CN111166722A - Bendamustine hydrochloride pre-freeze-drying liquid medicine for injection and preparation method thereof - Google Patents
Bendamustine hydrochloride pre-freeze-drying liquid medicine for injection and preparation method thereof Download PDFInfo
- Publication number
- CN111166722A CN111166722A CN201911245962.2A CN201911245962A CN111166722A CN 111166722 A CN111166722 A CN 111166722A CN 201911245962 A CN201911245962 A CN 201911245962A CN 111166722 A CN111166722 A CN 111166722A
- Authority
- CN
- China
- Prior art keywords
- bendamustine hydrochloride
- solution
- injection
- acetic acid
- freeze
- 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
Images
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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a pre-freeze-drying medicinal liquid for injection of bendamustine hydrochloride and a preparation method thereof, wherein the preparation method comprises the following steps: (1) adding mannitol into water for injection, stirring to dissolve completely, adding glacial acetic acid, and stirring to obtain solution A; (2) adding bendamustine hydrochloride into the solution A, stirring to completely dissolve the bendamustine hydrochloride to obtain a solution B, filling nitrogen into the solution B to remove oxygen, and cooling to below 15 ℃ to obtain a liquid medicine before injection of bendamustine hydrochloride freeze-drying. In the pre-lyophilization medicinal liquid for bendamustine hydrochloride, the acetic acid solution is used as a solvent to dissolve the bendamustine hydrochloride, which is beneficial to improving the stability of the bendamustine hydrochloride; meanwhile, the glacial acetic acid is diluted before the bendamustine hydrochloride is dissolved, so that the bendamustine hydrochloride can be prevented from being decomposed due to overhigh concentration of the acetic acid, the stability of the bendamustine hydrochloride in the liquid medicine is further improved, and the content of related substances in the liquid medicine and a finished product is reduced.
Description
Technical Field
The invention relates to a bendamustine hydrochloride pre-freeze-drying liquid medicine for injection and a preparation method thereof, belonging to the technical field of pharmaceutical preparations.
Background
Bendamustine hydrochloride is a bifunctional alkylating agent, mainly causes the cross-linking of single strands and double strands of DNA through alkylation, interferes with the function and synthesis of DNA, plays an antitumor role, and has been widely used for anticancer treatment in Germany in the 70 th 20 th century.
Bendamustine hydrochloride is unstable in water and is subject to hydrolytic metabolism to HP1 (impurity D) and HP2 (impurity E). Currently marketed injection contains high levels of bendamustine hydrochloride impurity D and impurity E.
Chinese patent publication No. CN104173300A discloses a method for preparing bendamustine hydrochloride lyophilized powder injection, in which the volume percentage of acetic acid in the finally obtained bendamustine hydrochloride composition solution is 50% -75%, and in the bendamustine hydrochloride composition solution, although the solubility of bendamustine raw material drug is increased, the stability of bendamustine hydrochloride is lower, and the related substances of the finally obtained product are increased.
Disclosure of Invention
The invention aims to overcome the defects that the preparation method of the freeze-dried prodrug of bendamustine hydrochloride for injection in the prior art causes the reduction of the stability of bendamustine hydrochloride and the increase of the content of related substances, and provides a preparation method of a liquid medicine before freeze-drying of bendamustine hydrochloride for injection, so as to improve the stability of bendamustine hydrochloride and reduce the content of related substances in a finished product.
In order to achieve the above purpose, the invention provides the following technical scheme:
a preparation method of bendamustine hydrochloride freeze-dried prodrug solution for injection comprises the following steps:
(1) adding mannitol with a prescription amount into injection water with a prescription amount, stirring to completely dissolve, then adding glacial acetic acid with a prescription amount, and uniformly stirring to obtain a solution A;
(2) adding the bendamustine hydrochloride with the prescription amount into the solution A, stirring to completely dissolve the bendamustine hydrochloride to obtain a solution B, filling nitrogen into the solution B to remove oxygen, and cooling to below 15 ℃ to obtain the liquid medicine before the bendamustine hydrochloride is freeze-dried for injection.
In the preparation method, the concentration of acetic acid in the solution B is more than 10 percent. In the invention, the acetic acid solution is used as a solvent in the preparation method of bendamustine hydrochloride, and is beneficial to improving the stability of bendamustine compared with water for injection; meanwhile, before the bendamustine hydrochloride is added, the glacial acetic acid is added into the mannitol and the water for injection to dilute the glacial acetic acid, so that the bendamustine hydrochloride is prevented from being decomposed due to overhigh concentration of the acetic acid, the stability of the bendamustine hydrochloride in the liquid medicine is further improved, and the content of related substances in the liquid medicine and a finished product is reduced.
Preferably, the volume percentage of the glacial acetic acid in the solution B is 35% to 45% (i.e. the volume of the glacial acetic acid accounts for 35% to 45% of the total volume of the solution B). During the preparation process of the liquid medicine before freeze-drying of bendamustine hydrochloride for injection (namely, the solution B in the step (2)), the stability of bendamustine hydrochloride is deteriorated due to overhigh concentration of acetic acid, the content of related substances in the liquid medicine is increased, and the concentration of acetic acid is overlow, so that the risk of reducing the stability of bendamustine hydrochloride is caused, the eutectic point of the liquid medicine before freeze-drying is reduced, and the freeze-drying difficulty is increased. In the liquid medicine before freeze-drying (namely the solution B), the acetic acid solution with the acetic acid concentration of 35-45 percent not only can keep the bendamustine hydrochloride with higher stability, but also can improve the eutectic point (about-32 ℃) of the liquid medicine before freeze-drying and reduce the freeze-drying difficulty. More preferably, the volume percentage of the glacial acetic acid in the solution B is preferably 40%.
Preferably, in step (2), oxygen is removed to less than 0.5mg/L of dissolved oxygen in solution B.
A bendamustine hydrochloride pre-lyophilization medicine liquid for injection, which is obtained by any one of the preparation methods.
Compared with the prior art, the invention has the beneficial effects that:
1. compared with water for injection, the bendamustine hydrochloride liquid medicine before freeze-drying and the acetic acid solution as the solvent are applied to the preparation method of the bendamustine hydrochloride, and are beneficial to improving the stability of the bendamustine hydrochloride; meanwhile, before the bendamustine hydrochloride is added, the glacial acetic acid is added into the mannitol and the water for injection to dilute the glacial acetic acid, so that the bendamustine hydrochloride is prevented from being decomposed due to overhigh concentration of the acetic acid, the stability of the bendamustine hydrochloride in the liquid medicine is further improved, and the content of related substances in the liquid medicine and a finished product is reduced. The liquid medicine before freeze-drying of the bendamustine hydrochloride for injection can be directly subjected to sterilization filtration, filling and freeze-drying to obtain a freeze-dried bendamustine hydrochloride product for injection.
2. In the liquid medicine before freeze-drying (namely the solution B), the acetic acid solution with the acetic acid concentration of 35-45% can not only keep the bendamustine hydrochloride with higher stability, but also improve the eutectic point (about-32 ℃) of the liquid medicine before freeze-drying and reduce the freeze-drying difficulty.
3. According to the preparation method of the bendamustine hydrochloride freeze-dried prodrug solution for injection, the temperature of the liquid medicine is reduced to below 15 ℃, and the dissolved oxygen is reduced to below 0.5mg/L, so that the degradation of bendamustine hydrochloride can be remarkably reduced.
Description of the drawings:
FIG. 1 is a test pattern of substances related to example 1.
FIG. 2 is a test pattern of the relevant substances in comparative example 1.
Detailed Description
The present invention will be described in further detail with reference to test examples and specific embodiments. It should be understood that the scope of the above-described subject matter is not limited to the following examples, and any techniques implemented based on the disclosure of the present invention are within the scope of the present invention.
In each of the examples and comparative examples of the present invention, the amount of glacial acetic acid used was 35-45% (v/v), i.e., the glacial acetic acid was 35-45% by volume of the pre-lyophilized drug solution of bendamustine hydrochloride.
Example 1:
prescription information
The method of preparing the lyophilized prodrug solution of bendamustine hydrochloride for injection of example 1, comprising the steps of:
(1) adding mannitol with a prescription amount into injection water with a prescription amount, stirring to completely dissolve, then adding glacial acetic acid with a prescription amount, and uniformly stirring to obtain a solution A;
(2) adding bendamustine hydrochloride with the amount of the prescription into the solution A, stirring to completely dissolve the bendamustine hydrochloride to obtain a solution B, filling nitrogen into the solution B to remove oxygen until the dissolved oxygen in the solution B is lower than 0.5mg/L, and keeping the solution B until the filling is finished; cooling the solution B to below 15 ℃;
(3) and (4) sterilizing, filtering, filling and freeze-drying the solution B. The method comprises the following specific steps:
introducing clean nitrogen into the liquid preparation tank for pressurization, filtering the solution B by 2 paths of 0.22 mu m PTFE filter elements, and filling the solution B into a medium borosilicate glass injection bottle, wherein the filling volume is 5 ml/bottle; and (4) keeping the dissolved oxygen in the solution B to be lower than 0.5mg/L before and after filling until the filling is finished. After half plugging, freeze drying is carried out according to the following parameters:
example 2
The method for preparing the lyophilized prodrug solution of bendamustine hydrochloride for injection in example 2 is different from that in example 1 in that: the amount of glacial acetic acid used in example 2 was 45% (v/v). Prescription information for example 2 is as follows:
example 3
The process for preparing the lyophilized prodrug solution of bendamustine hydrochloride for injection of example 3 differs from example 1 in that: the amount of glacial acetic acid used in example 3 was 35% (v/v). Prescription information for example 3 is as follows:
comparative example:
comparative example 1
Prescription information
The method of preparing the lyophilized prodrug solution of bendamustine hydrochloride for injection of comparative example 1, comprising the steps of:
(1) adding mannitol in a prescription amount into injection water in a prescription amount, and stirring to completely dissolve to obtain a solution A;
(2) adding the bendamustine hydrochloride with the prescription amount into the glacial acetic acid with the prescription amount, and stirring to completely dissolve the bendamustine hydrochloride to obtain a solution B;
(3) uniformly mixing the solution A and the solution B to obtain a solution C; filling nitrogen to remove oxygen until the dissolved oxygen in the solution C is lower than 0.5mg/L, and keeping until the filling is finished; cooling the solution C to below 15 ℃;
(4) and (4) sterilizing, filtering, filling and freeze-drying the solution C.
Wherein the sterilization, filtration, filling and freeze drying in the step (4) are the same as the example 1.
Comparative example 2
The method for preparing the lyophilized prodrug solution of bendamustine hydrochloride for injection of comparative example 2 is different from that of example 1 in that: the amount of glacial acetic acid used in comparative example 2 was 75% (v/v). The prescription information for comparative example 2 is as follows:
comparative example 3
The method for preparing the lyophilized prodrug solution of bendamustine hydrochloride for injection of comparative example 3 is different from that of example 1 in that: the amount of glacial acetic acid used in comparative example 3 was 25% (v/v). The prescription information for comparative example 3 is as follows:
experimental test results and analysis:
the freeze-drying process observation and freeze-drying products obtained in the examples and the comparative examples are analyzed, and the statistics of the results are as follows:
from the above experimental results, it can be seen that:
the bendamustine hydrochloride freeze-dried products obtained by the preparation method of the examples 1 to 3 have no spray bottle phenomenon in the freeze-drying process, and the content of related substances of the obtained freeze-dried products is less than 0.2 percent. The bendamustine hydrochloride lyophilized products prepared by the preparation method of the comparative examples 1-2 have the degradation related substance content higher than 72 percent because the bendamustine hydrochloride is dissolved in glacial acetic acid with higher concentration (volume content is more than or equal to 75 percent); the quality and stability of the obtained freeze-dried product are obviously reduced; in contrast, the lyophilized product of bendamustine hydrochloride obtained by the preparation method of comparative example 3, in which the eutectic point of the drug solution before lyophilization is lowered (about 45 ℃) due to the low acetic acid usage (25%), was lyophilized according to the lyophilization method of comparative example 1 (i.e., example 1), had a low quality due to the high probability of bottle ejection occurring because the pre-freezing process was not frozen. The results of measuring the contents of the substances in example 1 and comparative example 1 are shown in FIGS. 1 and 2. In FIGS. 1 and 2, the maximum single-impurity detection spectrum is near 21.2; and the vicinity of 31.3 is the detection spectrum of bendamustine hydrochloride.
In conclusion, the pre-freeze-drying medicinal liquid for injection of bendamustine hydrochloride prepared by the invention is directly subjected to aseptic filtration, filling and freeze drying, so that the freeze-drying difficulty is reduced, and the content of related substances in the freeze-dried finished product obtained by the method is obviously reduced.
Claims (5)
1. A preparation method of bendamustine hydrochloride freeze-dried prodrug solution for injection is characterized by comprising the following steps:
(1) adding mannitol with a prescription amount into injection water with a prescription amount, stirring to completely dissolve, then adding glacial acetic acid with a prescription amount, and uniformly stirring to obtain a solution A;
(2) adding the bendamustine hydrochloride with the prescription amount into the solution A, stirring to completely dissolve the bendamustine hydrochloride to obtain a solution B, filling nitrogen into the solution B to remove oxygen, and cooling to below 15 ℃ to obtain the liquid medicine before the bendamustine hydrochloride is freeze-dried for injection.
2. The method for preparing a lyophilized prodrug solution of bendamustine hydrochloride for injection according to claim 1, wherein: the volume percentage of the glacial acetic acid in the solution B is 35-45%.
3. The method of preparing a lyophilized prodrug solution of bendamustine hydrochloride for injection according to claim 2, wherein: the volume percentage of glacial acetic acid in the solution B is preferably 40%.
4. The method for preparing a lyophilized prodrug solution of bendamustine hydrochloride for injection according to claim 1, wherein: in the step (2), oxygen is removed until the dissolved oxygen in the solution B is less than 0.5 mg/L.
5. A pre-lyophilization medical solution for injection of bendamustine hydrochloride, wherein the pre-lyophilization medical solution for injection of bendamustine hydrochloride is obtained by the preparation method according to any one of claims 1 to 4.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201911245962.2A CN111166722B (en) | 2019-12-07 | 2019-12-07 | Bendamustine hydrochloride pre-freeze-drying liquid medicine for injection and preparation method thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201911245962.2A CN111166722B (en) | 2019-12-07 | 2019-12-07 | Bendamustine hydrochloride pre-freeze-drying liquid medicine for injection and preparation method thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CN111166722A true CN111166722A (en) | 2020-05-19 |
CN111166722B CN111166722B (en) | 2022-03-25 |
Family
ID=70618007
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201911245962.2A Active CN111166722B (en) | 2019-12-07 | 2019-12-07 | Bendamustine hydrochloride pre-freeze-drying liquid medicine for injection and preparation method thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN111166722B (en) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101219112A (en) * | 2008-01-28 | 2008-07-16 | 济南帅华医药科技有限公司 | Compound anticancer sustained-release injection containing bendamustine |
CN101966158A (en) * | 2010-09-28 | 2011-02-09 | 上海丽思化工科技有限公司 | Bendamustine hydrochloride freeze-dried powder injection for injection and preparation method thereof |
WO2014127802A1 (en) * | 2013-02-19 | 2014-08-28 | Synthon Bv | Stable compositions of bendamustine |
CN104173300A (en) * | 2014-08-29 | 2014-12-03 | 四川汇宇制药有限公司 | Preparation method of bendamustine hydrochloride freeze-dried injection |
CN109157535A (en) * | 2012-02-14 | 2019-01-08 | 赛多斯有限责任公司 | The preparation of bendamustine |
-
2019
- 2019-12-07 CN CN201911245962.2A patent/CN111166722B/en active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101219112A (en) * | 2008-01-28 | 2008-07-16 | 济南帅华医药科技有限公司 | Compound anticancer sustained-release injection containing bendamustine |
CN101966158A (en) * | 2010-09-28 | 2011-02-09 | 上海丽思化工科技有限公司 | Bendamustine hydrochloride freeze-dried powder injection for injection and preparation method thereof |
CN109157535A (en) * | 2012-02-14 | 2019-01-08 | 赛多斯有限责任公司 | The preparation of bendamustine |
WO2014127802A1 (en) * | 2013-02-19 | 2014-08-28 | Synthon Bv | Stable compositions of bendamustine |
CN104173300A (en) * | 2014-08-29 | 2014-12-03 | 四川汇宇制药有限公司 | Preparation method of bendamustine hydrochloride freeze-dried injection |
Also Published As
Publication number | Publication date |
---|---|
CN111166722B (en) | 2022-03-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN102133199B (en) | Doxofylline lyophilized preparation for injection and preparation method thereof | |
JP2021516685A (en) | How to reduce endotoxins in gelatin | |
US9655876B2 (en) | Liquid composition containing taxane-based active ingredient, process for producing same, and liquid preparation | |
CN111166722B (en) | Bendamustine hydrochloride pre-freeze-drying liquid medicine for injection and preparation method thereof | |
CN111166721B (en) | Stable bendamustine hydrochloride for injection and preparation method thereof | |
CN104414977A (en) | Artesunate and L-arginine composition for injection and preparation method thereof | |
CN101627967A (en) | Ambroxol hydrochloride liquid preparation and preparation method thereof | |
CN108606955A (en) | The Pharmaceutical composition and preparation method thereof of trainingization Xihai sea horse peptide | |
CN109044969B (en) | Preparation method of paclitaxel injection | |
CN114159396A (en) | Espressol omeprazole sodium freeze-dried preparation for injection and preparation method thereof | |
CN114681409A (en) | Famotidine for injection and preparation method thereof | |
CN109044980B (en) | Somatostatin freeze-dried powder injection pharmaceutical composition and preparation method thereof | |
CN101856334B (en) | Asarin composite freeze-dried powder for injection | |
CN108096199B (en) | Omeprazole sodium for injection and preparation method thereof | |
CN103877010B (en) | A kind of preparation method of romidepsin solution | |
CN103142511B (en) | High-purity and high-stability composition containing oxaliplatin and preparation method of composition | |
CN103720666A (en) | Preparation method for bortezomib freeze-dried preparation for injection | |
CN112137989B (en) | Enzalutamide soft capsule quick-release preparation and preparation method thereof | |
CN103520122B (en) | Preparation method for Bumetanide freeze-dried powder preparation for injection | |
CN108498531A (en) | A kind of chitosan oral solution and preparation method thereof | |
CN115590825B (en) | Daptomycin for injection and preparation method thereof | |
CN112587486B (en) | Pantoprazole sodium freeze-dried powder injection for injection and preparation method thereof | |
CN109876136B (en) | Octreotide acetate freeze-dried powder injection and preparation method thereof | |
CN109771371B (en) | Clindamycin phosphate injection and preparation method thereof | |
CN113797170A (en) | Fluorouracil freeze-dried preparation for injection and preparation method thereof |
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 | ||
CB02 | Change of applicant information | ||
CB02 | Change of applicant information |
Address after: 641000 No. 333, Hanyang Road, economic and Technological Development Zone, Shizhong District, Neijiang City, Sichuan Province Applicant after: Sichuan Huiyu Pharmaceutical Co.,Ltd. Address before: 641000 No. 333, Hanyang Road, economic and Technological Development Zone, Shizhong District, Neijiang City, Sichuan Province Applicant before: Sichuan Huiyu Pharmaceutical Co.,Ltd. |
|
GR01 | Patent grant | ||
GR01 | Patent grant |