index is with mean ± standard deviation before every treated animal medicine and behind the medicine
Expression.Behind each medicine group medicine behind changing value and the blank group medicine changing value carry out t check, to judge the effect of medicine.1, the argatroban intravenous fluid to the influence of normal dogs whole blood clotting time (CT) (
N=6)
* compare with the blank group P＜0.05 * * P＜0.01
Contrast normal control group, S body and R body all can obviously prolong whole blood clotting time (CT), and wherein the action effect of S body is about the twice of R body.
2, the argatroban intravenous fluid to the influence of normal dogs recalcification time (RT) (
N=6)
* compare with the blank group P＜0.05 * * P＜0.01
Contrast normal control group, S body and R body all can obviously prolong recalcification time (RT), and wherein the action effect of S body is about three times of R body.
3, the argatroban intravenous fluid to the influence of normal dogs platelet adhesion rate (
N=6)
Compare with the blank group P＞0.05
R body and S body all have certain reduction effect to platelet adhesion rate, but compare there was no significant difference (P＞0.05) with the blank group.
4, the argatroban intravenous fluid to the influence of normal dogs platelet aggregation rate (
N=6)
Compare with the blank group P＞0.05
R body and S body all have certain reduction effect to platelet aggregation rate, but compare there was no significant difference (P＞0.05) with the blank group.
5, the argatroban intravenous fluid to the influence of normal dogs prothrombin time (PT) (
N=6)
* compare with the blank group P＜0.05 * * P＜0.01
The S physical ability obviously prolongs dog prothrombin time (PT), compares with the blank group, and significant difference (P＜0.05 or P＜0.01) is arranged; The R body also has certain effect, but compares there was no significant difference (P＞0.05) with matched group.The action effect of S body is about the twice of R body.
6, the argatroban intravenous fluid to the influence of normal dogs thrombin time (TT) (
N=6)
* compare with the blank group P＜0.05 * * P＜0.01
R body and S body all can both obviously prolong dog thrombin time (TT), compare with the blank group, and significant difference (P＜0.01) is arranged, and wherein the action effect of S body slightly is better than the R body.
7, the argatroban intravenous fluid to the influence of normal dogs KPTT (APTT) (
N=6)
* compare with the blank group P＜0.05 * * P＜0.01
The S physical ability obviously prolongs dog KPTT (APTT), compares with the blank group, and significant difference (P＜0.05) is arranged; The R body also has certain effect, but compares there was no significant difference (P＞0.05) with matched group.The action effect of S body is about the twice of R body.
Conclusion:
Above result of the test shows: argatroban S body and R body all can obviously prolong dog whole blood clotting time (CT), recalcification time (RT) and thrombin time (TT); The S physical ability obviously prolongs dog prothrombin time (PT) and KPTT (APTT), and the R body is not obvious to prolonging the effect of prothrombin time (PT) and KPTT (APTT); S body and R body also have certain effect to reduction platelet adhesion rate, platelet aggregation rate.Overall merit, the S body all has tangible effect to each coagulation indexes of dog, and the R body is only obvious to the effect of part coagulation indexes, the blood coagulation resisting function of S body is about 2-3 times of R body.
Claims (3)
1. one kind with 21 (S) argatroban intravenous fluid of alcohol as solubilizing agent, and it is characterized in that: described intravenous fluid comprises 21 (S) argatroban and alcohols; The amount ratio of 21 (S) argatrobans and alcohols is 1-10mg: 0.5-1.0g; Alcohols is selected from least a in dehydrated alcohol, propylene glycol, glycerol and the D-sorbitol.
2. according to claim 1 with 21 (S) argatroban intravenous fluid of alcohol as solubilizing agent, it is characterized in that: describedly also comprise Osmolyte regulator as 21 (S) argatroban intravenous fluid of solubilizing agent with alcohol; The amount ratio of 21 (S) argatrobans and Osmolyte regulator is 1-10mg: 1-100g; Osmolyte regulator is selected from least a in sodium chloride, calcium chloride, potassium chloride, glucose and the lactose sodium.
3. according to claim 1 with 21 (S) argatroban intravenous fluid of alcohol as solubilizing agent, it is characterized in that: describedly also comprise sodium hydroxide or the phosphoric acid that is used to regulate pH as 21 (S) argatroban intravenous fluid of solubilizing agent with alcohol.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100514779A CN102120026A (en) | 2011-03-03 | 2011-03-03 | 21(S) argatroban intravenous injection with alcohol as solubilizer |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011100514779A CN102120026A (en) | 2011-03-03 | 2011-03-03 | 21(S) argatroban intravenous injection with alcohol as solubilizer |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102784382A (en) * | 2012-09-05 | 2012-11-21 | 江苏奥赛康药业股份有限公司 | Argatroban drug composition and preparation method and application of argatroban drug composition |
| CN103070822A (en) * | 2011-10-26 | 2013-05-01 | 山东新时代药业有限公司 | Argatroban injection and preparation method thereof |
| CN103432066A (en) * | 2013-07-23 | 2013-12-11 | 蚌埠丰原涂山制药有限公司 | Compound mannitol injection and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5214052A (en) * | 1987-07-28 | 1993-05-25 | Mitsubishi Kasei Corporation | Method for dissolving arginineamides and pharmaceutical compositions containing them |
| CN1761661A (en) * | 2003-03-20 | 2006-04-19 | 三菱制药株式会社 | Pharmaceutical preparations containing arginine amides |
| CN101032485A (en) * | 2007-04-13 | 2007-09-12 | 天津市炜杰科技有限公司 | Application of 21(S) argatroban |
| CN101257890A (en) * | 2005-09-01 | 2008-09-03 | 巴克斯特国际公司 | Argatroban formulation comprising an acid as solubilizer |
-
2011
- 2011-03-03 CN CN2011100514779A patent/CN102120026A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5214052A (en) * | 1987-07-28 | 1993-05-25 | Mitsubishi Kasei Corporation | Method for dissolving arginineamides and pharmaceutical compositions containing them |
| CN1761661A (en) * | 2003-03-20 | 2006-04-19 | 三菱制药株式会社 | Pharmaceutical preparations containing arginine amides |
| CN101257890A (en) * | 2005-09-01 | 2008-09-03 | 巴克斯特国际公司 | Argatroban formulation comprising an acid as solubilizer |
| CN101032485A (en) * | 2007-04-13 | 2007-09-12 | 天津市炜杰科技有限公司 | Application of 21(S) argatroban |
Non-Patent Citations (1)
| Title |
|---|
| 毕殿洲: "《药剂学》", 30 April 2000 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103070822A (en) * | 2011-10-26 | 2013-05-01 | 山东新时代药业有限公司 | Argatroban injection and preparation method thereof |
| CN103070822B (en) * | 2011-10-26 | 2016-01-27 | 山东新时代药业有限公司 | A kind of Argatroban injection and preparation method thereof |
| CN102784382A (en) * | 2012-09-05 | 2012-11-21 | 江苏奥赛康药业股份有限公司 | Argatroban drug composition and preparation method and application of argatroban drug composition |
| CN102784382B (en) * | 2012-09-05 | 2014-02-19 | 江苏奥赛康药业股份有限公司 | Argatroban drug composition and preparation method and application of argatroban drug composition |
| CN103432066A (en) * | 2013-07-23 | 2013-12-11 | 蚌埠丰原涂山制药有限公司 | Compound mannitol injection and preparation method thereof |
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Application publication date: 20110713 |