CN102161666B - Preparation method of mezlocillin sodium and mezlocillin sodium for injection - Google Patents
Preparation method of mezlocillin sodium and mezlocillin sodium for injection Download PDFInfo
- Publication number
- CN102161666B CN102161666B CN 201110088165 CN201110088165A CN102161666B CN 102161666 B CN102161666 B CN 102161666B CN 201110088165 CN201110088165 CN 201110088165 CN 201110088165 A CN201110088165 A CN 201110088165A CN 102161666 B CN102161666 B CN 102161666B
- Authority
- CN
- China
- Prior art keywords
- mezlocillin
- preparation
- sodium
- product
- temperature
- 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
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method of mezlocillin sodium and mezlocillin sodium for injection. The preparation method comprises the following steps of: (a) adding mezlocillin acid into water for injection, and cooling material liquor at 12-15 DEG C; (b) dropwise adding a NaHCO3 solution, adjusting the pH value at 5.8-6.5, and stirring until the material liquor is clean and the pH value is stable; (c) raising the temperature of the material liquor to be 20 DGE C+/-2 DEG C, and stirring for 30-60 minutes; (d) adding active carbon for injections, stirring for 15-30 minutes, and decarburizing by a plate frame filter; (e) degerming and filtering the decarburized filtrate by a 0.45mu m filter and a 0.22mu m filter; and (f) freeze-drying to obtain the mezlocillin sodium finished product. By improving the conventional freeze-drying technology and combining with the improved preparation method of the mezlocillin acid, the method prepares the mezlocillin sodium product with low polymer content, so that the product quality is obviously improved, and the possibility of allergy caused by the product is greatly reduced.
Description
Technical field
The invention belongs to the synthetic field of medicine, relate to the preparation method of Sodium mezlocillin, more specifically, relate to a kind of preparation method of Sodium mezlocillin of low-grade polymer content.
Background technology
The chemical name of Sodium mezlocillin (mezlocilln sodium) is (2S; 5R; 6R)-3; 3-dimethyl--6-[(R)-2 [3-(methylsulfonyl)-2-oxo-1-imidazolidine formamido group]-2-phenylacetylamino]-7-oxo-4-thia-1-azabicyclo [3.2.O]-heptane-2-formic acid sodium salt; Be a kind of semi-synthetic penicillins microbiotic, bacteriostatic action all arranged to Pseudomonas aeruginosa, escherichia coli, pneumobacillus, Bacillus proteus, enterobacter, citrobacter, Serratia, acinetobacter and to the responsive GPC of penicillium mould.
The preparation method of Sodium mezlocillin mainly contains reaction-crystallization method and freeze-drying at present.
In reaction-crystallization method, carry out acidification in the mezlocillin adding ETHYLE ACETATE, get ethyl acetate layer again and add methyl alcohol formation mixed solvent, add the ethyl acetate solution of salt forming agent Sodium isooctanoate then, crystallization obtains the Sodium mezlocillin finished product.Yet the reactive crystallization mixed solvent is difficult to reclaim in this method, and ethyl acetate residual quantity is higher, is difficult to reach ICH international standard (≤0.5%).
Traditional freeze-drying is that the mezlocillin acid cpd is suspended in the water, adds sodium hydroxide and makes its dissolving, isolates sodium salt through lyophilize.Yet the content of polymkeric substance and impurity is higher in the product that traditional freeze-drying obtains, and is prone to cause anaphylaxis.
Its application in clinical is being perplexed in the anaphylaxis that PCs causes for a long time always.According to domestic and international clinical study report, the sensitization source of PCs kind medicine mainly is the polymkeric substance that itself is contained.Thereby the content that reduces polymkeric substance in the penicillin medicine becomes and reduces its hypersensitive important channel.The limit of Chinese Pharmacopoeia regulation polymkeric substance is≤0.3%.In the prior art, usually need carry out chromatography purification and just can make product satisfy the polymkeric substance limit requirement of pharmacopeia regulation the Sodium mezlocillin product.The polymer content that does not propose as yet in this area to reduce the Sodium mezlocillin product is the preparation method of main purpose.
The present invention is through the further improvement to traditional freeze-drying, and the improved preparation method of combination mezlocillin, has obtained the Sodium mezlocillin product of low-grade polymer content.The polymer content of product≤0.2% need not further chromatography purification operation, directly obtains to satisfy the mezlocillin for inj lyophilisate of NF requirement.
Summary of the invention
The invention provides a kind of preparation method of Sodium mezlocillin of low-grade polymer content, comprise step:
(a) mezlocillin is joined in the water for injection, feed liquid is cooled to 12～15 ℃;
(b) drip NaHCO
3Solution is adjusted to pH5.8～6.5, is stirred to feed clarification and pH value stabilization;
(c) feed temperature is risen to 20 ℃ ± 2 ℃, stirred 30～60 minutes;
(d) add needle-use activated carbon, stir after 15～30 minutes, take off charcoal through plate filter;
(e) take off filtrating behind the charcoal through 0.45 μ m, 0.22 μ m strainer, Sterile Filtration; With
(f) freeze-drying obtains the Sodium mezlocillin finished product.
Further, in above-mentioned preparation method, NaHCO in the step (b)
3The concentration of solution is 14%w/w; The pH value is adjusted to pH 6.0～6.3; Preferably, pH 6.1～6.2.
Further, in aforesaid preparation method, the weight ratio of mezlocillin and water for injection is in the step (a): 1:2.8～3.5.
Further, in aforesaid preparation method, the consumption of needle-use activated carbon is 2～4% of a mezlocillin weight in the step (d).
Further, in aforesaid preparation method, step (e) was accomplished in 4 hours.
Further, in aforesaid preparation method, the preparation method of mezlocillin comprises step in the step (a):
(i) add pure water in the reaction kettle, temperature in the kettle is reduced to 2 ℃ also keep stable;
(ii) Ampicillin Trihydrate acid trihydrate is added reaction kettle, stirring mixes Ampicillin Trihydrate acid trihydrate and water;
(iii) drip the 10%w/w sodium hydrogen carbonate solution to reaction soln dissolving clarification;
(iv) add 1-chloroformyl-3-methylsulfonyl-2-imidazolidone and carry out condensation reaction, reaction process is through dripping 10%w/w sodium hydrogen carbonate solution control reaction solution in pH8.0～8.2, and controlled temperature is at 5 ± 2 ℃ simultaneously, and stirring velocity is controlled at 170 rev/mins;
(after v) reaction finished, filtering reacting liquid changed filtrating over to crystallization kettle;
(vi) add ethanol, stirring mixes ethanol and feed liquid, and 25 ± 2 ℃ of control feed temperatures stop when dripping 1N Hydrogen chloride to pH=2.0 dripping, and stir 60 minutes, and 130 rev/mins of rotating speeds carry out crystallization; With
(vii) slurry is put to whizzer and is got rid of filter, gets rid of after filter finishes, and use the 25%v/v washing with alcohol earlier, uses ETHYLE ACETATE washing lotion drip washing filter cake then, continues to get rid of to filter the centrifugal end discharging of 4～6h.
Further, in aforesaid preparation method, the freeze-drying of step (f) comprises step:
(i) filtrating after the Sterile Filtration is filled in the freeze-drying dish, and every dish dress liquid thickness is 10 mm, when the flaggy temperature is reduced to below-30 ℃ with product dish inlet;
(ii) continue cooling, product temperature is incubated 1～2hr after reaching-40 ℃;
(iii) the fs is dry: the open vacuum system, and vacuum tightness reaches about 50Pa and begins sublimation drying, slowly intensification under the condition of the following vacuum tightness of maintenance 50Pa, about 11-13 hour when following in the case; With
(iv) subordinate phase is dry, and when product temperature arrived 0 ℃, shelf temperature was increased to the highest design temperature below 45 ℃, product temperature to 40 ℃, insulation 4 ~ 6 h.
Further, in aforesaid preparation method, said Sodium mezlocillin is a mezlocillin for inj.
In the preparation method of Sodium mezlocillin of the present invention, through improvement, and combine the improved preparation method of mezlocillin to traditional freeze-dry process, obtained the Sodium mezlocillin product of low-grade polymer content.Measure through the HPLC method, the polymer content of a plurality of batches product all≤0.2% has improved quality product significantly, greatly reduces the anaphylactic possibility of product.
Embodiment
Describe technical scheme of the present invention in detail below in conjunction with concrete embodiment, still following embodiment only is used to explain principle of the present invention and the proof about feasibility of the present invention is provided, rather than constitutes the restriction to scope of the present invention.
Embodiment 1---the preparation of mezlocillin.
1, condensation reaction.
1.1 dissolving.In reaction kettle, add the 700L purified water; Open and stir; The still chuck feeds heat-eliminating medium, and purified water in the still steadily is cooled to 2 ℃, with 50kg Ampicillin Trihydrate acid trihydrate (quality control standard: Chinese Pharmacopoeia 2005) add reaction kettle; After stirring mixes Ampicillin Trihydrate acid trihydrate and water, drip the 10%w/w sodium hydrogen carbonate solution to reaction soln dissolving clarification.
1.2 condensation.After the Ampicillin Trihydrate acid trihydrate dissolving clarification; Add 33kg 1-chloroformyl-3-methylsulfonyl-2-imidazolidone in batches and carry out condensation reaction; Reaction process is through dripping the 10%w/w sodium hydrogen carbonate solution; The control reaction solution is at pH 8.0～8.2, and controlled temperature is at 5 ± 2 ℃ simultaneously, and stirring velocity is controlled at 170 rev/mins.
1.3 filter.After condensation reaction finished, off-response still manhole blowing filtered at once, changes in the crystallization kettle through the secondary filter rear filtrate.
2, crystallization.
2.1 crystallization.After filtrating all gets into crystallization kettle, open crystallization kettle and stir, put into 250L ethanol; Stirring mixes ethanol and feed liquid; 25 ± 2 ℃ of control feed temperatures stop when dripping 1N Hydrogen chloride to pH=2.0 dripping, and stir 60min (130 rev/mins of rotating speeds) post crystallization and prepare blowing fully.
2.2 centrifugal and washing.Slurry put to whizzer get rid of filter, get rid of after filter finishes, with 25%v/v ethanol 300L washing, use 50L ETHYLE ACETATE washing lotion drip washing filter cake then earlier, continue to get rid of and filter the centrifugal end discharging of 4～6h.
3, drying and packaging.
3.1 granulate.After the centrifugal discharge, material is carried out the precomminution granulation with waving granulator.
3.2 oven dry.Material changes DoubletaperedVacuumdrier over to and dries behind the prefabricated grain, 60 ± 2 ℃ of temperature controls, dry 7 hours, 64kg left and right sides finished product, sampling, packing.
3.3 group batch warehouse-in.Be up to the standards, group is criticized, packing, warehouse-in.
Embodiment 2---the preparation of Sodium mezlocillin.
Mezlocillin is joined in the water for injection, and the weight ratio of mezlocillin and water for injection is 1:2.8, and feed liquid is cooled to 12 ~ 15 ℃.Drip 14%w/w NaHCO
3Regulate pH5.8, it is stable to be stirred to feed clarification pH, and feed temperature is risen to 20 ℃ ± 2 ℃, stirs after 30 ~ 60 minutes, and 2% needle-use activated carbon of adding mezlocillin weight stirred after 15 ~ 30 minutes, took off charcoal through plate filter.Take off filtrating behind the charcoal through 0.45 μ m, 0.22 μ m strainer, Sterile Filtration to ten thousand grade clean area under hundred grades of laminar flows sabot to freeze drying box.
Embodiment 3---the preparation of Sodium mezlocillin.
Mezlocillin is joined in the water for injection, and the weight ratio of mezlocillin and water for injection is 1:3.5, and feed liquid is cooled to 12 ~ 15 ℃.Drip 14%w/w NaHCO
3Regulate pH6.5, it is stable to be stirred to feed clarification pH, and feed temperature is risen to 20 ℃ ± 2 ℃, stirs after 30 ~ 60 minutes, and 4% needle-use activated carbon of adding mezlocillin weight stirred after 15 ~ 30 minutes, took off charcoal through plate filter.Take off filtrating behind the charcoal through 0.45 μ m, 0.22 μ m strainer, Sterile Filtration to ten thousand grade clean area under hundred grades of laminar flows sabot to freeze drying box.
Embodiment 4---the preparation of Sodium mezlocillin.
Mezlocillin is joined in the water for injection, and the weight ratio of mezlocillin and water for injection is 1:3.5, and feed liquid is cooled to 12～15 ℃.Drip 14%w/w NaHCO
3Regulate pH6.0, it is stable to be stirred to feed clarification pH, and feed temperature is risen to 20 ℃ ± 2 ℃, stirs after 30 ~ 60 minutes, and 3% needle-use activated carbon of adding mezlocillin weight stirred after 15 ~ 30 minutes, took off charcoal through plate filter.Take off filtrating behind the charcoal through 0.45 μ m, 0.22 μ m strainer, Sterile Filtration to ten thousand grade clean area under hundred grades of laminar flows sabot to freeze drying box.
Embodiment 5---freeze-drying, pulverizing and the packing of Sodium mezlocillin.
Filtrating after the embodiment 2-4 Sterile Filtration is filled in the freeze-drying dish, and every dish dress liquid thickness is 10 mm.When the flaggy temperature is reduced to below-30 ℃ with product dish inlet.Continue cooling, product temperature is incubated 1～2hr after reaching-40 ℃.The open vacuum system, vacuum tightness reaches about 50Pa and begins sublimation drying when following and be the fs drying, slowly intensification (about 11～13h) under the condition of the following vacuum tightness of maintenance 50Pa in the case.
Subordinate phase is dry, when product temperature is 0 ℃, is adsorption stripping and dry.Shelf temperature is increased to the highest design temperature below 45 ℃, product temperature to 40 ℃, insulation 4～6 h.The whole time is 22 ~ 26h.Freeze-drying curve is following:
.
Lyophilized powder is packed in the special-purpose stainless steel cask after sterilizing of finished product in will coil after freeze-drying finishes.Pouring the Grindingandgranulatemachine pulverizing into sieves through 40 orders.Work in-process after sieving are packed into and are covered bung in the stainless steel cask with above-mentioned similarity condition.
To make-up room, under hundred grades of laminar flows, pack with back around the 75%v/v spirituous solution wiping outer wall.
A plurality of batches the product that is obtained is carried out the HPLC check, and polymer content is between 0.17～0.20%, much smaller than 0.3% of NF requirement in the Sodium mezlocillin pulvis that makes.And the Sodium mezlocillin polymer content that traditional method makes is about 3%-10%.
Claims (9)
1. the preparation method of the Sodium mezlocillin of a low-grade polymer content comprises step:
(a) mezlocillin is joined in the water for injection, feed liquid is cooled to 12～15 ℃;
(b) drip NaHCO
3Solution is adjusted to pH5.8～6.5, is stirred to feed clarification and pH value stabilization;
(c) feed temperature is risen to 20 ℃ ± 2 ℃, stirred 30～60 minutes;
(d) add needle-use activated carbon, stir after 15～30 minutes, take off charcoal through plate filter;
(e) take off filtrating behind the charcoal through 0.45 μ m, 0.22 μ m strainer, Sterile Filtration; With
(f) freeze-drying obtains the Sodium mezlocillin finished product.
2. according to the preparation method of claim 1, wherein, NaHCO in the step (b)
3The concentration of solution is 14%w/w; The pH value is adjusted to pH 6.0～6.3.
3. according to the preparation method of claim 2, wherein further, said pH value is adjusted to pH 6.1 ~ 6.2.
4. according to the preparation method of claim 1, wherein, the weight ratio of mezlocillin and water for injection is in the step (a): 1:2.8～3.5.
5. according to the preparation method of claim 1, wherein, the consumption of needle-use activated carbon is 2～4% of a mezlocillin weight in the step (d).
6. according to the preparation method of claim 1, wherein, step (e) was accomplished in 4 hours.
7. according to the preparation method of claim 1, wherein, the preparation method of mezlocillin comprises step in the step (a):
(i) add pure water in the reaction kettle, temperature in the kettle is reduced to 2 ℃ also keep stable;
(ii) Ampicillin Trihydrate acid trihydrate is added reaction kettle, stirring mixes Ampicillin Trihydrate acid trihydrate and water;
(iii) drip the 10%w/w sodium hydrogen carbonate solution to reaction soln dissolving clarification;
(iv) add 1-chloroformyl-3-methylsulfonyl-2-imidazolidone and carry out condensation reaction, reaction process is through dripping 10%w/w sodium hydrogen carbonate solution control reaction solution in pH8.0～8.2, and controlled temperature is at 5 ± 2 ℃ simultaneously, and stirring velocity is controlled at 170 rev/mins;
(after v) reaction finished, filtering reacting liquid changed filtrating over to crystallization kettle;
(vi) add ethanol, stirring mixes ethanol and feed liquid, and 25 ± 2 ℃ of control feed temperatures stop when dripping 1N Hydrogen chloride to pH=2.0 dripping, and stir 60 minutes, and 130 rev/mins of rotating speeds carry out crystallization; With
(vii) slurry is put to whizzer and is got rid of filter, gets rid of after filter finishes, and use the 25%v/v washing with alcohol earlier, uses ETHYLE ACETATE washing lotion drip washing filter cake then, continues to get rid of to filter the centrifugal end discharging of 4～6h.
8. according to the preparation method of claim 1, wherein, the freeze-drying of step (f) comprises step:
(i) filtrating after the Sterile Filtration is filled in the freeze-drying dish, and every dish dress liquid thickness is 10 mm, when the flaggy degree is reduced to below-30 ℃ with product dish inlet;
(ii) continue cooling, product temperature is incubated 1～2hr after reaching-40 ℃;
(iii) the fs is dry: the open vacuum system, and vacuum tightness reaches 50Pa and begins sublimation drying when following in the case, keeps slowly intensification under the condition of the following vacuum tightness of 50Pa, 11-13 hour; With
(iv) subordinate phase is dry, and when product temperature arrived 0 ℃, shelf temperature was increased to the highest design temperature below 45 ℃, product temperature to 40 ℃, insulation 4 ~ 6 h.
9. according to the preparation method of claim 1, wherein, said Sodium mezlocillin is a mezlocillin for inj.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110088165 CN102161666B (en) | 2011-04-08 | 2011-04-08 | Preparation method of mezlocillin sodium and mezlocillin sodium for injection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110088165 CN102161666B (en) | 2011-04-08 | 2011-04-08 | Preparation method of mezlocillin sodium and mezlocillin sodium for injection |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102161666A CN102161666A (en) | 2011-08-24 |
| CN102161666B true CN102161666B (en) | 2012-02-08 |
Family
ID=44463154
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201110088165 Active CN102161666B (en) | 2011-04-08 | 2011-04-08 | Preparation method of mezlocillin sodium and mezlocillin sodium for injection |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102161666B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104922680A (en) * | 2015-05-28 | 2015-09-23 | 浙江长典医药有限公司 | Child-type medicinal composition with mezlocillin sodium and low-sodium carrier |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102895181B (en) * | 2012-10-22 | 2013-10-16 | 四川制药制剂有限公司 | Method for preparing mezlocillin sodium for injection |
| CN103012430B (en) * | 2013-01-16 | 2014-08-06 | 湖北济生医药有限公司 | Mezlocillin sodium compound and medicine composition thereof |
| CN104739781A (en) * | 2015-04-03 | 2015-07-01 | 海南通用康力制药有限公司 | Preparation method of mezlocillin sodium aseptic powder for injection |
| CN104910182A (en) * | 2015-05-28 | 2015-09-16 | 浙江长典医药有限公司 | Mezlocillin sodium chemical entity for children and preparation thereof |
| CN105902543B (en) * | 2016-04-28 | 2019-02-12 | 华北制药股份有限公司 | A kind of high-purity mezlocillin sodium preparation and preparation method thereof |
| CN108434107A (en) * | 2018-05-28 | 2018-08-24 | 江苏海宏制药有限公司 | A kind of mezlocillin for injection prescription and technique |
| CN108610352B (en) * | 2018-06-12 | 2020-08-04 | 山东鲁抗医药股份有限公司 | Method for preparing mezlocillin sodium by solvent crystallization |
| CN111978334A (en) * | 2020-08-26 | 2020-11-24 | 山东鲁抗医药股份有限公司 | Preparation method of penicillin salt for injection |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101265264A (en) * | 2008-05-12 | 2008-09-17 | 海南百那医药发展有限公司 | Method for producing high-purity mezlocillin sodium and powder injection thereof |
-
2011
- 2011-04-08 CN CN 201110088165 patent/CN102161666B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101265264A (en) * | 2008-05-12 | 2008-09-17 | 海南百那医药发展有限公司 | Method for producing high-purity mezlocillin sodium and powder injection thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104922680A (en) * | 2015-05-28 | 2015-09-23 | 浙江长典医药有限公司 | Child-type medicinal composition with mezlocillin sodium and low-sodium carrier |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102161666A (en) | 2011-08-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102161666B (en) | Preparation method of mezlocillin sodium and mezlocillin sodium for injection | |
| CN101439022B (en) | Method for preparing clindamycin phosphate powder injection raw medicine | |
| CN105440057B (en) | A kind of method for preparing cefoperazone sodium | |
| CN102161665B (en) | Preparation method of azlocillin sodium and azlocillin sodium used for injection | |
| CN101972479A (en) | Preparation process of intravenous injection human immunoglobulin | |
| CN102924483A (en) | Ceftazidime crystal compound, preparation method of compound and pharmaceutical composition of compound in sterile mixed powder form | |
| CN102731585B (en) | New active clindamycin phosphate compound and medicinal composition thereof | |
| CN102367243B (en) | Stable potassium sodium dehydroandroan drographolide succinate compound and pharmaceutical composition thereof | |
| CN103232449A (en) | Aztreonam compound, as well as preparation method and pharmaceutical composition thereof | |
| CN102643255A (en) | Andrographolide compound | |
| CN102391259A (en) | Nifuratel compound and preparation method thereof | |
| CN109971797B (en) | Method for producing tyrosol by using rhodotorula glutinis | |
| CN103191062A (en) | Sulbenicillin sodium injection | |
| CN1868451A (en) | Injection prepn. contg. cardxacin, and its prepn. method | |
| CN103554136A (en) | Preparation method of cefmenoxine hydrochloride dry powder | |
| CN112300225A (en) | Method for processing powder for extracting D-ribose capable of being screened | |
| CN104817557B (en) | Stable crystal form of moxifloxacin hydrochloride and preparation method thereof | |
| CN102584812B (en) | Preparation method of tebipenem pivoxil impurities | |
| CN102976979B (en) | Preparation method of water-soluble probenecid salt | |
| CN102276378B (en) | Treatment method of fermentation broth | |
| CN113045611A (en) | Preparation method of high-purity lincomycin hydrochloride | |
| CN104876949A (en) | Ceftazidime compound entity and preparation thereof for children | |
| CN116284254B (en) | Method for extracting high-purity high-content polymyxin B sulfate single component from fermentation liquor | |
| CN104725377B (en) | Crystal form of moxifloxacin hydrochloride and preparation method thereof | |
| CN102898443A (en) | Method for refining cefodizime sodium at high yield, high cleanliness and high purity |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |