CN101978945A - Ibuprofen medicinal composition - Google Patents
Ibuprofen medicinal composition Download PDFInfo
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- CN101978945A CN101978945A CN2010105249421A CN201010524942A CN101978945A CN 101978945 A CN101978945 A CN 101978945A CN 2010105249421 A CN2010105249421 A CN 2010105249421A CN 201010524942 A CN201010524942 A CN 201010524942A CN 101978945 A CN101978945 A CN 101978945A
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- Prior art keywords
- ibuprofen
- injection
- arginine
- composition solution
- pharmaceutical composition
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- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 title claims abstract description 111
- 229960001680 ibuprofen Drugs 0.000 title claims abstract description 104
- 239000000203 mixture Substances 0.000 title claims abstract description 58
- 239000004475 Arginine Substances 0.000 claims abstract description 47
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims abstract description 47
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims abstract description 41
- 229960000281 trometamol Drugs 0.000 claims abstract description 41
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims abstract description 26
- 235000009697 arginine Nutrition 0.000 claims description 46
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 40
- 239000008194 pharmaceutical composition Substances 0.000 claims description 34
- 229960003121 arginine Drugs 0.000 claims description 20
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 18
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 8
- HEFNNWSXXWATRW-JTQLQIEISA-N dexibuprofen Chemical compound CC(C)CC1=CC=C([C@H](C)C(O)=O)C=C1 HEFNNWSXXWATRW-JTQLQIEISA-N 0.000 claims description 7
- HEFNNWSXXWATRW-SNVBAGLBSA-N levibuprofen Chemical compound CC(C)CC1=CC=C([C@@H](C)C(O)=O)C=C1 HEFNNWSXXWATRW-SNVBAGLBSA-N 0.000 claims description 6
- 229930064664 L-arginine Natural products 0.000 claims description 5
- 235000014852 L-arginine Nutrition 0.000 claims description 5
- 208000002193 Pain Diseases 0.000 claims description 5
- 230000036407 pain Effects 0.000 claims description 5
- ODKSFYDXXFIFQN-SCSAIBSYSA-N D-arginine Chemical compound OC(=O)[C@H](N)CCCNC(N)=N ODKSFYDXXFIFQN-SCSAIBSYSA-N 0.000 claims description 4
- 229930028154 D-arginine Natural products 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 206010061218 Inflammation Diseases 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 230000004054 inflammatory process Effects 0.000 claims description 2
- 125000002059 L-arginyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C([H])([H])C([H])([H])N([H])C(=N[H])N([H])[H] 0.000 claims 1
- 239000000243 solution Substances 0.000 abstract description 67
- 229940090044 injection Drugs 0.000 abstract description 21
- 239000007924 injection Substances 0.000 abstract description 21
- 238000002347 injection Methods 0.000 abstract description 21
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 abstract description 20
- 229940093181 glucose injection Drugs 0.000 abstract description 19
- 239000008354 sodium chloride injection Substances 0.000 abstract description 19
- CYDQOEWLBCCFJZ-UHFFFAOYSA-N 4-(4-fluorophenyl)oxane-4-carboxylic acid Chemical compound C=1C=C(F)C=CC=1C1(C(=O)O)CCOCC1 CYDQOEWLBCCFJZ-UHFFFAOYSA-N 0.000 abstract description 17
- 229940005581 sodium lactate Drugs 0.000 abstract description 17
- 239000001540 sodium lactate Substances 0.000 abstract description 17
- 235000011088 sodium lactate Nutrition 0.000 abstract description 17
- 239000008156 Ringer's lactate solution Substances 0.000 abstract description 16
- 238000002474 experimental method Methods 0.000 abstract description 2
- 238000003756 stirring Methods 0.000 description 27
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 24
- 239000008215 water for injection Substances 0.000 description 24
- BMLSTPRTEKLIPM-UHFFFAOYSA-I calcium;potassium;disodium;hydrogen carbonate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].OC([O-])=O BMLSTPRTEKLIPM-UHFFFAOYSA-I 0.000 description 15
- 229910052799 carbon Inorganic materials 0.000 description 13
- 239000012528 membrane Substances 0.000 description 12
- 238000000034 method Methods 0.000 description 12
- 239000003610 charcoal Substances 0.000 description 11
- 229940105082 medicinal charcoal Drugs 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 239000007788 liquid Substances 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 238000010790 dilution Methods 0.000 description 5
- 239000012895 dilution Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 4
- 229940088523 ibuprofen injection Drugs 0.000 description 4
- 230000000694 effects Effects 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 238000012856 packing Methods 0.000 description 3
- 230000001954 sterilising effect Effects 0.000 description 3
- 238000004659 sterilization and disinfection Methods 0.000 description 3
- 102000004452 Arginase Human genes 0.000 description 2
- 108700024123 Arginases Proteins 0.000 description 2
- GCCOJNYCFNSJII-VWMHFEHESA-N [n'-[(4s)-4-amino-4-carboxybutyl]carbamimidoyl]azanium;2-[4-(2-methylpropyl)phenyl]propanoate Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N.CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 GCCOJNYCFNSJII-VWMHFEHESA-N 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000010494 opalescence Effects 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 230000006340 racemization Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 208000005171 Dysmenorrhea Diseases 0.000 description 1
- 206010013935 Dysmenorrhoea Diseases 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 235000019658 bitter taste Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229940072709 motrin Drugs 0.000 description 1
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 239000011265 semifinished product Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses an ibuprofen medicinal composition for injection. By adding tromethamine into solution of ibuprofen and arginine, the stability of the ibuprofen medicinal composition in clinical application is improved. Experiments prove that: after being diluted by the sodium chloride injection or glucose injection or sodium lactate Ringers injection, the composition solution can be stably stored for at least 12 hours.
Description
Technical field
The invention discloses a kind of pharmaceutical composition solution of ibuprofen, concrete is the pharmaceutical composition that comprises Bu Luo, arginine, trometamol, belongs to field of medicaments.
Background technology
Ibuprofen is a nonsteroidal antiinflammatory and analgesic medicine commonly used clinically, chemical name 2-(4-isobutyl phenenyl) propanoic acid, have analgesic significantly, analgesia, anti-inflammatory effect, main treatment of arthritis, alleviate the polytype that causes such as flu, dysmenorrhea etc. slightly and moderate pain.At present the ibuprofen of using mainly is a raceme, and the existing S-of studies confirm that ibuprofen has pharmacologically active in human body, and the R-ibuprofen is invalid substantially, after the R-ibuprofen enters human body, just has pharmacologically active after having 60% to be converted to the S-ibuprofen approximately.Because the S-ibuprofen is compared the ibuprofen mouthfeel better (not having bitterness) of racemization, therefore receives an acclaim day by day in field of medicaments.
Because the dissolubility of ibuprofen in water is very low, therefore preparing a kind of brufen composition soluble in water becomes the problem that a medicine industry is paid close attention to.Although normally clinically preferential selection of oral formulations, but all there are technical problems such as stripping is slow, absorption is incomplete in common ibuprofen dosage form such as tablet, powder, capsule etc., in addition for some can not, uncomfortable or inconvenience uses the oral drugs patient, if injectable ibuprofen can be provided, provide a kind of new pain relief or fever therapy to select then can for these patients.Therefore the ibuprofen for injection compositions has become the hot technology of present pharmaceutical field.
Existing technology, as US5200558 by ibuprofen and the arginine that is not less than the ibuprofen consumption are prepared into ibuprofen arginine, but this can cause arginic consumption waste, need adopt unnecessary technology operation that arginine is separated when producing simultaneously; CN018237649 has carried out certain technological improvement at the problems referred to above, be controlled at less than 1: 1 by mol ratio arginine and ibuprofen, thereby reduced production stage, but find in the practical application, rear stability is not good behind compositions that this technical scheme provides and sodium chloride injection or glucose injection or the sodium lactate ringer's injection compatibility, can become rapidly muddy and visible medicine will occur and separate out with interior, bring very big difficulty to practical clinical at 2 hours; CN031455042 discloses the mixture of a kind of arginine and ibuprofen, by the two being dissolved in ethanol evaporate to dryness ethanol acquisition then, yet this application does not still overcome the ibuprofen arginine composition dissolves in sodium chloride injection or glucose injection or the not good problem of sodium lactate ringer's injection stability, the reduction of further aggravation stability of simultaneously residual ethanol; The similar techniques scheme has also prepared the complex similar to CN031455042 as CN2009100933135, can not solve the long-time stability problem after glucose injection or sodium chloride injection dilution equally.
Because ibuprofen solution (injection) ibuprofen concentration is higher, direct injection is known from experience in the people and is produced serious injection pain and side reaction, so all need dilute laggard row vein infusion during clinical practice.Normally adopt the glucose injection of 0.9% sodium chloride injection or 5% or sodium lactate ringer's injection is diluted to 4mg/mL or lower concentration can use to patient, as mentioned above, though the ibuprofen solution that the prior art field provides has tentatively solved the low problem of ibuprofen dissolubility, but the ibuprofen solution that it provided stable very poor in sodium chloride injection, glucose injection or sodium lactate Green injection etc. when clinical practice, usually will occur precipitation in 2 hours, clinical practice is difficulty very.
Therefore, this area still need a kind ofly not only solve the water solublity problem of cloth Lip river branch but also can keep long-time stable ibuprofen for injection compositions in environment such as sodium chloride injection, glucose injection and sodium lactate ringer's injection.
Summary of the invention
The applicant is surprised to find in a large amount of experimental studies, by trometamol being joined the problem that has not only solved the ibuprofen poorly water-soluble in ibuprofen, the arginic solution, and the stability of prepared composition solution in sodium chloride injection or glucose injection or sodium lactate ringer's injection has had raising extremely significantly, obviously is better than the stability of ibuprofen injection in sodium chloride injection or glucose injection or sodium lactate ringer's injection that prior art provides.The experiment that the applicant carries out shows, at least can stable existence after present composition solution dilutes with sodium chloride injection or glucose injection or sodium lactate ringer's injection 12 hours.
Ibuprofen pharmaceutical composition solution of the present invention comprises ibuprofen, arginine, trometamol.Wherein the mass ratio of ibuprofen, arginine, trometamol can be 1: 0.1-10: 0.05-5, the mass ratio of preferred ibuprofen, arginine, trometamol can be 1: 0.2-5: 0.1-3, the mass ratio of preferred ibuprofen, arginine, trometamol can be 1: 0.5-1.5: 0.2-1.
In pharmaceutical composition solution of the present invention, described ibuprofen can be the R-ibuprofen, S-ibuprofen or the mixture racemic ibuprofen of the two (RS-ibuprofen), although have only the S-ibuprofen in human body, to have direct physiologically active, but it is as well known to those skilled in the art, can be converted into the S-ibuprofen under the effect of R-ibuprofen relevant protease in human body, existing most Ibuprofen medicinal preparation also is the ibuprofen (mixture of R-ibuprofen and S-ibuprofen) that adopts racemization, therefore do not limit the type of ibuprofen among the present invention, the pharmacologically active that adopts which kind of ibuprofen enantiomer to be played in human body at last all is consistent, based on the consideration of production and raw material sources, the present composition preferably adopts racemic ibuprofen.
In pharmaceutical composition solution of the present invention, described arginine is a kind of of common amino acid, the aminoacid of majority as well known to those skilled in the art all has D or two kinds of configurations of L, same arginine also has two kinds of D-arginine and L-arginine, the difference of the two only is the optic left hand and the right hand, do not influence its pharmacy physicochemical property, therefore being applied to arginine of the present invention can be D-arginine, L-arginine or the mixture of the two.The consideration of backbone production and raw material sources, the present invention preferably adopts the L-arginine.
In pharmaceutical composition solution of the present invention, trometamol is as stabilizing agent, thereby makes present composition solution clear and bright and significantly improve its stability at sodium chloride injection or glucose injection, do not separate out for a long time.By adding trometamol, present composition solution can reach more suitably alkaline environment, the present composition be fit to pH be 7-10, the pH that preferably is fit to present composition solution is 7.4-9.After adding the stabilizing agent of trometamol as present composition solution, present composition solution can keep 12 hours steady statue after adopting common clinically glucose injection or sodium chloride injection or sodium lactate ringer's injection dilution at least, obviously is better than the ibuprofen injection (promptly separating out in two hours usually) that prior art provides.
On the basis of the above, present composition solution ethylene glycol, propylene glycol or the mixture of the two that can also add ibuprofen consumption (in mass) 1-10% further increases the stability of the present composition self and in the stability of glucose injection or sodium chloride injection or sodium lactate ringer's injection.
Further, the invention provides the preparation method of described brufen composition solution, may further comprise the steps:
1. with arginine, trometamol and ibuprofen are added to the water, and are stirred to dissolving, and be clear and bright.
2. in above-mentioned solution, add active carbon, filter, remove active carbon then; Add water for injection,, use 0.22 μ m microporous filter membrane fine straining then, both got present composition solution to desired concn.
In above-mentioned preparation method,, therefore can in step 2, add the step that is cooled to room temperature according to demand of practical production owing in actual production, adopt 60 or 80 ℃ water for injection usually.
On the basis of the above, be semi-finished product with above-mentioned ibuprofen pharmaceutical composition solution, further be prepared into the common injection of pharmaceutical field, include but not limited to following several injection type:
1. ibuprofen injection: the ibuprofen pharmaceutical composition solution is packaged in the ampoule bottle, seals, high temperature 115-126 ℃ (normally 121 ℃) are sterilization 10-30min down, packing, stores.When clinical use, it is diluted to desired concn with sodium chloride injection or glucose injection or sodium lactate ringer's injection.
2. ibuprofen transfusion: earlier that article such as infusion bottle, plug washing sterilization is standby; With ibuprofen pharmaceutical composition solution and conventional transfusion with the adjuvant aqueous solution evenly the back fill in infusion bottle, tamponade, high temperature 115-126 ℃ (normally 121 ℃) are sterilization 10-40min down, packing, stores.
Although the ibuprofen of using in this area is this dosage form of injection of ibuprofen pharmaceutical compositions, ibuprofen pharmaceutical composition solution of the present invention is not restricted to be prepared into above-mentioned ejection preparation, those skilled in the art's spirit according to the present invention is prepared into other ejection preparation with it, lyophilized formulations for example, also be fine, this still belongs to scope of the present invention.
Accordingly, the present invention also provides the purposes of injection in the medicine of the treatable diseases of any Motrin known in the art such as preparation treatment pain, inflammation, heating of above-mentioned ibuprofen pharmaceutical composition solution and preparation thereof.To those skilled in the art, the effect that present composition solution has the treatment relevant disease is conspicuous, and medication and dosage can be adjusted accordingly according to clinical requirement.
The specific embodiment
In the following embodiments, given embodiment only is used to illustrate the technical step that can realize the present invention program, does not limit the present invention and only implements with following method.In the following embodiments, used ibuprofen is racemic ibuprofen, used arginine is the L-arginine, as the applicant described in the summary of the invention, R as well known to those skilled in the art or S ibuprofen, D-arginine or D and the arginine mixed compound of L can do be equal to alternative.
Embodiment 1
Ibuprofen 500g
Arginine 400g
Trometamol 100g
Add water to 5L
Get 3L water for injection, add arginine and ibuprofen, be stirred to dissolving, add trometamol then, stirring makes dissolving and mix homogeneously, add 0.2% (2g/L) medical active carbon, stir 30min, remove by filter medicinal charcoal, be cooled to room temperature, add water to 5L then, 0.22 μ m microporous filter membrane fine straining had both got present composition solution.The gained solution PH is 8.3, and concentration is 100mg/mL.
The ibuprofen pharmaceutical composition solution is packaged in the ampoule bottle, 121 ℃ of 15min that sterilize down, packing stores then, is packed as 1000 bottles.When clinical use, it is diluted to desired concn with normal saline or glucose solution.
Embodiment 2
Ibuprofen 500g
Arginine 500g
Trometamol 5g
Add water to 5L
Get 2.5L water for injection, add arginine and ibuprofen, be stirred to dissolving, add trometamol then, stir and make dissolving and mix homogeneously, add 0.2% medical active carbon, stir 30min, remove by filter medicinal charcoal, continue to add water for injection then and be diluted to 5L, 0.22 μ m microporous filter membrane fine straining had both got present composition solution.Concentration is 100mg/mL.
Method according to embodiment 1 is prepared into injection.
Embodiment 3
Ibuprofen 500g
Arginine 1000g
Trometamol 25g
Propylene glycol 100g
Thin up is to 5L
Get 3L water for injection, add arginine, ibuprofen, trometamol, be stirred to dissolving, add propylene glycol then, stir and make mix homogeneously, add 0.2% (2g/L) medical active carbon, stir 30min, remove by filter medicinal charcoal, continue to add water for injection then and be diluted to 5L, 0.22 μ m microporous filter membrane fine straining had both got present composition solution.Concentration is 100mg/mL.
Method according to embodiment 1 is prepared into injection.
Embodiment 4
Ibuprofen 500g
Arginine 400g
Trometamol 150g
Thin up is to 5L
Get 3L water for injection, add arginine, ibuprofen, trometamol, stirring makes mix homogeneously, add 0.2% (2g/L) medical active carbon, stir 30min, remove by filter medicinal charcoal, continue to add water for injection then and be diluted to 5L, 0.22 μ m microporous filter membrane fine straining had both got present composition solution.The gained solution PH is 7.8, and concentration is 100mg/ml.
Method according to embodiment 1 is prepared into injection.
Embodiment 5
Ibuprofen 500g
Arginine 1000g
Trometamol 25g
Thin up 5L
Get 2L water for injection, add arginine, ibuprofen, trometamol, stirring makes mix homogeneously, add 0.2% (2g/L) medical active carbon, stir 30min, remove by filter medicinal charcoal, continue to add water for injection then and be diluted to 5L, 0.22 μ m microporous filter membrane fine straining had both got present composition solution.Concentration is 100mg/mL.
Method according to embodiment 1 is prepared into injection.
Embodiment 6
Ibuprofen 500g
Arginine 500g
Trometamol 25g
Thin up is to 3.3L
Get 2L water for injection, add arginine, ibuprofen, trometamol, stirring makes mix homogeneously, add 0.2% (2g/L) medical active carbon, stir 30min, remove by filter medicinal charcoal, continue to add water for injection then and be diluted to 3.3L, 0.22 μ m microporous filter membrane fine straining had both got present composition solution.Concentration is 152mg/ml.
Method according to embodiment 1 is prepared into injection.
Embodiment 7
Ibuprofen 400g
Arginine 300g
Trometamol 120g
Thin up is to 5L
Get 2L water for injection, add arginine, ibuprofen, trometamol, stirring makes mix homogeneously, add 0.2% (2g/L) medical active carbon, stir 30min, remove by filter medicinal charcoal, continue to add water for injection then and be diluted to 5L, 0.22 μ m microporous filter membrane fine straining had both got present composition solution.Concentration is 80mg/ml.
Method according to embodiment 1 is prepared into injection.
Embodiment 8
Ibuprofen 300g
Arginase 12 40g
Trometamol 120g
Thin up is to 5L
Get 2L water for injection, add arginine, ibuprofen, trometamol, stirring makes mix homogeneously, add 0.2% (2g/L) medical active carbon, stir 30min, remove by filter medicinal charcoal, continue to add water for injection then and be diluted to 5L, 0.22 μ m microporous filter membrane fine straining had both got present composition solution.Concentration is 60mg/ml.
Method according to embodiment 1 is prepared into injection.
Embodiment 9
Ibuprofen 200g
Arginine 600g
Trometamol 120g
Thin up is to 5L
Get 2L water for injection, add arginine, ibuprofen, trometamol, stir and make mix homogeneously, add 0.2% (2g/L) medical active carbon, stir 30min, remove by filter medicinal charcoal, continue to add water for injection then and be diluted to 5L, 0.22 μ m microporous filter membrane fine straining had both got present composition solution.Concentration is 40mg/ml.
Method according to embodiment 1 is prepared into injection.
Embodiment 10
Ibuprofen 100g
Arginine 30g
Trometamol 20g
Thin up is to 5L
Get 2L water for injection, add arginine, ibuprofen, trometamol, stirring makes mix homogeneously, add 0.2% (2g/L) medical active carbon, stir 30min, remove by filter medicinal charcoal, continue to add water for injection then and be diluted to 5L, 0.22 μ m microporous filter membrane fine straining had both got present composition solution.Concentration is 20mg/ml.
Method according to embodiment 1 is prepared into injection.
Embodiment 11
Ibuprofen 100g
Arginase 12 20g
Trometamol 120g
Thin up is to 5L
Get 2L water for injection, add arginine, ibuprofen, trometamol, stirring makes mix homogeneously, add 0.2% (2g/L) medical active carbon, stir 30min, remove by filter medicinal charcoal, continue to add water for injection then and be diluted to 5L, 0.22 μ m microporous filter membrane fine straining had both got present composition solution.Concentration is 20mg/ml.
Method according to embodiment 1 is prepared into injection.
The comparative example 1
Arginine 4.384kg
Ibuprofen 5.62kg
Thin up is to 56.2L
Arginine joined in the 45L water for injection dissolve, add ibuprofen then and be stirred to mix homogeneously, the gained solution PH is 7.4, and the gained solution with water is diluted to 56.2L, and produce arginine: the ibuprofen mol ratio is the solution of 0.92: 1 100mg/mL.
The comparative example 2
Arginine 7.1g
Ibuprofen 10g
Add water to 100mL
Arginine is placed the 100mL volumetric flask, add and be stirred to dissolving fully under 30mL distilled water and the room temperature, again ibuprofen is slowly joined after with anhydrous alcohol solution stir 30min in the volumetric flask after adding distil water to the standardize solution scale, it is clear and bright to solution to add a cover 25 ℃ of stirrings of constant temperature 10h, uncap and continue to stir 2h, wave diffusing ethanol, gained ibuprofen solution concentration is 100mg/mL, and PH is 7.2.
The comparative example 3
Trometamol 6g
Ibuprofen 10g
Add water to 100ml.
Trometamol is placed the 100mL volumetric flask, add and be stirred to dissolving fully under 50mL distilled water and the room temperature, again ibuprofen is slowly joined after with anhydrous alcohol solution stir 30min in the volumetric flask after adding distil water to the standardize solution scale, find that gained solution is stopping to stir back generation precipitation rapidly this moment, the solution muddiness illustrates that trometamol can't improve the dissolubility of ibuprofen in water.
The ibuprofen solution that the applicant provides the ibuprofen pharmaceutical composition solution and the prior art of the present invention preparation is observed through 0.9% sodium chloride injection, 5% glucose injection and the stability after the sodium lactate ringer's injection dilution.
Sample 1: the embodiment of the invention 4 gained ibuprofen pharmaceutical composition solution 4mL.
Sample 2: the embodiment of the invention 10 gained ibuprofen pharmaceutical composition solution 4mL.
Sample 3: the embodiment of the invention 11 gained ibuprofen pharmaceutical composition solution 4mL.
Sample 4: comparative example 1 gained ibuprofen pharmaceutical composition solution 4mL.
Sample 5: comparative example 2 gained ibuprofen pharmaceutical composition solution 4mL.
Method of testing: under the room temperature sample is joined respectively in the sodium chloride injection, 5% glucose injection and sodium lactate ringer's injection of 100mL.9%, observe it and can keep the clear and bright time under clarity test instrument lamp, the gained result is as shown in the table:
Table 1: the clear and bright time of different samples
By table 1 as seen, ibuprofen pharmaceutical composition solution of the present invention is when clinical practice, and the stability after the sodium chloride injection of employing 0.9% or 5% glucose injection or the sodium lactate ringer's injection dilution significantly is better than the ibuprofen injection that prior art can provide.
The applicant observes the effect that adds propylene glycol, ethylene glycol etc. in the pharmaceutical composition solution of the present invention, method of testing as above, gained result such as following table:
Sample 1: the embodiment of the invention 5 composition solutions.
Sample 2: the embodiment of the invention 3 composition solutions.
Table 2: the clear and bright time of different samples
| Sample 1 | Sample 2 | |
| 0.9% sodium chloride injection | Clear liquid, 3h have slight opalescence | Clear liquid, 4h have slight opalescence |
| 5% glucose injection | Be clear liquid in 12 hours | Be clear liquid in 12 hours |
| Sodium lactate ringer's injection | Be clear liquid in 12 hours | Be clear liquid in 12 hours |
By table 2 as seen, can further improve solution through the glucose injection of 0.9% sodium chloride injection and 5% and clear and bright time and the stabilization time after the sodium lactate ringer's injection dilution adding propylene glycol etc. on the basis of pharmaceutical composition solution of the present invention.
Claims (11)
1. an ibuprofen pharmaceutical composition solution comprises ibuprofen, arginine and trometamol.
2. according to 1 ibuprofen pharmaceutical composition solution of claim, described ibuprofen is R-ibuprofen, S-ibuprofen or the mixture of the two.
3. according to 1 ibuprofen pharmaceutical composition solution of claim, described arginine is L-arginine, D-arginine or the mixture of the two.
4. according to the ibuprofen pharmaceutical composition solution of claim 1, wherein the mass ratio of ibuprofen, arginine, trometamol is 1: 0.1-10: 0.05-5.
5. according to the ibuprofen pharmaceutical composition solution of claim 4, wherein the mass ratio of ibuprofen, arginine, trometamol is 1: 0.2-5: 0.1-3.
6. according to the ibuprofen pharmaceutical composition solution of claim 5, wherein the mass ratio of ibuprofen, arginine, trometamol is 1: 0.5-1.5: 0.2-1.
7. according to the ibuprofen pharmaceutical composition solution of claim 1, also comprise ethylene glycol, propylene glycol or the mixture of the two.
8. the ibuprofen pharmaceutical composition solution of above-mentioned arbitrary claim, PH is 7-10.
9. ibuprofen pharmaceutical composition solution according to Claim 8, PH is 7.4-9.
10. the preparation method of the arbitrary ibuprofen pharmaceutical composition solution of claim 1-9 comprises the step that ibuprofen, arginine, trometamol is dissolved in the water mix homogeneously.
11. the described ibuprofen pharmaceutical composition solution of the arbitrary claim of claim 1-9 is used to prepare the purposes of medicine of the disease of treatment pain, heating, inflammation.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105055389A (en) * | 2015-08-03 | 2015-11-18 | 北京蓝丹医药科技有限公司 | Ibuprofen pharmaceutical composition for treating congenital heart disease in premature infants |
| WO2016082413A1 (en) * | 2014-11-27 | 2016-06-02 | 北京蓝丹医药科技有限公司 | Dexibuprofen pharmaceutical composition for injection and preparation method thereof |
| 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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| US5200558A (en) * | 1989-10-17 | 1993-04-06 | Merck & Co., Inc. | S(+)-ibuprofen-L-amino acid and S(+)-ibuprofen-D-amino acid as onset-hastened enhanced analgesics |
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| WO2016082413A1 (en) * | 2014-11-27 | 2016-06-02 | 北京蓝丹医药科技有限公司 | Dexibuprofen pharmaceutical composition for injection and preparation method thereof |
| CN105055389A (en) * | 2015-08-03 | 2015-11-18 | 北京蓝丹医药科技有限公司 | Ibuprofen pharmaceutical composition for treating congenital heart disease in premature infants |
| CN105055389B (en) * | 2015-08-03 | 2018-08-10 | 北京蓝丹医药科技有限公司 | A kind of ibuprofen medicinal composition for premature's congenital heart disease |
| 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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| CN101978945B (en) | 2016-03-30 |
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