CN106075403A - A kind of oral insulin selenium nanometer formulation and preparation method thereof - Google Patents

Abstract

The invention belongs to technical field of medicine, disclose a kind of can promote oral insulin absorb have selenium oral insulin selenium nanometer formulation working in coordination with hypoglycemic effect and preparation method thereof concurrently.This preparation method adds containing seleno reagent in insulin and the solution of chitosan or suspension, generates the selenium/chitosan nano carrying insulin under reducing agent effect.The oral insulin selenium nanometer formulation of the present invention can effectively wrap load insulin, insulin efficient packet is made to be loaded in the nanoparticle of chitosan and selenium formation, reduce after oral administration its release in the gastrointestinal tract and exposure, thus improve the gastrointestinal tract stability of insulin, improve absorbability and the biological activity of selenium, thus the bioavailability of insulin and selenium can be improved.Additionally, the addition of selenium makes said preparation can work in coordination with blood sugar lowering by the ILA of selenium, it is achieved the effect of diabetes treating both the principal and secondary aspects of a disease hypoglycemic meanwhile, it is capable to reconstruct body function by the antioxidation of selenium, blood glucose regulation and ILA.

Description

Oral selenium nano-preparation for insulin and preparation method thereof

technical field

The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to an oral selenium nano-preparation for insulin capable of promoting oral absorption of insulin and having synergistic hypoglycemic effect of selenium and a preparation method thereof.

Background technique

Diabetes is a common and frequently-occurring disease that seriously endangers human health. In recent years, the incidence of diabetes has been on the rise. According to WTO estimates, the incidence of diabetes in adults is as high as 9%. Insulin is the first-line drug for the treatment of insulin-dependent type I diabetes, and it is also the adjuvant drug for the treatment of advanced type II diabetes. At present, subcutaneous injection is the most basic way of administering insulin. However, there are many disadvantages in administration via subcutaneous injection, such as frequent administration, painful injections, large blood sugar fluctuations, prone to insulinemia, and organic lesions at the injection site. Therefore, the research and development of insulin non-injection drug delivery preparations has very important clinical significance for the treatment of diabetes.

Among various non-injection routes of administration, oral administration is the most convenient and most accepted by patients. In recent years, domestic and foreign research institutions and pharmaceutical companies have invested a lot of manpower and material resources in the research and development of insulin oral preparations. However, because insulin is a biomacromolecular therapeutic agent, it is (1) unstable in the gastrointestinal tract and easily digested and degraded by pepsin and trypsin in the gastrointestinal tract; (2) has a large molecular weight and poor biofilm permeability, making it difficult to penetrate the gastrointestinal tract The problem of epithelial absorption. Therefore, oral bioavailability is extremely low, and it is difficult to achieve therapeutic purposes through oral administration. To improve the bioavailability of orally administered insulin, various technical means have been tried and used. Commonly used methods to improve the oral absorption of insulin include: (1) modifying the structure of insulin to improve its gastrointestinal stability, such as adding PEG chains; (2) using osmotic agents, enzyme inhibitors and insulin supply drugs to reduce insulin degradation and increase its oral absorption; (3) encapsulate insulin in nanocarriers, such as nanospheres, nanocapsules, liposomes to reduce insulin exposure and improve gastrointestinal absorption; (4) use ligands or transmembrane Peptide-modified insulin-loaded nanoparticles for improved gastrointestinal stability and oral absorption. However, due to the complicated preparation or technical defects or high cost of these preparations, satisfactory research results have not been obtained. In addition, simple insulin administration can only lower blood sugar, but cannot reverse and repair damaged islet β cells, and the treatment of diabetes only stays at the palliative level. There is an urgent need for a pharmaceutical preparation that can not only realize the oral delivery of insulin, but also balance the blood sugar level in the body to treat both the symptoms and root causes of diabetes.

There is a certain intrinsic connection between trace elements in the human body and diabetes. Studies have shown that selenium exhibits a post-insulin receptor kinase inhibitory effect, has a certain physiological insulin-like effect, and has a regulatory effect on glucose metabolism. Selenium deficiency can cause changes in the secretory function of pancreatic β cells, and reduce insulin secretion and reserves. The mean value of serum selenium in patients with type II diabetes was significantly lower than that of healthy people, and the blood sugar level decreased significantly after selenium supplementation. Selenium is a component of the GSH-Px enzyme system. In the pentose phosphate pathway of glucose metabolism, it restores the GSH-Px activity in the liver tissue of diabetic patients, thereby maintaining the balance of glucose metabolism in the liver. The peroxide decomposition function of GSH-Px can also prevent free radicals and peroxides from destroying the disulfide bond between insulin A/B peptides, and play a role in sensitizing insulin. Therefore, the formulation of insulin and selenium, and the development of therapeutic agents that can promote the oral absorption of insulin and supplement selenium have potential application prospects in the prevention and treatment of diabetes.

Contents of the invention

In order to overcome the disadvantages and deficiencies of low oral bioavailability and weak hypoglycemic effect of insulin in the above-mentioned prior art, the primary purpose of the present invention is to provide an oral selenium nano-preparation of insulin that can promote the oral absorption of insulin and has synergistic hypoglycemic effect of selenium .

The insulin oral selenium nano preparation of the present invention consists of insulin, chitosan and selenium, wherein the insulin is encapsulated in the nano particles formed by the chitosan and selenium.

Another object of the present invention is to provide a preparation method of the oral selenium nano-preparation of insulin which can promote the oral absorption of insulin and has synergistic hypoglycemic effect of selenium.

In the preparation method of the present invention, insulin is electrostatically compounded with chitosan in a solution to form a coarse dispersion suspension, and a reducible selenium-containing reagent is added to generate low-priced selenium under the action of a reducing agent, which precipitates or attaches to insulin/chitosan Coated nanoparticles are formed on the carbohydrate complex. The selenium/chitosan nanoparticles can effectively entrap insulin, realize high entrapment of insulin, reduce its release and exposure in the gastrointestinal tract after oral administration, thereby improving the gastrointestinal tract stability and oral bioavailability of insulin Spend. In addition to improving the bioavailability of insulin, the insulin-loaded selenium nano-preparation of the present invention can also synergistically lower blood sugar through the insulin-like effect of selenium.

The object of the present invention is achieved through the following solutions:

A method for preparing an oral selenium nano-preparation of insulin capable of promoting oral absorption of insulin and having a synergistic hypoglycemic effect of selenium, comprising the following steps: adding a selenium-containing reagent to the solution or suspension of insulin and chitosan; Generation of insulin-loaded selenium/chitosan nanoparticles.

In the above preparation method, insulin and chitosan are electrostatically compounded to form a coarse dispersion suspension, and a reducible selenium-containing reagent is added to generate low-priced selenium under the action of a reducing agent, which precipitates or attaches to insulin/chitosan Coated nanoparticles are formed on the complex. Wherein, the insulin is encapsulated in the nano-skeleton or reservoir formed by selenium and chitosan.

In the above preparation method, the dosage ratio of the insulin, chitosan and selenium-containing reagent is 1:(0.25-10):(0.5-20).

In the above preparation method, the stoichiometric ratio of the selenium-containing reagent to the reducing agent is 1:0.1˜1:50.

In the above preparation method, the selenium-containing reagent is a reducible selenium-containing reagent, which can be selected from at least one of compounds containing +6-valent selenium or +4-valent selenium and elemental selenium, preferably selenic acid, selenium At least one of selenium acid, selenate, selenite and gray-black elemental selenium, more preferably at least one of selenous acid and selenite.

In the above preparation method, the chitosan may be selected from at least one of low-molecular-weight chitosan, high-molecular-weight chitosan and chitosan derivatives, preferably low-molecular-weight chitosan.

In the above preparation method, the reducing agent can be selected from at least one of glutathione, vitamin C (ascorbic acid), mercaptoethanol, cysteine, polyphenols or polyhydroxy compounds, unsaturated olefins or aromatics, Preferably it is at least one of glutathione and vitamin C.

In the above preparation method, the insulin and chitosan are preferably prepared into solutions respectively and then mixed to obtain a solution or suspension. Preferably, an acidic medium is used to dissolve insulin and chitosan respectively to obtain an insulin solution and a chitosan solution.

The acidic medium may be selected from inorganic acids, organic acids or mixed acid solutions thereof. The inorganic acid can be hydrochloric acid, sulfuric acid, etc.; the organic acid can be monobasic acid, dibasic acid or polybasic acid, such as formic acid, acetic acid, oxalic acid, etc. The acidic medium is preferably at least one of hydrochloric acid, sulfuric acid, formic acid, acetic acid and oxalic acid. More preferably, the acidic medium for dissolving chitosan is acetic acid, and the acidic medium for dissolving insulin is hydrochloric acid.

Above-mentioned preparation method specifically comprises the following steps:

The chitosan solution and the insulin solution are mixed, and the pH is adjusted until the insulin precipitates to form a suspension; a selenium-containing reagent and a reducing agent are added for reaction to obtain an oral selenium nanometer preparation for insulin.

The reaction time can range from 0.5 h to several days.

The pH adjustment can be adjusted to 5.5-8.0. By adjusting the pH to above the isoelectric point of insulin, the solubility of insulin is reduced, and its precipitation is coupled with chitosan.

In order to better realize the present invention, the above-mentioned preparation method more specifically comprises the following steps:

Use an acidic medium to dissolve insulin and chitosan, and prepare insulin solution and chitosan solution respectively; mix the insulin solution and chitosan solution, adjust the pH value of the system to above the isoelectric point, and precipitate insulin and form a complex with chitosan Adding selenium-containing reagents and reducing agents to react to generate low-priced selenium and form oral selenium nano-preparations for insulin.

The invention provides the oral selenium nano preparation of insulin obtained by the above preparation method, the encapsulation rate of insulin is 10-100%, and the drug loading is 1-50%.

Through the above preparation method, the insulin is entrapped in the nanoparticle formed by chitosan and selenium. The nanoparticle preparation enhances the gastrointestinal tract stability and oral absorption performance of insulin, and also improves the absorbability and biological activity of selenium, thereby improving the bioavailability of insulin and selenium. In addition, the addition of selenium enables the preparation to not only lower blood sugar, but also reconstruct body functions through selenium’s anti-oxidation, blood sugar regulation and insulin-like effects, so as to achieve the effect of treating both symptoms and root causes of diabetes. It is a very promising preparation .

The present invention has carried out in vitro stability and in vivo hypoglycemic experiments. The results show that the oral selenium nano-preparation of insulin prepared by the present invention has good stability in simulated artificial gastric juice, and can significantly reduce the blood sugar levels of normal and diabetic rats after oral administration, and the maintenance time is longer than that of the subcutaneous insulin injection group.

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

(1) The preparation of the present invention has a high insulin drug loading capacity. Usually, the drug loading rate of nanoparticles to insulin is lower than 30%, and the drug loading rate of the insulin-loaded selenium nanoparticles prepared by the present invention can reach more than 45%;

(2) The preparation of the present invention has a very high gastrointestinal protective effect on insulin, and can significantly reduce the enzyme or body fluid degradation of insulin after oral administration;

(3) The preparation of the present invention can promote the oral absorption of insulin, and by virtue of the nanoscale effect of nanoparticles, the absorption of insulin across the gastrointestinal epithelium is improved, thereby improving the oral bioavailability of insulin;

(4) The preparation of the present invention contains the trace element selenium. While realizing the oral absorption of insulin to lower blood sugar, the physiological regulation effect of selenium in the treatment of diabetes can also be utilized to realize the function of treating both the symptoms and root causes of diabetes.

Description of drawings

Fig. 1 is the particle size distribution figure of insulin selenium nano-preparation.

Fig. 2 is a graph comparing the stability of insulin selenium nano-preparation and insulin solution in simulated artificial gastric juice.

Fig. 3 is a graph showing the hypoglycemic effect of the insulin selenium nano-preparation in normal rats.

Fig. 4 is a diagram of the hypoglycemic effect of insulin selenium nano-preparation in diabetic rats.

detailed description

The present invention will be further described in detail below with reference to the examples and drawings, but the implementation of the present invention is not limited thereto.

The reagents in the following examples are all available from commercial sources.

Example 1: Preparation of Oral Selenium Nano-Preparation for Insulin

Dissolve insulin in hydrochloric acid solution at pH 2 to prepare a 5 mg/mL insulin solution; then dissolve chitosan in 1% acetic acid solution to make the concentration 5 mg/mL; then prepare 2.5 mg/mL sub Sodium selenate (Na ₂ SeO ₃ ) solution and 10 mg/mL glutathione (GSH) solution. Take 10 mL of chitosan solution, slowly add 5 mL of insulin solution dropwise under stirring, and incubate for 15 min. Then, 5 mL of Na ₂ SeO ₃ solution was slowly added, and the incubation was continued for 1 h. Then slowly add 5 mL of GSH solution and react for 1 hour to obtain a red transparent and opalescent insulin-loaded selenium nanoparticle suspension.

Example 2: Preparation of Oral Selenium Nano-Preparation for Insulin

Dissolve insulin in hydrochloric acid solution at pH 2 to prepare a 5 mg/mL insulin solution; then dissolve chitosan in 1% acetic acid solution to make the concentration 5 mg/mL; then prepare 2.5 mg/mL selenium Na ₂ SeO ₄ ) solution and 10 mg/mL glutathione (GSH) solution. Take 10 mL of chitosan solution, slowly add 5 mL of insulin solution dropwise under stirring, and incubate for 15 min. Then, 5 mL of Na ₂ SeO ₄ solution was slowly added, and the incubation was continued for 1 h. Then slowly add 5 mL of GSH solution and react for 1 hour to obtain a red transparent and opalescent insulin-loaded selenium nanoparticle suspension.

Example 3: Preparation of Oral Selenium Nano-Preparation for Insulin

Dissolve insulin in hydrochloric acid solution with pH 2 to prepare insulin solution with a concentration of 5 mg/mL; then dissolve chitosan in 1% acetic acid solution to make its concentration 5 mg/mL; then, prepare 2.5 mg/mL sub Sodium selenate (Na ₂ SeO ₃ ) solution and 10 mg/mL vitamin C solution. Take 10 mL of chitosan solution and place it on a magnetic stirrer, slowly add 5 mL of insulin solution dropwise, and incubate for 15 min. Then, 5 mL of Na ₂ SeO ₃ solution was slowly added, and the incubation was continued for 1 h. Slowly add 5 mL of vitamin C solution and react for 1 hour to obtain a red transparent and opalescent insulin-loaded selenium nanoparticle suspension.

Example 4: Preparation of Oral Selenium Nano-Preparation for Insulin

Dissolve insulin in hydrochloric acid solution at pH 2 to prepare a 5 mg/mL insulin solution; then dissolve chitosan in 1% acetic acid solution to make the concentration 5 mg/mL; then prepare 2.5 mg/mL selenium Na ₂ SeO ₄ ) solution and 10 mg/mL vitamin C solution. Take 10 mL of chitosan solution and place it on a magnetic stirrer, slowly add 5 mL of insulin solution dropwise, and incubate for 15 min. Then, 5 mL of Na ₂ SeO ₄ solution was slowly added, and the incubation was continued for 1 h. Slowly add 5 mL of vitamin C solution and react for 1 hour to obtain a red transparent and opalescent insulin-loaded selenium nanoparticle suspension.

Example 5: Preparation of Oral Selenium Nano-Preparation for Insulin

Dissolve insulin in hydrochloric acid solution with pH 2 to prepare insulin solution with a concentration of 5 mg/mL; then dissolve chitosan in 1% acetic acid solution to make its concentration 5 mg/mL; then, prepare 2.5 mg/mL sub Sodium selenate (Na ₂ SeO ₃ ) solution and 10% 2-mercaptoethanol solution (v/v). Take 10 mL of chitosan solution and place it on a magnetic stirrer, slowly add 5 mL of insulin solution dropwise, and incubate for 15 min. Then, 5 mL of Na ₂ SeO ₃ solution was slowly added, and the incubation was continued for 1 h. Slowly add 5 mL of 2-mercaptoethanol solution and react for 1 hour to obtain a red transparent and opalescent insulin-loaded selenium nanoparticle suspension.

Example 6: Preparation of Oral Selenium Nano-Preparation for Insulin

Dissolve insulin in hydrochloric acid solution at pH 2 to prepare a 5 mg/mL insulin solution; then dissolve chitosan in 1% acetic acid solution to make the concentration 5 mg/mL; then prepare 2.5 mg/mL sub Sodium selenate (Na ₂ SeO ₃ ) solution and 10 mg/mL cysteine solution. Take 10 mL of chitosan solution and place it on a magnetic stirrer, slowly add 5 mL of insulin solution dropwise, and incubate for 15 min. Then, 5 mL of Na ₂ SeO ₃ solution was slowly added, and the incubation was continued for 1 h. Then slowly add 5 mL of cysteine solution, and react for 1 hour to obtain a red transparent and opalescent insulin-loaded selenium nanoparticle suspension.

Example 7: Preparation of Oral Selenium Nano-Preparation for Insulin

Dissolve insulin in hydrochloric acid solution at pH 2 to prepare a 5 mg/mL insulin solution; then dissolve chitosan in 1% acetic acid solution to make its concentration 2.5 mg/mL; then prepare 5 mg/mL sub Sodium selenate (Na ₂ SeO ₃ ) solution and 5 mg/mL GSH solution. Take 10 mL of chitosan solution and place it on a magnetic stirrer, slowly add 5 mL of insulin solution dropwise, and incubate for 30 min. Then, 2.5 mL of Na ₂ SeO ₃ solution was slowly added, and the incubation was continued for 4 h. Then slowly add 10 mL of GSH solution and react for 12 hours to obtain a red transparent and opalescent insulin-loaded selenium nanoparticle suspension.

Example 8: Preparation of Oral Selenium Nano-Preparation for Insulin

Dissolve insulin in hydrochloric acid solution at pH 2 to prepare a 2.5mg/mL insulin solution; then dissolve chitosan in 1% acetic acid solution to make the concentration 2.5mg/mL; then prepare 10mg/mL insulin Sodium selenite (Na ₂ SeO ₃ ) solution, 10 mg/mL vitamin C solution and 10 mg/mL GSH solution. Take 10 mL of chitosan solution and place it on a magnetic stirrer, slowly add 10 mL of insulin solution dropwise, and incubate for 30 min. Then, slowly add Na ₂ SeO ₃ solution 5mL and continue to incubate for 8h. Slowly add 50 mL each of vitamin C and GSH solutions, and react for 24 hours to obtain a red transparent and opalescent insulin-loaded selenium nanoparticle suspension.

Embodiment 9: Particle size and in vitro stability of insulin selenium nanoparticles

Particle size measurement: the insulin-selenium nanoparticle suspension in Example 1 was taken, and the particle size of the insulin-selenium nanoparticle was measured by dynamic light scattering technique. The specific operation is: measure 10 μL of insulin-selenium nanoparticles in Example 1, dilute to 1 mL with deionized water, place in the sample cell for particle size determination, and equilibrate for 120 s at 25 ° C. The instrument automatically optimizes the measurement parameters and is directly read by the embedded software. Take the Z-average particle size as the average particle size of the insulin selenium nanoparticles. The particle size distribution results are shown in Figure 1. It can be seen from the figure that the particle size of the prepared insulin-loaded selenium nanoparticles is about 120nm. Nanoparticles with small particle size can effectively pass through the mucosal layer of the gastrointestinal tract and the stagnant layer on the mucosa, thereby increasing the transmembrane transport of the loaded drug. The particle size of the insulin-loaded selenium nanoparticles prepared by the invention is small, which creates favorable conditions for the transmembrane absorption of insulin.

Stability test: Prepare simulated artificial gastric juice (SGF, containing 0.32% pepsin, pH 1.2), weigh 3.2g of pepsin, add dilute hydrochloric acid with pH 1.2 to dissolve it, and dilute to 1000mL to get ready. Take 1 mL of the insulin solution or the insulin-selenium nanoparticle suspension in Example 1 and add it to 4 mL of artificial gastric juice, and incubate at 37° C. with shaking at 100 rpm. At the set time points (5, 15, 30, 60, 120 and 240 min), 200 μL of samples were taken, and the degradation reaction was immediately terminated with 200 μL of 0.1M NaOH. The sample was then treated with methanol-water solution to release the encapsulated insulin, the residual insulin concentration was measured by HPLC, and the residual insulin concentration versus incubation time was plotted to evaluate the stabilizing effect of selenium nanoparticles on insulin. The result is shown in Figure 2. It can be seen from the figure that free insulin degrades very quickly in the simulated artificial gastric juice, and is completely degraded within 5 minutes; while the insulin-loaded selenium nanoparticles prepared by the present invention can significantly resist the degradation of pepsin, and the cumulative degradation percentage after incubation for 4 hours is small at 20%. Selenium nanoparticles can significantly improve the stability of insulin in the gastrointestinal tract, thereby solving the problem of insulin being degraded and inactivated in the gastrointestinal tract and unable to be administered orally.

Example 10: Hypoglycemic effect of insulin selenium nanoparticles in vivo

(1) Hypoglycemic effect after oral administration in normal SD rats

Twelve SD rats were fasted for 12 hours before the experiment, and allowed to drink water freely during the fasting period. During the experiment, they were randomly divided into four groups with 6 rats in each group. The first group subcutaneously injected insulin solution with a dose of 1IU/kg as a positive control (s.c); the second group orally administered a dose of 50IU/kg insulin solution (dissolved in pH 7.4 buffer) as a negative control (i.g); the third group took The insulin-selenium nanoparticle preparation in Example 1 was orally administered with a dose of 50 IU/kg insulin-selenium nanosuspension (i.g); the fourth group was orally administered with normal saline as a blank control group. Before administration, 250 μL of blood was drawn from the tail vein. After administration in the subcutaneous injection group, 250 μL of blood was collected from the tail vein at 0.15, 0.25, 1, 2, 3, 4, 6, 8 and 10 hours. After intragastric administration, 250 μL of blood was collected through the tail vein at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hours, respectively. Immediately after the blood sample was taken out, it was centrifuged with a centrifugal force of 5000g for 10min, and the supernatant plasma was separated. The glucose concentration in the plasma was measured by the glucose oxidase method, and the measurement results are shown in FIG. 3 . It can be seen from the figure that compared with the control group, oral administration of the insulin solution group basically has no hypoglycemic effect, while the insulin-loaded selenium nanoparticles group has a significant hypoglycemic effect, and its hypoglycemic effect is close to that of the insulin subcutaneous injection group. It is worth noting that the hypoglycemic effect of the insulin-loaded selenium nanoparticles group can last for a long time, which is an advantage that subcutaneous injection of insulin solution does not have. This hypoglycemic effect can not only reduce the number of administrations, but also avoid discomfort to patients caused by fluctuations in blood sugar.

(2) Hypoglycemic effect after oral administration in GK diabetic rats

The experiment was carried out in the same manner as in (1) above using gene knockout rats, and the changes in blood glucose over time after oral administration of different insulin preparations to diabetic rats are shown in Figure 4 . It can be seen from the figure that the hypoglycemic effect of insulin-loaded selenium nanoparticles on diabetic rats is similar to that obtained on normal rats, and also has a significant and lasting hypoglycemic effect. The insulin-loaded selenium nanoparticles of the present invention have achieved significant hypoglycemic effects in two animal models, which shows that the insulin-selenium nanoparticle preparations mentioned in the present invention have great application prospects and development potential.

The above-mentioned embodiment is a preferred embodiment of the present invention, but the embodiment of the present invention is not limited by the above-mentioned embodiment, and any other changes, modifications, substitutions, combinations, Simplifications should be equivalent replacement methods, and all are included in the protection scope of the present invention.

Claims (10)

1. a preparation method of insulin oral selenium nano-preparation, it is characterized in that comprising the following steps: add selenium-containing reagent in the solution or the suspension of insulin and chitosan, generate the selenium/shell that loads insulin under the action of reducing agent Polysaccharide nanoparticles. 2. The preparation method of insulin oral selenium nano-preparation according to claim 1, characterized in that: the dosage ratio of the insulin, chitosan and selenium-containing reagent is 1: (0.25～10): (0.5～20) . 3. The preparation method of oral selenium nano-preparation for insulin according to claim 1, characterized in that: the stoichiometric ratio of the selenium-containing reagent to the reducing agent is 1:0.1-1:50. 4. The preparation method of insulin oral selenium nano-preparation according to claim 1, characterized in that: said selenium-containing reagent is at least one of compounds containing +6-valent selenium or +4-valent selenium and elemental selenium; The chitosan is at least one of low-molecular chitosan, high-molecular chitosan and chitosan derivatives; the reducing agent is glutathione, vitamin C, mercaptoethanol, cysteine At least one of acids, polyphenols or polyols, unsaturated olefins or aromatics. 5. The preparation method of insulin oral selenium nano-preparation according to claim 1, characterized in that: said selenium-containing reagent is selenic acid, selenous acid, selenate, selenite and gray black elemental selenium said chitosan is low molecular weight chitosan; said reducing agent is at least one of glutathione and vitamin C. 6. The preparation method of insulin oral selenium nano-preparation according to claim 1, is characterized in that: described insulin and chitosan are respectively made into solution and then mix to obtain solution or suspension, and described solution refers to use The acidic medium dissolves insulin and chitosan respectively to obtain insulin solution and chitosan solution. 7. The preparation method of insulin oral selenium nano-preparation according to claim 6, characterized in that: the acidic medium is an inorganic acid, an organic acid or a mixed acid solution thereof. 8. The preparation method of insulin oral selenium nano-preparation according to claim 1, is characterized in that specifically comprising the following steps: The chitosan solution and the insulin solution are mixed, and the pH is adjusted until the insulin precipitates to form a suspension; a selenium-containing reagent and a reducing agent are added for reaction to obtain an oral selenium nanometer preparation for insulin. 9. The preparation method of insulin oral selenium nano-preparation according to claim 1, is characterized in that specifically comprising the following steps: Use an acidic medium to dissolve insulin and chitosan, and prepare insulin solution and chitosan solution respectively; mix the insulin solution and chitosan solution, adjust the pH value of the system to above the isoelectric point, and precipitate insulin and form a complex with chitosan Adding selenium-containing reagents and reducing agents to react to generate low-priced selenium and form oral selenium nano-preparations for insulin. 10. An oral selenium nano-preparation for insulin, characterized in that it is obtained according to the preparation method described in any one of claims 1-9.