CN105997901A - Ibuprofen tromethamine freeze-dried powder injection composition for infantile injection and preparation method - Google Patents
Ibuprofen tromethamine freeze-dried powder injection composition for infantile injection and preparation method Download PDFInfo
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- CN105997901A CN105997901A CN201610597957.8A CN201610597957A CN105997901A CN 105997901 A CN105997901 A CN 105997901A CN 201610597957 A CN201610597957 A CN 201610597957A CN 105997901 A CN105997901 A CN 105997901A
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- ibuprofen
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- tromethamine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- Oil, Petroleum & Natural Gas (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention provides a stable ibuprofentromethamine freeze-dried powder injection composition for infantile injection and a preparation method. The freeze-dried powder injection composition is prepared from ibuprofen, a solubilizer of tromethamine, an excipient, an osmotic pressure regulator and a pH (potential of hydrogen) regulator. The freeze-dried powder injection composition has the advantagesthat the technology is simple, the cost is low, and the quality can be easily controlled.
Description
Technical field
The present invention relates to containing a kind of children's's freeze-drying preparation for injection that ibuprofen is main pharmacodynamics composition and preparation side thereof
Method.
Background technology
PDA (Patent Ductus Arteriosus, PDA) is that ductus arteriosus is the most not closed
And the pathological state of continuous openness.Ductus arteriosus is the normal channel between Fetal Lung tremulous pulse and aorta, be fetal circulation not
The part that can lack.Along with the foundation of first breath after fetal birth, blood oxygen pressure steeply rises, and catheter wall muscle can be made to send out
Raw contraction；Simultaneously because the activation of prokininase Kallidin I system, some vaso-active substances, the synthesis such as prostaglandin is subject to
Suppression, also promotes ductus arteriosus to shrink and closes.If its continuous openness also produces pathophysiological change, it is PDA.PDA is shadow
Ring survival rate of premature infants and the one of the main reasons of sequelae rate.
Indomethacin is to be found the non-steroidal antiinflammation pain-stopping pharmaceutical effective to PDA the earliest
(NSAID), the synthesis of prostaglandin can be suppressed, but the untoward reaction ratio of its impaired renal function is more prominent.Ibuprofen also falls within non-
Steroidal anti-inflammatory drugs, is nonselective cyclooxygenase-2 inhibitor, and closedown ductus arteriosus mechanism is similar with anti-inflammatory analgetic, and effect is also
Similar, but do not affect the blood flow of brain, mesentery and kidney, also gastrointestinal tract cell is had protective effect.Europe approval in-formation shows
Showing, ibuprofen is better than indomethacin for PDA effect.
At present the preparation of ibuprofen has injection, tablet, dry suspension, granule, drop, effervescent oral cavity disintegration tablet and soft
The dosage form such as cream, gel.Owing to oral formulations needs, with water delivery service, to take inconvenience for pediatric patient more.Injection can be bright
The aobvious compliance improving patient, but there is data to show, and ibuprofen injection stability is bad, in consideration of it, for improving ibuprofen
The stability of preparation, proposes the present invention.Children's's ibuprofen for injection of the present invention tromethamine freezing-dried compositions good stability,
Improve safety, diluent dilution can use, easy to use, and bioavailability is high, is particularly suitable for pediatric patient.
Summary of the invention
It is an object of the invention to provide a kind of stable tromethamine freezing-dried compositions of children's's ibuprofen for injection and
Preparation method.
The present invention provides a kind of stable tromethamine freezing-dried compositions of children's's ibuprofen for injection, and said composition contains
There are ibuprofen, trometamol, excipient, osmotic pressure regulator and pH adjusting agent.
The present invention provides a kind of stable tromethamine freezing-dried compositions of children's's ibuprofen for injection, determination of ibuprofen
Being 2%～10%, preferably determination of ibuprofen is 3%～8%.
The present invention provides a kind of stable tromethamine freezing-dried compositions of children's's ibuprofen for injection, ibuprofen and ammonia
Butantriol is 1:0.8～1.2 in molar ratio；Excipient content is 60%～90%.
The present invention provides a kind of stable tromethamine freezing-dried compositions of children's's ibuprofen for injection, and excipient includes
One or more following compositions: mannitol, sorbitol, lactose, glucose, sucrose, levulose acid anhydride, amino acids, glucosan and
Polyethylene Glycol etc., preferably mannitol, sorbitol, lactose.
The present invention provides a kind of stable tromethamine freezing-dried compositions of children's's ibuprofen for injection, pH value regulator
Including: sodium hydroxide solution and hydrochloric acid solution etc..
The present invention provides a kind of stable tromethamine freezing-dried compositions of children's's ibuprofen for injection, and osmotic pressure regulates
The preferred sodium chloride of agent.
The present invention provides the preparation method of a kind of stable tromethamine freezing-dried compositions of children's's ibuprofen for injection,
Preparation method is as follows: a dissolves: add the excipient of dosage, trometamol, sodium chloride and ibuprofen mixing in material-compound tank,
Inject and blunge to being completely dissolved, use appropriate sodium hydroxide solution or hydrochloric acid solution regulation solution ph, control pH
Value scope is between 6.0～8.0；B ultrafiltration: solution is carried out in the environment of aseptic ultrafiltration, then carries out aseptic subpackaged, score
Solution after dress；C lyophilization: canned semi-finished product are carried out lyophilization, obtains white lyophilized powder, is children's's injection
By tromethamine freezing-dried dose of compositions of ibuprofen, this ibuprofen lyophilized injectable powder is carried out aseptic subpackaged and nitrogen charging is airtight
Envelope.
The present invention provides the preparation method of a kind of stable tromethamine freezing-dried compositions of children's's ibuprofen for injection,
It is characterized in that: one or more adjuvants being initially charged dosage in step a are completely dissolved, and under stirring, then are slowly added into
Ibuprofen, to being completely dissolved；Or addition ibuprofen, stirring is lower adds other adjuvants；Or add ibuprofen with one or both with
Upper adjuvant, stirring is lower adds other adjuvants；Use appropriate sodium hydroxide solution or hydrochloric acid solution regulation solution ph, control pH
Value scope is between 6.0～8.0.B ultrafiltration: solution is carried out in the environment of aseptic ultrafiltration, then carries out aseptic subpackaged, score
Solution after dress；C lyophilization: canned semi-finished product are carried out lyophilization, obtains white lyophilized powder, is children's's injection
By tromethamine freezing-dried dose of compositions of ibuprofen, this ibuprofen lyophilized injectable powder is carried out aseptic subpackaged and nitrogen charging is airtight
Envelope.
The present invention provides the preparation method of a kind of stable tromethamine freezing-dried compositions of children's's ibuprofen for injection,
It is characterized in that in wherein step a, the mass ratio of water for injection and ibuprofen is 200:1～80:1.
The present invention provides the preparation method of a kind of stable tromethamine freezing-dried compositions of children's's ibuprofen for injection,
Its feature adds 25 DEG C～the water for injection of 80 DEG C in step a.
Detailed description of the invention
Technical solution of the present invention is not limited to act detailed description of the invention set forth below, also includes between each detailed description of the invention
Combination in any.
Example 1
Preparation method:
1) mixing of dosage trometamol, mannitol, sodium chloride and ibuprofen being added 60 DEG C of waters for injection, stirring is to the most molten
Solve；
2) ultrafiltration: solution is carried out in the environment of aseptic ultrafiltration, then carries out aseptic subpackaged, obtain the solution after subpackage；
3) canned semi-finished product are carried out lyophilization, freeze-drying curve technological parameter: be cooled to-40 DEG C at full speed, be incubated 2～5
Hour；Vacuum is down to below 10Pa, opens heating, is warming up to-15 DEG C, is incubated 6～10 hours；0 DEG C, it is incubated 1～5 hour,
It is warming up to 25 DEG C, is incubated 8～20 hours；Lyophilizing terminates, nitrogen charging, vacuum tamponade, seals aluminium lid.
Example 2
Preparation method:
1) mixing of dosage trometamol, mannitol, sodium chloride and ibuprofen being added 60 DEG C of waters for injection, stirring is to the most molten
Solve；
2) ultrafiltration: solution is carried out in the environment of aseptic ultrafiltration, then carries out aseptic subpackaged, obtain the solution after subpackage；
3) canned semi-finished product are carried out lyophilization, freeze-drying curve technological parameter: be cooled to-40 DEG C at full speed, be incubated 2～5
Hour；Vacuum is down to below 10Pa, opens heating, is warming up to-15 DEG C, is incubated 6～10 hours；0 DEG C, it is incubated 1～5 hour,
It is warming up to 25 DEG C, is incubated 8～20 hours；Lyophilizing terminates, nitrogen charging, vacuum tamponade, seals aluminium lid.
Example 3
Preparation method:
1) mixing of dosage ibuprofen is added 60 DEG C of waters for injection, add trometamol, mannitol, sodium chloride under stirring to complete
CL；
2) ultrafiltration: solution is carried out in the environment of aseptic ultrafiltration, then carries out aseptic subpackaged, obtain the solution after subpackage；
3) canned semi-finished product are carried out lyophilization, freeze-drying curve technological parameter: be cooled to-40 DEG C at full speed, be incubated 2～5
Hour；Vacuum is down to below 10Pa, opens heating, is warming up to-15 DEG C, is incubated 6～10 hours；0 DEG C, it is incubated 1～5 hour,
It is warming up to 25 DEG C, is incubated 8～20 hours；Lyophilizing terminates, nitrogen charging, vacuum tamponade, seals aluminium lid.
Example 4
Preparation method:
1) dosage sodium chloride and ibuprofen being mixed 60 DEG C of waters for injection of addition, stirring lower addition trometamol and mannitol are complete
CL；
2) ultrafiltration: solution is carried out in the environment of aseptic ultrafiltration, then carries out aseptic subpackaged, obtain the solution after subpackage；
3) canned semi-finished product are carried out lyophilization, freeze-drying curve technological parameter: be cooled to-40 DEG C at full speed, be incubated 2～5
Hour；Vacuum is down to below 10Pa, opens heating, is warming up to-15 DEG C, is incubated 6～10 hours；0 DEG C, it is incubated 1～5 hour,
It is warming up to 25 DEG C, is incubated 8～20 hours；Lyophilizing terminates, nitrogen charging, vacuum tamponade, seals aluminium lid.
Sample prepared by examples detailed above 2 is set low respectively temperature 4 DEG C, high temperature 60 DEG C, under the conditions of illumination 4500Lx 10 days, point
Not the 5th day, sampling detection in 10 days, testing result is shown in Table 1.Result understands, and self-control sample is in low temperature 4 DEG C, high temperature 60 DEG C, illumination
Stablizing under the conditions of 4500Lux, content and other every examination indexs are the most unchanged.
The related test results 1 of table 1 injection trometamol ibuprofen freeze-dried powder compositions
Claims (12)
1. the stable tromethamine freezing-dried compositions of children's's ibuprofen for injection, it is characterised in that said composition contains
Ibuprofen, trometamol, excipient, osmotic pressure regulator and pH adjusting agent, determination of ibuprofen is 2%～10%.
Compositions the most according to claim 1, preferably determination of ibuprofen are 3%～8%.
Compositions the most according to claim 1, it is characterised in that ibuprofen and trometamol be in molar ratio 1:0.8～
1.2。
Compositions the most according to claim 1, it is characterised in that excipient content is 60%～90%.
Compositions the most according to claim 1, it is characterised in that described excipient includes one or more following compositions:
Mannitol, sorbitol, lactose, glucose, sucrose, levulose acid anhydride, amino acids, glucosan and Polyethylene Glycol.
Compositions the most according to claim 5, preferably mannitol, sorbitol, lactose etc..
Tromethamine freezing-dried dose of compositions of children's's ibuprofen for injection the most according to claim 6, it is characterised in that
Described pH value regulator includes: sodium hydroxide solution and hydrochloric acid solution etc..
Tromethamine freezing-dried dose of compositions of children's's ibuprofen for injection the most according to claim 6, it is characterised in that
The described preferred sodium chloride of osmotic pressure regulator.
The preparation method of tromethamine freezing-dried dose of compositions of children's's ibuprofen for injection the most according to claim 6,
It is characterized in that a dissolves: in material-compound tank, add the excipient of dosage, trometamol, sodium chloride and ibuprofen, inject use
Water stirs to being completely dissolved, and uses sodium hydroxide solution or hydrochloric acid solution regulation solution ph, pH value range control 6.0～
Between 8.0；B ultrafiltration: solution is carried out in the environment of aseptic ultrafiltration, then carries out aseptic subpackaged, obtain the solution after subpackage；c
Lyophilization: canned semi-finished product are carried out lyophilization, obtains white lyophilized powder, is children's's ibuprofen for injection ammonia fourth
Triol lyophilized injectable powder compositions, carries out aseptic subpackaged and inflated with nitrogen sealing by this ibuprofen lyophilized injectable powder.
The preparation method of tromethamine freezing-dried dose of compositions of children's's ibuprofen for injection the most according to claim 9,
It is characterized in that in wherein step a, the mass ratio of water for injection and ibuprofen is 200:1～80:1.
11. according to the preparation of the tromethamine freezing-dried dose of compositions of children's's ibuprofen for injection described in claim 9 or 10
Method, it is characterised in that one or more adjuvants being initially charged dosage in step a are completely dissolved, under stirring, more slowly
Add ibuprofen, to being completely dissolved；Or addition ibuprofen, stirring is lower adds other adjuvants；Or add ibuprofen and one or two
Planting above adjuvant, stirring is lower adds other adjuvants.
12. according to the preparation of the tromethamine freezing-dried dose of compositions of children's's ibuprofen for injection described in claim 9～10
Method, it is characterised in that add 20 DEG C～the water for injection of 80 DEG C in step a.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610597957.8A CN105997901A (en) | 2016-07-27 | 2016-07-27 | Ibuprofen tromethamine freeze-dried powder injection composition for infantile injection and preparation method |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610597957.8A CN105997901A (en) | 2016-07-27 | 2016-07-27 | Ibuprofen tromethamine freeze-dried powder injection composition for infantile injection and preparation method |
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| CN105997901A true CN105997901A (en) | 2016-10-12 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111494308A (en) * | 2019-01-30 | 2020-08-07 | 北京蓝丹医药科技有限公司 | Stable flurbiprofen injection |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000056325A2 (en) * | 1999-03-19 | 2000-09-28 | Merckle Gmbh | Ibuprofen solution |
| CN101069681A (en) * | 2006-05-10 | 2007-11-14 | 汪洪湖 | Injection containing burufen |
| CN101077336A (en) * | 2006-06-02 | 2007-11-28 | 汪洪湖 | Injection containing ketoprofen and preparation method thereof |
| CN102370615A (en) * | 2010-08-19 | 2012-03-14 | 四川科伦药物研究有限公司 | Ibuprofen injection preparation and preparation method thereof |
| CN102892410A (en) * | 2010-05-18 | 2013-01-23 | 西班牙制药公司 | Pharmaceutical composition of ibuprofen for injection |
| CN104622816A (en) * | 2015-01-04 | 2015-05-20 | 济南东方开元医药新技术有限公司 | Ibuprofenlyophilized powder composition and preparation method |
| CN105616347A (en) * | 2016-03-22 | 2016-06-01 | 陕西天宇制药有限公司 | Medicinal composition containing ibuprofen and preparation method of medicinal composition |
-
2016
- 2016-07-27 CN CN201610597957.8A patent/CN105997901A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000056325A2 (en) * | 1999-03-19 | 2000-09-28 | Merckle Gmbh | Ibuprofen solution |
| CN101069681A (en) * | 2006-05-10 | 2007-11-14 | 汪洪湖 | Injection containing burufen |
| CN101077336A (en) * | 2006-06-02 | 2007-11-28 | 汪洪湖 | Injection containing ketoprofen and preparation method thereof |
| CN102892410A (en) * | 2010-05-18 | 2013-01-23 | 西班牙制药公司 | Pharmaceutical composition of ibuprofen for injection |
| CN102370615A (en) * | 2010-08-19 | 2012-03-14 | 四川科伦药物研究有限公司 | Ibuprofen injection preparation and preparation method thereof |
| CN104622816A (en) * | 2015-01-04 | 2015-05-20 | 济南东方开元医药新技术有限公司 | Ibuprofenlyophilized powder composition and preparation method |
| CN105616347A (en) * | 2016-03-22 | 2016-06-01 | 陕西天宇制药有限公司 | Medicinal composition containing ibuprofen and preparation method of medicinal composition |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111494308A (en) * | 2019-01-30 | 2020-08-07 | 北京蓝丹医药科技有限公司 | Stable flurbiprofen injection |
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