CN1110134A - Liposome preparing technology and preparation thereof - Google Patents
Liposome preparing technology and preparation thereof Download PDFInfo
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- CN1110134A CN1110134A CN 94112420 CN94112420A CN1110134A CN 1110134 A CN1110134 A CN 1110134A CN 94112420 CN94112420 CN 94112420 CN 94112420 A CN94112420 A CN 94112420A CN 1110134 A CN1110134 A CN 1110134A
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Abstract
The present invention relates to a liposome preparation process and its preparation. In particular, it is a preparation process to form compound medicines in the form of liposome and its liposome injection medicaments of carmustine, elemene and ginsenocide, etc. prepared by using said preparation process. Its technological process is as follows: the fat-soluble medicine and liposome matrix are dissolved in organic solvent and made into lipid-soluble liquor or only the liposome matrix is dissolved in organic solvent and made into lipid-soluble liquor, and then the lipid-soluble liquor is placed in an ampule, and at the same time, a water-soluble liquid medicine can be added, and then its organic solvent is removed by using vacuum drying method, and then nitrogen gas is charged, and a dispersing liquor is injected in the ampule, and then sealed, and stood still or oscillated and dispersed into the liposome liquid medicine.
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 patent application prospectus CN1055483A(application number 91101790.0 of state's invention in 23 days October in 1991) the long-acting liposome preparation and the preparation thereof of disclosed peptide medicine, 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 the also numerous rope of more complicated.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 that liposome substrate, fat-soluble medicine are dissolved in the lipoprotein solution that organic solvent forms.Be characterized in: lipoprotein solution is loaded on the peace bottle, 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 the peace bottle 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 the peace bottle.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 peace bottle end 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 the peace bottle, carries out vacuum drying, removes organic solvent, recyclable organic solvent.After removing organic solvent, charge into nitrogen and after the peace bottle 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 An bottle bottle, reduced contacting of medicinal liquid manufacturing process and the external world, be suitable for production operation.The peace bottle 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 for directly being used in numerous big production peace bottles, can under the constant situation of process conditions, operating process and proportioning, guarantee the quality and the stability of producing in peace processing step condition of bottle test and proportioning.In the peace bottle, 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 peace bottle 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 the peace bottle through vacuum remove organic solvent, fill nitrogen and add water for injection seal after formation.Because liposome directly forms in peace bottle, 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 peace bottle, it is to form lipoprotein solution by carmustine and liposome stromatolysis in organic solvent, lipoprotein solution is sub-packed in the peace bottle, 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 peace bottle.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 the peace bottle, 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 peace bottle.It is all to be loaded on the peace bottle 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 the peace bottle.The peace bottle 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 peace bottle, and after the peace bottle adds water for injection, will pacify bottle closure.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 the peace bottle.The water for injection that adds close or equivalent again to the peace bottle.Remove ether through vacuum drying, charge into nitrogen and after the peace bottle 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 the peace bottle, the peace bottle that ginsenoside's aqueous solution and lipoprotein solution are housed is put in the vacuum desiccator, remove ether, charge into nitrogen and after the peace bottle 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 to expand and disperse and form, forming process does not contact with the external world liposome, has simplified operating process, has reduced the chance of pollution in peace bottle.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 peace bottle arranged side by side, is 1ml in a peace bottle addition.To pacify bottle and insert 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, will pacify bottle closure respectively.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 expanded 12-24 hour 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 peace bottle with the sterilization of 0.45 μ mF type membrane filtration, each peace bottle addition is 1ml, and can add the water for injection of 1ml.To pacify bottle puts into vacuum desiccator and carries out that vacuum drying is removed and reclaim 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 peace bottle, will pacify bottle closure 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 every peace bottle of saturated aqueous solution is added 0.5ml, in each peace bottle, add lipidic matrix solution 0.5ml again.To pacify the bottle arrangement and put into the vacuum desiccator removal and reclaim ether, keep 5 minutes when vacuum reaches 0.1mpa, and 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 peace bottle of a peek 10ml with the amount of every peace bottle of ginsenoside's saturated aqueous solution adding 1ml, adds the lipoprotein solution of the elemene of 1ml again to every peace bottle.To pacify the bottle arrangement places vacuum desiccator to get rid of and the recovery ether so that 0.09mpa vacuum is dry.Then charge into the filtering high pure nitrogen of no thermal source, and in the peace bottle, add water for injection 10ml.To pacify and be put into about 100 ℃ of Steam Heating sterilization tank internal heating behind the bottle closure 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, it is characterized in that: lipoprotein solution is loaded on the peace bottle, carries out vacuum drying and removes organic solvent, charges into nitrogen again and seals after the peace bottle 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 peace bottle 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 peace bottle closure, carry out high temperature sterilize.
5, liposome preparation technology is liposome substrate to be dissolved in organic solvent become lipoprotein solution, and base is characterised in that: lipoprotein solution and water solublity medicinal liquid successively all are loaded on the peace bottle, carry out vacuum drying and remove organic solvent, charge into nitrogen again and seal after the peace bottle 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.
7, as claim 5 or 6 molten liposome preparation technology, it is characterized in that: carry out high temperature sterilize behind the peace bottle closure.
8, carmustine lipidosome injection, it is characterized in that: carmustine, lecithin, cephalin, cholesterol are in ether, divide and install to installation, remove ether through vacuum drying, charge into nitrogen and seal after peace bottle 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 the peace bottle, and the water for injection of or equivalent close to the adding of peace bottle, remove ether through vacuum drying, charge into nitrogen and seal after peace bottle 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 the peace bottle, get soybean phospholipid, cephalin, cholesterol or lecithin, cephalin, cholesterol becomes lipoprotein solution with ether dissolution, divide the peace bottle that installs to aqueous solution, remove ether through vacuum drying, charge into nitrogen and seal after peace bottle 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 true CN1110134A (en) | 1995-10-18 |
| CN1062733C 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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| CN (1) | CN1062733C (en) |
Cited By (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 |
| WO2018096466A1 (en) | 2016-11-25 | 2018-05-31 | Emcure Pharmaceuticals Limited | Lipid formulations of carmustine |
| WO2019193477A1 (en) | 2018-04-05 | 2019-10-10 | Emcure Pharmaceuticals Limited | Carmustine formulation |
| CN113518611A (en) * | 2019-09-24 | 2021-10-19 | 科丝美诗株式会社 | Multilamellar cationic liposome for enhancing skin absorption and preparation method thereof |
| US11865206B2 (en) | 2018-09-05 | 2024-01-09 | Emcure Pharmaceuticals Ltd | Stable ready-to-use carmustine pharmaceutical composition |
Families Citing this family (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 |
Family Cites Families (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
Cited By (7)
| 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 |
| WO2018096466A1 (en) | 2016-11-25 | 2018-05-31 | Emcure Pharmaceuticals Limited | Lipid formulations of carmustine |
| US10583101B2 (en) | 2016-11-25 | 2020-03-10 | Emcure Pharmaceuticals Limited | Lipid formulations of carmustine |
| WO2019193477A1 (en) | 2018-04-05 | 2019-10-10 | Emcure Pharmaceuticals Limited | Carmustine formulation |
| US11865206B2 (en) | 2018-09-05 | 2024-01-09 | Emcure Pharmaceuticals Ltd | Stable ready-to-use carmustine pharmaceutical composition |
| CN113518611A (en) * | 2019-09-24 | 2021-10-19 | 科丝美诗株式会社 | Multilamellar cationic liposome for enhancing skin absorption and preparation method thereof |
| CN113518611B (en) * | 2019-09-24 | 2024-01-12 | 科丝美诗株式会社 | Multilamellar cationic liposomes for enhanced skin absorption and method of making same |
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| Publication number | Publication date |
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| CN1062733C (en) | 2001-03-07 |
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