CN106074376A - A kind of glucagon-like peptide 1 slow release nanometer formulation, preparation method and application - Google Patents
A kind of glucagon-like peptide 1 slow release nanometer formulation, preparation method and application Download PDFInfo
- Publication number
- CN106074376A CN106074376A CN201610476511.XA CN201610476511A CN106074376A CN 106074376 A CN106074376 A CN 106074376A CN 201610476511 A CN201610476511 A CN 201610476511A CN 106074376 A CN106074376 A CN 106074376A
- Authority
- CN
- China
- Prior art keywords
- glp
- peptide
- glucagon
- slow release
- nanometer formulation
- 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.)
- Pending
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/26—Glucagons
-
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Zoology (AREA)
- Endocrinology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Dispersion Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention provides a kind of glucagon-like peptide 1 (GLP 1) slow release nanometer formulation and synthetic method thereof.Glucagon-like peptide 1 (GLP 1) in this nano controlled-release preparation refers to human glucagon-like-peptide 1(GLP 1 (7 37) OH) or human glucagon-like-peptide 1(GLP 1 (7 36) NH2), this nano controlled-release preparation is made up of DSPE Polyethylene Glycol (DSPE PEG).Obtain having GLP 1 durative action preparation of longer pharmacological action time by preparing the nano controlled-release preparation of GLP 1, such that it is able to be applied to the treatment of diabetes and obesity.Glucagon-like peptide 1 (GLP 1) the slow release nanometer formulation preparation of the present invention is simple, and the biological stability of glucagon-like peptide 1 is greatly improved, and the half-life significantly extends, and bioavailability is high.
Description
Technical field
The present invention relates to a kind of glucagon-like-peptide-1 (GLP-1) slow release nanometer formulation and application thereof.
Background technology
Diabetes (diabetes mellitus, DM) are that one is due to defect of insulin secretion and/or insulin action barrier
Hinder the caused metabolic disease being characterized with hyperglycemia.Diabetes are a kind of global high morbidities, according to World Health Organization (WHO)
Prediction, is up to 300,000,000 to whole world diabetics in 2025, and the recent report on Epidemiological of China shows, China
Diabetes prevalence is up to 9.7%, far above the average prevalence 6.4% in the whole world, estimates by this prevalence, China patient of diabetes patient
Number is more than 90,000,000, i.e. China's diabetes number of patients accounts for the 1/3 of whole world diabetes number, and it is latent to there is also about 1.5 hundred million
Risk of diabetes crowd.Diabetes are broadly divided into 1 type and type 2 diabetes mellitus, the latter account for diabetics sum 90% with
On.Type 2 diabetes mellitus (Type 2 Diabetes Mellitus, T2DM) is mainly due to islet beta cell function obstacle and islets of langerhans
Element opposing and cause, and along with the development of the course of disease, type 2 diabetes mellitus be usually associated with islet beta cell function damage until
Apoptosis.Owing to many type 2 diabetes mellitus patients are simultaneously with overweight or fat, exploitation has blood sugar lowering and the medicine of fat-reducing dual function
Thing, becomes the important topic that current researcher is paid close attention to.
It is mainly insulin treatment currently for the treatment means of type 1 diabetes, and the clinical treatment means of type 2 diabetes mellitus
Mainly use orally-taken blood sugar reducing medicine.But, oral diabetes drug has a lot of defect in treatment type 2 diabetes mellitus disease, its
The deficiency of middle maximum be cannot the cause of disease of reverting diabetes, i.e. " take stopgap measures and do not know this ", for beta Cell of islet growth, break up, increase
Grow without obvious effect.Additionally, most of oral hypoglycaemic medicines have effect of gain, this makes overweight or obese diabetic patients
Treatment more challenge.
Glucagon-like-peptide-1 (glucagon like peptide-1, GLP-1) is the one of Intestinal L cells secretion
Many peptides incretin, it mainly has GLP-1 (7-37)-OH and GLP-1 (7-36)-NH2Two kinds of existence forms.Pancreas
Glucagon protogene, at pancreas and intestinal L cell inner expression, generates the Proglucagon being made up of 160 aminoacid
(proglucagon, PG), the product that Proglucagon converts after cracking in pancreas with intestinal is different.PG is main in intestinal
It is cracked into: enteroglucagon (Glicentin:PG 1-69), enteroglucagon molecule continues to be cracked into oxyntomodulin
(Oxyntomodulin: PG 33-69)；Insert peptide-2 (IP-2:PG 111-123)；Glucagon-like-peptide-2 (GLP-2:
PG 126-158)；With GLP-1 (1-37)-OH (PG 72-108).GLP-1 (1-37)-OH is inactive peptide chain, needs enzymolysis to cut
Except N end 6 peptide, the aminoacid sequence becoming GLP-1 (7-37)-OH, GLP-1 (the 7-37)-OH with physiologically active is His-
Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-
Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-
Gly-Arg-Gly-COOH, its C-terminal Gly can be as the substrates of amidating enzyme, the C-terminal amidatioon of GLP-1 (7-37)-OH
Rear generation GLP-1 (7-36)-NH2。GLP-1(7-36)-NH2Being native form main for GLP-1 in human body, account for 80%, it promotees
The effect entering insulin secretion is the strongest.Additionally GLP-1 (7-37)-OH accounts for 20%, and both have identical physiological function.
GLP-1 has the insulin secretion accelerating characteristic of glucose dependency, it is to avoid in clinical diabetes treatment, patient is normal
The danger producing hypoglycemia existed.It addition, GLP-1 has protection beta Cell of islet and promotes the spy of beta Cell of islet propagation
Property, can fundamentally improve the symptom of type 2 diabetes mellitus patient, additionally, GLP-1 can be by appetite-suppressing and delay gastric emptying
Losing weight, this becomes the overweight or new way of obese type 2 diabetes mellitus for the treatment of.Therefore, exploitation GLP-1 is as a kind of glycosuria
Sick and Bariatric medicine has good prospect.
But, natural GLP-1 can be lost biological living by DPP IV (DPP-IV) excision N-terminal dipeptides in vivo
Property, also can quickly be filtered elimination by kidney simultaneously, its Half-life in vivo only has about two minutes, therefore natural GLP-1 is difficult to obtain
Clinical practice.It is therefore desirable to we carry out structure of modification to GLP-1, or prepare its durative action preparation, to extend the half of GLP-1
Decline the phase so that it is the treatment of diabetes and obesity can be applied to.
Summary of the invention
The present invention relates to a kind of glucagon-like-peptide-1 (GLP-1) slow release nanometer formulation (GLP-1-SSM), hard by two
What fatty acyl group PHOSPHATIDYL ETHANOLAMINE-Polyethylene Glycol (DSPE-PEG) was formed nano-micelle, wrap up GLP-1, it is to avoid GLP-1
Kidney quickly filter and enzymes metabolism inactivation, and significantly extend half-life and in vivo bioactivity action time.
A kind of glucagon-like-peptide-1 (GLP-1) slow release nanometer formulation, is made up of substrate and medicine, it is characterised in that
Substrate is DSPE-PEG (DSPE-PEG, molecular weight 2000～10000), and medicine is that pancreas is high
Blood glucose element sample peptide-1, the mol ratio of substrate and medicine is between 50:1 to 150:1.
Further, glucagon-like-peptide-1 is GLP-1 (7-37)-OH or GLP-1 (7-36)-NH2。
Glucagon-like-peptide-1 (GLP-1) slow release nanometer formulation that the present invention provides, it is possible to by promoting the α of GLP-1
Spiral improves the biological activity of GLP-1, it can be made should not to be filtered by kidney and by two internal peptidyls by slow release simultaneously
Peptidase IV (DPP-IV) is degraded, thus significantly extends the half-life of GLP-1.By the preparation of nanometer formulation, the blood plasma of GLP-1 half
The phase of declining has reached 48 more than h, relatively prototype GLP-1(half-life 2min) increase significantly, thus overcome GLP-1 and must hold
Continuous intravenous drip or continuous subcutaneous infusion could produce the defect of curative effect.
It addition, glucagon-like-peptide-1 (GLP-1) slow release nanometer formulation that the present invention provides is used for reducing internal blood glucose
When concentration and body weight, the longest existing plasma half-life (48 more than h), there is again significant blood sugar lowering and fat-reducing effect.
Invention further provides the preparation method of glucagon-like-peptide-1 (GLP-1) slow release nanometer formulation, operation
Step is as follows:
The first step: be dissolved in appropriate normal saline by the DSPE-PEG of 100 or 150 parts moles, 37 DEG C of temperature under the conditions of lucifuge
Apply 2-3 hour, form blank micelle；
Second step: be dissolved in appropriate normal saline by the glucagon-like-peptide-1 (GLP-1) of 1 or 2 parts moles, adds first
In the solution of step, both continue at 37 DEG C of temperature and apply 1-2 hour after mix homogeneously；
3rd step: second step solution is placed in-20 DEG C of stopped reaction, is then placed in quick-freezing 5-10 minute in liquid nitrogen by solution；
4th step: be placed in freeze dryer by the solution after the 3rd step liquid nitrogen flash freezer, is not added with any freeze drying protectant, direct lyophilizing 48
Hour, obtain glucagon-like-peptide-1 (GLP-1) slow release nanometer formulation.
Further, above-mentioned glucagon-like-peptide-1 is GLP-1 (7-37)-OH or GLP-1 (7-36)-NH2。
A kind of glucagon-like-peptide-1 (GLP-1) slow release nanometer formulation can be applicable to prepare diabetes medicament or appetrol
Thing.
It is an advantage of the current invention that:
1, a kind of glucagon-like-peptide-1 (GLP-1) slow release nanometer formulation proposed, can not only improve the biological of GLP-1 and live
Property, it is also possible to protection GLP-1 filters and DPP-IV zymolysis from kidney, thus significantly improves the biological half-life of GLP-1,
The GLP-1 biological action time has reached more than 48 hours, extends blood sugar lowering and antiobesity action time greatly.
2, the DSPE-PEG (DSPE-PEG) that this nanometer formulation is used, due to it
Good biocompatibility and biological degradability, be approved by the FDA in the United States and used as medicine macromolecular material.Even more important
It is that polypeptide wraps up through DSPE-PEG, it is possible to reduce the immune prototype of polypeptide, thus reduce the immunoreactive generation of people.
The preparation process of glucagon-like-peptide-1 (GLP-1) slow release nanometer formulation 3, involved in the present invention is simple, no
Needing complicated preparation process, decrease the generation of impurity in preparation process, meanwhile, this nanometer formulation is owing to employing DSPE-
PEG, as substrate, need not when lyophilizing add freeze drying protectant, it is easy to accomplish automatization, large-scale, this makes it be more suitable for
Industrialized production
Therefore glucagon-like-peptide-1 (GLP-1) slow release nanometer formulation that the present invention provides, easily preparation, synthesis cycle are short, no
Needing purification, production cost is low, be prone to industrial automation produces.Glucagon-like-peptide-1 (GLP-1) slow release prepared
Nanometer formulation, is suitable as treating diabetes and the active ingredient of antiobesity agents.
Accompanying drawing explanation
Fig. 1 is that GLP-1 Yu GLP-1-SSM temperature in blood plasma applies degraded figure.
Fig. 2 is GLP-1-SSM Yu Exenatide abdominal cavity carbohydrate tolerance experiment blood glucose figure in kunming mice body.
Fig. 3 is that GLP-1-SSM Yu Exenatide single-dose in db/db model mice body is repeatedly to sugar abdominal cavity sugar
Tolerance test blood glucose figure.
Fig. 4 is GLP-1-SSM Yu the Exenatide food-intake at long-term treatment experiment small mouse.
Fig. 5 is GLP-1-SSM Yu the Exenatide body weight evolution at long-term treatment experiment small mouse.
Detailed description of the invention
The present invention combines the following example and accompanying drawing is specifically described.
Embodiment 1
The synthesis of glucagon-like-peptide-1 (GLP-1) slow release nanometer formulation
(1) synthesis of blank micelle
Weigh 0.056 g DSPE-PEG (DSPE-PEG2000), it is dissolved in 2 ml's
In normal saline, under the conditions of lucifuge, 37 DEG C of temperature are applied 2 hours, to form blank micelle.
(2) configuration of GLP-1 solution
Weigh 0.7 mg GLP-1, be dissolved in the normal saline of 2 ml, store stand-by.
(3) synthesis of GLP-1 slow release nanometer formulation (GLP-1-SSM)
Being added in blank micellar solution by GLP-1 solution, under the conditions of lucifuge, 37 DEG C of temperature are applied 2 hours, and temperature is applied after terminating, rapidly
Using liquid nitrogen flash freezer solution, quick-freezing is direct lyophilizing 36 h after terminating, and is not added with any freeze drying protectant, obtains GLP-1-SSM.
Embodiment 2
GLP-1 and glucagon-like-peptide-1 (GLP-1) slow release nanometer formulation (GLP-1-SSM) stability experiment to blood plasma
Rat eye takes blood, and blood loads in the centrifuge tube containing heparin, and 3000rpm is centrifuged 10 minutes, takes supernatant blood plasma conduct
Temperature incubates blood plasma, utilizes LC-MS to carry out the response signal of detection compound.GLP-1 and the GLP-1-SSM solution of 100ul is with 100ul's
Blood plasma, inserts in 37 DEG C of water-baths after vortex mixed, temperature is incubated 96 hours, when 0,0.5,1,2,4,8,12,24,36,48,72,96h
Between point take 10 ul, add 20 ul acetonitrile precipitations, 14000 rpm be centrifuged, taking supernatant enters LC-MS, calculates each time point
Peak area, makes attenuation curve, calculates the half-life.As it is shown in figure 1, only do not pass through the prototype GLP-1 half-life of transformation
15min, and the half-life of GLP-1-SSM is more than 50 hours.
Embodiment 3
The internal abdominal cavity carbohydrate tolerance experiment of GLP-1-SSM and Exenatide
10 week old male mouse of kunming, after adaptability raises one week, random packet, often group 6.Only give drinking-water, overnight fasting.Real
When testing beginning, 0.5 h gives GLP-1-SSM (25 nmol/kg) in advance；Negative control group mice received saline injection；Positive right
According to group injected in mice Exenatide (25 nmol/kg).0 h abdominal cavity gives glucose (2 g/kg), 0,0.25,0.5,1,2
H blood glucose meter measures blood glucose numerical value.As in figure 2 it is shown, after nano-micelle wraps up, the hypoglycemic activity of GLP-1-SSM is higher than
Exenatide, illustrates that nano-micelle can improve the hypoglycemic activity of GLP-1.
Embodiment 4
The single-dose of GLP-1-SSM and Exenatide repeatedly gives sugar experiment
6 week old db/db diabetic mices, adaptability raising one week, random packet, often group six.Mice at fasting 18 h,
0.5 h abdominal cavity gives positive control Exenatide (25 nmol/kg), negative control normal saline and GLP-1-SSM in advance
(25 nmol/L), 0 h abdominal cavity gives glucose (1 g/kg), and 0,0.25,0.5,1,2,3 h blood glucose meter monitors blood glucose water
Flat.For the first time after abdominal cavity carbohydrate tolerance end cycle, it is repeated twice lumbar injection glucose, each carbohydrate tolerance cycle at 6 and 12 h
The assay intervals of blood glucose is identical with first time.As it is shown on figure 3, GLP-1-SSM demonstrates during whole carbohydrate tolerance very well
Hypoglycemic activity, and matched group Exenatide the 2nd time give sugar time activity be just remarkably decreased, the 3rd time give sugar time entirely without work
Property, illustrate that GLP-1-SSM has the long-time ability controlling blood glucose.
Embodiment 5
The long-term treatment experiment of GLP-1-SSM and Exenatide
6 week old db/db diabetic mices, adaptability raising one week, random packet, often group 6.Mice gives for 2 times every day
Positive control Exenatide (25 nmol/kg), negative control normal saline, give GLP-1-SSM (25 two days 1 time
Nmol/L), body weight and the food-intake of mice are detected every day.As shown in Figure 4 and Figure 5, GLP-1-SSM can significantly inhibit mice
Food-intake and losing weight, and its effect of losing weight and appetite inhibiting effect be better than positive control Exenatide, shows
GLP-1-SSM has good treatment diabetes and a prospect in medicine of fat-reducing.
Claims (4)
1. a glucagon-like-peptide-1 slow release nanometer formulation, is made up of substrate and medicine, it is characterised in that substrate is two hard
Fatty acyl group PHOSPHATIDYL ETHANOLAMINE-Polyethylene Glycol, medicine is that the mol ratio of glucagon-like-peptide-1, substrate and medicine is between 50:1
Between 150:1.
A kind of glucagon-like-peptide-1 slow release nanometer formulation the most according to claim 1, it is characterised in that described pancreas
Glucagon-like peptide-1 is GLP-1 (7-37)-OH or GLP-1 (7-36)-NH2。
3. the preparation method of a glucagon-like-peptide-1 slow release nanometer formulation, it is characterised in that operating procedure is as follows:
The first step, is dissolved in the DSPE-PEG of 100 or 150 parts moles in normal saline,
Apply 2-3 hour 37 DEG C of temperature under the conditions of lucifuge, form blank micelle；
Second step, is dissolved in the glucagon-like-peptide-1 of 1 or 2 parts moles in normal saline, the solution that in addition, step prepares
In, both continue at 37 DEG C of temperature and apply 1-2 hour after mix homogeneously；
3rd step, is placed in-20 DEG C of stopped reaction by the solution that second step produces, then solution is placed in quick-freezing 5-10 in liquid nitrogen and divides
Clock；
4th step, is placed in the solution after the 3rd step liquid nitrogen flash freezer in freeze dryer, direct lyophilizing 24-48 hour, obtains pancreas height blood
Sugar element sample peptide-1 slow release nanometer formulation.
4. a glucagon-like-peptide-1 slow release nanometer formulation, it is characterised in that be applied to prepare diabetes medicament or fat-reducing
Medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610476511.XA CN106074376A (en) | 2016-06-27 | 2016-06-27 | A kind of glucagon-like peptide 1 slow release nanometer formulation, preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610476511.XA CN106074376A (en) | 2016-06-27 | 2016-06-27 | A kind of glucagon-like peptide 1 slow release nanometer formulation, preparation method and application |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106074376A true CN106074376A (en) | 2016-11-09 |
Family
ID=57253822
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610476511.XA Pending CN106074376A (en) | 2016-06-27 | 2016-06-27 | A kind of glucagon-like peptide 1 slow release nanometer formulation, preparation method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106074376A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109091459A (en) * | 2018-09-10 | 2018-12-28 | 中国科学院生物物理研究所 | A kind of sorbefacient promoting the oral absorptions of macromolecular drugs such as insulin |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1524516A (en) * | 2003-09-18 | 2004-09-01 | 中国人民解放军第二军医大学 | Glicetin -1 slow release microspheric preparation and its use |
| CN101559041A (en) * | 2009-05-19 | 2009-10-21 | 中国科学院过程工程研究所 | Polypeptide medicament sustained release microsphere or microcapsule preparation with uniform grain size and preparation method thereof |
| CN104083325A (en) * | 2014-07-18 | 2014-10-08 | 国家纳米科学中心 | Irinotecan hydrochloride nanometer fat beam preparation and preparation method thereof |
| CN105241793A (en) * | 2015-09-07 | 2016-01-13 | 国家纳米科学中心 | Assay method of morphologic particle size of drug carrying micelle |
| CN105561331A (en) * | 2016-01-26 | 2016-05-11 | 北京大学 | Anti-tumor medicine coupler decorated with saturated fatty acid and self-assembling nanometer system and preparation method of anti-tumor medicine coupler |
-
2016
- 2016-06-27 CN CN201610476511.XA patent/CN106074376A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1524516A (en) * | 2003-09-18 | 2004-09-01 | 中国人民解放军第二军医大学 | Glicetin -1 slow release microspheric preparation and its use |
| CN101559041A (en) * | 2009-05-19 | 2009-10-21 | 中国科学院过程工程研究所 | Polypeptide medicament sustained release microsphere or microcapsule preparation with uniform grain size and preparation method thereof |
| CN104083325A (en) * | 2014-07-18 | 2014-10-08 | 国家纳米科学中心 | Irinotecan hydrochloride nanometer fat beam preparation and preparation method thereof |
| CN105241793A (en) * | 2015-09-07 | 2016-01-13 | 国家纳米科学中心 | Assay method of morphologic particle size of drug carrying micelle |
| CN105561331A (en) * | 2016-01-26 | 2016-05-11 | 北京大学 | Anti-tumor medicine coupler decorated with saturated fatty acid and self-assembling nanometer system and preparation method of anti-tumor medicine coupler |
Non-Patent Citations (6)
| Title |
|---|
| HACER CESUR, ET AL: "Self-associated indisulam in phospholipid-based nanomicelles:a potential nanomedicine for cancer", 《NANOMEDICINE:NANOTECHNOLOGY,BIOLOGY,AND MEDICINE》 * |
| HAYAT ONYUKSEL, ET AL: "A Novel Formulation of VIP in Sterically Stabilized Micelles Amplifies Vasodilation In Vivo", 《PHARMACEUTICAL RESEARCH》 * |
| SOK BEE LIM, ET AL: "Freeze Drying of Peptide Drugs Self-Associated with Long-Circulating,Biocompatible and Biodegradable Sterically Stabilized Phospholipid Nanomicelles", 《INTERNATIONAL JOURNAL OF PHARMACEUTICS》 * |
| ZHE WANG, ET AL: "Self-Assembled Core-Shell Vascular-Targeted Nanocapsules for Temporal Antivasculature and Anticancer Activities", 《SMALL》 * |
| 王江滨主编: "《CBL内科学》", 31 August 2012 * |
| 管又飞等主编: "《医学生理学》", 31 December 2013 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109091459A (en) * | 2018-09-10 | 2018-12-28 | 中国科学院生物物理研究所 | A kind of sorbefacient promoting the oral absorptions of macromolecular drugs such as insulin |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5658619B2 (en) | Oral insulin treatment and protocol | |
| US9981013B2 (en) | Use of AVE0010 for the treatment of diabetes mellitus type 2 | |
| EP2771024B1 (en) | Treatment protocol of diabetes type 2 | |
| WO2022111370A1 (en) | Glp-1/glucagon receptor dual-agonist and application thereof | |
| US20200038488A1 (en) | Insulin glargine/lixisenatide fixed ratio formulation | |
| US20130090285A1 (en) | Methods of treatment with glp-1 receptor agonists | |
| CN110437329B (en) | Oral hypoglycemic peptide, its fatty acid derivative and use | |
| White Jr et al. | Insulin analogues: new agents for improving glycemic control | |
| Simpson et al. | Insulin aspart | |
| CN102552883B (en) | Polypeptide compound, pharmaceutical composition, its preparation method and application thereof | |
| CN104840415A (en) | Long-acting controlled release liposome gel combination containing blood sugar reducing active component, and preparation method thereof | |
| CN104055735A (en) | Semaglutide liposome and preparation method thereof | |
| US20210052703A1 (en) | Glp-1 composition for treating obesity and weight management | |
| CN106074376A (en) | A kind of glucagon-like peptide 1 slow release nanometer formulation, preparation method and application | |
| EP4360641A1 (en) | Use of mazdutide | |
| CN112057619A (en) | A pharmaceutical composition with blood sugar lowering effect | |
| US10842851B2 (en) | Relaxin for treating patients afflicted of impaired glucose tolerance | |
| Bethel et al. | Insulin analogues: new therapies for type 2 diabetes mellitus | |
| CN110099719A (en) | For improving glycemic control and reducing acute and long term diabetes complications moral paddy insulin | |
| CN104402990A (en) | Polypeptide for treating diabetes | |
| JP2006519881A (en) | Oral insulin treatment and protocol | |
| CN113509544B (en) | Pharmaceutical composition with blood sugar reducing effect | |
| US20210213104A1 (en) | Glucagon and glp-1 co-agonists for the treatment of chronic kidney disease and diabetic kidney disease in type 2 diabetes | |
| WO2023235724A1 (en) | Methods of using a gcg/glp1 co-agonist for therapy | |
| CN104262462B (en) | Glucose transporter suppression polypeptide and preparation method thereof, application |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20161109 |
|
| WD01 | Invention patent application deemed withdrawn after publication |