CN106176608A - Pemetrexed disodium injection and preparation method thereof - Google Patents
Pemetrexed disodium injection and preparation method thereof Download PDFInfo
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- CN106176608A CN106176608A CN201610586902.7A CN201610586902A CN106176608A CN 106176608 A CN106176608 A CN 106176608A CN 201610586902 A CN201610586902 A CN 201610586902A CN 106176608 A CN106176608 A CN 106176608A
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- injection
- phospholipid
- pemetrexed disodium
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
Abstract
The present invention relates to injection of a kind of pemetrexed disodium and preparation method thereof, this injection contains pemetrexed disodium, neutral phospholipid, electrically charged phospholipid, cholesterol, antioxidant and suspending agent.The injection of the present invention has the distribution of suitable particle diameter, envelop rate height, good stability, it is possible to Targeting distribution, cancerous organ, improves the curative effect of pemetrexed disodium, decreases toxic and side effects.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, be specifically related to injection of a kind of pemetrexed disodium and preparation method thereof.
Background technology
Pemetrexed disodium (Pemetrexed disodium), chemical name be N-[4-[2-(2-amino-4,7-dihydro-
4-oxygen-1H-pyrrolo-[2,3-d] pyrimidine-5-alkyl) ethyl] benzoyl]-Pidolidone disodium.
Pemetrexed disodium is Mutiple Targets antifol, Lilly Co., Eli. be developed for treating tumor, combine suitable
Platinum can treat the malignant pleural mesothelioma that cannot perform the operation, and at present, pemetrexed disodium is in the world between sole therapy malignant pleural
The medicine of rind gall (MPM), is simultaneously used for Metastatic Nsclc second line treatment.Pemetrexed list medicine or combined chemotherapy are to many
Planting tumor and have obvious therapeutical effect, the especially patient to the past Endodontic failure, pemetrexed disodium brings new to them
Chance and hope.The less stable of pemetrexed disodium, easily degrades under high temperature, oxidizing condition, produces and may cause
The impurity of toxic and side effects, is not suitable for making the injection needing high temperature sterilize, thus pemetrexed disodium is usually made lyophilized powder
Injection, but the lyophilized injectable powder of existing pemetrexed disodium is during transport and storage, and also Chang Yinwei temperature controls not
Strictly impurity content in lyophilized injectable powder is caused substantially to increase.
Open a kind of pemetrexed disodium freeze-dried injection of CN102106833A and preparation method thereof, this pemetrexed disodium
Lyophilized injectable powder is made up of pemetrexed disodium and mannitol, the mass ratio of described mannitol and pemetrexed disodium be 0.6～
2.0∶1.CN101411710A discloses a kind of pemetrexed disodium freeze-dried injection and preparation method thereof, and this injectable powder is by pemetrexed
Disodium, mannitol and sodium sulfite composition, wherein raw materials quality part proportioning: pemetrexed disodium 50, mannitol 10～50, sulfurous
Acid sodium 0.1～1；The pH value of described pemetrexed disodium freeze-dried injection is 7.0～8.0.Sodium sulfite is conventional antioxygen
Agent, has stronger activity of invigorating blood circulation, has a certain impact principal agent.
In pharmaceutical carrier induction system, the research of liposome is relatively broad, and liposome has good targeting in vivo
Property and biocompatibility.As a kind of new medicinal preparation, Liposomal formulation has the advantage that (1) has slow releasing function: live
Property composition slowly discharge, delay renal excretion and metabolism, thus extend action time, improve mass effect；(2) medicine poison is reduced
Property；(3) increase the dissolubility of medicine, improve the quality of the pharmaceutical preparations；(4) there is targeting: the contained medicine of liposome is netted at liver, spleen
Endothelial system internal organs local maintains high concentration, thus plays medicine organ targeting effect；(5) have active pharmaceutical ingredient
Protective effect.
Along with the continuous progress of biotechnology, liposome preparation technology gradual perfection, liposome mechanism of action is explained further
Bright, liposome is suitable for vivo degradation, avirulence and non-immunogenicity, particularly great number tested data in addition proves liposome conduct
Pharmaceutical carrier can change medicine distribution in vivo, increases the medicine abundance at target organ, improves drug therapeutic indices, fall
Low drug toxicity and minimizing drug side effect, and reduce the advantages such as drug dose.
CN201210551378.1 discloses a kind of pemetrexed disodium lipidosome injection, and this lipidosome injection is by training
U.S. bent plug disodium, DSPG, dipalmitoyl phosphatidyl choline, PEG600, cholesterol and mannitol are made.Should
Lipidosome injection have liposomal particle size little and be evenly distributed, envelop rate is high, percolation ratio is low, good stability.Although
Pemetrexed disodium lipidosome injection disclosed in CN201210551378.1 has " internal release rate slows down, at body
In circulation, distribution time extends, and has reached part slow release effect, and bioavailability increases " technique effect, but still the most real
The effect of existing target administration.
Due to pemetrexed disodium injection and the deficiency of lipidosome injection, presently, there are pemetrexed disodium targeting to
The demand of medicine preparation.
Summary of the invention
For solving above-mentioned technical problem, it is an object of the invention to provide a kind of pemetrexed disodium lipid advantageously
Body injection.
The pemetrexed disodium lipidosome injection that the present invention provides contains pemetrexed disodium, neutral phospholipid, electrically charged
Phospholipid, cholesterol, antioxidant, optional containing suspending agent, the size controlling of liposome is at 100-150nm.
Described pemetrexed disodium and the mass ratio of neutral phospholipid are 0.01～0.2:1, electrically charged phospholipid and neutral phosphor
The mass ratio of fat is 0.01～0.4:1；Cholesterol and neutral phospholipid mass ratio are 0.1～0.3:1；Antioxidant and neutral phosphor lipid
Amount ratio is 0～0.02:1；Preferably pemetrexed disodium: electrically charged phospholipid: cholesterol: antioxidant: neutral phospholipid=0.1～0.2:
0.1～0.4:0.1～0.3: 0.01～0.02:1.Cholesterol can make liposome bilayers film solidify, thus reduces freedom
The generation of base, reduces oxidation level, makes liposome stability be obviously enhanced.In order to reduce the phospholipid forming liposome further
With the chemical degradation of liposome institute packaging medicine, antioxidant is by reacting with phospholipid peroxylradicals and the oxygen of quencher singlet state
Molecule and the bilayer to phospholipid are ranked up (such as the mobility of restricted lipid layer molecule) equimolecular mechanism and play it and resist
Oxidation.The antioxidant of the present invention is selected from vitamin E or vitamin C.
Further, described neutral phospholipid is Ovum Gallus domesticus Flavus lecithin, hydrogenated yolk lecithin, DSPC, big
Bean lecithin, hydrogenated soy phosphatidyl choline, DPPC or DMPC；
Described electrically charged phospholipid is electronegative phospholipid or positively charged phospholipid；Wherein negative charge phospholipid is selected from double nutmeg acid
Phosphatidyl glycerol, dilaurate phosphatidyl glycerol, double palmitic acid phosphatidyl glycerol, DSPG, double nutmeg
Acid phosphatidic acid, double stearic acid phosphatidic acid, dilaurate phosphatidic acid, double palmitic acid phosphatidic acid, double oleic acid Phosphatidylserine or double
Linoleic acid phosphatidylinositols one or more of which；
It is two palmityl phosphatidyl ethylaminos-1B, two oleic acid phosphatidyl silks that described positively charged phospholipid is selected from
In propylhomoserin, G 12S3P or 18-amine. one or more.The main lecithin selecting neutrality of liposome preparation at present, but
Affecting its drug effect owing to the particle diameter of the liposome containing lecithin can change during storing, the present invention adds in formula
Entering charged phospholipid can make liposomal particle size change during storing be reduced to minimum low degree.
The suspending agent that the present invention adds in formula is selected from carboxymethyl cellulose, methylcellulose or Polyethylene Glycol.Suspending
Agent is when Polyethylene Glycol, and the molecular weight of Polyethylene Glycol is 200 to 400, and preferably 300.The present invention is by adding suspending agent especially
It is preferred Liquid Macrogol, adds the viscosity of injection system, reduce the sedimentation velocity of microgranule, decrease between microgranule
Mutually assemble so that liposome stability is obviously enhanced.
Lipidosome injection of the present invention, mainly by pemetrexed disodium, DPPC, double stearic acid phosphorus
Phosphatidyl glycerol, cholesterol, vitamin E and Polyethylene Glycol composition.
Lipidosome injection of the present invention, preferably main by pemetrexed disodium, DPPC, double tristearin
Acid phosphatidyl glycerol, cholesterol, vitamin E and Liquid Macrogol composition.
The present invention also aims to provide the preparation method of a kind of pemetrexed disodium lipidosome injection, step is such as
Under:
(1) pemetrexed disodium, neutral phospholipid, electrically charged phospholipid, cholesterol and antioxidant are made lipid membrane；
(2) the aqueous solution aquation of suspending agent is added；
(3) homogenizing liposome is to required particle diameter and the uniformity；
(4) constant volume, degerming, subpackage.
More specifically, the preparation method step of pemetrexed disodium lipidosome injection is as follows:
1) pemetrexed or pemetrexed disodium liposome are prepared: select pemetrexed disodium, neutral phospholipid, charged according to formula
Lotus phospholipid, cholesterol and antioxidant are dissolved in methanol, mix homogeneously；With Rotary Evaporators, solvent under reduced pressure in solution is removed, shape
Become lipid membrane；2) add suspending agent aqueous solution aquation, hydration temperature typically between 30 DEG C-50 DEG C, obtain pemetrexed or
Pemetrexed disodium suspension；3) homogenizing liposome: aquation completely after with high pressure equal grain machine prepare liposome to required particle diameter and
The uniformity, the size controlling of liposome comes at 100-150nm, liposomal particle size and uniformity multi-angle nanoparticle analyzer
Detection；4) constant volume, degerming, subpackage, preservation: use water for injection constant volume；Pemetrexed or pemetrexed disodium liposome are suspended
Liquid micro-pore-film filtration is degerming, and subpackage gets product, and finished product can preserve to using at 2 DEG C-8 DEG C.
Pemetrexed disodium Liposomal formulation of the present invention control liposomal particle size is at 100-150nm, by water miscible training U.S.
Bent plug disodium is wrapped in lipid internal milieu, controls by controlling liposomal particle size so that the tumor group of selected liposomal
Blood vessel wall in knitting, is transported to lesions position medicine, reaches the purpose of target administration.Pemetrexed disodium liposome of the present invention
Preparation can significantly improve the curative effect of pemetrexed disodium by pemetrexed disodium Targeting distribution cancerous organ, decrease
Toxic and side effects.
The pemetrexed disodium lipidosome injection envelop rate of the present invention is high, good stability, and production technology is simple and reliable, keeps away
The related substance that has having exempted from production and the degraded generation of storing process pemetrexed disodium improves, and significantly relaxes pemetrexed disodium fat
The preservation condition of liposome injection.
Accompanying drawing explanation
Fig. 1 is the tissue distribution figure after rat intravenous injection 3mg/kg embodiment 2 pemetrexed disodium lipidosome injection
Specific embodiment
The following stated is only the certain preferred embodiments of the present invention, it is noted that for the common skill of the art
Art personnel, without departing from the inventive concept of the premise, it is also possible to make some improvements and modifications, these improvements and modifications also should
It is considered within the scope of protection of the present invention.
Embodiment 1
Preparation prescription
Preparation process is as follows:
Pemetrexed disodium, phospholipid, cholesterol and vitamin E is selected to be dissolved in mix homogeneously in methanol according to formula；Steam with rotating
Send out instrument methanol decompression in solution to be removed, form lipid membrane；PEG300 is dissolved in water for injection 10ml, and aquation lipid is thin
Film, hydration temperature is 40 DEG C, obtains pemetrexed disodium liposome suspension；Liposome is prepared with high pressure equal grain machine after aquation is complete
Being 130 ± 10nm to mean diameter, liposomal particle size and uniformity multi-angle nanoparticle analyzer detect；Use injection
Water constant volume to regulate concentration extremely be 2.0mg/ml solution, by pemetrexed disodium liposome suspension by 0.22 micron pore size
Micro-pore-film filtration is degerming, and subpackage gets product, and finished product can preserve at 2 DEG C-8 DEG C.
Embodiment 2
Preparation prescription
Preparation process is as follows:
Pemetrexed disodium, phospholipid, cholesterol and vitamin E is selected to be dissolved in mix homogeneously in methanol according to formula；Steam with rotating
Send out instrument methanol decompression in solution to be removed, form lipid membrane；PEG300 is dissolved in water for injection 10ml, and aquation lipid is thin
Film, hydration temperature is 30 DEG C, obtains pemetrexed disodium liposome suspension；Liposome is prepared with high pressure equal grain machine after aquation is complete
Being 120 ± 10nm to mean diameter, liposomal particle size and uniformity multi-angle nanoparticle analyzer detect；Use injection
Water constant volume to regulate concentration extremely be 2.0mg/ml solution, by pemetrexed disodium liposome suspension by 0.22 micron pore size
Micro-pore-film filtration is degerming, and subpackage gets product, and finished product can preserve at 2 DEG C-8 DEG C.
Embodiment 3
Preparation prescription
Preparation process is as follows:
Pemetrexed disodium, phospholipid, cholesterol and vitamin E is selected to be dissolved in mix homogeneously in methanol according to formula；Steam with rotating
Send out instrument methanol decompression in solution to be removed, form lipid membrane；PEG300 is dissolved in water for injection 10ml, and aquation lipid is thin
Film, hydration temperature is 50 DEG C, obtains pemetrexed disodium liposome suspension；Liposome is prepared with high pressure equal grain machine after aquation is complete
Being 110 ± 10nm to mean diameter, liposomal particle size and uniformity multi-angle nanoparticle analyzer detect；Use injection
Water constant volume to regulate concentration extremely be 2.0mg/ml solution, by pemetrexed disodium liposome suspension by 0.22 micron pore size
Micro-pore-film filtration is degerming, and subpackage gets product, and finished product can preserve at 2 DEG C-8 DEG C.
Embodiment 4
Preparation prescription
Preparation process is as follows:
Pemetrexed disodium, phospholipid, cholesterol is selected to be dissolved in mix homogeneously in methanol according to formula；With Rotary Evaporators by solution
The decompression of middle methanol removes, and forms lipid membrane；PEG300 is dissolved in water for injection 10ml, and aquation lipid membrane, hydration temperature
It is 30 DEG C, obtains pemetrexed disodium liposome suspension；Liposome is prepared to mean diameter with high pressure equal grain machine after aquation is complete
Being 120 ± 10nm, liposomal particle size and uniformity multi-angle nanoparticle analyzer detect；With water for injection constant volume and adjust
Joint concentration extremely is 2.0mg/ml solution, by the pemetrexed disodium liposome suspension micro-pore-film filtration of 0.22 micron pore size
Degerming, subpackage gets product, and finished product can preserve at 2 DEG C-8 DEG C.
Test example 1
Use through trachea puncture method, Non-small cell lung carcinoma H460SM cell be inoculated in the left lung of nude rat after radiation,
Build Non-small cell lung carcinoma orthotopic animal model.At random animal being divided into 5 groups, often group 8, male and female half and half, single is quiet respectively
Arteries and veins injection 3mg/kg experimental example two preparation pemetrexed disodium lipidosome injection, measure upon administration 0.25h, 2h, 8h,
In each Main Tissues of 24h and blood plasma, the concentration of pemetrexed disodium, evaluates its distribution situation, and scattergram is as shown in Figure 1.
Test example 2
The sample of embodiment of the present invention 1-4 is respectively placed under conditions of high temperature 40 DEG C, relative humidity 75% 6 months, is accelerated
Stability test is investigated, and investigates result and see table:
Claims (13)
1. an injection for pemetrexed, containing pemetrexed disodium, neutral phospholipid, electrically charged phospholipid, cholesterol and suspending
Agent；Optional, containing antioxidant.
Injection the most according to claim 1, it is characterised in that the size controlling of liposome is at 100-150nm.
Injection the most according to claim 1, it is characterised in that pemetrexed disodium: electrically charged phospholipid: cholesterol: anti-
Oxygen agent: neutral phospholipid=0.01～0.2:0.01～0.4:0.1～0.3: 0～0.02:1, preferably pemetrexed disodium: charged
Lotus phospholipid: cholesterol: antioxidant: neutral phospholipid=0.1～0.2:0.1～0.4:0.1～0.3: 0.01～0.02:1.
Injection the most according to claim 1, it is characterised in that described antioxidant is selected from vitamin E or vitamin C.
Injection the most according to claim 1, it is characterised in that described suspending agent is selected from carboxymethyl cellulose, methyl
Cellulose or Polyethylene Glycol.
Injection the most according to claim 1, it is characterised in that described suspending agent is Polyethylene Glycol, the most poly-second two
The molecular weight of alcohol is 200 to 400, preferably 300.
Injection the most according to claim 1, it is characterised in that described neutral phospholipid is selected from Ovum Gallus domesticus Flavus lecithin, hydrogenation
Ovum Gallus domesticus Flavus lecithin, DSPC, soybean lecithin, hydrogenated soy phosphatidyl choline, DPPC or double nutmeg
Acid lecithin.
Injection the most according to claim 1, it is characterised in that described electrically charged phospholipid is electronegative phospholipid or band
Positive charge phospholipid.
Injection the most according to claim 8, it is characterised in that wherein negative charge phospholipid is selected from double nutmeg acid phosphatidyls
Glycerol, dilaurate phosphatidyl glycerol, double palmitic acid phosphatidyl glycerol, DSPG, double nutmeg acid phospholipid
Stearic acid phosphatidic acid sour, double, dilaurate phosphatidic acid, double palmitic acid phosphatidic acid, double oleic acid Phosphatidylserine or dilinoleic acid
Phosphatidylinositols one or more of which；It is two palmityl phosphatidyl ethylamino-L-that described positively charged phospholipid is selected from
In lysine, two oleic acid Phosphatidylserine, G 12S3P or 18-amine. one or more.
Injection the most according to claim 1, it is characterised in that main by pemetrexed disodium, double palmitic acid ovum phosphorus
Fat, DSPG, cholesterol, vitamin E and Polyethylene Glycol composition.
11. injections according to claim 1, it is characterised in that main by pemetrexed disodium, double palmitic acid ovum phosphorus
Fat, DSPG, cholesterol, vitamin E and Liquid Macrogol composition.
12. injections according to claim 1, it is characterised in that be mainly made up of the composition of following weight proportion:
13. the preparation method according to the injection described in any one of claim 1～12, it is characterised in that comprise the following steps:
(1), pemetrexed disodium, neutral phospholipid, electrically charged phospholipid, cholesterol and antioxidant are made lipid membrane；
(2) the aqueous solution aquation of suspending agent, is added；
(3), homogenizing liposome is to required particle diameter and the uniformity；
(4), constant volume, degerming, subpackage.
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| CN201610586902.7A CN106176608A (en) | 2016-07-25 | 2016-07-25 | Pemetrexed disodium injection and preparation method thereof |
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| CN201610586902.7A CN106176608A (en) | 2016-07-25 | 2016-07-25 | Pemetrexed disodium injection and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109077997A (en) * | 2017-06-13 | 2018-12-25 | 佛山英特医药科技有限公司 | Pemetrexed disodium lipid complex and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103040748A (en) * | 2012-12-18 | 2013-04-17 | 海南百思特医药科技有限公司 | Pemetrexed disodium liposome injection |
| CN104546723A (en) * | 2015-02-11 | 2015-04-29 | 上海交通大学医学院附属新华医院 | Pemetrexed liposome and preparation method thereof |
-
2016
- 2016-07-25 CN CN201610586902.7A patent/CN106176608A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103040748A (en) * | 2012-12-18 | 2013-04-17 | 海南百思特医药科技有限公司 | Pemetrexed disodium liposome injection |
| CN104546723A (en) * | 2015-02-11 | 2015-04-29 | 上海交通大学医学院附属新华医院 | Pemetrexed liposome and preparation method thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109077997A (en) * | 2017-06-13 | 2018-12-25 | 佛山英特医药科技有限公司 | Pemetrexed disodium lipid complex and preparation method thereof |
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Application publication date: 20161207 |