CN103127097A - Ertapenem pharmaceutical composition - Google Patents
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- CN103127097A CN103127097A CN2011103894479A CN201110389447A CN103127097A CN 103127097 A CN103127097 A CN 103127097A CN 2011103894479 A CN2011103894479 A CN 2011103894479A CN 201110389447 A CN201110389447 A CN 201110389447A CN 103127097 A CN103127097 A CN 103127097A
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Abstract
The invention relates to Ertapenem pharmaceutical composition which comprises Ertapenem and protective agents. The Ertapenem pharmaceutical composition obviously improves the stability of active ingredients in the preparation of the composition and a long-term storage process.
Description
Technical field
The invention belongs to medical technical field, relate to particularly pharmaceutical composition of a kind of carbapenem antibiotic and preparation method thereof.
Background technology
Ertapenem (ertapenem) has good antibacterial activity and pharmacokinetic properties as a kind of wide spectrum carbapenem antibiotic, long half time, and administration every day 1 time, mixed infection has fabulous efficacy and saferry to Community-acquired.
Similar with other carbapenem antibiotic, the dosage form of ertapenem is also freezing-dried powder injection.Ertapenem is preserved extremely unstable under the condition more than-20 ℃, polymerization and hydrolysis easily occur and form polymer and the open-loop products of non-activity, and it is more unstable in solution, even-20 ℃ of preservations, polymerization and hydrolysis occur easily also.For this reason, people have carried out a large amount of tests and have groped, and have proposed some methods preferably.
Chinese patent ZL97190911.3 discloses the Pharmaceutical composition of a kind of ertapenem and carbon dioxide source (sodium carbonate or sodium bicarbonate) composition.CN1481385 discloses a kind of preparation method, is also to use carbon dioxide source.Protect, keep the ertapenem solution of pre-lyophilizing to be in low temperature environment and certain pH value scope although adopt carbon dioxide source; can play certain Stabilization; but the content of ertapenem still is reduced to 94.7% (data are referring to the embodiment table 7 of CN1481385) from 99.2% after lyophilizing, and is still stable not.
Therefore, be necessary to continue research, invent a kind of stable ertapenem compositions, said composition can prevent farthest in preparation process that not only it from polymerization and hydrolysis occuring, and can satisfy the needs of long term storage.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of pharmaceutical composition of stable ertapenem, and said composition can prevent farthest in preparation process that not only it from polymerization and hydrolysis occuring, and can satisfy the needs of long term storage.
For solving the problems of the technologies described above, one aspect of the present invention provides a kind of pharmaceutical composition of ertapenem, and said composition comprises ertapenem and protective agent.
Protective agent of the present invention is the structure of ertapenem to be played the non-active ingredient of Stabilization; comprise a kind of or two kinds and multiple combination in citric acid, malic acid, tartaric acid and hetastarch; optimization citric acid and hetastarch, more preferably citric acid.Wherein the mean molecule quantity of hetastarch be 100000～300000 and molar substitution be 0.3～0.5, preferred mean molecule quantity be 200000 and molar substitution be 0.5 hetastarch and mean molecule quantity be 130000 and molar substitution be 0.4 hetastarch, more preferably mean molecule quantity be 130000 and molar substitution be 0.4 hetastarch.
In pharmaceutical composition of the present invention, each protectant amount can change in a big way, and generally the mol ratio of each protective agent and ertapenem is 0.15～6: 1, and preferred 0.3～5: 1, more preferably 1～3: 1.When protective agent contained hetastarch, the weight ratio of protective agent and ertapenem was 0.005～1: 1, preferred 0.005～0.7: 1, more preferably 0.01～0.25: 1, more preferably 0.05～0.15: 1.
Pharmaceutical composition of the present invention can also comprise water or aqueous solution, and the pH of the solution that it forms in water or aqueous solution is 7.0～8.0, and preferred pH value is 7.2～7.8.As required, can also add the pH value regulator in the present composition, with the pH value that keeps the present composition in above-mentioned scope.The pH value regulator can be the pH value regulator that uses in common injection preparation, such as sodium hydroxide or potassium hydroxide etc.
As required, pharmaceutical composition of the present invention can also comprise various pharmaceutical excipients, diluent, buffer agent, antiseptic, tension regulator and other compositions.Wherein pharmaceutical excipient comprises mannitol, Sorbitol, lactose, glucose, sucrose, maltose, mannose, glycine, glutamic acid, serine etc.Diluent comprises the Ringer's mixture of sterile water for injection, normal saline, 5% D/W, lactic acid etc., preferred normal saline, sterile water for injection.
The present invention also provides a kind of preparation method of pharmaceutical composition of ertapenem; the method comprises: ertapenem and protective agent are dissolved in the water for injection of 0～5 ℃ of pre-cooling; the concentration that makes the active component ertapenem is 50～200mg/ml; the pH of regulator solution is 7.0～8.0, and aseptic filtration, packing obtain containing the medicinal composition solution of ertapenem.
The present invention also provides a kind of preparation method that contains the freeze-dried powder of ertapenem on the other hand; the method comprises: ertapenem and protective agent are dissolved in the water for injection of 0～5 ℃ of pre-cooling; the concentration that makes the active component ertapenem is 50～200mg/ml; the pH of regulator solution is 7.0～8.0; aseptic filtration, packing obtain containing the medicinal composition solution of ertapenem; then carry out lyophilization; the pre-freeze temperature is-25～-80 ℃; the baking temperature upper limit is 40～60 ℃ again, obtains containing the freeze-dried powder of ertapenem.
The present invention also provides the pharmaceutical composition that contains ertapenem to treat and/or prevent application in the medicine of responsive microbial infection in preparation.
The present invention is by using protective agent; significantly improved the stability of active component in compositions preparation and long-term storage process; prevent that effectively it from polymerization and hydrolysis occuring; the lyophilized injectable powder for preparing by the present invention; content can reach more than 96%; and being reduced in 3% of product content in freeze-drying process, significantly lower than open source literature.Stability study shows: the lyophilized injectable powder that the present invention prepares is long preservation at room temperature.
The specific embodiment
The below describes the present invention in detail with specific embodiment, and the purpose of following examples is for content of the present invention is described better, and does not mean that any limitation of the invention.
Embodiment 1
Taking mean molecule quantity is each 1.0g of hetastarch of 130000 (molar substitution is 0.4) and 200000 (molar substitution is 0.5), is dissolved in water to 10ml, is placed on 4 ℃ of refrigerator and cooled standby.(it is 99.1% that HPLC analyzes its content, and below the content with raw material represents to take ertapenem raw material 2.25g.Specific analytical method is referring to Sajonz P, Vailaya A, Sudah O, McPherson L, et al.Development of a gradient elution preparative high performance liquid chromatography method for the recovery of the antibiotic ertapenem from crystallization process streams.J Chromatogr is A.2006; 1126:365-372.), add 4 ℃ of water 10ml dissolvings.Be 12ml and shake up with a small amount of 4 ℃ of water of the rear benefit of pH to 7.3 of 2mol/L NaOH regulator solution to volume.Draw respectively in 4ml ertapenem solution to 2 cillin bottle, then respectively adding above-mentioned 2 kind of 10% hetastarch 1ml to make its final concentration is 2% also abundant mixing, 2 composition solutions are carried out respectively aseptic filtration, filtrate collection is placed on-70 ℃ of pre-freeze 4h in through in the cillin bottle of sterilization treatment.
After pre-freeze is completed, with the sample lyophilization, vacuum degree control is in 15 ± 5Pa left and right, and drying stage is controlled temperature upper limit and is 50 ℃ and keeps 3h, and dry rear temperature returns to 25 ℃ and stops vacuum control, and after tamponade, outlet is completed lyophilization.HPLC analyzes the content of ertapenem after lyophilizing, and to add mean molecule quantity after lyophilizing be 130000 and 200000 hetastarch is respectively as the content of protectant ertapenem: 96.7% and 96.1%.
Embodiment 2
Taking mean molecule quantity is the hetastarch 5.0g of 130000 (molar substitution is 0.4), is dissolved in water to 20ml, and it is 25% hydroxyethyl starch solution that mixing gets concentration.Then progressively being diluted to concentration is 15%, 10%, 5%, 2.5%, 1% and 0.5% (w/v), is placed in 4 ℃ of refrigerator and cooled standby.Take ertapenem raw material 7.01g, add 4 ℃ of water dissolutioies to 28ml and mixing, draw respectively in 4ml to 7 cillin bottle.Get respectively concentration and be 25%, 15%, 10%, 5%, 2.5%, 1% and 0.5% hydroxyethyl starch solution 1ml to cillin bottle, make the weight ratio of itself and ertapenem be followed successively by 0.25,0.15,0.1,0.05,0.025,0.01 and 0.005.Fully regulate respectively pH to 7.5 ± 0.3 with 2mol/L NaOH after mixing.7 composition solutions are carried out respectively aseptic filtration, and then filtrate collection is placed in whole samples-25 ℃ of pre-freeze 4h in through in the cillin bottle of sterilization treatment.
After pre-freeze is completed, with the sample lyophilization, vacuum degree control is in 15 ± 5Pa left and right, and drying stage is controlled temperature upper limit and is 60 ℃ and keeps 3h, and dry rear temperature returns to 25 ℃ and stops vacuum control, and after tamponade, outlet is completed lyophilization.The content of ertapenem after HPLC analysis lyophilizing, result is as shown in table 1.
Table 1:
Embodiment 3
Take anhydrous citric acid 12.10g, regulate pH to 7.40 with 10mol/L NaOH after adding water 15ml dissolving, adding that water mends to volume is that 20ml gets the 3.15mol/L citric acid solution.This solution progressively is diluted to the citric acid solution that concentration is 2.63mol/L, 2.10mol/L, 1.58mol/L, 1.05mol/L, 0.53mol/L, 0.32mol/L, 0.16mol/L and 0.08mol/L, be placed in 4 ℃ cooling standby.
Take ertapenem raw material 4.5g, add 4 ℃ of cold water 20ml dissolvings rear with 2mol/L NaOH adjusting pH to 7.62, adding 4 ℃ of cold water to volume is 27ml, then with every part of 3ml, it is divided into 9 parts.Draw respectively each 2ml of citric acid solution of above-mentioned pre-cooled 3.15mol/L, 2.63mol/L, 2.10mol/L, 1.58mol/L, 1.05mol/L, 0.53mol/L, 0.32mol/L, 0.16mol/L and 0.08mol/L to ertapenem solution, make the mol ratio of citric acid and ertapenem be respectively 6,5,4,3,2,1,0.6,0.3 and 0.15, measure respectively and record pH after mixing.Respectively composition solution is carried out aseptic filtration subsequently, filtrate collection is in through in the cillin bottle of sterilization treatment, and is placed in-80 ℃ of pre-freeze 3h.
After pre-freeze is completed, with the sample lyophilization, vacuum degree control is in 15 ± 5Pa left and right, and drying stage is controlled temperature upper limit and is 40 ℃ and keeps 3h, and dry rear temperature returns to 25 ℃ and stops vacuum control, and after tamponade, outlet is completed lyophilization.After HPLC analysis lyophilizing, the content of ertapenem, the results are shown in Table 2.
Table 2:
Embodiment 4
Take malic acid 8.45g, regulate pH to 7.74 with 10mol/L NaOH after adding water 15ml dissolving, adding that water mends to volume is that 20ml gets the 3.15mol/L malic acid solution.This solution progressively is diluted to the malic acid solution that concentration is 2.63mol/L, 2.10mol/L, 1.58mol/L, 1.05mol/L, 0.53mol/L, 0.32mol/L, 0.16mol/L and 0.08mol/L, be placed in 4 ℃ cooling standby.
Take ertapenem raw material 4.5g, add 4 ℃ of cold water 20ml dissolvings rear with 2mol/L NaOH adjusting pH to 7.40, adding 4 ℃ of cold water to volume is 27ml, then with every part of 3ml, it is divided into 9 parts.Draw respectively each 2ml of malic acid solution of above-mentioned pre-cooled 3.15mol/L, 2.63mol/L, 2.10mol/L, 1.58mol/L, 1.05mol/L, 0.53mol/L, 0.32mol/L, 0.16mol/L and 0.08mol/L to ertapenem solution, make the mol ratio of malic acid and ertapenem be respectively 6,5,4,3,2,1,0.6,0.3 and 0.15, measure respectively and record pH after mixing.Respectively composition solution is carried out aseptic filtration subsequently, filtrate collection is in through in the cillin bottle of sterilization treatment, and is placed in-25 ℃ of pre-freeze 5h.
After pre-freeze is completed, with the sample lyophilization, vacuum degree control is in 15 ± 5Pa left and right, and drying stage is controlled temperature upper limit and is 45 ℃ and keeps 3h, and dry rear temperature returns to 25 ℃ and stops vacuum control, and after tamponade, outlet is completed lyophilization.After HPLC analysis lyophilizing, the content of ertapenem, the results are shown in Table 3.
Table 3:
Embodiment 5
Take tartaric acid 9.47g, regulate pH to 7.24 with 10mol/L NaOH after adding water 15ml dissolving, adding that water mends to volume is that 20ml gets the 3.15mol/L tartaric acid solution.This solution progressively is diluted to the sodium tartrate solution that concentration is 2.63mol/L, 2.1mol/L, 1.58mol/L, 1.05mol/L, 0.53mol/L, 0.32mol/L, 0.16mol/L and 0.08mol/L, be placed in 4 ℃ cooling standby.
Take ertapenem raw material 4.5g, add 4 ℃ of cold water 20ml dissolvings rear with 2mol/L NaOH adjusting pH to 7.66, adding 4 ℃ of cold water to volume is 27ml, then with every part of 3ml, it is divided into 9 parts.Draw respectively each 2ml of tartaric acid solution of above-mentioned pre-cooled 3.15mol/L, 2.63mol/L, 2.1mol/L, 1.58mol/L, 1.05mol/L, 0.53mol/L, 0.32mol/L, 0.16mol/L and 0.08mol/L to ertapenem solution, make the mol ratio of tartaric acid and ertapenem be respectively 6,5,4,3,2,1,0.6,0.3 and 0.15, measure respectively and record pH after mixing.Respectively composition solution is carried out aseptic filtration subsequently, filtrate collection is in through in the cillin bottle of sterilization treatment, and is placed in-70 ℃ of pre-freeze 4h.
After pre-freeze is completed, with the sample lyophilization, vacuum degree control is in 15 ± 5Pa left and right, and drying stage is controlled temperature upper limit and is 50 ℃ and keeps 3h, and dry rear temperature returns to 25 ℃ and stops vacuum control, and after tamponade, outlet is completed lyophilization.After HPLC analysis lyophilizing, the content of ertapenem, the results are shown in Table 4.
Table 4:
Embodiment 6
Take anhydrous citric acid 6.05g, regulate pH to 7.38 with 10mol/L NaOH after adding water 7ml dissolving, adding that water mends to volume is that 10ml gets the 3.15mol/L citric acid solution.Take malic acid 4.23g, regulate pH to 7.64 with 10mol/L NaOH after adding water 8ml dissolving, adding that water mends to volume is that 10ml gets the 3.15mol/L malic acid solution.Citric acid solution and malic acid solution are placed in 4 ℃ of refrigerator and cooled standby.
Take ertapenem raw material 2.25g, add 4 ℃ of cold water 10ml dissolvings rear with 2mol/L NaOH adjusting pH to 7.55, adding 4 ℃ of cold water to volume is 12ml.Be divided into every part of 4ml after mixing.Draw respectively pre-cooled 0.75ml citric acid and 0.25ml malic acid solution, 0.5ml citric acid and 0.5ml malic acid solution, 0.25ml citric acid and 0.75ml malic acid solution and join in three parts of ertapenem solution, measure and record pH after mixing.Then respectively composition solution is carried out aseptic filtration, filtrate collection is in through in the cillin bottle of sterilization treatment, and is placed in-60 ℃ of pre-freeze 5h.
After pre-freeze is completed, with the sample lyophilization, vacuum degree control is in 15 ± 5Pa left and right, and drying stage is controlled temperature upper limit and is 60 ℃ and keeps 2.5h, and dry rear temperature returns to 25 ℃ and stops vacuum control, and after tamponade, outlet is completed lyophilization.After HPLC analysis lyophilizing, the changes of contents of ertapenem, the results are shown in Table 5.
Table 5:
Embodiment 7
Take anhydrous citric acid 6.05g, regulate pH to 7.68 with 10mol/L NaOH after adding water 7ml dissolving, adding that water mends to volume is that 10ml gets the 3.15mol/L citric acid solution.Take mean molecule quantity and be 130000 hetastarch 0.4g, be dissolved in water to volume be 10ml, namely get 4% hydroxyethyl starch solution.Citric acid solution and hydroxyethyl starch solution are placed in 4 ℃ of refrigerator and cooled standby.
Take ertapenem raw material 3.75g, add 4 ℃ of cold water 16ml dissolvings rear with 2mol/L NaOH solution adjusting pH to 7.44, replenishing 4 ℃ of cold water to volumes is 20ml and mixing.Ertapenem solution is divided into 5 parts, every part of 4ml.Draw respectively 0.8ml citric acid solution and 0.2ml hydroxyethyl starch solution, 0.67ml citric acid solution and 0.33ml hydroxyethyl starch solution, 0.5ml citric acid solution and 0.5ml hydroxyethyl starch solution, 0.33ml citric acid solution and 0.67ml hydroxyethyl starch solution, 0.2ml citric acid solution and 0.8ml hydroxyethyl starch solution and join in above-mentioned 5 parts of ertapenem solution, measure and record the pH of every part of combination solution after mixing.Then respectively composition solution is carried out aseptic filtration, filtrate collection is in through in the cillin bottle of sterilization treatment, and is placed in-50 ℃ of pre-freeze 5h.
After pre-freeze is completed, with the sample lyophilization, vacuum degree control is in 15 ± 5Pa left and right, and drying stage is controlled temperature upper limit and is 60 ℃ and keeps 2.5h, and dry rear temperature returns to 25 ℃ and stops vacuum control, and after tamponade, outlet is completed lyophilization.After HPLC analysis lyophilizing, the changes of contents of ertapenem, the results are shown in Table 6.
Table 6:
Embodiment 8 long-term stable experiments
Take anhydrous citric acid 404.2g, regulate pH to 7.57 with 10mol/L NaOH after adding water 800ml dissolving, adding that water mends to volume is that 1000ml gets the 2.10mol/L citric acid solution.Mixing be placed on 4 ℃ cooling standby.Take ertapenem raw material 500g, regulate pH to 7.46 with 2mol/L NaOH solution after adding 4 ℃ of cold water 3500ml dissolving, with 4 ℃ of cold water mend to volume be 4000ml.Citric acid solution and ertapenem solution are merged to get the 5000ml mixed solution, and fully surveying its pH after mixing is 7.51, and wherein the mol ratio of citric acid and ertapenem is 2: 1.The gained mixed solution is carried out aseptic filtration and aseptic subpackaged in the cillin bottle of 1000 sterilizations in advance with every part of 5ml, and be placed at once-70 ℃ of pre-freeze 4h.
After pre-freeze is completed, with the sample lyophilization, vacuum degree control is in 15 ± 5Pa left and right, and drying stage is controlled temperature upper limit and is 50 ℃ and keeps 3h, and dry rear temperature returns to 25 ℃ and stops vacuum control, and after tamponade, outlet is completed lyophilization, is denoted as A and criticizes.With legal system standby other two batches, be denoted as respectively B and criticize with C and criticize.After HPLC analyzes lyophilizing, ertapenem in 25 ℃ ± 2 ℃ changes of contents of placing 0,3,6,9,12,18 and 24 month, the results are shown in Table 7.
Table 7:
Embodiment 9 intravenous injection solution stability testings
Get according to the cryodesiccated injection ertapenem sample of implementing 8 preparations, every sodium chloride solution dissolving that adds 10ml water or 0.9%, move to immediately in the sodium chloride solution of 50ml 0.9% after the shake well dissolving, the variation of ertapenem content in 0,1,2,4,6 and 8 hour (ambient temperature is 25 ℃) comparison solution respectively the results are shown in Table 8.
Table 8:
| Time | 0h | 1h | 2h | 4h | 6h | 8h |
| The content of ertapenem | 96.8％ | 96.5％ | 96.1％ | 95.6％ | 94.5％ | 94.1％ |
The comparative example
With do not contain protective agent and not the ertapenem freeze-dried powder in carbonated source (Comparative Examples 1) use citric acid to compare as protectant ertapenem freeze-dried powder with ertapenem freeze-dried powder (Comparative Examples 2) and the present invention of using carbon dioxide source, the content of ertapenem after lyophilizing relatively.
Comparative Examples 1: preparation does not contain protectant ertapenem freeze-dried powder
Take ertapenem raw material 2.0g, regulate pH to 7.58 with 2mol/L NaOH after adding 4 ℃ of cold water 16ml dissolvings, adding 4 ℃ of cold water to volume is 20ml, shake up rear HPLC and analyze its content, then solution is carried out aseptic filtration, with every bottle of 5ml, filtrate is sub-packed in cillin bottle through sterilization treatment, and is placed in-70 ℃ of pre-freeze 4h.
After pre-freeze is completed, with the sample lyophilization, vacuum degree control is in 15 ± 5Pa left and right, and drying stage is controlled temperature upper limit and is 40 ℃ and keeps 3h, and dry rear temperature returns to 25 ℃ and stops vacuum control, and after tamponade, outlet is completed lyophilization.The content of ertapenem after HPLC analysis lyophilizing.
Comparative Examples 2: preparation contains the ertapenem freeze-dried powder of sodium bicarbonate (carbon dioxide source)
Take sodium bicarbonate 0.67g, add 4 ℃ of cold water 20ml dissolvings.Take ertapenem raw material 3.8g, slowly join in above-mentioned sodium bicarbonate solution, and stir to promote all the time dissolving, the NaOH that drips 2mol/L when adding ertapenem with the pH that controls mixed solution in 7.2～7.8 scope.All continuing to stir 20min in 4 ℃ of environment after the ertapenems dissolving, and adding appropriate NaOH and make pH be stabilized in 7.8.Finally obtain the ertapenem solution 38ml in carbonated source, it is carried out dividing in the cillin bottle that installs to first sterilization with every bottle of 5m1 after aseptic filtration, and be placed at once-80 ℃ of pre-freeze 3h.
Divide in the cillin bottle that installs to first sterilization, and be placed at once-80 ℃ of pre-freeze 3h.
After pre-freeze is completed, with the sample lyophilization, vacuum degree control is in 15 ± 5Pa left and right, and drying stage is controlled temperature upper limit and is 55 ℃ and keeps 4h, and dry rear temperature returns to 25 ℃ and stops vacuum control, and after tamponade, outlet is completed lyophilization.The content of ertapenem after HPLC analysis lyophilizing.
Be that 2 result of the test compares with mol ratio in the measurement result of above-mentioned Comparative Examples 1 and Comparative Examples 2 and the embodiment of the present invention 3, the results are shown in Table 9.
Table 9:
Claims (10)
1. the pharmaceutical composition of an ertapenem, said composition comprises ertapenem and protective agent.
2. pharmaceutical composition claimed in claim 1, wherein protective agent comprises a kind of or two kinds and the multiple combination in citric acid, malic acid, tartaric acid and hetastarch.
3. pharmaceutical composition claimed in claim 2, wherein protective agent is citric acid and hetastarch.
4. pharmaceutical composition claimed in claim 3, wherein protective agent is citric acid.
5. the described pharmaceutical composition of claim 1～4 any one, wherein the mol ratio of protective agent and ertapenem is 0.15～6: 1.
6. pharmaceutical composition claimed in claim 5, wherein the mol ratio of protective agent and ertapenem is 0.3～5: 1.
7. pharmaceutical composition claimed in claim 6, wherein the mol ratio of protective agent and ertapenem is 1～3: 1.
8. the preparation method of the pharmaceutical composition of an ertapenem; the method comprises: ertapenem and protective agent are dissolved in the water for injection of 0～5 ℃ of pre-cooling; the concentration that makes the active component ertapenem is 50～200mg/ml; the pH of regulator solution is 7.0～8.0, and aseptic filtration, packing obtain containing the medicinal composition solution of ertapenem.
9. preparation method that contains the freeze-dried powder of ertapenem; the method comprises: ertapenem and protective agent are dissolved in the water for injection of 0～5 ℃ of pre-cooling; the concentration that makes the active component ertapenem is 50～200mg/ml; the pH of regulator solution is 7.0～8.0; aseptic filtration, packing obtain containing the medicinal composition solution of ertapenem, then carry out lyophilization, and the pre-freeze temperature is-25～-80 ℃; the baking temperature upper limit is 40～60 ℃ again, obtains containing the freeze-dried powder of ertapenem.
10. the pharmaceutical composition that contains ertapenem treats and/or prevents application in the medicine of responsive microbial infection in preparation.
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| CN103127097B (en) | 2015-09-02 |
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Effective date of registration: 20200825 Address after: 200040 No. 1320 West Beijing Road, Shanghai, Jingan District Co-patentee after: CHIA TAI TIANQING PHARMACEUTICAL GROUP Co.,Ltd. Patentee after: SHANGHAI INSTITUTE OF PHARMACEUTICAL INDUSTRY Co-patentee after: SHANGHAI DUOMIRUI BIOTECHNOLOGY Co.,Ltd. Address before: 200040 No. 1320 West Beijing Road, Shanghai Co-patentee before: CHIA TAI TIANQING PHARMACEUTICAL GROUP Co.,Ltd. Patentee before: SHANGHAI INSTITUTE OF PHARMACEUTICAL INDUSTRY |
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