CN109954145A - A kind of Exenatide oral administration nanometer particle - Google Patents
A kind of Exenatide oral administration nanometer particle Download PDFInfo
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- CN109954145A CN109954145A CN201711430408.2A CN201711430408A CN109954145A CN 109954145 A CN109954145 A CN 109954145A CN 201711430408 A CN201711430408 A CN 201711430408A CN 109954145 A CN109954145 A CN 109954145A
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- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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Abstract
The present invention provides a kind of Exenatide oral administration nanometer grain, nanoparticle is combined with Fc antibody fragment (- SH) again by poly lactide-glycolide acid (PLGA) or its high molecular polymer package Exenatide for changing structure.Fc antibody fragment (- SH) and high molecular polymer occur Michael addition reaction modification nanoparticle and improve the oral administration biaavailability of Exenatide to improve nanoparticle in the absorption efficiency of small intestine site.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, and in particular to oral administration nanometer grain containing Exenatide and preparation method thereof.
Background technique
Diabetes are a kind of general metabolism diseases characterized by chronic hyperglycemia, show as defect of insulin secretion or
There is obstacle in biological insulin effect.According to statistics, there are about 1.4 hundred million diabetics in global range at present, and since population is old
In age, the factors such as incidence of obesity increase, in 2025, global diabetic was up to 300,000,000 for estimation.Type-1 diabetes mellitus, it is special
Sign is that insulin secreting ability is reduced or thoroughly lost, and clinical treatment needs daily subcutaneous insulin injections；Type-2 diabetes mellitus, it is special
Sign is that human body can not efficiently use insulin, and having 90% in diabetic is type-2 diabetes mellitus.
Exenatide is a kind of type-2 diabetes mellitus therapeutic agent of brand new class, is that currently the only can help II type glycosuria
Patient controls the therapeutic agent of blood glucose and weight simultaneously.Exenatide is clinically commonly given at present as polypeptide drug
Prescription formula is subcutaneous administrations, and (hundred secrete and reach Exenatide injection) listed in 2005 in the U.S., 2007
It is listed in Europe, obtains within 2009 Chinese CFDA approval listing, the adjuvant therapy medicaments as melbine drug.Partly decline
Phase is short (t1/2 about 2.4h), cannot continue control blood glucose, drug effect is caused centainly to be limited to,；BeBase
What is further researched and developed on plinth is Exenatide long-acting slow-release microballoon, and European EMEA approval was obtained in 2011 and is listed, 2012 years
Obtain U.S. FDA approval listing.Exenatide injection (Byetta) and Exenatide release microsphere (Bydureon) are used at present
Type-2 diabetes mellitus is treated, can both control blood glucose level well, and hypoglycemia will not be caused.However, existing clinic
Exenatide clinical administration is drug administration by injection, and treating diabetes need patient's long term injections to be administered, this brings to patient
Very big pain, while injection is inconvenient for use, needs to be injected by the man skilled in the art, and manufacturing process is complicated, high production cost.
Oral route is administration mode most widely used, more convenient at present, but is administered orally and absorbs by gastrointestinal tract,
Gastrointestinal tract not only plays a part of absorbing moisture, nutriment and electrolysis, while still body resists first of external source foreign matter
Effective barrier.Therefore the oral administration research of protein and peptide drugs is very challenging.The protein and peptides such as Exenatide
Drug gives the destruction that would generally be degraded in the gastrointestinal tract by oral administration, while small intestine epithelium can hinder the absorption of drug.Due to above
Reason, so that protein and peptide drugs oral administration biaavailability is low, most protein polypeptide drug is seldom or cannot be through stomach
Intestinal absorption limits its clinical application.If Exenatide can be taken orally, patient's compliance can be greatlyd improve,
And production process sterility requirements are lower, can reduce production cost.Therefore, in order to which the clinic for expanding Exenatide formulation is answered
With urgent need, which is developed, a kind of is administered more convenient Exenatide oral preparation.
Summary of the invention
The present invention provides a kind of Exenatide oral administration nanometer grains, and nanoparticle is by poly lactide-glycolide acid
(PLGA) or its high molecular polymer package Exenatide for changing structure is combined with Fc antibody fragment (- SH) again.Fc antibody fragment (-
SH Michael addition reaction) occurs with high molecular polymer and modifies nanoparticle, to improve nanoparticle in the absorption of small intestine site
Efficiency improves the oral administration biaavailability of Exenatide.
A kind of Exenatide nanoparticle provided by the invention, Exenatide is wrapped in polylactic acid-glycolic base in the nanoparticle
Acetate multipolymer (PLGA) or its change and form nanoparticle in the high molecular polymer of structure, Exenatide and poly lactic-co-glycolic acid
Copolymer (PLGA) or its high molecular polymer for changing structure, weight ratio are 1:50~1:1, preferably 1:16.7.
Nanoparticle of the present invention, can be Exenatide poly lactide-glycolide acid (PLGA) or its change
The nanoparticle that the high molecular polymer of structure is formed is formed in conjunction with Fc antibody fragment, and the poly lactic-co-glycolic acid of Exenatide is total
The molar ratio ratio of polymers (PLGA) or its high molecular polymer nanoparticle for changing structure and Fc antibody fragment is 100:1~30:1, excellent
Select 60:1.
Exenatide oral administration nanometer grain of the present invention is prepared using following methods: weighing Exenatide and polylactic acid-glycolic
Acetic acid copolymer (PLGA) or its high molecular polymer for changing structure dissolve poly lactide-glycolide acid with organic solvent
(PLGA) or its high molecular polymer for changing structure, obtained oil are added in Exenatide powder, and ultrasound obtains colostrum, will be first
Cream is added in pva solution, and ultrasound obtains emulsion, and emulsion is added in pva solution and is stirred, and volatile organic solvent obtains nanometer
The nanoparticle of preparation is concentrated, the nanoparticle of concentration is used glucan G50 under a nitrogen to react with Fc antibody fragment by grain
Post separation target nano particle and free LMWP obtain the Exenatide PEG-PLGA nanoparticle that Fc antibody fragment combines.
In the preparation method, organic solvent is the mixed solution of acetone and methylene chloride, preferably acetone: methylene chloride 1:
1 mixed solution, the preferably described Exenatide and poly lactide-glycolide acid (PLGA) or its high molecular polymer for changing structure
Weight ratio be 1:16.7, the preferably poly lactide-glycolide acid (PLGA) or its polyphosphazene polymer for changing structure of Exenatide
The molar ratio for closing object nanoparticle and Fc antibody fragment is 60:1.It is preferred that the poly lactide-glycolide acid (PLGA) or its
The high molecular polymer for changing structure is mPEG-PLGA:PEG-PLGA-mal, and the ratio of preferred polymers is 9:1.
The Exenatide oral administration nanometer grain exists with oral dosage form, and the oral preparation can be conventional using pharmacy
Method is prepared, preferably capsulae enterosolubilis.
Detailed description of the invention
The vivo biodistribution availability of Fig. 1: 5 kinds of preparations compares figure
The hypoglycemic result of Fig. 2: 5 kinds of preparations compares figure
Specific embodiment
Further instruction is subject to the present invention below by embodiment, but the invention is not limited in any way.
1 oil of embodiment is mutually the Exenatide oral administration nanometer grain of methylene chloride preparation
The PLGA-PEG-mal (molecular weight 20000) of the PLGA-mPEG and 3.34mg of 30.06mg is taken to be dissolved in methylene chloride
(2ml), as oily phase.The Exenatide aqueous solution of 800ul 2.5mgmL-1 is taken, oil is added and is mutually ultrasonically formed colostrum, ultrasound
Power is 300W, ultrasonic time 100s.It adds 4mL 3%PVA outer aqueous phase and is ultrasonically formed emulsion.Finally ice-water bath,
Under the revolving speed of 500rpm, it is added drop-wise in the ultrapure water of 40mL 0.5%PVA.Volatile organic solvent about 5h.Nanoparticle crosses 0.45um
Moisture film, measuring partial size is 220nm, measures encapsulation rate 67%.
2 oil of embodiment is mutually the Exenatide oral administration nanometer grain of acetone preparation
The PLGA-PEG-mal (molecular weight 20000) of the PLGA-mPEG and 3.34mg of 30.06mg is taken to be dissolved in acetone
(2ml), as oily phase.The Exenatide aqueous solution of 800ul 2.5mgmL-1 is taken, oil is added and is mutually ultrasonically formed colostrum, ultrasound
Power is 300W, ultrasonic time 100s.It adds 4mL 3%PVA outer aqueous phase and is ultrasonically formed emulsion.Finally ice-water bath,
Under the revolving speed of 500rpm, it is added drop-wise in the ultrapure water of 40mL 0.5%PVA.Volatile organic solvent about 5h.Nanoparticle crosses 0.45um
Moisture film, measuring partial size is 150nm, measures encapsulation rate 54%.
3 oil of embodiment is mutually Exenatide oral administration nanometer grain prepared by acetone and methylene chloride (3:1)
The PLGA-PEG-mal (molecular weight 20000) of the PLGA-mPEG and 3.34mg of 30.06mg is taken to be dissolved in acetone
The mixed solvent of (1.5ml) and methylene chloride (0.5ml), as oily phase.Take the Exenatide of 800ul 2.5mgmL-1 water-soluble
Liquid is added oil and is mutually ultrasonically formed colostrum, ultrasonic power 300W, ultrasonic time 100s.Add 4mL 3%PVA outer aqueous phase
It is ultrasonically formed emulsion.Finally ice-water bath, 500rpm revolving speed under, be added drop-wise in the ultrapure water of 40mL 0.5%PVA.Volatilization has
Solvent about 5h.Nanoparticle crosses 0.45um moisture film, and measuring partial size is 170nm, measures encapsulation rate 52%.
4 oil of embodiment is mutually Exenatide oral administration nanometer grain prepared by acetone and methylene chloride (1:1)
The PLGA-PEG-mal (molecular weight 20000) of the PLGA-mPEG and 3.34mg of 30.06mg is taken to be dissolved in acetone
The mixed solvent of (1.0ml) and methylene chloride (1.0ml), as oily phase.Take the Exenatide of 800ul 2.5mgmL-1 water-soluble
Liquid is added oil and is mutually ultrasonically formed colostrum, ultrasonic power 300W, ultrasonic time 100s.Add 4mL 3%PVA outer aqueous phase
It is ultrasonically formed emulsion.Finally ice-water bath, 500rpm revolving speed under, be added drop-wise in the ultrapure water of 40mL 0.5%PVA.Volatilization has
Solvent about 5h.Nanoparticle crosses 0.45um moisture film, and measuring partial size is 139nm, measures encapsulation rate 88%.
Embodiment 5 prepares Exenatide PEG-PLGA nanoparticle
Weigh mPEG-PLGA (5,000-20,000Da, 50:50LA:GA, w/w): PEG-PLGA-mal (5,000-20,
000Da, 50:50LA:GA, w/w) ratio is the total 16.7mg high molecular polymer of 9:1, with acetone: methylene chloride 1:1 is (respectively
It 0.5ml) dissolves, obtains oily phase, be added in 400ul Exenatide 2.5mg/ml, 300w ultrasound 30s obtains w/O colostrum, by colostrum
It is added in 1% PVA solution, 300w ultrasound 100s obtains W/O/W emulsion in ice-water bath, and emulsion is added in 1%PVA solution
Magnetic agitation, volatile organic solvent acetone and methylene chloride.The encapsulation rate for measuring nanoparticle is 85.07%.
Embodiment 6 prepares Exenatide PEG-PLGA nanoparticle
Weigh mPEG-PLGA (5,000-20,000Da, 50:50LA:GA, w/w): PEG-PLGA-mal (5,000-20,
000Da, 50:50LA:GA, w/w) ratio is the total 16.7mg high molecular polymer of 9:1, with acetone: methylene chloride 1:1 is (respectively
It 0.5ml) dissolves, obtains oily phase, be added in 800ul Exenatide 2.5mg/ml, 300w ultrasound 30s obtains W/O colostrum, by colostrum
It is added in 1% PVA solution, 300w ultrasound 100s obtains W/O/W emulsion in ice-water bath, and emulsion is added to 1% PVA solution
Middle magnetic agitation, volatile organic solvent acetone and methylene chloride, the encapsulation rate for measuring nanoparticle is 67.70%.
Embodiment 7 prepares Exenatide nanoparticle
Weigh mPEG-PLGA (5,000-20,000Da, 50:50LA:GA, w/w): PEG-PLGA-mal (5,000-20,
000Da, 50:50LA:GA, w/w) ratio is the total 16.7mg high molecular polymer of 9:1, with acetone: methylene chloride 1:1 is (respectively
It 0.5ml) dissolves, obtains oily phase, be added in 200ul Exenatide 2.5mg/ml, 300w ultrasound 30s obtains W/O colostrum, by colostrum
It is added in 1% PVA solution, 300w ultrasound 100s obtains W/O/W emulsion in ice-water bath, and emulsion is added to 1% PVA solution
Middle magnetic agitation, volatile organic solvent acetone and methylene chloride, the encapsulation rate for measuring nanoparticle is 57.90%.
The oral administration nanometer grain of 8 Exenatide monoclonal antibody Fc of embodiment modification
Monoclonal antibody Fc sulfhydrylation: Traut ' the s reagent of the 1mg/mL of the Fc and 41.85ul of the 1.5mg/mL of 1mL are taken
G-25 sephadex chromatography column is crossed in reaction, is isolated free Fc using the detection of BCA protein concentration detection kit, is obtained
The Fc monoclonal antibody of sulfhydrylation.
The nanoparticle about 1mL of previous embodiment preparation is concentrated, then with the ratio of molar ratio PLGA-PEG-mal:Fc=60:1
Example with the sulfhydrylation Fc of 166ug be protected from light, inflated with nitrogen, ice-water bath under conditions of react 1h.Then be concentrated using 100k super filter tube,
It washs nanoparticle three times, removes free sulfhydrylation Fc monoclonal antibody, the Exenatide for obtaining the modification of Fc monoclonal antibody is received
The grain of rice.
Test example 1: vivo biodistribution availability development test
Experimental animal: the db/db mouse of six week old 30 is randomly divided into 5 groups, and every group 6, half male and half female, weight 40-
45g.Single-dose:
(1) 100 μ g/kg gives preparation oral Exenatide solution group, oral administration group；
(2) 100 μ g/kg give the Exenatide-Fc targeted nano granule of the preparation of embodiment 8, oral administration group；
(3) 100 μ g/kg give the Exenatide nanoparticle group of the preparation of embodiment 5, oral administration group；
(4) 100 μ g/kg give the Exenatide solution of preparation: intravenously administrable group；
(5) 100 μ g/kg give the Exenatide solution of preparation: subcutaneous administration group；
Distinguish 0min, 1min, 5min, 15min, 20min, 30min, 45min, 1h, 2h, 4h, 6h, 8h upon administration,
12h takes blood for 24 hours, test.
Table 1: different preparation bioavailability study results
Interpretation of result: the medicine of Exenatide difference preparation releases curve and pharmacokinetic parameter is shown in Fig. 1 and table 1, Ai Saina
The Exenatide of (oral) the group detection of peptide is very low always, and Exenatide (SC) group reaches maximal plasma concentration in 0.5h.It is small to be administered 4
Shi Hou, it is very low that Exenatide detects content in blood plasma, and Fc-exenatide-NP can extend the internal of Exenatide
Half-life period reaches maximal plasma concentration after nano particle is applied 8 hours, and 12 although maximal plasma concentration is lower
Hour still detects the Exenatide of high level.Compared with Exenatide (oral) group, the significant increasing of Exenatide nanoparticle
The plasma concentration of Exenatide in the gastrointestinal tract is added, to improve the relative bioavailability of oral Exenatide.
Test example 2: blood sugar test is reduced
Experimental animal: the db/db mouse of six week old 30 is randomly divided into 5 groups, and every group 6, half male and half female, weight 40-
45g.Single-dose:
(1) 100 μ g/kg gives the Exenatide nanoparticle group of the preparation of embodiment 5:, oral administration group；
(2) 100 μ g/kg give the Exenatide-Fc targeted nano granule of the preparation of embodiment 8, oral administration group；
(3) 100 μ g/kg give oral Exenatide solution, oral administration group；
(4) isometric physiological saline oral administration group.
(5) 10ug/kg Exenatide subcutaneous injection group:
Distinguish 0min, 1h, 2h, 4h, 6h, 8h, 10h, 12h upon administration, for 24 hours, 48h collects blood from tail portion, uses blood glucose
It counts (Roche blood glucose meter, Shanghai) and measures blood glucose value.
Table 2: the blood glucose value measured after single-dose
Interpretation of result: the reduction blood sugar effects of Exenatide difference preparation are shown in Fig. 2 and table 2, and (1) nanoparticle group compares physiology
Salt water group, oral Exenatide group have hypoglycemic advantage；(2) subcutaneous administrations group blood glucose level has an apparent decline
The process gone up again, 1h is minimum, and about 10h restores level before administration；(3) Fc targeting group becomes apparent from drop blood compared to common nanoparticle
Sugared advantage, interior for 24 hours all steadily to reduce blood glucose, (4) Fc targeting group is obvious compared to other nanoparticle group blood sugar decreasing effects.
Claims (8)
1. a kind of Exenatide nanoparticle, it is characterised in that Exenatide is wrapped in poly lactic-co-glycolic acid in the nanoparticle
Copolymer (PLGA) or its change and form nanoparticle in the high molecular polymer of structure, Exenatide and poly lactic-co-glycolic acid are copolymerized
Object (PLGA) or its high molecular polymer for changing structure, weight ratio are 1:50~1:1, preferably 1:16.7.
2. nanoparticle according to claim 2, it is characterised in that the polylactic acid-glycolic base second of Exenatide in the nanoparticle
The nanoparticle and the white combination of Fc antibody fragment that acid copolymer (PLGA) or its high molecular polymer for changing structure are formed, Exenatide
Poly lactide-glycolide acid (PLGA) or its high molecular polymer nanoparticle for changing structure and the molar ratio of Fc antibody fragment are
100:1~30:1, preferably 60:1.
3. nanoparticle according to claim 3, it is characterised in that the combination of the nanoparticle and Fc antibody fragment is chemistry
Bond is closed.
4. a kind of preparation method of nanoparticle according to claim 1, prepares nanoparticle using following step:
A: Exenatide and poly lactide-glycolide acid (PLGA) or its high molecular polymer for changing structure, polylactic acid-are weighed
Co-glycolic acid (PLGA) or its high molecular polymer for changing structure are dissolved with organic solvent, obtained oily phase；
The oil obtained in b:a is added in Exenatide powder, and ultrasound obtains colostrum, and colostrum is added in pva solution, is surpassed
Sound obtains emulsion, and emulsion is added in pva solution and is stirred, and volatile organic solvent obtains nanoparticle；
C: the nanoparticle of preparation is concentrated, the nanoparticle of concentration is used into glucan under a nitrogen to react with Fc antibody fragment
G50 post separation targeted nano particle and free LMWP, obtain the PEG-PLGA nanometer for the Exenatide that Fc antibody fragment combines
Grain.
5. the preparation method of nanoparticle according to claim 4, it is characterised in that the organic solvent is acetone and dichloro
Methane, the preferably ratio of the two are 1:1.
6. the preparation method of nanoparticle according to claim 4, it is characterised in that the Exenatide and polylactic acid-glycolic base
The weight ratio of acetate multipolymer (PLGA) or its high molecular polymer for changing structure is 1:16.7, the polylactic acid-glycolic base of Exenatide
The molar ratio of acetate multipolymer (PLGA) or its high molecular polymer nanoparticle for changing structure and Fc antibody fragment is 60:1.
7. according to any nanoparticle of claim 2-6, it is characterised in that the poly lactide-glycolide acid
(PLGA) or its high molecular polymer for changing structure is mPEG-PLGA:PEG-PLGA-mal, and the ratio of preferably two polymer is 9:
1。
8. nanoparticle according to claim 1, it is characterised in that nanoparticle exists with oral dosage form, preferably enteric glue
Capsule.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112336873A (en) * | 2020-08-04 | 2021-02-09 | 华南理工大学 | Protein type nanoparticle for multi-specific antibody delivery and application and preparation method thereof |
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- 2017-12-26 CN CN201711430408.2A patent/CN109954145A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112336873A (en) * | 2020-08-04 | 2021-02-09 | 华南理工大学 | Protein type nanoparticle for multi-specific antibody delivery and application and preparation method thereof |
| US11957764B2 (en) | 2020-08-04 | 2024-04-16 | South China University Of Technology | Protein-type nanoparticles, preparation methods, and application thereof |
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Application publication date: 20190702 |