CN109010310B - Composition and application thereof comprising orlistat Yu GLP-1 receptor stimulating agent - Google Patents
Composition and application thereof comprising orlistat Yu GLP-1 receptor stimulating agent Download PDFInfo
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- CN109010310B CN109010310B CN201810936722.6A CN201810936722A CN109010310B CN 109010310 B CN109010310 B CN 109010310B CN 201810936722 A CN201810936722 A CN 201810936722A CN 109010310 B CN109010310 B CN 109010310B
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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Abstract
The invention belongs to pharmaceutical technology fields, and in particular to a kind of composition and application thereof comprising orlistat Yu GLP-1 receptor stimulating agent.Composition provided by the invention comprising orlistat and GLP-1 receptor stimulating agent includes orlistat, and the nanoparticle comprising GLP-1 receptor stimulating agent and copolymer.The Combined with Oral medication of orlistat Yu GLP-1 receptor stimulating agent may be implemented in composition provided by the invention comprising orlistat and GLP-1 receptor stimulating agent, and bioavilability is high, has good inhibition weight gain and fat-reducing effect.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of group comprising orlistat Yu GLP-1 receptor stimulating agent
Close object and application thereof.
Background technique
Orlistat (orlistat) is to research and develop lipase inhibitor class slimming drugs, trade name by company, Roche Group
Xenical, the 1990s end take the lead in listing in America and Europe, are eaten in Discussion on Chinese Listed, and in 2005 by China within 2001
The approval of product Drug Administration switchs to non-prescribed medicine.Entitled N- formyl-L-Leu (the s) -1- of its chemistry [(2s, 3s) -3- oneself
- 4 oxygroup -2- glycidyl methyl of base] ten diester, also referred to as tetrahydrolipostatin (Tetrahydrolipstatin, THL) they are a kind of
Semi-synthetic lipstatin derivative, chemical structural formula are shown below:
The serine residue of orlistat and stomach pancreatic lipase forms covalence key, can not will be in food so that enzyme be made to inactivate
Triglyceride hydrolysis at absorbable fatty acid, and then reduce the uptake of fat.Currently, orlistat is unique both at home and abroad
The chemical slimming drugs for not influencing appetite, not acting on central nervous system, security features are superior, and Bray GA is in " lancet "
Orlistat is described as " most safe " in the article for the entitled Management of Obesity that magazine is delivered
(safest) slimming drugs.However, being only capable of inhibiting the absorption of 30% fat in diet after orlistat oral administration, because before this
It states Bray GA and the weight loss effect of orlistat is rated " modest " (moderate) in identical article.
GLP-1, full name glucagon-like-peptide-1 are a kind of endogenous polypeptides for being expressed in central nervous system, with
Corresponding receptor can produce the effect of regulation appetite and calorie intake after combining.GLP-1 receptor stimulant medicine mainly as
Clinic is developed and be used for antidiabetic drug, and the GLP-1 receptor stimulant medicine listed at present includes Exenatide
(exenatide), Liraglutide (liraglutide), A Bilu peptide (albiglutide), Du Lalu peptide
(dulaglutide), sharp hila peptide (lixisenatide), Si Meilu peptide (semaglutide).Above-mentioned GLP-1 receptor agonism
Agent class drug shows good loss of weight effect in clinical test, and wherein Liraglutide has been used for the idicatio of loss of weight
Obtain FDA approval.Therefore, if realizing that orlistat is administered simultaneously with GLP-1 receptor stimulating agent in single pharmaceutical preparation,
The weight loss effect at least summed it up can be generated.However, orlistat can only be by oral since lipase exists only in alimentary canal
Administration, and the essence of GLP-1 receptor stimulating agent " peptide " make easily to be destroyed and lose with digestive ferment by gastric acid in alimentary canal after it is oral
Activity, furthermore gastral a variety of physiologic barriers also constitute the malabsorption of GLP-1 receptor stimulating agent.It is that exploitation is same above
When include that the pharmaceutical composition of orlistat and GLP-1 receptor stimulating agent necessarily overcomes the problems, such as.
In recent years, with the development of drug preparation technique, nano medicament carrying system starts applied to the oral of polypeptide drug
Administration.Nano medicament carrying system partial size is generally 10~200nm, and polypeptide drug can be dissolved, wraps up or be adsorbed in wherein, avoid
Destruction by gastric acid and digestive ferment.The M cell that nano medicament carrying system can send Yi Ershi to tie by cell bypass or intestinal mucosa
Phagocytosis approach absorbs, and can also directly be absorbed by enterocyte.The design object of oral administration nanometer drug-loading system is by controlling grain
Diameter size, surface characteristic (charge, hydrophilic and hydrophobic etc.) and support shapes etc. improve medicine stability, promote drug oral
It absorbs, to improve the oral administration biaavailability of drug.Nano medicament carrying system for polypeptide drug oral administration includes receiving
Rice ball/nanocapsule, nano liposomes, solid lipid nano granule, polymer micelle, nanocrystal, polymeric medicine composite Nano
Grain etc..
Polylactic-co-glycolic acid (PLGA) is most common polymer in the nanometer formulation of GLP-1 receptor stimulant medicine
One of carrier, wherein the Exenatide slow release microphere for injection using PLGA as carrier has obtained FDA approval listing, trade name
For Bydureon.J.W.Joseph et al. uses PLGA to can be improved as the nanometer formulation comprising GLP-1 that carrier is prepared
The oral administration biaavailability (Diabetologia (2000) 43:1319~1328) of GLP-1.
Chinese patent application CN104740647A (hereinafter referred to as " documents 1 ") discloses one kind by Exenatide and band
Oral microparticles made of charge auxiliary material, wherein the electrically charged auxiliary material be selected from chitosan, acrylic resin, sodium alginate and
One or more of polyamide-amide polymer.And the patent oral receiving of only disclosing when electrically charged auxiliary material is chitosan
The bioavilability of rice particle, only 15.3%.
Chinese patent application CN107708667A (hereinafter referred to as " documents 2 ") discloses a kind of effective comprising a) treatment
The Liraglutide of amount, b) block copolymer or graft copolymer or their mixing comprising hydrophilic parts and hydrophobic part
Object, c) at least one amphipath and the d) durable action composition of aqueous carrier, and pointed out in its specification, described " connects
Graft copolymer " includes 2- methylacryoyloxyethyl phosphocholine (MPCTM) and n-BMA (BMA) copolymer
(PUREBRIGHT mb-37-50T and PUREBRIGHT mb-37-100T), but composition described in the patent is in the shape of gel
Formula only for drug administration by injection, and does not provide embodiment related with MPC/BMA copolymer.
It is therefore still necessary to carry out structure of modification to MPC/BMA copolymer, and using it as carrier, oral absorption is prepared
The nanometer formulation of effect more preferably GLP-1 receptor stimulating agent, so that it be made to be better achieved and administration while orlistat.
Summary of the invention
It is an object of the present invention to provide a kind of nanoparticles that can be for oral administration comprising GLP-1 receptor stimulating agent.
The oral drugs group comprising orlistat Yu GLP-1 receptor stimulating agent that it is a further object to provide a kind of
Close object.
In order to realize the above object, one aspect of the present invention provides a kind of comprising GLP-1 receptor stimulating agent and copolymer
Nanoparticle, the structure of the copolymer as shown in formula I,
Wherein, x is any one integer selected from 0~19, and m:n is 51:49~86:14；
The mass ratio of the GLP-1 receptor stimulating agent and copolymer is 1:10~1:1；
The weight average molecular weight of the copolymer is 10800~61700.
Further, the GLP-1 receptor stimulating agent be selected from Exenatide, Liraglutide, A Bilu peptide, Du Lalu peptide,
One of sharp hila peptide, Si Meilu peptide.
Further, the preparation method of the nanoparticle comprising GLP-1 receptor stimulating agent and copolymer, including it is following
Step:
(1) copolymer is taken, above-mentioned copolymer is dissolved in dispersed phase, being configured to copolymer concentration is 50~200mg/mL's
Oil phase substrate solution, then disperse above-mentioned oil phase substrate solution for GLP-1 receptor stimulating agent and form oily phase, gained oil is mutually existed
10~30min is stirred under the revolving speed of 100~800rpm, is uniformly mixed it, is obtained solution A；
(2) surfactant is taken, is taken water as a solvent, the water phase that the mass concentration of forming surfactants is 0.5~5% is prepared
Solution, ie in solution B；
(3) step (1) acquired solution A is added drop-wise in step (2) acquired solution B, the volume of solution B is the body of solution A
Long-pending 4~20 times stir 10~14h under 500~2000rpm revolving speed, then high speed centrifugation under 5000~15000rpm revolving speed, receive
The step of collecting resulting nanoparticle, take precipitating, add distillation water dispersion, repeating centrifuging and taking precipitating, until surfactant is washed
Completely, finally by pellet frozen it is dry to get.
Further, dispersed phase described in the step (1) be selected from ethyl alcohol, methylene chloride, chloroform, ethyl acetate,
One of acetone.
Further, surfactant described in the step (2) is selected from polyethylene, gelatin, hypromellose, spits
One of temperature 80.
Another aspect of the present invention provides the composition comprising orlistat Yu GLP-1 receptor stimulating agent, includes Ao Lisi
He, the nanoparticle as previously described comprising GLP-1 receptor stimulating agent and copolymer.
Further, the composition comprising orlistat and GLP-1 receptor stimulating agent is oral solid formulation, described
Oral solid formulation is one of granule, capsule, tablet.
Further, the composition comprising orlistat and GLP-1 receptor stimulating agent also includes diluent and lubrication
Agent.
Further, the diluent is selected from pregelatinized starch, starch, dextrin, sucrose, microcrystalline cellulose, sorbierite, sweet
Reveal one of alcohol, lactose, calcium sulfate, calcium monohydrogen phosphate, calcium phosphate or a variety of；The lubricant be selected from fumaric acid sodium, stearic acid,
Magnesium stearate, calcium stearate, paraffin, paraffin oil, glycerin monostearate, monopalmitin, sodium acetate, sodium chloride, DL-
One of leucine, sldium lauryl sulfate, magnesium laurylsulfate, polyethylene glycol are a variety of.
A further object of the present invention is to provide the above-mentioned compositions comprising orlistat and GLP-1 receptor stimulating agent to make
Purposes in the fat drug of standby prevention and treatment.
Compared with prior art, the beneficial effects of the present invention are:
(1) factors influencing test result show the minimum encapsulation rate of nanoparticle provided by the present invention be above by
The obtained nanoparticle of method of documents 1 and documents 2.
(2) preferred nanoparticle provided by the present invention is significantly higher than in documents 1 oral administration biaavailability of rat
Nanoparticle.
(3) Ao Lisi may be implemented in the composition provided by the present invention comprising orlistat and GLP-1 receptor stimulating agent
The Combined with Oral medication of he and GLP-1 receptor stimulating agent, bioavilability is high, has good inhibition weight gain and weight-reducing effect
Fruit.
Specific embodiment
Below in conjunction with the embodiment of the present invention, clear, complete description is carried out to technical solution of the present invention.Significantly,
Described embodiment is only a part of the embodiments of the present invention, instead of all the embodiments.Based on described below
Embodiment, the every other technical side that those of ordinary skill in the art obtain without making creative work
Case shall fall within the protection scope of the present invention.
1 copolymer and preparation method thereof and structural identification
Using structure copolymer as shown in formula I, as carrier, the nanoparticle has been prepared in the present invention.
Wherein, substituent R is selected from one of following group:
Copolymer shown in formula I is not found in the record of any prior art.
The preparation of 1.1 copolymers
Copolymer shown in formula I has been prepared using synthetic reaction route as follows in the present invention, for description
Convenient, hereafter known as " copolymer 1 ", and number consecutively is copolymer 1 a~1t from small to large according to the x of R substituent.
In the above reaction equation, compound 2a~2t is the cyclopentenyl fatty acid acid that structure is shown below:
Wherein, x is any one integer in 0~19.
Compound 2a~2t is present in nature or commercially available, or is reported using W.M.Stanley et al.
Method (Journal of the American Chemical Society, 1929,51 (5): 1515~1518) from few two
The cyclopentenyl fatty acid acid of a carbon is prepared.
Compound 3 and compound 5 are common industrial chemicals.
Compound 7 is 2- methylacryoyloxyethyl phosphocholine (MPC), can be commercial product, see also
Ishihara K et al.(Polym J 1990；22:355-360.) and Ueda T et al. (Polym J 1992；24:
1259-1269.) method disclosed by is prepared.
Reaction reagent, condition and the operating method of the step a are as follows: oxalyl chloride, n,N-Dimethylformamide (DMF), three
Ethamine, methylene chloride, -10 DEG C.The reaction is conventional acylation reaction, and low-temp reaction condition ensure that the selectivity to amino
It is acylated, operation can according to but be not limited to " drug synthetic reaction " (publication Chemical Industry Press's in April, 2017) of Wen Ren chief editor
Delivered with Sun Cuiling et al. " synthesis of Oleoylethanolamide Analogues " (Xiamen University's journal (natural science edition), 2007
The phase of volume 46 the 6th, page 808~812) method that discloses carries out.
Reaction reagent, condition and the operating method of the step b are as follows: p-methyl benzenesulfonic acid, hydroquinone, toluene, reflux.It should
Reaction is conventional acylation reaction, operation can according to but be not limited to Wen Ren chief editor " drug synthetic reaction " (chemical industry goes out
Version is published society's in April, 2017) " synthesis of hexadecyl metrhacrylate and the structural characterization " delivered with military jump et al. (Dalian is national
Institute's journal, the 3rd phase of volume 6 in 2004, page 10~13) disclosed by method carry out.
Reaction reagent, condition and the operating method of the step c are as follows: azodiisobutyronitrile (AIBN), methanol/tetrahydrofuran
(MeOH/THF).The Preparation of that the step operation can be delivered according to Kazuhiko Ishihara et al.
Phospholipid Polymers and Their Properties as Polymer Hydrogel Membranes.
Method disclosed by (Polymer Journal, Volume 22, Issue 5,355~360) carries out, and is disclosed according to the document
Method structural identification is carried out to the copolymer 1 that is prepared.Specifically, take quantitative compound 6a~6t, compound 7 with
AIBN is added quantitative methanol/tetrahydrofuran (1:4) mixed solvent, is configured to the mass concentration (wt%) of compound 6a~6t
Quality for 20% solution, and AIBN is the 1% of compound 6a~6t and 7 gross mass of compound.Acquired solution is moved to
After in polymerisation tube, argon gas is passed through into solution to remove the oxygen in solution.Reaction tube is sealed, and is shaken at 60 DEG C
It is cooling after 16h, to stop polymerization reaction.Reaction solution is poured onto ether, the solid of precipitation is collected by filtration, is dried under vacuum,
Up to corresponding copolymer 1 a~1t.
Specifically, in above-mentioned steps c compound 6a~6t and compound 7 feed ratio confirmation method are as follows: using 1:1 as change
The minimum molar feed ratio of object 6 and compound 7 is closed, and using the solubility >=50mg/mL of gained copolymer in water as index, knot
Fruit is as shown in table 2.
The structural identification of 1.2 copolymer 1s
(1)1H-NMR
The present invention uses1H-NMR (400Hz, CDCl3), it is true that structure has been carried out to raw material and the product of aforementioned every single step reaction
Card, and by comparing product and raw material1The similarities and differences of H-NMR spectrum data, to conclude the generation of reaction.
It should be pointed out that compound 6a~6t carries out the resulting difference m:n that feeds intake from compound 7 with different molar ratios
The copolymer 1 of ratio1The δ value that H-NMR schemes each characteristic peak has no significant difference (between ± 0.05ppm), only each characteristic peak
Relative peak area can because m:n difference and have differences and m:n described below than calculation method foundation, in table
The δ value of the preparation-obtained copolymer of maximum molar feed ratio is only gived in 1.
1 copolymer 1 a~1t's of table1H-NMR TuPu method
(2) in copolymer 1 structural formula m:n ratio calculating
The present invention is by calculating copolymer 11The total hydrogen of peak area Zhan of the characteristic peak of 3 hydrogen of-N+ (CH3) in H-NMR map
The ratio of peak area calculates the m:n ratio in copolymer 1 structure.M:n ratio in copolymer structure is with compound 6 and chemical combination
The increase of the molar feed ratio of object 7 and increase, this is common sense known in those skilled in the art, and therefore, the present invention only calculates
Compound 6 and compound 7 with it is minimum reacted with maximum molar feed ratio when gained copolymer 1 structure in m:n ratio, tie
Fruit is as shown in table 2.
(3) molecular weight determination of copolymer 1
The present invention uses GPC/ALC 150C type gel permeation chrommatograph well-known to those skilled in the art, at 25 DEG C, with
Tetrahydrofuran is solvent, using polystyrene as control, determines compound 6a~6t and compound 7 with mole of 1:1~6:4
Than the weight average molecular weight (Mw) and number-average molecular weight (Mn) of the reaction gained copolymer 1 that feeds intake, and molecular weight distribution is calculated as follows
(D), the results are shown in Table 2.
The m:n ratio and molecular weight determination of 2 copolymer 1 a~1t of table
2.GLP-1 receptor stimulating agent
GLP-1 receptor stimulating agent of the present invention is Exenatide, Liraglutide, A Bilu peptide, Du Lalu peptide, Li Xi
One of peptide, Si Meilu peptide are drawn, the structure feature of polypeptide is all had.
3. the preparation and factors influencing of the nanoparticle comprising GLP-1 receptor stimulating agent and copolymer
3.1 preparation method
The present invention provides the nanoparticle comprising the GLP-1 receptor stimulating agent and copolymer 1a~1t, the nanoparticles
It is prepared using emulsification-evaporation method well-known to those skilled in the art, preparation method is as described below:
(1) quantitative copolymer (m:n in copolymer structure is set as " influence factor I ") is taken, above-mentioned copolymer is dissolved in
In dispersed phase, it is configured to the oil phase substrate solution that copolymer concentration is 50~200mg/mL (influence factor II), then will be quantitative
The GLP-1 receptor stimulating agent is scattered in above-mentioned oil phase substrate solution and forms oily phase, wherein the GLP-1 receptor stimulating agent
Mass ratio with copolymer 1 is 1:10~1:1 (influence factor III), by gained oil mutually in 100~800rpm (influence factor IV)
Revolving speed under stir 10~30min (influence factor V), make its be uniformly mixed, obtain solution A；
(2) quantitative surfactant is taken, is taken water as a solvent, the mass concentration for preparing forming surfactants is 0.5~5%
The aqueous phase solution of (influence factor VI), ie in solution B；
(3) step (1) acquired solution A is added drop-wise in step (2) acquired solution B, the volume of solution B is the body of solution A
4~20 times long-pending (influence factors VII) stir 10~14h (influence factor under 500~2000rpm revolving speed (influence factor VIII)
Ⅸ), then high speed centrifugation under 5000~15000rpm revolving speed (influence factor Ⅹ), collects resulting nanoparticle, takes precipitating, add steaming
Distilled water dispersion, repeats the step of centrifuging and taking precipitates, until surfactant is by wash clean, it is finally that pellet frozen is dry, i.e., and
?.
Wherein, dispersed phase described in the step (1) is selected from ethyl alcohol, methylene chloride, chloroform, ethyl acetate, acetone
One of；Surfactant described in the step (2) is in polyethylene, gelatin, hypromellose, Tween 80
It is a kind of.
3.2 factors influencing
The present invention has successively investigated each variable parameter (influence factor I in above-mentioned preparation method using quadrature factor test
~Ⅹ) to the influence of nanoparticle encapsulation rate.
Wherein, the encapsulation rate is measured using method well-known to those skilled in the art.Specifically, take 5~
6mg nanoparticle is dissolved in quantitative dimethyl sulfoxide, and filtering then carries out HPLC analysis to filtrate, calculates the GLP- of free state
1 receptor agonism agent content, and according to formula computational envelope rate below.
Foregoing HPLC measuring method are as follows: chromatographic column: reverse phase C18 column (250 × 4.6mm, 5 μm of partial size)；Detector:
UV, 254nm；Sample volume: 20 μ L；Mobile phase: n-octyl phosphoric acid/acetonitrile/methanol (3/4/3, V/V/V, pH5.5)；Flow velocity:
1.0mL.The HPLC method applies also for the test of nanoparticle sustained-release effect in vitro.
Quadrature factor test concrete operation step of the present invention is as described below:
Firstly, using polyethylene as surfactant, and factor I~Ⅹ will be will affect using ethyl alcohol as dispersed phase
It is fixed as Q2 value shown in table 3, it is preparation-obtained when calculating using different GLP-1 receptor stimulating agents with copolymer 1a~1t
The encapsulation rate of nanoparticle.As a result, it has been found that the type of copolymer 1 a~1t, i.e., the x size in structure, there is the encapsulation rate of nanoparticle
Significant impact, as shown in table 4.
Each influence factor of table 3 receives the numerical value investigated
Table 4 is copolymerized influence of the species to nanoparticle encapsulation rate
As a comparison, the present invention has been prepared according to method disclosed by embodiment 2 in documents 1 comprising Chinese mugwort
The nanoparticle of that peptide and acrylic resin is filled in, and its encapsulation rate is determined, result 12.7%.
Furthermore as a comparison, the present invention using PUREBRIGHT mb-37-50T disclosed in documents 2 with
PUREBRIGHT mb-37-100T is as carrier, and for ethyl alcohol as dispersed phase, polyethylene, and will be such as preceding institute as surfactant
The influence factor II~Ⅹ stated is fixed as Q2 value shown in table 3, using foregoing preparation method, comparison has been prepared and has received
The grain of rice.Its encapsulation rate is as shown in table 5.
The encapsulation rate of the comparison nanoparticle of table 5
It can be seen that the minimum encapsulation rate of each GLP-1 receptor stimulating agent nanoparticle in table 4, it is corresponding right in table 5 to be above
Than the encapsulation rate of nanoparticle.
Next the present invention has investigated encapsulation rate of the type to nanoparticle of foregoing dispersed phase and surfactant
Influence.Specifically, using copolymer 1 a corresponding to the nanoparticle maximum encapsulation rate of each GLP-1 receptor stimulating agent shown in table 4
~1t, and will affect factor I~Ⅹ and be fixed as Q2 value shown in table 3, it is received using different dispersed phases and surfactant preparation
Rice, and the encapsulation rate of gained nanoparticle is measured, the results are shown in Table 6.
Influence of the type of 6 dispersed phase of table and surfactant to nanoparticle encapsulation rate
Establishing various GLP-1 receptor stimulating agent copolymer 1 dispersed phase surfactants of the present invention
After best collocation, then the present invention has successively investigated the influence of I~Ⅹ pair of nanoparticle encapsulation rate of influence factor, specifically, will
GLP-1 receptor stimulating agent, copolymer 1, dispersed phase and surfactant are fixed as number corresponding to maximum value described in table 4,6
Value, factor to be investigated take L, Q1, Q2, Q3 and U value shown in table 3 (wherein, influence factor I only takes L, Q2 and U value), have investigated
Influence factor take its fixed optimum value, the factor that do not investigate takes Q2 value shown in table 3, according to method system as previously shown
Standby nanoparticle, and the encapsulation rate of gained nanoparticle is measured, determine the optimum value of influence factor, the results are shown in Table 7.
The influence of 7 I~Ⅹ pair of nanoparticle encapsulation rate of influence factor of table
The average grain diameter for the nanoparticle being prepared in the factors influencing that the present invention also measures is 509 ± 286nm
(14nm~998nm).
4. combination of oral medication
On the basis of providing the nanoparticle comprising GLP-1 receptor stimulating agent and copolymer, the present invention further provides
Combination of oral medication comprising orlistat Yu the nanoparticle.The dosage form of the combination of oral medication includes piece
Agent, capsule, granule, and can be prepared by method well-known to those skilled in the art.
Specifically, the preparation method of granule of the present invention is preferably by orlistat, as previously described comprising GLP-1
After the nanoparticle of receptor stimulating agent and copolymer, diluent and mix lubricant, pelletize to get the granule.
Wherein, the technological means that the method for granulating is well known to those skilled in the art, it is not specifically limited to this by the present invention.
The preparation method of capsule of the present invention preferably swashs by orlistat, as previously described comprising GLP-1 receptor
After the nanoparticle of dynamic agent and copolymer, diluent and mix lubricant, filling capsule is to get the capsule.Wherein, institute
The technological means that the capsule packaging process stated is well known to those skilled in the art, it is not specifically limited to this by the present invention.
The preparation method of tablet of the present invention is preferably by orlistat, as previously described comprising GLP-1 receptor agonism
After the nanoparticle of agent and copolymer, diluent and mix lubricant, tabletting is carried out to get the tablet.It is of the present invention
The technological means that is well known to those skilled in the art of tabletting method, it is not specifically limited to this by the present invention.
Wherein, foregoing diluent is selected from pregelatinized starch, starch, dextrin, sucrose, microcrystalline cellulose, sorb
One of alcohol, mannitol, lactose, calcium sulfate, calcium monohydrogen phosphate, calcium phosphate are a variety of.Foregoing lubricant is selected from richness
Horse acid sodium, stearic acid, magnesium stearate, calcium stearate, paraffin, paraffin oil, glycerin monostearate, monopalmitin, vinegar
One of sour sodium, sodium chloride, DL-leucine, sldium lauryl sulfate, magnesium laurylsulfate, polyethylene glycol are a variety of.
Orlistat in combination of oral medication of the present invention, as previously described comprising GLP-1 receptor stimulating agent together
The dosage of the nanoparticle of polymers, diluent and lubricant can be used technological means well known to those skilled in the art and be determined.
The preparation of 1 compound 4k of embodiment and structural identification
Preparation: take 0.252g compound 2k (1mmol), be dissolved in 5mL methylene chloride, stirred at -10 DEG C after five minutes, to
The 5mL dichloromethane solution of 0.087mL oxalyl chloride (1mmol) is wherein slowly added dropwise, is dripped off in 20 minutes, then drop a N, N- is added dropwise
Dimethylformamide continues at -10 DEG C to stir 2h, obtains solution A；0.063mL ethylaminoethanol (1.05mmol) separately is taken, is dissolved in 5mL
In methylene chloride, then 0.276mL triethylamine (2mmol) is added dropwise thereto, is stirred evenly at -10 DEG C, obtain solution B.Solution A is delayed
It is slow to be added drop-wise in solution B, continue to stir 2h at -10 DEG C.Reaction solution is washed with 10% sodium carbonate liquor of 10mL, water layer dichloro
Methane extracts (3 × 5mL), organic layer 10mL saturated common salt water washing.Anhydrous slufuric acid is used after merging aforementioned all organic phases
Magnesium dries, filters, and is concentrated under reduced pressure, and crude product Flash silica column chromatographs (ethyl acetate: petroleum ether=1:1, V/V) and purifies, and obtains
0.251g white solid, yield 85.1%.
Structural identification:
Compound 2k:1H-NMR(CDCl3) δ (ppm): 6.068 (1H, dd), 5.600 (1H, m), 2.844 (1H, m),
2.309~2.245 (2H, m), 2.188 (2H, t), 1.964 (1H, m), 1.741 (1H, m), 1.569 (2H, m), 1.341~
1.234 (16H, m).
Compound 4k:1H-NMR(CDCl3) δ (ppm): 6.062 (1H, dd), 5.616 (1H, m), 3.477 (2H, t),
3.227 (2H, t), 2.831 (1H, m), 2.342~2.246 (2H, m), 2.107~1.943 (3H, m), 1.748 (1H, m),
1.530 (2H, m), 1.298~1.244 (16H, m).
The preparation of 2 compound 6k of embodiment and structural identification
Preparation: take 0.296g compound 4k (1mmol), 10mL toluene, 0.125g p-methyl benzenesulfonic acid and 0.038g to benzene two
Phenol, mixing are placed in the three-neck flask equipped with water segregator, and heating stirring to solid all dissolves, then to gained mixed system
Middle addition 0.130g methacrylic acid (1.5mmol).Continue to be heated to reflux temperature, water and toluene azeotropic, while being steamed
Out.When the water in water segregator is suitable with theoretical value (about 0.018g), vacuum distillation remove unreacted methacrylic acid with
Toluene.Thick ester in flask is cooled to room temperature, appropriate petroleum ether is added and is completely dissolved, with including 5% sodium carbonate and 1% hydrogen-oxygen
Change in the lye of sodium and wash to alkalescence, removes a small amount of toluene and methacrylic acid, p-methyl benzenesulfonic acid and hydroquinone, then
Be washed to neutrality with distillation, after dried, filtered with anhydrous calcium chloride after steam petroleum ether, obtain 0.318g pale solid, yield
87.5%.
Structural identification:
Compound 6k:1H-NMR(CDCl3) δ (ppm): 6.503 (1H, s), 6.429 (1H, s), 6.221 (1H, dd),
5.601 (1H, m), 4.560 (2H, t), 3.306 (2H, t), 2.820 (1H, m), 2.35 (1H, m), 2.216 (1H, m), 2.117
(2H, t), 1.986~1.980 (having at 4H, m, 1.985 unimodal in absorbing by force), 1.733 (1H, m), 1.506 (2H, m),
1.319~1.312 (4H, m), 1.289~1.245 (12H, m).
The preparation of 3 2- methylacryoyloxyethyl phosphocholine (compound 7, MPC) of embodiment and structural identification
Preparation:
(1) 20g HEMA and 15.6mg triethylamine are taken, is placed in 500mL three-necked bottle, 200mL anhydrous tetrahydro furan is added
Dissolve above-mentioned solid.The 100mL anhydrous tetrahydrofuran solution of lower drop 21.9g COP is stirred after acquired solution is cooled to -20 DEG C,
1h is added dropwise, and reacts 3h at -20 DEG C~-30 DEG C, is filtered to remove the three second ammonium solid of chlorination of precipitation, gained filtrate decompression
Distillation.50mL anhydrous ether is added into the residue after distillation, is filtered to remove the three second ammonium of a small amount of chlorination of precipitation, filtrate decompression
It distills to get being in the intermediate OPEMA 32.6g of colorless liquid.
(2) it takes 5.0g OPEMA to be dissolved in 30mL anhydrous acetonitrile to be placed in 200mL glass pressure bottle, is cooled to -20 DEG C
It is rapidly added 2mL Trimethylamine Anhydrous thereto afterwards.Sealing pressure bottle is cooled to -20 DEG C, argon gas after being warming up to 60 DEG C of reaction 16h
The white solid of precipitation is filtered under atmosphere, is then dried under reduced pressure to get MPC (compound 7,3.1g).
Structural identification: compound 7:1H-NMR(CDCl3) δ (ppm): 6.102 (1H, s), 5.608 (1H, s), 4.263 (4H,
M), 4.051 (2H, t, J=6.1), 3.757 (2H, t, J=6.1), 3.322 (9H, s), 1.902 (3H, s), with document report phase
Unanimously.
The preparation of 4 copolymer 1 k (m:n=76:24) of embodiment
Take 3.61g compound 6k (0.01mol), 0.99g 2- methylacryoyloxyethyl phosphocholine (compound 7,
MPC, 3.33mmol) with 0.046g AIBN, the amount of reordering methanol/tetrahydrofuran (1/4, v/v) mixed solvent is configured to chemical combination
The solution that the mass concentration (wt%) of object 6b is 20%.After acquired solution is moved in polymerisation tube, argon is passed through into solution
Gas is to remove the oxygen in solution.Reaction tube is sealed, and cooling after concussion 16h at 60 DEG C, to stop polymerization reaction.It will reaction
Liquid is poured onto normal heptane, and the solid of precipitation is collected by filtration, and drying under vacuum obtains solid 4.08g.
The preparation of 5 compound 4m of embodiment and structural identification
Preparation: taking 0.280g compound 2m (1mmol), be dissolved in 5mL methylene chloride, after stirring 5min at -10 DEG C, Xiang Qi
In the 5mL dichloromethane solution of 0.087mL oxalyl chloride (1mmol) is slowly added dropwise, dripped off in 20min, then drop a N, N- bis- is added dropwise
Methylformamide continues at -10 DEG C to stir 2h, obtains solution A；0.063mL ethylaminoethanol (1.05mmol) separately is taken, is dissolved in 5mL bis-
In chloromethanes, then 0.276mL triethylamine (2mmol) is added dropwise thereto, is stirred evenly at -10 DEG C, obtain solution B.Slowly by solution A
It is added dropwise in solution B, continues to stir 2h at -10 DEG C.Reaction solution is washed with 10% sodium carbonate liquor of 10mL, water layer dichloromethane
Alkane extracts (3 × 5mL), organic layer 10mL saturated common salt water washing.Anhydrous magnesium sulfate is used after merging aforementioned all organic phases
It dries, filters, is concentrated under reduced pressure, crude product Flash silica column chromatographs (ethyl acetate: petroleum ether=1:1, V/V) and purifies, and obtains
0.255g white solid, yield 78.9%.
Structural identification:
Compound 2m:1H-NMR(CDCl3) δ (ppm): 6.251 (1H, dd), 5.582 (1H, m), 2.839 (1H, m),
2.332 (1H, m), 2.234~2.218 (3H, m), 1.969 (1H, m), 1.705 (1H, m), 1.518 (2H, m), 1.331~
1.248 (20H, m)
Compound 4m:1H-NMR(CDCl3) δ (ppm): 6.247 (1H, dd), 5.571 (1H, m), 3.493 (2H, t),
3.205 (2H, t), 2.827 (1H, m), 2.309~2.236 (2H, m), 2.135 (2H, t), 1.958 (1H, m), 1.709 (1H,
M), 1.553 (2H, t), 1.288~1.267 (20H, m).
The preparation of 6 compound 6m of embodiment and structural identification
Preparation: take 0.324g compound 4m (1mmol), 10mL toluene, 0.126g p-methyl benzenesulfonic acid and 0.036g to benzene two
Phenol, mixing are placed in the three-neck flask equipped with water segregator, and heating stirring to solid all dissolves, then to resulting mixture
0.129g methacrylic acid (1.5mmol) is added in system.Continue to be heated to reflux temperature, water and toluene azeotropic, while quilt
It steams.When the water in water segregator is suitable with theoretical value (about 0.018g), vacuum distillation removes unreacted methacrylic acid
With toluene.Thick ester in flask is cooled to room temperature, appropriate petroleum ether is added and is completely dissolved, with including 5% sodium carbonate and 1% hydrogen
It in the lye of sodium oxide molybdena and washs to alkalescence, removes a small amount of toluene and methacrylic acid, p-methyl benzenesulfonic acid and hydroquinone,
Again with distillation be washed to neutrality, after dried, filtered with anhydrous calcium chloride after steam petroleum ether, obtain grey 0.371g white solid powder
End, yield 93.1%.
Structural identification:
Compound 6m:1H-NMR(CDCl3) δ (ppm): 6.472 (1H, s), 6.418 (1H, s), 6.204 (1H, dd),
5.601 (1H, m), 4.564 (2H, t), 3.296 (2H, t), 2.825 (1H, m), 2.305~2.259 (2H, m), 2.150 (2H,
T), 1.999 (3H, s), 1.959 (1H, m), 1.700 (1H, m), 1.531 (2H, m), 1.316~1.227 (20H, m).
The preparation of 7 copolymer 1 m (m:n=76:24) of embodiment
Take 3.91g compound 6m (0.01mol), 0.99g 2- methylacryoyloxyethyl phosphocholine (compound 7,
MPC, 3.33mmol) with 0.049g AIBN, the amount of reordering methanol/tetrahydrofuran (1:4, v/v) mixed solvent is configured to chemical combination
The solution that the mass concentration (wt%) of object 6m is 20%.After acquired solution is moved in polymerisation tube, argon is passed through into solution
Gas is to remove the oxygen in solution.Reaction tube is sealed, and cooling after concussion 16h at 60 DEG C, to stop polymerization reaction.It will reaction
Liquid is poured onto ether, and the solid of precipitation is collected by filtration, and drying under vacuum obtains solid 4.25g.
(number is " nanoparticle to nanoparticle of the embodiment 8 comprising Exenatide and copolymer 1k (m:n=76:24)EXE")
Preparation
The copolymer 1 k for taking 1g embodiment 4 to be prepared, is dissolved in methylene chloride, is configured to copolymer 1 k concentration and is
The oil phase substrate solution of 125mg/mL takes 0.18g Exenatide to be scattered in above-mentioned matrix solution and forms oily phase.By resulting oily phase
20min is stirred under the revolving speed of 450rpm, it is uniformly mixed, obtains solution A.Quantitative hypromellose is taken, is with water
Solvent, the concentration for being configured to hypromellose is the aqueous phase solution of (w/w) 2.75%, ie in solution B.Solution A is added drop-wise to
In solution B, wherein the volume of solution B is 12 times of solution A volume, stirs 12h under 1250rpm revolving speed.Then 1000rpm turns
The lower high speed centrifugation of speed, the step of collecting resulting nanoparticle, take precipitating, add distillation water dispersion, repeat centrifuging and taking precipitating, until
Hypromellose is finally dry to get target nanoparticle by pellet frozen by wash clean.
(number is " nanoparticle to nanoparticle of the embodiment 9 comprising Liraglutide and copolymer 1m (m:n=76:24)LIR")
Preparation
The copolymer 1 m for taking 1g embodiment 7 to be prepared, is dissolved in ethyl alcohol, is configured to copolymer 1 m concentration and is
The oil phase substrate solution of 125mg/mL takes 0.18g Liraglutide to be scattered in above-mentioned matrix solution and forms oily phase.By resulting oily phase
20min is stirred under the revolving speed of 450rpm, it is uniformly mixed, obtains solution A.Quantitative polyethylene is taken, is taken water as a solvent, is prepared
The aqueous phase solution for being (w/w) 2.75% at polyethylene, ie in solution B.Solution A is added drop-wise in solution B, wherein the volume of solution B
It is 12 times of solution A volume, stirs 12h under 1250rpm revolving speed.Then high speed centrifugation under 1000rpm revolving speed collects resulting receive
The step of grain of rice takes precipitating, adds distillation water dispersion, repeats centrifuging and taking precipitating, until polyethylene by wash clean, will finally precipitate
Freeze-drying is to get target nanoparticle.
(number is " nanoparticle to nanoparticle of the embodiment 10 comprising A Bilu peptide and copolymer 1k (m:n=76:24)ALB”)
Preparation
The copolymer 1 k for taking 1g embodiment 4 to be prepared, is dissolved in methylene chloride, is configured to copolymer 1 k concentration and is
The oil phase substrate solution of 125mg/mL takes 0.18g Ah to be scattered in above-mentioned matrix solution than Shandong peptide and forms oily phase.By resulting oily phase
20min is stirred under the revolving speed of 450rpm, it is uniformly mixed, obtains solution A.Quantitative Tween 80 is taken, is taken water as a solvent, is prepared
The aqueous phase solution that concentration at Tween 80 is (w/w) 2.75%, ie in solution B.Solution A is added drop-wise in solution B, wherein solution B
Volume be 12 times of solution A volume, stir 12h under 1250rpm revolving speed.Then high speed centrifugation under 1000rpm revolving speed collects institute
Nanoparticle, take precipitating, add distillation water dispersion, repeat centrifuging and taking precipitating the step of, up to Tween 80 by wash clean, finally
Pellet frozen is dry to get target nanoparticle.
11 including degree of embodiment draws the nanoparticle of Shandong peptide and copolymer 1k (m:n=76:24), and (number is " nanoparticleDUL”)
Preparation
The copolymer 1 k for taking 1g embodiment 4 to be prepared, is dissolved in methylene chloride, is configured to copolymer 1 k concentration and is
The oil phase substrate solution of 125mg/mL takes 0.18g Du Lalu peptide to be scattered in above-mentioned matrix solution and forms oily phase.By resulting oily phase
20min is stirred under the revolving speed of 450rpm, it is uniformly mixed, obtains solution A.Quantitative Tween 80 is taken, is taken water as a solvent, is prepared
The aqueous phase solution that concentration at Tween 80 is (w/w) 2.75%, ie in solution B.Solution A is added drop-wise in solution B, wherein solution B
Volume be 12 times of solution A volume, stir 12h under 1250rpm revolving speed.Then high speed centrifugation under 1000rpm revolving speed collects institute
Nanoparticle, take precipitating, add distillation water dispersion, repeat centrifuging and taking precipitating the step of, up to Tween 80 by wash clean, finally
Pellet frozen is dry to get target nanoparticle.
(number is " nanoparticle to nanoparticle of the embodiment 12 comprising sharp hila peptide and copolymer 1m (m:n=76:24)LIX”)
Preparation
The copolymer 1 m for taking 1g embodiment 7 to be prepared, is dissolved in chloroform, is configured to copolymer 1 m concentration and is
The oil phase substrate solution of 125mg/mL takes 0.18g benefit hila peptide to be scattered in above-mentioned matrix solution and forms oily phase.By resulting oily phase
20min is stirred under the revolving speed of 450rpm, it is uniformly mixed, obtains solution A.Quantitative gelatin is taken, is taken water as a solvent, is configured to
The concentration of gelatin is the aqueous phase solution of (w/w) 2.75%, ie in solution B.Solution A is added drop-wise in solution B, wherein the body of solution B
Product is 12 times of solution A volume, stirs 12h under 1250rpm revolving speed.Then high speed centrifugation under 1000rpm revolving speed is collected resulting
The step of nanoparticle takes precipitating, adds distillation water dispersion, repeats centrifuging and taking precipitating, until gelatin by wash clean, will finally precipitate
Freeze-drying is to get target nanoparticle.
(number is " nanoparticle to nanoparticle of the embodiment 13 comprising Si Meilu peptide and copolymer 1m (m:n=76:24)SEM”)
Preparation
The copolymer 1 m for taking 1g embodiment 7 to be prepared, is dissolved in ethyl alcohol, is configured to copolymer 1 m concentration and is
The oil phase substrate solution of 125mg/mL takes 0.18g Si Meilu peptide to be scattered in above-mentioned matrix solution and forms oily phase.Gained oil is mutually existed
20min is stirred under the revolving speed of 450rpm, it is uniformly mixed, obtains solution A.Quantitative polyethylene is taken, is taken water as a solvent, is configured to
The concentration of polyethylene is the aqueous phase solution of (w/w) 2.75%, ie in solution B.Solution A is added drop-wise in solution B, wherein solution B
Volume is 12 times of solution A, stirs 12h under 1250rpm revolving speed.Then high speed centrifugation under 1000rpm revolving speed collects resulting receive
The step of grain of rice takes precipitating, adds distillation water dispersion, repeats centrifuging and taking precipitating, until polyethylene by wash clean, will finally precipitate
Freeze-drying is to get target nanoparticle.
Embodiment 14 includes orlistat and nanoparticleEXEGranule preparation
The nanoparticle for taking 120g orlistat, embodiment 8 to be preparedEXE(Exenatide containing 18mg), 90g pregelatinated form sediment
Powder, 0.6g magnesium stearate, pelletize after mixing, be distributed into 1000 bags to get.
Embodiment 15 includes orlistat and nanoparticleLIRGranule preparation
The nanoparticle for taking 120g orlistat, embodiment 9 to be preparedLIR(Liraglutide containing 2.6g), 85 grams of dextrin,
The mono- stearyl ester glyceride of 0.8g, pelletizes after mixing, be distributed into 1000 bags to get.
Embodiment 16 includes orlistat and nanoparticleALBCapsule preparation
The nanoparticle for taking 120g orlistat, embodiment 10 to be preparedALB(Ah containing 76g is than Shandong peptide), 95g microcrystalline cellulose
Element, 0.6g monopalmitin, after mixing it is filling at 1000 capsules to get.
Embodiment 17 includes orlistat and nanoparticleDULCapsule preparation
The nanoparticle for taking 120g orlistat, embodiment 11 to be preparedDUL(peptide of Du Lalu containing 2.2g), 85g sorbierite,
0.6g magnesium laurylsulfate, after mixing it is filling at 1000 capsules to get.
Embodiment 18 includes orlistat and nanoparticleLIXTablet preparation
Take 120g orlistat, embodiment 12 that nanoparticle is preparedLIX(hila of benefit containing 28mg peptide), 96g mannitol,
0.8g sldium lauryl sulfate, be pressed into after mixing 1000 to get.
Embodiment 19 includes orlistat and nanoparticleSEMTablet preparation
The nanoparticle for taking 120g orlistat, embodiment 13 to be preparedSEM(peptide of Si Meilu containing 1.5g), 90g lactose,
0.8g polyethylene glycol, be pressed into after mixing 1000 to get.
Test example one, comprising the nanoparticles oral of GLP-1 receptor stimulating agent and copolymer administration after in the intracorporal life of rat
The research of object availability
1, trial drug: nanoparticle prepared by embodiment 8EXE, prepared according to method disclosed by 1 embodiment 2 of documents
Obtained nanoparticle (comparison nanoparticle), all nanoparticles are being configured to drinking water according to GLP-1 receptor stimulating agent before use
Count the solution that concentration is 10 μ g/mL；Exenatide is configured to the injection solution that concentration is 5 μ g/mL with water for injection.
2, experimental animal: SD rat, 12, half male and half female, 200 ± 20g of weight.
3, test method:
SD rat is randomly divided into three groups, every group 4 average, and half male and half female can feed food and water freely.
Two groups of rats use nanoparticle of the present invention respectivelyEXE, comparison the disposable gastric infusion of nanoparticle, dosage is 300 μ g/
kg；Another group of rat Exenatide injection subcutaneous administrations, dosage are 50 μ g/mL.Every rat is in gastric infusion
0,0.5h, 1h, 2h, 4h, 6h, 8h, 10h, 12h, for 24 hours, after 30h, 48h and 75h through taking blood by tail vein, every 200 μ L every time.
All plasma samples are added heparin and are then centrifuged 5min under 4 DEG C and 3000 × g revolving speed immediately for anticoagulant, and use Ai Sai
That peptide EIA kit carries out quantitative analysis to the Exenatide in sample, opposite after nanoparticles oral is calculated further according to following formula
Bioavilability.
4, test result:
It is computed, nanoparticle prepared by the embodiment of the present invention 8EXERelative bioavailability to be significantly higher than documents 1 real
Apply the nanoparticle (63.5%Vs.16.9%) of the preparation of example 2.
The weight-reducing of test example two, the composition comprising orlistat and GLP-1 receptor stimulating agent to nutritive obesity in rats
Effect study
1,70 male cleaning grade SD rats, weight about 80g, by Zhongshan University's Experimental Animal Center experimental animal: are chosen
It provides.
2, test feed: normal diet and nutrition type feed are provided by Zhongshan University's Experimental Animal Center, two kinds of feedings
The composition of material is as shown in table 8.
3, trial drug: embodiment 16 obtained includes orlistat and nanoparticleALBCapsule (composition A group), real
It is obtained comprising orlistat and nanoparticle to apply example 17DULCapsule (composition B group), orlistat capsule (orlistat
Group, the production of specification 120mg, Zhong Shanwanhan pharmaceutical Co. Ltd), all capsules are taking its content before use, are used in combination
0.5% carboxymethylcellulose sodium solution is made into the stomach-filling liquid of 3g/L (according to orlistat meter), by the dosage of 60mg/kg/d (according to Austria
Li Sita meter) stomach-filling.The nanoparticle that another Example 10 is preparedALB(nanoparticle A group) is received with what embodiment 11 was prepared
The grain of riceDUL(nanoparticle B group), being made into concentration as solvent using 0.5% carboxymethylcellulose sodium solution is respectively 1.9g/L (according to Ah ratio
Shandong peptide meter) with the stomach-filling liquid of 0.055g/L (Yi Dulalu peptide meter), respectively by 38mg/kg/d (based on Yi Abilu peptide) and 1.1mg/
The dosage stomach-filling of kg/d (Yi Dulalu peptide meter).
4, test method:
4.1 modelings, grouping and administration
According to obesity pharmacodynamic study and evaluation method in " Herbal pharmacodynamics research and evaluation ", using pre- preventing obesity mould
Type method.Experimental animal is randomly divided into 7 groups by weight, every group 10, respectively blank control group, model control group, Ao Lisi
His group, nanoparticle A group, nanoparticle B group, composition A group, composition B group.
Groups of animals feeds normal diet to blank control group when every morning 9, and model control group and experimental group feed nutrition
Type feed, at night 7 when take food away, it is quantitative daily to food (eaten up with most animals and adjust feed administered dose daily for principle).
Experimental group is at the morning 9 and 3 time-division of afternoon 2 times are pressed 10mLkg-10.5% carboxymethylcellulose sodium solution is dissolved in corresponding drug
Stomach-filling, blank control group and the isometric 0.5%CMC-Na solution of model control group stomach-filling, week for 7 weeks.
5, test result:
Test result is as shown in table 9.
Table 8: the composition of normal diet and nutrition type feed
Table 9: test front and back each group rat body weight situation of change compares
As can be seen from Table 9, after test, the weight of model control group rat is apparently higher than blank control group, this illustrates to seek
Fat rats modeling of nourishing one's nature success.Compared with model control group, nanoparticle A group, the weight of nanoparticle B group rat and weight gain become
Change more apparent, this explanation, nanoparticleALB, nanoparticleDULPlay the role of mitigating rat body weight, while also illustrating the present invention to be copolymerized
Object is oral administration biaavailability of carrier the nanoparticle obtained that can be for oral administration comprising GLP-1 receptor stimulating agent to rat
Height has good inhibition weight gain and fat-reducing effect.Compared with model control group, orlistat group, composition A group, group
Weight and the weight gain variation for closing object B group rat are more apparent, this illustrates, orlistat and includes orlistat and nanoparticleALBGlue
Wafer includes orlistat and nanoparticleDULCapsule have and preferable inhibit weight gain and fat-reducing effect.With Ao Lisi
His group, nanoparticle A group, nanoparticle B group are compared, and composition A group, composition B, which have, preferably inhibits weight gain and weight-reducing effect
Fruit.It can be seen that in the present invention, after the nanoparticle comprising GLP-1 receptor stimulating agent and copolymer is used cooperatively with orlistat,
The two plays synergistic effect.
Claims (10)
1. a kind of nanoparticle comprising GLP-1 receptor stimulating agent and copolymer, which is characterized in that the structure such as formula of the copolymer
Shown in I,
The mass ratio of the GLP-1 receptor stimulating agent and copolymer is 1:10~1:1；Wherein, x is to be selected from 10 selected from 10,12, x
When, m:n is 53:47~76:24, and the weight average molecular weight of the copolymer is 39900~61700；Or x be selected from 12 when, m:n is
50:50~76:24, the weight average molecular weight of the copolymer are 18500~30900.
2. as described in claim 1 including the nanoparticle of GLP-1 receptor stimulating agent and copolymer, which is characterized in that described
GLP-1 receptor stimulating agent is in Exenatide, Liraglutide, A Bilu peptide, Du Lalu peptide, sharp hila peptide, Si Meilu peptide
It is a kind of.
3. the preparation method of the nanoparticle as described in claim 1 comprising GLP-1 receptor stimulating agent and copolymer, feature exist
In, comprising the following steps:
(1) copolymer is taken, above-mentioned copolymer is dissolved in dispersed phase, is configured to the oily phase that copolymer concentration is 50~200mg/mL
Matrix solution, then disperse above-mentioned oil phase substrate solution for GLP-1 receptor stimulating agent and form oily phase, by gained oil mutually 100~
10~30min is stirred under the revolving speed of 800rpm, is uniformly mixed it, is obtained solution A；
(2) surfactant is taken, is taken water as a solvent, the water phase that the mass concentration for preparing forming surfactants is 0.5~5% is molten
Liquid, ie in solution B；
(3) step (1) acquired solution A is added drop-wise in step (2) acquired solution B, the volume of solution B is the 4 of the volume of solution A
, 10~14h is stirred under 500~2000rpm revolving speed, then high speed centrifugation under 5000~15000rpm revolving speed, collect institute by~20 times
Nanoparticle, the step of taking precipitating, add distillation water dispersion, repeat centrifuging and taking precipitating, up to surfactant is by wash clean,
Finally by pellet frozen it is dry to get.
4. the preparation method of the nanoparticle as claimed in claim 3 comprising GLP-1 receptor stimulating agent and copolymer, feature exist
In dispersed phase described in the step (1) is selected from one of ethyl alcohol, methylene chloride, chloroform, ethyl acetate, acetone.
5. the preparation method of the nanoparticle as claimed in claim 3 comprising GLP-1 receptor stimulating agent and copolymer, feature exist
In surfactant described in the step (2) is selected from one of gelatin, hypromellose, Tween 80.
6. a kind of composition comprising orlistat Yu GLP-1 receptor stimulating agent, which is characterized in that include orlistat and right
It is required that including the nanoparticle of GLP-1 receptor stimulating agent and copolymer described in 1.
7. as claimed in claim 6 including the composition of orlistat and GLP-1 receptor stimulating agent, which is characterized in that also wrap
Containing diluent and lubricant.
8. as claimed in claim 7 including the composition of orlistat and GLP-1 receptor stimulating agent, which is characterized in that described
Diluent is selected from pregelatinized starch, starch, dextrin, sucrose, microcrystalline cellulose, sorbierite, mannitol, lactose, calcium sulfate, phosphoric acid
One of hydrogen calcium, calcium phosphate are a variety of；The lubricant is selected from fumaric acid sodium, stearic acid, magnesium stearate, calcium stearate, stone
Wax, paraffin oil, glycerin monostearate, monopalmitin, sodium acetate, sodium chloride, DL-leucine, sldium lauryl sulfate,
One of magnesium laurylsulfate, polyethylene glycol are a variety of.
9. as claimed in claim 6 including the composition of orlistat and GLP-1 receptor stimulating agent, which is characterized in that described
Composition is oral solid formulation, and the oral solid formulation is one of granule, capsule, tablet.
10. the composition comprising orlistat and GLP-1 receptor stimulating agent as claim in any one of claims 6-9 is anti-in preparation
Control the purposes in fat drug.
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