CN116173188A - Oral GLP-1 analogue solid lipid nanoparticle, and preparation method and application thereof - Google Patents
Oral GLP-1 analogue solid lipid nanoparticle, and preparation method and application thereof Download PDFInfo
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- CN116173188A CN116173188A CN202310074882.5A CN202310074882A CN116173188A CN 116173188 A CN116173188 A CN 116173188A CN 202310074882 A CN202310074882 A CN 202310074882A CN 116173188 A CN116173188 A CN 116173188A
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- solid lipid
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Abstract
The invention discloses oral GLP-1 analogue solid lipid nanoparticles, a preparation method and application thereof, and belongs to the field of pharmaceutical preparations, wherein the GLP-1 analogue solid lipid nanoparticles comprise GLP-1 analogues and lipid materials coated with the GLP-1 analogues; is prepared from GLP-1 analogue, a first lipid material and a second lipid material by a solvent diffusion method; compounding the first lipid material with the second lipid material can enhance drug loading. The solid lipid nanoparticle can protect GLP-1 analogues from being damaged by gastrointestinal tracts, can realize high-efficiency oral absorption without opening intestinal barriers by virtue of the advantage of high compatibility of intestinal parietal cells, has good biological safety, can remarkably improve the oral bioavailability of the GLP-1 analogues, reduces the drug cost and increases the application prospect of the GLP-1 analogues in the field of diabetes treatment compared with a commercially available preparation Rybelsus.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to oral GLP-1 analogue solid lipid nanoparticles, and a preparation method and application thereof.
Background
Diabetes and cardiovascular diseases, respiratory diseases and are known as "chronic killers". Among them, diabetes mellitus has a large number of people with high prevalence and a huge market scale. Reports issued by the international diabetes consortium show that about 4.63 million adults 20 to 79 years old all over the world have diabetes; the number of diabetics is continuously rising, and the diabetes medicine demand market is huge.
The glucagon-like peptide-1 (GLP-1) analogues such as semaglutin and liraglutide can promote insulin secretion, reduce glucagon secretion, avoid enzymolysis of dipeptidyl peptidase 4, have longer half-life with albumin, can not cause hypoglycemia, and have safe and long-acting hypoglycemic effect compared with traditional insulin. However, GLP-1 analogues are orally administered in a form that is easily broken by gastric acid, and thus subcutaneous injection is commonly used. Until day 20 of 9 of 2019, once daily oral semaglutin tablets (trade name: rybellus) from danish and nod are marketed in FDA, breaking the dosing limit.
However, there are no oral formulations of liraglutide on the market at present, and rybellus itself still has some drawbacks. First, the extent of semaglutin absorption depends on the amount of the co-formulated pro-absorber sodium 8- (2-hydroxybenzoamido) octoate (SNAC), but the biological safety hazards presented by SNAC's frequent opening of the intestinal wall barrier and the alteration of the intestinal microbiota still require further attention. In addition, rybellus is orally administered at a dose of 7 to 14 mg/day, subcutaneously injected at a dose of 1 mg/week, orally administered at a dose of 49 to 98 times the injection, and rybellus needs to be administered at a high dose to achieve clinical effects similar to subcutaneous injection, which greatly increases the administration cost. )
In the prior art, the Chinese patent document with the publication number of CN114712488A discloses a pharmaceutical composition of dorzagliptin and glucagon-like peptide-1 analogue, and the dorzagliptin multi-column Ai Ting and the GLP-1 analogue are combined to effectively control blood sugar, so that the blood sugar reducing efficacy of the dorzagliptin or the GLP-1 analogue of the existing hypoglycemic agent is improved; the Chinese patent publication No. CN106729717A discloses a GLP-1 analogue and ziconotide composition slow release microsphere preparation, which comprises a GLP-1 analogue, ziconotide, a biodegradable and biocompatible polymer material, a stabilizer and a freeze-drying protective agent; the GLP-1 analogue and the ziconotide are combined for use, so that diabetes and PDN complications thereof can be effectively treated, chronic pain is obviously relieved without drug resistance, and pain of patients is relieved. However, the above methods all require the combination of multiple drugs, and can not fundamentally solve the problem of low bioavailability of oral GLP-1 analogues.
Solid lipid nanoparticles (Solid Lipid Nanoparticles, SLN) are receiving widespread attention as oral nano-drug delivery systems. SLN uses biocompatible lipid as a framework material, can adsorb or encapsulate various hydrophobic or hydrophilic drugs, has the advantages of good physiological compatibility, stability, targeting property, sustained and controlled release and the like, and has wide application prospect. The development of oral GLP-1 analogue solid lipid nanoparticles is expected to solve the problems in the prior art.
Disclosure of Invention
The invention provides GLP-1 analogue solid lipid nanoparticles which can protect GLP-1 analogues from being damaged by gastrointestinal tracts, and can realize high-efficiency oral absorption without opening intestinal barriers by virtue of the advantage of high compatibility of intestinal parietal cells, and have good biological safety, good medication compliance and wide application prospects in the field of diabetes prevention/treatment.
The technical scheme adopted is as follows:
a GLP-1 analogue solid lipid nanoparticle comprising a GLP-1 analogue and a lipid material coating the GLP-1 analogue; is prepared from GLP-1 analogue, a first lipid material and a second lipid material by a solvent diffusion method;
the first lipid material is at least one of a fatty acid, a fatty alcohol, or a fatty glyceride, including, but not limited to, one or more combinations of glyceryl monostearate, glyceryl distearate, glyceryl behenate, stearyl alcohol, stearic acid, oleic acid, and the like; the second lipid material is at least one of a cationic lipid, a zwitterionic lipid, or an ionizable cationic lipid, including, but not limited to, one or more combinations including, but not limited to, 1, 2-dioctadienyloxy-3-methylammonium propane (DOTMA), 3β - [ N- (N ', N' -dimethylaminoethyl) carbamoyl ] cholesterol hydrochloride (DC-CHOL), (1, 2-dioleoxypropyl) trimethylammonium chloride (DOTAP), lecithin, distearoyl phosphatidylethanolamine polyethylene glycol (DSPE-PEG), 1, 2-dioleol-3-dimethylamino-propane (DODMA), octadecylamine, 4- (N, N-dimethylamino) butanoic acid (dioleyl) methyl ester (DLin-MC 3-DMA), and the like.
The GLP-1 analogs include, but are not limited to, semaglutin, liraglutide, and the like.
The mass ratio of GLP-1 analogue, first lipid material and second lipid material is 1:2-19:0.2-4.
The second lipid material is compounded with the GLP-1 analogue through interaction of electrostatic force, similar compatibility and the like, so that the fat solubility of the second lipid material is further improved, solid lipid nanoparticles are formed by the polypeptide and the lipid material, the GLP-1 analogue can be effectively encapsulated by the solid lipid nanoparticles, the gastrointestinal stability and oral bioavailability of the GLP-1 analogue are remarkably improved by relying on the advantage of high compatibility of the solid lipid nanoparticles and intestinal wall cells, and the medication cost is reduced.
The particle size of the GLP-1 analogue solid lipid nanoparticle is 50-800nm.
The GLP-1 analogue solid lipid nanoparticle has a drug loading of 0.1-10.1 wt%, preferably 0.9-8.1 wt%.
The invention also provides a preparation method of the GLP-1 analogue solid lipid nanoparticle, which specifically comprises the following steps:
(1) Preparing an organic phase from a GLP-1 analogue, a first lipid material and a second lipid material; taking poloxamer water solution as water phase;
preferably, the preparation method of the organic phase comprises the following steps: weighing GLP-1 analogue, a first lipid material and a second lipid material, dissolving in an organic solvent, and uniformly mixing to obtain an organic phase; or preparing GLP-1 analogue and a second lipid material into a drug-lipid complex, dispersing the drug-lipid complex into an organic solvent containing the first lipid material, and uniformly mixing to obtain an organic phase;
the organic solvent includes, but is not limited to, one or more combinations of methanol, ethanol, dimethyl sulfoxide, and the like;
(2) Injecting the organic phase into the water phase, stirring and diffusing to obtain solid lipid nanoparticle dispersion liquid loaded with GLP-1 analogues;
(3) Adjusting the pH value or the ionic strength of the solid lipid nanoparticle dispersion liquid loaded with the GLP-1 analogue to a target value to enable the solid lipid nanoparticle to precipitate (the target value of the pH is 0.8-1.2, the target value of the ionic strength is 4.0-4.5 mol/L), further centrifuging, taking the precipitate, redispersing the precipitate by using a poloxamer aqueous solution, and keeping the pH value of the solution neutral to obtain the GLP-1 analogue solid lipid nanoparticle.
The invention also provides application of the GLP-1 analogue solid lipid nanoparticle in preparing a medicament for preventing and/or treating diabetes.
Preferably, the GLP-1 analogue solid lipid nanoparticle is delivered orally.
Compared with the prior art, the invention has the beneficial effects that:
(1) The GLP-1 analogue solid lipid nanoparticle provided by the invention takes intestinal wall cell high-compatibility lipid as a carrier material, and efficiently encapsulates the polypeptide drug GLP-1 analogue. The solid lipid nanoparticle not only protects GLP-1 analogues from being damaged by gastrointestinal tracts, but also can realize high-efficiency oral absorption without opening intestinal barriers by virtue of the advantage of high compatibility of intestinal wall cells, and avoids the biological potential safety hazard caused by frequent opening of the intestinal barriers. In addition, the solid lipid nanoparticle can help patients get rid of injection anxiety, and improve medication compliance.
(2) The commercially available semegalternatively Lu Jiliang mg/week for injection and the commercially available oral semeglutide tablet (trade name: rybelsus) have a dose of 7-14 mg/day, the oral tablet needs to be given with a dose of 49-98 times to achieve the effect equivalent to subcutaneous injection, the oral relative bioavailability is extremely low, and the bioavailability of GLP-1 analogue solid lipid nano-particles in the invention relative to GLP-1 analogue subcutaneous injection reaches 9.5% -12.0%, which is far-supermarket sold preparation; namely, the solid lipid nanoparticle can obviously improve the oral bioavailability of the GLP-1 analogue, reduce the drug cost and increase the application prospect of the GLP-1 analogue in the field of diabetes treatment.
Drawings
Fig. 1 shows the particle size distribution and Zeta potential map of the 3 semaglutin solid lipid nanoparticles according to the prescription of example 1, wherein a is the particle size distribution map and B is the Zeta potential map.
FIG. 2 is a transmission electron microscope image of the 3-step solid lipid nanoparticle of semaglutinin of example 1.
FIG. 3 is a graph showing the results of oral glucose tolerance test of normal ICR mice after oral administration of the 3-solid lipid nanoparticles of semaglutinin prescribed in example 1.
Fig. 4 shows the particle size distribution and Zeta potential plot of the solid lipid nanoparticles of liraglutide of formulation 7 of example 1, wherein a is the particle size distribution and B is the Zeta potential plot.
FIG. 5 is a graph showing the in vivo blood glucose change after oral administration of solid lipid nanoparticles of liraglutide 7 prescribed in example 1 to type II diabetic mice.
Detailed Description
The invention is further elucidated below in connection with the examples and the accompanying drawing. It is to be understood that these examples are for illustration of the invention only and are not intended to limit the scope of the invention.
EXAMPLE 1 preparation of GLP-1 analog solid lipid nanoparticles
Prescriptions 1-9: the GLP-1 analogue solid lipid nanoparticles were prepared according to the following formulation and method, see table 1.
Method one: weighing GLP-1 analogue, dissolving in phosphate aqueous solution to obtain aqueous solution, dissolving the prescribed amount of second lipid material in methanol or ethanol to obtain organic solution, compounding the aqueous solution with the organic solution, and removing solvent by rotary evaporation to obtain the medicinal lipid compound; dispersing the lipid complex in an organic solvent containing a prescribed amount of a first lipid material to obtain an organic phase; taking poloxamer aqueous solution as a water phase, injecting an organic phase into the water phase, stirring and diffusing to obtain solid lipid nanoparticle dispersion liquid loaded with GLP-1 analogues;
and a second method: weighing GLP-1 analogue, a first lipid material and a second lipid material with prescription amounts, dissolving in an organic solvent, and vortex mixing to obtain an organic phase; taking poloxamer aqueous solution as water phase, injecting organic phase into the water phase, stirring and diffusing to obtain solid lipid nanoparticle dispersion liquid loaded with GLP-1 analogues.
And (3) taking solid lipid nanoparticle dispersion liquid loaded with GLP-1 analogue prepared by the first or second method, regulating the pH value to 0.8-1.2 by using hydrochloric acid solution, or regulating the ionic strength to 4.0-4.5 mol/L by using sodium chloride solution, centrifuging, taking precipitate, redispersing by using poloxamer aqueous solution, and keeping the pH value of the solution neutral to obtain the target substance.
TABLE 1 preparation method and prescription composition of solid lipid nanoparticles loaded with GLP-1 analog
Example 2 physicochemical Properties of preparation of GLP-1 analog solid lipid nanoparticles
GLP-1 analogue solid lipid nanoparticles prepared in each prescription in example 1 are taken, poloxamer water solution is taken as a diluent, diluted to 0.1mg/mL concentration, and the particle size and Zeta potential of the solid lipid nanoparticles are measured by a particle size and surface potential analyzer.
The encapsulation efficiency and drug loading rate of the GLP-1 analogues in the GLP-1 analogue solid lipid nanoparticles prepared by each prescription in the example 1 are determined by using a high performance liquid chromatography.
Chromatographic conditions of semaglutin: chromatographic column: a carbon 18 column; mobile phase: mobile phase a (90% nh) 4 H 2 PO 4 Aqueous +10% acetonitrile): mobile phase B (20% water+60% acetonitrile+20% isopropanol) =37:63 (v/v); column temperature: 30 ℃; detection wavelength: 210nm; flow rate: 1mL/min; sample injection amount: 20. Mu.L.
Chromatographic conditions of liraglutide: chromatographic column: a carbon 18 column; mobile phase: mobile phase a (acetonitrile+0.1% trifluoroacetic acid): mobile phase B (water+0.1% trifluoroacetic acid) =53:47 (v/v); column temperature: 25 ℃; detection wavelength: 220nm; flow rate: 1mL/min; sample injection amount: 20. Mu.L.
Taking a proper amount of solid lipid nanoparticles, diluting a mobile phase for 20 times, measuring the GLP-1 analogue drug quantity W according to the liquid chromatography condition, and calculating the GLP-1 analogue encapsulation efficiency and drug loading rate according to the formula (1) and the formula (2) respectively:
GLP-1 analog encapsulation efficiency (%) = W/W Total dosage of administration X 100% type (1)
GLP-1 analog drug loading (%) =W/(W+amount of first lipid material+amount of second lipid material) ×100% formula (2)
The results of measurement of physical and chemical properties such as particle diameter, zeta potential, encapsulation efficiency and drug loading of GLP-1 analog solid lipid nanoparticles prepared in each prescription in example 1 are shown in Table 2.
TABLE 2 physicochemical Properties of GLP-1 analog solid lipid nanoparticles prepared by each formulation in example 1
Example 3 investigation of the Properties, morphology and efficacy of the solid lipid nanoparticles of semaglutin prepared according to the formulation 3 of example 1
The solid lipid nanoparticle of semaglutin prepared in the prescription 3 in the example 1 is diluted to a concentration of 0.1mg/mL by taking poloxamer aqueous solution as a diluent, and the particle size and Zeta potential of the solid lipid nanoparticle are measured by using a particle size and surface potential analyzer. The solid lipid nanoparticle loaded with the semaglutin has the particle size of 75.5+/-3.0 nm, the Zeta potential of 40.8+/-0.9 mV, and the particle size distribution and the Zeta potential result are shown as A and B in figure 1 respectively.
Taking the semaglutin solid lipid nanoparticle, diluting to 0.1mg/mL concentration by taking poloxamer aqueous solution as a diluent, sucking 20 mu L of the poloxamer aqueous solution to be dropped on a copper net, airing, dyeing with 2% (w/v) phosphotungstic acid, and sucking the phosphotungstic acid by filter paper; the high-resolution transmission electron microscope is used for observing the morphology and the structure, and the result is shown in figure 2, and the semaglutin solid lipid nanoparticle is spherical, regular in appearance and uniform in particle size distribution.
The encapsulation efficiency and drug loading rate of the semaglutin solid lipid nanoparticle were measured by high performance liquid chromatography, wherein the chromatographic conditions and calculation method are the same as in example 2. According to the measurement, the encapsulation rate of the semaglutin solid lipid nanoparticle is 78.6%, and the drug loading rate is 5.2wt%.
The in vivo hypoglycemic efficacy of the semaglutin solid lipid nanoparticles prepared by prescription 3 in example 1 was examined by using a normal ICR mouse oral glucose tolerance test: taking 20-25g male ICR mice, 5 mice in each group, taking mouse tail venous blood at the morning after the next day, and measuring the fasting blood glucose value by using an Omron HGM-112 glucometer. The in vivo hypoglycemic efficacy of the solid lipid nanoparticle loaded with semaglutin was evaluated by administering 1h before glucose lavage (control group: physiological saline lavage; subcutaneous injection group: semaglutin subcutaneous injection; oral administration group: semaglutin solid lipid nanoparticle prepared by the formulation 3 in oral example 1), and then measuring the blood glucose level of mice at 7 time points of 5, 10, 15, 30, 45, 60, 120min after glucose lavage, respectively, and comparing the blood glucose change curves of the groups of mice. The results are shown in FIG. 3.
As shown in figure 3, the single oral solid lipid nanoparticles of the semaglutin in the mice can achieve the same hypoglycemic effect as that of a subcutaneous injection, which indicates that the oral solid lipid nanoparticles of the semaglutin can become a good substitute product of the semaglutin subcutaneous injection, help patients get rid of injection anxiety, improve medication compliance and show good application prospect in the field of diabetes treatment.
The difference in the area under the blood glucose level-time curve (Area under the curve, AUC) between the experimental group and the control group can reflect the hypoglycemic effect of the oral glucose tolerance test of the mice, and the relative bioavailability (F) can be calculated according to the difference in the area under the blood glucose level-time curve calculated by GraphPad Prism 8, and the calculation method is shown in the following formula (3):
F(％)＝{[AUC (0-t) control group -AUC (0-t) oral group ]×Dose Subcutaneous injection group }/{[AUC (0-t) control group -AUC (0-t)
Subcutaneous injection group ]×Dose Oral group 100% of the world Wide Web (3)
Wherein AUC (0-t) The AUC values calculated in the time period from 0 to t are shown, the control group is a normal saline gastric lavage group, the subcutaneous injection group is a subcutaneous injection semaglutin solution group, the oral administration group is an oral semaglutin solid lipid nanoparticle group, and the Dose is the administration amount of semaglutin.
Area under the curve AUC according to blood glucose level versus time curve (0-2h) The bioavailability of the solid lipid nanoparticles of the semaglutin reaches 9.5 percent relative to the oral bioavailability of a commercial preparation Rybelsus reported in far-beyond literature.
Example 4 investigation of Properties and efficacy of Liraglutide solid lipid nanoparticles prepared according to formulation 7 in example 1
The solid lipid nanoparticles of liraglutide prepared in the prescription 7 in the example 1 were diluted to a concentration of 0.1mg/mL with poloxamer aqueous solution as a diluent, and the particle size and Zeta potential were measured using a particle size and surface potential analyzer. The particle size of the solid lipid nanoparticle loaded with the liraglutide analogue is 60.5+/-2.0 nm, the Zeta potential is 29.6+/-1.2 mV, and the particle size distribution and the Zeta potential result are shown as A and B in figure 4 respectively.
The encapsulation efficiency and drug loading rate of liraglutide in the solid lipid nanoparticle were determined by high performance liquid chromatography, wherein the chromatographic conditions and calculation method are the same as in example 2. The encapsulation rate of the solid lipid nanoparticle loaded with the liraglutide is 69.8%, and the drug loading rate is 4.6% by weight.
Examine the hypoglycemic effect of the liraglutide solid lipid nanoparticle prepared by the prescription 7 in the example 1 in the type ii diabetic mice: weighing a plurality of KM mice fed with high fat and high sugar for 4 weeks, weighing streptozotocin according to the dosage of 50mg/kg, dissolving in 0.1M citric acid buffer solution (pH=4.5), immediately injecting into the body of the mice intraperitoneally, continuously injecting for 5 days, feeding for two weeks, and obtaining mice with the blood sugar value higher than 11.1mmol/L as II type diabetes mice for subsequent experiments; type ii diabetic mice were randomly divided into 3 groups of 5 mice each: the model control group, the subcutaneous injection group and the oral administration group are fasted for 12 hours before administration, and water is not forbidden. Wherein, the model control group does not carry out liraglutide treatment and irrigates the stomach with normal saline; subcutaneous injection group subcutaneously injected with liraglutide, oral administration group perfused with solid lipid nanoparticles of liraglutide prepared in the formulation 7 of example 1, periodically collecting mouse tail venous blood, and determining blood glucose change by Omron HGM-112 blood glucose meter. The blood glucose profiles of the mice in each group are compared to evaluate the in vivo blood glucose-lowering efficacy of the liraglutide solid lipid nanoparticle, and the results are shown in fig. 5.
As shown in fig. 5, the blood glucose of the mice in the blank group was always at a high blood glucose level within 24 hours, and the blood glucose was reduced to a low point within 6 hours in both the subcutaneous injection group and the oral administration group, and then the blood glucose was slowly raised. In addition, the oral nanoparticle group was milder in potency and longer in duration than the subcutaneous injection group.
The area on the initial blood glucose percentage-time curve (Area above the curve, AAC) was calculated from GraphPad Prism 8 using the initial blood glucose value as a baseline, and the relative bioavailability (F) was calculated using the AAC of the subcutaneous injection group as a control, as shown in the following formula (4):
F(％)＝{[AAC (0-t) oral group ]×Dose Subcutaneous injection group }/{[AAC (0-t) subcutaneous injection group ]×Dose Oral group }×
100% type (4)
Wherein AAC (0-t) Representing AAC values calculated in the time from 0 to t, wherein the subcutaneous injection group is a subcutaneous injection liraglutide solution group, and the oral administration group is an oral liraglutide solid lipid nanoparticle groupDose is the Dose of liraglutide.
The bioavailability of the liraglutide solid lipid nanoparticle relative to the liraglutide subcutaneous injection was as high as 12.0% calculated from the area on the initial percent blood glucose versus time curve.
The results show that the invention can obviously improve the oral bioavailability of the GLP-1 analogue, reduce the medication cost, provide possibility for further popularization and application of oral polypeptide, further relieve the injection anxiety of patients, improve the medication compliance and have wide application prospect in the field of diabetes treatment.
While the foregoing embodiments have been described in detail in connection with the embodiments of the invention, it should be understood that the foregoing embodiments are merely illustrative of the invention and are not intended to limit the invention, and any modifications, additions, substitutions and the like made within the principles of the invention are intended to be included within the scope of the invention.
Claims (10)
1. A GLP-1 analogue solid lipid nanoparticle, characterized in that the GLP-1 analogue solid lipid nanoparticle comprises a GLP-1 analogue and a lipid material coating the GLP-1 analogue; is prepared from GLP-1 analogue, a first lipid material and a second lipid material by a solvent diffusion method;
the first lipid material is at least one of fatty acid, fatty alcohol or fatty glyceride, and the second lipid material is at least one of cationic lipid, zwitterionic lipid or ionizable cationic lipid.
2. The GLP-1 analogue solid lipid nanoparticle according to claim 1, wherein the GLP-1 analogue comprises semaglutin or liraglutide.
3. The GLP-1 analogue solid lipid nanoparticle according to claim 1, wherein the first lipid material comprises glycerol monostearate, glycerol distearate, glycerol behenate, stearyl alcohol, stearic acid or oleic acid.
4. The GLP-1 analogue solid lipid nanoparticle according to claim 1, wherein the second lipid material comprises DOTMA, DC-CHOL, DOTAP, lecithin, DSPE-PEG, DODMA, octadecylamine or DLin-MC3-DMA.
5. The GLP-1 analogue solid lipid nanoparticle according to claim 1, wherein the drug loading of the GLP-1 analogue solid lipid nanoparticle is 0.1-10.1 wt%.
6. The method for preparing solid lipid nanoparticles of GLP-1 analogues according to any of the claims 1-5, comprising the steps of:
(1) Preparing an organic phase from a GLP-1 analogue, a first lipid material and a second lipid material; taking poloxamer water solution as water phase;
(2) Injecting the organic phase into the water phase, stirring and diffusing to obtain solid lipid nanoparticle dispersion liquid loaded with GLP-1 analogues;
(3) And regulating the pH value or the ionic strength of the GLP-1 analogue-loaded solid lipid nanoparticle dispersion liquid to a target value, centrifuging, taking a precipitate, redispersing by using a poloxamer aqueous solution, and keeping the pH value of the solution neutral to obtain the GLP-1 analogue solid lipid nanoparticle.
7. The method for preparing GLP-1 analogue solid lipid nanoparticles according to claim 6, wherein the method for preparing the organic phase comprises the following steps: weighing GLP-1 analogue, a first lipid material and a second lipid material, dissolving in an organic solvent, and uniformly mixing to obtain an organic phase; or preparing GLP-1 analogue and a second lipid material into a drug-lipid complex, dispersing the drug-lipid complex into an organic solvent containing the first lipid material, and uniformly mixing to obtain an organic phase.
8. The method for preparing GLP-1 analogue solid lipid nanoparticles according to claim 7, wherein the organic solvent comprises methanol, ethanol or dimethyl sulfoxide.
9. Use of GLP-1 analogue solid lipid nanoparticles according to any one of claims 1-5 for the preparation of a medicament for the prevention and/or treatment of diabetes.
10. Use of GLP-1 analogue solid lipid nanoparticles according to claim 9 for the preparation of a medicament for the prevention and/or treatment of diabetes, characterized in that said GLP-1 analogue solid lipid nanoparticles are delivered orally.
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