CN103356478A - Ibuprofen injection composition and preparation method thereof - Google Patents
Ibuprofen injection composition and preparation method thereof Download PDFInfo
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- CN103356478A CN103356478A CN2013102999006A CN201310299900A CN103356478A CN 103356478 A CN103356478 A CN 103356478A CN 2013102999006 A CN2013102999006 A CN 2013102999006A CN 201310299900 A CN201310299900 A CN 201310299900A CN 103356478 A CN103356478 A CN 103356478A
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Abstract
The invention relates to an ibuprofen injection. The injection consists of an active component ibuprofen and a cosolvent arginine, and is characterized in that the molar ratio of ibuprofen to arginine is 1:1.08-1.12, pH conditioning agents are not used, the amount and kind of accessories during injection preparation are reduced, irritation is low and security is higher. The prepared ibuprofen injection is substantially improved in resistance of high temperature and hard light; not only insoluble particles are obviously minimized, but also the compatibility problems of the injection with common salt and glucose injections are solved; and the product quality stability is substantially improved, and clinic compatibility demands are satisfied. Also, the invention provides a preparation method which is simple in technology and suitable for industrialized production.
Description
Technical field:
The invention belongs to field of pharmaceutical preparations, be specifically related to a kind of ibuprofen injection composition and method of making the same.
Background technology:
Ibuprofen is the non_steroidal anti_inflammatory drug with following structural, has antiinflammatory, analgesia, refrigeration function.
Alpha-Methyl-4-(2-methyl-propyl) phenylacetic acid
After being developed in 1964, ibuprofen is widely used in antiinflammatory, analgesia, analgesic, rheumatism etc.Because ibuprofen can produce the gastrointestinal side effect that general NSAID (non-steroidal anti-inflammatory drug) has, and its biological half-life is shorter, keep treatment concentration and need frequent medication, thereby further increased the gastrointestinal reaction of this medicine, such as abdominal distention, dyspepsia, nausea,vomiting,diarrhea, digestive tract ulcer etc., even cause gastrointestinal hemorrhage, also increased the detrimental effect of kidney simultaneously, so people are devoted to the aspects such as this medicine novel formulation and new agent technology always and study.
The dosage form of ibuprofen mainly contains tablet on the domestic market, slow releasing tablet, slow releasing capsule, granule, oral liquid, suppository, emulsifiable paste, compound preparation etc.Although ibuprofen has many advantages than other analgesic such as aspirin and acetaminophen, its unusual indissoluble in water.Therefore, some dosage form of ibuprofen, particularly oral or injection is difficult to exploitation.But injection absorbs soon, effect is rapid, and this advantage can not be substituted, particularly intravenous injection, and medicinal liquid can directly enter blood circulation, is more suitable for rescuing
The usefulness of critical illness, and injection is not subjected to the impact of digestive system and food without gastrointestinal tract.Its side effect be can greatly alleviate therefore ibuprofen is made injection, and speed of action and the reliability of ibuprofen improved.
Patent CN101190889 etc. also once disclosed the preparation method of ibuprofen amino acid salt, by these methods, can obtain the fabulous ibuprofen amino acid salt of water solublity, can prepare the injection that contains ibuprofen composition with this.The shortcoming of the method is and need to first ibuprofen be made into salt, again dissolving after the separation and purification, and therefore necessary separation and detection ibuprofen amino acid salt before producing injection has increased production stage.Patent CN101889997B discloses a kind of pharmaceutical composition that contains ibuprofen of injection, and said composition comprises basic amino acid and ibuprofen, and the mol ratio that it is characterized in that basic amino acid and ibuprofen is 1:1～10:1.This invention has improved the content ratio of basic amino acid in described pharmaceutical composition, the dissolubility of ibuprofen is improved, but the adjuvant that adopts comprises the multiple auxiliary materials such as chelating agen, pH adjusting agent, amino acid composition, and zest is large, has reduced the safety of injection.Patent CN102258507B, CN102370615A, CN102716107A also disclose pharmaceutical composition of ibuprofen injection and preparation method thereof, but the method is come solubilising by adding propylene glycol, meglumine, tween respectively, increase the application kind of adjuvant, reduced the safety of intravenous administration formulation medication.Patent CN102085179B provides a kind of preparation method that contains the ibuprofen injection of ibuprofen and alkaline auxiliary solvent, and the method adopts multiple alkaline, inorganic salts hydrotropy, and the stability of solution of formation is not high, and clinical compatibility uses also certain safety issue.Among the patent CN101966147B prescription that is comprised of ibuprofen and cosolvent (arginine) is advised that ibuprofen and arginic mol ratio are 1:1.001-2, this prescription can guarantee that ibuprofen can not separated out under suitable pH value, but must use the pH regulator to reduce the pH value and accept scope to reach blood of human body, and large as the required quantitative change of the arginine of pharmaceutic adjuvant, cost also uprises thereupon.
US Patent No. 6727286 discloses a kind of ibuprofen injection, this injection is comprised of ibuprofen and arginine, this patent suggestion ibuprofen and arginic mol ratio are less than 1:1, but visible foreign matters and particulate matter situation in this patent and the not mentioned this ibuprofen injection finished product inspection item, and with the compatibility compatibility situations such as glucose injection and sodium chloride injection.Through verification experimental verification, this ibuprofen injection is used with glucose injection and sodium chloride injection compatibility respectively, last liquor strength is respectively 2mg/ml and 4mg/ml, all appearance opalescence in various degree and the phenomenon of particulate matter increase.Ibuprofen and arginic mol ratio are 1:0.85～0.95 among the patent CN103040734, also have same compatibility consistency problem.
Summary of the invention:
The present invention is directed to the deficiency that existing ibuprofen injection exists, provide a kind of and can significantly improve product quality, ibuprofen injection compositions and preparation method that zest is low.
The inventor finds by lot of experiments and research, improve ibuprofen and arginic proportioning, not only make the particulate matter of ibuprofen injection that obvious minimizing is arranged, and solved the compatibility consistency problem of injection and sodium chloride and glucose injection, improve the compliance of patient's medication, realized the industrialized mass of ibuprofen injection, the external hemolytic test of its product is negative, the intravenous drip administration is to allergic response with cavy, rabbit is had no the vascular stimulation effect, thereby finished the present invention.
The invention provides a kind of ibuprofen injection, this injection is comprised of active constituents of medicine ibuprofen, cosolvent arginine and water for injection.
Above-mentioned ibuprofen injection, ibuprofen and arginic mol ratio are 1:1.08～1:1.12.
Above-mentioned ibuprofen injection does not use any pH adjusting agent, and adjuvant is used kind still less.
Above-mentioned ibuprofen injection, pH are 7.5-9.0.
Above-mentioned ibuprofen injection, pH value is near human plasma during use, and zest is lower.
The present invention also provides a kind of ibuprofen injection preparation method, the steps include:
(1) takes by weighing arginine by recipe quantity and place the water for injection of answering part long-pending 80%, stir and make it dissolving, add again ibuprofen, the stirring at room dissolve complete;
(2) press 0.05%(W/V) add needle-use activated carbon, 25 ℃ of lower 20min that stir, coarse filtration, filtrate is used 0.22 μ m filtering with microporous membrane again;
(3) intermediate inspection;
(4) logical nitrogen protection, embedding is in ampoule bottle;
(5) 121 ℃, 15min high pressure steam sterilization, leak detection;
(6) ampoule is pursued the Zhi Jinhang lamp inspection;
(7) full inspection of sampling;
(8) packing.
The ibuprofen injection that makes by said method and be that the ibuprofen injection of US 6727286 disclosed technology preparations (is called commercially available Comparative formulation in the following text by U.S. Patent number, prescription is: ibuprofen, arginine, pH value regulator and water for injection, the mol ratio of arginine and ibuprofen are 0.92:1) carry out stable contrast test and clinical compatibility test demonstration: the present invention can significantly improve the visible foreign matters check item of ibuprofen injection.
Show according to influence factor, acceleration and long-term 6 months stability test results, the ibuprofen injection of the present invention's preparation is good to the tolerance of high temperature and high light, and quality stability is better.
Carry out the clinical compatibility result of the test as can be known by sample of the present invention, the venoclysis liquid of the ibuprofen injection clinical compatibility of the present invention's preparation, character is colourless clear liquid, without visible foreign matters, that particulate matter checks is up to specification, content, related substance have no significant change, and the pH of solution is more near human plasma after the preparation, and zest is lower.These data fully show the ibuprofen injection that the present invention prepares, and can satisfy the requirement that clinical vein instils, and patient's compliance is better.
Test 1: the variation of ibuprofen and arginine mol ratio is on the impact of injection pH value and compatibility test
Be that 1:0.92～1:1.20 takes by weighing respectively ibuprofen and arginine by ibuprofen and arginic mol ratio, according to above-mentioned preparation method preparation ibuprofen injection, investigate the variation of ibuprofen and arginine different mol ratio to the impact of injection pH value; Description according to Caldolor: before this medicine intravenous drip, must be diluted to ultimate density is 4mg/ml or lower, suitable diluent comprises 0.9% sodium chloride injection, 5% glucose injection or sodium lactate ringer's injection, we carry out prescription screening with the clarity of solution of the compatibility test of this product and three kinds of diluent as investigating index.Testing result sees Table 1
The variation of table 1 ibuprofen and arginine mol ratio is on the impact of injection pH value and compatibility test
Conclusion: dissolubility and the pH value of solution of ibuprofen in water is closely related, according to the ibuprofen injection description of FDA approval as can be known, this product should be first when clinical use be diluted to ibuprofen concentration with sodium chloride or glucose injection and be not more than 4mg/ml and carries out intravenous drip again.
This experimental result shows when ibuprofen and arginic mol ratio during less than 1:1, when using with compatibility agent glucose injection (pH value is 3.2～5.5) or sodium chloride injection (pH value is 4.5～7.0) or newborn ringer's injection (pH value is 6.5～7.5) because the reduction of pH value and easily cause separating out of ibuprofen.Ibuprofen and arginic mol ratio are during greater than 1:1.08, do not use the pH value regulator, pH value is remained between 7.5～9.0, reduced supplementary product consumption kind in the injection preparation, solved simultaneously the compatibility consistency problem of this injection and sodium chloride and glucose injection, significantly improve the quality stability of product, satisfied the clinical compatibility demand.But consider that supplementary product consumption is more few better in the injection preparation, and the rear pH value of injection preparation is more near human plasma in use, zest is lower, and we select ibuprofen and arginic mol ratio is 1:1.08～1.12.
Test 2: will carry out quality comparative study with commercially available Comparative formulation 5401NNX by the ibuprofen injection of the embodiment of the invention 1 preparation, the result is as follows:
Test example 1: hot test
60 ℃ of heat damages: this product was placed 10 days under 60 ℃ of hot conditionss, and with comparison in 0 day, appearance color was unchanged, and related substance, content substantially become, and this product is more stable to heat.
1 batch of ibuprofen injection hot test of table 2 embodiment testing result
The commercially available 5401NNX of table 3 criticizes the hot test testing result
Test example 2: highlight test
The 4500LX photo damage: this product is under the strong illumination condition, and with comparison in 0 day, appearance color was without significant change, and related substance, content substantially become, and this product is more stable to light.
1 batch of ibuprofen injection strong illumination test of table 4 embodiment testing result
The commercially available 5401NNX of table 5 criticizes strong illumination test testing result
Test example 3: low-temperature test
Freeze cycle: appearance color is without significant change, and related substance, content do not become substantially, and this product is more stable under the freeze cycle condition.
1 batch of ibuprofen injection freeze cycle test of table 6 embodiment testing result
The commercially available 5401NNX of table 7 criticizes freeze cycle test testing result
Test example 4: accelerate and long term test:
This product commercially available back, accelerated test is 6 months under 40 ℃, the condition of relative humidity 75%, at 25 ℃, places 6 months every detection indexs under the RH60% condition and has no significant change, all the conformance with standard regulation.
Table 8 embodiment 1 batch sample stability test measurement result
The commercially available 5401NNX batch sample of table 9 stability test measurement result
Test example 5: compatibility test
Get 1 of 1 batch of ibuprofen injection of embodiment, join respectively in 5% glucose injection (hereinafter to be referred as glucose) of 0.9% sodium chloride injection (hereinafter to be referred as sodium chloride), 100ml of 100ml, in the sodium lactate ringer's injection (hereinafter to be referred as sodium lactate ringer's) of 100ml, its ibuprofen diluted concentration is 4mg/ml, shake up, in 0h, 2h, 4h, 6h, 8h, precision measures the above-mentioned sample of 5ml and puts in the 10ml measuring bottle respectively, compatibility solution dissolved dilution is to scale, precision measures 20 μ l sample introductions, measures related substance.It the results are shown in Table 9.Investigate simultaneously pH value, visible foreign matters, osmotic pressure and particulate matter, and with diluted concentration be that the commercially available control formulation ibuprofen injection of 2mg/ml compares, its result of the test: the self-control ibuprofen injection is diluted to respectively in 0.9% sodium chloride injection, 5% glucose injection and the sodium lactate ringer's injection, concentration 4mg/ml, solution are stable in 8h; Visible foreign matters and particulate matter passed examination; Osmotic pressure is up to specification; Compatibility solution ibuprofen related substance in 8h without significant change; The control formulation ibuprofen injection is when diluted concentration is 4mg/ml in three kinds of compatibility solution, and solution is muddy at once, and visible foreign matters checks defective; When diluted concentration was 2mg/ml, although visible foreign matters passed examination in 4 hours inherent 5% glucose injections and the sodium lactate ringer's injection, particulate matter checked defective.
Table 10 Experiment of Compatibility testing result
Test example 6: specific safety test
For understanding the safety of self-control ibuprofen injection, carry out external hemolytic test, Cavia porcellus systemic allergy test and Vascular stimulation test by " chemical drugs zest, anaphylaxis and hemolytic investigative technique guideline ", the result is as follows: (1) external hemolytic test: concentration is that the ibuprofen injection of 4mg/ml has no haemolysis within the observation period, also has no erythroagglutination; (2) systemic allergy test: ibuprofen injection low dose group (2mg/ml) and high dose group (4mg/ml) excited administration (injection capacity is that 1.0mg/ props up) on the 10th day respectively after 1,3,5,7,9 day sensitization (injection capacity is that 0.5mg/ props up) of test, last sensitization, tested Cavia porcellus is showed no anaphylaxis within the observation period; (3) vascular stimulation tests: through family rabbit ear vein instillation ibuprofen injection (2mg/ml and 4mg/ml, once a day, continuous 7 days), perusal and the result of histopathologic examination show: ibuprofen injection has no irritative response to family's rabbit ear vein, and convalescent period observes and histopathologic examination's no abnormality seen.Conclusion: the made ibuprofen injection intravenous drip of the method administration has no obvious anaphylaxis to Cavia porcellus, and rabbit is had no obvious vascular stimulation effect, and external hemolytic test result is negative.
The specific embodiment
The present invention is described in further detail below in conjunction with embodiment, but be not limitation of the present invention, all any this areas of doing according to the disclosure of invention be equal to replacement, all belong to protection scope of the present invention.
Embodiment 1
Per 1000 injection formulations contain following compositions:
Ibuprofen 400 g(1.94mol)
Arginine 365g (2.10mol)
Water for injection adds to 4000ml
Take by weighing ibuprofen 400g by recipe quantity, arginine 365g joins in the 3200ml water for injection stirring at room dissolve complete; Press 0.05%(W/V) add needle-use activated carbon, 25 ℃ of lower 20min that stir, coarse filtration, filtrate is used 0.22 μ m filtering with microporous membrane again; Add at last water for injection and be settled to 4000ml; Intermediate checks; Logical nitrogen protection, embedding is in the 5ml ampoule bottle, and 4ml/ props up; 121 ℃, 15min high pressure steam sterilization, leak detection; Ampoule is pursued the Zhi Jinhang lamp inspection; The full inspection of sampling; Packing.
Embodiment 2
Per 1000 injection formulations contain following compositions:
Ibuprofen 400 g(1.94mol)
Arginine 372g (2.14mol)
Water for injection adds to 4000ml
Take by weighing ibuprofen 400g by recipe quantity, arginine 372g joins in the 3200ml water for injection, the stirring at room dissolve complete; Press 0.05%(W/V) add needle-use activated carbon, 25 ℃ of lower 20min that stir, coarse filtration, filtrate is used 0.22 μ m filtering with microporous membrane again; Add at last water for injection and be settled to 4000ml; Intermediate checks; Logical nitrogen protection, embedding is in the 5ml ampoule bottle, and 4ml/ props up; 121 ℃, 15min high pressure steam sterilization, leak detection; Ampoule is pursued the Zhi Jinhang lamp inspection; The full inspection of sampling; Packing.
Embodiment 3
Per 1000 injection formulations contain following compositions:
Ibuprofen 400 g(1.94mol)
Arginine 379g (2.18mol)
Water for injection adds to 4000ml
Take by weighing ibuprofen 400g by recipe quantity, arginine 379g joins in the 3200ml water for injection, the stirring at room dissolve complete; Press 0.05%(W/V) add needle-use activated carbon, 25 ℃ of lower 20min that stir, coarse filtration, filtrate is used 0.22 μ m filtering with microporous membrane again; Add at last water for injection and be settled to 4000ml; Intermediate checks; Logical nitrogen protection, embedding is in the 5ml ampoule bottle, and 4ml/ props up; 121 ℃, 15min high pressure steam sterilization, leak detection; Ampoule is pursued the Zhi Jinhang lamp inspection; The full inspection of sampling; Packing.
Claims (6)
1. ibuprofen injection, it is characterized in that: active constituents of medicine is that ibuprofen, adjuvant are cosolvent arginine and water for injection.
2. injection according to claim 1, it is characterized in that: ibuprofen and arginic mol ratio are 1:1.08～1:1.12.
3. injection according to claim 1 is characterized in that: do not use any pH adjusting agent.
4. injection according to claim 1, it is characterized in that: the pH of this injection is 7.5-9.0.
5. according to claim 1 to 4 each described injection, it is characterized in that: injection preparation is:
(1) ibuprofen and arginic mol ratio are 1:1.08～1:1.12, make a gesture of measuring by above-mentioned mole and take by weighing arginine, ibuprofen, arginine are placed the water for injection of answering part long-pending 80%, stir and make it dissolving, add ibuprofen, the stirring at room dissolve complete again; (2) press 0.05%(W/V) add needle-use activated carbon, 25 ℃ of lower 20min that stir, coarse filtration, filtrate is used 0.22 μ m filtering with microporous membrane again;
(3) intermediate inspection;
(4) logical nitrogen protection, embedding is in ampoule bottle;
(5) 121 ℃, 15min high pressure steam sterilization, leak detection;
(6) ampoule is pursued the Zhi Jinhang lamp inspection;
(7) full inspection of sampling;
(8) packing.
6. injection according to claim 5 is characterized in that: all be filled with nitrogen protection in the described step (4) before and after the ampoule filling medicinal liquid.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107198676A (en) * | 2017-06-23 | 2017-09-26 | 江苏神龙药业股份有限公司 | A kind of ibuprofen injection for intravenously administrable |
| CN107233307A (en) * | 2017-07-03 | 2017-10-10 | 华润双鹤利民药业（济南）有限公司 | A kind of ibuprofen injection and preparation method thereof |
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| CN102100686A (en) * | 2009-12-21 | 2011-06-22 | 北京润德康医药技术有限公司 | Medicinal composition containing ibuprofen and arginine and preparation method and application thereof |
| CN102160852A (en) * | 2010-02-23 | 2011-08-24 | 付正香 | Ibuprofen injection and preparation method thereof |
| CN102697718A (en) * | 2012-06-28 | 2012-10-03 | 武汉武药科技有限公司 | Ibuprofen liquid injection composition and preparation method thereof |
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- 2013-07-17 CN CN2013102999006A patent/CN103356478A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102100686A (en) * | 2009-12-21 | 2011-06-22 | 北京润德康医药技术有限公司 | Medicinal composition containing ibuprofen and arginine and preparation method and application thereof |
| CN102160852A (en) * | 2010-02-23 | 2011-08-24 | 付正香 | Ibuprofen injection and preparation method thereof |
| CN102697718A (en) * | 2012-06-28 | 2012-10-03 | 武汉武药科技有限公司 | Ibuprofen liquid injection composition and preparation method thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107198676A (en) * | 2017-06-23 | 2017-09-26 | 江苏神龙药业股份有限公司 | A kind of ibuprofen injection for intravenously administrable |
| CN107233307A (en) * | 2017-07-03 | 2017-10-10 | 华润双鹤利民药业（济南）有限公司 | A kind of ibuprofen injection and preparation method thereof |
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Application publication date: 20131023 |