CN102512360B - Torasemide pharmaceutical composition with stabilization and safety for injection - Google Patents
Torasemide pharmaceutical composition with stabilization and safety for injection Download PDFInfo
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- CN102512360B CN102512360B CN201110408358.4A CN201110408358A CN102512360B CN 102512360 B CN102512360 B CN 102512360B CN 201110408358 A CN201110408358 A CN 201110408358A CN 102512360 B CN102512360 B CN 102512360B
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Abstract
The invention relates to a torasemide pharmaceutical composition with stabilization and safety for injection and its preparation method, especially relates to the torasemide pharmaceutical composition used for patients with requirement of rapid diuresis or congestive cardiac failure without oral diuresis, cirrhosis ascites, oedema caused by kidney diseases, the torasemide pharmaceutical composition is an injection preferably. The pharmaceutical composition is composed of active component torasemide, ethanol and polysorbate 80. The torasemide pharmaceutical composition for injection possesses stable pH value and low impurity content, and is capable of effectively raising the treatment effect of the products, minimizing the side reaction, raising the yield, reducing the cost and creating higher benefit.
Description
Technical field
The invention belongs to medical technical field, be specifically related to injection torasemide pharmaceutical composition of stability and safety and preparation method thereof.
Background technology
Hypertension is one of clinical frequently-occurring disease, how with multiple cardiovascular risk factors.China once carried out 3 large-scale Hypertensive Population sampling survey, and the last 2002, China's more than 18 years old prevalence of hypertension rate was 18.8%, and is obviously rising trend, estimated that the existing hyperpietic of China exceedes 1.6 hundred million.
Diuretic is by natriuretic diuretic, and the content of sodium and water in minimizing body-internal-circulation, makes blood volume decline and reduce blood pressure.According to its not same-action feature can be divided into thiazide, medullary loop diuretic and isokalaemic diuretic.The hypotensive effect gentleness of diuretic, have no drug resistance and cheap, Chang Zuowei basis medicine and other multiple antihypertensive drugs use in conjunction, be used for the treatment of light, moderate hypertension, is specially adapted to the patients with hypertension of old people, merging heart failure.
Torasemide is nearly first loop diuretic of approval during the last ten years of FDA, several national list marketings in the world 40 at present.Due to its powerful diuresis, less side effect, is widely used in clinical.Along with hypertensive sickness rate raises year by year, the sales volume of torasemide also will increase year by year.China at present mainly with torasemide injection for wanting dosage form, only two of SFDA approval torasemide injections, competitive pressure is relatively less.Good market prospect.
Common name: torasemide;
English name:
torsemide;
Its structural formula is as follows:
Relative molecular mass: 348.43;
Molecular formula: C
16h
20n
4o
3s;
Chemical name: 1-isopropyl-3-［ (toluidino-3-pyridine radicals between 4-) sulfonyl ］ urea;
Indication: be applicable to need the edema patient due to rapid diuresis or congestive heart failure that can not oral diuresis, cirrhotic ascites, kidney disease.
Mechanism of action: this product is sulfonylureas pyridines diuretic, and it acts on Heng Lishi ascending thick limb of Henle's loop, suppresses Na+/K+/2CL-carrier system, make Na+ in urine, the excretion of CL-and water increases, but to glomerular filtration rate, in renal plasma flow or body, acid-base balance does not make significant difference.
Usage and dosage: the edema due to congestive heart failure, cirrhotic ascites: general predose is 5mg or 10mg, once a day, slowly intravenous injection, also can inject with 5% glucose solution or the laggard row vein of normal saline dilution; Can increase dosage to 20mg as curative effect is dissatisfied, once a day, every day, maximal dose was 40mg, was no more than one week the course for the treatment of.
Torasemide has following characteristics:
(1) diuresis is strong: action intensity is at least 2 times of FRUSEMIDE.
(2) antihypertensive function is strong: hypotensive effect is stronger than hydrochlorothiazide, suitable with indopamide, and side effect is less than indopamide.
(3) acting duration is long: this product only needs day clothes once.
(4) oral administration biaavailability is high, can reach 76～92%, is about 2 times of furosemide.Oral almost identical with parenterai administration curative effect.
(5) better tolerance, toxicity incidence rate is low, and a little less than the effect of row's potassium, the unlikely hypokalemia of life-time service, without liver, nephrotoxicity.
(6) this product clinical practice is extensive, and market and consumption are large.
The invention of patent 200610039693.0 relates to field of pharmaceutical preparations, is specifically related to a kind of torasemide freeze-drying preparation and preparation method.Effectively increased the water solublity of torasemide by adding sodium bicarbonate.Torasemide freeze-drying preparation of the present invention, steady quality, storage ability is good, and freeze-dried composition while dissolving again solution clarity high, dissolve rapidly, be applicable to clinical use.
The invention of patent 200710019868.6 provides a kind of injection take torasemide as active ingredient and the preparation method of this injection.Torasemide injection stability of the present invention has had significantly raising compared to existing technology.Said preparation contains solubilizing agent and stabilizing agent, and the pH value of solution is more than or equal to 9.0.Its preparation method is: measure a certain amount of water for injection, add after the solubilizing agent that accounts for raw material gross weight 1%-50%, add torasemide by preparation conventional amount used, to be dissolved completely after, add the stabilizing agent that accounts for raw material gross weight 0.1-5%, moisturizing is to full dose, stir, add active carbon high-temp absorption 30 minutes, decarburization is filtered, and adds medicinal basic, regulate pH value to be more than or equal to 9.0, aseptic filtration, through intermediate fill after the assay was approved, sterilizing, packing warehouse-in.Said preparation good stability, the dosing time is short, and production cost is low, and the injection making is without hemolytic, blood vessel irritation and anaphylaxis, related substance growth rate is also slower simultaneously.
Routine is prepared torasemide's pharmaceutical composition of injection, maximum deficiency, sterilising conditions is non-excessive sterilizing, do not reach 121 ℃ 15 minutes, related substance is higher, of poor quality, in storage, storage condition is required highly, needs cool dark place to preserve.
The injection torasemide pharmaceutical composition that the present invention obtains on the basis of great many of experiments, has advantages of: safe, maximum contaminant is less than 5 ‰; Good stability, though room temperature preservation, reliable in quality.
Summary of the invention
In order to overcome the above-mentioned defect of prior art, a kind of stable torasemide's injection is provided, and the inventor has passed through further investigation, is surprisingly found out that, select specific adjuvant (polyoxyethylene sorbitan monoleate), can obtain torasemide's injection of good stability, effective and safe.
Therefore, an object of the present invention is to provide that a kind of formulation and technology is simple, the injection torasemide pharmaceutical composition of good stability, effective and safe, this pharmaceutical composition contains torasemide, polyoxyethylene sorbitan monoleate.Torasemide of the present invention pharmaceutical composition, the pharmaceutical preparation that is applicable to drug administration by injection, be preferably injection, and in the time that this injection is injection, its by torasemide, polyoxyethylene sorbitan monoleate, that other pharmaceutic adjuvant (such as ethanol etc.) injects water is formulated.
Another object of the present invention is to provide one and is convenient to industrialized mass, the preparation method of the simple torasemide of technique pharmaceutical composition.
Torasemide of the present invention pharmaceutical composition, wherein the prescription of compositions consists of: torasemide, ethanol, polyoxyethylene sorbitan monoleate and water for injection.
The 5-50g of torasemide
Ethanol 0.1-2.5L
Polyoxyethylene sorbitan monoleate 1-10g
Water for injection adds to 1L-5L
Make 1000
The prescription of injection is preferably: torasemide, ethanol, polyoxyethylene sorbitan monoleate and water for injection, and the weight ratio of each component is: torasemide: ethanol: polyoxyethylene sorbitan monoleate: water=5-50:100-2500:1-10:1000-5000, preferably aforementioned proportion is: 10-50:500-2500:1-5:1000-5000.
Preferred preparation method is:
In clean area, first the polyoxyethylene sorbitan monoleate of recipe quantity is added in appropriate 70-90 ℃ water for injection, stirring and dissolving, cooling, add the ethanol of recipe quantity, add again the torasemide of recipe quantity, be stirred to and dissolve completely, regulate pH value to 7.0-8.0, get the 0.1%-0.5%(W/V that accounts for solution total amount) active carbon add appropriate water for injection and stir evenly, benefit injects water to entirely bright, agitation cycle is more than 15 minutes, the de-charcoal of first coarse filtration, for example, by microporous filter membrane (0.22um filter membrane) fine straining, after microporous filter membrane fine straining, can get fine straining liquid and carry out content, pH value, endotoxin, the projects such as visible foreign matters detect, qualified rear inflated with nitrogen, embedding, more than 121 ℃ pressure sterilizing 15 minutes, lamp inspection, obtain.
In torasemide freeze-drying injectable powder of the present invention, contain active component torasemide and adjuvant ethanol, polyoxyethylene sorbitan monoleate.
Torasemide of the present invention pharmaceutical composition dosage range is: 5-100mg/ props up, and is preferably 10-50mg/ and props up.
Active component torasemide in prescription is easily molten in water, so while making injection, in research process, find, in neutral solution, torasemide is unstable, in put procedure, easily related substance increases, the easy flavescence of solution colour, the quality of medicine and the safety of clinical practice are affected, find through lot of experiments research, add polyoxyethylene sorbitan monoleate available buffer pH value to play Stabilization to Pharmaceutical, not only having solved related substance in the storage of injection exceeds standard, the problem of solution changes color, also solved freeze-dried powder related substance in storage increases simultaneously, guarantee the quality of medicine and stablized.
the specific embodiment:
Below in conjunction with embodiment, the present invention is described further, makes professional and technical personnel in the field better understand the present invention.Embodiment is only indicative, never means that it limits the scope of the invention by any way.
Torasemide's injection of the present invention and prior art contrasts, and according to torasemide's injection pertinent literature and the disclosed prescription of package insert, prepares corresponding torasemide injection, as a comparison case.
embodiment 1
The 50g of torasemide
Ethanol 2.5L
Polyoxyethylene sorbitan monoleate 10g
Water for injection 5L
Make 1000
Preparation method is:
In clean area, first the polyoxyethylene sorbitan monoleate of recipe quantity is added in appropriate 70-90 ℃ water for injection, stirring and dissolving, cooling, add the ethanol of recipe quantity, add again the torasemide of recipe quantity, be stirred to and dissolve completely, regulate pH value to 7.0-8.0, get the 0.1%-0.5%(W/V that accounts for solution total amount) active carbon add appropriate water for injection and stir evenly, benefit injects water to entirely bright, agitation cycle is more than 15 minutes, the de-charcoal of first coarse filtration, for example, by microporous filter membrane (0.22um filter membrane) fine straining, after microporous filter membrane fine straining, can get fine straining liquid and carry out content, pH value, endotoxin, the projects such as visible foreign matters detect, qualified rear inflated with nitrogen, embedding, more than 121 ℃ pressure sterilizing 15 minutes, lamp inspection, obtain.
embodiment 2
The 20g of torasemide
Ethanol 1L
Polyoxyethylene sorbitan monoleate 4g
Water for injection 2L
Make 1000
Preparation method is:
In clean area, first the polyoxyethylene sorbitan monoleate of recipe quantity is added in appropriate 70-90 ℃ water for injection, stirring and dissolving, cooling, add the ethanol of recipe quantity, add again the torasemide of recipe quantity, be stirred to and dissolve completely, regulate pH value to 7.0-8.0, get the 0.1%-0.5%(W/V that accounts for solution total amount) active carbon add appropriate water for injection and stir evenly, benefit injects water to entirely bright, agitation cycle is more than 15 minutes, the de-charcoal of first coarse filtration, for example, by microporous filter membrane (0.22um filter membrane) fine straining, after microporous filter membrane fine straining, can get fine straining liquid and carry out content, pH value, endotoxin, the projects such as visible foreign matters detect, qualified rear inflated with nitrogen, embedding, more than 121 ℃ pressure sterilizing 15 minutes, lamp inspection, obtain.
embodiment 3
The 10g of torasemide
Ethanol 0.5L
Polyoxyethylene sorbitan monoleate 2g
Water for injection 1L
Make 1000
Preparation method is:
In clean area, first the polyoxyethylene sorbitan monoleate of recipe quantity is added in appropriate 70-90 ℃ water for injection, stirring and dissolving, cooling, add the ethanol of recipe quantity, add again the torasemide of recipe quantity, be stirred to and dissolve completely, regulate pH value to 7.0-8.0, get the 0.1%-0.5%(W/V that accounts for solution total amount) active carbon add appropriate water for injection and stir evenly, benefit injects water to entirely bright, agitation cycle is more than 15 minutes, the de-charcoal of first coarse filtration, for example, by microporous filter membrane (0.22um filter membrane) fine straining, after microporous filter membrane fine straining, can get fine straining liquid and carry out content, pH value, endotoxin, the projects such as visible foreign matters detect, qualified rear inflated with nitrogen, embedding, more than 121 ℃ pressure sterilizing 15 minutes, lamp inspection, obtain.
embodiment 4
The 10g of torasemide
Ethanol 0.5L
Polyoxyethylene sorbitan monoleate 2g
Water for injection 2L
Make 1000
Preparation method is:
In clean area, first the polyoxyethylene sorbitan monoleate of recipe quantity is added in appropriate 70-90 ℃ water for injection, stirring and dissolving, cooling, add the ethanol of recipe quantity, add again the torasemide of recipe quantity, be stirred to and dissolve completely, regulate pH value to 7.0-8.0, get the 0.1%-0.5%(W/V that accounts for solution total amount) active carbon add appropriate water for injection and stir evenly, benefit injects water to entirely bright, agitation cycle is more than 15 minutes, the de-charcoal of first coarse filtration, for example, by microporous filter membrane (0.22um filter membrane) fine straining, after microporous filter membrane fine straining, can get fine straining liquid and carry out content, pH value, endotoxin, the projects such as visible foreign matters detect, qualified rear inflated with nitrogen, embedding, more than 121 ℃ pressure sterilizing 15 minutes, lamp inspection, obtain.
comparative example 1
200710019868.6 prescription 1
Prescription 1
The 20g of torasemide
Trometamol 2g
Sodium hydroxide 2g
Polyethylene Glycol 100g
Water for injection adds to 1000ml
Preparation technology: measure a certain amount of water for injection, add torasemide after adding solubilizing agent, to be dissolvedly add stabilizing agent after completely, moisturizing is to entirely bright, stir, add active carbon high-temp absorption 30 minutes, decarbonization filtering, adding is used as medicine alkali (sodium hydroxide, sodium-acetate buffer), regulate pH to 9.5 aseptic filtration, through intermediate fill after the assay was approved, sterilizing, packing warehouse-in.
test example 1
Torasemide injection key index prepared by the embodiment of the present invention and comparative example: character, pH value, visible foreign matters, clarity, related substance and content etc. are tested, and the results are shown in Table 1.
Result of the test shows that torasemide of the present invention pharmaceutical composition quality is better than comparative example.
test example 2
Test according to 2010 editions two appendix XIXC stability test guidelines of Chinese Pharmacopoeia, key index to embodiment and comparative example: character, acidity (pH), visible foreign matters, clarity, related substance and content are tested, and testing result is in table 2,3.
Influence factor's high temperature (temperature 60 C ± 2 ℃) illumination (illumination 4500 ± 500LX) result of the test is in table 2.
Sample thief, accelerate (temperature is under 40 ℃ ± 2 ℃, the relative humidity condition that is 75% ± 5%) 6 months and long-term (temperature is under 25 ℃ ± 2 ℃, the relative humidity condition that is 60% ± 10%) experimental study in 24 months by paid packing, detect according to table 3 point in time sampling, result is as follows.
Every key index is without significant change in influence factor, acceleration, long term test for product prepared by the present invention, and especially clarity and visible foreign matters item are better than comparative example, quality assurance, good stability.
test example 3
The specific safety test of torasemide's injection that preparation method of the present invention obtains
Hemolytic test
Torasemide injection 0.1mg/ml of the present invention, without obvious haemolysis, meets the requirement of intravenous injection medication security inspection.Show that concentration is that the torasemide injection of 0.1mg/ml has no haemolysis and agglutination, its result intravenous injection medication vascular stimulation tests meets security requirement.
The injection torasemide pharmaceutical composition pH value that the present invention obtains is stable, and impurity content is low, has effectively improved the therapeutic effect of product, has reduced side reaction; Improve yield simultaneously, reduced cost, created higher benefit.
Claims (2)
1. torasemide's pharmaceutical composition of injection, is characterized in that said composition is injection, and wherein in injection, each component is: torasemide, ethanol, polyoxyethylene sorbitan monoleate and water for injection, and the formula of making 1000 is composed as follows:
The 5-50g of torasemide
Ethanol 0.1-2.5L
Polyoxyethylene sorbitan monoleate 1-10g
Water for injection adds to 1L-5L.
2. the preparation method of torasemide according to claim 1 pharmaceutical composition, wherein the preparation method of injection comprises the following steps:
In clean area, first the polyoxyethylene sorbitan monoleate of recipe quantity is added in appropriate 70-90 ℃ water for injection, stirring and dissolving, cooling, add the ethanol of recipe quantity, add again the torasemide of recipe quantity, be stirred to and dissolve completely, regulate pH value to 7.0-8.0, get the 0.1%-0.5%(W/V that accounts for solution total amount) active carbon add appropriate water for injection and stir evenly, benefit adds to the full amount of water for injection, agitation cycle is more than 15 minutes, the de-charcoal of first coarse filtration, by 0.22 μ m microporous filter membrane fine straining, after microporous filter membrane fine straining, can get fine straining liquid and carry out content, pH value, endotoxin, visible foreign matters project detects, qualified rear inflated with nitrogen, embedding, more than 121 ℃ pressure sterilizing 15 minutes, lamp inspection, obtain.
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| CN109200022B (en) * | 2017-06-29 | 2021-09-10 | 南京优科生物医药研究有限公司 | Torasemide for injection and preparation process thereof |
| FR3077984B1 (en) * | 2018-02-16 | 2020-02-21 | Vetoquinol Sa | MULTI-PURPOSE COMPOSITION OF TORASEMIDE |
| CN112168776B (en) * | 2020-10-30 | 2022-05-03 | 康普药业股份有限公司 | Low-impurity high-stability torasemide injection and preparation method thereof |
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| CN100372534C (en) * | 2006-04-20 | 2008-03-05 | 南京海辰药业有限公司 | Torasemide freeze-drying preparation and prepn. method |
| CN1872032A (en) * | 2006-06-30 | 2006-12-06 | 宛六一 | Torasemide soft capsule, and preparation method |
| CN101007003A (en) * | 2007-02-01 | 2007-08-01 | 扬子江药业集团南京海陵药业有限公司 | A stable torasemide injection and its preparation method |
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