CN102266285A - Low excitant ibuprofen injection - Google Patents
Low excitant ibuprofen injection Download PDFInfo
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- CN102266285A CN102266285A CN2010101901469A CN201010190146A CN102266285A CN 102266285 A CN102266285 A CN 102266285A CN 2010101901469 A CN2010101901469 A CN 2010101901469A CN 201010190146 A CN201010190146 A CN 201010190146A CN 102266285 A CN102266285 A CN 102266285A
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- ibuprofen
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Abstract
The invention discloses a low excitant ibuprofen injection and a preparation method thereof. The ibuprofen injection includes medicinal active components of ibuprofen and accessories of amino acid and injection water. A molar ratio range of the ibuprofen to the amino acid is 1:1.0-1:1.4. The ibuprofen injection of the present invention mainly employs amino acid as a solubilizer and a pH modifier; varieties of accessories used in a preparation process of the injection are reduced, so as to prepare the low excitant ibuprofen injection which is conducive to clinic application. The injection of the invention is mainly used for treating ache, inflammation, heating and / or other diseases that can be alleviated by ibuprofen.
Description
Technical field
The present invention relates to ibuprofen injection of a kind of low irritant and preparation method thereof, specifically, is that intravital low irritant injection and preparation method thereof is injected in a kind of confession of being made by active component ibuprofen and adjuvant, belongs to field of pharmaceutical preparations.
Background technology
Ibuprofen (Ibuprofen) is phenylpropionic acid non-steroidal anti-inflammatory analgesics (NSAID), chemistry 2-(4-isobutyl phenenyl) propanoic acid by name, and molecular weight is 206.28, molecular structural formula is as follows:
1966, ibuprofen, went on the market in the U.S. at first in Britain listing as prescription drugs in 1974.And in Britain, nineteen eighty-three ibuprofen become first NSAID (non-steroidal anti-inflammatory drug) that can sell by the nonprescription drugs mode; Ibuprofen also became nonprescription drugs in the U.S. in 1984.Ibuprofen has stronger antiinflammatory, rheumatism and antipyretic effect, and its antiinflammatory, analgesia, refrigeration function are all greater than aspirin.Ibuprofen is to liver and hemopoietic system non-evident effect, and its mechanism of action is the same with other derivants of propanoic acid class, all is the powerful inhibitor of Cycloxygenase.This Cycloxygenase is a kind of prostaglandin synthetase, is the requisite enzyme of synthesis of prostaglandins, and prostaglandin then is intravital a kind of from the body active substance, can cause inflammation, heating, pain under the situation of inappropriate generation and release; Thereby, can play antiinflammatory, analgesic, analgesic activity by suppressing generation and the release that Cycloxygenase reduces prostaglandin.Ibuprofen is as a kind of determined curative effect, little, the safe phenylpropionic acid antipyretic-antalgic anti-inflammatory agent extensive use clinically of untoward reaction, and its application prospect also may be included in the protective action that has in some cancer and the Alzheimer.The ibuprofen dosage form of listing has conventional tablet, chewable tablet, slow releasing tablet, capsule, suspensoid, drop, gel, injection etc. both at home and abroad at present.
Compare with oral formulations, injection has incomparable superiority, as the bioavailability height, individual variation is little, onset is rapid etc.When the medicine of some poorly water-solubles was made ejection preparation, for improving the dissolubility and the stability of medicine, often adding multiple adjuvant increased dissolubility and the stability of active component in solution, because adjuvant adding kind is more, therefore very easily caused untoward reaction.Ibuprofen is water-soluble hardly, has inconvenience in preparation production, and it is the form of its effective medicinal ingredient that its injection often adopts ibuprofen amino acid salt.For example, the commodity NeoProfen by name of the northern pharmaceuticals of Denmark's spirit research and development
The Ibuproben-Lysiante injection by FDA approval listing.Patent CN1923798, CN101190889 etc. also once disclosed the preparation method of ibuprofen amino acid salt, by these methods, can obtain the fabulous ibuprofen amino acid salt of water solublity, can prepare the injection that contains ibuprofen composition with this.The shortcoming of this method is to need earlier ibuprofen to be made into salt, dissolves after the separation and purification again, therefore must separate before producing injection and the detection ibuprofen amino acid salt, has increased production stage.Patent CN101069681 discloses a kind of method for preparing ibuprofen for injection of simplification, is about to raw material and is dissolved in respectively in water and the organic solvent, is prepared into freeze-dried powder; There is not the salify step in this method.The disclosed patent CN1302771 of U.S. Cumberland company directly utilizes the arginine aqueous solution to dissolve ibuprofen in the preparation of pharmaceutical formulations process, replaces earlier ibuprofen being made the form of ibuprofen amino acid salt.The commodity of the said firm's research and development at present Caldolor by name
Ibuprofen injection, by FDA approval listing, in being used for the treatment of-severe pain, also can be used as patronage medicine and opioid analgesic agent coupling treat in-severe pain, can also be used for adult patient treatment fever, but the crowd of being suitable for is mainly and needs hospitalization, and the patient that can't adopt oral drugs to cure.
A FAQs of drug administration by injection is exactly that zest is stronger, and this may be that the active substance of medicine own, pharmaceutical formulation are improper caused.Document (Grace Poon.Proc (Bayl Univ Med Cent) 2007 is arranged; Point out that 20:83-85) ibuprofen solution may stimulate tissue, therefore, must be careful in the administration process, avoid exosmosing.In fact, we are according to the ibuprofen injection Caldolor of FDA approval listing
Prescription to have made ibuprofen and arginine mol ratio be 1: 0.92 injection, and it is carried out blood vessel and muscle irritation test.Find that by summing up result of the test this injection is very big to the stimulation of rabbit blood vessel, muscle, phenomenons such as massive inflammatory cells infiltrated can be clearly observed between blood vessel congestion, interstitial edema, muscle in the matter in the rabbit local organization section after the administration.Therefore, the present invention studies the ibuprofen injection of preparing a low irritant significant meaning in clinical practice.
The ibuprofen injection of a kind of low irritant of the present invention, adopting adjuvant aminoacid is solubilizing agent and pH regulator agent, reduce adjuvant application kind in the injection preparation process, the molar ratio of preferred amino acid, by irritation test proof when ibuprofen and amino acid whose molar ratio range are 1: 1.0～1: 1.4, be that its pH value scope is about at 7.3～9.0 o'clock, prepared ibuprofen injection zest minimum benefits clinical practice.
Summary of the invention
The object of the present invention is to provide a kind of ibuprofen injection of low irritant, it is characterized in that: active constituents of medicine is an ibuprofen, and adjuvant is aminoacid and water for injection, and does not contain antiseptic, cosolvent and auxiliary substance.Described ibuprofen is (RS)-ibuprofen or S-ibuprofen.Described aminoacid preferred bases acidic amino acid comprises lysine, arginine, histidine; Most preferably be the L-arginine.
Low irritant ibuprofen injection of the present invention is characterized in that: ibuprofen and amino acid whose molar ratio range are 1: 1.0～1: 1.4; Preferred 1: 1.2; And the concentration of ibuprofen is 100mg/mL.
Another object of the present invention is to provides a kind of new being used for the treatment of to be selected from pain, inflammation, heating and/or the selection of the medicine of the other diseases alleviated by ibuprofen for the patient (as stupor, digestive tract ulcer patient etc.) who is not suitable for oral administration.
The present invention obtains the ibuprofen solution of different pH value by adjusting ibuprofen and amino acid whose mol ratio, passes through pharmacology test, proves that its zest is less when ibuprofen and amino acid whose molar ratio range are 1: 1.0～1: 1.4; When ibuprofen and amino acid whose mol ratio are 1: 1.2, its zest minimum.
The present invention is in the pharmaceutical preparation process, to be that a certain proportion of basic amino acid is dissolved in a certain amount of water for injection with ibuprofen, make the aqueous solution of basic amino acid, dissolve ibuprofen and add water for injection with this aqueous solution to quantitative, obtain having the ibuprofen aqueous solution of certain pH value, this aqueous solution is through taking off charcoal, fine straining, fill, high temperature sterilize, and making the ibuprofen solution concentration is the sterilization injection with small volume of 100mg/mL.
The present invention can adopt following technical scheme to realize: the aminoacid of getting weight portion adds 80%～90% water for injection dissolving of about total amount, and the ibuprofen of adding weight portion is stirred to moltenly entirely, adds water for injection to ormal weight; Activated carbon adsorption, decarburization, microporous filter membrane filter, and it is qualified to detect solution content, fill, and sealing by fusing, sterilization, promptly getting ibuprofen concentration is the sterilization injection with small volume of 100mg/mL.
Following examples provide the specific embodiment of foregoing invention, but they are not limited to gamut of the present invention.Ibuprofen among the embodiment and arginine are pharmaceutically acceptable material.
The specific embodiment
Embodiment 1
Ibuprofen 100.0g
Arginine 84.5g
Water for injection adds to 1000mL
The arginine of getting recipe quantity adds in about 800mL water for injection, and after the stirring and dissolving, the ibuprofen of adding recipe quantity continues to be stirred to molten entirely, adds water for injection to 1000mL; Activated carbon adsorption, decarburization, microporous filter membrane filter; Detect solution content, fill, sealing by fusing, sterilization, (ibuprofen: be 1: 1.0 arginine), pH is about 7.3, and concentration is 100mg/mL solution promptly to get mol ratio.
Embodiment 2
Ibuprofen 100.0g
Arginine 101.3g
Water for injection adds to 1000mL
The arginine of getting recipe quantity adds in about 800mL water for injection, and after the stirring and dissolving, the ibuprofen of adding recipe quantity continues to be stirred to molten entirely, adds water for injection to 1000mL; Activated carbon adsorption, decarburization, microporous filter membrane filter; Detect solution content, fill, sealing by fusing, sterilization, (ibuprofen: be 1: 1.2 arginine), pH is about 8.5, and concentration is 100mg/mL solution promptly to get mol ratio.
Embodiment 3
Ibuprofen 100.0g
Arginine 115.6g
Water for injection adds to 1000mL
The arginine of getting recipe quantity adds in about 800mL water for injection, after the stirring and dissolving, adds the ibuprofen of recipe quantity, continues to be stirred to molten entirely, adds water for injection to 1000mL, activated carbon adsorption, decarburization, microporous filter membrane filtration; Detect solution content, fill, sealing by fusing, sterilization, (ibuprofen: be 1: 1.4 arginine), pH is about 9.0, and concentration is 100mg/mL solution promptly to get mol ratio.
The ibuprofen injection blood vessel irritation of embodiment 4 different mol ratio (ibuprofen and arginine) preparation and muscle irritation test
Be subjected to the reagent thing:
B1: reference preparation:
Ibuprofen injection Caldolor according to FDA approval listing
The reference preparation that prescription makes, promptly ibuprofen and arginic mol ratio are 1: 0.92, ibuprofen concentration is 100mg/mL.
Ibuprofen 100.0g
Arginine 77.7g
Water for injection adds to 1000mL
The arginine of getting recipe quantity adds in about 800mL water for injection, after the stirring and dissolving, adds the ibuprofen of recipe quantity, continues to be stirred to molten entirely, adds water for injection to 1000mL, activated carbon adsorption, decarburization, microporous filter membrane filtration; Detect solution content, fill, sealing by fusing, sterilization, (ibuprofen: be 1: 0.92 arginine), pH is about 7.3, and concentration is the solution of 100mg/mL promptly to get mol ratio.
Ibuprofen that B2: embodiment 1 makes and arginic mol ratio are 1: 1.0 ibuprofen injection.
Ibuprofen that B3: embodiment 2 makes and arginic mol ratio are 1: 1.2 ibuprofen injection.
Ibuprofen that B4: embodiment 3 makes and arginic mol ratio are 1: 1.4 ibuprofen injection.
Laboratory animal:
8 of healthy qualified one-level new zealand rabbits, the male and female dual-purpose, body weight 2.0～3.0kg is provided by Shenyang Pharmaceutical University's Experimental Animal Center.Credit number: SCXK (the Liao Dynasty) 2009-0002.
Test method:
Route of administration: intend the clinical administration approach, the auricular vein drug administration by injection is adopted in the blood vessel irritation test, and the quadriceps femoris drug administration by injection is adopted in the muscle irritation test.
Administration concentration and administration cycle: convert to such an extent that rabbit is 23mg/kg with dosage according to clinical human dosage, 2 times/day, successive administration three days.
1) blood vessel irritation test: get rabbit and inject in auricular vein with sterile working's method that to be subjected to reagent, dosage be 0.2mL/kg.Observe animal every day, with general state, behavior, sign and administration local organization redness, situations such as hyperemia are observation index, and behind last administration 24h the air tap inserting method with sacrifice of animal, entad hold apart from entry point 2cm place, injection site respectively and cut the about 2cm of ear edge as specimen, the specimen formalin fixed, the conventional organization section, change around observing blood vessel, the vascular damaged degree, the endothelial denudation degree, have or not thrombosis and other pathological change situations etc., pressing lesion degree divides normal, gently, in, heavy level Four, respectively with (-), (+), (++), (+++) expression, concrete outcome sees Table 1.
2) muscle irritation test: each injects and is subjected to reagent in the two lower limb quadriceps femoris about it respectively with aseptic manipulation to get rabbit, dosage is 1.0mL/, injection back 48h puts to death animal, dissect and take out quadriceps femoris, vertically cut, observe the part, injection site and have or not hyperemia, edema, and get its tissue and do the pathology inspection, press lesion degree divide normal, light, in, heavy level Four, with (-), (+), (++), (+++) expression, concrete outcome sees Table 1 respectively.
Table 1 irritation test result
Conclusion: B1 is subjected to the muscle inflammatory of reagent thing heavier, and B3 is subjected to the inflammatory reaction light (blood vessel, muscle) of reagent thing, and B4 is subjected to the vascular reaction of reagent thing heavier.
Low irritant ibuprofen injection of the present invention, in the formulation preparation process, adopting adjuvant aminoacid is solubilizing agent and pH regulator agent, reduce supplementary product kind, adjust ibuprofen and amino acid whose molar ratio, the ibuprofen injection for preparing different pH value, ibuprofen injection by different pH value carries out blood vessel and muscle irritation test, when ibuprofen and amino acid whose molar ratio range are 1: 1～1: 1.4, be that its pH value scope is about at 7.3～9.0 o'clock, its zest minimum is lower than according to Caldolor
The ibuprofen injection that prescription makes.
Claims (6)
1. the ibuprofen injection of a low irritant, it is characterized in that: active constituents of medicine is an ibuprofen, adjuvant is aminoacid and water for injection.
2. low irritant ibuprofen injection as claimed in claim 1 is characterized in that: described ibuprofen is (RS)-ibuprofen or S-ibuprofen.
3. low irritant ibuprofen injection as claimed in claim 1 is characterized in that: described aminoacid preferred bases acidic amino acid comprises lysine, arginine, histidine; L-arginine most preferably.
4. low irritant ibuprofen injection as claimed in claim 1 is characterized in that: ibuprofen and amino acid whose molar ratio range are 1: 1.0～1: 1.4; Preferred 1: 1.2.
5. low irritant ibuprofen injection as claimed in claim 1 is characterized in that: the concentration of ibuprofen is 100mg/mL.
6. the other diseases that low irritant ibuprofen injection as claimed in claim 1 is used for the treatment of pain, inflammation, heating and/or alleviates by ibuprofen.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN2010101901469A CN102266285A (en) | 2010-06-03 | 2010-06-03 | Low excitant ibuprofen injection |
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| CN2010101901469A CN102266285A (en) | 2010-06-03 | 2010-06-03 | Low excitant ibuprofen injection |
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| CN102266285A true CN102266285A (en) | 2011-12-07 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| ES2422563A1 (en) * | 2012-03-08 | 2013-09-12 | Farmalider Sa | Injectable pharmaceutical composition of ibuprofen and arginine, its preparation procedure, unit dosage form and use thereof (Machine-translation by Google Translate, not legally binding) |
| 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 |
| CN111481563A (en) * | 2019-01-15 | 2020-08-04 | 富力 | Injection of forsythin and forsythiaside and derivatives thereof for children |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101669929A (en) * | 2009-09-27 | 2010-03-17 | 北京博时安泰液体制剂科技有限公司 | Preparation method and application of ibuprofen liquid preparation |
| 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 |
| CN102160852A (en) * | 2010-02-23 | 2011-08-24 | 付正香 | Ibuprofen injection and preparation method thereof |
-
2010
- 2010-06-03 CN CN2010101901469A patent/CN102266285A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101669929A (en) * | 2009-09-27 | 2010-03-17 | 北京博时安泰液体制剂科技有限公司 | Preparation method and application of ibuprofen liquid preparation |
| CN102160852A (en) * | 2010-02-23 | 2011-08-24 | 付正香 | Ibuprofen injection and preparation method thereof |
| 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 |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2422563A1 (en) * | 2012-03-08 | 2013-09-12 | Farmalider Sa | Injectable pharmaceutical composition of ibuprofen and arginine, its preparation procedure, unit dosage form and use thereof (Machine-translation by Google Translate, not legally binding) |
| 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 |
| 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 |
| CN111481563A (en) * | 2019-01-15 | 2020-08-04 | 富力 | Injection of forsythin and forsythiaside and derivatives thereof for children |
| CN111481563B (en) * | 2019-01-15 | 2022-11-15 | 富力 | Injection of forsythin and forsythiaside and derivatives thereof for children |
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Owner name: SHUANGDING PHARMACEUTICAL CO., LTD, SHENYANG Free format text: FORMER OWNER: SHENYANG SHUANGDING TECHNOLOGY CO., LTD. Effective date: 20120117 |
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Effective date of registration: 20120117 Address after: Hi Tech road Shenyang city Liaoning province 110179 Hunnan New District No. 15 Applicant after: Shuangding Pharmaceutical Co., Ltd, Shenyang Address before: Hi Tech road Shenyang city Liaoning province 110179 Hunnan New District No. 15 Applicant before: Shenyang Shuangding Technology Co., Ltd. |
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Application publication date: 20111207 |