CN109077997B - Pemetrexed disodium lipid compound and preparation method thereof - Google Patents
Pemetrexed disodium lipid compound and preparation method thereof Download PDFInfo
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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
- A61K47/24—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
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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
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
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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
- A61K9/1277—Processes for preparing; Proliposomes
Abstract
The invention discloses a pemetrexed disodium lipid complex suitable for administration by inhalation and a preparation method thereof. The compound comprises pemetrexed disodium, lipid materials, buffer solution and the like; the lipid complex may comprise one or more lipids. In addition, the ratio of pemetrexed disodium to lipid in the complex is also disclosed. The pemetrexed disodium lipid complex prepared by the invention can be combined with a pharmaceutically acceptable carrier or any medicament formula to prevent or treat related diseases, and has the characteristics of good stability, strong targeting property, low toxic and side effects and the like. The preparation method provided by the invention is simple, strong in operability and easy to realize industrial production.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a pemetrexed disodium lipid complex suitable for inhalation administration or other administration modes and a preparation method thereof.
Background
The pemetrexed disodium structurally contains a pyrrole pyrimidine group, so that the pemetrexed disodium can destroy the folic acid dependent normal metabolic process in cells and inhibit cell replication, thereby having the effect of inhibiting tumor growth. At present, pemetrexed disodium is widely used for combined cisplatin to treat Malignant Pleural Mesothelioma (MPM) clinically, is also used for second-line treatment of metastatic non-small cell lung cancer, and has obvious treatment effect on other various tumors by adopting single medicine or combined chemotherapy.
At present, pemetrexed disodium is prepared into injection for treating related tumors, and the injection comprises common injection and liposome injection. The liposome injection has sustained release effect, and can prolong the distribution time of the medicine in systemic circulation and increase the bioavailability. CN201210551378.1 discloses a pemetrexed disodium liposome injection, which is mainly prepared from pemetrexed disodium, distearoyl phosphatidyl glycerol, dipalmitoyl phosphatidyl choline, PEG600, cholesterol and mannitol; in addition, CN201610586902.7 discloses a pemetrexed disodium liposome injection with targeting effect, which mainly comprises pemetrexed disodium, neutral phospholipid, charged phospholipid, cholesterol, antioxidant and suspending agent, and the injection can selectively enter tumor tissue to exert effect by controlling liposome particle size, thereby achieving the purpose of targeted drug delivery.
In summary, the currently available pemetrexed disodium liposome is only suitable for injection administration, but is suitable for administration by inhalation, and the like, and a pemetrexed disodium lipid complex capable of achieving targeted administration by inhalation has not been applied in clinical treatment. The pemetrexed disodium lipid complex provided by the invention can enable a medicament to directly reach lung parts and other parts to play a role in an inhalation mode, and has the characteristics of stability, slow release, high encapsulation rate and uniform active medicament distribution on the basis of direct targeting effect.
Summary of The Invention
The present invention aims to provide a novel pemetrexed disodium lipid complex suitable for administration by inhalation and a method of preparing to form the novel complex.
The present invention provides a complex comprising a lipid and pemetrexed disodium embedded therein, the lipid complex comprising one or more lipids, wherein the weight ratio of pemetrexed disodium to lipid is 1. The one or more lipids may include DPPC, or cholesterol, or both DPPC and cholesterol. For example, the one or more lipids can comprise 55-100mol% DPPC and 0-45mol% cholesterol, further for example 55-70mol% DPPC and 30-45mol% cholesterol, and further, the one or more lipids can comprise E80, or SPC3.
The invention also provides a preparation method of the pemetrexed disodium lipid complex, which comprises the following steps: (a) Dissolving pemetrexed disodium in an aqueous medium to prepare a pemetrexed disodium solution; (b) mixing the pemetrexed disodium solution with the lipid solution; (c) forming a complex at a first temperature; (d) Subsequently forming a composite at a second temperature lower than the first temperature; and (e) filtering using a membrane or molecular sieve having a selective function for the molecular weight size of the substance to remove unencapsulated pemetrexed drug and retain the desired lipid complex. Also, the preparing step further comprises continuing to repeat steps (c) and (d) for one or more cycles. In the preparation process, step (c) is generally carried out by heating and step (d) by cooling. In an alternative embodiment, the cycle begins with a cooling step, transitions to a heating step, and repeats these three steps. According to the method, a pemetrexed disodium solution may be prepared by dissolving pemetrexed disodium in an aqueous medium, and a lipid solution may be prepared by dissolving a lipid material in one or more organic solvents including anhydrous ethanol; the pemetrexed disodium solution is then mixed with the lipid solution. In an alternative embodiment, the aqueous medium is normal saline.
The invention also provides another preparation method of the pemetrexed disodium lipid complex, which comprises the following steps: (a) Dissolving pemetrexed disodium in an aqueous medium to prepare a pemetrexed disodium solution; (b) Fully mixing the pemetrexed disodium solution and the lipid solution; (c) Removing the organic solvent from the suspension obtained in the step (b) under reduced pressure; and (e) filtering using a membrane or molecular sieve having a selective function for the molecular weight of the substance to remove unencapsulated pemetrexed disodium drug, leaving the desired pemetrexed disodium lipid complex. Step (b) of the preparation process requires thorough mixing of the two-phase solution, and in alternative embodiments, thorough mixing of the two-phase solution is achieved by shaking and bath ultrasound. According to the method, a pemetrexed disodium solution may be prepared by dissolving pemetrexed disodium in an aqueous medium, and a lipid solution may be prepared by dissolving a lipid material in one or more organic solvents including chloroform. In an alternative embodiment, the aqueous medium in which the pemetrexed disodium is dissolved is physiological saline.
The invention further provides a pharmaceutical formulation of the pemetrexed disodium lipid complex prepared according to the method of the invention. The formulation includes a pharmaceutically acceptable carrier or diluent or delivery means suitable for inhalation or the like to a patient.
Disclosure of Invention
The present invention includes a novel pemetrexed disodium lipid complex in which the ratio of pemetrexed disodium to lipid is high. The weight ratio of pemetrexed disodium to lipid in the present invention is between 1; or preferably, the weight ratio of pemetrexed disodium to lipid is between 1; or more preferably, the weight ratio of pemetrexed disodium to lipid is between 1.
The preparation method of the pemetrexed disodium lipid complex suitable for being administrated by an inhalation mode, which is described by the invention, comprises the following characteristics: dissolving pemetrexed disodium in water-containing medium such as normal saline, phosphate Buffer Solution (PBS), ammonium sulfate solution or isotonic glucose solution to obtain pemetrexed disodium solution; heating lipid material, dissolving in water-soluble organic solvent such as ethanol and methanol to obtain lipid solution; stirring and injecting the pemetrexed disodium solution preheated to the temperature above the phase transition temperature of the lipid material into the lipid solution to obtain a lipid compound suspension; removing free pemetrexed disodium by ultrafiltration, dialysis or Sephadex column to obtain pemetrexed disodium lipid complex.
The preparation method of the pemetrexed disodium lipid complex comprises the steps of mixing a pemetrexed disodium solution with a lipid solution and subjecting the complex formed after mixing to one or more cycles at two separate temperatures.
As can be determined by routine experimentation, in some cases the appropriate temperature to be used in the process may vary depending on the lipid mixture used in the process.
The test results clearly show that pemetrexed disodium is entrapped during lipid vesicle formation. The results further show that the physical state of pemetrexed disodium is solid or bound to lipids, since pemetrexed disodium concentration is higher than the solubility limit. The results further show that freezing of the mixture is not required in the process, but cooling to a temperature above freezing can produce better results. The results further show that the embedding effect is similar for 1 cycle of cooling and heating and for 3 cycles of embedding, which demonstrates that 1 cycle of temperature treatment is sufficient to achieve a preferred level of embedding.
Another process for the preparation of the pemetrexed disodium lipid complex suitable for administration by inhalation described in the present invention comprises the following features: dissolving pemetrexed disodium in water-containing medium such as normal saline, isotonic glucose solution or Phosphate Buffer Solution (PBS) to obtain pemetrexed disodium solution; dissolving lipid material in one or more organic solvents including chloroform to obtain lipid solution; then fully mixing the pemetrexed disodium solution and the lipid solution by methods of shaking, water bath ultrasound and the like; placing the obtained suspension in a rotary evaporator to evaporate the organic solvent to dryness; removing free pemetrexed disodium by ultrafiltration, dialysis or Sephadex column to obtain pemetrexed disodium lipid complex.
The method of thoroughly mixing the two phases employed in the method is not limited to the method of shaking and water bath ultrasound employed in the present invention, as can be determined by routine experimentation; the method of evaporating the organic solvent is not limited to the rotary evaporation method used in the embodiment of the present invention.
In the method, the lipid material is dissolved in chloroform to form a lipid solution, the aqueous phase solution in which the pemetrexed disodium is dissolved is added, and then the two-phase solution forms a water-in-oil type emulsion, and the ultrasonic treatment is adopted to ensure that the emulsification is more sufficient and the emulsion is more uniform, thereby being beneficial to the formation of a lipid compound.
The pemetrexed disodium lipid complex prepared by the two methods has high drug-to-lipid ratio. The formulation may be adapted for inhalation or other modes of administration.
The lipids used in the present invention may be synthetic, semi-synthetic or naturally occurring lipids including phospholipids, vitamin E, sterols, fatty acids, glycolipids, anionic lipids, cationic lipids. The phospholipids can include lecithin (EPC), phosphatidylglycerol (EPG), phosphatidylinositol (EPI), phosphatidylserine (EPS), phosphatidylethanolamine (EPE), and phosphatidic acid (EPA); soybean phospholipids (SPC, SPG, SPS, SPI, SPE and SPA); hydrogenated lecithin and soya lecithin (HEPC, HSPC); and other phospholipids and corresponding phosphatidic acids consisting of ester bonds of fatty acids containing 12-26 carbon atoms in positions 2 and 3 of glycerol and different head groups (including choline, glycerol, inositol, serine, ethanolamine) in position 1 of glycerol. These fatty acid chains may be saturated or unsaturated, and the phospholipids may be composed of fatty acids of varying chain lengths and varying degrees of unsaturation. In particular, the complex of the formulation may comprise DPPC, the main component of naturally occurring lung surfactants. In addition, lipids also include myristoylphosphatidylcholine (DMPC), dimyristoylphosphatidylglycerol (DMPG), dipalmitoylphosphatidylcholine (DPPC), dipalmitoylphosphatidylglycerol (DPPG), distearoylphosphatidylcholine (DSPC), distearoylphosphatidylglycerol (DSPG), dioleoylphosphatidylcholine (PSPC), palmitoylstearoylglycerol (PSPG), triacylglycerol, diacylglycerol, sphingosine, sphingomyelin, and monoacylphospholipids such as mono-oleoyl-phosphatidylethanolamine (MOPE).
The results of the invention further show that both preparation processes can be scaled up while improving the efficiency of embedding pemetrexed disodium. Thus, the invention further provides a method for supplying 200mLS or more, or 800LS or more (suitably a small increase) suitable for total administration. All other things being equal, it is believed that higher volume production is generally easier to achieve than small scale production to increase encapsulation efficiency. If such a volume is used for administration, the volume can be reduced to make it suitable for storage.
The results further show that the stability of lipid-embedded pemetrexed disodium prepared by the method of the present invention can be maintained for more than one year due to minimal leakage. The uniqueness of the formulation further shows that pemetrexed disodium is entrapped in the lipid complex structure and is not easily leaked.
Examples
Example 1
Weighing 12mg of pemetrexed disodium, dissolving in 3ml of normal saline, heating for dissolving, and keeping the temperature at 60 ℃ for later use; then respectively weighing 60mg of DPPC and 24mg of cholesterol in 300ul of absolute ethanol, heating and dissolving to prepare lipid solution, and keeping the temperature at 60 ℃ for later use; injecting the pemetrexed disodium solution which is kept at the constant temperature of 60 ℃ into the lipid solution under stirring, slowly stirring for 2 hours at the constant temperature of 60 ℃, and then slowly cooling to the room temperature. And obtaining pemetrexed disodium lipid complex suspension. And removing the free pemetrexed disodium by a dialysis method to obtain the pemetrexed disodium lipid complex solution. The encapsulation efficiency after removing the free drug is 95%, and the average particle size is 250nm.
Example 2
Weighing 12mg of pemetrexed disodium, dissolving in 3ml of normal saline, heating for dissolving, and keeping the temperature at 60 ℃ for later use; then respectively weighing 60mg of DPPC and 24mg of cholesterol in 300ul of absolute ethyl alcohol, heating and dissolving to prepare lipid solution, and keeping the temperature at 60 ℃ for later use; injecting the pemetrexed disodium solution which is kept at the constant temperature of 60 ℃ into the lipid solution under stirring, slowly stirring for 2 hours at the constant temperature of 60 ℃, then slowly cooling to 10 ℃, heating to 55 ℃, repeatedly heating and cooling for 3 times, and then cooling to room temperature. Obtaining pemetrexed disodium lipid complex suspension. And removing the free pemetrexed disodium by a dialysis method to obtain the pemetrexed disodium lipid complex solution. The encapsulation efficiency after removing the free drug is 97%, and the average size of the particle size is 280nm.
Example 3
Weighing 4mg of pemetrexed disodium, dissolving in 1ml of physiological saline, and mixing uniformly to prepare a pemetrexed disodium solution for later use; weighing 20mg of DPPC and 8mg of cholesterol, and dissolving in 3ml of chloroform to obtain lipid solution; adding the prepared pemetrexed disodium solution into the lipid solution, shaking for 10min, performing ultrasonic treatment in water bath for 10min, and performing rotary evaporation at 25 deg.C under a vacuum degree of 200mbar and a rotation speed of 40rpm until the organic solvent in the mixed solution is evaporated to dryness; adding 1ml of normal saline, washing thoroughly, and mixing well. Obtaining pemetrexed disodium lipid complex suspension. And removing the free pemetrexed disodium by a dialysis method to obtain the pemetrexed disodium lipid complex solution. The encapsulation efficiency after removing the free drug is 95%, and the average particle size is 270nm.
Example 4
Weighing 2.3mg of pemetrexed disodium, dissolving in 2ml of water, and mixing uniformly to prepare a pemetrexed disodium solution for later use; then 5mg of E80 is weighed and dissolved in 3ml of chloroform; adding 1ml of prepared pemetrexed disodium solution into E80 chloroform solution, vortexing for 10min, performing water bath ultrasound for 5min, and then performing rotary evaporation at 25 ℃ for 1h at a vacuum degree of 200mbar and a rotating speed of 50rpm until organic solvent in the mixed solution is evaporated to dryness; adding 1ml of water, washing thoroughly, and mixing. And removing the free pemetrexed disodium by a dialysis method to obtain the pemetrexed disodium lipid complex solution. The encapsulation efficiency after removal of free drug was 93%.
Example 5
Weighing 2.3mg of pemetrexed disodium, dissolving in 2ml of water, and mixing to obtain a pemetrexed disodium solution for later use; then 5mg of SPC3 is weighed and dissolved in 3ml of chloroform; adding 1ml of prepared pemetrexed disodium solution into an SPC3 chloroform solution, swirling for 10min, performing water bath ultrasound for 5min, and then performing rotary evaporation at the rotation speed of 150mbar and 30rpm at 25 ℃ for 1h until organic solvent in the mixed solution is evaporated to dryness; adding 1ml water, washing thoroughly, and mixing. And removing the free pemetrexed disodium by a dialysis method to obtain the pemetrexed disodium lipid complex solution. The encapsulation efficiency after removal of free drug was 90%.
While the invention has been described with emphasis upon preferred embodiments, it will be obvious to those of ordinary skill in the art that variations of the preferred apparatus and methods may be used and that variations other than those described herein may be attempted. Accordingly, this invention includes all modifications encompassed within the spirit and scope of the following claims.
Claims (28)
1. A complex consisting of one or more lipids selected from dipalmitoylphosphatidylcholine and cholesterol in a ratio of 55-70%:30-45% of mixed lipid; the complex is suitable for administration by inhalation; wherein the weight ratio of the pemetrexed disodium to the one or more lipids is from 1 to 7 to 1;
the preparation method of the compound is a preparation method A or a preparation method B, wherein the preparation method A comprises the following steps: (a) Dissolving pemetrexed disodium in normal saline or water to prepare a pemetrexed disodium solution, and dissolving one or more lipids in absolute ethanol or methanol to prepare a solution of one or more lipids; (b) Mixing a pemetrexed disodium solution with a solution of one or more lipids; (c) Forming a composite at a first temperature of 55 degrees Celsius to 60 degrees Celsius; (d) Subsequently forming a composite at a second temperature of 10 degrees Celsius to room temperature, the first temperature and the second temperature having a temperature difference of 25 degrees Celsius or more; and (e) removing unencapsulated pemetrexed disodium using dialysis methods, retaining the complex in need; wherein steps (c) and (d) are effective to increase the encapsulation efficiency of pemetrexed disodium;
the preparation method B comprises the following steps: (a) Dissolving pemetrexed disodium in normal saline or water to prepare a pemetrexed disodium solution, and dissolving one or more lipids in chloroform to prepare a solution of one or more lipids; (b) Thoroughly mixing the pemetrexed disodium solution with one or more lipid solutions; (c) Removing the organic solvent from the suspension obtained in the step (b) under reduced pressure; and (e) removing unencapsulated pemetrexed disodium using a dialysis procedure, leaving the complex in need.
2. The complex of claim 1, wherein the weight ratio of pemetrexed disodium to the one or more lipids is from 1.
3. The complex of claim 1, wherein said preparation method a further comprises repeating steps (c) and (d) for one or more further cycles to obtain said complex with a high encapsulation efficiency.
4. The composition of claim 1, wherein in Process B, the solution of pemetrexed disodium and the solution of one or more lipids are mixed thoroughly by shaking or sonication in a water bath.
5. The composite according to claim 1, wherein the reduced pressure in step (c) in the preparation method B is 50 to 350mbar.
6. The composite according to claim 5, wherein the reduced pressure condition in step (c) in the preparation method B is a vacuum degree of 100mbar to 300mbar.
7. The composite according to claim 6, wherein the reduced pressure in step (c) in the preparation method B is 150 to 250mbar.
8. The composite according to claim 1, wherein in the preparation method B, the method for removing the organic solvent under reduced pressure in the step (c) adopts a rotary evaporation method.
9. The compound of claim 8, wherein in the preparation method B, the temperature for removing the organic solvent by rotary evaporation in the step (c) is 10 to 45 ℃.
10. The composite of claim 9, wherein the temperature for removing the organic solvent by rotary evaporation in step (c) in the preparation method B is 15 to 40 ℃.
11. The composite of claim 10, wherein the temperature for removing the organic solvent by rotary evaporation in step (c) in the preparation method B is 20 to 35 ℃.
12. The composite according to claim 8, wherein in the preparation method B, the rotation speed of the rotary evaporation in the step (c) is 10rpm to 100rpm.
13. The composite according to claim 12, wherein in the preparation method B, the rotation speed of the rotary evaporation in the step (c) is 10rpm to 80rpm.
14. The composite according to claim 13, wherein in the preparation method B, the rotation speed of the rotary evaporation in the step (c) is 10rpm to 60rpm.
15. A complex consisting of one or more lipids selected from the group consisting of pharmaceutical egg yolk lecithin or hydrogenated soy lecithin, and pemetrexed disodium entrapped therein; the complex is suitable for administration by inhalation; wherein the weight ratio of the pemetrexed disodium to the one or more lipids is from 1 to 1;
the preparation method of the compound comprises the following steps: (a) Dissolving pemetrexed disodium in normal saline or water to prepare a pemetrexed disodium solution, and dissolving one or more lipids in chloroform to prepare a solution of one or more lipids; (b) Thoroughly mixing the pemetrexed disodium solution with one or more lipid solutions; (c) Removing the organic solvent from the suspension obtained in step (b) under reduced pressure; and (e) removing unencapsulated pemetrexed disodium using dialysis methods, leaving the complex in need.
16. The complex of claim 15, wherein the weight ratio of pemetrexed disodium to the one or more lipids is from 1.
17. The composition of claim 15, wherein the means for intimately mixing the solution of pemetrexed disodium with the solution of one or more lipids is shaking or water bath sonication.
18. The composite according to claim 15, wherein the reduced pressure condition of step (c) means that the vacuum degree is 50mbar to 350mbar.
19. The compound of claim 18, wherein the reduced pressure condition of step (c) is a vacuum degree of 100mbar to 300mbar.
20. The composite of claim 19, wherein the reduced pressure condition of step (c) is a vacuum degree of 150mbar to 250mbar.
21. The compound according to claim 15, wherein the organic solvent is removed under reduced pressure in step (c) by rotary evaporation.
22. The composite of claim 21, wherein the temperature at which the organic solvent is removed by rotary evaporation in step (c) is from 10 to 45 degrees celsius.
23. The composite of claim 22, wherein the temperature at which the organic solvent is removed by rotary evaporation in step (c) is 15 to 40 degrees celsius.
24. The compound of claim 23, wherein the temperature at which the organic solvent is removed by rotary evaporation in step (c) is from 20 to 35 degrees celsius.
25. The composite of claim 21, wherein the rotational speed of the rotary evaporation in step (c) is 10rpm to 100rpm.
26. The composite of claim 25, wherein the rotational speed of the rotary evaporation of step (c) is 10rpm to 80rpm.
27. The compound of claim 26, wherein the rotational speed of the rotary evaporation of step (c) is from 10rpm to 60rpm.
28. A pharmaceutical composition comprising the complex of any one of claims 1-27 and a pharmaceutically acceptable carrier.
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| CN104546723B (en) * | 2015-02-11 | 2017-07-18 | 上海交通大学医学院附属新华医院 | A kind of pemetrexed liposome and preparation method thereof |
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Effective date of registration: 20220224 Address after: 510005 floor 5, building 4C, phase II, standard industrial unit, No. 9, helix 4th Road, International Biological Island, Guangzhou, Guangdong Applicant after: Enkang Pharmaceutical Technology (Guangzhou) Co.,Ltd. Applicant after: FOSHAN INTELGEN PHARMACEUTICALS Co.,Ltd. Address before: 528000 4th floor, building B, group I, Guangdong biomedical industry base, Xianxi section, national highway 321, Shishan town, Foshan City, Guangdong Province Applicant before: FOSHAN INTELGEN PHARMACEUTICALS Co.,Ltd. Applicant before: INTELGEN (GUANGZHOU) Ltd. |
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