CN102552121B - Milrinone injection - Google Patents
Milrinone injection Download PDFInfo
- Publication number
- CN102552121B CN102552121B CN201010617283.6A CN201010617283A CN102552121B CN 102552121 B CN102552121 B CN 102552121B CN 201010617283 A CN201010617283 A CN 201010617283A CN 102552121 B CN102552121 B CN 102552121B
- Authority
- CN
- China
- Prior art keywords
- milrinone
- injection
- sodium chloride
- lactic acid
- liters
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 229940082795 milrinone injection Drugs 0.000 title claims abstract description 11
- PZRHRDRVRGEVNW-UHFFFAOYSA-N milrinone Chemical compound N1C(=O)C(C#N)=CC(C=2C=CN=CC=2)=C1C PZRHRDRVRGEVNW-UHFFFAOYSA-N 0.000 claims abstract description 29
- 229960003574 milrinone Drugs 0.000 claims abstract description 29
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 34
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 30
- 239000011780 sodium chloride Substances 0.000 claims description 17
- 239000004310 lactic acid Substances 0.000 claims description 15
- 235000014655 lactic acid Nutrition 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 229940090044 injection Drugs 0.000 claims description 14
- 238000002347 injection Methods 0.000 claims description 14
- 239000007924 injection Substances 0.000 claims description 14
- 239000008215 water for injection Substances 0.000 claims description 10
- 239000000126 substance Substances 0.000 abstract description 10
- 239000003814 drug Substances 0.000 abstract description 6
- 238000002360 preparation method Methods 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 4
- 239000000243 solution Substances 0.000 description 10
- 230000001186 cumulative effect Effects 0.000 description 8
- 206010019280 Heart failures Diseases 0.000 description 6
- 239000003978 infusion fluid Substances 0.000 description 6
- 159000000000 sodium salts Chemical class 0.000 description 5
- 238000001914 filtration Methods 0.000 description 4
- 239000012982 microporous membrane Substances 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 230000009090 positive inotropic effect Effects 0.000 description 4
- 230000001954 sterilising effect Effects 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 206010030113 Oedema Diseases 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000000747 cardiac effect Effects 0.000 description 3
- 230000003204 osmotic effect Effects 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 229960002105 amrinone Drugs 0.000 description 2
- RNLQIBCLLYYYFJ-UHFFFAOYSA-N amrinone Chemical compound N1C(=O)C(N)=CC(C=2C=CN=CC=2)=C1 RNLQIBCLLYYYFJ-UHFFFAOYSA-N 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 230000002107 myocardial effect Effects 0.000 description 2
- 230000001196 vasorelaxation Effects 0.000 description 2
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 1
- 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 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229940099471 Phosphodiesterase inhibitor Drugs 0.000 description 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 206010041277 Sodium retention Diseases 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000004872 arterial blood pressure Effects 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000000916 dilatatory effect Effects 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000013401 experimental design Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 229940093181 glucose injection Drugs 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- FPLYNRPOIZEADP-UHFFFAOYSA-N octylsilane Chemical group CCCCCCCC[SiH3] FPLYNRPOIZEADP-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides milrinone injection and a preparation method of the milrinone injection, and belongs to the technical field of chemical medicine preparations. The milrinone injection provided by the invention has the advantages that the stability is good, the milrinone relevant substance content is low, and the clinic use effect is good.
Description
Technical field
The present invention relates to a kind of Milrinone injection and preparation method thereof, belong to technical field of medicine.
Background technology
Milrinone (Milrinone) is a kind of cardiac tonic, is phosphodiesterase inhibitor, is the succedaneum of amrinone, but its to act on comparatively amrinone strong 10 ~ 30 times, toleration is better.Milrinone is oral and quiet note is all effective, but time oral, untoward reaction is heavier.Milrinone has positive inotropic action and vasorelaxation action concurrently.This product positive inotropic action mainly by suppressing phosphodiesterase, makes cyclic adenosine monophosphate in myocardial cell (CAMP) concentration increase, and intracellular Ca2+ increases, and myocardial contraction is strengthened, and cardiac output increases.Its vasorelaxation action may be directly act on small artery or caused by, thus the forward and backward load of heart can be reduced, reduce left ventricular filling pressure, improve left chamber function, increase cardiac index, but mean arterial pressure and heart rate are had no significant effect.The cardiovascular effect of milrinone is relevant with dosage, and time low dose of, main manifestations is positive inotropic action, and when dosage strengthens, when reaching the maximum positive inotropic effect of stable state gradually, its blood vessel dilating effect also can be strengthened with the increase of dosage gradually.Milrinone is safer to the patient with conduction block.
Chinese patent 200410030826.9 discloses a kind of milrinone infusion solutions, discloses the preparation prescription of milrinone 20mg, sodium chloride 872mg, lactic acid 28mg in embodiment.This prescription belongs to great transfusion preparation, there is following shortcoming in actual applications: infusion solutions solvent is but sodium chloride solution, every 100ml contains 872mg sodium chloride, the untoward reaction brought due to the sodium salt " additionally added " in infusion solutions just brings the risk of extra safety aspect to patient, the particularly patient of cardiac insufficiency, heart failure, the regulation of " restriction sodium salt is taken in " is had in its Therapeutic Principle, because, the patient of heart failure generally has the clinical manifestation of water-sodium retention, and edema increases the weight of along with increasing the weight of of heart failure.Sodium in vivo retention is more, and edema is then more obvious.Infusion solutions also has transport inconvenience in addition, increases the light levels of medicine thus affect the shortcomings such as stability of drug products.So milrinone infusion solutions disclosed in Chinese patent 200410030826.9 can not adapt to and meet the needs of clinical application.
Summary of the invention
The invention provides a kind of new Milrinone injection and preparation method thereof.Milrinone injection of the present invention is little liquid drugs injection (also claiming small size injection), good stability, milrinone related substance (impurity) content is low, Clinical practice is effective, do not increase the sodium salt of patient takes in, and can configure posterior vein instil when Clinical practice according to the concrete condition of patient and glucose injection or sodium chloride injection.
Milrinone injection of the present invention is mainly made up of milrinone, sodium chloride, lactic acid and water for injection.The effect of lactic acid is used as injection pH value regulator, regulates pH scope between 2.8 ~ 4.0.The effect of sodium chloride is as osmotic pressure regulator, for regulating the osmotic pressure of injection consistent with human body osmotic pressure, prevents hypotonic or hyperosmotic solution to the damage of human body.
Milrinone concentration range is in the solution 0.8-1.2mg/ml, further preferred 1mg/ml.
Sodium chloride concentration range is in the solution 0.85 ~ 0.92mg/ml.
Lactic acid concentration range is in the solution 0.96 ~ 1.29mg/ml.
Milrinone injection provided by the present invention has following advantage:
(1) good stability, decreases the light levels of medicine, thus increases stability;
(2) compared with Chinese patent 200410030826.9, Corotrope of the present invention adopts the concentration range of milrinone 1mg/ml, and its related substances is lower, and quality is higher, and stability is better;
(3) untoward reaction that the sodium salt owing to " additionally adding " in infusion solutions brings just brings extra safety aspect risk to patient is avoided, special in needing the cardiac insufficiency of milrinone in treatment, the patient of heart failure, meet the regulation of " restriction sodium salt is taken in " in its Therapeutic Principle, avoid the possibility because medicine causes patient's edema degree to increase;
(4) convenient transportation;
(5) Clinical practice therapeutic effect is good.
Injection of the present invention and Chinese patent 200410030826.9 comparative study:
EXPERIMENTAL DESIGN: after injection of the present invention and Chinese patent 200410030826.9 supplementary material prepare by recipe quantity, each sample is placed 10 days respectively under high temperature 60 degree with 4500LX illumination condition, measured its related substances of each sample respectively at 0,5,10 day.
Assay method:
Determination of related substances: measure according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex VD methods).
Chromatographic condition: octyl silane group silica gel is filler; With phosphoric acid hydrogen dimethylamino solution (get dipotassium hydrogen phosphate 2.7g, the 800ml that adds water adds triethylamine 2.4ml, with phosphorus acid for adjusting pH to 7.5 after dissolving) ,-acetonitrile (80: 20) is mobile phase, and determined wavelength is 220nm.
Related substance: milrinone related substance A [1,6-dihydro-2-methyl-6-oxo-(3,4 '-two pyridine)-5-amide] two prescription determination of related substances results contrast:
Table 1: injection embodiment 1 of the present invention contrasts with Chinese patent 200410030826.9 claim 2 (every 100ml injection is containing milrinone 20mg, sodium chloride 872mg, lactic acid 28mg)
Above-mentioned test shows, adopt Corotrope prescription its related substances of the present invention significantly to reduce, product quality significantly improves.
Detailed description of the invention
Embodiment 1:
Milrinone 10 grams
Lactic acid 11.2 grams
8.8 grams, sodium chloride
Water for injection adds to cumulative volume 10 liters
Take milrinone, add water for injection 6 liters, stir, regulate solution ph to 3.0 with lactic acid, continue to be stirred to entirely molten, add sodium chloride, be stirred to entirely molten, inject water to cumulative volume 10 liters, mixing, filtering with microporous membrane, fill 2000 bottles, sterilizing.
Embodiment 2:
Milrinone 10 grams
Lactic acid 9.6 grams
8.5 grams, sodium chloride
Water for injection adds to cumulative volume 10 liters
Take milrinone, add water for injection 6 liters, stir, regulate solution ph to 3.5 with lactic acid, continue to be stirred to entirely molten, add sodium chloride, be stirred to entirely molten, inject water to cumulative volume 10 liters, mixing, filtering with microporous membrane, fill 2000 bottles, sterilizing.
Embodiment 3:
Milrinone 10 grams
Lactic acid 12.9 grams
9.2 grams, sodium chloride
Water for injection adds to cumulative volume 10 liters
Take milrinone, add water for injection 6 liters, stir, regulate solution ph to 2.8 with lactic acid, continue to be stirred to entirely molten, add sodium chloride, be stirred to entirely molten, inject water to cumulative volume 10 liters, mixing, filtering with microporous membrane, fill 2000 bottles, sterilizing.
Embodiment 4:
Milrinone 10 grams
Lactic acid 9.6 grams
9.2 grams, sodium chloride
Water for injection adds to cumulative volume 10 liters
Take milrinone, add water for injection 6 liters, stir, regulate solution ph to 4.0 with lactic acid, continue to be stirred to entirely molten, add sodium chloride, be stirred to entirely molten, inject water to cumulative volume 10 liters, mixing, filtering with microporous membrane, fill 2000 bottles, sterilizing.
Claims (1)
1. a Milrinone injection, it is composed of the following components: milrinone, lactic acid, sodium chloride, water for injection, it is characterized in that, described injection is small size injection, the concentration of described milrinone in injection is 1mg/ml, the concentration range of described sodium chloride in injection is 0.85 ~ 0.92mg/ml, and the concentration range of described lactic acid in injection is 0.96 ~ 1.29mg/ml, and the pH value range of described injection is 2.8 ~ 4.0.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010617283.6A CN102552121B (en) | 2010-12-22 | 2010-12-22 | Milrinone injection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010617283.6A CN102552121B (en) | 2010-12-22 | 2010-12-22 | Milrinone injection |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102552121A CN102552121A (en) | 2012-07-11 |
| CN102552121B true CN102552121B (en) | 2015-04-15 |
Family
ID=46399592
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201010617283.6A Expired - Fee Related CN102552121B (en) | 2010-12-22 | 2010-12-22 | Milrinone injection |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102552121B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104173343B (en) * | 2014-08-15 | 2015-06-17 | 朗天药业(湖北)有限公司 | Milrinone compound and pharmaceutical composition containing milrinone compound |
| CN108158988B (en) * | 2018-02-27 | 2021-03-23 | 河北化工医药职业技术学院 | Preparation method of milrinone injection |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100337629C (en) * | 2004-04-07 | 2007-09-19 | 鲁南制药集团股份有限公司 | Milrinone sodium chloride injection and production thereof |
-
2010
- 2010-12-22 CN CN201010617283.6A patent/CN102552121B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN102552121A (en) | 2012-07-11 |
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Legal Events
| Date | Code | Title | Description |
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| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CP01 | Change in the name or title of a patent holder | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 100871, Beijing, Haidian District Cheng Fu Road 298, founder building, 5 floor Patentee after: PEKING UNIVERSITY FOUNDER GROUP Co.,Ltd. Patentee after: PKUCARE PHARMACEUTICAL R&D CENTER Patentee after: PKU HEALTHCARE INDUSTRY Group Address before: 100871, Beijing, Haidian District Cheng Fu Road 298, founder building, 5 floor Patentee before: PEKING UNIVERSITY FOUNDER GROUP Co.,Ltd. Patentee before: PKUCARE PHARMACEUTICAL R&D CENTER Patentee before: Pku Healthcare Industry Group Co.,Ltd. |
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| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20221012 Address after: 3007, Hengqin international financial center building, No. 58, Huajin street, Hengqin new area, Zhuhai, Guangdong 519031 Patentee after: New founder holdings development Co.,Ltd. Patentee after: PKUCARE PHARMACEUTICAL R&D CENTER Patentee after: Peking University Medical Management Co.,Ltd. Address before: 100871, Beijing, Haidian District Cheng Fu Road 298, founder building, 5 floor Patentee before: PEKING UNIVERSITY FOUNDER GROUP Co.,Ltd. Patentee before: PKUCARE PHARMACEUTICAL R&D CENTER Patentee before: PKU HEALTHCARE INDUSTRY Group |
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| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20150415 |