CN111840236B - Meropenem probenecid compound freeze-dried preparation for injection - Google Patents
Meropenem probenecid compound freeze-dried preparation for injection Download PDFInfo
- Publication number
- CN111840236B CN111840236B CN202010787262.2A CN202010787262A CN111840236B CN 111840236 B CN111840236 B CN 111840236B CN 202010787262 A CN202010787262 A CN 202010787262A CN 111840236 B CN111840236 B CN 111840236B
- Authority
- CN
- China
- Prior art keywords
- probenecid
- meropenem
- freeze
- drying
- solution
- 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.)
- Active
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Medicinal Preparation (AREA)
- Communicable Diseases (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Engineering & Computer Science (AREA)
Abstract
The invention relates to a compound lyophilized preparation of meropenem probenecid for injection, which is characterized in that 300 g of meropenem and 100 g of probenecid are prepared into compound preparation solution, and the pH value is 7.3-7.8; starting a freeze dryer for pre-freezing, carrying out resolution drying after sublimation drying, stably heating the plate layer to about 40 ℃ after the sublimation stage is finished, keeping the temperature for 3 hours to fully volatilize water, judging according to the pressure change condition in a freeze-drying box, discharging the box after the box is qualified, and carrying out freeze-drying for 23 hours; taking out the sample, rolling the cover, and inspecting. The addition of the probenecid sodium plays a role of an excipient, and other excipients do not need to be added into a freeze-dried compound preparation consisting of the meropenem and the probenecid sodium, so that the lyophilized compound preparation has great significance for ensuring the purity and the safety of a product.
Description
Technical Field
The invention relates to a compound lyophilized preparation of meropenem probenecid for injection, belonging to the technical field of medicines.
Background
Meropenem is a very important antibiotic and a heavy-weight product for treating severe infections. Probenecid can remarkably improve the pharmacokinetic/pharmacodynamic characteristics of meropenem and greatly improve the success rate of anti-infection empirical therapy. Therefore, the compound injection consisting of the meropenem and the probenecid has great clinical significance. However, only oral probenecid bulk drugs and preparations exist in the world at present, and no probenecid sodium product for intravenous injection administration exists at all. Therefore, no compound freeze-dried preparation consisting of meropenem and probenecid exists in nature all over the world at present. The compound injection is prepared by two ways, one is a sterile raw material powder mixing process, and the other is a freeze-drying process. Because of the special physical and chemical properties of probenecid, high viscosity, high hygroscopicity and poor fluidity, the product is not suitable for preparing compound preparations by adopting a sterile powder mixing process because of difficult uniform mixing. The prepared product has large loading difference and low qualification rate. Once such products are introduced into the market, they will inevitably have a detrimental effect on clinical anti-infective therapy.
Disclosure of Invention
The invention aims to provide a compound freeze-dried preparation of meropenem and probenecid for injection, wherein the first step of the freeze-drying process is to dissolve two components (such as meropenem and probenecid), the two components are mixed completely and uniformly in the solution, the problem of different loading amounts does not exist at all, and the quality of the product is absolutely guaranteed.
The technical scheme of the invention is realized as follows: a compound lyophilized preparation of meropenem sodium probenecid for injection is characterized in that 300 g of meropenem 200-sodium probenecid and 100 g of probenecid are prepared into compound preparation solution according to the weight portion, and the formula proportion of the compound lyophilized preparation is as follows: the probenecid sodium is 2-3: 1, adjusting the pH value of the solution to 7.3-7.8 by using sodium carbonate.
The specific freeze-drying steps are as follows:
(1) and the freeze dryer is started in the pre-freezing stage
Firstly, cooling the plate layer from room temperature to-25 ℃ at the speed of about 3 ℃/min, and preserving heat for 30-60 minutes;
secondly, raising the temperature of the plate layer to 1-2 ℃ at the speed of 1.5-2 ℃/min, and preserving the temperature for 40-60 minutes;
thirdly, cooling to-40 ℃ at the speed of about 3 ℃/min, and preserving heat for 40-60 minutes;
(2) and sublimation drying: after the pre-freezing stage is finished, gradually heating the plate layer to 20 ℃ within 12-16 hours to ensure that the sublimation line is basically invisible to naked eyes;
(3) and (3) resolving and drying: after the sublimation stage is finished, the plate layer is stably heated to about 40 ℃ and is kept warm for 3 hours, so that the moisture is fully volatilized, the plate layer is taken out of the box after being qualified according to the change condition of the pressure in the freeze-drying box, and the total freeze-drying time is about 23 hours; and (3) rolling a cover: after the sample is frozen and dried, the rubber plug is pressed down in vacuum, the vacuum of the freeze dryer is removed, the sample is taken out, and the sample is rolled and covered for inspection.
The compound freeze-drying proportion of the meropenem and the probenecid sodium is 2: 1.
the invention has the advantages that the compound preparation of the meropenem and the probenecid sodium is prepared by the freeze-drying process for the first time, and the addition of the probenecid sodium as the compound preparation has some unexpected benefits. First, as an important antibiotic, meropenem has its own lyophilized dosage form. However, excipients such as albumin, mannitol and the like must be added in the freeze-drying process of meropenem, otherwise the appearance of the freeze-dried meropenem collapses; however, the addition of probenecid can completely play a role of an excipient, so that other excipients are not required to be added into the freeze-dried compound preparation consisting of the meropenem and the probenecid, and great significance is achieved for ensuring the purity and the safety of the product. In addition, because the probenecid sodium has the characteristic of needle-shaped crystals, the probenecid sodium can play a role of a dendritic framework so as to play a supporting role, and the meropenem can be uniformly attached to the framework of the probenecid sodium, so that the volatilization of water is promoted, and the total freeze-drying time is shortened. The freeze-drying process adopts a three-stage repeated pre-freezing mode, so that the freeze-dried product has uniform color, and the two components are not layered with each other.
Detailed Description
The invention is further described with reference to the following examples:
example 1
The prescription proportion of the compound preparation is as follows: the probenecid sodium is 2.5: 1.
preparing a compound preparation solution 1 (meropenem and probenecid sodium):
the total amount of the solution is 1,500ml, and the solution contains: 250 g of meropenem (calculated on dry basis and purity) and 100 g of probenecid sodium (calculated on dry basis and purity), and adjusting the pH value of the solution to 7.3-7.8 by using sodium carbonate;
preparing a single preparation solution 2 (meropenem):
the total amount of the solution is 1,500ml, and the solution contains: 250 g of meropenem (calculated on a dry basis and a pure basis), and adjusting the pH value of the solution to 7.3-7.8 by using sodium carbonate. The difference between solution 1 and solution 2 was that the former contained 100 g of probenecid sodium and the latter did not.
Wherein 10 ml penicillin bottles are adopted, and 500 bottles are respectively filled with 3 ml solution 1, wherein the solution contains 0.5g of meropenem and 0.2 g of probenecid; 500 bottles each contain 3 ml of solution 2 containing 0.5g of meropenem and no probenecid sodium. Half-stoppered a total of 1,000 vials containing solution 1 and solution 2 were placed on a lyophilizer plate for lyophilization, and two solution samples were placed on the same lyophilizer for lyophilization for comparison.
The specific freeze-drying steps are as follows:
1. starting freeze dryer in pre-freezing stage
Firstly, cooling the plate layer from room temperature to-25 ℃ at the speed of about 3 ℃/min, and preserving heat for 30-60 minutes;
secondly, raising the temperature of the plate layer to 1-2 ℃ at the speed of 1.5-2 ℃/min, and preserving the temperature for 40-60 minutes;
thirdly, cooling to-40 ℃ at the speed of about 3 ℃/min, and preserving heat for 40-60 minutes;
2. sublimation drying: after the pre-freezing stage is finished, gradually heating the plate layer to 20 ℃ within 12-16 hours to ensure that the sublimation line is basically invisible to naked eyes;
3. and (3) resolving and drying: after the sublimation stage is finished, the temperature of the plate layer is stably raised to about 40 ℃ and is kept for 3 hours, so that the moisture is fully volatilized, the plate layer is taken out of the box after being qualified according to the pressure change condition in the freeze-drying box, and the total freeze-drying time is about 23 hours; and (3) rolling a cover: after the sample is frozen and dried, the rubber plug is pressed down in vacuum, the vacuum of the freeze dryer is removed, the sample is taken out, and the sample is rolled and covered for inspection.
Example 2
The prescription proportion of the compound preparation is as follows: the probenecid sodium is 3:1
Preparing a compound preparation solution 1 (meropenem and probenecid sodium):
the total amount of the solution was 1,500ml, which contained: 300 g of meropenem (calculated on dry basis and on pure basis), 100 g of probenecid sodium (calculated on dry basis and on pure basis), and adjusting the pH value of the solution to 7.3-7.8 by using sodium carbonate;
preparing a single preparation solution 2 (meropenem):
the total amount of the solution is 1,500ml, and the solution contains: 300 g of meropenem (calculated on a dry basis and a pure basis), and adjusting the pH value of the solution to 7.3-7.8 by using sodium carbonate. The difference between solution 1 and solution 2 was that the former contained 100 g of probenecid sodium and the latter did not.
Adopting 10 ml penicillin bottles, wherein 500 bottles are respectively filled with 3 ml solution 1, wherein the solution contains 0.6g of meropenem and 0.2 g of probenecid; 500 bottles each contain 3 ml of solution 2 containing 0.6g of meropenem and no probenecid sodium. Half-stoppered total 1,000 vials containing solution 1 and solution 2 were placed on a lyophilizer plate and lyophilized, and the two solution samples were placed on the same lyophilizer for comparison.
The specific freeze-drying steps are as follows:
1. starting freeze dryer in pre-freezing stage
Firstly, cooling the plate layer from room temperature to-25 ℃ at the speed of about 3 ℃/min, and preserving heat for 30-60 minutes;
secondly, raising the temperature of the plate layer to 1-2 ℃ at the speed of 1.5-2 ℃/min, and preserving the temperature for 40-60 minutes;
thirdly, cooling to-40 ℃ at the speed of about 3 ℃/min, and preserving heat for 40-60 minutes;
2. sublimation drying: after the pre-freezing stage is finished, gradually heating the plate layer to 20 ℃ within 12-16 hours to ensure that the sublimation line is basically invisible to naked eyes;
3. and (3) resolving and drying: after the sublimation stage is finished, the temperature of the plate layer is stably raised to about 40 ℃ and is kept for 3 hours, so that the moisture is fully volatilized, the plate layer is taken out of the box after being qualified according to the pressure change condition in the freeze-drying box, and the total freeze-drying time is about 23 hours; and (3) rolling a cover: after the sample is frozen and dried, the rubber plug is pressed down in vacuum, the vacuum of the freeze dryer is released, the sample is taken out, and the sample is rolled and covered for inspection.
Example 3
The prescription proportion of the compound preparation is as follows: probenecid sodium is 2: 1.
preparing a compound preparation solution 1 (meropenem and probenecid sodium):
the total amount of the solution is 1,500ml, and the solution contains: 200 g of meropenem (calculated on dry basis and pure basis), 100 g of probenecid sodium (calculated on dry basis and pure basis), and adjusting the pH value of the solution to 7.3-7.8 by using sodium carbonate;
preparing a single-prescription preparation solution 2 (meropenem):
the total amount of the solution is 1,500ml, and the solution contains: 200 g of meropenem (calculated on a dry basis and a pure basis), and adjusting the pH value of the solution to 7.3-7.8 by using sodium carbonate. The difference between solution 1 and solution 2 was that the former contained 100 g of probenecid sodium and the latter did not.
Adopting 10 ml penicillin bottles, wherein 500 bottles are respectively filled with 3 ml solution 1, wherein the solution contains 0.4g of meropenem and 0.2 g of probenecid; 500 bottles each contain 3 ml of solution 2 containing 0.4g of meropenem and no probenecid sodium. Half-stoppered a total of 1,000 vials containing solution 1 and solution 2 were placed on a lyophilizer plate for lyophilization, and two solution samples were placed on the same lyophilizer for lyophilization for comparison.
The specific freeze-drying steps are as follows:
1. freeze-dryer is opened in prefreezing stage
Firstly, cooling the plate layer from room temperature to-25 ℃ at the speed of about 3 ℃/min, and preserving heat for 30-60 minutes;
raising the temperature of the plate layer to 1-2 ℃ at the speed of 1.5-2 ℃/min, and preserving the heat for 40-60 minutes;
thirdly, cooling to-40 ℃ at the speed of about 3 ℃/min, and preserving heat for 40-60 minutes;
2. sublimation drying: after the pre-freezing stage is finished, gradually heating the plate layer to 20 ℃ within 12-16 hours to ensure that the sublimation line is basically invisible to naked eyes;
3. and (3) resolving and drying: after the sublimation stage is finished, the temperature of the plate layer is stably raised to about 40 ℃ and is kept for 3 hours, so that the moisture is fully volatilized, the plate layer is taken out of the box after being qualified according to the pressure change condition in the freeze-drying box, and the total freeze-drying time is about 23 hours; and (3) rolling a cover: after the sample is frozen and dried, the rubber plug is pressed down in vacuum, the vacuum of the freeze dryer is removed, the sample is taken out, and the sample is rolled and covered for inspection.
And (4) analyzing results:
the addition of probenecid sodium has two beneficial effects on the freeze-drying of meropenem: firstly, the acicular crystal shape of probenecid can play a role in supporting a framework, promote the volatilization of water and shorten the total freeze-drying time. The sample solutions of solution 1 and solution 2 were all the same in volume, and were 3 ml, with solution 1 having 50% more probenecid sodium by weight than solution 2. However, the water content of the lyophilized sample of solution 1 was still significantly lower than that of the lyophilized sample of solution 2 at about 23 hours of total lyophilization time, which means that the addition of probenecid sodium can shorten the lyophilization time of meropenem. Second, solution 2 freeze-dried the sample, and the appearance after freeze-drying was collapsed and not qualified, while solution 1 sample freeze-dried the appearance was cake-like and qualified. It follows that probenecid sodium can act as an excipient.
TABLE 1 comparison of appearance and moisture of single and compound formulations and products of different formulation ratios
Claims (2)
1. A compound lyophilized preparation of meropenem sodium probenecid for injection is characterized in that 300 g of meropenem 200-sodium probenecid and 100 g of probenecid are prepared into compound preparation solution according to the weight portion, and the formula proportion of the compound lyophilized preparation is as follows: probenecid sodium is 2-3: 1, adjusting the pH value of the solution to 7.3-7.8 by using sodium carbonate;
the specific freeze-drying steps are as follows:
(1) starting freeze dryer in pre-freezing stage
Firstly, cooling the plate layer from room temperature to-25 ℃ at the speed of about 3 ℃/min, and preserving heat for 30-60 minutes;
secondly, raising the temperature of the plate layer to 1-2 ℃ at the speed of 1.5-2 ℃/min, and preserving the temperature for 40-60 minutes;
thirdly, cooling to-40 ℃ at the speed of about 3 ℃/min, and preserving heat for 40-60 minutes;
(2) sublimation drying: after the pre-freezing stage is finished, gradually heating the plate layer to 20 ℃ within 12-16 hours to ensure that the sublimation line is basically invisible to naked eyes;
(3) and (3) resolving and drying: after the sublimation stage is finished, the temperature of the plate layer is stably raised to about 40 ℃ and is kept for 3 hours, so that the moisture is fully volatilized, the plate layer is taken out of the box after being qualified according to the pressure change condition in the freeze-drying box, and the total freeze-drying time is about 23 hours;
(4) and (3) rolling a cover: after the sample is frozen and dried, the rubber plug is pressed down in vacuum, the vacuum of the freeze dryer is removed, the sample is taken out, and the sample is rolled and covered for inspection.
2. The compound lyophilized preparation of meropenem and probenecid for injection according to claim 1, wherein the compound lyophilized ratio of the meropenem to the probenecid is 2: 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010787262.2A CN111840236B (en) | 2020-08-07 | 2020-08-07 | Meropenem probenecid compound freeze-dried preparation for injection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010787262.2A CN111840236B (en) | 2020-08-07 | 2020-08-07 | Meropenem probenecid compound freeze-dried preparation for injection |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111840236A CN111840236A (en) | 2020-10-30 |
| CN111840236B true CN111840236B (en) | 2022-09-02 |
Family
ID=72972604
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010787262.2A Active CN111840236B (en) | 2020-08-07 | 2020-08-07 | Meropenem probenecid compound freeze-dried preparation for injection |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111840236B (en) |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090018111A1 (en) * | 2004-10-08 | 2009-01-15 | Makoto Sunagawa | Novel Antimicrobial Medicament |
| CN100387574C (en) * | 2004-12-01 | 2008-05-14 | 吴晓辉 | Preparation of sodium probenecid and potassium probenecid, compound injection prepared by sodium probenecid, potassium probenecid and beta-lactam antibiotics, and use thereof |
| US20100003276A1 (en) * | 2004-12-07 | 2010-01-07 | Hermes Jeffery D | Methods for treating anthrax and inhibiting lethal factor |
| CN1698896A (en) * | 2005-05-30 | 2005-11-23 | 西安交通大学 | Method for preparing compound beta lactam sodium salt/sodium benemid for injection |
| CN102335136B (en) * | 2011-08-02 | 2013-06-12 | 天津市嵩锐医药科技有限公司 | Meropenem medicinal composition for injection and preparation method thereof |
| CN102525961B (en) * | 2012-01-17 | 2013-02-13 | 山东罗欣药业股份有限公司 | Powder injection of meropenem composition for injection |
| US11554112B2 (en) * | 2018-06-07 | 2023-01-17 | Herum Therapeutics International Limited | Combinations of β-lactam compounds and probenecid and uses thereof |
-
2020
- 2020-08-07 CN CN202010787262.2A patent/CN111840236B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN111840236A (en) | 2020-10-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0271622B1 (en) | Process for freeze drying cyclophosphamide | |
| WO2022147932A1 (en) | Preparation method for tedizolid phosphate freeze-dried preparation for injection | |
| CA1326211C (en) | Antibiotic solutions and the lyophilization thereof | |
| CN111840236B (en) | Meropenem probenecid compound freeze-dried preparation for injection | |
| CN1994461A (en) | Lyophilization process of glutathione for injection | |
| CN101756897B (en) | Clindamycin hydrochloride injection and preparation method thereof | |
| EP0251657B1 (en) | Therapeutic compositions with galactitol as carrier | |
| CN102657622A (en) | Preparation process of freeze-dry powder injection containing esomeprazole sodium | |
| CN111228226B (en) | Freeze-dried preparation of pyrrosia faberi for injection and preparation method thereof | |
| CN112076162A (en) | Piperacillin sodium tazobactam sodium probenecid three-part freeze-dried preparation for injection | |
| CN112076161B (en) | Compound freeze-dried preparation consisting of cephalosporin sodium salt and probenecid sodium | |
| JPH0374643B2 (en) | ||
| CN102125550B (en) | Ondansetron hydrochloride composition for injection and preparation method thereof | |
| CN110960493B (en) | Parecoxib sodium freeze-dried preparation and preparation method thereof | |
| CN104434818B (en) | A kind of daunoblastina HC1 vial | |
| CN103462909B (en) | Formulation of nizatidine for injection and preparation technology thereof | |
| CN112137969A (en) | Enoxaparin sodium for injection containing enoxaparin sodium and preparation method thereof | |
| CN111821462A (en) | Compound freeze-dried preparation composed of penicillin sodium salt and probenecid sodium | |
| CN103520192A (en) | Invert sugar freeze-dried powder preparation for injection and preparation method thereof | |
| CN114177147B (en) | Preparation method of terlipressin for injection and terlipressin for injection prepared by preparation method | |
| CN114028345B (en) | Aspoxicillin freeze-dried agent for injection and preparation process thereof | |
| CN102512385A (en) | Doxofylline freeze-dried powder injection | |
| CN112691083B (en) | Freeze-drying process of vancomycin hydrochloride | |
| CN100477998C (en) | Instant pyrobixi freeze-drying powdery injection and its production | |
| CN105106930A (en) | Nitric oxide donor type glutathione peptide compound freeze-dried powder injection and application |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CP02 | Change in the address of a patent holder |
Address after: Room A3-201, Phase I, Innovation Industrial Park, No. 800, Wangjiang West Road, High-tech Zone, Hefei, Anhui Province, 230000 Patentee after: Anhui Kangzheng kangren Pharmaceutical Co.,Ltd. Address before: 230000, Floor 2, Building 3, Mingzhu Industrial Park, High-tech Zone, Hefei, Anhui Province Patentee before: Anhui Kangzheng kangren Pharmaceutical Co.,Ltd. |
|
| CP02 | Change in the address of a patent holder |