CN108938572B - Entecavir-containing long-acting injection microsphere and preparation method thereof - Google Patents
Entecavir-containing long-acting injection microsphere and preparation method thereof Download PDFInfo
- Publication number
- CN108938572B CN108938572B CN201811131804.XA CN201811131804A CN108938572B CN 108938572 B CN108938572 B CN 108938572B CN 201811131804 A CN201811131804 A CN 201811131804A CN 108938572 B CN108938572 B CN 108938572B
- Authority
- CN
- China
- Prior art keywords
- entecavir
- plga
- preparation
- solution
- days
- 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.)
- Active
Links
Images
Classifications
-
- 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
-
- 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
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
- A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Virology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Molecular Biology (AREA)
- Biotechnology (AREA)
- Dermatology (AREA)
- Gastroenterology & Hepatology (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to a long-acting injection microsphere containing entecavir and a preparation method thereof. The preparation method of the long-acting injection microsphere containing entecavir comprises the following steps: adding the entecavir crushed by an air flow crusher into a PLGA solution to obtain an entecavir-PLGA suspension, rapidly dropping the suspension into a polyvinyl alcohol solution after ultrasonic and high-speed dispersion, shearing, stirring and emulsifying at 800-1500r/min for 3-5min, transferring into polyvinyl alcohol, magnetically stirring for 4-6h, sieving, collecting precipitates, and freeze-drying to obtain the microspheres. The entecavir-PLGA slow release microsphere in the prior art has the in vitro slow release time of only 20 days, the microsphere prepared by the invention releases in vitro drug for 60 days, releases in vivo drug for 6 weeks, maintains the effective blood concentration for 42 days, and is expected to be developed into a long-acting injection which is injected once every 42 days.
Description
Technical Field
The invention relates to a long-acting injection microsphere containing entecavir and a preparation method thereof.
Background
Entecavir is the first choice drug for treating chronic hepatitis B recommended in 2015 edition of guidelines for prevention and treatment of chronic hepatitis B, and the currently marketed dosage forms are oral liquid and tablets, and the recommended dosage of the tablets is 0.5mg once a day. The following 2 points are needed in the process of taking entecavir oral liquid and tablets:
1. eating reduced the peak drug concentration (Cmax) by 63% and the bioavailability (AUC)0-t) The decrease is 22%, and the peak time of the drug (Tmax) is delayed by 1.5h, so that the drug should be taken on an empty stomach (before or after meal at least2 hours);
2. in the using process, the medicine can not be stopped at will before the medicine stopping indication is not available, otherwise, the virus rebound is easy to happen.
Chronic hepatitis b is a disease that requires prolonged drug administration for maintenance therapy, but it has been reported that 63% of patients stop taking their drugs by themselves during the course of oral administration of antiviral drugs, and 57% of patients get worse. In the using process, the medicine can not be stopped at will before the medicine stopping indication is not available, otherwise, virus rebound is easy to generate after the medicine is stopped, approximately 8 percent of people have serious rebound symptoms, and jaundice and liver dysfunction metabolism disorder occur. Clinically, patients need to take the medicine on an empty stomach, and adverse reactions such as nausea, vomiting, abdominal pain, diarrhea, abdominal discomfort, dyspepsia and the like are aggravated.
Therefore, the safe and stable chronic hepatitis B antiviral drug is developed, so that the side effect of the gastrointestinal tract can be avoided, the probability of virus rebound is reduced, the action time of the drug is prolonged, the side effect is reduced, and the drug compliance of a patient is improved.
Disclosure of Invention
In view of the defects of the prior art, the application provides a preparation method of long-acting injection microspheres containing entecavir, which can prolong the drug release period.
A preparation method of entecavir-containing long-acting injection microspheres comprises the following steps: adding the entecavir subjected to airflow crushing into a PLGA solution to obtain an entecavir-PLGA suspension, rapidly dropping the suspension into a polyvinyl alcohol aqueous solution with the mass concentration of 0.5-2% after ultrasonic and high-speed dispersion, stirring and emulsifying for 3-5min at the speed of 800-1500r/min, rapidly transferring into the polyvinyl alcohol aqueous solution with the mass concentration of 0.1-0.5%, magnetically stirring for 4-6h, sieving, collecting, and freeze-drying to obtain the microspheres.
Preferably, the PLGA is: and the LA/GA is 50:50-85:15, and the viscosity of the PLGA is 0.15-0.80 dL/g.
Preferably, the weight ratio of entecavir to PLGA is 1: (5-10).
Preferably, the PLGA solution is PLGA-dichloromethane solution, and the mass concentration is 150-300 mg/mL.
Preferably, the volume ratio of the polyvinyl alcohol solution with the mass concentration of 0.5% -2% to the PLGA solution is 5:1-20: 1.
Preferably, the volume ratio of the polyvinyl alcohol solution with the mass concentration of 0.1-0.5% to the PLGA solution is 50:1-100: 1.
The application also provides a long-acting injection microsphere containing entecavir, which is prepared by adopting the preparation method.
Has the advantages that:
the entecavir microspheres are prepared by an S/W/O (solid in oil and water) process, an ultrasonic dispersion method is adopted in the preparation process, the particle size of the medicine is reduced, the aggregation of medicine particles is avoided, the solid medicine is uniformly dispersed in an oil phase, and the medicine release period is prolonged.
In the entecavir-PLGA sustained release microspheres in the prior art, the in vitro sustained release time is only 20 days, the microspheres prepared by the invention release in vitro for 60 days, the microspheres release in vivo for 6 weeks, and the microspheres can still maintain the effective blood concentration for 42 days, so that the entecavir-PLGA sustained release microspheres are expected to be developed into long-acting injection which is injected once every 42 days.
Drawings
FIG. 1 is a scanning electron micrograph of microspheres according to example 1 of the present invention.
FIG. 2 is a particle size distribution diagram of microspheres of example 1 of the present invention.
Fig. 3 is the in vitro release curve (n-3) of the microspheres of examples 1-6 of the present invention.
Figure 4 is the release profile in microspheres of examples 3-4 of the present invention (n-6).
Detailed Description
Example 1
The invention adopts S/W/O (solid in oil and water) technology to prepare entecavir microspheres, and the specific preparation method comprises the following steps:
weighing 4g of PLGA, dissolving in 20mL of dichloromethane, adding 0.4-0.8 g of entecavir subjected to jet milling to obtain an entecavir-PLGA suspension, and ultrasonically dispersing the suspension at a high speed, specifically 6500-10000/min for 3-5 min;
quickly dropping the entecavir-PLGA dispersion solution into a 1% polyvinyl alcohol (PVA) aqueous solution, stirring and emulsifying for 3-5min at a speed of 1000r/min, quickly transferring into 0.1% PVA, magnetically stirring for 4-6h to remove dichloromethane, collecting washing balls by a 1000-sand 1200-mesh sieve, and freeze-drying to obtain the finished product of entecavir microspheres.
The method has the advantages that the entecavir is subjected to airflow pulverization and then added into the PLGA solution, and the airflow pulverization can reduce the particle size of the entecavir, so that the particle size of the entecavir is optimal to be 1-5 microns; meanwhile, the entecavir particles with the particle size of 1-5 microns are easy to aggregate and precipitate in the process of dispersing into the PLGA solution, and the problem is solved by adopting an ultrasonic and high-speed dispersion method; entecavir is slightly soluble in water and almost insoluble in dichloromethane, and needs to be crushed into smaller particle size on the premise of keeping the crystal form unchanged; in conclusion, the method overcomes the great difficulty in exploring the process for preparing the entecavir microspheres, thereby effectively increasing the encapsulation efficiency and the drug-loading rate of the microspheres.
After the entecavir-PLGA suspension is subjected to ultrasonic high-speed dispersion, the entecavir-PLGA suspension is quickly dropped into a polyvinyl alcohol aqueous solution with the mass concentration of 1 percent, the entecavir particles can be uniformly dispersed into the PLGA solution through ultrasonic high-speed dispersion, and aggregation or precipitation of the uniformly dispersed entecavir particles can be prevented through quick dropping.
And (3) observing the microsphere form:
10mg of the entecavir microspheres prepared in example 1 were uniformly dispersed on a conductive gel, and after gold spraying at 10Kv, the microspheres were observed by scanning electron microscopy (SEM, Coxem, korea) for appearance, and the microspheres obtained in this study were round in shape and smooth in surface, and the observation results are shown in fig. 1.
Testing the particle size distribution:
200mg of entecavir microspheres prepared in example 1 were dispersed in a laser particle sizer (MALVERN, Mastersizer 2000), and the particle size distribution of the microspheres was determined as shown in FIG. 2, wherein D (10) was 54.386 μm, D (50) was 91.273 μm, D (90) was 150.696 μm, D [3,2] was 84.213 μm, Span: 1.055.
Examples 2-6, the preparation was the same as in example 1. The differences are only the type and viscosity of PLGA, as shown in table 1.
TABLE 1 type and viscosity of PLGA for examples 1-6
Remarking: in PLGA models, 5050, 6535, and 8515 indicate that lactic acid/glycolic acid (LA/GA) in the polymer material is 50:50, 65: 35, 85:15, A represents that the polymer is terminated with carboxyl, E represents that the polymer is terminated with ester.
And (3) determining the drug loading and encapsulation efficiency:
high performance liquid chromatography conditions: a chromatographic column: c18 column (200 mm. times.4.6 mm, 5 μm), mobile phase: methanol: water 20:80, detection wavelength: 254nm, flow rate: 1.0 mL/min-1Column temperature: 40 ℃, sample introduction: 100 μ L.
Accurately weighing 10mg of the entecavir microspheres prepared in the embodiment 1, adding a proper amount of dichloromethane to dissolve PLGA, extracting the entecavir by using a mobile phase, measuring the peak area by HPLC, and calculating the drug loading rate and the encapsulation rate according to the following formulas:
the drug loading capacity (%) is equal to the weight of the drug in the microsphere/the total weight of the microsphere multiplied by 100 percent
The encapsulation ratio (%) < actual drug loading/theoretical drug loading x 100%
The average drug loading and encapsulation efficiency results for microspheres prepared according to examples 1-6 are shown in Table 2.
TABLE 2 average drug loading and encapsulation efficiency results for microspheres from examples 1-6
In vitro drug release experiments:
an appropriate amount of entecavir microspheres prepared in examples 1-6 are placed in 50ml of phosphate buffer solution with pH7.4, shaken in a shaking table at 37 ℃ at 50r/min, sampled every other day for 1h, 6h, 24h and 2-60 days respectively, and supplemented with an equal amount of buffer solution, and the release curve of the drug determined by high performance liquid chromatography is shown in figure 3.
Rat in vivo drug release experiments:
the entecavir is orally administered to adults once a day at a dose of 0.5mg for each time, with reference to the clinical dose. The total dose was 21mg administered for 6 consecutive weeks. The dosage of the rat is about 7 times of that of the human body by weight, and the equivalent dosage of the rat is 2.25mg/kg of body weight by 6-week dosage conversion. A certain amount of entecavir microspheres prepared in the embodiment 3-4 are weighed, added with 1% CMC-Na solution, shaken and mixed evenly to prepare a suspension, and the suspension is injected into SD rats (male, 200 +/-20 g, 4-5 weeks old) through hind leg muscles, and the obtained in vivo drug release curve is shown in figure 4.
The invention develops safe and stable entecavir long-acting microsphere injection, the in vitro drug release can reach 60 days (2 months), and the rat in vivo drug release experiment proves that: effective blood levels were still monitored in rats after 6 weeks (42 days) of injection. The long-acting injection microsphere can avoid gastrointestinal side effects, reduce the probability of virus rebound, prolong the action time of the medicine, reduce side effects, reduce the administration frequency and improve the medication compliance of patients.
The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The above-described embodiments of the invention are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims, and not by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
Claims (7)
1. A preparation method of entecavir-containing long-acting injection microspheres is characterized by comprising the following steps:
adding the entecavir subjected to airflow crushing into a PLGA-dichloromethane solution to obtain an entecavir-PLGA suspension, rapidly dropping the suspension into a polyvinyl alcohol aqueous solution with the mass concentration of 1% after ultrasonic and high-speed dispersion, stirring and emulsifying for 3-5min at 1500-.
2. The method of claim 1, wherein the PLGA is: and the LA/GA is 50:50-85:15, and the viscosity of the PLGA is 0.15-0.80 dL/g.
3. The preparation method of claim 2, wherein the weight ratio of entecavir to PLGA is 1: (5-10).
4. The method of claim 3, wherein the PLGA-dichloromethane solution has a mass concentration of 150-300 mg/mL.
5. The method according to claim 4, wherein the volume ratio of the 0.5-2% by mass polyvinyl alcohol solution to the PLGA solution is 5:1 to 20: 1.
6. The method according to claim 5, wherein the ratio of the 0.1-0.5% by mass polyvinyl alcohol solution to the PLGA solution is 50:1 to 100:1 by volume.
7. Long-acting injection microsphere containing entecavir, which is prepared by the preparation method of claim 6.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811131804.XA CN108938572B (en) | 2018-09-27 | 2018-09-27 | Entecavir-containing long-acting injection microsphere and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811131804.XA CN108938572B (en) | 2018-09-27 | 2018-09-27 | Entecavir-containing long-acting injection microsphere and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108938572A CN108938572A (en) | 2018-12-07 |
| CN108938572B true CN108938572B (en) | 2021-04-20 |
Family
ID=64472560
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811131804.XA Active CN108938572B (en) | 2018-09-27 | 2018-09-27 | Entecavir-containing long-acting injection microsphere and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108938572B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109549932A (en) * | 2018-12-29 | 2019-04-02 | 四川制药制剂有限公司 | A kind of preparation method of Fosaprepitant freeze drying powder injection |
| CN113081952A (en) * | 2021-04-12 | 2021-07-09 | 山东谷雨春生物科技有限公司 | Long-acting injection gel containing entecavir |
| CN113398063A (en) * | 2021-06-27 | 2021-09-17 | 烟台大学 | Long-acting injection microsphere gel containing meloxicam and preparation method thereof |
| CN113398096A (en) * | 2021-06-27 | 2021-09-17 | 烟台大学 | Long-acting injection microsphere containing meloxicam and preparation method thereof |
| CN114903859A (en) * | 2022-06-07 | 2022-08-16 | 烟台大学 | Letrozole microsphere preparation and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101583351B1 (en) * | 2014-11-28 | 2016-01-07 | 동국제약 주식회사 | Sustained-release microspheres enhancing removal rate of residual solvent and method of manufacturing thereof |
| CN105722503A (en) * | 2013-08-06 | 2016-06-29 | 东国制药株式会社 | Entecavir microspheres and pharmaceutical composition for parenteral administration containing same |
| CN106822039A (en) * | 2017-01-24 | 2017-06-13 | 广州帝奇医药技术有限公司 | Shipwreck is molten or microsolubility pharmaceutical sustained release compositions and preparation method thereof |
-
2018
- 2018-09-27 CN CN201811131804.XA patent/CN108938572B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105722503A (en) * | 2013-08-06 | 2016-06-29 | 东国制药株式会社 | Entecavir microspheres and pharmaceutical composition for parenteral administration containing same |
| KR101583351B1 (en) * | 2014-11-28 | 2016-01-07 | 동국제약 주식회사 | Sustained-release microspheres enhancing removal rate of residual solvent and method of manufacturing thereof |
| CN106822039A (en) * | 2017-01-24 | 2017-06-13 | 广州帝奇医药技术有限公司 | Shipwreck is molten or microsolubility pharmaceutical sustained release compositions and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| "恩替卡韦-PLGA缓释微球的处方优化及体外释药研究";林凤云等;《中国药房》;20161231;第27卷(第25期);第3549-3552页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108938572A (en) | 2018-12-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108938572B (en) | Entecavir-containing long-acting injection microsphere and preparation method thereof | |
| Bhalekar et al. | Formulation and characterization of solid lipid nanoparticles for an anti-retroviral drug darunavir | |
| DE60222160T2 (en) | COMPOSITIONS COMPRISING PROPERTIES OF IMMEDIATE RELEASE AND CONTROLLED RELEASE | |
| TWI354568B (en) | Insoluble drug particle compositions with improved | |
| CN109078006B (en) | Medicinal preparation of palbociclib and preparation method thereof | |
| AU2014227473B2 (en) | A Novel Formulation of Metaxalone | |
| US20150313857A1 (en) | Novel Formulation of Naproxen | |
| TW200403079A (en) | Nanoparticulate fibrate formulations | |
| SG175314A1 (en) | A novel formulation of diclofenac | |
| JP2016514707A (en) | Abiraterone acetate preparation | |
| WO2011134369A1 (en) | Pharmaceutical composition for improving solubility of prasugrel and its preparation method | |
| CN102958515A (en) | Fexofenadine microcapsules and compositions containing them | |
| CN101283982B (en) | Fenofibrate nanometer suspension and preparation method thereof | |
| WO2018108163A1 (en) | Talazoparib pharmaceutical composition and applications thereof | |
| Gazi et al. | Preparation and evaluation of paracetamol solid lipid nanoparticle by hot homogenization method | |
| CN114681406B (en) | Carilazine long-acting slow-release microsphere and preparation method thereof | |
| CN101810586B (en) | L-dopa methyl ester sustained-release microsphere composite and preparation method thereof | |
| CN112121028B (en) | Simvastatin solid nanoparticle preparation and preparation method thereof | |
| CN109419771B (en) | Testosterone undecanoate sustained-release pharmaceutical composition, and preparation method and application thereof | |
| CN1194683C (en) | Silymarin behenic acid glyceride lipid nano particle oral solution dosage and its preparation method | |
| CN111557914A (en) | Pharmaceutical composition containing ereoxib | |
| CN107157956B (en) | Skeleton type progesterone sustained release microspheres, preparation method thereof and progesterone sustained release injection | |
| CN103356506A (en) | Solid lipid nanoparticles of alendronate sodium and preparation method thereof | |
| CN115068427B (en) | Artemisinin B microsphere capable of being slowly released for 7 days and 14 days and preparation method thereof | |
| KR20170110285A (en) | Erlotinib nanoparticles and a method for preparing the same, and a pharmaceutical composition containing Erlotinib nanoparticles |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |