CN103301118A - Arginine ibuprofen composition for injection - Google Patents
Arginine ibuprofen composition for injection Download PDFInfo
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- CN103301118A CN103301118A CN2013102636233A CN201310263623A CN103301118A CN 103301118 A CN103301118 A CN 103301118A CN 2013102636233 A CN2013102636233 A CN 2013102636233A CN 201310263623 A CN201310263623 A CN 201310263623A CN 103301118 A CN103301118 A CN 103301118A
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- melatonin
- arginine ibuprofen
- injection
- ibuprofen
- arginine
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Abstract
The invention provides an arginine ibuprofen composition for injection, and relates to the technical field of medicine manufacturing. The main medicine of the composition comprises arginine ibuprofen and melatonin, wherein the melatonin comprises a quick release part and a cyclodextrin-included slow release part. According to the arginine ibuprofen composition for injection provided by the invention, the therapeutic effect of the arginine ibuprofen is improved, instability caused by oral administration of MT (Melatonin) is avoided and MT is quick to distribute and eliminate and the like, and the first pass effect of MT is reduced. The dosage of MT is reduced. The design of dosage combining quick release and slow release is in accordance with secretion characteristic of MT, so that the problem of half-life period of MT is solved and the bioavailability of a product is improved. Melatonin combined with arginine ibuprofen has a good synergistic effect for treating arthritis.
Description
Technical field:
The present invention relates to medicine and medicine manufacture technology field, relate in particular to a kind of injection arginine Ibuprofen compositions, more specifically, relate to a kind of injection freeze-dried composition that contains arginine Ibuprofen, melatonin.
Background technology:
The arginine Ibuprofen chemical name is: trans-4-[(2-amino 3, and the 5-dibromo-benzyl) amino] Hexalin, molecular formula: its structural formula of C19H32O4N4 molecular weight 380.47. is as follows:
Arginine Ibuprofen (ibuprofen) is a kind of NSAID (non-steroidal anti-inflammatory drug) (NSAID).With the same alpha position at the propionic ester group of derivant of other 2-arylprop acid esters chiral centre is arranged, so ibuprofen has two enantiomers, and can be to producing different influences in physiology and the metabolism.Though true laboratory detect and clinical trial in, (S)-(+)-ibuprofen (being (S)-ibuprofen) just has obvious activity.The ibuprofen of selling in market at present is racemic modification, and it often is used to releasing arthritis, dysmenorrhoea, symptoms such as heating.It also is a kind of analgesic in addition, especially for the pain of inflammation initiation.Ibuprofen has the hematoblastic effectiveness of inhibition, but the persistent period is short compared with aspirin.Ibuprofen is one of required medicines of World Health Organization's appointment [1].Ibuprofen has antiinflammatory, analgesia, refrigeration function.The curative effect for the treatment of rheumatism and rheumatoid arthritis is slightly poorer than aspirin and Phenylbutazone.Be applicable to treatment rheumatic arthritis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and neuritis etc.
Melatonin (Melatonin, MT, melatonin) is exactly a kind of hormone with peak paddy in daytime rhythm and pace of moving things characteristics at obvious night, is secreted by human or animal's pinus, to photosensitivity.Concentration was low rule and not influenced by age and sex daytime.The activity of MT descends with the increase at age, begins after adolescence to descend, and the old people is very low, may be because due to the calculus,pineal.MT has physiologically active and immunoregulation effect widely, can promote the propagation of bone-marrow-derived lymphocyte, suppress growth of tumour cell, active cell endogenous anti-oxidative defense system and free radical scavenging system, prevent that effectively the O-DNA damage from causing the generation of cancer, can improve sleep regulation and control people's Sleep-Wake biological cycle effectively, play a part biological clock.Though MT has different physiological roles and pharmacological action, in kinetics the oral absorption instability is arranged, distribute, remove soon, t
1/2Short (30-50min), individual variation is big, and first pass effect is strong, absolute bioavailability low (1%-37%), the characteristics of hold time in the body short (1-3h).
Summary of the invention:
The object of the invention is to overcome the defective of prior art, provides a kind of therapeutic effect good injection arginine Ibuprofen compositions.
For realizing the object of the invention, technical scheme realizes in the following way:
A kind of injection arginine Ibuprofen compositions is characterized in that the principal agent of said composition is: arginine Ibuprofen, melatonin, described melatonin comprises the slow-released part of immediate release section and cyclodextrin inclusion compound.
The applicant finds arginine Ibuprofen under study for action when releasing arthritis, and medicine is fat-soluble poor, transhipment in vivo and special when transforming to spend the biomembrane time longer, and low with plasma protein binding rate, and have slight untoward reaction such as gastrointestinal tract report.And single melatonin can not cut any ice to treatment of arthritis, but it is lipophilic molecule, with strengthening it to preceding inflammatory cytokine after the arginine Ibuprofen combination, the inhibitory action of COX-2 and the activity of the expression that induces type NO synthase and NF-kB, thereby when untoward reaction such as treatment of arthritis disease alleviation digestive tract damage, have good synergism, thereby reach therapeutic purposes.Not only the distribution to tissue rapidly and significantly, lung, liver, kidney distribute more from blood for said composition, and other tissue distribution are less, and plasma protein binding rate is about 90%, and toleration is fine.The melatonin that adds the 3mg cyclodextrin inclusion compound through test of many times discovery 1mg melatonin is combined as optimum with the 30mg arginine Ibuprofen.
Another object of the present invention provides a kind of injection freeze-dried powder of injection arginine Ibuprofen compositions, it is characterized in that: this freeze-dried powder is principal agent with arginine Ibuprofen, melatonin, wherein to account for the mass percent of principal agent be 0.1%～7.5% to the immediate release section of melatonin, and the mass percent that the slow-released part of the cyclodextrin inclusion compound of melatonin accounts for principal agent is 1.5%～18.5%.
Another purpose of the present invention provides a kind of production method of production injection freeze-dried powder, it is characterized in that, step is:
A) mannitol with 2～10 times of arginine Ibuprofen and arginine Ibuprofen group components is added to stirring and dissolving in the water for injection, adds that to account for the principal agent mass percent be that 0.1%～7.5% melatonin stirs again;
B) will account for the principal agent mass percent is that medium substitution value hydroxypropyl-β-cyclodextrin that 1.5%～18.5% melatonin and mol ratio are 1:1 adds in the water for injection, stir all with, detection melatonin envelop rate is greater than 90%;
C) mix and add HCL solution behind above-mentioned a, the b group solution and regulate pH value to 6.7, the active carbon of adding 0.1% stirred 30 minutes, and filtering active carbon, medicinal liquid are again through 0.45 μ m and 0.22 μ m filtering with microporous membrane, detect intermediate content, by every bottle of 30mg of arginine Ibuprofen;
D) require fill according to detection, send in the freezer dryer after half tamponade, be cooled to-40 ℃, insulation 2 as a child slowly is warming up to-5 ℃～0 ℃ sublimation drying, be warming up to 35 ℃ again after, be incubated 3 hours, lyophilization end, outlet.
A kind of application of injection arginine Ibuprofen combination treatment arthritis, treatment of arthritis not only clinically, improve arginine Ibuprofen to the therapeutic effect of arthritis, shorten the course for the treatment of, also reduced the consumption of arginine Ibuprofen, reduce the side effect of arginine Ibuprofen, and can improve body immunity.
Beneficial effect of the present invention is:
Compositions provided by the invention has following advantage: the therapeutic effect that 1) has improved arginine Ibuprofen; 2) instability of having avoided MT to cause because of oral absorption distributes, removes fast etc., reduces the first pass effect of MT; 3) reduced the dosage of MT; 4) the administration design that combines of rapid release and slow release meets the secretion characteristic of MT, and the half-life that has solved MT is short, has improved the bioavailability of product; 5) melatonin combination arginine Ibuprofen has good synergism to treatment of arthritis disease.The melatonin that adds the 3mg cyclodextrin inclusion compound through test of many times discovery 1mg melatonin is combined as optimum with the 30mg arginine Ibuprofen.
The specific embodiment:
For technological means, creation characteristic that the present invention is realized, reach purpose and effect is easy to understand, below in conjunction with specific embodiment, further set forth the present invention.
The preparation of embodiment one, injection arginine Ibuprofen composite freeze-dried powder is in 1000.
Prescription
2. preparation technology
A) 70g mannitol is added to stirring and the dissolving of adding 30g arginine Ibuprofen in the 1500ml water for injection, adds the 0.6g melatonin again and stir;
B) 1.8g melatonin and the medium substitution value hydroxypropyl-β of 16.59g-cyclodextrin are added in the 500ml water for injection, 50 ℃ were stirred 6 hours, detected the melatonin envelop rate greater than 90%;
C) mix and add HCL solution behind above-mentioned a, the b group solution and regulate pH value to 6.7, the active carbon of adding 0.1% stirs 30 minutes filtering active carbons, and medicinal liquid detects intermediate content again through 0.45 μ m and 0.22 μ m filtering with microporous membrane, press arginine Ibuprofen, count every bottle of 30mg;
D) require fill according to detection, send in the freezer dryer after half tamponade, be cooled to-40 ℃, insulation 2 as a child slowly is warming up to-5 ℃～0 ℃ sublimation drying, be warming up to 35 ℃ again after, be incubated 3 hours, lyophilization end, outlet.
The preparation of embodiment two, injection arginine Ibuprofen composite freeze-dried powder is in 1000.
1. write out a prescription
2. preparation technology
A) 70g mannitol is added to stirring and the dissolving of adding 30g arginine Ibuprofen in the 1500ml water for injection, adds the 1g melatonin again and stir;
B) 3g melatonin and the medium substitution value hydroxypropyl-β of 21.38g-cyclodextrin are added in the 500ml water for injection, 50 ℃ were stirred 6 hours, detected the melatonin envelop rate greater than 90%;
C) mix and add HCL solution behind above-mentioned a, the b group solution and regulate pH value to 6.7, the active carbon of adding 0.1% stirs 30 minutes filtering active carbons, and medicinal liquid detects intermediate content again through 0.45 μ m and 0.22 μ m filtering with microporous membrane, press arginine Ibuprofen, count every bottle of 30mg;
D) require fill according to detection, send in the freezer dryer after half tamponade, be cooled to-40 ℃, insulation 2 as a child slowly is warming up to-5 ℃～0 ℃ sublimation drying, be warming up to 35 ℃ again after, be incubated 3 hours, lyophilization end, outlet.
The preparation of embodiment three, injection arginine Ibuprofen composite freeze-dried powder is in 1000.
1. write out a prescription
2. preparation technology
A) 70g mannitol is added to stirring and the dissolving of adding 30g arginine Ibuprofen in the 1500ml water for injection, adds the 1.3g melatonin again and stir;
B) 3.9g melatonin and the medium substitution value hydroxypropyl-β of 16.92g-cyclodextrin are added in the 500ml water for injection, 50 ℃ were stirred 5 hours, detected the melatonin envelop rate greater than 90%;
C) mix and add HCL solution behind above-mentioned a, the b group solution and regulate pH value to 6.7, add 0.1% active carbon and stirred the filtering active carbon 30 minutes, medicinal liquid is again through 0.45 μ m and 0.22 μ m filtering with microporous membrane, detect intermediate content, press arginine Ibuprofen, count every bottle of 30mg;
D) require fill according to detection, send in the freezer dryer after half tamponade, be cooled to-40 ℃, insulation 2 as a child slowly is warming up to-5 ℃～0 ℃ sublimation drying, be warming up to 35 ℃ again after, be incubated 3 hours, lyophilization end, outlet.
More than show and described ultimate principle of the present invention, principal character and advantage of the present invention.The technical staff of the industry should understand; the present invention is not restricted to the described embodiments; what describe in above-described embodiment and the description only is preference of the present invention; be not used for limiting the present invention; without departing from the spirit and scope of the present invention; the present invention also has various changes and modifications, and these changes and improvements all fall in the claimed scope of the invention.The claimed scope of the present invention is defined by appending claims and equivalent thereof.
Claims (4)
1. injection arginine Ibuprofen compositions, it is characterized in that the principal agent of said composition is: arginine Ibuprofen, melatonin, described melatonin comprises the slow-released part of immediate release section and cyclodextrin inclusion compound.
2. the injection freeze-dried powder of the described compositions of claim 1, it is characterized in that: this freeze-dried powder is principal agent with arginine Ibuprofen, melatonin, wherein to account for the mass percent of principal agent be 0.1%～7.5% to the immediate release section of melatonin, and the mass percent that the slow-released part of the cyclodextrin inclusion compound of melatonin accounts for principal agent is 1.5%～18.5%.
3. a production method of producing the described injection freeze-dried powder of claim 2 is characterized in that, step is:
A) mannitol with 2～10 times of arginine Ibuprofen and arginine Ibuprofen group components is added to stirring and dissolving in the water for injection, adds that to account for the principal agent mass percent be that 0.1%～7.5% melatonin stirs again;
B) will account for the principal agent mass percent is that medium substitution value hydroxypropyl-β-cyclodextrin that 1.5%～18.5% melatonin and mol ratio are 1:1 adds in the water for injection, stir all with, detection melatonin envelop rate is greater than 90%;
C) mix and add HCL solution behind above-mentioned a, the b group solution and regulate pH value to 6.7, the active carbon of adding 0.1% stirred 30 minutes, and filtering active carbon, medicinal liquid are again through 0.45 μ m and 0.22 μ m filtering with microporous membrane, detect intermediate content, by every bottle of 30mg of arginine Ibuprofen;
D) require fill according to detection, send in the freezer dryer after half tamponade, be cooled to-40 ℃, insulation 2 as a child slowly is warming up to-5 ℃～0 ℃ sublimation drying, be warming up to 35 ℃ again after, be incubated 3 hours, lyophilization end, outlet.
4. the application of the described injection arginine Ibuprofen of claim 1 a combination treatment arthritis.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN2013102636233A CN103301118A (en) | 2013-06-27 | 2013-06-27 | Arginine ibuprofen composition for injection |
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| CN2013102636233A CN103301118A (en) | 2013-06-27 | 2013-06-27 | Arginine ibuprofen composition for injection |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ITMI20132116A1 (en) * | 2013-12-18 | 2015-06-19 | Apharm Srl | ASSOCIATION OF GLYCOSAMINOGLICANS AND CYCLODESTRINES |
| WO2018025128A1 (en) * | 2016-08-02 | 2018-02-08 | Jamil Irfan | Stable ibuprofen injectable composition |
| WO2020206348A1 (en) * | 2019-04-04 | 2020-10-08 | The Texas A&M University System | Delivery devices for localized delivery of antimicrobial, anti-inflammatory, and antioxidant agents |
Citations (1)
| 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 |
-
2013
- 2013-06-27 CN CN2013102636233A patent/CN103301118A/en active Pending
Patent Citations (1)
| 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 |
Non-Patent Citations (2)
| Title |
|---|
| RUSSEL J. REITER: "Melatonin: reducing the toxicity and increasing the efficacy of drugs", 《JOURNAL OF PHARMACY AND PHARMACOLOGY》, no. 54, 31 December 2002 (2002-12-31), pages 1299 - 1321 * |
| 赵次英等: "褪黑激素应用中的影响因素", 《江苏药学与临床研究》, vol. 7, no. 3, 31 December 1999 (1999-12-31), pages 3 - 5 * |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ITMI20132116A1 (en) * | 2013-12-18 | 2015-06-19 | Apharm Srl | ASSOCIATION OF GLYCOSAMINOGLICANS AND CYCLODESTRINES |
| WO2015092516A1 (en) * | 2013-12-18 | 2015-06-25 | Apharm S.R.L. | Combination of glycosaminoglycans and cyclodextrins |
| US9974803B2 (en) | 2013-12-18 | 2018-05-22 | Apharm S.R.L. | Combination of glycosaminoglycans and cyclodextrins |
| EA032372B1 (en) * | 2013-12-18 | 2019-05-31 | Афарм С.Р.Л. | Combination of glycosaminoglycans and cyclodextrins |
| WO2018025128A1 (en) * | 2016-08-02 | 2018-02-08 | Jamil Irfan | Stable ibuprofen injectable composition |
| CN109843266A (en) * | 2016-08-02 | 2019-06-04 | 安巴知识产权有限公司 | Stable brufen injectable composition |
| US20190183823A1 (en) * | 2016-08-02 | 2019-06-20 | Ambah Ip Limited | Stable ibuprofen injectable composition |
| AU2017307313B2 (en) * | 2016-08-02 | 2021-09-09 | Ambah Ip Limited | Stable ibuprofen injectable composition |
| US11541024B2 (en) * | 2016-08-02 | 2023-01-03 | Ambah Ip Limited | Stable ibuprofen injectable composition |
| CN109843266B (en) * | 2016-08-02 | 2023-08-11 | 安巴知识产权有限公司 | Stable ibuprofen injection composition |
| WO2020206348A1 (en) * | 2019-04-04 | 2020-10-08 | The Texas A&M University System | Delivery devices for localized delivery of antimicrobial, anti-inflammatory, and antioxidant agents |
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Application publication date: 20130918 |