CN101966147A - Ibuprofen injection composite and preparation method thereof - Google Patents
Ibuprofen injection composite and preparation method thereof Download PDFInfo
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- CN101966147A CN101966147A CN 201010293328 CN201010293328A CN101966147A CN 101966147 A CN101966147 A CN 101966147A CN 201010293328 CN201010293328 CN 201010293328 CN 201010293328 A CN201010293328 A CN 201010293328A CN 101966147 A CN101966147 A CN 101966147A
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- ibuprofen
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- 229940088523 ibuprofen injection Drugs 0.000 title claims abstract description 62
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- 239000002131 composite material Substances 0.000 title abstract 2
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims abstract description 57
- 229960001680 ibuprofen Drugs 0.000 claims abstract description 56
- 239000007924 injection Substances 0.000 claims abstract description 45
- 238000002347 injection Methods 0.000 claims abstract description 45
- 229940090044 injection Drugs 0.000 claims abstract description 42
- 239000006184 cosolvent Substances 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 6
- 239000000203 mixture Substances 0.000 claims description 58
- 239000000243 solution Substances 0.000 claims description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 47
- 239000008215 water for injection Substances 0.000 claims description 33
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 26
- 239000003708 ampul Substances 0.000 claims description 26
- 238000003756 stirring Methods 0.000 claims description 25
- 239000004475 Arginine Substances 0.000 claims description 21
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 230000001954 sterilising effect Effects 0.000 claims description 17
- 238000004659 sterilization and disinfection Methods 0.000 claims description 17
- 238000005303 weighing Methods 0.000 claims description 14
- 239000003610 charcoal Substances 0.000 claims description 13
- 239000000706 filtrate Substances 0.000 claims description 13
- 239000012528 membrane Substances 0.000 claims description 13
- 238000012856 packing Methods 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 8
- 239000004472 Lysine Substances 0.000 claims description 8
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims description 3
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 2
- 238000010521 absorption reaction Methods 0.000 claims description 2
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 claims description 2
- 229940098416 ibuprofen 400 mg Drugs 0.000 claims description 2
- 229940082177 ibuprofen 800 mg Drugs 0.000 claims description 2
- 238000001990 intravenous administration Methods 0.000 abstract description 2
- 230000007547 defect Effects 0.000 abstract 1
- 239000002085 irritant Substances 0.000 abstract 1
- 231100000021 irritant Toxicity 0.000 abstract 1
- 238000009472 formulation Methods 0.000 description 32
- 238000012360 testing method Methods 0.000 description 32
- 238000007689 inspection Methods 0.000 description 23
- 230000000052 comparative effect Effects 0.000 description 20
- KEAGRYYGYWZVPC-UHFFFAOYSA-N 1-[4-(2-methylpropyl)phenyl]ethanone Chemical compound CC(C)CC1=CC=C(C(C)=O)C=C1 KEAGRYYGYWZVPC-UHFFFAOYSA-N 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 239000000126 substance Substances 0.000 description 15
- 239000003814 drug Substances 0.000 description 13
- 238000001514 detection method Methods 0.000 description 12
- 229940079593 drug Drugs 0.000 description 12
- 239000011265 semifinished product Substances 0.000 description 11
- 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 description 10
- 229940093181 glucose injection Drugs 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 239000008354 sodium chloride injection Substances 0.000 description 10
- 238000001914 filtration Methods 0.000 description 8
- 230000002949 hemolytic effect Effects 0.000 description 5
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- 206010018910 Haemolysis Diseases 0.000 description 4
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- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 3
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- 230000036592 analgesia Effects 0.000 description 1
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- 239000003907 antipyretic analgesic agent Substances 0.000 description 1
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Abstract
The invention discloses an ibuprofen injection composite which can obviously improve the quality stability of products and meet the clinical compatibility demand and a preparation method thereof to overcome the defect of the traditional ibuprofen injection. The injection is prepared by mixing ibuprofen and cosolvent according to a molar ratio of 1: 1.001-2, and the pH value of the injection is 7.5-9.0. The ibuprofen injection prepared through the method has obviously improved tolerance capability to high temperature and strong light and better stability and no irritant to vessels, and can effectively meet the requirement of the clinical intravenous drip. Moreover, the preparation method of the invention has the advantages of simple process and good stability of the prepared product.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to a kind of ibuprofen injection and preparation method thereof.
Background technology
Ibuprofen is the classical medicine in the antipyretic analgesic, can suppress the synthetic of prostaglandin, has analgesia, analgesic and antiphlogistic effect.Because of evident in efficacy, untoward reaction is few, extensive use in the world rapidly after the listing, and market constantly enlarges, and in the later stage eighties 20th century, American-European many countries transfer it to nonprescription drugs, and its sales growth is quickened, and have now become one of global best-selling OTC medicine.The listing of dosage forms such as domestic existing ibuprofen tablet, ibuprofen dispersible tablet, ibuprofen oral disintegrating tablets, ibuprofen soft gelatin capsule, ibuprofen syrup, ibuprofen chewable tablet brufen soft capsule, ibuprofen modified release capsule, ibuprofen oral administration mixed suspension.
Because ibuprofen is almost insoluble in water, only easily molten in alkaline solution, illustrate that 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 at first be diluted to ibuprofen concentration with sodium chloride injection and glucose injection and be not more than 4mg/ml when clinical use, carry out intravenous drip again.And the pH value of glucose injection (pH value is 3.2～5.5) and sodium chloride injection (pH value is 4.5～7.0) all is lower than 7.0, causes separating out of ibuprofen owing to the solution pH value changes when using with this product compatibility.
U.S. Pat 6727286 discloses a kind of ibuprofen injection, this injection is made up of ibuprofen and arginine, this patent suggestion ibuprofen and arginic mol ratio are less than 1: 1, but the situation that clinical compatibilities such as this patent and not mentioned this ibuprofen injection and glucose injection and sodium chloride injection use.Through verification experimental verification, this ibuprofen injection is used the back appearance opalescence in various degree and the phenomenon of visible foreign matters increase with glucose injection and sodium chloride injection compatibility respectively, and this injection is under 60 ℃ of hot conditionss, also occurring sample character color after 10 days obviously changes, related substance significantly increases, and 4-isobutyl acetophenone impurity is greater than 0.1% phenomenon; This injection is placed the change that sample character color not only took place in 6 months under the room temperature storage condition, and related substance obviously increases, and its long-time stability are relatively poor, are unfavorable for its Long-term Storage and clinical use.
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 stability, satisfy the ibuprofen injection and the preparation method of clinical compatibility demand.
The inventor is by a large amount of tests and discover, change the proportioning of ibuprofen and cosolvent, not only improved the stability of injection greatly, and this injection and glucose injection and sodium chloride injection compatibility consistency problem have been solved, realize the industrialized mass of ibuprofen injection, thereby finished the present invention.
The invention provides a kind of ibuprofen injection, this injection is made by 1: 1.001～2 mol ratio by ibuprofen and cosolvent, and wherein cosolvent is a kind of of arginine, lysine, histidine or their mixture, and most preferred cosolvent is an arginine.
Per unit dosage ibuprofen injection of the present invention is made by following raw materials according:
Ibuprofen 100～1000mg
Cosolvent 72～1688mg
Water for injection adds to 1～10ml
Per unit dosage ibuprofen injection of the present invention also can be made by following raw materials according:
Ibuprofen 200～800mg
Cosolvent 144～1350mg
Water for injection adds to 2～8ml
Per unit dosage ibuprofen injection of the present invention also can be made by following raw materials according:
Ibuprofen 400mg
Cosolvent 288～675mg
Water for injection adds to 4ml
Per unit dosage ibuprofen injection of the present invention also can be made by following raw materials according:
Ibuprofen 800mg
Cosolvent 576～1350mg
Water for injection adds to 8ml
The present invention also provides a kind of ibuprofen injection preparation method, the steps include:
1., the ratio in recipe quantity (mol ratio 1: 1.001～2) takes by weighing ibuprofen and cosolvent, earlier cosolvent is injected water for injection and make it dissolving, add ibuprofen again, constantly stir and make it dissolving, check the pH value of solution, if the pH value of solution is in 7.5～9.0 scope, then directly add to the full amount of water for injection and mix, if the pH value of solution is less than 7.5 or greater than 9.0, be 7.5～9.0 then with pH regulator agent regulator solution pH value, add to the full amount of water for injection again, mix;
2., in the solution that 1. step obtains, add the needle-use activated carbon of 0.05～0.5% (W/V), 40～60 ℃ of insulated and stirred absorption 10～30 minutes, filter take off behind the charcoal standby;
3., solution that 2. step is obtained is clear and bright to filtrate with 0.22～0.45 μ m microporous filter membrane fine straining, check, packing, embedding makes that drug content is 100～1000mg in every ampoule bottle in ampoule bottle, sterilization (by the wet-hot steam sterilization), leak detection, lamp inspection gets finished product.
The 1. middle pH regulator agent of using of above-mentioned steps is sodium hydroxide or hydrochloric acid solution.
The 3. in the step, with embedding in the ibuprofen solution of ampoule bottle in 115 ℃ of wet-hot steams sterilizations 30 minutes, perhaps in 121 ℃ of wet-hot steams sterilizations 8～15 minutes.
The ibuprofen injection pH value that makes by said method is 7.5～9.0.
By ibuprofen injection that the present invention is made with by U.S. Patent number is that the ibuprofen injection (calling Comparative formulation in the following text) of US 6727286 disclosed technology preparations carries out stable contrast test and the clinical compatibility test shows:
1, the present invention can significantly improve the stability of ibuprofen injection
Show that according to influence factor's test and long-term 6 months stability test results the ibuprofen injection of the present invention's preparation is compared than the obvious raising of preparation the tolerance of high temperature and high light, stability is better.4-isobutyl acetophenone content is far below Comparative formulation in the ibuprofen injection that the present invention makes, and further specifies the ibuprofen injection safety that the present invention makes and is better than Comparative formulation.
2, the ibuprofen injection of the present invention's preparation can effectively satisfy the demand of clinical application
The clinical compatibility result of the test that the sample of being placed 6 months by room temperature placement 2 days and room temperature carries out as can be known, the venoclysis liquid of the ibuprofen injection clinical compatibility of the present invention's preparation, character is colourless clear liquid, no visible foreign matters, pH value, content, 4-isobutyl acetophenone, related substance have no significant change, quality stability is better, these data prove absolutely that the ibuprofen injection that the present invention prepares can satisfy the requirement that clinical vein instils, and quality stability significantly improves, and patient's compliance is better.
3, the present invention can significantly improve the safety of ibuprofen injection
Specific safety test (hemolytic and local irritation test) is the result show, the ibuprofen injection of the present invention preparation is to the blood vessel nonirritant, no hemolytic, and safety meets the needs of clinical application.
Simultaneously, preparation method of the present invention, it is simple to have technology, the advantage of manufactured goods good stability.
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 100g
Lysine 72g
Water for injection adds to 1000ml
Take by weighing lysine by recipe quantity, add 600～900ml water for injection, stirring makes it dissolving, the ibuprofen that adds recipe quantity again, constantly stir and make it dissolving, the pH value of measuring solution is about 7.3, is 7.5～8.5 with the pH value of sodium hydroxide solution regulator solution, add the injection water again to 1000ml, mix; The needle-use activated carbon that adds configuration total amount 0.1% (W/V), 40～60 ℃ of insulated and stirred were adsorbed 20 minutes, and it is standby that charcoal is taken off in filtration; Above-mentioned solution is clear and bright to filtrate with 0.22 μ m and 0.45 μ m microporous filter membrane fine straining, after the inspection of semifinished product is qualified, packing, embedding made that drug content is 100mg in every ampoule bottle in 1000 1ml ampoule bottles, in 115 ℃ of wet-hot steams sterilizations 30 minutes, leak detection, lamp inspection gets finished product.
Embodiment 2
Per 1000 injection formulations contain following compositions:
Ibuprofen 200g
Histidine 155g
Water for injection adds to 2000ml
Take by weighing histidine by recipe quantity, add 1200～1800ml water for injection, stirring makes it dissolving, the ibuprofen that adds recipe quantity again, constantly stir and make it dissolving, the pH value of measuring solution is about 7.2, is 8.0～9.0 with the pH value of sodium hydroxide solution regulator solution, add the injection water again to 2000ml, mix; The needle-use activated carbon that adds configuration total amount 0.2% (W/V), 40～60 ℃ of insulated and stirred were adsorbed 20 minutes, and it is standby that charcoal is taken off in filtration; Above-mentioned solution is clear and bright to filtrate with 0.22 μ m and 0.45 μ m microporous filter membrane fine straining, after the inspection of semifinished product is qualified, packing, embedding made that drug content is 200mg in every ampoule bottle in 1000 2ml ampoule bottles, in 115 ℃ of wet-hot steams sterilizations 30 minutes, leak detection, lamp inspection gets finished product.
Embodiment 3
Per 1000 injection formulations contain following compositions:
Ibuprofen 400g
Arginine 354g
Water for injection adds to 4000ml
Take by weighing arginine by recipe quantity, add 2400～3600ml water for injection, stir and make it dissolving, add the ibuprofen of recipe quantity again, constantly stir and make it dissolving, the pH value of measuring solution is 7.8～8.8, adds the injection water again to 4000ml, mixes; The needle-use activated carbon that adds configuration total amount 0.1% (W/V), 40～60 ℃ of insulated and stirred were adsorbed 20 minutes, and it is standby that charcoal is taken off in filtration; Above-mentioned solution is clear and bright to filtrate with 0.22 μ m microporous filter membrane fine straining, after the inspection of semifinished product is qualified, packing, embedding made that drug content is 400mg in every ampoule bottle in 1000 5ml ampoule bottles, in 115 ℃ of wet-hot steams sterilizations 30 minutes, leak detection, lamp inspection gets finished product.
Embodiment 4
Per 1000 injection formulations contain following compositions:
Ibuprofen 400g
Arginine 506g
Water for injection adds to 4000ml
The supplementary material of above-mentioned prescription is prepared into 1000 ibuprofen injection preparations according to the method for embodiment 3.
Embodiment 5
Per 1000 injection formulations contain following compositions:
Ibuprofen 400g
Arginine 675g
Water for injection adds to 4000ml
Take by weighing arginine by recipe quantity, add 2400～3600ml water for injection, stirring makes it dissolving, the ibuprofen that adds recipe quantity again, constantly stir and make it dissolving, the pH value of measuring solution is about 9.3, is 8.0～9.0 with the pH value of hydrochloric acid solution regulator solution, add the injection water again to 4000ml, mix; The needle-use activated carbon that adds configuration total amount 0.2% (W/V), 40～60 ℃ of insulated and stirred were adsorbed 30 minutes, and it is standby that charcoal is taken off in filtration; Above-mentioned solution is clear and bright to filtrate with 0.22 μ m microporous filter membrane fine straining, after the inspection of semifinished product is qualified, packing, embedding made that drug content is 400mg in every ampoule bottle in 1000 5ml ampoule bottles, in 115 ℃ of wet-hot steams sterilizations 30 minutes, leak detection, lamp inspection gets finished product.
Embodiment 6
Per 1000 injection formulations contain following compositions:
Ibuprofen 800g
Arginine 708g
Water for injection adds to 8000ml
Take by weighing arginine by recipe quantity, add 4800～7200ml water for injection, stir and make it dissolving, add the ibuprofen of recipe quantity again, constantly stir and make it dissolving, the pH value of measuring solution is 8.0～9.0, adds the injection water again to 8000ml, mixes; The needle-use activated carbon that adds configuration total amount 0.1% (W/V), 40～60 ℃ of insulated and stirred were adsorbed 20 minutes, and it is standby that charcoal is taken off in filtration; Above-mentioned solution is clear and bright to filtrate with 0.22 μ m microporous filter membrane fine straining, after the inspection of semifinished product is qualified, packing, embedding made that drug content is 800mg in every ampoule bottle in 1000 10ml ampoule bottles, in 115 ℃ of wet-hot steams sterilizations 30 minutes, leak detection, lamp inspection gets finished product.
Embodiment 7
Per 1000 injection formulations contain following compositions:
Ibuprofen 800g
Arginine 1010g
Water for injection adds to 8000ml
The supplementary material of above-mentioned prescription is prepared into 1000 ibuprofen injection preparations according to the method for embodiment 6.
Embodiment 8
Per 1000 injection formulations contain following compositions:
Ibuprofen 800g
Arginine 1350g
Water for injection adds to 8000ml
Take by weighing arginine by recipe quantity, add 4800～7200ml water for injection, stirring makes it dissolving, the ibuprofen that adds recipe quantity again, constantly stir and make it dissolving, the pH value of measuring solution is about 9.3, is 7.8～8.8 with hydrochloric acid solution regulator solution pH value, add the injection water again to 8000ml, mix; The needle-use activated carbon that adds configuration total amount 0.2% (W/V), 40～60 ℃ of insulated and stirred were adsorbed 30 minutes, and it is standby that charcoal is taken off in filtration; Above-mentioned solution is clear and bright to filtrate with 0.22 μ m microporous filter membrane fine straining, after the inspection of semifinished product is qualified, packing, embedding made that drug content is 800mg in every ampoule bottle in 1000 10ml ampoule bottles, in 115 ℃ of wet-hot steams sterilizations 30 minutes, leak detection, lamp inspection gets finished product.
Embodiment 9
Per 1000 injection formulations contain following compositions:
Ibuprofen 400g
Lysine 566g
Water for injection adds to 4000ml
Take by weighing lysine by recipe quantity, add 2400～3600ml water for injection, stirring makes it dissolving, the ibuprofen that adds recipe quantity again, constantly stir and make it dissolving, the pH value of measuring solution is about 7.3, is 8.0～9.0 with the pH value of sodium hydroxide solution regulator solution, add the injection water again to 4000ml, mix; The needle-use activated carbon that adds configuration total amount 0.1% (W/V), 40～60 ℃ of insulated and stirred were adsorbed 20 minutes, and it is standby that charcoal is taken off in filtration; Above-mentioned solution is clear and bright to filtrate with 0.22 μ m microporous filter membrane fine straining, after the inspection of semifinished product is qualified, packing, embedding made that drug content is 400mg in every ampoule bottle in 1000 5ml ampoule bottles, in 115 ℃ of wet-hot steams sterilizations 30 minutes, leak detection, lamp inspection gets finished product.
Embodiment 10
Per 1000 injection formulations contain following compositions:
Ibuprofen 800g
Histidine 620g
Water for injection adds to 8000ml
Take by weighing histidine by recipe quantity, add 4800～7200ml water for injection, stirring makes it dissolving, the ibuprofen that adds recipe quantity again, constantly stir and make it dissolving, the pH value of measuring solution is about 7.2, is 8.0～9.0 with the pH value of sodium hydroxide solution regulator solution, add the injection water again to 8000ml, mix; The needle-use activated carbon that adds configuration total amount 0.1% (W/V), 40～60 ℃ of insulated and stirred were adsorbed 20 minutes, filtered to take off charcoal usefulness; Above-mentioned solution is clear and bright to filtrate with 0.22 μ m microporous filter membrane fine straining, after the inspection of semifinished product is qualified, packing, embedding made that drug content is 800mg in every ampoule bottle in 1000 8ml ampoule bottles, in 115 ℃ of wet-hot steams sterilizations 30 minutes, leak detection, lamp inspection gets finished product.
Embodiment 11
Per 1000 injection formulations contain following compositions:
Ibuprofen 400g
Lysine 284g
Arginine 340g
Water for injection adds to 4000ml
Take by weighing lysine and arginine by recipe quantity, add 2400～3600ml water for injection, stir and make it dissolving, the ibuprofen that adds recipe quantity more constantly stirs and makes it dissolving, and the pH value of measuring solution is 7.5～8.0, add the injection water again to 4000ml, mix; The needle-use activated carbon that adds configuration total amount 0.2% (W/V), 40～60 ℃ of insulated and stirred were adsorbed 20 minutes, filtered to take off charcoal usefulness; Above-mentioned solution is clear and bright to filtrate with 0.22 μ m microporous filter membrane fine straining, after the inspection of semifinished product is qualified, packing, embedding made that drug content is 400mg in every ampoule bottle in 1000 5ml ampoule bottles, in 121 ℃ of wet-hot steams sterilizations 10 minutes, leak detection, lamp inspection gets finished product.
Embodiment 12
Per 1000 injection formulations contain following compositions:
Ibuprofen 800g
Histidine 620g
Arginine 780g
Water for injection adds to 8000ml
Take by weighing histidine and arginine by recipe quantity, add 4800～7200ml water for injection, stir and make it dissolving, the ibuprofen that adds recipe quantity more constantly stirs and makes it dissolving, and the pH value of measuring solution is 7.5～8.0, add the injection water again to 8000ml, mix; The needle-use activated carbon that adds configuration total amount 0.2% (W/V), 40～60 ℃ of insulated and stirred were adsorbed 20 minutes, filtered to take off charcoal usefulness; Above-mentioned solution is clear and bright to filtrate with 0.22 μ m microporous filter membrane fine straining, after the inspection of semifinished product is qualified, packing, embedding made that drug content is 800mg in every ampoule bottle in 1000 8ml ampoule bottles, in 121 ℃ of wet-hot steams sterilizations 10 minutes, leak detection, lamp inspection gets finished product.
Embodiment 13
Per 1000 injection formulations contain following compositions:
Ibuprofen 1000g
Arginine 900g
Water for injection adds to 10000ml
Take by weighing arginine by recipe quantity, add 6000～9000ml water for injection, stir and make it dissolving, add the ibuprofen of recipe quantity again, constantly stir and make it dissolving, the pH value of measuring solution is 7.8～8.8, adds the injection water again to 10000ml, mixes; The needle-use activated carbon that adds configuration total amount 0.1% (W/V), 40～60 ℃ of insulated and stirred were adsorbed 20 minutes, and it is standby that charcoal is taken off in filtration; Above-mentioned solution is clear and bright to filtrate with 0.22 μ m microporous filter membrane fine straining, after the inspection of semifinished product is qualified, packing, embedding made that drug content is 1000mg in every ampoule bottle in 1000 10ml ampoule bottles, in 121 ℃ of wet-hot steams sterilizations 10 minutes, leak detection, lamp inspection gets finished product.
The test example:
The preparation of Comparative formulation
According to the proportioning of US6727286 embodiment 1 each component, take by weighing the 8.2g arginine, the 10.0g ibuprofen adds water 100ml and makes Comparative formulation, and to regulate its pH value be 7.4, and sterilization, encapsulation obtain Comparative formulation.
The ibuprofen injection and the Comparative formulation of the present invention's preparation are carried out quality comparative study, and the result is as follows:
Test example 1: hot test
The ibuprofen injections and the Comparative formulation of the embodiment of the invention 3 and 6 preparations are carried out hot test respectively under 60 ℃ and 40 ℃ of temperature, respectively at the 5th day and 10 days pick test, detect by the emphasis quality index, investigate projects such as character, pH value, related substance, 4-isobutyl acetophenone and content respectively, the results are shown in Table 1,2.
60 ℃ of result of the tests of table 1 high temperature
40 ℃ of result of the tests of table 2 high temperature
The above results shows that the ibuprofen injection sample of the embodiment of the invention 3 and 6 preparations is compared with 0 day through 60 ℃ of placements 10 days, character, pH value, content have no significant change, related substance and 4-isobutyl acetophenone increase to some extent, but still in acceptability limit, and significantly better than Comparative formulation; The ibuprofen injection sample of the embodiment of the invention 3 and 6 preparations is compared with 0 day through 40 ℃ of placements 10 days, and character, pH value, content, related substance and 4-isobutyl acetophenone have no significant change, and significantly better than Comparative formulation.Explanation thus, than the obvious raising of preparation, stability is better to pyritous tolerance comparison for ibuprofen injection of the present invention.
Test example 2: highlight test
The ibuprofen injection and the Comparative formulation of the embodiment of the invention 3 and 6 preparations are carried out highlight test under 4500 ± 500Lux condition, respectively at the 5th day and 10 days pick test, detect by the emphasis quality index, investigate projects such as character, pH value, related substance, 4-isobutyl acetophenone and content respectively, the results are shown in Table 3.
Table 3 high light (4500 ± 500Lux) result of the tests
The above results shows, (4500 ± 500Lux) placed 10 days the ibuprofen injection sample of the embodiment of the invention 3 and 6 preparations through high light, compared with 0 day, character, pH value, content have no significant change, related substance and 4-isobutyl acetophenone increase to some extent, but still in acceptability limit, and significantly better than Comparative formulation.Explanation thus, ibuprofen injection of the present invention is compared than the obvious raising of preparation the tolerance of high light, and stability is better.
Test example 3: long-term stable experiment
With the embodiment of the invention 3 and 6 the preparation ibuprofen injections and Comparative formulation 25 ℃ ± 2 ℃ of temperature, relative humidity carries out long-term stable experiment 60% ± 10% time, respectively at the 3rd, 6 month pick test, detect by the emphasis quality index, investigate projects such as character, pH value, related substance, 4-isobutyl acetophenone and content respectively, the results are shown in Table 4.
Table 4 long-term stable experiment result
The above results shows, the ibuprofen injection sample of the embodiment of the invention 3 and 6 preparations is through 25 ℃ ± 2 ℃ of temperature, relative humidity was placed 6 months for 60% ± 10% time, compared with 0 month, and character, pH value, content, related substance and 4-isobutyl acetophenone have no significant change; And Comparative formulation is through 25 ℃ ± 2 ℃ of temperature, and relative humidity was placed 6 months for 60% ± 10% time, compared with 0 month, and character obviously changes, and related substance and 4-isobutyl acetophenone obviously increase, and content obviously descends.Explanation thus, the quality stability comparison of ibuprofen injection of the present invention is than the obvious raising of preparation, and stability is better.
Test example 4: clinical compatibility test
The usage and dosage of stipulating on the ibuprofen injection description according to the FDA approval, investigated the ibuprofen injections and the Comparative formulation of the embodiment of the invention 3 and 6 preparations and placed 2 days and 6 months, to the stability of 0.9% sodium chloride injection and the 5% glucose injection compatibility of different pH value in room temperature.Result of study is seen following table:
Table 5 room temperature is placed inventive embodiments 3 samples on the 2nd and is tested with 0.9% sodium chloride injection compatibility
Table 6 room temperature is placed inventive embodiments 3 samples on the 2nd and is tested with 5% glucose injection compatibility
Table 7 room temperature is placed inventive embodiments 6 samples on the 2nd and is tested with 0.9% sodium chloride injection compatibility
Table 8 room temperature is placed inventive embodiments 6 samples on the 2nd and is tested with 5% glucose injection compatibility
Table 9 room temperature is placed Comparative formulation on the 2nd and is tested with 0.9% sodium chloride injection compatibility
Table 10 room temperature is placed Comparative formulation on the 2nd and is tested with 5% glucose injection compatibility
By above-mentioned result of the test as can be known, room temperature is placed the venoclysis liquid of the ibuprofen injection clinical compatibilities of the embodiment of the invention 3 on the 2nd and 6 preparations, character is colourless clear liquid, no visible foreign matters, and pH value, content, related substance, 4-isobutyl acetophenone have no significant change; And the venoclysis liquid of Comparative formulation clinical compatibility, character has the graininess precipitation for opalescence is arranged, and related substance and 4-isobutyl acetophenone all are significantly increased.
Table 11 room temperature is placed 6 months three kinds of samples and is tested with 0.9% sodium chloride injection compatibility
Table 12 room temperature is placed 6 months three kinds of samples and is tested with 5% glucose injection compatibility
By above-mentioned result of the test as can be known, room temperature was placed 6 months, the venoclysis liquid of the ibuprofen injection clinical compatibility of the embodiment of the invention 3 and 6 preparations, and character is colourless clear liquid, no visible foreign matters, pH value, content, related substance, 4-isobutyl acetophenone have no significant change; And the venoclysis liquid of Comparative formulation clinical compatibility, character has the graininess precipitation for opalescence is arranged, and related substance and 4-isobutyl acetophenone all are significantly increased, as seen its quality stability existing problems.This shows that ibuprofen injection of the present invention can satisfy the requirement that clinical vein instils, and quality stability significantly improves, patient's compliance is better.
Test example 5: specific safety test
Irritation test
Ibuprofen injection to the embodiment of the invention 6 carries out the local irritation test, and the result is as follows:
During the administration and perusal injection site, administration end back outward appearance is not seen obvious stimulation phenomenons such as hyperemia, edema, histopathologic examination shows, No. 2,4,5,48h and continue to observe and finish the 14th day 1,3, No. 6 animal instillation reference substance side in back and the instillation test sample edge duct of Arantius intracavity of picking up the ears to administration and do not see thrombosis after the last administration, tube wall chamber face is smooth, endotheliocyte is flat, nuclear is tiny, engrain, middle film smooth muscle fiber rareness, the adventitia fibrous tissue is red dyes.Each layer tissue of tube wall is not seen cellular swelling, degeneration and necrosis, does not see the acute and chronic cell infiltration.Epiderm skin and appendages show no obvious abnormalities, and subcutaneous tissue is not seen congestion and edema and inflammatory cell infiltration, does not see proliferation of fibrous tissue.
The hemolytic test
Ibuprofen injection to the embodiment of the invention 6 carries out the hemolytic test, and the result is as follows:
Each pipe of ibuprofen injection is all seen upper strata liquid achromatism and clarity during perusal, erythrocyte all sinks, and the reaction of haemolysis and red blood cell condensation does not all appear in the fine dispersion of energy after the jolting, and is identical with the negative control pipe.Haemolysis promptly appearred in 15 minutes in the positive control pipe, the clear and bright redness of upper strata liquid, the pipe acellular remnants in the end.Adopt ultraviolet-uisible spectrophotometer to test at 545nm wavelength place and respectively manage absorbance (seeing Table 13), the hemolysis rate of each pipe of ibuprofen injection is all less than 5%.
Table 13 ultraviolet-uisible spectrophotometer test absorbance and hemolysis rate
In sum, ibuprofen injection of the present invention is to the blood vessel nonirritant, no hemolytic, and safety meets the needs of clinical application.
Claims (11)
1. an ibuprofen injection is characterized in that, this injection is made by 1: 1.001～2 mol ratio by ibuprofen and cosolvent.
2. ibuprofen injection according to claim 1 is characterized in that, described cosolvent is arginine, lysine, histidine or their mixture.
3. ibuprofen injection according to claim 1 and 2 is characterized in that, contains ibuprofen 100～1000mg, cosolvent 72～1688mg in per 1～10ml injection.
4. ibuprofen injection according to claim 3 is characterized in that containing ibuprofen 200～800mg in per 2～8ml injection, cosolvent 144～1350mg.
5. ibuprofen injection according to claim 4, its special type are that every 4ml injection contains ibuprofen 400mg, cosolvent 288～675mg.
6. ibuprofen injection according to claim 4, its special type are that every 8ml injection contains ibuprofen 800mg, cosolvent 576～1350mg.
7. ibuprofen injection according to claim 1 is characterized in that, ibuprofen and arginic mol ratio are 1: 1.05.
8. according to any described ibuprofen injection in the claim 1～7, it is characterized in that the pH value of this injection is 7.5～9.0.
9. the preparation method of any one ibuprofen injection in the claim 1～8 is characterized in that, this method comprises the following steps:
A, take by weighing ibuprofen and cosolvent, get cosolvent earlier and place container, add water for injection by recipe quantity, stirring makes it dissolving, adds ibuprofen again, constantly stirs to make it dissolving, pH value with pH regulator agent control solution is 7.5～9.0, adds to the full amount of water for injection again, mixes;
B, in the solution that the A step obtains, add the needle-use activated carbon of 0.05～0.5% (W/V), 40～60 ℃ of insulated and stirred absorption 10～30 minutes, filter take off behind the charcoal standby;
C, the solution of B step acquisition is clear and bright to filtrate with 0.22～0.45 μ m microporous filter membrane fine straining, check, the injection that meets the injection requirement is made in packing, embedding in ampoule bottle.
10. ibuprofen injection preparation method according to claim 9 is characterized in that among the step C by making described injection after the wet-hot steam sterilization.
11. ibuprofen injection preparation method according to claim 9 is characterized in that, described pH regulator agent is sodium hydroxide or hydrochloric acid solution.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102579332A (en) * | 2012-03-26 | 2012-07-18 | 北京阜康仁生物制药科技有限公司 | Method for preparing ibuprofen injection |
| CN102716069A (en) * | 2012-06-07 | 2012-10-10 | 无锡康福特药物科技有限公司 | Injection liquid containing ibuprofen and preparation process of injection liquid |
| CN103027890A (en) * | 2011-09-29 | 2013-04-10 | 天津市汉康医药生物技术有限公司 | Ibuprofen medicine composition for injection |
| CN103893767A (en) * | 2013-09-17 | 2014-07-02 | 天津市嵩锐医药科技有限公司 | Ibuprofen medicine composition with stable quality |
| CN106511360A (en) * | 2016-12-02 | 2017-03-22 | 上海芮范生物科技有限公司 | Composition containing ginsenoside Rg3 and silymarin and medicine |
| CN108158980A (en) * | 2016-12-07 | 2018-06-15 | 浙江普利药业有限公司 | Arginine Ibuprofen parenteral solution and preparation method thereof |
| CN108619087A (en) * | 2017-03-21 | 2018-10-09 | 长春海悦药业股份有限公司 | A kind of pharmaceutical composition containing brufen |
| CN112957323A (en) * | 2021-03-29 | 2021-06-15 | 北京佳诚医药有限公司 | Dexibuprofen injection |
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| US6727286B2 (en) * | 2001-11-02 | 2004-04-27 | Cumberland Pharmaceuticals Inc. | Pharmaceutical composition of 2-(4-isobutylphenyl) propionic acid |
| CN101810568A (en) * | 2010-03-29 | 2010-08-25 | 南京泛太化工医药研究所 | Injection containing ibuprofen and preparation method thereof |
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| US6727286B2 (en) * | 2001-11-02 | 2004-04-27 | Cumberland Pharmaceuticals Inc. | Pharmaceutical composition of 2-(4-isobutylphenyl) propionic acid |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103027890A (en) * | 2011-09-29 | 2013-04-10 | 天津市汉康医药生物技术有限公司 | Ibuprofen medicine composition for injection |
| CN103027890B (en) * | 2011-09-29 | 2014-06-18 | 天津市汉康医药生物技术有限公司 | Ibuprofen medicine composition for injection |
| CN102579332A (en) * | 2012-03-26 | 2012-07-18 | 北京阜康仁生物制药科技有限公司 | Method for preparing ibuprofen injection |
| CN102716069A (en) * | 2012-06-07 | 2012-10-10 | 无锡康福特药物科技有限公司 | Injection liquid containing ibuprofen and preparation process of injection liquid |
| CN103893767A (en) * | 2013-09-17 | 2014-07-02 | 天津市嵩锐医药科技有限公司 | Ibuprofen medicine composition with stable quality |
| CN106511360A (en) * | 2016-12-02 | 2017-03-22 | 上海芮范生物科技有限公司 | Composition containing ginsenoside Rg3 and silymarin and medicine |
| CN108158980A (en) * | 2016-12-07 | 2018-06-15 | 浙江普利药业有限公司 | Arginine Ibuprofen parenteral solution and preparation method thereof |
| CN108619087A (en) * | 2017-03-21 | 2018-10-09 | 长春海悦药业股份有限公司 | A kind of pharmaceutical composition containing brufen |
| CN112957323A (en) * | 2021-03-29 | 2021-06-15 | 北京佳诚医药有限公司 | Dexibuprofen injection |
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| CN101966147B (en) | 2012-02-01 |
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