CN104825405A - Liraglutide multi-emulsion microsphere and preparation method thereof - Google Patents
Liraglutide multi-emulsion microsphere and preparation method thereof Download PDFInfo
- Publication number
- CN104825405A CN104825405A CN201510239616.9A CN201510239616A CN104825405A CN 104825405 A CN104825405 A CN 104825405A CN 201510239616 A CN201510239616 A CN 201510239616A CN 104825405 A CN104825405 A CN 104825405A
- Authority
- CN
- China
- Prior art keywords
- emulsion
- glp
- arg34lys26
- glutamyl
- palmitoyl
- 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
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
The invention relates to liraglutide multi-emulsion microspheres and a preparation method thereof. The liraglutide multi-emulsion microspheres comprise components, namely polylactic acid-glycolic acid copolymer PLGA and polyving alcohol PVA. The preparation method comprises the following steps: dissolving liraglutide freeze-dried powder by using a natrium aceticum solution so as to obtain an internal water phase, performing ultrasonic mixing with the dichloromethane solution of PLGA, stirring so as to obtain primary emulsion, dropping the primary emulsion into the PVA solution, stirring so as to obtain multi-emulsion, stirring, centrifuging, collecting microspheres, washing, and performing freeze-drying, thereby obtaining multi-emulsion microspheres, wherein the ratio of V internal water phase to V oil phase is 1:100, and the ratio of V oil phase to V external water phase is 1:20. The multi-emulsion microspheres provided by the invention have the characteristics of slow and continuous blood sugar reduction, the medicine effect of liraglutide wrapped by the microspheres can last as long as 30 days, the treatment effect of the medicine of a same dosage is greatly better than that of a medicine which is injected every day, and thus very good practical values can be achieved.
Description
Technical field
The invention belongs to Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] and preparation field thereof, particularly a kind of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] emulsion microsphere and preparation method thereof.
Background technology
Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] is gone on the market in July, 2009, and it mainly by gene recombination technology, utilizes people's glicentin-1 (GLP-1) analog of yeast production, by 39 amino acid whose polypeptide, and molecular formula: C
172h
265n
43o
51; Molecular weight: 3751.20Da, current Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] is mainly used in improving the glycemic control using metformin and undesirable 2 diabeticss of sulfonylureas, Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] is a kind of GLP-1 analog, with people GLP-1, there is the sequence homology of 97%, can in conjunction with and activate GLP-1 receptor, GLP-1 itself is a kind of glucagon sample tire, does not have blood sugar reducing function, but it can promote the release of insulin, finally reach the effect of blood sugar lowering.
As a kind of novel material, Poly(D,L-lactide-co-glycolide (poly (lactic-co-glycolic acid, PLGA) be polymerized at random by two kinds of monomer-lactic acid and hydroxyacetic acid, lactic acid and hydroxyacetic acid are degradable functional polymer organic compound, there is the performance of good biocompatibility, nontoxic, good encystation and film forming, be widely used in pharmacy, medical engineering material and modernization industrial circle.At U.S. PLGA by FDA certification, formally included into American Pharmacopeia as pharmaceutic adjuvant.
Polyvinyl alcohol is a kind of organic compound, white plates, cotton-shaped or pulverulent solids, tasteless, water-soluble, be insoluble to gasoline, kerosene, vegetable oil, benzene, toluene, dichloroethanes, carbon tetrachloride, acetone, ethyl acetate, methanol, ethylene glycol etc., be slightly soluble in dimethyl sulfoxide.Polyvinyl alcohol is important industrial chemicals, for the manufacture of Pioloform, polyvinyl acetal, resistance to gasoline pipeline and vinylon synthetic fibers, fabric-treating agent, emulsifying agent, paper coating, binding agent, glue etc.
Because the pharmacokinetics of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in human body and pharmacodynamic characteristics are all applicable to dosage regimen once a day.But subcutaneous administration once a day brings a lot of inconvenience to patient, also bring great body and mind to patient painful simultaneously, conventional slow releasing preparation therefore whether can be utilized to improve the action time of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37], reduce the frequency injection of patient.Retrieval is both at home and abroad about long-acting hypoglycemic medicine and patent show: much with the long lasting drug formulations that PLGA makes, but does not also have bibliographical information about long-acting the current of hypoglycemic medicine Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] research.Utilize PLGA and PVA making emulsion microsphere can expand PLGA emulsion microsphere further and quote scope clinical medical.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] emulsion microsphere and preparation method thereof, and the method is simple to operate, reaction condition is gentle, and the Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] emulsion microsphere charging ratio that PLGA and PVA makes is high, and has the characteristic of long-acting release property.
A kind of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] emulsion microsphere, described emulsion microsphere comprises: Poly(D,L-lactide-co-glycolide PLGA and PVAC polyvinylalcohol.
The molecular weight of described PLGA is 13KD, PVA is PVA-217.
A preparation method for Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] emulsion microsphere, comprising: take Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] lyophilized powder, dissolves as interior aqueous phase by sodium acetate solution, then mix with the dichloromethane solution of PLGA is ultrasonic, obtain colostrum after stirring, colostrum is added drop-wise in PVA aqueous solution, stir, obtain emulsion, stir, collected after centrifugation microsphere, washing, lyophilization, obtains emulsion microsphere; Wherein, with the dichloromethane solution of PLGA for oil phase, be outer aqueous phase with PVA aqueous solution, in V, aqueous phase/V oil phase is the outer aqueous phase of 1:100, V oil phase/V is 1:20.
Described preparation method can complete at normal temperatures.
The described ultrasonic time is 5min.
The mass fraction of described PVA aqueous solution is 2%.
The mixing speed of described emulsion is 1200r/min, and the time is 4h.
Described microsphere distilled water wash three times.
The described cryodesiccated time is 24h.
The diameter of described emulsion microsphere is within 10 μm.
Described emulsion microsphere can not bring any discomfort sense through lumbar injection.
Described emulsion microsphere is used for medical industry as long-acting hypoglycemic medicine.
beneficial effect
(1) preparation method of the present invention is simple to operate, experiment condition is gentle;
(2) the Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] microsphere drug useful load of making of the present invention is high, can long-acting slow-release, and stablizes in vivo, and its catabolite does not have toxic and side effects in vivo, has clinical value from now on.
Accompanying drawing explanation
Fig. 1 is the SEM picture of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] emulsion microsphere in embodiment 1;
Fig. 2 is the grain size distribution of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] emulsion microsphere in embodiment 2;
Fig. 3 is the In-vitro release curves of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] emulsion microsphere in embodiment 2;
Fig. 4 is the change of blood sugar of type 2 diabetes mellitus rat before injection Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] emulsion microsphere of different group in embodiment 3;
Fig. 5 is that the type 2 diabetes mellitus rat of different group is in the change of blood sugar of injection Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] emulsion microsphere after 5 days;
Fig. 6 is that the type 2 diabetes mellitus rat of different group is in the change of blood sugar of injection Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] emulsion microsphere after 10 days;
Fig. 7 is that the type 2 diabetes mellitus rat of different group is in the change of blood sugar of injection Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] emulsion microsphere after 15 days;
Fig. 8 is that the type 2 diabetes mellitus rat of different group is in the change of blood sugar of injection Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] emulsion microsphere after 20 days;
Fig. 9 is that the type 2 diabetes mellitus rat of different group is in the change of blood sugar of injection Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] emulsion microsphere after 25 days;
Figure 10 is that the type 2 diabetes mellitus rat of different group is in the change of blood sugar of injection Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] emulsion microsphere after 30 days;
Detailed description of the invention
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.In addition should be understood that those skilled in the art can make various changes or modifications the present invention, and these equivalent form of values fall within the application's appended claims limited range equally after the content of having read the present invention's instruction.
Embodiment 1
The making of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] emulsion microsphere.
(1) take the Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] lyophilized powder of 10mg, dissolve as interior aqueous phase by the sodium acetate solution that mass fraction is 1%, being that the dichloromethane solution (50mL) of the PLGA of 2% is ultrasonic with mass fraction mixes, ultrasonic 5 minutes obtained colostrums.
(2) be in 2%PVA aqueous solution by the colostrum fast drop made to mass fraction, homogenizer high-speed stirred (1200r/min) obtains emulsion, continues to stir 4h, collected by centrifugation microsphere, distilled water wash three times, lyophilization 24h and get final product, SEM figure as shown in Figure 1.
Embodiment 2
The release in vitro of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] microsphere measures.
(1) Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] microsphere 20mg in precise embodiment 1, is suspended in 10mmolL
-1pH 7.4 phosphate buffer is (containing 0.01% sodium azide and 5mmolL
-1sDS),
(2) shake in shaking bath, speed 100rpm, temperature 37 DEG C, take out centrifuge tube in the centrifugal 10min of 4000rpm every 1d, take out whole supernatant, measure the content of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] with HPLC and measure, result as shown in Figure 3.
Embodiment 3
In the body of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] emulsion microsphere, blood sugar lowering is observed.
(1) foundation of type 2 diabetes mellitus rat animal model, give high lipid food feeding and within 6 months, set up type 2 diabetes mellitus rat model, high lipid food by the Adeps Sus domestica of 10%, the egg albumen powder of 18.9%, the normal diet of 70%, the cholesterol of 1% and 0.1% sodium cholate form.
(2) in experiment start the 0th, measure rat blood sugar before 5,10,15,20,25,30 day morning, Rat Fast 12h before measurement, tail venous blood sampling, carries out blood sugar detection by three promise blood glucose meter, observe the blood glucose feature within rat, as shown in Figure 5-10.Give rat Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] microsphere (preparing in embodiment 1) lumbar injection afterwards, injection volume is 9mg; Mice fasting 12h before administration, observes each group of change of blood sugar situation upon administration in 6h, as shown in Figure 5-10.In figure, CG refers to blank group rat, HFG finger print type control rats, LLG refers to microsphere low dose group rat (6mg is every kg rat body weight monthly), LMG refers to dosage group rat in microsphere (12mg is every kg rat body weight monthly), LHG refers to microsphere high dose group rat 24mg monthly every kg rat body weight, and LCIG refers to common Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] injection group.
Claims (9)
1. an Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] emulsion microsphere, is characterized in that, described emulsion microsphere comprises: Poly(D,L-lactide-co-glycolide PLGA and PVAC polyvinylalcohol.
2. a kind of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] emulsion microsphere according to claim 1, is characterized in that, the molecular weight of described PLGA is 13KD, PVA is PVA-217.
3. a preparation method for Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] emulsion microsphere, comprising: take Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] lyophilized powder, dissolves as interior aqueous phase by sodium acetate solution, then mix with the dichloromethane solution of PLGA is ultrasonic, obtain colostrum after stirring, colostrum is added drop-wise in PVA aqueous solution, stir, obtain emulsion, stir, collected after centrifugation microsphere, washing, lyophilization, obtains emulsion microsphere; Wherein, with the dichloromethane solution of PLGA for oil phase, be outer aqueous phase with PVA aqueous solution, in V, aqueous phase/V oil phase is the outer aqueous phase of 1:100, V oil phase/V is 1:20.
4. the preparation method of a kind of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] emulsion microsphere according to claim 3, it is characterized in that, the described ultrasonic time is 5min.
5. the preparation method of a kind of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] emulsion microsphere according to claim 3, is characterized in that, the mass fraction of described PVA aqueous solution is 2%.
6. the preparation method of a kind of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] emulsion microsphere according to claim 3, is characterized in that, the mixing speed of described emulsion is 1200r/min, and the time is 4h.
7. the preparation method of a kind of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] emulsion microsphere according to claim 3, is characterized in that, described microsphere distilled water wash three times.
8. the preparation method of a kind of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] emulsion microsphere according to claim 3, it is characterized in that, the described cryodesiccated time is 24h.
9. the preparation method of a kind of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] emulsion microsphere according to claim 3, it is characterized in that, the diameter of described emulsion microsphere is within 10 μm.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510239616.9A CN104825405B (en) | 2015-05-12 | 2015-05-12 | A kind of Liraglutide emulsion microballoon and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510239616.9A CN104825405B (en) | 2015-05-12 | 2015-05-12 | A kind of Liraglutide emulsion microballoon and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104825405A true CN104825405A (en) | 2015-08-12 |
| CN104825405B CN104825405B (en) | 2018-08-03 |
Family
ID=53803875
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510239616.9A Expired - Fee Related CN104825405B (en) | 2015-05-12 | 2015-05-12 | A kind of Liraglutide emulsion microballoon and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104825405B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106177916A (en) * | 2016-07-15 | 2016-12-07 | 东华大学 | A kind of long-acting glucose-sensitive LBL self-assembly porous microsphere and preparation method thereof |
| CN111870582A (en) * | 2020-06-28 | 2020-11-03 | 苏州天微肽生物医药科技有限公司 | Ethyl orthosilicate-liraglutide composite microsphere preparation and preparation method and application thereof |
| CN112159698A (en) * | 2020-09-15 | 2021-01-01 | 中建材中岩科技有限公司 | Environment-friendly shield tail sealing grease and preparation method thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102085355A (en) * | 2011-01-27 | 2011-06-08 | 蚌埠丰原涂山制药有限公司 | Liraglutide long-acting microsphere injection and preparation method thereof |
| CN103142488A (en) * | 2011-12-16 | 2013-06-12 | 深圳市健元医药科技有限公司 | GLP-I analogue liraglutide sustained-release microspheres and preparation method thereof |
| CN103893744A (en) * | 2012-12-24 | 2014-07-02 | 杭州九源基因工程有限公司 | Pharmaceutical preparation for treating diabetes and preparation method thereof |
| CN104382860A (en) * | 2014-10-30 | 2015-03-04 | 浙江美华鼎昌医药科技有限公司 | Liraglutide sustained-release microsphere preparation and preparation method thereof |
| CN104434817A (en) * | 2014-09-17 | 2015-03-25 | 黑龙江泰华源生物技术有限责任公司 | Sustained release microsphere preparation for injection of liraglutide |
-
2015
- 2015-05-12 CN CN201510239616.9A patent/CN104825405B/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102085355A (en) * | 2011-01-27 | 2011-06-08 | 蚌埠丰原涂山制药有限公司 | Liraglutide long-acting microsphere injection and preparation method thereof |
| CN103142488A (en) * | 2011-12-16 | 2013-06-12 | 深圳市健元医药科技有限公司 | GLP-I analogue liraglutide sustained-release microspheres and preparation method thereof |
| CN103893744A (en) * | 2012-12-24 | 2014-07-02 | 杭州九源基因工程有限公司 | Pharmaceutical preparation for treating diabetes and preparation method thereof |
| CN104434817A (en) * | 2014-09-17 | 2015-03-25 | 黑龙江泰华源生物技术有限责任公司 | Sustained release microsphere preparation for injection of liraglutide |
| CN104382860A (en) * | 2014-10-30 | 2015-03-04 | 浙江美华鼎昌医药科技有限公司 | Liraglutide sustained-release microsphere preparation and preparation method thereof |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106177916A (en) * | 2016-07-15 | 2016-12-07 | 东华大学 | A kind of long-acting glucose-sensitive LBL self-assembly porous microsphere and preparation method thereof |
| CN111870582A (en) * | 2020-06-28 | 2020-11-03 | 苏州天微肽生物医药科技有限公司 | Ethyl orthosilicate-liraglutide composite microsphere preparation and preparation method and application thereof |
| CN111870582B (en) * | 2020-06-28 | 2022-03-18 | 苏州天微肽生物医药科技有限公司 | Ethyl orthosilicate-liraglutide composite microsphere preparation and preparation method and application thereof |
| CN112159698A (en) * | 2020-09-15 | 2021-01-01 | 中建材中岩科技有限公司 | Environment-friendly shield tail sealing grease and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104825405B (en) | 2018-08-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102085355B (en) | Liraglutide long-acting microsphere injection and preparation method thereof | |
| RU2586306C2 (en) | Risperidone sustained release microsphere composition | |
| CN102120781B (en) | Preparation and application of novel oral insulin nanoparticles | |
| JP2015502939A (en) | Microspheres for controlled or sustained release of medication | |
| CN101658496A (en) | Exenatide release microsphere preparation, preparation method and application thereof | |
| KR102507678B1 (en) | Aripiprazole sustained-release microspheres and preparation method thereof | |
| CN114601918B (en) | Glucose-responsive insulin microneedle patch and preparation method thereof | |
| CN102688195B (en) | Preparation method for doxorubicin hydrochloride-entrapped chitosan carboxymethyl chitosan nanometer controlled-release particle with pH sensibility | |
| CN100415221C (en) | Method for preparing curcumin lyophilized liposome | |
| Yang et al. | Preparation, characterization and in vivo evaluation of pH‐sensitive oral insulin‐loaded poly (lactic‐co‐glycolicacid) nanoparticles | |
| CN104825405A (en) | Liraglutide multi-emulsion microsphere and preparation method thereof | |
| CN102188756A (en) | Preparation method of medicated slow-release degradable bone scaffold | |
| CN102657871B (en) | Oral slow release preparation, entrapment material and preparation method | |
| CN103417957B (en) | Exenatide slow release sustained release microsphere, and preparation method and preparation thereof | |
| CN101612111B (en) | Sustained-release microsphere of nomegestrol acetate of analogs thereof and preparation method and application thereof | |
| WO2023116517A1 (en) | Continuous delivery preparation capable of being stably released and preparation method therefor | |
| CN113893333B (en) | Insulin slow-release oral patch and preparation method and application thereof | |
| JP2017511371A (en) | Exenatide-containing composition and method for producing the same | |
| CN102293748B (en) | Oral PEGylated insulin pH-sensitive naonparticle and preparation method thereof | |
| CN102188391B (en) | Method for preparing granulocyte-macrophage colony stimulating factor microsphere | |
| CN104117056A (en) | Placental growth factor loaded nano-particle, as well as preparation method and application thereof | |
| CN102652736A (en) | Method for preparing soybean isoflavone sustained-release microspheres | |
| CN101797234A (en) | Pramlintide acetate slow release microballoon preparation and preparation method thereof | |
| CN101947206B (en) | Method for preparing recombinant pancreotropic hormone secretion peptide medicament microspheres | |
| CN103191059A (en) | Neostigmine bromide muhivescular liposome and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| EXSB | Decision made by sipo to initiate substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20180803 Termination date: 20210512 |