CN1062733C - Liposome preparing technology and preparation thereof - Google Patents
Liposome preparing technology and preparation thereof Download PDFInfo
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- CN1062733C CN1062733C CN94112420A CN94112420A CN1062733C CN 1062733 C CN1062733 C CN 1062733C CN 94112420 A CN94112420 A CN 94112420A CN 94112420 A CN94112420 A CN 94112420A CN 1062733 C CN1062733 C CN 1062733C
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Abstract
The present invention relates to a liposome preparing technology and a preparation thereof, particularly to a preparing technology for forming a medical preparation in the shape of liposome and the liposome injecta of the medicines of bis chloroethyl nitrosourea, elemene and ginsenoside prepared by the technology. In the liposome preparing technology, the liposolubility medicines and a liposome substrate are dissolved in organic solvent to form lipid solution, or the liposome substrate is dissolved in the organic solvent to form the lipid solution; the lipid solution is put into an ampoule, water solubility medical liquid can be simultaneously added, and the organic solvent is removed by a vacuum drying process; nitrogen is filled, and the ampoule is sealed after dispersion liquid is injected into the ampoule; the liposome medical liquid is formed by placing or oscillating and dispersing. The present invention has the simple technology, and the present invention can be suitable for large-scale continuous production.
Description
Liposome preparation technology and preparation are to form the preparation technology of pharmaceutical product and with the Liposomal formulation of this prepared with the liposome form.
The long-acting liposome preparation and the preparation thereof of the disclosed peptide medicine of patent application prospectus CN1055483A (application number 91101790.) of state's invention in 23 days October in 1991, be with phospholipid composition, be dissolved in together in the appropriate organic solvent with lipophilic additive in case of necessity, remove lipid matrix dissolving formation liposome behind the aqueous solution that adds peptide that this solvent obtains; Perhaps with phospholipid composition, in case of necessity with lipophilic additive, and peptide is dissolved in the appropriate organic solvent together, removes this solvent, the liposome that the use medium dissolves obtains; Perhaps with phospholipid composition, be dissolved in together in volatile organic solvent with lipophilic additive in case of necessity, the adding aqueous, with the immiscible peptide solution of organic facies, more than the phase transition temperature of phospholipid composition through homogenization, make the binary system that obtains change into a kind of stable emulsion, remove organic solvent and then generate liposome.The solution that its liposome substrate becomes with organic solvent dissolution mixes with water miscible peptide (medicine), form emulsion earlier after, could remove and solvent, form liposome.Will be through homogenization process, the technology more complicated.Add the aqueous solution of peptide again behind the formation lipid matrix and dissolve the formation liposome, encapsulation ratio is low, and most of peptide (medicine) is dissolved in the outer solution of liposome.Particularly in this preparation process, removing organic molten system is to adopt rotary evaporator, and bigger rotary evaporation equipment be arranged, and removes solvent equipment complexity.Remove organic solvent, immersion lipid film and vibration form liposome and all carry out in the bulk container of rotary evaporation, and then inborn ability installs in the injection bottle.The medicinal liquid transformation process is many, and the chance that contacts with bacterium is more, operates that also more complicated is loaded down with trivial details.The lipid matrix from level to level that rotary evaporation forms, each component content is inhomogeneous up and down.Successively liposome form and the size that forms is also inhomogeneous.Above-mentioned technical process only is applicable to test chamber or small-scale test production, is unsuitable for extensive successive production process.The needs of the unfavorable large-scale production of condition of test.Its parcel (sealing) rate is lower, has only 20%.
The object of the present invention is to provide a kind of operation of being convenient to, be suitable for large-scale continuous production, and can must higher entrapment and the liposome preparation technology of encystation rate and with the liposome medicament of this explained hereafter.
Liposome preparation technology of the present invention is liposome substrate, fat-soluble medicine to be dissolved in organic solvent form lipoprotein solution.Be characterized in: lipoprotein solution is loaded on ampoule, carries out vacuum drying and remove organic solvent, can reclaim organic solvent (organic solvent) simultaneously; Inflated with nitrogen behind the removal organic solvent, and after ampoule adds dispersion liquid, seal.Disperse just can form lipidosome injection through long-time the immersion like this.Dispersion liquid is the same with existing dispersion liquid, generally is that water, glucose, saline also have other buffer etc.Particularly before vacuum drying, the water solublity medicinal liquid is also added ampoule.Perhaps add a spot of dispersion liquid such as water, glucose solution, hydrochloric acid solution etc.Enter vacuum drying so again, when removing organic solvent formation liposome matrix, water solublity medicinal liquid or water etc. just immerse the liposome matrix, and soaking of acceleration liposome is bloated.Water-soluble fluidity medicinal liquid that adds and low amounts of water etc. can also prevent that the dried lipid matrix is bonded at the bottom of the ampoule and wall.Then add to seal behind the dispersion liquid and soak that to disperse to form liposome just faster.The water soluble drug envelop rate is also just higher like this.The concentration of water solublity medicinal liquid is high more good more, preferably is bordering on or equals saturated concentration, more can increase the envelop rate to water soluble drug.The present invention can also only liposome substrate is dissolved in organic solvent becomes lipoprotein solution, and lipoprotein solution and water solublity medicinal liquid all are loaded on ampoule, carries out vacuum drying, removes organic solvent, recyclable organic solvent.After removing organic solvent, charge into nitrogen and after ampoule adds injection, seal the liposome of a formation coated water-soluble medicine.The water solublity medicinal liquid also is that concentration is high more good more, preferably is bordering on or equals saturated solution, helps forming higher entrapment.The formation that vacuum drying of the present invention removes organic solvent, soak bloated (comprising the coated water-soluble medicine), liposome to the lipid matrix all be in same container-carry out in the ampoule bottle; Reduce medicinal liquid manufacturing process and extraneous contacting, be suitable for production operation.The ampoule that preparation process only needs to arrange places in the vacuum chamber the amount doesn't matterly, does not need large-scale slewing, can carry out large-scale continuous production easily.Particularly can directly be used in numerous big production ampoules, can under the constant situation of process conditions, operating process and proportioning, guarantee the quality and the stability of producing for processing step condition and proportioning in ampoule test.In ampoule, make the rapid evaporative removal of organic solvent by vacuum, the uniformly fast shape lipid matrix that obtains easily forms multilamellar liposome (MLV), and the liposome cavity is more, parcel fat-soluble medicine and water soluble drug amount are higher, have particularly improved the envelop rate of water soluble drug greatly.Liposome is to form in the ampoule after sealing, and the liposome of formation can not be oxidized rotten, also can not destroy because of packing and other operating process.Liposome preparation technology of the present invention is for resistant to elevated temperatures medicine, can be after sealing, just do not carry out high temperature sterilize before forming liposome, in case after forming liposome high temperature sterilize and destroy the lipid somatocyst again, or, guarantee to have higher mouthful rate and the encystation rate sealed because of the high messenger drug hydrorrhea of temperature goes out the phenomenon of liposome.
Lipidosome injection of the present invention is by the fat-soluble medicine of liposome or water soluble drug or is wrapped in fat-soluble medicine and water soluble drug simultaneously.Be characterized in that liposome is to be in the water for injection, and liposome is fat-soluble medicinal liquid or fat-soluble solution and water-soluble solution coexistence, in ampoule, removes organic solvent, fill nitrogen and add water for injection and seal back formation through vacuum.Because liposome directly forms in ampoule, the medicine encapsulation ratio is higher, is dispersed in outer few of liposome in the injection, and the water that is adopted has significantly reduced the medicine irritation of lipidosome injection as dispersion liquid, and has guaranteed the stability of liposome.
As carmustine lipidosome injection of the present invention, be by the fat-soluble carmustine of liposome and be in the water for injection in the ampoule, it is to form lipoprotein solution by carmustine and liposome stromatolysis in organic solvent, lipoprotein solution is sub-packed in the ampoule, through vacuum drying, seal after filling nitrogen and adding water for injection and form.Originally operate under the 4-10 ℃ of aseptic condition and carry out.
Elemene fat body injection of the present invention is made of the fat-soluble elemene of liposome and the water for injection that is in the ampoule.It is to be dissolved in organic solvent by its matter of elemene and liposome to become lipoprotein solution, and it is interior through vacuum drying that lipoprotein solution is loaded on ampoule, seals after filling nitrogen and adding water for injection to form.As in order to quicken the formation of liposome, can carry out jolting.Originally operate under the room temperature aseptic condition and carry out.
Ginsenoside's lipidosome injection of the present invention is made of the water solublity ginsenoside solution of liposome and the water for injection that is in the ampoule.It is all to be loaded on ampoule by liposome matrix organic solution and ginsenoside's aqueous solution, removes organic solvent and fills nitrogen through vacuum drying, seals behind the adding water for injection to form.
The carmustine lipidosome injection is to be dissolved in ether by carmustine, lecithin, cephalin, cholesterol, forms the lipoprotein solution of carmustine, divides to install to ampoule.The ampoule that the carmustine lipoprotein solution is housed is placed in the vacuum desiccator through vacuum drying the evaporative removal ether.Inflated with nitrogen in vacuum drying cabinet and ampoule, and after ampoule adds people's water for injection, with ampule sealing.This just is scattered in water for injection by the liposome that carmustine, lecithin, cephalin, cholesterol form, and forms the carmustine lipidosome injection.
Elemene liposome injecta is to be dissolved in ether by elemene, soybean phospholipid, cholesterol or elemene, lecithin, cephalin, cholesterol, divides to install to ampoule.The water for injection that adds close or equal quantities again to ampoule.Remove ether through vacuum drying, charge into nitrogen and after ampoule adds water for injection, seal.The liposome that is formed by elemene, soybean phospholipid, cholesterol or elemene, lecithin, cephalin, cholesterol is scattered in water for injection and forms elemene liposome injecta.
Ginsenoside's lipidosome injection is similar to saturated aqueous solution by the water-soluble one-tenth of ginsenoside, uses ether melt into lipoprotein solution admittedly by soybean phospholipid, cephalin, cholesterol or lecithin, cephalin, gallbladder again.The all close equivalent layering with lipoprotein solution of ginsenoside's aqueous solution is added ampoule, the ampoule that ginsenoside's aqueous solution and lipoprotein solution are housed is put in the vacuum desiccator, remove ether, charge into nitrogen and after ampoule adds water for injection, seal through vacuum drying.The liposome that is formed by ginsenoside's aqueous solution, soybean phospholipid, cephalin, cholesterol or ginsenoside's aqueous solution, lecithin, cephalin, cholesterol is scattered in water for injection and constitutes ginsenoside's lipidosome injection.
Liposome preparation technology of the present invention and preparation are compared with existing technology, and through vacuum drying and soak and expand to disperse and form, forming process contact with the external world liposome, has simplified operating process, has reduced the chance of pollution in ampoule.The liposome that forms is difficult for destroyed.The process conditions of small test can directly expand in the big production and go, and are suitable for large-scale continuous production.Because the lipid piece that forms behind the vacuum drying is more even, the liposome of formation and is a multilamellar liposome also relatively evenly, and the liposome of formation can not destroy or oxidized because of being subjected to fierce the impact, so have higher entrapment and encystation rate.As before vacuum drying, adding water soluble drug aqueous solution or water together with lipoprotein solution, then more can accelerate soaking of liposome and expand and formation, improve encapsulation ratio to water soluble drug.Operating process can be carried out at normal temperatures, also is convenient to carry out under cryogenic conditions.Can also carry out high temperature sterilize after sealing, the dispersion that then is only liposome is shaped, can be because of high temperature sterilize does not destroy liposome, overcome liposome be difficult to sterilize shortcoming except that thermal source.The lipidosome injection that forms, the ratio of liposomal encapsulated medicine is higher.The liposome stability that is in the water for injection dispersion medium is good, and is less to the human body zest.
Further specify liposome preparation technology of the present invention and preparation below in conjunction with example.
Example 1
Get the carmustine A of 0.5-1.5g, the lecithin B of 1.5-6g, the cephalin C of 0-6g, the cholesterol D of 0-6g, the ether E of 5-200ml, the water for injection F of 5-200ml.Under 4-10 ℃ of condition, carmustine A and liposome substrate B, C, D are dissolved in organic solvent ether E.The solution that forms is through the Kynoar membrane filtration, and is sub-packed in the 5ml ampoule arranged side by side, is 1ml in the ampoule addition.Ampoule is inserted in the vacuum desiccator, evaporation ether and with its recovery, vacuum reaches 1.00mpa and keeps filling high pure nitrogen after 2 minutes, and adds the water for injection of 5ml, respectively with ampule sealing.Through place very long soak to expand be dispersed into the carmustine liposome, and be suspended from and form the carmustine lipidosome injection in the water for injection.As for quickening to form liposome, soak in placement and expand 12 ... 24 hours after jolting disperseed also available ultrasonic shaping 10-24 hour.
Example 2
Get 0.25-1g elemene a, 0.5-3g soybean phospholipid b, the lecithin C of 0.5-6g, 0-6g cephalin D, the cholesterol E of 0-6g, the ether F of 5-100ml, the water for injection of 5-200ml.Get a, b, e or a, b, e or a, c, d, e places in the container and is dissolved to clear and bright solution with F.Be divided in the 10ml ampoule with the sterilization of 0.45 μ mF type membrane filtration, each ampoule addition is 1ml, and can add the water for injection of 1ml.Ampoule is put people's vacuum desiccator to carry out the vacuum drying removal and reclaims ether.Vacuum is in the 0.08-0.1mpa scope.Charge into high pure nitrogen,, inject the water for injection of 10ml again to each ampoule, ampule sealing to get rid of remaining ether.Be put under the 4-6 ℃ of temperature to store through (about 100 ℃) behind the high temperature sterilize and soak bloatedly, soak and expand after 24 hours, jolting is shaped.Also can long time storedly soak bloated, natural shaped.The elemene envelop rate reaches more than 85%.
Example 3
Get soybean phospholipid 1.5g, cephalin 1.5g, cholesterol 0.6g becomes clear and bright liposome matrix solution with the 10ml ether dissolution, and uses membrane filtration.Get the 2.5g ginsenoside and become to be bordering on saturated aqueous solution with injection water and heating for dissolving.The saturated aqueous solution per ampoule is added 0.5ml, in each ampoule, add lipidic matrix solution 0.5ml again.Removal and recovery ether in people's vacuum desiccator are put in the ampoule arrangement, kept 5 minutes when vacuum reaches 0.1mpa, charge into high pure nitrogen, and inject water for injection and behind 5ml, seal.Sterilize by Steam Heating.After soaking bloated 24 hours under 4-6 ℃, through gap jolting, ultra-sonic dispersion shaping.Ginsenoside's envelop rate reaches more than 70%.
Example 4
Get ginsenoside 2.5g and put into glass container, add entry and heat 50-80 ℃ and be dissolved into saturated aqueous solution also after filtration.Get elemene 0.5g again, lecithin 2.25g, cephalin 0.75g, cholesterol 0.3g joins in the ether of 10ml and is dissolved to clear and bright lipoprotein solution, places 24 hours.The ampoule of a peek 10ml with the amount of every ampoule adding of ginsenoside's saturated aqueous solution 1ml, adds the lipoprotein solution of the elemene of 1ml again to every ampoule.Place vacuum desiccator to get rid of and the recovery ether ampoule arrangement so that 0.09mpa vacuum is dry.Then filling the people does not have the filtering high pure nitrogen of thermal source, and adds water for injection 10ml in ampoule.To be put into about 100 ℃ of Steam Heating sterilization tank internal heating behind the ampule sealing 30 minutes.Be put under the 4-6 ℃ of condition and store, soak and expand after 12-24 hour intermittent oscillating and ultrasonic shaping.Form the elemene of one bottle of bottle and ginsenoside's lipidosome injection.
Claims (10)
1. liposome preparation technology is fat-soluble medicine and liposome substrate to be dissolved in organic solvent become lipoprotein solution, and it is characterized in that: lipoprotein solution is loaded on ampoule, carries out vacuum drying and removes organic solvent, charges into nitrogen again and seals after ampoule injects dispersion liquid water.
2. as the said liposome preparation technology of claim 1, it is characterized in that: lipoprotein solution is sub-packed in the front and back of ampoule or adds the water solublity medicinal liquid simultaneously or the part dispersion liquid, carries out vacuum drying again.
3. as the said liposome preparation technology of claim 2, it is characterized in that: the water solublity medicinal liquid is to approach saturated or saturated drug solns.
4. as claim 1 or 2 or 3 said liposome preparation technologies, it is characterized in that: behind the ampule sealing, carry out high temperature sterilize.
5. liposome preparation technology is liposome substrate to be dissolved in organic solvent become lipoprotein solution, it is characterized in that: lipoprotein solution and water solublity medicinal liquid successively all are loaded on ampoule, carry out vacuum drying and remove organic solvent, charge into nitrogen again and seal after ampoule adds dispersion liquid.
6. as the said liposome preparation technology of claim 5, it is characterized in that: the water solublity medicinal liquid is concentrated solution or saturated solution.
As claim 5 or 6 molten liposome preparation technology, it is characterized in that: carry out high temperature sterilize behind the ampule sealing.
8. carmustine lipidosome injection, it is characterized in that: carmustine, lecithin, cephalin, cholesterol are in ether, divide and install to ampoule, remove ether through vacuum drying, fill people's nitrogen and seal after ampoule adds water for injection, the liposome that is formed by carmustine, lecithin, cephalin, cholesterol is scattered in water for injection and forms.
9. elemene liposome injecta, it is characterized in that: elemene, soybean phospholipid, cholesterol or elemene, lecithin, cephalin, cholesterol are dissolved in ether, divide and install to ampoule, and the water for injection of or equivalent close to the ampoule adding, remove ether through vacuum drying, charge into nitrogen and seal after ampoule adds water for injection, the liposome that is formed by elemene, soybean phospholipid, cholesterol or elemene, lecithin, cephalin, cholesterol is scattered in water for injection and forms.
10. ginsenoside's lipidosome injection, it is characterized in that: the water-soluble one-tenth of ginsenoside is similar to saturated aqueous solution, divide and install to ampoule, get soybean phospholipid, cephalin, cholesterol or lecithin, cephalin, cholesterol becomes lipoprotein solution with ether dissolution, divide the ampoule that installs to aqueous solution, remove ether through vacuum drying, fill people's nitrogen and seal after ampoule adds water for injection, the liposome that is formed by ginsenoside's aqueous solution, soybean phospholipid, cephalin, cholesterol or ginsenoside's aqueous solution, lecithin, cephalin, cholesterol is scattered in injection water and forms.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN94112420A CN1062733C (en) | 1994-07-30 | 1994-07-30 | Liposome preparing technology and preparation thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN94112420A CN1062733C (en) | 1994-07-30 | 1994-07-30 | Liposome preparing technology and preparation thereof |
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| Publication Number | Publication Date |
|---|---|
| CN1110134A CN1110134A (en) | 1995-10-18 |
| CN1062733C true CN1062733C (en) | 2001-03-07 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN94112420A Expired - Fee Related CN1062733C (en) | 1994-07-30 | 1994-07-30 | Liposome preparing technology and preparation thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100434066C (en) * | 2002-04-17 | 2008-11-19 | 谢恬 | Curcuma longa extract injection, and preparing process and use thereof |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1650846B (en) * | 2004-12-07 | 2011-11-16 | 沈阳药科大学 | Elemene liposome and its preparation method |
| ES2878284T3 (en) | 2016-11-25 | 2021-11-18 | Emcure Pharmaceuticals Ltd | Carmustine lipid formulations |
| EP3773484A4 (en) | 2018-04-05 | 2021-12-29 | Emcure Pharmaceuticals Limited | Carmustine formulation |
| US20210322304A1 (en) | 2018-09-05 | 2021-10-21 | Emcure Pharmaceuticals Ltd. | Stable ready-to-use carmustine pharmaceutical composition |
| KR102164218B1 (en) * | 2019-09-24 | 2020-10-12 | 코스맥스 주식회사 | Multilayer cationic liposome for enhancing the skin penetration and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4830858A (en) * | 1985-02-11 | 1989-05-16 | E. R. Squibb & Sons, Inc. | Spray-drying method for preparing liposomes and products produced thereby |
| JPH0558879A (en) * | 1991-08-30 | 1993-03-09 | Taiho Yakuhin Kogyo Kk | Carcinostatic agent-containing liposome pharmaceutical |
-
1994
- 1994-07-30 CN CN94112420A patent/CN1062733C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4830858A (en) * | 1985-02-11 | 1989-05-16 | E. R. Squibb & Sons, Inc. | Spray-drying method for preparing liposomes and products produced thereby |
| JPH0558879A (en) * | 1991-08-30 | 1993-03-09 | Taiho Yakuhin Kogyo Kk | Carcinostatic agent-containing liposome pharmaceutical |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100434066C (en) * | 2002-04-17 | 2008-11-19 | 谢恬 | Curcuma longa extract injection, and preparing process and use thereof |
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| Publication number | Publication date |
|---|---|
| CN1110134A (en) | 1995-10-18 |
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