CN102293748B - Oral PEGylated insulin pH-sensitive naonparticle and preparation method thereof - Google Patents

Abstract

The invention discloses an oral pegylated insulin pH-sensitive nanoparticle and a preparation method thereof. The nanoparticle of the present invention consists of: pegylated insulin, pH sensitive polymer, carrier, additive and stabilizer. The preparation method of the nanoparticle of the present invention comprises the following steps: preparing W/O colostrum of pegylated insulin, pH-sensitive polymer and carrier, and W/O colostrum is dispersed in a stabilizer solution to form a W/O/W double emulsion , the crude product obtained after solvent volatilization is purified and freeze-dried to obtain the nanoparticles of the present invention. The pegylated insulin pH-sensitive nanoparticles of the present invention are evenly dispersed and have a high drug encapsulation rate; after the insulin is modified with polyethylene glycol, the aggregation of insulin molecules can be reduced, the half-life in the body can be prolonged, and the blood sugar can be lowered for a longer time ; The release rate of insulin is reduced in the gastric acid environment, while the nanoparticles are swollen and released in the intestinal environment, which has oral application value.

Description

A kind of oral pegylated insulin pH-sensitive nanoparticles and preparation method thereof

technical field

The invention belongs to the field of biomedicine and relates to a pH-sensitive nanoparticle and a preparation method thereof, in particular to an oral pegylated insulin pH-sensitive nanoparticle and a preparation method thereof.

Background technique

Common routes of drug administration include: oral, intravenous, intramuscular, and subcutaneous injections. Compared with other methods of administration, oral administration has the advantages of convenience, safety, relatively low cost, and good patient compliance. However, the route of oral administration has many limitations, and many factors in the administration process will affect the absorption of oral drugs. Most peptide and protein drugs are difficult to pass through the biomembrane barrier due to their large molecular weight and poor fat solubility. Moreover, due to the presence of a large number of peptidases and proteolytic enzymes in the gastrointestinal tract, they are easily eliminated by liver metabolism due to the first-pass effect after oral administration. These drugs are inherently chemically and conformationally unstable and have little or no gastrointestinal absorption. Therefore, the oral drug delivery system of peptide and protein drugs is very difficult. Improving the biomembrane permeability and resistance to protease degradation of peptide and protein drugs are the difficulties in the research and development of oral preparations.

Insulin is a protein hormone secreted by pancreatic β cells stimulated by endogenous or exogenous substances such as glucose, lactose, ribose, arginine, and glucagon. Exogenous insulin is mainly used for the treatment of diabetes, and the main treatment method is to directly inject insulin into diabetic patients. This method brings great pain to patients and is inconvenient to administer. However, when insulin is taken orally, there are problems such as short half-life, easy to be degraded by enzymes in the acidic environment of the stomach, easy to aggregate insulin, and difficult to absorb through the intestinal membrane in the intestinal tract, resulting in very low bioavailability.

After insulin is modified by polyethylene glycol, it can effectively extend its half-life, reduce the aggregation between molecules, and prolong the residence time in the body. Disclosed a kind of PLGA preparation containing pegylated insulin in U.S. Patent No.09/999,82 as Lewis et al., this preparation can reduce blood sugar concentration through subcutaneous injection into animal body, but can not be directly used for oral administration, and it comprises The sealing rate is only 33~49.2%; while Hinds et al [Kenneth Hinds, Kathleen Campbell, Kathleen Holland, PEGylated insulin in PLGA microparticles. In vivo and in vitro analysis, J Control Release, 2005, 104: 447-460] adopted the single emulsion method Using PLGA to encapsulate PEGylated insulin, the prepared microparticles have a higher drug loading capacity, but they are also not pH sensitive and can only be used for injection preparations. Existing pH-sensitive PEGylated insulin also has many deficiencies, such as [P. Calceti, S. Salmaso, G. Walker, A. Bernkop-Schnürch, Development and in vivo evaluation of an oral insulin–PEG delivery by Calceti et al. system, Eur J Pharm Sci, 2004, 22: 315] to prepare pegylated insulin tablets for improving the stability and oral bioavailability of pegylated insulin, the pegylated insulin tablets are adhered by membrane Composed of polyacrylic acid-cysteine, the surface layer of the tablet is L100-55 enteric coating, the tablet shows pH-sensitive release characteristics, but the ability of the drug to be absorbed is poor, and it is not as good as nanoparticles, which is more conducive to the absorption of biomacromolecules absorb.

Contents of the invention

The purpose of the present invention is to address the above-mentioned deficiencies in the prior art and combine the characteristics of pegylated insulin and pH-sensitive polymer nanoparticles to provide an oral pegylated insulin pH-sensitive nanoparticle and a preparation method thereof. In the present invention, PEGylated insulin is entrapped with a pH-sensitive polymer to form nanoparticles, which prevents the release of insulin in the acidic environment of the stomach and prevents pepsin from degrading insulin; while in the intestinal environment, the pH-sensitive polymer swells , or even dissolve, to promote the rapid release of insulin, while nanoparticles are also conducive to the absorption of insulin and improve its relative bioavailability.

In order to achieve the above object, the present invention adopts the following technical solutions:

An oral PEGylated insulin pH-sensitive nanoparticle, which consists of: 3-8% by mass of PEGylated insulin, 46-68% by mass of a pH-sensitive polymer, 100% by mass 22-47% carrier, 0.5-2% additive by mass and 1-5% stabilizer by mass.

The mass ratio of the pH-sensitive polymer and the carrier in the present invention is (1-3):1.

The PEGylated insulin of the present invention is insulin modified by monomethoxy polyethylene glycol butyraldehyde, the molecular weight of the monomethoxy polyethylene glycol butyraldehyde is 5000; the pH sensitive polymer is hydroxypropyl methyl cellulose phthalate; the carrier is polyethylene lactide or polylactic acid; the additive is one or both of glycerin or starch; the stabilizer is polyvinyl alcohol.

The average molecular weight of the carrier of the present invention is 5,000-100,000, wherein the molar ratio of lactide to glycolide in the polyethylene lactide molecular segment is 50:50.

The preparation method of oral pegylated insulin pH-sensitive nanoparticles of the present invention comprises the following steps:

(1) Prepare W/O colostrum of PEGylated insulin, pH-sensitive polymer and carrier material by ultrasonic emulsification: weigh the additive according to the formula of claim 1, dissolve it in deionized water, and prepare a mass fraction of 0.1-0.5 % of the additive solution; add PEGylated insulin to the additive solution at a mass volume ratio of 10 to 40 mg/mL and dissolve it to form an inner aqueous phase; mix acetone and dichloromethane at a volume ratio of 1:4 to obtain a mixed solvent, According to claim 1, the pH-sensitive polymer and the carrier are added to the mixed solvent and dissolved to form an oil phase, the total concentration of the pH-sensitive polymer and the carrier in the oil phase is 20-40 mg/mL, and the pH-sensitive polymer The mass ratio with the carrier is (1~3):1; the inner water phase and the oil phase are mixed according to the volume ratio of 1:(5~20), and 40~60W ultrasonic emulsification is performed for 0.5~4min to obtain W/O colostrum;

(2) Ultrasonic dispersion of W/O colostrum in the stabilizer solution to form W/O/W double emulsion: Weigh the stabilizer according to the formula of claim 1, dissolve it in deionized water to form an external water phase, and the external The concentration of the stabilizer in the water phase is 0.1~3%; the above-mentioned outer water phase is mixed with the W/O colostrum obtained in step (1), and ultrasonically emulsified at 40~60W for 0.5~4min to obtain a W/O/W double emulsion. The volume ratio of the above-mentioned water phase to the oil phase in W/O colostrum is (2~8):1;

(3) The W/O/W double emulsion solvent is volatilized to obtain the crude product of nanoparticles: the W/O/W double emulsion obtained in step (2) is volatilized in a water bath at 35~45°C under reduced pressure at 400~500mbar to obtain polyethylene glycol Glycolated insulin pH-sensitive nanoparticle crude product;

(4) Purification and freeze-drying of the crude product of PEGylated insulin pH-sensitive nanoparticles: centrifuge the crude product of PEGylated insulin pH-sensitive nanoparticles obtained in step (3) at 15000-25000 r/min for 5-15 minutes, Washed with water, pre-frozen at -15~-25°C for 8~12 h, and then vacuum freeze-dried at -40~-60°C for 16~32 h to obtain PEGylated insulin pH-sensitive nanoparticles.

In step (1) of the present invention, the pegylated insulin is insulin modified with monomethoxypolyethylene glycol butyraldehyde, and the molecular weight of the monomethoxypolyethylene glycol butyraldehyde is 5000; the pH The sensitive polymer is hydroxypropyl methylcellulose phthalate; the carrier is polylactide or polylactic acid; and the additive is one or both of glycerin or starch.

In step (2) of the present invention, the stabilizer is polyvinyl alcohol.

In the step (1) of the present invention, the average molecular weight of the carrier is 5,000-100,000, and the molar ratio of lactide to glycolide in the polyglycolide molecular segment is 50:50.

The present invention also provides the application of pegylated insulin pH-sensitive nanoparticles in treating diabetes by oral administration.

Compared with the prior art, the present invention has the following beneficial effects:

(1) Use hydroxypropyl methylcellulose phthalate (abbreviation: HP55) as a pH-sensitive polymer to control the release of polyethylene glycol insulin, prevent the release of insulin in the acidic environment of the stomach, and prevent Pepsin degrades insulin, while in the intestinal environment, HP55 swells and even dissolves, promoting the rapid release of insulin;

(2) The carrier material is polyethylene lactide (abbreviation: PLGA) or polylactic acid (abbreviation: PLA), and polyethylene glycol insulin is dispersed in the carrier material to prevent aggregation; the pH-sensitive polymer swells or When dissolving and promoting the release of polyethylene glycol insulin, the carrier material can also play a role in controlling the release and stabilizing;

(3) Adding glycerol or water-soluble starch to the inner aqueous phase A increases the loading rate of polyethylene glycol insulin;

(4) Polyvinyl alcohol (referred to as: PVA) is used as a stabilizer to stabilize the emulsion formed during the preparation process and the dried nanoparticles to prevent the aggregation of the emulsion and nanoparticles;

(5) The polyethylene glycol modifier used to modify insulin is monomethoxypolyethylene glycol butyraldehyde, and low molecular weight polyethylene glycol modifies insulin, which is beneficial to transport and absorb through the paracellular pathway;

(6) The raw materials used in the present invention are safe and non-toxic, the product has good safety performance and is harmless to the human body;

(7) PEGylated insulin is dispersed in PLGA/HP55 or PLA/HP55 mixed polymer nanoparticles, the encapsulation efficiency reaches 70-85%, the particle size of the nanoparticles is about 300 nm, and the distribution is uniform;

(8) The pH-sensitive response release performance of the PEGylated insulin nanoparticles of the present invention is good, which can effectively reduce the release of insulin in gastric acidic environment and prevent the degradation of insulin by pepsin; while in the intestinal environment, the pH The sensitive polymer swells and even dissolves, promoting the rapid release of insulin;

(9) The preparation method of the present invention does not affect the biological activity of insulin, and the preparation process is simple and the cost is low.

Description of drawings

FIG. 1 is a scanning electron microscope (abbreviation: SEM) image of the PEGylated insulin pH-sensitive nanoparticles of Example 6 of the present invention.

Fig. 2 is a particle size distribution diagram of the PEGylated insulin pH-sensitive nanoparticles of Example 6 of the present invention.

Fig. 3 is the in vitro release curve of the PEGylated insulin pH-sensitive nanoparticles of Example 6 of the present invention.

Detailed ways

The present invention will be further explained below in conjunction with the examples, but the protection scope of the present invention is not limited thereto.

Example 1

(1) Phacoemulsification to prepare W/O colostrum of PEGylated insulin, pH-sensitive polymer and carrier material: Weigh 40 mg of starch and dissolve it in 40 mL of deionized water to obtain a starch solution with a mass fraction of 0.1%. PEGylated insulin was dissolved in 0.5 mL of the above starch solution to form an internal aqueous phase; 1 mL of acetone and 4 mL of methylene chloride were mixed, and 50 mg of hydroxypropylmethylcellulose phthalate (abbreviation: HP55) was added to it Dissolve with 50mg polylactide (abbreviation: PLGA) to form an oil phase; mix 0.5mL internal water phase with 5mL oil phase, and ultrasonically emulsify at 40W for 0.5min to obtain W/O colostrum;

(2) Ultrasonic dispersion of W/O colostrum in the stabilizer solution to form W/O/W double emulsion: Weigh 100mg of polyvinyl alcohol (abbreviation: PVA), dissolve it in 10mL of deionized water, and form a PVA mass fraction of 1% The external water phase; mix 10mL of the external water phase with 5.5mL of W/O colostrum obtained in step (1), and ultrasonic emulsify at 60W for 0.5min to obtain W/O/W double emulsion;

(3) The W/O/W double emulsion solvent is volatilized to obtain the crude nanoparticle product: the W/O/W double emulsion obtained in step (2) is removed by rotary evaporation under reduced pressure at 40°C water bath and 450 mbar to remove acetone and dichloromethane , obtaining the crude product of PEGylated insulin pH-sensitive nanoparticles;

(4) Purification and freeze-drying of the crude product of PEGylated insulin pH-sensitive nanoparticles: centrifuge the crude product of PEGylated insulin pH-sensitive nanoparticles obtained in step (3) at 20,000 r/min for 10 min, wash with water, and Pre-freezing at ℃ for 10 hours, and then vacuum freeze-drying at -50 ℃ for 24 hours to obtain pegylated insulin pH-sensitive nanoparticles.

The encapsulation efficiency of the PEGylated insulin pH-sensitive nanoparticles obtained in Example 1 was 69.8%, and the mass percentage of residual PVA on the surface of the particles was 2%.

Example 2

(1) Phacoemulsification to prepare W/O colostrum of PEGylated insulin, pH-sensitive polymer and carrier material: Weigh 200 mg of glycerol and add it into 40 mL of deionized water to obtain a glycerol solution with a mass fraction of 0.5%. PEGylated insulin was dissolved in 0.5mL of the above glycerin solution to form an internal water phase; 1mL of acetone and 4mL of dichloromethane were mixed, and 100mg of HP55 and 100mg of polylactic acid (PLA for short) were added to dissolve to form an oil phase; 0.5 Mix mL internal water phase and 5 mL oil phase, and ultrasonically emulsify at 40W for 4min to obtain W/O colostrum;

(2) Ultrasonic dispersion of W/O colostrum in stabilizer solution to form W/O/W double emulsion: Weigh 600mg of PVA and dissolve it in 20mL of deionized water to form an external aqueous phase with a mass fraction of PVA of 3%; Mix the external water phase with 5.5mL of W/O colostrum obtained in step (1), and ultrasonically emulsify at 60W for 2min to obtain W/O/W double emulsion;

(3) The W/O/W double emulsion solvent is volatilized to obtain the crude product of nanoparticles: the W/O/W double emulsion obtained in step (2) is evaporated under reduced pressure in a 35°C water bath and 400 mbar to remove acetone and dichloromethane , obtaining the crude product of PEGylated insulin pH-sensitive nanoparticles;

(4) Purification and freeze-drying of the crude product of PEGylated insulin pH-sensitive nanoparticles: centrifuge the crude product of PEGylated insulin pH-sensitive nanoparticles obtained in step (3) at 15,000 r/min for 15 min, wash with water, and Pre-freezing at ℃ for 12 hours, and then vacuum freeze-drying at -40 ℃ for 32 hours to obtain pegylated insulin pH-sensitive nanoparticles.

The encapsulation efficiency of the pegylated insulin pH-sensitive nanoparticles obtained in Example 2 was 65.1%, and the residual PVA mass percentage on the surface of the particles was 5%.

Example 3

(1) Prepare W/O colostrum of PEGylated insulin, pH-sensitive polymer and carrier material by ultrasonic emulsification: Weigh 0.1 g of starch and dissolve it in 40 mL of deionized water to obtain a starch solution with a mass fraction of 0.25%. 10 mg of pegylated insulin was dissolved in 0.5 mL of the above starch solution to form an internal water phase; 1 mL of acetone and 4 mL of methylene chloride were mixed, and 100 mg of HP55 and 50 mg of PLGA were added to dissolve to form an oil phase; 0.5 mL of the internal water phase Mix with 5mL oil phase, 50W ultrasonic emulsification for 4min, get W/O colostrum;

(2) Ultrasonic dispersion of W/O colostrum in stabilizer solution to form W/O/W double emulsion: Weigh 0.8g of PVA and dissolve it in 40mL of deionized water to form an external aqueous phase with a mass fraction of PVA of 2%; Mix 40mL of the external water phase with 5.5mL of the W/O colostrum obtained in step (1), and ultrasonically emulsify at 50W for 4 minutes to obtain W/O/W double emulsion;

(3) The W/O/W double emulsion solvent is volatilized to obtain the crude nanoparticle product: the W/O/W double emulsion obtained in step (2) is evaporated under reduced pressure in a 45°C water bath and 500 mbar to remove acetone and dichloromethane , obtaining the crude product of PEGylated insulin pH-sensitive nanoparticles;

(4) Purification and freeze-drying of the crude product of PEGylated insulin pH-sensitive nanoparticles: centrifuge the crude product of PEGylated insulin pH-sensitive nanoparticles obtained in step (3) at 25,000 r/min for 5 min, wash with water, and repeat centrifugation , washed with water, pre-frozen at -25°C for 8 hours, and then vacuum freeze-dried at -60°C for 16 hours to obtain pegylated insulin pH-sensitive nanoparticles.

The encapsulation efficiency of the PEGylated insulin pH-sensitive nanoparticles obtained in Example 3 was 68.3%, and the residual PVA mass percentage on the surface of the particles was 4%.

Example 4

(1) Prepare W/O colostrum of PEGylated insulin, pH-sensitive polymer and carrier material by ultrasonic emulsification: Weigh 0.1 g of starch and dissolve it in 40 mL of deionized water to obtain a starch solution with a mass fraction of 0.25%. 10 mg of pegylated insulin was dissolved in 1 mL of the above starch solution to form an internal water phase; 1 mL of acetone and 4 mL of methylene chloride were mixed, and 75 mg of HP55 and 25 mg of PLA were added to dissolve to form an oil phase; 1 mL of the internal water phase and 5 mL of The oil phase is mixed, 60W ultrasonic emulsification for 1min, and W/O colostrum is obtained;

(2) Ultrasonic dispersion of W/O colostrum in stabilizer solution to form W/O/W double emulsion: Weigh 0.2g of PVA and dissolve it in 40mL of deionized water to form an external aqueous phase with a mass fraction of 0.5% of PVA; Mix 30mL of the external water phase with 6mL of the W/O colostrum obtained in step (1), and ultrasonically emulsify at 40W for 3 minutes to obtain W/O/W double emulsion;

(3) The W/O/W double emulsion solvent is volatilized to obtain the crude nanoparticle product: the W/O/W double emulsion obtained in step (2) is removed by rotary evaporation under reduced pressure at 40°C water bath and 450 mbar to remove acetone and dichloromethane , obtaining the crude product of PEGylated insulin pH-sensitive nanoparticles;

(4) Purification and freeze-drying of the crude product of PEGylated insulin pH-sensitive nanoparticles: centrifuge the crude product of PEGylated insulin pH-sensitive nanoparticles obtained in step (3) at 20,000 r/min for 10 min, wash with water, and repeat centrifugation , washed with water, pre-frozen at -20°C for 10 hours, and then vacuum freeze-dried at -50°C for 24 hours to obtain pegylated insulin pH-sensitive nanoparticles.

The encapsulation efficiency of the pegylated insulin pH-sensitive nanoparticles obtained in Example 4 was 78.6%, and the mass percentage of residual PVA on the surface of the particles was 2%.

Example 5

(1) Prepare W/O colostrum of PEGylated insulin, pH-sensitive polymer and carrier material by ultrasonic emulsification: Weigh 0.2 g of starch and dissolve it in 40 mL of deionized water to obtain a starch solution with a mass fraction of 0.5%. 10 mg of pegylated insulin was dissolved in 0.25 mL of the above starch solution to form an internal water phase; 1 mL of acetone and 4 mL of methylene chloride were mixed, and 75 mg of HP55 and 75 mg of PLGA were added to dissolve to form an oil phase; 0.25 mL of an internal water phase and 5 mL of The oil phase is mixed, 60W ultrasonic emulsification for 0.5min, and W/O colostrum is obtained;

(2) Ultrasonic dispersion of W/O colostrum in stabilizer solution to form W/O/W double emulsion: Weigh 20mg of PVA and dissolve it in 20mL of deionized water to form an external aqueous phase with a mass fraction of PVA of 0.1%; Mix the outer water phase with 5.25mL of W/O colostrum obtained in step (1), and ultrasonically emulsify at 40W for 2min to obtain W/O/W double emulsion;

(3) The W/O/W double emulsion solvent is volatilized to obtain the crude nanoparticle product: the W/O/W double emulsion obtained in step (2) is removed by rotary evaporation under reduced pressure at 35°C water bath and 500 mbar to remove acetone and dichloromethane , obtaining the crude product of PEGylated insulin pH-sensitive nanoparticles;

(4) Purification and freeze-drying of the crude product of PEGylated insulin pH-sensitive nanoparticles: centrifuge the crude product of PEGylated insulin pH-sensitive nanoparticles obtained in step (3) at 15,000 r/min for 15 min, wash with water, and repeat centrifugation , washed with water, pre-frozen at -15°C for 12 hours, and then vacuum freeze-dried at -60°C for 16 hours to obtain pegylated insulin pH-sensitive nanoparticles.

The encapsulation efficiency of the pegylated insulin pH-sensitive nanoparticles obtained in Example 5 was 80.9%, and the residual PVA mass percentage on the particle surface was 1%.

Example 6

(1) Preparation of W/O colostrum of PEGylated insulin, pH-sensitive polymer and carrier material by ultrasonic emulsification: Weigh 0.05 g of starch and 0.05 g of glycerol, dissolve them in 40 mL of deionized water, and obtain a mass fraction of 0.25% Starch-glycerol mixed solution, 10 mg of pegylated insulin was dissolved in 0.25 mL of the above-mentioned starch-glycerol mixed solution to form an internal water phase; 1 mL of acetone and 4 mL of methylene chloride were mixed, and 75 mg of HP55 and 25 mg of PLGA were added to dissolve to form an oil phase ;Mix 0.25mL internal water phase and 5mL oil phase, 40W ultrasonic emulsification for 2min, to obtain W/O colostrum;

(2) Ultrasonic dispersion of W/O colostrum in stabilizer solution to form W/O/W double emulsion: Weigh 0.04g of PVA and dissolve it in 40mL of deionized water to form an external aqueous phase with a mass fraction of PVA of 0.1%; Mix 40mL of the external water phase with 5.25mL of the W/O colostrum obtained in step (1), and ultrasonically emulsify at 60W for 0.5min to obtain W/O/W double emulsion;

(3) The W/O/W double emulsion solvent is volatilized to obtain the crude nanoparticle product: the W/O/W double emulsion obtained in step (2) is evaporated under reduced pressure in a 45°C water bath and 400 mbar to remove acetone and dichloromethane , obtaining the crude product of PEGylated insulin pH-sensitive nanoparticles;

(4) Purification and freeze-drying of the crude product of PEGylated insulin pH-sensitive nanoparticles: centrifuge the crude product of PEGylated insulin pH-sensitive nanoparticles obtained in step (3) at 25,000 r/min for 5 min, wash with water, and repeat centrifugation , washed with water, pre-frozen at -25°C for 8 hours, and then vacuum freeze-dried at -60°C for 16 hours to obtain pegylated insulin pH-sensitive nanoparticles.

The encapsulation efficiency of the PEGylated insulin pH-sensitive nanoparticles obtained in Example 6 was 83.5%, and the mass percentage of residual PVA on the surface of the particles was 1%.

The pegylated insulin of the present invention is dispersed in PLGA/HP55 or PLA/HP55 mixed polymer nanoparticles, and the encapsulation efficiency reaches 70-85%.

As shown in Figure 1, the nanoparticles of the present invention are spherical in shape, with a particle size of 100-300nm and relatively uniform distribution.

As shown in Figure 2, the average particle diameter of the nanoparticles of the present invention is 251nm, the dispersion index (abbreviation: PDI)=0.290, and the distribution is relatively uniform.

As shown in Figure 3, in vitro release experiments show that the pH-sensitive response release performance of the PEGylated insulin nanoparticles of the present invention is good. In the simulated intestinal environment of pH=7.4, the pH-sensitive polymer swells and even dissolves, promoting the rapid release of insulin.

Claims (6)

1. A pH-sensitive nanoparticle of oral pegylated insulin, characterized in that, the nanoparticle is composed of: pegylated insulin with a mass percentage of 3 to 8%, and a mass percentage of 46 to 8%. 68% pH-sensitive polymer, 22-47% carrier by mass, 0.5-2% additive by mass and 1-5% stabilizer by mass, the polyethylene glycol Alcoholized insulin is insulin modified by monomethoxypolyethylene glycol butyraldehyde, the molecular weight of said monomethoxypolyethylene glycol butyraldehyde is 5000; said pH sensitive polymer is hydroxypropyl methylcellulose ophthalmic Diformic acid ester; the carrier is polyethylene lactide or polylactic acid; the additive is one or both of glycerin or starch; the stabilizer is polyvinyl alcohol. 2. The oral pegylated insulin pH-sensitive nanoparticles according to claim 1, characterized in that the mass ratio of the pH-sensitive polymer to the carrier is 1:1-3:1. 3. The oral pegylated insulin pH-sensitive nanoparticles according to claim 1, characterized in that the average molecular weight of the carrier is 5000-100000, wherein lactide and glycolide in the polyethylene lactide molecular segment The molar ratio of lactide is 50:50. 4. The preparation method of oral pegylated insulin pH-sensitive nanoparticles according to claim 1, characterized in that it comprises the steps of: (1) Preparation of W/O colostrum of PEGylated insulin, pH-sensitive polymer and carrier material by ultrasonic emulsification: Weigh the additive according to the formula in claim 1, dissolve it in deionized water, and prepare a mass fraction of 0.1-0.5 % additive solution; add PEGylated insulin to the additive solution at a mass volume ratio of 10-40 mg/mL and dissolve it to form an inner aqueous phase; mix acetone and dichloromethane at a volume ratio of 1:4 to obtain a mixed solvent, According to claim 1, the pH-sensitive polymer and the carrier are added to the mixed solvent and dissolved to form an oil phase, the total concentration of the pH-sensitive polymer and the carrier in the oil phase is 20-40 mg/mL, and the pH-sensitive polymer The mass ratio to the carrier is 1:1~3:1; the inner water phase and the oil phase are mixed at a volume ratio of 1:5~1:20, and ultrasonically emulsified at 40~60W for 0.5~4min to obtain W/O colostrum; (2) Ultrasonic dispersion of W/O colostrum in the stabilizer solution to form W/O/W double emulsion: Weigh the stabilizer according to the formula of claim 1, dissolve it in deionized water to form an external water phase, and the external The concentration of the stabilizer in the water phase is 0.1-3%; the above-mentioned external water phase is mixed with the W/O colostrum obtained in step (1), and ultrasonically emulsified at 40-60W for 0.5-4min to obtain W/O/W double emulsion. The volume ratio of the above-mentioned water phase to the oil phase in the W/O colostrum is 2:1 to 8:1; (3) The W/O/W double emulsion solvent is volatilized to obtain the crude product of nanoparticles: the W/O/W double emulsion obtained in step (2) is volatilized in a water bath at 35-45°C under reduced pressure at 400-500mbar to obtain polyethylene Glycolated insulin pH-sensitive nanoparticle crude product; (4) Purification and freeze-drying of the crude product of pegylated insulin pH-sensitive nanoparticles: centrifuge the crude product of pegylated insulin pH-sensitive nanoparticles obtained in step (3) at 15000-25000 r/min for 5-15 minutes, washing with water, pre-freezing at -15 to -25°C for 8 to 12 hours, and then vacuum freeze-drying at -40 to -60°C for 16 to 32 hours to obtain pegylated insulin pH-sensitive nanoparticles. 5. The preparation method according to claim 4, characterized in that, the PEGylated insulin is insulin modified by monomethoxypolyethylene glycol butyraldehyde, and the monomethoxypolyethylene glycol butyraldehyde The molecular weight is 5000; the pH sensitive polymer is hydroxypropyl methylcellulose phthalate; the carrier is polylactide or polylactic acid; the additive is one of glycerin or starch or two; the stabilizer is polyvinyl alcohol. 6. preparation method according to claim 5, is characterized in that, the average molecular weight of described carrier is 5000～100000, and wherein the mol ratio of lactide and glycolide in polylactide molecular segment is 50: 50.

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