CN102327236A - Esomeprazole sodium liposome injection - Google Patents
Esomeprazole sodium liposome injection Download PDFInfo
- Publication number
- CN102327236A CN102327236A CN 201110196429 CN201110196429A CN102327236A CN 102327236 A CN102327236 A CN 102327236A CN 201110196429 CN201110196429 CN 201110196429 CN 201110196429 A CN201110196429 A CN 201110196429A CN 102327236 A CN102327236 A CN 102327236A
- Authority
- CN
- China
- Prior art keywords
- esomeprazole sodium
- esomeprazole
- buffer solution
- sodium
- lipidosome injection
- 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
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses an esomeprazole sodium liposome injection. The esomeprazole sodium liposome injection is characterized by being mainly prepared from esomeprazole sodium, phosphatidylcholine, cholesterol, myelin, antioxygen and a protective agent. The prepared liposome injection is high in dissolvability, stability and entrapment rate and is small in a side effect, improves quality of preparation products, reduces toxic and side effects, improves bioavailability, and has an obvious curative effect.
Description
Technical field
The present invention relates to a kind of novel formulation of esomeprazole sodium, particularly relate to esomeprazole sodium lipidosome injection and method for making thereof.
Background technology
Esomeprazole sodium (Esomeprazole), chemical name is: 5-methoxyl group-2-II (4-methoxyl group-3.5 dioxy base-2-pyridine radicals)-1H-benzimidazole sodium, molecular formula: C
17H
18N
3O
3SNa, molecular weight: 344.1, structural formula is:
Esomeprazole sodium is a kind of proton pump inhibitor, reduces gastric acid secretion through the H+/Na+-ATP enzyme that suppresses parietal cell.Esomeprazole is the s isomer of omeprazole; Be that first can be used for clinical proton pump inhibitor (ppi) individual isomer; It has not available materia medica of omeprazole raceme and clinical advantages; Compare with omeprazole, esomeprazole has higher with more consistent bioavailability, and area is also bigger under the PC time graph; Area determines them to arrive the amount of parietal cell under the PC time graph of esomeprazole and omeprazole, therefore controls the gastric acid secretion degree that is reached.The same with other proton pump inhibitor; Esomeprazole has higher specificity to the parietal cell sour environment; And gathering in this environment, activation and covalency inhibition proton pump, and the proton pump at other positions of human body does not reach esomeprazole gathering and the needed acidity of activation.Esomeprazole sodium is mainly used in the treatment of erosive reflux esophagitis clinically; The long term maintenance treatment that the esophagitis patient who has cured prevents to recur; The symptom control of GORD (GERD) is with suitable antimicrobial therapy drug combination eradicate helicobacter pylori.
Patent documentation CN 101513387A discloses a kind of esomeprazole magnesium injection, and mainly by esomeprazole magnesium or its officinal salt, antioxidant and solvent for injection are formed; The method adopts the routine prescription and the production technology of this area; And the sample of preparation, less stable is unfavorable for long-term storage; Bioavailability is low, has influenced the curative effect of medicine greatly.
Patent documentation CN101269037A discloses a kind of esomeprazole magnesium oral sustained release drop pill; It is characterized in that by esomeprazole magnesium; Glyceryl monostearate or stearic acid or hypromellose or their mixture are formed and vitamin E is formed; Yet the esomeprazole sodium dropping balls can produce catabiosis in long term store, the related substance of medicine increases.
The product of the esomeprazole class medicine of listing has injection and tablet at present, and the esomeprazole bioavailability of these two kinds of dosage forms is low.
Liposome (liposomes) is dispersed in phospholipid by Britain scholar Bangham and Standish at first and finds when carrying out electron microscopic observation in the water.Liposome is a kind of novel targeting microgranule drug administration carrier, is the bimolecular folliculus with similar biofilm structure.Liposome can be divided into unilamelar liposome and multilamelar liposome according to the double-deck immobilized artificial membrane number of plies that its structure comprised, and the vesicle that contains the double-deck immobilized artificial membrane of monolayer is called unilamelar liposome, and the vesicle that contains the double-deck immobilized artificial membrane of multilamellar is called multilamelar liposome.General particle diameter is less than the small unilamellar vesicle that is called of 100nm, and the unilamelar liposome of particle diameter between 100nm-1000nm is called large unilamellar vesicle, and the particle diameter of multilamelar liposome is between 1-5 μ m.
In order to improve the bioavailability of esomeprazole, strengthen its targeting property, the inventor studies esomeprazole sodium lipidosome injection, strengthens the effect of esomeprazole sodium.
Summary of the invention
The purpose of this invention is to provide a kind of esomeprazole sodium lipidosome injection, the liposome excipient through esomeprazole sodium and particular combination makes the esomeprazole sodium lipidosome, and lyophilization again is aseptic subpackaged, makes lipidosome injection.
The stability of liposome is the major issue of restriction liposome development, and the liposome ubiquity is prone to assemble, merge, and causes the entrapped drug seepage.The present invention has not only solved the stability and the not good technical problem of envelop rate of liposome through the combination of particular excipient, has also obtained beyond thought preparation effect, thereby superior in quality liposome is provided.Though do not want to receive one theory, the common and/or synergistic result that effect of the present invention possibly be.
The esomeprazole sodium lipidosome injection solubility that the present invention makes is good, good stability, and envelop rate is high, has improved the formulation products quality, has reduced toxic and side effects, and bioavailability improves greatly, more remarkable treatment effect.
Preparation liposome membrane material commonly used is phospholipid and additives.The phospholipid that is used to prepare liposome at present has: natural phospholipid such as lecithin and fabaceous lecithin, synthetic phospholipid such as dipalmitoyl phosphatidyl choline and DSPC.Above-mentioned phospholipid all has two hydrophobic chains, no matter its hydrophilic group structure is how, and the formation lipid bilayer that they all can be spontaneous in water; Additives are commonly used has cholesterol, 18-amine., a phosphatidic acid etc., and cholesterol can the bilayer flowability, permeability etc., and 18-amine. and phosphatidic acid can change the charge property of surface of liposome.
Bound by theory not; The inventor is through the unexpected discovery of secular test; Can obtain the esomeprazole sodium lipidosome of excellent in stability with the combination of Yolk lecithin, cholesterol and sphingo, it has good stable property, adds specific freeze drying protectant again; Liposome can not break because of dehydration, fusion, ice crystal generation etc. in the freeze-drying process thereby make, and the lipid physical ability kept good envelop rate after aquation was redissolved.
The present invention provides a kind of esomeprazole sodium lipidosome injection, is mainly processed by the composition of following ratio of weight and number:
In a preferred embodiment of the present invention, each composition weight umber of esomeprazole sodium lipidosome injection is:
Antioxidant can prevent the oxidation of liposome substrate, increases the stability of blank liposome, is the adjuvant a kind of commonly used of preparation liposome.In the preferred embodiments of the invention, antioxidant can be selected from propyl gallate.
When not full or atrophy becomes granule when the freeze-dried products external form, add protective agent, play solid support effect, make dried residue can keep original volume basically, and keep enough intensity, fragmentation when avoiding storing.The protective agent that uses also should possess and draw moist for a short time except that the general requirement that must possess injection supplementary material, and eutectic point is high, dissolution velocity is fast, outward appearance is pure white, even, fine and smooth, cheap and easy to get etc. after the lyophilizing.
In the preferred embodiments of the invention, protective agent is selected from the combination of sorbitol and dextran, and most preferably being weight ratio is the combination of 1: 1 sorbitol and dextran.
The particle diameter of liposome of the present invention can be controlled between the 50-300nm between 20nm-400nm further, and envelop rate can reach more than 85%.Simultaneously, use Freeze Drying Technique to carry out lyophilization, process freeze-dried powder, the water in the weeding of grease plastid has further strengthened the stability of esomeprazole sodium lipidosome, and preservation condition is also more wide in range.In addition, redissolve the various physicochemical properties of back liposome be as good as with lyophilizing before.
The present invention also provides a kind of method for preparing above-mentioned esomeprazole sodium lipidosome injection, may further comprise the steps:
(1) Yolk lecithin, cholesterol, sphingo and antioxidant are added in an amount of organic solvent, heated and stirred is uniformly dispersed, and organic solvent is removed in decompression on rotary evaporator, makes immobilized artificial membrane;
(2) add an amount of buffer solution, jolting is stirred, and makes the complete aquation of immobilized artificial membrane, at a high speed even matter emulsifying, and filtering with microporous membrane makes the blank liposome suspension;
(3) esomeprazole sodium is water-soluble, filtering with microporous membrane, filtrating adds in the blank liposome suspension, is incubated 45-60 ℃ and stirs 20-40 minute, adds protective agent again, stirs and makes its dissolving, and cool to room temperature gets esomeprazole sodium lipidosome solution then;
(4) above-mentioned solution is removed through ultrafilter membrane degerm and thermal source, flowing steam sterilization then, lyophilization under aseptic condition, packing makes esomeprazole sodium lipidosome injection.
In the method for preparing of the present invention, organic solvent can be selected from one or more in n-butyl alcohol, the tert-butyl alcohol, isopropyl alcohol and the acetonitrile, and preferred volume ratio is 4: 1 the n-butyl alcohol and the mixed solvent of acetonitrile.
In the method for preparing of the present invention, buffer solution is selected from one or more in citrate buffer solution, borate buffer solution and the carbonate buffer solution, is preferably PH and is 6.4 citrate buffer solution.
Compared with prior art, esomeprazole sodium lipidosome injection provided by the invention and preparation method thereof has the following advantages: envelop rate is high; Stability is high, has improved the therapeutic index of medicine, has reduced the toxicity of medicine; Reduce toxic and side effects, improved the formulation products quality; The inventive method preparation technology is simple, is suitable for industrialized great production.
The specific embodiment
Further set forth the present invention in detail with reference to embodiment below, but it will be appreciated by those skilled in the art that the present invention is not limited to the method for preparing of these embodiment and use.And those skilled in the art can carry out it is equal to replacement, combination, improvement or modification according to description of the invention to the present invention, but these all will comprise within the scope of the invention.
The preparation of the sodium lipidosome freeze-dried injectable powder of embodiment 1 esomeprazole
Prescription (1000 bottles):
Preparation technology:
(1) 120g Yolk lecithin, 20g cholesterol, 4g sphingo and 2g propyl gallate being added the 600ml volume ratio is in 4: 1 the n-butyl alcohol and acetonitrile; Heated and stirred is uniformly dispersed; N-butyl alcohol and acetonitrile are removed in decompression on rotary evaporator, make immobilized artificial membrane;
(2) PH of adding 600ml is 6.4 citrate buffer solution, and jolting is stirred, and makes the complete aquation of immobilized artificial membrane, at a high speed even matter emulsifying, and filtering with microporous membrane makes the blank liposome suspension;
(3) 40g esomeprazole sodium is water-soluble, filtering with microporous membrane, filtrating adds in the blank liposome suspension; Be incubated 45-60 ℃ and stirred 20-40 minute, add 100g sorbitol and 100g dextran again, stir and make its dissolving; Cool to room temperature gets esomeprazole sodium lipidosome solution then;
(4) above-mentioned solution is removed through ultrafilter membrane degerm and thermal source, the flowing steam sterilization is 30 minutes then, lyophilization under the aseptic condition, and packing makes the sodium lipidosome freeze-dried injectable powder of esomeprazole.
The preparation of the sodium lipidosome freeze-dried injectable powder of embodiment 2 esomeprazoles
Prescription (1000 bottles):
Preparation technology:
(1) 240g Yolk lecithin, 160g cholesterol, 40g sphingo and 20g propyl gallate being added the 3000ml volume ratio is in 4: 1 the n-butyl alcohol and acetonitrile; Heated and stirred is uniformly dispersed; N-butyl alcohol and acetonitrile are removed in decompression on rotary evaporator, make immobilized artificial membrane;
(2) adding 3000mlPH is 6.4 citrate buffer solution, and jolting is stirred, and makes the complete aquation of immobilized artificial membrane, at a high speed even matter emulsifying, and filtering with microporous membrane makes the blank liposome suspension;
(3) 40g esomeprazole sodium is water-soluble, filtering with microporous membrane, filtrating adds in the blank liposome suspension; Be incubated 45-60 ℃ and stirred 20-40 minute, add 300g sorbitol and 300g dextran again, stir and make its dissolving; Cool to room temperature gets esomeprazole sodium lipidosome solution then;
(4) above-mentioned solution is removed through ultrafilter membrane degerm and thermal source, the flowing steam sterilization is 30 minutes then, lyophilization under the aseptic condition, and packing makes the sodium lipidosome freeze-dried injectable powder of esomeprazole.
Embodiment 3
Prescription (1000 bottles):
Preparation technology:
(1) 160g Yolk lecithin, 80g cholesterol, 20g sphingo and 10g propyl gallate being added the 1000ml volume ratio is in 4: 1 the n-butyl alcohol and acetonitrile; Heated and stirred is uniformly dispersed; N-butyl alcohol and acetonitrile are removed in decompression on rotary evaporator, make immobilized artificial membrane;
(2) adding 1000mlPH is 6.4 citrate buffer solution, and jolting is stirred, and makes the complete aquation of immobilized artificial membrane, at a high speed even matter emulsifying, and filtering with microporous membrane makes the blank liposome suspension;
(3) 40g esomeprazole sodium is water-soluble, filtering with microporous membrane, filtrating adds in the blank liposome suspension; Be incubated 45-60 ℃ and stirred 20-40 minute, add 200g sorbitol and 200g dextran again, stir and make its dissolving; Cool to room temperature gets esomeprazole sodium lipidosome solution then;
(4) above-mentioned solution is removed through ultrafilter membrane degerm and thermal source, the flowing steam sterilization is 30 minutes then, lyophilization under the aseptic condition, and packing makes the sodium lipidosome freeze-dried injectable powder of esomeprazole.
Embodiment 4 preparation Comparative Examples 1-3
| Form | Embodiment 1 | Comparative Examples 1 | Comparative Examples 2 | Comparative Examples 3 |
| Esomeprazole sodium | ?40g | ?40g | ?40g | ?40g |
| Yolk lecithin | ?120g | ?120g | ?120g | ?120g |
| Cholesterol | ?20g | ?/ | ?20g | ?20g |
| 18-amine. | ?/ | ?20g | ||
| Sphingo | ?4g | ?4g | ?4g | ?4g |
| Propyl gallate | ?2g | ?/ | ?2g | ?/ |
| Vitamin C | ?2g | ?/ | ?2g | |
| Sorbitol | ?100g | ?100g | ?/ | ?100g |
| Dextran | ?100g | ?100g | ?/ | ?100g |
| Mannitol | ?/ | ?/ | ?100g | ?/ |
Above Comparative Examples is accomplished according to the technology of embodiment 1.
The mensuration of Test Example 1 particle diameter
Under the room temperature condition; Get the sodium lipidosome freeze-dried injectable powder of esomeprazole of embodiment and Comparative Examples; Be made into 0.1% solution with normal saline, place the sample cell of Submicron Particle Sizer Model 370 particle diameter detectors, measure particle size distribution and mean diameter; Observe particle shape with projection electron microscope.Result such as table 1:
Table 1 particle diameter testing result
| Embodiment | Mean diameter | Outward appearance |
| Embodiment 1 | 252.7±20.3nm | Spherical, evenly |
| Comparative Examples 1 | 430.6±26.7nm | Inhomogeneous, mixed and disorderly |
| Embodiment 2 | 230.3±19.8nm | Spherical, evenly |
| Comparative Examples 2 | 426.6±20.9nm | Inhomogeneous, mixed and disorderly |
| Embodiment 3 | 205.4±18.0nm | Spherical, evenly |
| Comparative Examples 3 | 217.5±16.1nm | Spherical, more inhomogeneous |
Can know that by above result the solid lipid nanoparticle particle diameter that embodiment 1-3 makes is even, show spherical, big or small homogeneous; The solid lipid nanoparticle particle diameter that Comparative Examples 1-2 makes is inhomogeneous, and shape is indefinite, and is not of uniform size; Though the particle diameter of Comparative Examples 3 Liposomal formulations meets the requirements, it is even to be not so good as embodiment 3 described liposome particle size distribution.
The mensuration of Test Example 2 envelop rates
The esomeprazole sodium lipidosome preparation of embodiment and Comparative Examples preparation is dissolved in water is diluted to 0.1% solution, high speed centrifugation, 5000r/min; Centrifugal 20 minutes, get supernatant, use dissolve with methanol; The HPLC method is measured the esomeprazole sodium content, the computational envelope rate, and result such as table 2:
Table 2 entrapment efficiency determination result
Can know that by above result the envelop rate of the Liposomal formulation of embodiment 1-3 preparation is higher than the envelop rate of the Liposomal formulation of Comparative Examples 1-3 significantly, explains that product of the present invention has unforeseeable effect.
Test Example 3 study on the stability
With the sample of embodiment of the invention 1-3 and Comparative Examples 1-3 preparation and listing injection esomeprazole sodium (lot number: place following 6 months of the condition of 40 ℃ of high temperature, relative humidity 75% respectively H20093314 AstraZeneca pharmaceutical Co. Ltd); Carry out accelerated test and investigate experimental result such as table 3:
Table 3 accelerated test result
Can be known that by above result when quickening June, the listing preparation becomes pale yellow powder, content reduces, and related substance raises; The product content of Comparative Examples reduces, and related substance raises; And sample character of the present invention, content and related substance variation are all not obvious, explain that product stability of the present invention is good.
The test of Test Example 4 percolation ratios
Get the sample of Test Example 1-3 and Comparative Examples 1-3 preparation, under the room temperature condition,, make regular check on respectively, measure envelop rate respectively at 0 day, 30 days, 60 days, 90 days and 180 days, with the dose of sealing in 0 day relatively, calculate percolation ratio, the result sees table 4
Table 4 percolation ratio result of the test
| Time | Embodiment 1 | Embodiment 2 | Embodiment 3 | Comparative Examples 1 | Comparative Examples 2 | Comparative Examples 3 |
| 0 day | ?0.34 | ?0.33 | ?0.32 | ?0.79 | ?0.86 | 1.20 |
| 30 days | ?0.39 | ?0.37 | ?0.36 | ?1.34 | ?1.67 | 2.34 |
| 60 days | ?0.60 | ?0.56 | ?0.54 | ?3.72 | ?3.65 | 5.02 |
| 90 days | ?0.66 | ?0.64 | ?0.65 | ?5.04 | ?4.95 | 10.44 |
| 180 days | ?0.71 | ?0.72 | ?0.69 | ?6.56 | ?6.88 | 19.56 |
Can know by above result of the test; The sample of embodiment of the invention preparation percolation ratio in long term storage is long changes little; And the sample percolation ratio of Comparative Examples increases gradually, and the liposome seepage is serious, and the esomeprazole sodium lipidosome injection of this explanation the present invention preparation has advantages of higher stability.
The test of Test Example 4 bioavailability
24 1 years old left and right sides beasle dogs are divided into 4 groups at random, and vein gives the esomeprazole sodium 0.04g of embodiment 1 and Comparative Examples 1-, and administration finishes back 0,0.25; 0.5,1,1.5,2.5; 3.5 5.5 and 7.5 gather venous blood 1ml, inject and get blood vessel, high speed centrifugation separation of serum; Accurately draw blood serum sample 190 μ L and place 1.5mL Eppendorf microcentrifugal tube, add the saturated methotrexate solution of mark in the 10 μ L, add methanol 400 μ L again; Vortex mixed 1min, 16000rpm high speed centrifugation 5min gets supernatant 200 μ L and adds 200 μ L water; 2500rpm vortex 30s mixing carries out HPLC and analyzes, and carries out pharmacokinetic data available with WinNonline version5.2 program and handles.Result of the test such as following table:
Relevant pharmacokinetic parameters
Can find out by above experimental data; The esomeprazole sodium lipidosome injection of embodiment of the invention preparation is compared with Comparative Examples; Bioavailability improves greatly, has proved absolutely the present invention because the esomeprazole sodium lipidosome injection of processing of excipient and active component has synergism; The injection of preparation improves bioavailability widely, has obtained unexpected technical effect.
Claims (7)
1. esomeprazole sodium lipidosome injection is characterized in that mainly being processed by the composition of following ratio of weight and number:
2. esomeprazole sodium lipidosome injection according to claim 1 is characterized in that mainly being processed by the composition of following ratio of weight and number:
3. esomeprazole sodium lipidosome injection according to claim 1 and 2; It is characterized in that described antioxidant is selected from one or more in vitamin E, sodium sulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate, thiourea, vitamin C, the propyl gallate, is preferably propyl gallate.
4. according to each described esomeprazole sodium lipidosome injection of above claim; It is characterized in that protective agent is selected from one or more in glycine, lactose, sorbitol, sorbose, dextran, the manna alcohol and glucose, being preferably weight ratio is the combination of 1: 1 sorbitol and dextran.
5. a method for preparing esomeprazole sodium lipidosome injection is characterized in that comprising the steps:
(1) Yolk lecithin, cholesterol, sphingo and antioxidant are added in an amount of organic solvent, heated and stirred is uniformly dispersed, and organic solvent is removed in decompression on rotary evaporator, makes immobilized artificial membrane;
(2) add an amount of buffer solution, jolting is stirred, and makes the complete aquation of immobilized artificial membrane, at a high speed even matter emulsifying, and filtering with microporous membrane makes the blank liposome suspension;
(3) esomeprazole sodium is water-soluble, filtering with microporous membrane, filtrating adds in the blank liposome suspension, is incubated 45-60 ℃ and stirs 20-40 minute, adds protective agent again, stirs and makes its dissolving, and cool to room temperature gets esomeprazole sodium lipidosome solution then;
(4) above-mentioned solution is removed through ultrafilter membrane degerm and thermal source, flowing steam sterilization then, lyophilization under the aseptic condition, packing makes esomeprazole sodium lipidosome injection.
6. method for preparing according to claim 5 is characterized in that organic solvent can be selected from one or more in n-butyl alcohol, the tert-butyl alcohol, isopropyl alcohol and the acetonitrile, and preferred volume ratio is 4: 1 the n-butyl alcohol and the mixed solvent of acetonitrile.
7. according to claim 5 or 6 arbitrary described method for preparinies, it is characterized in that buffer solution is selected from one or more in citrate buffer solution, borate buffer solution and the carbonate buffer solution, be preferably PH and be 6.4 citrate buffer solution.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110196429 CN102327236B (en) | 2011-07-14 | 2011-07-14 | Esomeprazole sodium liposome injection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110196429 CN102327236B (en) | 2011-07-14 | 2011-07-14 | Esomeprazole sodium liposome injection |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102327236A true CN102327236A (en) | 2012-01-25 |
| CN102327236B CN102327236B (en) | 2013-03-20 |
Family
ID=45479371
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201110196429 Expired - Fee Related CN102327236B (en) | 2011-07-14 | 2011-07-14 | Esomeprazole sodium liposome injection |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102327236B (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101513387A (en) * | 2008-11-20 | 2009-08-26 | 李铁军 | Esomeprazole magnesium injection liquid |
-
2011
- 2011-07-14 CN CN 201110196429 patent/CN102327236B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101513387A (en) * | 2008-11-20 | 2009-08-26 | 李铁军 | Esomeprazole magnesium injection liquid |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102327236B (en) | 2013-03-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103040748B (en) | Pemetrexed disodium liposome injection | |
| JP2009507049A (en) | Nanomicelle formulation of vinca alkaloid anticancer drug encapsulated in polyethylene glycol derivative of phospholipid | |
| JP2008534525A (en) | Nanomicelle formulation of anthracycline antitumor antibiotic encapsulated in polyethylene glycol derivative of phospholipid | |
| CN104337851B (en) | The preparation method of brucea fruit oil nano structured lipid carrier and its freeze-dried powder | |
| KR101768681B1 (en) | Liposome for taxane family drug delivery and preparation method thereof | |
| US8962017B2 (en) | Formulation of silymarin with high efficacy and prolonged action and the preparation method thereof | |
| EP3138555B1 (en) | Liposome composition and production method therefor | |
| US9023388B2 (en) | Formulation of silibinin with high efficacy and prolonged action and the preparation method thereof | |
| CN103622909A (en) | Cardiolipin-containing new liposome preparation, and its application in antitumor drugs | |
| CN102525930A (en) | Lipoic acid liposome injection | |
| CN102626390B (en) | Gastrodin multiphase liposome injection | |
| CN109432009A (en) | A kind of cefpiramide sodium lipidosome and its preparation method and application | |
| CN102716089B (en) | Gemcitabine hydrochloride liposome injection | |
| JP5466174B2 (en) | Drug delivery system for administering water-soluble, cationic and amphiphilic pharmaceutically active substances | |
| CN102327236B (en) | Esomeprazole sodium liposome injection | |
| CN102188379A (en) | Preparation method of drug-carrying liposome | |
| MXPA05008284A (en) | Stable sterile filterable liposomal encapsulated taxane and other antineoplastic drugs. | |
| CN103040764B (en) | Bleomycin hydrocloride lipidosome injection | |
| CN109700782B (en) | High-drug-loading-rate disulfiram nanoparticles and application thereof in tumor prevention and treatment | |
| CN104546718B (en) | A kind of long circulating Rabeprazole liposome composition and its preparation method and application | |
| CN103040723B (en) | Xiyanping lipidosome injection | |
| CN103040751B (en) | Asarone lipidosome injection | |
| CN102309450B (en) | Doxycycline hydrochloride liposome injection | |
| CN102697720B (en) | Irinotecan hydrochloride lipid nanoparticles injection | |
| CN101822640B (en) | Sulbenicillin sodium liposome injection |
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 | ||
| ASS | Succession or assignment of patent right |
Owner name: HAINAN LINGKANG PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: HAINAN LIONCO PHARMACEUTICAL GROUP CO., LTD. Effective date: 20130926 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| C56 | Change in the name or address of the patentee |
Owner name: HAINAN LIONCO PHARMACEUTICAL GROUP CO., LTD. Free format text: FORMER NAME: HAINAN LINGKANG PHARMACEUTICAL CO., LTD. |
|
| CP01 | Change in the name or title of a patent holder |
Address after: 570216 No. 8 workshop, Haikou Free Trade Zone, Hainan Patentee after: Hainan Ling Kang Pharmaceutical Group Limited by Share Ltd. Address before: 570216 No. 8 workshop, Haikou Free Trade Zone, Hainan Patentee before: Hainan Lingkang Pharmaceutical Co.,Ltd. |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20130926 Address after: 570216 Hainan Province, Haikou city Jinpan Industrial Development Zone Industrial Village No. 3-6 building Patentee after: Hainan Lingkang Pharmaceutical Co.,Ltd. Address before: 570216 No. 8 workshop, Haikou Free Trade Zone, Hainan Patentee before: Hainan Ling Kang Pharmaceutical Group Limited by Share Ltd. |
|
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20130320 Termination date: 20160714 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |