CN102085179B - Ibuprofen injection and preparation method thereof - Google Patents
Ibuprofen injection and preparation method thereof Download PDFInfo
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- CN102085179B CN102085179B CN201110023170A CN201110023170A CN102085179B CN 102085179 B CN102085179 B CN 102085179B CN 201110023170 A CN201110023170 A CN 201110023170A CN 201110023170 A CN201110023170 A CN 201110023170A CN 102085179 B CN102085179 B CN 102085179B
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Abstract
The invention relates to an ibuprofen injection, which comprises ibuprofen and one or a plurality of alkaline cosolvents pharmaceutically acceptable selected from anhydrides or hydrates of sodium carbonate, sodium bicarbonate,sodium citrate, sodium citrate, sodium phosphate, disodium dihydrogen pyrophosphate, sodium tartrate and sodium acetate. The invention also relates to a preparation method of the ibuprofen injection.
Description
Technical field
The present invention relates to a kind of ibuprofen injection and preparation method thereof.
Background technology
Ibuprofen (Ibuprofen) has another name called the isobutylbenzene propanol, is the nonsteroidal antiinflammatory and analgesic medicine, and its antiinflammatory, analgesia, refrigeration function are respond well, and untoward reaction is less.Extensive use in the world at present; Become one of global best-selling over-the-counter drug; Be listed as antipyretic analgesic three big pillar products together with aspirin, acetaminophen, because ibuprofen has rheumatism and analgesic analgesic curative effect concurrently, and toxicity is low; All be superior to aspirin and acetaminophen at aspects such as curative effect and side effect, thereby market enlarges rapidly.
Ordinary preparations such as Genpril, capsule, dispersible tablet, oral administration mixed suspension clinically at present; The same with other NSAID; Exist dissolubility little, absorb slow, bioavailability is low, onset waits shortcoming relatively slowly; And old man and the patient of solid preparation of can not swallowing made troubles, and ibuprofen injection has the incomparable superiority of oral formulations, like advantages such as biological utilisation are high, onset is rapid.
Cumberland drugmaker carries out clinical trial to the ibuprofen intravenous fluid, and the result shows: the ibuprofen intravenous fluid eases the pain to 1400 routine inpatients and brings down a fever safe and effective.In III phase clinical research, use ibuprofen intravenous fluid patient significantly to alleviate the intensity of first 24 hours pain of postoperative, also significantly reduce the morphine amount that they use simultaneously.Clinical research comprise be critically ill with the non-fever patient of being critically ill significantly reduce body temperature than placebo.In these clinical researches, serious adverse reaction does not appear in the ibuprofen intravenous fluid.The commercially available injection that eases the pain only has opioid drug morphine and Pethidine and non-steroid antiinflammatory drug ketone to cough up sweet smell at present.Opioid drug can cause calmness, feels sick, vomiting, cognitive impairment and inhibition are breathed.Ketone is coughed up sweet smell has the increase danger of bleeding.
U.S. food Drug Administration (FDA) is in approval on June 11st, 2009 nonsteroidal anti-inflammatory drug (NSAIDS) ibuprofen injection (ibuprofen, Caldolor) listing, the ibuprofen intravenous injection novel formulation of first treatment pain and heating.Up to the present, the most NSAIDS medicine of the U.S. only has peroral dosage form to be used for pain relieving.Caldolor then is first ibuprofen injection preparation of FDA approval so far, can be can not, uncomfortable or inconvenience uses the oral drugs patient to provide a kind of new pain relief or fever therapy to select.Caldolor also is that the fever therapy medicine is used in first venoclysis that gets the Green Light in U.S.A so far.
Aspect patent application; The Chinese invention patent ublic specification of application discloses a kind of name and has been called " pharmaceutical composition of 2-(4-isobutylphenyl) propanoic acid "; Application number is 01823764.9; Authorizing publication number is CN 1302771C, and on the November 2 calendar year 2001 applying date, this application mainly provides a kind of pharmaceutical composition that contains arginine and ibuprofen aqueous solution and preparation method thereof.This patent selects for use arginine as the alkaline auxiliary solvent, and in this compositions the mol ratio of arginine and ibuprofen less than 1: 1.
In the existing ibuprofen injection, be cosolvent with the arginine like U.S.'s listing preparation, still arginic aqueous solution is to responsive to temperature, and quickening possibly influence product related substance and content with long-term placement.
How ibuprofen overcomes its dissolubility and guarantees that safety is the technical barrier of this area on its liquid preparation of preparation as a kind of medicine of slightly solubility.With reference to U.S.'s listing preparation; If select for use arginine as cosolvent; Because its unstability does not have the corresponding protection measure to protect again; So the growth of its related substance is difficult to suppress, though this novel form is clinically to have brought convenience there is certain drug risk in it like this, for the patient has stayed hidden danger.
Therefore, need a kind of standing time of long and stay-in-grade ibuprofen injection.
Summary of the invention
The purpose of this invention is to provide a kind of ibuprofen injection.
Another object of the present invention provides a kind of method for preparing of ibuprofen injection.
Ibuprofen injection of the present invention comprises ibuprofen and is selected from the anhydride of sodium carbonate, sodium bicarbonate, sodium citrate, sodium citrate, sodium phosphate, dibastic sodium phosphate, sodium tartrate, sodium acetate or one or more the pharmaceutically acceptable alkaline auxiliary solvents in the hydrate.
In one embodiment; Comprise 80g-120g ibuprofen and 30g-55g in every 1000ml ibuprofen injection and be selected from the anhydride of sodium carbonate, sodium bicarbonate, sodium citrate, sodium citrate, sodium phosphate, dibastic sodium phosphate, sodium tartrate, sodium acetate or one or more the pharmaceutically acceptable alkaline auxiliary solvents in the hydrate, and the pH value of injection is 8.0-9.0.
In one embodiment, preferably, comprise ibuprofen 80g-120g in every 1000ml injection, sodium carbonate 30g-55g, surplus is a water for injection; More preferably, comprise ibuprofen 95g-105g and sodium carbonate 40g-48g in every 1000ml ibuprofen injection, surplus is a water for injection; And most preferably, contain ibuprofen 100g in every 1000ml injection, sodium carbonate 45g, surplus is a water for injection.
The method for preparing ibuprofen injection of the present invention comprises the steps:
(1) with 80% water for injection of cumulative volume be selected from the anhydride of sodium carbonate, sodium bicarbonate, sodium citrate, sodium citrate, sodium phosphate, dibastic sodium phosphate, sodium tartrate, sodium acetate or one or more the pharmaceutically acceptable alkaline auxiliary solvent stirring and dissolving in the hydrate;
(2) under 50 ℃-60 ℃, add ibuprofen again, stirring and dissolving, benefit adds to the full amount of water for injection;
(3) fine straining, embedding; And, promptly get 121 ℃ of following pressure sterilizings 15 minutes.
The method for preparing ibuprofen injection of the present invention also comprises the steps:
After said step (2), with activated carbon adsorption, take off charcoal; And measure the content that filters medicinal liquid, article in the middle of checking.
Preferably, the method for preparing of ibuprofen injection of the present invention comprises the steps:
(1) 80% water for injection with cumulative volume mixes stirring and dissolving with sodium carbonate;
(2) under 50 ℃-60 ℃, add ibuprofen again, stirring and dissolving, benefit adds to the full amount of water for injection;
(3) fine straining, embedding; And, promptly get 121 ℃ of following pressure sterilizings 15 minutes.
In addition, this method also comprises the steps:
After said step (2), with activated carbon adsorption, take off charcoal; And measure the changes of contents that filters medicinal liquid, article in the middle of checking.
The present invention selects for use the alkaline auxiliary solvent not only to play the effect of hydrotropy but also can regulate finished product and is in the suitable receptible pH value scope of human injection; (this adjuvant meets the national drug registered standard to special selection injection rank adjuvant sodium carbonate; Particularly up to specification in chloride, ammonium salt, heavy metal, arsenic salt, inspection such as aseptic), this adjuvant is cheap, and is safe; Improve the stability of product acceleration and long term test, guaranteed clinical application safety effectively.Therefore, solve the stability problem of ibuprofen injection effectively, guaranteed the drug safety of these article in storage life, reduced the clinical application risk, widened the medicine scope of application clinically, made things convenient for doctors and patients, had promotional value.
Method for preparing of the present invention is simple to operate, has improved production efficiency, has reduced cost, is fit to large-scale production.
The specific embodiment
Each material among the embodiment all is commercial.
Embodiment 1:
In Agitation Tank, 45g injection stage sodium carbonate is mixed stirring and dissolving with 800ml water for injection; Under 50 ℃-60 ℃, the ibuprofen of 100g is joined in the above-mentioned solution stirring and dissolving; Add water for injection to 1000ml; Then, add needle-use activated carbon absorption 15min again, take off charcoal, and measure the changes of contents that filters medicinal liquid, article in the middle of the check; After middle article detection is qualified, fine straining, embedding, 121 ℃ of following pressure sterilizing 15min promptly get.
Embodiment 2-7:
Except 45g injection stage sodium carbonate is replaced by respectively 35g, 40g, 50g, 55g, 30g, the 42g injection stage sodium carbonate, all the other steps are identical with embodiment 1.
Embodiment 8:
In Agitation Tank, the 45g sodium citrate is mixed stirring and dissolving with 800ml water for injection; Under 50 ℃-60 ℃, the ibuprofen of 100g is joined in the above-mentioned solution stirring and dissolving; Add water for injection to 1000ml; Then, add needle-use activated carbon absorption 15min again, take off charcoal, and measure the changes of contents that filters medicinal liquid, article in the middle of the check; After middle article detection is qualified, fine straining, embedding, 121 ℃ of following pressure sterilizing 15min promptly get.
Embodiment 9-12:
Except the sodium citrate of the sodium tartrate of the sodium acetate of the sodium phosphate that the 45g sodium citrate is replaced by 48g respectively, 50g, 55g, 53g, all the other steps are identical with embodiment 1.
Result of the test:
1. the comparative test of different cosolvents
Because these article are almost insoluble in water; We select sodium hydroxide, sodium carbonate, sodium acetate and sodium citrate as cosolvent respectively; PH value is transferred to about 8.5 to make an experiment; Observe the dissolving situation and with the compatibility test of the glucose injection of 0.9% sodium chloride injection or 5%, the result is following:
The investigation of table 1 cosolvent kind
| Cosolvent | Sodium hydroxide | Sodium carbonate | Sodium acetate | Sodium citrate |
| The dissolving situation | Dissolving fully | Dissolving fully | Dissolving fully | Dissolving fully |
| Freeze and dissolve the back character | Supernatant liquid | Supernatant liquid | Supernatant liquid | Supernatant liquid |
| With the sodium chloride compatibility | Show muddy | Supernatant liquid | Supernatant liquid | Supernatant liquid |
| With the glucose compatibility | Show muddy | Supernatant liquid | Supernatant liquid | Supernatant liquid |
Know by above result; Alkaline auxiliary solvent sodium carbonate, sodium acetate, sodium citrate involved in the present invention can both make ibuprofen dissolve fully; Character does not change after the freeze thawing, with sodium chloride, glucose compatibility after the solution clarification, but that the test of the sample compatibility of dissolution of sodium hydroxide all shows is muddy; So finally select for use sodium carbonate except that sodium hydroxide, sodium acetate, sodium citrate as cosolvent, and the sodium carbonate of selecting wide material sources best is as cosolvent.
2. sodium carbonate is as the optimum selection of flux consumption
Select to add the injection stage sodium carbonate of 2%, 3%, 4.5%, 5.5%, 6% (w/v) respectively, the preparation ibuprofen injection is investigated the dissolving situation earlier, and the result is following:
The selection of table 2 sodium carbonate amount
| Sodium carbonate amount (%) | 2 | 3 | 4.5 | 5.5 | 6 |
| The dissolving situation | Can not dissolve | Dissolving | Dissolving | Dissolving | Dissolving |
| Freeze and dissolve the back character | Supernatant liquid | Supernatant liquid | Supernatant liquid | There is crystal to separate out |
Through 121 ℃ of pressure sterilizing 15min, investigate the variation of sterilization its content of front and back and related substance, select the suitable amounts of injection stage sodium carbonate.The result is following:
The selection of table 3 sodium carbonate amount
Learn by table 3 data, no significant change before and after the sterilization of the content of each sample and related substance before and after the sterilization, the pH value of 4.5% sodium carbonate sample is consistent with blood, and the optimum amount of finally choosing the injection stage sodium carbonate is 4.5% (w/v).
3. exposure experiments to light
The sample that arbitrary preparation embodiment is obtained places under low temperature (4 ℃), room temperature (25 ℃), high temperature (40 ℃), high temperature (60 ℃), 5 kinds of conditions of illumination (4500Lx) to be investigated, and (trade name Caldolor, lot number are W029420AA to get the listing preparation simultaneously; Manufacturer is Cumberland Pharmaceuticals Inc.Nashvile; TN USA) does contrast test, respectively at the 5th day under illumination (4500Lx) condition; Sampling in the 10th day detects, and compares with 0 day result.The result is following:
Table 4 influence factor test
Therefore, there is not obvious variation through sample each item index under each condition of this prepared.
4. accelerated test
Control sample preparation is (according to U.S.'s listing preparation description (source: the U.S. FDA official website)): in Agitation Tank, add 800ml water for injection, add the 78.5g arginine, stirring and dissolving; 50-60 ℃ adds ibuprofen 100.4g down, stirring and dissolving, and pH value is 7.5, benefit adds to the full amount of water for injection; Add 0.5g needle-use activated carbon absorption 15 minutes, take off charcoal, fine straining, fill in ampoule, sealing by fusing; 121 ℃ of pressure sterilizings 15 minutes promptly get.
With the sample of control sample and arbitrary preparation embodiment acquisition, accelerated tests condition (T:40 ℃ RH:75%) was placed 3 months and 6 months the content of investigation ibuprofen solution and the situation of change of related substance.The result is following:
The investigation of table 5 accelerated tests
Visible by table 5 data, ibuprofen injection of the present invention and reference substance injection compare, and content and related substance do not have significant change, and the control sample color burn, so ibuprofen injection of the present invention is placed the stability that has guaranteed product for a long time.
5. safety testing result and evaluation
5.1 adopt Cavia porcellus to carry out the hypersensitive test of these article: result of the test shows that the ibuprofen injection intravenously administrable does not have allergenic effect.
5.2 adopt rabbit to carry out the hemolytic test of these article: result of the test shows that the ibuprofen injection intravenous administration does not have the venous stimulation effect.
5.3 adopt rabbit to carry out the blood vessel irritation test of these article: result of the test shows that ibuprofen injection does not have external haemolysis and agglutination to tame rabbit erythrocyte.
Result of the test shows that these article intravenously administrable is safe.
Claims (8)
1. ibuprofen injection; Its by ibuprofen be selected from the anhydride of sodium carbonate, sodium bicarbonate, sodium citrate, sodium citrate, sodium phosphate, dibastic sodium phosphate, sodium tartrate, sodium acetate or one or more pharmaceutically acceptable alkaline auxiliary solvents and water for injection in the hydrate are formed; Comprise 80g-120g ibuprofen and 30g-55g in wherein every 1000ml ibuprofen injection and be selected from the anhydride of sodium carbonate, sodium bicarbonate, sodium citrate, sodium citrate, sodium phosphate, dibastic sodium phosphate, sodium tartrate, sodium acetate or one or more the pharmaceutically acceptable alkaline auxiliary solvents in the hydrate, and the pH value of injection is 8.0-9.0.
2. an ibuprofen injection comprises ibuprofen 80g-120g, sodium carbonate 30g-55g in wherein every 1000ml ibuprofen injection, and surplus is a water for injection.
3. ibuprofen injection as claimed in claim 2 comprises ibuprofen 95g-105g, sodium carbonate 40g-48g in wherein every 1000ml ibuprofen injection, surplus is a water for injection.
4. ibuprofen injection as claimed in claim 3 contains ibuprofen 100g, sodium carbonate 45g in wherein every 1000ml ibuprofen injection, surplus is a water for injection.
5. method for preparing ibuprofen injection as claimed in claim 1, it comprises the steps:
(1) with 80% water for injection of cumulative volume and the anhydride that is selected from sodium carbonate, sodium bicarbonate, sodium citrate, sodium citrate, sodium phosphate, dibastic sodium phosphate, sodium tartrate, sodium acetate of amount or one or more the pharmaceutically acceptable alkaline auxiliary solvent stirring and dissolving in the hydrate according to claim 1;
(2) under 50 ℃-60 ℃, add ibuprofen again, stirring and dissolving, benefit adds to the full amount of water for injection;
(3) fine straining, embedding; And, promptly get 121 ℃ of following pressure sterilizings 15 minutes.
6. method for preparing as claimed in claim 5, it also comprises the steps:
After said step (2), with activated carbon adsorption, take off charcoal; And
Measure the changes of contents that filters medicinal liquid, article in the middle of the check.
7. method for preparing ibuprofen injection as claimed in claim 2, it comprises the steps:
80% water for injection of cumulative volume is mixed stirring and dissolving with sodium carbonate like the said amount of claim 2;
Under 50 ℃-60 ℃, add ibuprofen again, stirring and dissolving, benefit adds to the full amount of water for injection; Fine straining, embedding; And, promptly get 121 ℃ of following pressure sterilizings 15 minutes.
8. method for preparing as claimed in claim 7, it also comprises the steps:
After said step (2), with activated carbon adsorption, take off charcoal; And
Measure the changes of contents that filters medicinal liquid, article in the middle of the check.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201110023170A CN102085179B (en) | 2011-01-20 | 2011-01-20 | Ibuprofen injection and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201110023170A CN102085179B (en) | 2011-01-20 | 2011-01-20 | Ibuprofen injection and preparation method thereof |
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| CN102085179A CN102085179A (en) | 2011-06-08 |
| CN102085179B true CN102085179B (en) | 2012-08-29 |
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Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9072710B2 (en) | 2012-03-16 | 2015-07-07 | Cumberland Pharmaceuticals Inc. | Injectable ibuprofen formulation |
| US9072661B2 (en) * | 2012-03-16 | 2015-07-07 | Cumberland Pharmaceuticals Inc. | Injectable ibuprofen formulation |
| DK2825039T3 (en) * | 2012-03-16 | 2017-11-27 | Cumberland Pharmaceuticals Inc | Injectable ibuprofen formulation |
| CN103432067A (en) * | 2013-08-31 | 2013-12-11 | 西南大学 | Ketoprofen solution and preparation method thereof |
| CN105796489A (en) * | 2016-03-30 | 2016-07-27 | 北京蓝丹医药科技有限公司 | Ibuprofen injection |
| CN106983718B (en) * | 2016-08-12 | 2019-01-11 | 广东中科药物研究有限公司 | A kind of preparation method of felbinac or its tromethamine saline injection |
| CN111494307A (en) * | 2019-01-30 | 2020-08-07 | 北京普德康利医药科技发展有限公司 | Flurbiprofen injection |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1047801A (en) * | 1990-05-18 | 1990-12-19 | 湖北省天门市兽药厂 | The preparation method of ibuprofen injection for animals |
| CN1513442A (en) * | 2003-06-26 | 2004-07-21 | 昆明市延安医院 | Preparation and use of arginine-ibuprofen mixture |
| CN101069681A (en) * | 2006-05-10 | 2007-11-14 | 汪洪湖 | Injection containing burufen |
-
2011
- 2011-01-20 CN CN201110023170A patent/CN102085179B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1047801A (en) * | 1990-05-18 | 1990-12-19 | 湖北省天门市兽药厂 | The preparation method of ibuprofen injection for animals |
| CN1513442A (en) * | 2003-06-26 | 2004-07-21 | 昆明市延安医院 | Preparation and use of arginine-ibuprofen mixture |
| CN101069681A (en) * | 2006-05-10 | 2007-11-14 | 汪洪湖 | Injection containing burufen |
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