CN102552121A - Milrinone injection - Google Patents
Milrinone injection Download PDFInfo
- Publication number
- CN102552121A CN102552121A CN2010106172836A CN201010617283A CN102552121A CN 102552121 A CN102552121 A CN 102552121A CN 2010106172836 A CN2010106172836 A CN 2010106172836A CN 201010617283 A CN201010617283 A CN 201010617283A CN 102552121 A CN102552121 A CN 102552121A
- Authority
- CN
- China
- Prior art keywords
- injection
- milrinone
- sodium chloride
- lactic acid
- add
- 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.)
- Granted
Links
- 229940082795 milrinone injection Drugs 0.000 title claims abstract description 16
- 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 30
- 229960003574 milrinone Drugs 0.000 claims abstract description 30
- 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
- 229940090044 injection Drugs 0.000 claims description 23
- 238000002347 injection Methods 0.000 claims description 23
- 239000007924 injection Substances 0.000 claims description 23
- 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 11
- 239000008215 water for injection Substances 0.000 claims description 6
- 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 5
- 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
- 238000004659 sterilization and disinfection Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000003643 water by type Substances 0.000 description 4
- 238000005303 weighing 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
- 238000005286 illumination Methods 0.000 description 3
- 230000003204 osmotic effect Effects 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 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 2
- 206010041277 Sodium retention Diseases 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 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
- 229960002105 amrinone Drugs 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
- 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
- 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
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 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
- 238000001514 detection method Methods 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
- 239000012535 impurity Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 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
- 230000002787 reinforcement Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel 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 effect is strong 10～30 times than amrinone, and toleration is better.Oral and the quiet notes of milrinone are all effective, but untoward reaction is heavier when oral.Milrinone has positive inotropic action and vasorelaxation action concurrently.The positive inotropic action of these article mainly is through suppressing phosphodiesterase, interior cyclic adenosine monophosphate (CAMP) concentration of myocardial cell being increased, intracellular Ca2+ increase, myocardial contraction reinforcement, cardiac output increase.Its vasorelaxation action possibly be directly act on small artery or due to, thereby can reduce the forward and backward load of heart, reduce left ventricular filling pressure, improve left chamber function, increase cardiac index, but mean arterial pressure and heart rate do not had obvious influence.The cardiovascular effect of milrinone is relevant with dosage, mainly shows as positive inotropic action when low dose of, 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 among the embodiment.This prescription belongs to great transfusion preparation; Following shortcoming is arranged in practical application: the infusion solutions solvent but is sodium chloride solution; Every 100ml contains 872mg sodium chloride, because the untoward reaction that sodium salt brought of " extra adding " has just brought the risk, particularly cardiac insufficiency of extra safety aspect, the patient of heart failure in the infusion solutions to the patient; The regulation that " the restriction sodium salt is taken in " arranged among its Therapeutic Principle; Because the patient of heart failure generally has the clinical manifestation of water-sodium retention, and edema is along with increasing the weight of of heart failure.Sodium retention in vivo is many more, and edema is then obvious more.Thereby infusion solutions also has the illumination degree of transportation inconvenience, increase medicine to influence shortcomings such as stability of drug products in addition.So Chinese patent 200410030826.9 disclosed milrinone infusion solutionses can not adapt to and satisfy the needs of clinical application.
Summary of the invention
The present 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 the small size injection); Good stability, low, the clinical result of use of milrinone related substance (impurity) content sodium salt good, that do not increase the patient is taken in, can be when clinical use according to patient's concrete condition and glucose injection or the instillation of sodium chloride injection configuration posterior vein.
Milrinone injection of the present invention mainly is made up of milrinone, sodium chloride, lactic acid and water for injection.The effect of lactic acid is as injection pH value regulator, regulates the pH scope between 2.8～4.0.The effect of sodium chloride is as osmotic pressure regulator, and the osmotic pressure that is used to regulate injection is consistent with the human body osmotic pressure, prevents the damage to human body of hypotonic or hyperosmotic solution.
The concentration range of milrinone in solution is 0.8-1.2mg/ml, further preferred 1mg/ml.
The concentration range of sodium chloride in solution is 0.85～0.92mg/ml.
The concentration range of lactic acid in solution is 0.96～1.29mg/ml.
Milrinone injection provided by the present invention has following advantage:
(1) good stability has reduced the illumination degree of medicine, thereby increases stability;
(2) compare 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) avoided since in the infusion solutions untoward reaction that sodium salt brought of " extra adding " just brought the risk of extra safety aspect to the patient; Especially for the cardiac insufficiency that needs the milrinone treatment, the patient of heart failure; Meet the regulation of " the restriction sodium salt is taken in " among its Therapeutic Principle, avoided because medicine causes the possibility that patient's edema degree increases;
(4) convenient transportation;
(5) clinical use therapeutic effect is good.
Injection of the present invention and Chinese patent 200410030826.9 comparative studies:
EXPERIMENTAL DESIGN: after injection of the present invention and Chinese patent 200410030826.9 supplementary materials prepare by recipe quantity; With each sample respectively high temperature 60 degree and 4500LX illumination condition held 10 days, respectively at its related substances of measuring each sample in 0,5,10 day.
Assay method:
Determination of related substances: measure according to HPLC (two appendix VD of Chinese Pharmacopoeia version in 2010 method).
Chromatographic condition: octyl silane group silica gel is filler; With phosphoric acid hydrogen dimethylamino solution (get dipotassium hydrogen phosphate 2.7g, add water 800ml dissolving after, add triethylamine 2.4ml, regulate pH to 7.5 with phosphoric acid)-acetonitrile (80: 20) is a mobile phase, the detection wavelength is 220nm.
Two prescriptions of related substance: milrinone related substance A [1,6-dihydro-2-methyl-6-oxo-(3,4 '-two pyridines)-5-amide] determination of related substances is the result compare:
Table 1: injection embodiment 1 of the present invention and Chinese patent 200410030826.9 claim 2 (every 100ml injection contains milrinone 20mg, sodium chloride 872mg, lactic acid 28mg) contrast
Above-mentioned test shows, adopts Corotrope prescription its related substances of the present invention significantly to reduce, and product quality significantly improves.
The specific embodiment
Embodiment 1:
Milrinone 10 grams
Lactic acid 11.2 grams
Sodium chloride 8.8 grams
Water for injection adds to 10 liters of cumulative volumes
Take by weighing milrinone, add 6 liters of waters for injection, stir,, continue to be stirred to complete dissolving, add sodium chloride, be stirred to complete dissolving, add 10 liters of injection water to cumulative volumes, mixing, filtering with microporous membrane, 2000 bottles of fills, sterilization with lactic acid regulator solution pH value to 3.0.
Embodiment 2:
Milrinone 10 grams
Lactic acid 9.6 grams
Sodium chloride 8.5 grams
Water for injection adds to 10 liters of cumulative volumes
Take by weighing milrinone, add 6 liters of waters for injection, stir,, continue to be stirred to complete dissolving, add sodium chloride, be stirred to complete dissolving, add 10 liters of injection water to cumulative volumes, mixing, filtering with microporous membrane, 2000 bottles of fills, sterilization with lactic acid regulator solution pH value to 3.5.
Embodiment 3:
Milrinone 10 grams
Lactic acid 12.9 grams
Sodium chloride 9.2 grams
Water for injection adds to 10 liters of cumulative volumes
Take by weighing milrinone, add 6 liters of waters for injection, stir,, continue to be stirred to complete dissolving, add sodium chloride, be stirred to complete dissolving, add 10 liters of injection water to cumulative volumes, mixing, filtering with microporous membrane, 2000 bottles of fills, sterilization with lactic acid regulator solution pH value to 2.8.
Embodiment 4:
Milrinone 10 grams
Lactic acid 9.6 grams
Sodium chloride 9.2 grams
Water for injection adds to 10 liters of cumulative volumes
Take by weighing milrinone, add 6 liters of waters for injection, stir,, continue to be stirred to complete dissolving, add sodium chloride, be stirred to complete dissolving, add 10 liters of injection water to cumulative volumes, mixing, filtering with microporous membrane, 2000 bottles of fills, sterilization with lactic acid regulator solution pH value to 4.0.
Claims (6)
1. milrinone injection, it is composed of the following components: milrinone, lactic acid, sodium chloride, water for injection is characterized in that the concentration range of said milrinone in injection is 0.8～1.2mg/ml.
2. milrinone injection according to claim 1 is characterized in that, the concentration range of said milrinone in injection is 1mg/ml.
3. milrinone injection according to claim 1 is characterized in that, the concentration range of said sodium chloride in injection is 0.85～0.92mg/ml.
4. milrinone injection according to claim 1 is characterized in that, the concentration range of said lactic acid in injection is 0.96～1.29mg/ml.
5. according to any described milrinone injection among the claim 1-4, it is characterized in that said injection is the small size injection.
6. according to any described milrinone injection among the claim 1-4, it is characterized in that the pH value scope of said 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 true CN102552121A (en) | 2012-07-11 |
| CN102552121B 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) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104173343A (en) * | 2014-08-15 | 2014-12-03 | 朗天药业(湖北)有限公司 | Milrinone compound and pharmaceutical composition containing milrinone compound |
| CN108158988A (en) * | 2018-02-27 | 2018-06-15 | 河北化工医药职业技术学院 | The preparation method of Milrinone injection |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1679566A (en) * | 2004-04-07 | 2005-10-12 | 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
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1679566A (en) * | 2004-04-07 | 2005-10-12 | 鲁南制药集团股份有限公司 | Milrinone sodium chloride injection and production thereof |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104173343A (en) * | 2014-08-15 | 2014-12-03 | 朗天药业(湖北)有限公司 | Milrinone compound and pharmaceutical composition containing milrinone compound |
| 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 |
| CN108158988A (en) * | 2018-02-27 | 2018-06-15 | 河北化工医药职业技术学院 | The preparation method of Milrinone injection |
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102552121B (en) | 2015-04-15 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 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 |
|
| 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 |