CN100386079C - Injection use-powder ampoule for inhibiting thrombocyte agglutination and its preparation method - Google Patents
Injection use-powder ampoule for inhibiting thrombocyte agglutination and its preparation method Download PDFInfo
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- CN100386079C CN100386079C CNB2005100184400A CN200510018440A CN100386079C CN 100386079 C CN100386079 C CN 100386079C CN B2005100184400 A CNB2005100184400 A CN B2005100184400A CN 200510018440 A CN200510018440 A CN 200510018440A CN 100386079 C CN100386079 C CN 100386079C
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Abstract
The present invention relates to a powder ampoule for injection for inhibiting thrombocyte agglutination and a preparation method thereof. The powder ampoule comprises the components of lactose, mannitol, cane sugar, dextrose, low molecular dextran, hydrolyzed gelatin and sodium chloride which are drug acceptable carriers. Tirofiban hydrochloride monohydrate and the selected drug acceptable carriers are weighed according to a formula. 1950 ml of water for injection is added until the water is up to about the full dose. An intermediate body is measured. After the content is qualified, the water is added to a specified amount. 0.45 um of microporous filtering film is used for filtering until the clarity is qualified. The powder ampoule is split and filled into tube type antibiotic bottles, the vacuum degree is maintained at 30 to 35Pa, and the frozen drying is carried out for 24 hours. By experimental verification, the stability index of the formula is superior to a formula using a citrate buffer solution, and the security of drug intravenous injection can be increased.
Description
Technical field
The present invention relates to a kind of injection powder pin that suppresses platelet aggregation and preparation method thereof.
Background technology
Tirofiban hydrochloride (English name: Tirofiban hydrochloride, chemical name: (S)-N-(normal-butyl sulfonyl)-O-[4-(4-piperidyl) butane]-L-tyrosine hydrochloride monohydrate) be the salt compounds of platelet suppressant drug.Tirofiban hydrochloride inhibition fibrinogen combines with platelet and combines the inhibition platelet aggregation with glycoprotein (GP) IIb/IIIa fibrinogen deceptor site by fibrinogen receptor anlagonists.The Chinese patent publication number 1200676A of U.S. Merck ﹠ Co., Inc has described the pharmaceutical composition of this chemical compound, this patent has been described the use citrate buffer agent and has been better than phosphate buffer, the citrate composition stable that contains tirofiban hydrochloride reached more than 18 months, was the granule of visible particle diameter greater than 50um and use phosphate buffer in the solution after storing 24 months.
We think that the injection that uses citrate buffer agent is used for intravenous injection and exists following shortcoming: citrate buffer agent is still a kind of material that is easier to produce particulate matter.
Summary of the invention
Purpose of the present invention is in order to overcome the defective that above-mentioned prior art exists, a kind of tirofiban hydrochloride preparation of more stable inhibition platelet aggregation is provided, said preparation is an injection powder pin, and the stability of injection powder pin is better than using the stability of the injection of citrate buffer agent.And the powder pin provides another administering mode and pharmaceutical dosage form, can be applicable to the drug administration by injection of the tirofiban hydrochloride of variable concentrations clinically, can satisfy the clinician and formulate the corresponding treatment scheme at different clinical settings.
The invention provides a kind of tirofiban hydrochloride injection powder pin, this powder pin by the active ingredient hydrochloric acid tirofiban, also can be tirofiban hydrochloride by active component and become to be grouped into the medicine acceptable carrier of this powder pin, its Chinese medicine acceptable carrier is lactose, mannitol, sucrose, glucose, low molecular dextran, gelatin hydrolysate and/or sodium chloride.
Injection powder pin of the present invention can prepare by the following method, carries out according to the following steps: take by weighing tirofiban hydrochloride and selected drug acceptable carrier by recipe quantity, add in the 1950ml water for injection, and add water to nearly full dose; Measure intermediate, after content is qualified, use the 0.45um filtering with microporous membrane, qualified to clarity; Be sub-packed in the control antibiotic bottle, keep vacuum 30-35Pa, lyophilizing got final product in 24 hours.
Injection powder pin of the present invention also can prepare by the following method, carries out according to the following steps: take by weighing tirofiban hydrochloride and selected drug acceptable carrier by recipe quantity, add in the 300ml alcoholic solution (ethanol: water, 95: 5); Under the aseptic condition, use the 0.45um filtering with microporous membrane, check that clarity is qualified after, oven dry, check intermediate content and ethanol residual qualified after, be sub-packed in the control antibiotic bottle, suppress compound aluminium lid and get final product.
We find by experiment, in the prescription of hydrochloride for injection tirofiban, can reach the injection stablizing effect that uses citrate buffer agent.This injection powder pin is tirofiban hydrochloride and drug acceptable carrier.This prescription stability indicator is better than using the prescription of the injection of citrate buffer, can increase the intravenous safety of medicine.
Injection powder needle set of the present invention has good stability, characteristics such as determined curative effect.Injection of the present invention is storing and can keep good stable between the delivery period.
Effective effect of the present invention example by experiment illustrates.
The specific embodiment
Embodiment 1 prescription injection freeze-dried powder of the present invention
Specification: 5mg/ props up (in anhydrous tirofiban), down together
Tirofiban hydrochloride 5.618g
Mannitol 100g
Water for injection is to 2000ml
Make 1000 on powder pin altogether
Preparation technology:
The preparation of medicinal liquid:
Take by weighing tirofiban hydrochloride and selected drug acceptable carrier by recipe quantity, add in the 1950ml water for injection, and add water to nearly full dose; Add the injection water behind ormal weight, measure intermediate content and should be 93.0%～107.0%, qualified after, use the 0.45um filtering with microporous membrane, check that clarity is qualified after, be sub-packed in the control antibiotic bottle friendship lyophilizing group.
Lyophilizing:
At first lowered the temperature 1 hour, temperature is reduced to-40 ℃, keeps this temperature about 5 hours; Beginning progressively is warming up to 25 ℃, requires vacuum state in this process, and keeping needs about 24 hours consuming time about vacuum 30-35Pa; Finish lyophilizing, gland, pack finished product.
Embodiment 2 prescription Injectable sterile packing powder pins of the present invention
Tirofiban hydrochloride 5.618g
Mannitol 100g
Make 1000 on powder pin altogether
Preparation technology:
Take by weighing tirofiban hydrochloride and selected drug acceptable carrier by recipe quantity, add in the 300ml alcoholic solution and dissolve ethanol: water is 95: 5, under the aseptic condition, uses the 0.45um filtering with microporous membrane, after the inspection clarity is qualified, and oven dry; Check intermediate content should be 93.0%～107.0%, ethanol residual qualified after, be sub-packed in the control antibiotic bottle, suppress compound aluminium lid, get final product.
The embodiment 3 contrast injection that contain citrate buffer agent
Tirofiban hydrochloride 5.618g
Sodium chloride: 900g
Sodium citrate 54g
Citric acid 3.2g
Make 1000 bottles of injection altogether
Preparation technology:
The medicinal liquid preparation:
Take by weighing sodium chloride, citric acid and sodium citrate by recipe quantity, add among the water for injection 5000ml of new system, be stirred to dissolving fully; Take by weighing the active carbon of 0.3% solution amount, stir evenly, heated and boiled 15 minutes, after the cooling, the filtering active carbon; Accurately take by weighing tirofiban hydrochloride by recipe quantity, dissolve fully, add in the above-mentioned sodium chloride solution, and add the injection water to nearly full dose with water for injection; Measure pH 5.5～6.5, add the injection water, measure intermediate content and should be 93.0%～107.0% to ormal weight, qualified after, use the 0.45um filtering with microporous membrane, after the inspection clarity is qualified, filtrate friendship fill group.
Fill:
The infusion bottle that the above-mentioned medicinal liquid adding fill for preparing is used is cleaned oven dry with injection water.The plated film butyl rubber plug is clean with the injection water rinsing simultaneously.Medicinal liquid enters the injection filling machine, and fill behind the capping plug, is suppressed compound aluminium lid in infusion bottle.
Sterilization:
The infusion bottle of building is put into the sterilization cabinet sterilize, 115 ℃ of sterilising temps, sterilization time 35 minutes, lamp inspection is qualified, and packing gets final product.
Embodiment 4 prescription injection freeze-dried powders of the present invention
Tirofiban hydrochloride 5.618g
Lactose 100g
Water for injection is to 2000ml
Make 1000 on powder pin altogether
Preparation technology:
Preparation method with embodiment 1.
Embodiment 5 prescription injection freeze-dried powders of the present invention
Tirofiban hydrochloride 5.618g
Sucrose 100g
Water for injection is to 2000ml
Make 1000 on powder pin altogether
Preparation technology:
Refined sucrose: take by weighing sucrose 250g, add 89% ethanol 1000ml, put in the 2500ml flask, on connect condenser, water-bath added backflow 1-2 hour, made whole dissolvings; Cold slightly, add active carbon 20g and refluxed again 15 minutes, with the buchner funnel filtered while hot carbon removal after the sterilization, filter with No. 3 sintered glass funnels immediately, close silk and the mulberry paper of wrapping beyond the Great Wall of filtrate, the placement refrigerator, jolting often prevents that the crystallization of separating out from luming in the bottom; After 2 days, crystallization is separated out fully, leaching crystallization under the aseptic condition, the absolute ethanol washing of usefulness filtering 2 times; Put in the electric vacuum drying oven, below 50 ℃ after dry 2 hours, in that to be dried to water content detection below 80 ℃ qualified, standby.
Its powder pin preparation is with the preparation of embodiment 1.
Embodiment 6 prescription injection freeze-dried powders of the present invention
Tirofiban hydrochloride 5.618g
Glucose 100g
Water for injection is to 2000ml
Make 1000 on powder pin altogether
Preparation technology:
Preparation method with embodiment 1.
Embodiment 7 prescription injection freeze-dried powders of the present invention
Tirofiban hydrochloride 5.618g
Low molecular dextran 100g
Water for injection is to 2000ml
Make 1000 on powder pin altogether
Preparation technology:
Preparation method with embodiment 1.
Embodiment 8 prescription injection freeze-dried powders of the present invention
Tirofiban hydrochloride 5.618g
Mannitol 50g
Gelatin hydrolysate 50g
Water for injection is to 2000ml
Make 1000 on powder pin altogether
Preparation technology:
Preparation method with embodiment 1.
Embodiment 9 prescription injection freeze-dried powders of the present invention
Tirofiban hydrochloride 5.618g
Mannitol 80g
Sodium chloride 10g
Water for injection is to 2000ml
Make 1000 on powder pin altogether
Preparation technology:
Preparation method with embodiment 1.
Embodiment 10 prescription injection freeze-dried powders of the present invention (specification: 2.5mg/ props up)
Tirofiban hydrochloride 2.809g
Mannitol 100g
Water for injection is to 2000ml
Make 1000 on powder pin altogether
Preparation technology:
Preparation method with embodiment 1.
Embodiment 11 prescription injection freeze-dried powders of the present invention (specification: 12.5mg/ props up)
Tirofiban hydrochloride 14.045g
Mannitol 100g
Water for injection is to 2000ml
Make 1000 on powder pin altogether
Preparation technology:
Preparation method with embodiment 1.
Embodiment 12 prescription injection freeze-dried powders of the present invention (specification: 25mg/ props up)
Tirofiban hydrochloride 28.09g
Mannitol 100g
Water for injection is to 3000ml
Make 1000 on powder pin altogether
Preparation technology:
The preparation of medicinal liquid:
Take by weighing tirofiban hydrochloride and selected drug acceptable carrier by recipe quantity, add in the 2900ml water for injection, and add water to nearly full dose; Add the injection water behind ormal weight, measure intermediate content and should be 93.0%～107.0%, qualified after, use the 0.45um filtering with microporous membrane, check that clarity is qualified after, be sub-packed in the control antibiotic bottle friendship lyophilizing group.
Lyophilizing: with the freeze drying process of embodiment 1.
The different prescription stability of tirofiban hydrochloride injection relatively.
Laboratory sample:
Prescription 1 injection freeze-dried powder specification 5mg/ of the present invention props up
Lot number 031104
Wuhan Yuanda Pharmaceutical Group Co., Ltd. of research institute
Wuhan Wuyao Technology Co., Ltd.
Prescription 2 Injectable sterile packing powder gauge 5mg/ of the present invention prop up
Lot number 031107
Wuhan Yuanda Pharmaceutical Group Co., Ltd. of research institute
The injection specification 100ml:5mg that contains citrate buffer agent
Lot number 031001
Wuhan Yuanda Pharmaceutical Group Co., Ltd. of research institute
Detection method:
Related substances: it is an amount of to get this product, adds mobile phase and makes the solution that contains 0.5mg among every 1ml, as need testing solution; Precision is measured need testing solution 1ml, puts in the 100ml measuring bottle, adds mobile phase and is diluted to scale, shakes up, in contrast solution.According to the method under the assay item, precision is measured contrast solution 10 μ l, injects chromatograph of liquid, regulates detection sensitivity, and the peak height that makes main constituent is 20% of a full scale; Precision is measured contrast solution and each 10 μ l of need testing solution again, injects chromatograph of liquid respectively, and the record chromatogram is to 2 times of need testing solution main peak retention time.As showing impurity peaks, the summation of each impurity peak area must not be greater than the main peak area (1.0%) of contrast solution in the chromatogram of need testing solution.
Clarity: black background, under the 4500Lx illumination, each prescription detection limit is 100 bottles.
Particulate matter: adopt the light blockage method of Chinese Pharmacopoeia regulation check particle diameter＞10um among the 1ml and＞population of 25um.
Test method one:
Test specimen is detected, then according to following method operation: sample is put into constant temperature reserved sample observing case, deposit for 60 ℃, respectively at the 5th, 10 day taking-up sample, after clinical use of powder pin and the processing of quality standard prescriptive procedure, full inspection.
60 ℃ of heating prescription powder pins of the present invention compare with the injection stability that contains citrate buffer agent
Test method two:
To detect before the test specimen sterilization and after the sterilization, then according to following method operation: with sample room temperature reserved sample observing, took out sample, check pH and clarity in 24 months.
Prescription powder pins of the present invention compared with the injection stability that contains the citrate buffer agent prescription in 24 months
Conclusion: prescription of the present invention and the comparison that contains the prescription of citrate buffer agent.In 10 days test of 60 ℃ of heating, outward appearance, content, pH, related substance and clarity are all qualified.But in the investigation that particulate matter is carried out, 12 months results find that the particle number of the injection powder pin of prescription of the present invention will be less than the prescription that contains citrate buffer.
Claims (3)
1. injection powder pin that suppresses platelet aggregation, after it adds water for injection 2ml mix homogeneously by tirofiban hydrochloride 5.618mg, mannitol 80mg, sodium chloride 10mg, using the 0.45um filtering with microporous membrane, is that lyophilizing is prepared under the condition of 30-35Pa in vacuum.
2. injection powder pin according to claim 1 is characterized in that: contain lactose, sucrose, glucose, low molecular dextran or gelatin hydrolysate medicine acceptable carrier in the described powder pin.
3. injection powder pin according to claim 1 is characterized in that: the concentration of the drug acceptable carrier in the described powder pin is: contain in every and can accept carrier 50mg～1000mg.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100184400A CN100386079C (en) | 2005-03-24 | 2005-03-24 | Injection use-powder ampoule for inhibiting thrombocyte agglutination and its preparation method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100184400A CN100386079C (en) | 2005-03-24 | 2005-03-24 | Injection use-powder ampoule for inhibiting thrombocyte agglutination and its preparation method |
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| Publication Number | Publication Date |
|---|---|
| CN1686127A CN1686127A (en) | 2005-10-26 |
| CN100386079C true CN100386079C (en) | 2008-05-07 |
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| CNB2005100184400A Active CN100386079C (en) | 2005-03-24 | 2005-03-24 | Injection use-powder ampoule for inhibiting thrombocyte agglutination and its preparation method |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108785261A (en) * | 2018-07-03 | 2018-11-13 | 马现梅 | A kind of pharmaceutical preparation and preparation method thereof containing tirofiban hydrochloride |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1850078B (en) * | 2006-01-20 | 2010-09-08 | 天津南开允公医药科技有限公司 | Anti-platelet aggregation medicinal injection and its preparing method |
| CN101756915B (en) * | 2010-02-25 | 2011-06-22 | 山东新时代药业有限公司 | Tirofiban hydrochloride lyophilized powder injection and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1200676A (en) * | 1995-10-27 | 1998-12-02 | 麦克公司 | Pharmaceutical compositions contg. platelet aggregation inhibitors |
| CN1416814A (en) * | 2002-11-22 | 2003-05-14 | 杭州华卫制药技术开发有限公司 | Medicine prepn for injection and its prepn process |
-
2005
- 2005-03-24 CN CNB2005100184400A patent/CN100386079C/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1200676A (en) * | 1995-10-27 | 1998-12-02 | 麦克公司 | Pharmaceutical compositions contg. platelet aggregation inhibitors |
| CN1416814A (en) * | 2002-11-22 | 2003-05-14 | 杭州华卫制药技术开发有限公司 | Medicine prepn for injection and its prepn process |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108785261A (en) * | 2018-07-03 | 2018-11-13 | 马现梅 | A kind of pharmaceutical preparation and preparation method thereof containing tirofiban hydrochloride |
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| Publication number | Publication date |
|---|---|
| CN1686127A (en) | 2005-10-26 |
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Effective date of registration: 20110330 Address after: 430035 No. 5, Gutian Road, Wuhan, Hubei, Hankou Patentee after: Wuhan Yuanda Pharmaceutical Group Co., Ltd. Address before: 430035 No. 5, Gutian Road, Wuhan, Hubei, Hankou Patentee before: Wuhan Yuanda Pharmaceutical Group Co., Ltd. |
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Owner name: GRANDPHARMA (CHINA) CO., LTD. Free format text: FORMER NAME: WUHAN GRAND PHARMACEUTICAL GROUP CO., LTD. |
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Address after: 430035 No. 5, Gutian Road, Wuhan, Hubei, Hankou Patentee after: Yuanda Pharmaceutical (China) Co., Ltd. Address before: 430035 No. 5, Gutian Road, Wuhan, Hubei, Hankou Patentee before: Wuhan Yuanda Pharmaceutical Group Co., Ltd. |