CN1568977A - Sodium ozagrel for injection and preparation thereof - Google Patents
Sodium ozagrel for injection and preparation thereof Download PDFInfo
- Publication number
- CN1568977A CN1568977A CN 03133783 CN03133783A CN1568977A CN 1568977 A CN1568977 A CN 1568977A CN 03133783 CN03133783 CN 03133783 CN 03133783 A CN03133783 A CN 03133783A CN 1568977 A CN1568977 A CN 1568977A
- Authority
- CN
- China
- Prior art keywords
- mannitol
- dextran
- ozagrel
- ozagrel sodium
- injection
- 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.)
- Pending
Links
- SHZKQBHERIJWAO-AATRIKPKSA-N ozagrel Chemical compound C1=CC(/C=C/C(=O)O)=CC=C1CN1C=NC=C1 SHZKQBHERIJWAO-AATRIKPKSA-N 0.000 title claims abstract description 31
- 229950003837 ozagrel Drugs 0.000 title claims abstract description 31
- 238000002347 injection Methods 0.000 title claims abstract description 15
- 239000007924 injection Substances 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 28
- 229930195725 Mannitol Natural products 0.000 claims abstract description 17
- 235000010355 mannitol Nutrition 0.000 claims abstract description 17
- 239000000594 mannitol Substances 0.000 claims abstract description 17
- 229920002307 Dextran Polymers 0.000 claims abstract description 16
- 239000000203 mixture Substances 0.000 claims abstract description 5
- 239000007864 aqueous solution Substances 0.000 claims abstract description 4
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 claims abstract description 3
- 239000002671 adjuvant Substances 0.000 claims description 7
- 239000003814 drug Substances 0.000 abstract description 11
- 239000007788 liquid Substances 0.000 abstract description 7
- 239000000243 solution Substances 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000000463 material Substances 0.000 abstract description 3
- 239000004480 active ingredient Substances 0.000 abstract 1
- 238000005336 cracking Methods 0.000 abstract 1
- 238000004090 dissolution Methods 0.000 abstract 1
- 238000004108 freeze drying Methods 0.000 abstract 1
- 238000007710 freezing Methods 0.000 abstract 1
- 230000008014 freezing Effects 0.000 abstract 1
- 230000007306 turnover Effects 0.000 abstract 1
- 230000002950 deficient Effects 0.000 description 16
- 238000002474 experimental method Methods 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000012360 testing method Methods 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 2
- 238000005352 clarification Methods 0.000 description 2
- 235000014510 cooky Nutrition 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000008676 import Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- XNCRUNXWPDJHGV-UHFFFAOYSA-N alpha-Methyl-cinnamic acid Chemical compound OC(=O)C(C)=CC1=CC=CC=C1 XNCRUNXWPDJHGV-UHFFFAOYSA-N 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 239000004531 microgranule Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 238000005057 refrigeration Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
The ozagrel sodium for injection takes ozagrel sodium as a main active ingredient, and is characterized in that: taking a mixture of mannitol and dextran as an auxiliary material, wherein the amount of mannitol is 5 +/-0.5 mg and the amount of dextran is 5 +/-0.5 mg based on 20mg of ozagrel sodium. The preparation method of the ozagrel sodium for injection comprises the steps of firstly pre-freezing an aqueous solution mixed with the ozagrel sodium, mannitol and dextran auxiliary materials twice, and then freeze-drying. The ozagrel sodium for injection provided by the invention has the advantages of flat surface, no liquid feeling, no concave, no dry cracking, complete medicine cake, no sticking to a bottle, turnover in the bottle, no damage, unobvious and perfect appearance difference compared with similar imported medicines, easy dissolution during redissolution, and clear and transparent solution.
Description
Technical field:
The present invention relates to medicine preparation, a kind of lyophilized formulations that can be used as antithrombotic is provided especially, it contains trans 4 (imidazoles-1-ylmethyl) cinnamic acid (be ozagrel, claim ozagrel below).
Background technology:
According to the literature, ozagrel is unstable in aqueous solution, but the part isomerization transfers cis imidazoles methyl cinnamic acid to, and its curative effect is reduced, and makes lyophilized preparation so suit, and lyophilized preparation can guarantee the stable existence of ozagrel.For this reason, the present inventor once adopted conventional adjuvant mannitol and dextran respectively separately, and the freeze-dried reagent of preparation ozagrel is attempted, found that the apparent effect of lyophilized formulations is unsatisfactory, and after the lyophilized preparation dissolving, the solution muddiness has particle.As a product of list marketing, appearance looks elegant is vital, and it can strengthen patient, doctor, nurse even medical distributing business to the confidence of product and relieved to quality.
Summary of the invention:
The object of the present invention is to provide a kind of injection sodium ozagrel, it has good apparent effect, and easily dissolves the solution clear when redissolving.
The invention provides a kind of injection sodium ozagrel, is main active component with sodium ozagrel, it is characterized in that: with the mixture of mannitol, dextran as adjuvant.
Injection sodium ozagrel provided by the present invention, if in the 20mg sodium ozagrel, the amount of mannitol should be 5 ± 0.5mg, the amount of dextran should be 5 ± 0.5mg.
In addition, the present invention also provides the preparation method of above-mentioned injection sodium ozagrel, it is characterized in that: at first will be mixed with the aqueous solution pre-freeze twice of sodium ozagrel and mannitol, dextran adjuvant, and carry out lyophilizing again.
In the preparation method of injection sodium ozagrel of the present invention, the pre-freeze temperature is-40 ℃～-50 ℃, and the time is 90～150 minutes; Freeze temperature is-40 ℃～-50 ℃, and the time is 20～30 hours.
Injection sodium ozagrel provided by the present invention, surfacing, the sense of aneroid sample, not recessed, not dry and cracked, the medicine cake is complete, and not sticking bottle can overturn in bottle, and is not damaged, compares with similar import drugs, difference in appearance is not obvious, and is comparatively perfect, and easily dissolves the solution clear when redissolving.
The specific embodiment:
Get ozagrel 18.6g, NaOH0.14g, water for injection 300ml.NaOH is dissolved in the 300ml water for injection, ozagrel 18.6g is put into above-mentioned NaOH solution stir.Divide then to install in 1000 3ml cillin bottles, standby.
Comparative example 1 mannitol, dextran are tested as a lyophilizing of adjuvant respectively:
Get mannitol respectively, dextran dissolves by the following experiment amount of testing, and divides to install in the above-mentioned standby bottle that medicinal liquid is housed again, every cillin bottle amount of liquid is 0.5ml.Put into-45 ℃ of freeze dryer lyophilizing 24 hours.The results are shown in Table 1
Table 1 (every group each 5)
| (milligram) | The mannitol group | The dextran group | ||
| The lyophilizing outward appearance | Dissolving again | The lyophilizing outward appearance | Dissolving again | |
| ????5 | Defective | Qualified | Defective | Qualified |
| ????10 | Defective | Qualified | Defective | Qualified |
| ????20 | Defective | Defective | Defective | Defective |
| ????40 | Defective | Defective | Defective | Defective |
Experiment finds that dextran group medicine cookies splits, and outward appearance is defective, and 5 milligrams of groups are omited, and finding 10,20,40 milligrams during redissolution has muddy microgranule.Mannitol group, 5 milligrams of groups, 10 milligrams of group surfaces are recessed, and the sense of liquid sample is arranged, and 20 and 40 milligrams of group outward appearances are omited, but a little muddy granule is arranged when redissolving,, organize clarification when redissolving for 5 milligrams and 10 milligrams than the clarification of dextran group, very easily dissolving, and find the sticking bottle of mannitol group medicine cake.
Comparative example 2 mannitol, dextran are respectively as adjuvant, and a lyophilizing of secondary pre-freeze is tested
Example 1 observation of testing first based on the comparison selects 5 milligrams of mannitol groups and 5 milligrams of dextran groups to carry out the experiment second time respectively, considers that the performance of mannitol group is slightly recessed, the sense of liquid sample is arranged, think that the pre-freeze temperature is not enough, determine degree of depth pre-freeze again, and accelerate to freeze dried transfer velocity by pre-freeze.Be specially, at-45 ℃, pre-freeze 120 minutes is taken out and at room temperature to be melted about 30 minutes, once more pre-freeze under equal conditions.At last the frozen material sabot is put into the lyophilizing 24 hours again of-45 ℃ of freeze dryers.The results are shown in Table 2.
Table 2 (every group each 10)
| (milligram) | Mannitol group (propping up) | Dextran group (propping up) | ||
| The lyophilizing outward appearance | Dissolving again | The lyophilizing outward appearance | Dissolving again | |
| ????5 | Slightly better than 1 | Qualified | Defective | Qualified |
Experiment is found: dextran group medicine cookies splits, and outward appearance is defective.Mannitol still surface is slightly recessed, shows slightly the sense of liquid sample, but test the outward appearance outline than first good, thinks that this is because the pre-freeze of the degree of depth and speed the resulting result of transfer velocity more.Two groups of all dissolvings rapidly during redissolution, and outward appearance clear.
Find through experiment for the second time 5 milligrams of groups can reach rapid dissolving, the requirement of solution clear when no matter being dextran group or the redissolution of mannitol group.But two groups of outward appearances are all attractive in appearance inadequately, and to compare outward appearance relatively poor with similar external and homemade medicine, though when considering refrigeration and lyophilizing in breadboard condition than poor in factory, difference in appearance is remarkable.Be difficult for the outward appearance that reaches more attractive in appearance in factory.
Embodiment mannitol, dextran mixed accessories secondary pre-freeze, lyophilizing experiment:
Find the dry and cracked and slightly liquid sample sense of mannitol group surface of dextran group outward appearance through above-mentioned twice experiment, both phenomenons are just the opposite, therefore decide to do following experiment: select 5 milligrams of mannitol groups, 5 milligrams of dextran groups, 5 milligrams of mannitol+5 milligram dextrans to test for the third time respectively, preparation method the results are shown in Table 3 with comparative example 2.
Table 3 (every group each 10)
| Mannitol group (5 milligrams) | Dextran group (5 milligrams) | Combined group (5 milligrams of mannitol+5 milligram dextrans) | |||
| The lyophilizing outward appearance | Dissolving again | The lyophilizing outward appearance | Dissolving again | The lyophilizing outward appearance | Dissolving again |
| Generally | Qualified | Defective | Qualified | Good | Qualified |
Experiment discovery combined group is compared obvious difference with mannitol group and dextran group, its surfacing, the sense of aneroid sample, not recessed, not dry and cracked, the medicine cake is complete, not sticking bottle, can in bottle, overturn, not damaged, compare with similar import drugs, difference in appearance is not obvious, comparatively perfect, and easily dissolve the solution clear when redissolving.
Claims (4)
1, a kind of injection sodium ozagrel is main active component with sodium ozagrel, it is characterized in that: with the mixture of mannitol, dextran as adjuvant.
2, according to the described injection sodium ozagrel of claim 1, it is characterized in that: in the 20mg sodium ozagrel, the amount of mannitol is 5 ± 0.5mg, and the amount of dextran is 5 ± 0.5mg.
3, the preparation method of the described injection sodium ozagrel of a kind of claim 1 is characterized in that: at first will be mixed with the aqueous solution pre-freeze twice of sodium ozagrel and mannitol, dextran adjuvant, and carry out lyophilizing again.
4, according to the preparation method of the described injection sodium ozagrel of claim 3, it is characterized in that: described pre-freeze temperature is-40 ℃～-50 ℃, and the time is 90 minutes～150 minutes; Freeze temperature is-40 ℃ to-50 ℃, and the time is 20～30 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03133783 CN1568977A (en) | 2003-07-24 | 2003-07-24 | Sodium ozagrel for injection and preparation thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03133783 CN1568977A (en) | 2003-07-24 | 2003-07-24 | Sodium ozagrel for injection and preparation thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1568977A true CN1568977A (en) | 2005-01-26 |
Family
ID=34470104
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 03133783 Pending CN1568977A (en) | 2003-07-24 | 2003-07-24 | Sodium ozagrel for injection and preparation thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1568977A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100402506C (en) * | 2006-06-20 | 2008-07-16 | 王绍杰 | Ozagrel lysine and preparation method and application thereof |
| CN101444491B (en) * | 2008-12-11 | 2010-04-14 | 海南数尔药物研究有限公司 | Ozagrel sodium microballoon lyophilized preparation and preparation method thereof |
| CN106361750A (en) * | 2016-11-10 | 2017-02-01 | 哈尔滨珍宝制药有限公司 | Pharmaceutical composition containing sodium ozagrel and preparation method thereof |
| CN113069420A (en) * | 2021-03-10 | 2021-07-06 | 海南卓华制药有限公司 | Sodium ozagrel for injection and preparation method thereof |
-
2003
- 2003-07-24 CN CN 03133783 patent/CN1568977A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100402506C (en) * | 2006-06-20 | 2008-07-16 | 王绍杰 | Ozagrel lysine and preparation method and application thereof |
| CN101444491B (en) * | 2008-12-11 | 2010-04-14 | 海南数尔药物研究有限公司 | Ozagrel sodium microballoon lyophilized preparation and preparation method thereof |
| CN106361750A (en) * | 2016-11-10 | 2017-02-01 | 哈尔滨珍宝制药有限公司 | Pharmaceutical composition containing sodium ozagrel and preparation method thereof |
| CN106361750B (en) * | 2016-11-10 | 2019-01-22 | 哈尔滨珍宝制药有限公司 | A kind of pharmaceutical composition and preparation method thereof containing sodium ozagrel |
| CN113069420A (en) * | 2021-03-10 | 2021-07-06 | 海南卓华制药有限公司 | Sodium ozagrel for injection and preparation method thereof |
| CN113069420B (en) * | 2021-03-10 | 2022-03-15 | 海南久常制药有限公司 | Sodium ozagrel for injection and preparation method thereof |
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| Date | Code | Title | Description |
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| C06 | Publication | ||
| PB01 | Publication | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |