CN102119922A - 21(S) Argatroban intravenous injection taking acid as solubilizer - Google Patents
21(S) Argatroban intravenous injection taking acid as solubilizer Download PDFInfo
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- CN102119922A CN102119922A CN 201110051362 CN201110051362A CN102119922A CN 102119922 A CN102119922 A CN 102119922A CN 201110051362 CN201110051362 CN 201110051362 CN 201110051362 A CN201110051362 A CN 201110051362A CN 102119922 A CN102119922 A CN 102119922A
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- acid
- argatroban
- intravenous fluid
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Abstract
The invention discloses 21(S) Argatroban intravenous injection taking acid as a solubilizer. The acid is used for increasing the dissolubility of 21(S) Argatroban, a buffering agent is used for maintaining pH and a penetration regulator is used for enhancing the infusion characteristic. According to tests, the intravenous injection can be effectively prevented from being subjected to hydrolytic degradation and other chemical reactions, is stable in storage under the conditions of light and heat, and can be stored 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 acid 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 acid as solubilizing agent.
In order to achieve the above object, provided by the inventionly comprise 21 (S) argatrobans and organic or inorganic acid as 21 (S) argatroban intravenous fluid of solubilizing agent with acid; The amount ratio of argatroban and organic or inorganic acid is 0.1-10g: 0.5-50g; Organic or inorganic acid is selected from least a in acetic acid, phosphoric acid, tartaric acid, citric acid, formic acid, hydrochloric acid, maleic acid, nitric acid, sulphuric acid and the malic acid.
Describedly also comprise buffer agent with acid as 21 (S) argatroban intravenous fluid of solubilizing agent, the amount ratio of 21 (S) argatrobans and buffer agent is 0.1-10g: 0.05-200mg; Buffer agent is selected from least a in acetate, tartrate, benzoate, gluconate, phosphate, glutamate, Glu, citrate, lactate, glycine and the malate.
Described buffer agent is the sodium salt of acetic acid, tartaric acid, benzoic acid, gluconic acid, phosphoric acid, glutamic acid, citric acid, lactic acid, sweet ammonia and malic acid.
Describedly also comprise Osmolyte regulator with acid as 21 (S) argatroban intravenous fluid of solubilizing agent, the amount ratio of 21 (S) argatrobans and Osmolyte regulator is 0.1-10g: 1-100g; Osmolyte regulator is selected from least a in sodium chloride, calcium chloride, potassium chloride, glucose, coenzyme Q10 sodium chloride and the sodium lactate.
Describedly also comprise sodium hydroxide or the acid that is used to regulate pH as 21 (S) argatroban intravenous fluid of solubilizing agent with acid.
Provided by the invention is to utilize acid to increase the dissolubility of 21 (S) argatroban with acid as 21 (S) argatroban intravenous fluid of solubilizing agent, utilizes buffer agent to keep pH, 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 acid to provided by the invention below in conjunction with specific embodiment as solubilizing agent.
Embodiment 1
21 (s) argatroban 10mg
Hydrochloric acid, USP 0.33mg
NaCl, USP Osmolyte regulator 0.6g
Hydrochloric acid or NaOH regulate pH as required
Water for injection, USP is an amount of
Embodiment 2
21 (s) argatroban 10mg
Phosphoric acid, USP 0.33mg
Sodium phosphate, buffer agent 2.8mg
Phosphoric acid or NaOH regulate pH as required
Water for injection, USP is an amount of
Embodiment 3
21 (s) argatroban 10mg
Citric acid, USP 0.33mg
Sodium citrate, buffer agent 1.8mg
Acetic acid or NaOH regulate pH as required
Water for injection, USP is an amount of
Embodiment 4
21 (s) argatroban 10mg
Tartaric acid, USP 0.33mg
Sodium tartrate, buffer agent 0.6mg
Tartaric acid or NaOH regulate pH as required
Water for injection, USP is an amount of
Embodiment 5
21 (s) argatroban 10mg
Phosphoric acid, USP 0.33mg
Sodium phosphate, USP 2.8mg
Glucose, USP Osmolyte regulator 50mg
Phosphoric acid or NaOH regulate pH as required
Water for injection, USP is an amount of
Embodiment 6
21 (s) argatroban 10mg
Phosphoric acid, USP 0.33mg
Sodium phosphate 2.8mg
NaCl, USP Osmolyte regulator 0.6mg
Phosphoric acid or NaOH regulate pH as required
Water for injection, USP is an amount of
Embodiment 7
21 (s) argatroban 20mg
Phosphoric acid, USP 0.33mg
Sodium phosphate 2.8mg
NaCl, USP Osmolyte regulator 0.6mg
Phosphoric acid or NaOH regulate pH as required
Water for injection, USP is an amount of
Preparation method:
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.In groove, add buffer agent then, stir until whole dissolvings.Add the injection water to 90% of groove final volume, mix.In another container, add 21 (s) argatroban, after with required acid it being dissolved, 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,, add the injection water to final volume, mix in solution state 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 is at 121 ℃ of sterilization 20min.
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 ℃, the temperature of 40 ℃ and 55 ℃ (lucifuge) 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:
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 (5)
1. one kind with 21 (S) argatroban intravenous fluid of acid as solubilizing agent, and it is characterized in that: described intravenous fluid comprises 21 (S) argatrobans and organic or inorganic acid; The amount ratio of argatroban and organic or inorganic acid is 0.1-10g: 0.5-50g; Organic or inorganic acid is selected from least a in acetic acid, phosphoric acid, tartaric acid, citric acid, formic acid, hydrochloric acid, maleic acid, nitric acid, sulphuric acid and the malic acid.
2. according to claim 1 it is characterized in that: described intravenous fluid also comprises buffer agent with 21 (S) argatroban intravenous fluid of acid as solubilizing agent, and the amount ratio of 21 (S) argatrobans and buffer agent is 0.1-10g: 0.05-200mg; Buffer agent is selected from least a in acetate, tartrate, benzoate, gluconate, phosphate, glutamate, Glu, citrate, lactate, glycine and the malate.
3. according to claim 2 with 21 (S) argatroban intravenous fluid of acid as solubilizing agent, it is characterized in that: described buffer agent is the sodium salt of acetic acid, tartaric acid, benzoic acid, gluconic acid, phosphoric acid, glutamic acid, citric acid, lactic acid, sweet ammonia and malic acid.
4. according to claim 1 with 21 (S) argatroban intravenous fluid of acid as solubilizing agent, it is characterized in that: described intravenous fluid also comprises Osmolyte regulator, and the amount ratio of 21 (S) argatrobans and Osmolyte regulator is 0.1-10g: 1-100g; Osmolyte regulator is selected from least a in sodium chloride, calcium chloride, potassium chloride, glucose, coenzyme Q10 sodium chloride and the sodium lactate.
5. according to claim 1 with 21 (S) argatroban intravenous fluid of acid as solubilizing agent, it is characterized in that: described intravenous fluid also comprises sodium hydroxide or the acid that is used to regulate pH.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110051362 CN102119922A (en) | 2011-03-03 | 2011-03-03 | 21(S) Argatroban intravenous injection taking acid as solubilizer |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110051362 CN102119922A (en) | 2011-03-03 | 2011-03-03 | 21(S) Argatroban intravenous injection taking acid as solubilizer |
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|---|---|
| CN102119922A true CN102119922A (en) | 2011-07-13 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN 201110051362 Pending CN102119922A (en) | 2011-03-03 | 2011-03-03 | 21(S) Argatroban intravenous injection taking acid as solubilizer |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107823131A (en) * | 2011-10-19 | 2018-03-23 | 大塚制药株式会社 | For oral solution |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 CN 201110051362 patent/CN102119922A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107823131A (en) * | 2011-10-19 | 2018-03-23 | 大塚制药株式会社 | For oral solution |
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Application publication date: 20110713 |