Gastrointestinal mucosal polymers, compositions, and methods of making and use

Abstract

The present application provides a gastrointestinal mucosal polymer, composition, preparation method and application. The gastrointestinal mucosal polymer comprises a sticky unit, the sticky unit comprises at least one structural unit, the structural unit simultaneously or individually comprises A and C, A is a group containing phenylboric acid, and C is a group containing pyridine disulfide. The sticky unit of the gastrointestinal mucosal polymer of the present application comprises a group containing phenylboric acid and a group containing pyridine disulfide, and the polymer can form a coating on the gastrointestinal mucosa to prevent the absorption of nutrients in the gastrointestinal tract, thereby simulating the effect of RYGB.

Description

Technical Field

[0001] This invention relates to the field of disease treatment drug technology, particularly to intestinal drugs, and even more particularly to intestinal mucosal polymers, compositions, preparation methods and applications. Background Technology

[0002] The modern obesity epidemic and its associated complications have caused global health problems. Most notably, obesity significantly increases the risk of type 2 diabetes (T2D) by 40 times in women with a body mass index (BMI) >30 and by 80 times in women with a BMI >35, affecting more than 650 million people worldwide and leading to high mortality, morbidity, and enormous healthcare expenditures. Current treatments for T2D primarily consist of oral and injectable medication regimens, which may be less than ideal for many patients, partly due to issues with systemic drug absorption. Reverse gastric bypass surgery (RYGB) has been shown to significantly improve T2D, with over 80% of patients reported achieving complete remission after RYGB. Official diabetes organizations have begun recommending bariatric surgery for treating some severely obese patients (stage III) with T2D. Therefore, there is significant interest in developing less invasive alternatives that promise to successfully replicate RYGB for the treatment of T2D patients.

[0003] For example, LuCI (Luminal Coating of the Intestine) is produced from sucralfate. Sucralfate is an FDA-approved drug that selectively coats gastric ulcers. Through engineering, LuCI forms a continuous coating on healthy mucosa. When exposed to gastrointestinal fluids, LuCI forms a viscous paste that binds to the mucosa and forms a barrier coating to prevent nutrient absorption in the gastrointestinal tract, mimicking the effect of RYGB. Alternatively, certain cationic polymers are used, and these polymers complex with gastrointestinal mucus to form an occlusive barrier in the duodenum to prevent nutrient absorption. Or, boric acid side groups are incorporated into certain cationic polymers to enhance the polymer's mucin-complexing activity. These polymers form a physical barrier in situ to prevent nutrient absorption by interacting with resident mucins in the gastrointestinal tract, thus mimicking the effect of RYGB.

[0004] Although these inorganic and organic materials can complex with mucins through physical processes (including electrostatic adsorption, hydrogen bonding, and van der Waals forces), the adhesive properties of the resulting mucosal coating are insufficient to achieve the desired effect; that is, the coating detaches from the gastrointestinal mucosa before it can fully exert its barrier function. Summary of the Invention

[0005] In view of the above problems, the purpose of this invention is to provide a gastrointestinal mucosal polymer and its application. This gastrointestinal mucosal polymer has high stability, adhesion and coating cohesive properties, and has a good shielding effect, which can effectively shield nutrients from entering the human blood circulation system.

[0006] To achieve the above objectives, the present invention provides a gastrointestinal mucosal polymer comprising a viscous unit, wherein the viscous unit comprises at least one structural unit. The structural unit may contain A and C simultaneously or individually, where A is a group containing phenylboronic acid and C is a group containing pyridine disulfide.

[0007] In this invention, the term "viscous unit" refers to a structural unit that can promote the adhesion of the polymer to the gastrointestinal tract wall. In this invention, the "viscous unit" adheres to the mucin inside the gastrointestinal tract through structural units containing A and C groups. In other embodiments of this invention, the polymer may include not only structural units with A and C viscous units, but also other functional units that do not contain A and C groups.

[0008] The adhesive unit of the gastrointestinal mucosal polymer of the present invention includes groups containing phenylboronic acid and groups containing pyridine disulfide. This polymer can form a coating on the gastrointestinal mucosa to prevent nutrient absorption in the gastrointestinal tract, mimicking the effect of RYGB. The phenylboronic acid-containing groups complex mucoproteins via hydrogen bonds and also have a certain adsorption effect on glucose.

[0009] In this invention, the pyridine disulfide structure has a -SS- bond and a pyridine group. The pyridine disulfide group has low reactivity; the disulfide bond is not easily broken during polymer storage and oral administration into the gastrointestinal tract, allowing the copolymer to penetrate deeper into the mucus layer of the gastrointestinal tract. After the disulfide bond breaks, it can form a disulfide bridge covalent bond with cysteine ​​residues on mucin, thereby improving the adhesion and longevity of the coating. Therefore, the pyridine disulfide group of this invention can provide sufficient local adhesion at a given target site for a prolonged period to ensure adequate dosage, reducing the frequency of administration and thus improving the bioavailability and patient compliance of oral medications.

[0010] In addition, sulfur polymers containing pyridine disulfide groups possess enzyme-inhibiting, osmotic-enhancing, and efflux pump-inhibiting properties, thus protecting peptide and protein drugs from enzymatic attack in the gastrointestinal tract. However, sulfur polymers are relatively unstable in solutions and gels, with thiols readily oxidized at around pH 5.

[0011] As a technical solution of the present invention, the structural unit further includes B, which is a group that is cationic in the gastric environment, preferably a group containing an amino group. The amino group can be cationic in the low pH gastrointestinal tract, providing electrostatic repulsion and dispersion to ensure a uniform coating without aggregation. Simultaneously, the cationic state can interact with negatively charged mucins, improving the adhesion of the polymer to the coating.

[0012] As one technical solution of the present invention, the structural formula is shown in Formula 1, Formula 2 or Formula 3.

[0013]

[0014] Wherein, A is a group containing phenylboronic acid, B is a group containing an amino group, C is a group containing pyridine disulfide, L, M, and N are each independently selected from succinimide and maleimide, n is an integer from 2 to 100,000, a and c are each independently an integer from 1 to 100,000, and b is an integer from 0 to 100,000. Preferably, b is not 0, that is, the gastrointestinal mucosal polymer simultaneously includes a group containing phenylboronic acid, a group containing an amino group, and a group containing pyridine disulfide. Through the action of these three groups, it can better adhere to mucin and have a better shielding effect on glucose.

[0015] As a technical solution of the present invention, the structural formula of A in Formula 1 and Formula 3 is as shown in Formula 1.

[0016]

[0017] The structural formula of A in Formula 2 is shown in Formula 2.

[0018]

[0019] Where X is selected from One of them, x is 0 or 1, y and z are each independent integers from 0 to 3, and v is an integer from 1 to 3.

[0020] As a technical solution of the present invention, the structural form of A in Formula 1 and Formula 3 is shown in Formula 3 or Formula 4.

[0021]

[0022] The structural formula of A in Formula 2 is shown in one of the structural formulas 5 to 8.

[0023]

[0024] As a technical solution of the present invention, the structural formula of B in Formula 2 is shown in Formula 9, Formula 10 or Formula 11.

[0025]

[0026] The structural formula of B in Formula 3 is shown in Formula 12, Formula 13, or Formula 14.

[0027]

[0028] Where Y is selected from In this context, R1, R2, and R3 are each independently selected from H, methyl, ethyl, and propyl, and p and q are each independent integers from 1 to 3. It is represented as an N-containing heterocyclic group of C2 to C7.

[0029] As a technical solution of the present invention, the structural formula of B in Formula 1 is shown in Structural Formula 15.

[0030]

[0031] The structural formula of B in Formula 2 is shown in Formulas 16 to 19.

[0032]

[0033] The structural formula of B in Formula 3 is shown in Formula 20.

[0034]

[0035] As a technical solution of the present invention, the structural form of C in Formulas 1 and 3 is shown in Structural Formula 21.

[0036]

[0037] The structural formula of group C in Formula 2 is shown in Structural Formula 22.

[0038]

[0039] Z is selected from One of them, R4 is selected from hydrogen, hydrocarbon group, carboxyl group or ester group, R is selected from hydrogen or hydrocarbon group, h and k are each independent integers from 0 to 3, and w is an integer from 1 to 3.

[0040] As a technical solution of the present invention, the structural formulas of the C group in Formulas 1 and 3 are shown in structural formulas 23 to 25.

[0041]

[0042] The structural formula of C in Equation 2 is shown in Structural Formulas 26 to 31.

[0043]

[0044]

[0045] As one technical solution of the present invention, the gastrointestinal mucosal polymer is selected from one of compounds I to IV.

[0046]

[0047]

[0048] Where n is an integer from 2 to 100,000, and a, b, and c are each an independent integer from 1 to 100,000.

[0049] As one technical solution of the present invention, n is an integer from 2 to 100.

[0050] As a technical solution of the present invention, a, b and c are each independently an integer from 1 to 100.

[0051] As one technical solution of the present invention, a:b:c is 30~60:30~60:10~20.

[0052] A second aspect of the present invention provides a gastrointestinal mucosal composition comprising at least one of the aforementioned gastrointestinal mucosal polymers and a pharmaceutically acceptable excipient.

[0053] A third aspect of this invention provides a method for preparing a gastrointestinal mucosal polymer, which is obtained by at least one of reactions one to four.

[0054] Reaction 1: Using a polyamine polymer containing B as a backbone, grafting compounds containing A and C onto it;

[0055] Reaction 2: Using a polyamine polymer containing A and B as a backbone, grafting a compound containing C;

[0056] Reaction 3: Free radical polymerization reaction involving compounds containing A, B, and C;

[0057] Reaction 4: Using polysuccinimide or polymaleimide as a backbone, graft compounds containing A, B, and C onto the structure.

[0058] The gastrointestinal mucosal polymer of the present invention can be prepared by various methods, and its synthesis is simple and convenient for industrial production.

[0059] As one technical solution of the present invention, the structural formula of the compound containing A is shown in structural formula 32.

[0060]

[0061] Where X is selected from One of them, K is selected from hydrogen or C1 to C6 olefin group, x and z are each independently 0 or 1, and x and z are not 0 at the same time, y is an integer from 0 to 3.

[0062] As a technical solution of the present invention, the compound containing A is selected from one of compounds one through six.

[0063]

[0064] As a technical solution of the present invention, the structural formula of the compound containing B is shown in structural formula 33, structural formula 34 or structural formula 35.

[0065]

[0066] Where Y is selected from In this context, R1, R2, and R3 are each independently selected from H, methyl, ethyl, and propyl; P is selected from hydrogen or a C1-C6 olefinic group; q and r are each independently 0 or 1, and q and r are not simultaneously 0; and p is an integer from 0 to 3. It is represented as an N-containing heterocyclic group of C2 to C7.

[0067] As one technical solution of the present invention, the compound containing B is selected from one of compounds seven to twelve.

[0068]

[0069]

[0070] As one technical solution of the present invention, the structural formula of the compound containing C is shown in structural formula 36.

[0071]

[0072] Z is selected from In the formula, Q is selected from hydrogen or an olefinic group of C1 to C6, R4 is selected from hydrogen, hydrocarbon, carboxyl or ester, R is selected from hydrogen or hydrocarbon, i and j are each independently 0 or 1, and i and j are not simultaneously 0, and h is an integer from 0 to 3.

[0073] As a technical solution of the present invention, the compound containing C is selected from one of compounds thirteen to twenty-one.

[0074]

[0075]

[0076] As one technical solution of the present invention, the structural formula of the polyamine polymer containing B is shown in Formula 4, the structural formula of the polyamine polymer containing A and B is shown in Formula 5, and the structural formula of polysuccinimide is shown in Formula 6, wherein n is an integer from 2 to 100,000.

[0077]

[0078] The fourth aspect of the present invention provides the use of gastrointestinal mucosal polymers or gastrointestinal mucosal compositions in the preparation of medicaments for regulating metabolism in obese or diabetic patients.

[0079] The fifth aspect of the present invention provides a medicament for treating obesity or diabetes, comprising the aforementioned gastrointestinal mucosal polymer or the aforementioned gastrointestinal mucosal composition.

[0080] As one technical solution of the present invention, the dosage form is liquid, tablet, capsule, or capsule form. Detailed Implementation

[0081] The gastrointestinal mucosal polymer or a composition of multiple polymers of the present invention can be used alone as a drug or mixed with pharmaceutically acceptable excipients. The gastrointestinal mucosal polymer in the drug can form a coating on the gastrointestinal mucosa to prevent nutrient absorption in the gastrointestinal tract, mimicking the effect of RYGB, thereby serving as a drug for regulating metabolism and diagnosis / treatment in obese or diabetic patients.

[0082] Gastrointestinal mucosal polymers include viscous units, each of which includes at least one structural unit. The structural unit contains A and C, either simultaneously or individually, where A is a group containing phenylboronic acid and C is a group containing pyridine disulfide.

[0083] Furthermore, the structural unit may also include B in a cationic state within the stomach.

[0084] The structural formula of gastrointestinal mucosal polymers can be as follows:

[0085]

[0086] That is, in the polymer, the sum of structural units containing A, B, and C is defined as "viscous unit", while the sum of other structural units not containing A, B, and C is defined as other functional units. The structural units of other functional units on the coated polymer of the present invention are optional.

[0087] B is preferably a group containing an amino group, wherein the amino group can provide electrostatic repulsion and dispersion in the low pH gastrointestinal tract to ensure a uniform coating without agglomeration. The groups containing phenylboronic acid include phenylboronic acid groups and partially substituted phenylboronic acid groups; the groups containing amino groups include amino groups and partially substituted amino groups; and the groups containing pyridine disulfide include pyridine disulfide groups and partially substituted pyridine disulfide groups.

[0088] The structural formula of the gastrointestinal mucosal polymer is shown in Formula 1, Formula 2 or Formula 3, wherein A is a group containing phenylboronic acid, B is a group containing an amino group, C is a group containing pyridine disulfide, L, M and N are each independently selected from succinimide and maleimide, n is an integer from 2 to 100,000, a and c are each independently an integer from 1 to 100,000, and b is an integer from 0 to 100,000.

[0089]

[0090] Wherein, L, M, and N can be the same group or not completely the same group. For example, L, M, and N can all be succinimides, or L, M, and N can all be maleimides, or some of L, M, and N can be succinimides and the remaining parts can be maleimides. n is an integer from 2 to 100,000. Preferably, n is an integer from 2 to 10,000. More preferably, n is an integer from 2 to 1,000. Even more preferably, n is an integer from 2 to 100. As an example, n can be, but is not limited to, an integer of 2, 5, 10, 20, 50, 100, 200, 500, 1000, 2000, 5000, 7000, 8000, 9000, 10000, 30000, 50000, 70000, 85000, or 100000. a, b, and c are each an independent integer from 1 to 100,000. Preferably, a and c are each an independent integer from 1 to 10,000. More preferably, a and c are each an independent integer from 1 to 1,000. Even more preferably, a and c are each an independent integer from 1 to 100. As examples, a and c are each independent, but not limited to, 2, 5, 10, 20, 50, 100, 200, 500, 1000, 2000, 5000, 7000, 8000, 9000, 10000, 30000, 50000, 70000, 85000, and 100000. b is an integer from 0 to 100,000. Preferably, b is an integer from 1 to 10,000. More preferably, b is an integer from 1 to 1,000. Even more preferably, b is an integer from 1 to 100. As an example, b can be, but is not limited to, 0, 2, 5, 10, 20, 50, 100, 200, 500, 1000, 2000, 5000, 7000, 8000, 9000, 10000, 30000, 50000, 70000, 85000, 100000. The ratio of a:b:c is 30-60:30-60:10-20. The ratio of a:b:c can be, but is not limited to, 30:30:10, 30:40:10, 30:50:10, 30:60:15, 30:60:20, 40:30:20, 40:50:20, 40:50:15, 50:50:20, 50:50:10, 50:30:20, 50:45:20, 60:30:20, 60:30:10, 50:30:20, 30:60:10, or 30:50:20.

[0091] In Equations 1 and 3, the structural formulas of A are shown in Equation 1, where X is selected from... One of them, x is 0 or 1, y and z are each independent integers from 0 to 3, and v is an integer from 1 to 3.

[0092]

[0093] The structural formula of A in Formula 2 is shown in Formula 2.

[0094]

[0095] As an example, the structural form of A in Equations 1 and 3 may be, but is not limited to, as shown in Equation 3 or Equation 4.

[0096]

[0097] The structural formula of A in Formula 2 is as shown in Formula 5 to Formula 8, but is not limited to one of the five to eight structural formulas.

[0098]

[0099] In structure A of the present invention, the boric acid groups at positions 1 and 4 have less steric hindrance, which allows the boric acid to better complex mucin and glucose. In the above-mentioned structural formulas four, six, seven, and eight, the amine or amide groups can provide lone pair electron conjugation to the benzene ring, improve the electronegativity of the boric acid, and enhance the complexing effect of hydrogen bonds.

[0100] The structural formula of B in Formula 1 is shown in Structural Formula 15.

[0101]

[0102] The structural formula of B in Formula 2 is shown in Formula 9, Formula 10, or Formula 11.

[0103]

[0104] Where Y is selected from In this composition, R1, R2, and R3 are each independently selected from H, methyl, ethyl, and propyl, and p and q are each independent integers from 1 to 3. It is represented as an N-containing heterocyclic group of C2 to C7.

[0105] The structural formula of B in Formula 3 is shown in Formula 12, Formula 13, or Formula 14.

[0106]

[0107] Where Y is selected from In this context, R1, R2, and R3 are each independently selected from one of H, methyl, ethyl, and propyl. It is represented as an N-containing heterocyclic group of C2 to C7, where p and q are each independent integers from 1 to 3.

[0108] As an example, the structural formula of B in Equation 2 is shown in Structural Formulas 16 to 19.

[0109]

[0110] As an example, the structural formula of B in Equation 3 is shown in Structural Formula 20.

[0111]

[0112] In this invention, in the acidic digestive environment of the stomach, the lone pair of electrons on the nitrogen atom of the amino group can combine with protons to form cations. The cations and negatively charged mucins can interact and adhere to each other. Although the contribution and influence of the amino group on the complexation of mucins is smaller compared to the hydrogen bonds of phenylboronic acid and the covalent bonds of pyridine disulfide, the electrostatic repulsion between the cationic amino groups allows the coating polymer to be uniformly dispersed on the inner wall of the gastrointestinal tract, ensuring that the coating is uniform and does not agglomerate. The full dispersion of the coating polymer also allows the phenylboronic acid groups and pyridine disulfide to better adhere to the mucins and have a better shielding effect on glucose.

[0113] Therefore, it can be seen that the charge of the polymer will affect the structure in the stomach environment. In the above structure, structural formula 15 has the entire B group as the backbone, and structural formula 20 has amine groups at both ends. In the stomach environment, it undergoes protonation, which increases the charge of the coating polymer, thereby improving the effect of electrostatic repulsion dispersion.

[0114] The structural formulas of C in Equations 1 and 3 are shown in Structural Formula 21.

[0115]

[0116] Z is selected from One of them, R4 is selected from hydrogen, hydrocarbon group, carboxyl group or ester group, R is selected from hydrogen or hydrocarbon group, h and k are each independent integers from 0 to 3, and w is an integer from 1 to 3.

[0117] The structural formula of group C in Formula 2 is shown in Structural Formula 22.

[0118]

[0119] Z is selected from One of them, R4 is selected from hydrogen, hydrocarbon group, carboxyl group or ester group, R is selected from hydrogen or hydrocarbon group, h and kk are each independent integers from 0 to 3, and w is an integer from 1 to 3.

[0120] As an example, the structural formulas of the C group in Formulas 1 and 3 are shown in structural formulas 23 to 25.

[0121]

[0122] The structural formula of C in Formula 2 is shown in Structural Formulas 26 to 31.

[0123]

[0124] Thiol functional groups can form disulfide bridge covalent bonds with cysteine ​​residues in mucin. However, thiol groups are easily oxidized before contacting mucin molecules, which may weaken the interaction between the thiopolymer and the gastrointestinal mucus layer. This invention specifically incorporates pyridine disulfide groups, which are relatively stable and allow the copolymer to penetrate deeper into the mucus layer of the gastrointestinal tract. After the disulfide bonds break, they can form disulfide bridge covalent bonds with cysteine ​​residues in mucin for adhesion.

[0125] Therefore, the breaking rate of the disulfide bond on the pyridine disulfide group will affect the covalent adhesion with mucin. In the above structure, a carboxyl group is introduced on the pyridine group to form a nicotinic acid structure. The electronic effect of the carboxyl group can preactivate the thiol group, and can also ensure that the sulfur polymer has certain stability, mucosal adhesion and coating cohesive properties, so as to effectively shield nutrients from entering the human blood circulation system.

[0126] The gastrointestinal mucosal polymer of the present invention can be selected from one of compounds I to IV. Of course, in practice, the gastrointestinal mucosal polymer can also be other polymers that satisfy the aforementioned combination of groups A, B, and C.

[0127]

[0128]

[0129] Where n is an integer from 2 to 100,000, and a, b, and c are each an independent integer from 1 to 100,000.

[0130] The gastrointestinal mucosal polymer of the present invention can be prepared by a variety of reactions, and the preparation process is as follows.

[0131] Reaction 1: Using a polyamine polymer containing B as the backbone, grafting compounds containing A and C onto it.

[0132] The structural formula of the polyamine polymer containing B is shown in Formula 4, where n is an integer from 2 to 100,000. Preferably, n is an integer from 2 to 10,000; more preferably, n is an integer from 2 to 1,000; and even more preferably, n is an integer from 2 to 100. As an example, n may be, but is not limited to, an integer of 2, 5, 10, 20, 50, 100, 200, 500, 1000, 2000, 5000, 7000, 8000, 9000, 10000, 30000, 50000, 70000, 85000, or 100000.

[0133]

[0134] The structural formula of a compound containing A is shown in structural formula 32, where X is selected from... One of them, K is selected from hydrogen or C1 to C6 olefin group, x and z are each independently 0 or 1, and x and z are not 0 at the same time, y is an integer from 0 to 3.

[0135]

[0136] As an example, the compound containing A is selected from one of compounds one through six.

[0137]

[0138] The structural formula of compounds containing C is shown in structural formula 36, ​​where Z is selected from... In the formula, Q is selected from hydrogen or an olefinic group of C1 to C6, R4 is selected from hydrogen, hydrocarbon, carboxyl or ester, R is selected from hydrogen or hydrocarbon, i and j are each independently 0 or 1, and i and j are not simultaneously 0, and h is an integer from 0 to 3.

[0139]

[0140] As an example, the compound containing C is selected from one of compounds thirteen to twenty-one.

[0141]

[0142]

[0143] The polymer in this respect can be prepared by the following reaction:

[0144] Reaction 1: Using a polyamine polymer containing B as a backbone, grafting compounds containing A and C onto it.

[0145] Taking compound I as an example, its reaction formula can be shown below.

[0146]

[0147] The preparation methods for compounds containing carbon are as follows:

[0148]

[0149] Reaction 2: Using a polyamine polymer containing A and B as a backbone, a compound containing C is grafted.

[0150] The structural formula of the polyamine polymer containing A and B is shown in Formula 5, where n is an integer from 2 to 100,000. Preferably, n is an integer from 2 to 10,000; more preferably, n is an integer from 2 to 1,000; and even more preferably, n is an integer from 2 to 100. As an example, n may be, but is not limited to, an integer of 2, 5, 10, 20, 50, 100, 200, 500, 1000, 2000, 5000, 7000, 8000, 9000, 10000, 30000, 50000, 70000, 85000, or 100000.

[0151]

[0152] Taking compound I as an example, the reaction formula for reaction II can be referenced from that for reaction I.

[0153] Reaction 3: Free radical polymerization via a compound containing A, a compound containing B, and a compound containing C. The compounds containing A and C can be found in the section on Reaction 1. The structural formulas of the compounds containing B are shown in Structural Formulas 33, 34, or 35, where Y is selected from... In this context, R1, R2, and R3 are each independently selected from one of H, methyl, ethyl, and propyl. It is represented as an N-containing heterocyclic group of C2 to C7, where P is selected from hydrogen or an olefinic group of C1 to C6, q and r are each independently 0 or 1, and q and r are not simultaneously 0, and p is an integer from 0 to 3.

[0154]

[0155] As an example, the compound containing B is selected from one of compounds seven through twelve.

[0156]

[0157]

[0158] In this free radical polymerization reaction, the initiator may be, but is not limited to, azobis(isobutyronitrile), azobis(4-cyanopentanoic acid), 2,2'-azobis(2-amidinylpropane) dihydrochloride, potassium persulfate, ammonium persulfate, and potassium peroxymonosulfate. Alternatively, initiation may be carried out by ionizing radiation or ultraviolet light. The initiator is preferably present in the reaction mixture in an amount of about 0.01 to 5 wt.% relative to the monomer.

[0159] Taking compound II as an example, its reaction formula can be shown below.

[0160]

[0161] Reaction 4: Using polysuccinimide or polymaleimide as a backbone, a compound containing A, a compound containing B, and a compound containing C are grafted onto it. The structural formula of polysuccinimide is shown in Formula 6, where n is an integer from 2 to 100,000. The compounds containing A and C can be found in the section on Reaction 1. The compound containing B can be found in the section on Reaction 3.

[0162]

[0163] Taking compound III as an example, its reaction formula can be shown below. It uses polysuccinimide as a backbone and adds groups containing phenylboronic acid, amine, and pyridine disulfide through a ring-opening reaction.

[0164]

[0165] To better illustrate the purpose, technical solution, and beneficial effects of this invention, the invention will be further described below with reference to specific embodiments. It should be noted that the methods described below are further explanations of this invention and should not be construed as limiting it.

[0166] I. Raw Material Preparation

[0167] (1) Preparation of 2-(2-amino-2-carboxyethyl)dimercaptonicotinic acid (Cys-MNA)

[0168] 2 g of 2-mercaptonicotinic acid (MNA) was dispersed in 80 mL of deionized water and sonicated for 10 min. The pH was adjusted to 8 with NaOH (5 M), resulting in a clear yellow solution. 2.5 mL of hydrogen peroxide (30% v / v) was added and stirred for 10 min until the MNA oxidized and the solution became colorless, maintaining the pH at 8-9 throughout the reaction. 40 mL of an aqueous solution containing 1 g of L-cysteine ​​(Cys) was then added dropwise to the oxidized solution over 60 min, maintaining the pH at 8.5-9.5 throughout the reaction, resulting in a clear, pale yellow solution. The pale yellow solution was lowered to pH 7.5, and the precipitate was removed by filtration. The filtrate was further purified using an ion exchange column to remove unbound L-cysteine ​​and the L-cysteine ​​reaction mixture.

[0169] (2) Preparation of 4-carboxyphenylboronic acid-polyallylamine hydrochloride (PAAn-CPBA, n=80)

[0170] A 50.3% PAAn-HCl solution (5.96 g) was placed in a beaker containing a magnetic stir bar and 90 ml of deionized water. NaOH solution was added dropwise with stirring to adjust the pH to 8.0. 99.7% 4-carboxyphenylboronic acid (0.91 g) was added to the beaker, and the resulting suspension was stirred. After stirring for 20 min, the pH dropped to 6.8. NaOH solution was then added in portions with stirring to completely dissolve the suspension. The resulting clear solution had a pH of 7.5. Solid 1-hydroxybenzotriazole (HOBt) hydrate powder (0.046 g) was then added to the clear reaction solution and dissolved after stirring for 20 min. Hydrochloric acid (1 M) was added to the reaction mixture to lower the pH to 5.4, and the reaction solution remained clear. Then, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC, 1.15 g), dissolved in 10 ml of deionized water, was slowly transferred into the reaction mixture. The reaction mixture was stirred for 18 h, and the pH of the reaction mixture was adjusted to 2.5 with 1 M HCl. Dialysis was then performed using a 20 kDa MWCO dialysis bag, with the first dialysate being a deionized aqueous solution containing 2.5% sodium chloride. The solution was then desalted with deionized water until the conductivity of the filtrate was <200 pS / cm. The retentate was then frozen and lyophilized to obtain a fluffy white solid.

[0171] Example 1

[0172] This embodiment describes PAAn-CPBA-MNA, prepared according to reaction two described above. The specific preparation process includes: dissolving 0.2 g of Cys-MNA in 100 mL of deionized water and adjusting the pH to 5.5. The carboxyl groups were activated by adding N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC, final concentration 150 mM) and N-hydroxysuccinimide (NHS, final concentration 40 mM). After stirring, activation was carried out at pH 5.5 for 15 min, then the pH was adjusted to 7, and the prepared PAAn-CPBA solution (0.86 g) was slowly added over 30 min. The mixture was stirred at room temperature for 3 h to obtain the modified copolymer of PAAn-CPBA-MNA. The solution was filled into a dialysis tube (20 kDa MWCO) and dialyzed three times with 2 L of deionized water, each time for at least 12 h, to obtain purified PAAn-CPBA-MNA. The dialysate was then freeze-dried and stored under dry conditions. The composition ratio of PAAn, CPBA, and MNA obtained was 60:30:10.

[0173] Example 2

[0174] The preparation steps were the same as in Example 1, and the composition ratio of PAAn, CPBA, and MNA obtained was 50:30:20.

[0175] Example 3

[0176] This embodiment describes P(APAAn-AAPB-PDSMA), prepared according to the aforementioned reaction three. The specific preparation process includes: first, obtaining three monomers—N-(3-aminopropyl)acrylamide salt (APAAn), m-acrylamide phenylboronic acid (AAPB), and ethyl dimercaptopyridine methacrylate (PDSMA)—through laboratory synthesis and purification. In a Schlenk reaction flask equipped with magnetic stirring and an argon atmosphere, different amounts of acrylate or acrylamide monomers are dissolved in dimethylformamide or other suitable water-miscible organic solvents. A small amount of water is introduced to completely dissolve the charged comonomers in the binary solvent system. An appropriate amount of AIBN initiator is added. The comonomer mixture is subjected to three freeze-vacuum-thaw cycles to remove any mixed oxygen, and finally, an inert argon gas is introduced. The reaction is then heated at 65°C for 6 hours under argon cover to carry out free radical polymerization. After the reaction is terminated, the copolymer solution or suspension is separated by acetone precipitation. Finally, the product can be dissolved in deionized water, frozen in liquid nitrogen, and lyophilized. The composition ratio of the three components in the prepared P(APAAn-AAPB-PDSMA) is 60:30:10.

[0177] Example 4

[0178] The preparation steps are the same as in Example 3, and the composition ratio of the three components in the prepared P(APAAn-AAPB-PDSMA) is 50:30:20.

[0179] Example 5

[0180] This embodiment describes a polysuccinimide-grafted modified polymer PSI-(APBA-DMAPA-AEDNA), prepared according to reaction four described above. The specific preparation process includes: weighing 4.0 g of polysuccinimide (PSI) into a 100 mL flask, adding 30 mL of DMSO, stirring thoroughly, and using ultrasound to ensure complete dissolution of the PSI. Argon gas is then introduced into the solution for at least 30 minutes to isolate the air and prevent side reactions. Next, 1.6 g of 3-aminophenylboronic acid (APBA) is weighed and dissolved in 10 mL of DMSO. Under stirring, the APBA solution is added to the PSI solution. Argon gas is then continuously introduced into the mixed solution, and the oil bath temperature is raised to 60°C. After 10 minutes, the reaction system is sealed. After stirring for 24 hours, the resulting reaction solution is added dropwise to 300 mL of methanol under rapid stirring to allow product precipitation. The precipitate is then transferred to a centrifuge tube and centrifuged at 8000 rpm for 5 minutes, after which the supernatant is discarded. The pink precipitate obtained by washing with methanol was re-dispersed by sonication and centrifuged again under the same conditions. The dried precipitate was redissolved in 30 mL of DMSO and transferred to a 100 mL flask. 10 mL of 3-(dimethylamino)propylamine (DMAPA) was added to the reaction system under an argon atmosphere, and the temperature was raised to 40 °C before sealing the reaction system. After reacting for 24 h, the reaction solution was added dropwise to 200 mL of ice-cold diethyl ether under rapid stirring for precipitation. The obtained precipitate was redissolved in 10 mL of methanol and added dropwise to 200 mL of diethyl ether for a second precipitation. The precipitate was then transferred to a 50 mL centrifuge tube and centrifuged at 8000 rpm for 5 min. The supernatant was discarded to thoroughly remove unreacted DMAPA. 6-(2-aminoethyl disulfonyl)nicotinic acid (AEDNA) was added to the reaction system, and after 24 h of reaction and precipitation, a copolymer modified with phenylboronic acid, tertiary amino group, and dimercaptonicotinic acid was finally obtained. The ratio of APBA, DMAPA and AEDNA in the prepared PSI-(APBA-DMAPA-AEDNA) is 30:60:10.

[0181] Example 6

[0182] The preparation steps are the same as in Example 5. The composition ratio of APBA, DMAPA and AEDNA in the prepared PSI-(APBA-DMAPA-AEDNA) is 30:50:20.

[0183] Example 7

[0184] Preparation steps: In this example, P(AAPB-PDSMA) is prepared using two monomers, m-acrylamide phenyl boric acid (AAPB) and ethyl dimercaptopyridine methacrylate (PDSMA), as raw materials. The preparation method is the same as in Example 3, and the composition of the two monomers in the prepared P(AAPB-PDSMA) is 60:40.

[0185] PAAn (CAS:30551-89-4) was used as Comparative Example 1, and the prepared 4-carboxyphenylboronic acid-polyallylamine hydrochloride (PAAn-CPBA) was used as Comparative Example 2.

[0186] Comparative Example 3

[0187] This embodiment is P(APAAn-PDSMA). The specific preparation process includes: firstly, N-(3-aminopropyl)acrylamide salt (APAAn) and ethyl dimercaptopyridine methacrylate (PDSMA) monomers are synthesized and purified in the laboratory. In a Schlenk reaction flask equipped with magnetic stirring and an argon atmosphere, different amounts of acrylate or acrylamide monomers are dissolved in dimethylformamide or other suitable water-miscible organic solvents. A small amount of water is introduced to completely dissolve the charged comonomers in the binary solvent system. An appropriate amount of AIBN initiator is added. The comonomer mixture is subjected to three freeze-vacuum-thaw cycles to remove mixed oxygen, and finally, an inert gas argon is introduced. The reaction is then heated at 65°C for 6 hours under argon cover to carry out free radical polymerization. After the reaction is stopped, the copolymer solution or suspension is separated by precipitation with acetone. Finally, the product can be dissolved in deionized water, frozen in liquid nitrogen, and lyophilized. The composition ratio of the three monomers in the prepared P(APAAn-PDSMA) is 60:40.

[0188] In this invention, the products in Examples 1-7 have been verified to have the relevant structures through infrared spectroscopy. The polymers of Examples 1-7 and Comparative Examples 1-3 were tested for their complexation properties with mucin, and the shielding effect of the resulting coatings was also examined.

[0189] (1) Mucin-polymer complexation test

[0190] Step 1: Prepare 0.1M MES saline buffer solution

[0191] Add 21.3 g of 2(N-morpholine)ethanesulfonic acid monohydrate (MES, Sigma) to a 1.5 L beaker. Add 9.0 g of sodium chloride (Sigma) and approximately 750 ml of deionized water to the beaker, then add a magnetic stir bar and a pH electrode, and begin stirring to dissolve all the solids. Add 1 N NaOH solution in portions to adjust the pH of the solution to the desired level. Finally, transfer the solution to a 1 L volumetric flask and add deionized water to bring the total volume to 1 L.

[0192] Step 2: Complexing mucin

[0193] Using the MES-saline buffer prepared above, 1.0% (w / w) solutions of the polymers to be tested in each example were then prepared. A 1.0% (w / w) solution of water-soluble porcine gastric mucin (MPS-3) was then prepared using the MES-saline buffer. The MPS-3 solution was placed in a 5 mL vial. An equal volume of the polymer solution to be tested was slowly added to the vial, gently shaken, and kept at a constant temperature of 37°C, while observing the physical changes in the vial.

[0194] Following the experimental procedures described above, the ability of the polymer to form insoluble complexes with mucin in MES buffer at pH 5.5, 6.0, and 6.5 was tested, and the results are shown in Table 1. The physical states of the complexes can be characterized using a scale of 1-5: 1 Clear (only slightly turbid, similar to the initial mucin solution); 2 Hazy (more hazy than the initial mucin solution, but text can be read through it); 3 Obscure (opaque, unreadable, but with good light transmission); 4 Precipitation (opaque); 5 Phase separation (thin film, gel deposition, a clear or turbid supernatant may be visible).

[0195] Table 1. Mucin-polymer complexation tests for each embodiment.

[0196]

[0197]

[0198] As shown in Table 1, when the polymers of Examples 1-7 were simultaneously grafted with groups containing phenylboronic acid, amino groups, and pyridine disulfide groups, or simultaneously grafted with groups containing phenylboronic acid and pyridine disulfide groups, the physical state of the complexes was precipitation or phase separation at all pH values, indicating that the polymers and mucin have relatively strong complexing behavior. Especially in Examples 5-6, which were obtained by grafting and modifying the polysuccinimide (PSI) backbone to introduce groups containing phenylboronic acid, amino groups, and pyridine disulfide groups, the complexing behavior was even stronger, indicating that the complexing ability of cationic polymers with mucin can be significantly improved over a relatively wide pH range, thereby enhancing the adhesion of the polymer to the gastrointestinal mucosa. In contrast, in Comparative Example 1, when pure cationic PAAn was mixed with mucin, it appeared hazy at all pH values, indicating that the polymer's ability to complex mucin was relatively weak. PAAn modified with phenylboronic acid (Comparative Example 2) also exhibited similar hazy dispersions when complexing with mucin at pH 5.5 and 6.0, indicating a weak complexation reaction. Comparative Example 3, containing only amine and pyridine disulfide groups P (APAAn-PDSMA), showed a strong complexation reaction at all pH values.

[0199] (2) Complex centrifugal filtration test

[0200] A 1.0% (w / w) solution of the polymer to be tested in each example was prepared using MES-saline buffer at pH 6. A 1.0% (w / w) solution of water-soluble porcine gastric mucin (MPS 3) was then prepared using MES-saline buffer. Spin-X centrifuge tube filters (Corning Inc.), 0.45 μm cellulose acetate cartridges, and 2 m tubes were used. 100 μL of the mucin solution was placed in each filter cup, ensuring complete filter coverage. 100 μL of the polymer solution to be tested was then placed in the filter cup. All centrifuge cups contained 200 μL of solution, and all centrifuge tubes were incubated at 37°C and 150 rpm for 30 min. The tubes were then centrifuged at 6000 rpm for 15 min. The filter cups were removed, the tubes were collected, and the weight of the filtered tubes was measured. The weight of the fluid filtered into the tubes was calculated by subtracting the weight of the tubes before filtration from the weight of the tubes after filtration. The fraction of weight retained in the cup (Fraction Retained, or FR) was calculated by subtracting the weight of the filtrate from the total weight of the mucin-polymer complex and dividing by 200 mg. The results are shown in Table 2.

[0201] Table 2. Centrifugal filtration tests of complexes in each embodiment.

[0202]

[0203]

[0204] As shown in Table 2, when the polymers in Examples 1-6 were simultaneously grafted with groups containing phenylboronic acid, amino groups, and pyridine disulfide groups, or simultaneously grafted with groups containing phenylboronic acid and pyridine disulfide groups, the retained weight fraction (FR) ranged from 0.72 to 0.94. This indicates that the polymers and mucin exhibited strong complexing behavior and high complexing stability. The complexes formed a non-liquid or gel-like physical state, making it difficult to permeate the filter membrane. Therefore, the adsorption effect of the polymers formed in Examples 1-6 on the gastrointestinal mucosa was stronger and more persistent, thus more effectively blocking the intake of nutrients. In contrast, in Comparative Example 1, the retained weight fraction (FR) of the pure polycationic PAAn complexed with mucin was only 0.02, indicating that the polymer could not form a stable complex with mucin. In Comparative Example 2, the retained fraction of the phenylboronic acid-modified polyamine polymer PAAn-CPBA after complexing with mucin was 0.56, indicating that the stability of the complex was not good. Comparative Example 3 contains only amino and pyridine disulfide groups P (APAAn-PDSMA), and the retention fraction after complexing with mucin is 0.96, indicating that the complex formed by the chemical reaction is very stable.

[0205] (3) In vitro glucose shielding efficiency test

[0206] A nitrocellulose membrane (0.4 μm pore size) was immersed in a 3% porcine gastric mucin solution (pH = 6) prepared with MES-saline buffer and gently shaken at room temperature for 2 h. The membrane was washed with deionized water to remove excess mucin solution. The mucin-coated cellulose membrane was used within 1 h of preparation. A 1.0% (w / w) solution of the polymer to be tested, prepared with MES-saline buffer, was then uniformly coated onto the mucin-coated membrane and reacted at 37 °C for 30 min to form a complex coating barrier. The surface of the complex-coated membrane was gently rinsed with buffer to remove excess polymer, and then it was installed in a Franz Cell system. 10 ml of glucose solution (40 g / L) was added to the sample cell, and the sample was collected from the receiver section of the system after 30 min. The glucose content in the collected sample was analyzed by HPLC, and the shielding efficiency of the complex membrane against glucose was evaluated by the ratio to the initial glucose concentration. The results are shown in Table 3.

[0207] Table 3. In vitro glucose shielding efficiency test

[0208]

[0209] As shown in Table 3, when the polymers in Examples 1-6 are simultaneously grafted with groups containing phenylboronic acid, amino groups, and pyridine disulfide groups, or simultaneously grafted with groups containing phenylboronic acid and pyridine disulfide groups, the shielding efficiency for glucose can reach 66-84%. This indicates that the polymer and mucin have a relatively strong complexing behavior, and the resulting coating can prevent the absorption of glucose by the mucin coating film (simulating the mucus surface of the gastrointestinal mucosa). In Comparative Example 1, the shielding efficiency of the pure polycationic PAAn complexed mucin film is only 8%, which cannot effectively isolate glucose molecules. In Comparative Example 2, the shielding efficiency of the phenylboronic acid-modified polyamine polymer PAAn-CPBA after complexing with mucin is 55%. Although it has a certain shielding effect, it is still inferior to the polymers simultaneously grafted with groups containing phenylboronic acid, amino groups, and pyridine disulfide groups. Comparative Example 3, containing only amino and pyridine disulfide groups (APAAn-PDSMA), exhibited a strong complexation with mucin, but its glucose shielding efficiency was only 63%, lower than that of polymers containing all three groups. This indicates that, in addition to the formation of a denser physical barrier between pyridine disulfide and mucin, the adsorption of glucose by phenylboronic acid is also crucial.

[0210] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to preferred embodiments, it is not limited to those listed in the embodiments. Those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. A gastrointestinal mucosal polymer, characterized in that, Including viscous units, the structural formulas are shown in Equation 1, Equation 2, or Equation 3. Formula one and formula two Formula 3 Wherein, A is a group containing phenylboronic acid, C is a group containing pyridine disulfide, B is a group that is cationic in the gastric environment, B is a group containing an amino group, L, M and N are each independently selected from succinimide and maleimide, n is an integer from 20 to 100, a, b and c are each an integer from 20 to 100, and a:b:c is 30~60:30~60:10~20.

2. The gastrointestinal mucosal polymer according to claim 1, characterized in that, The structural formula of A in Equations 1 and 3 is shown in Equation 1. Structural Formula 1 The structural formula of A in Formula 2 is shown in Formula 2. Structural Form 2 Where X is selected from , , and One of them, x is 0 or 1, y and z are each independent integers from 0 to 3, and v is an integer from 1 to 3.

3. The gastrointestinal mucosal polymer according to claim 2, characterized in that, The structural formulas of A described in Equations 1 and 3 are shown in Structural Formula 3 or Structural Formula 4. Structure three and structure four. The structural formula of A in Formula 2 is shown in one of Formulas 5 to 8. Structure 5, Structure 6, Structure 7, Structure 8.

4. The gastrointestinal mucosal polymer according to claim 1, characterized in that, The structural formula of B in Formula 2 is shown in Formula 9, Formula 10, or Formula 11. Structure Nine Structure Ten Structural Formula Eleven The structural formula of B mentioned in Formula 3 is shown in Formula XII, Formula XIII, or Formula XIV. Structure Twelve Structure Thirteen Structural Formula Fourteen Where Y is selected from , , and In this context, R1, R2, and R3 are each independently selected from H, methyl, ethyl, and propyl, and p and q are each independent integers from 1 to 3. It is represented as an N-containing heterocyclic group in the C2~C7 range.

5. The gastrointestinal mucosal polymer according to claim 1, characterized in that, The structural formula of B mentioned in Formula 1 is shown in Structural Formula 15. Structural Formula Fifteen The structural formula of B in Formula 2 is shown in Formulas 16 to 19. Structure Formula 16, Structure Formula 17, Structure Formula 18, Structure Formula 19 The structural formula of B in Formula 3 is shown in Formula 20. Structural formula twenty.

6. The gastrointestinal mucosal polymer according to claim 1, characterized in that, The structural formula of C mentioned in Equations 1 and 3 is shown in Structural Formula 21. Structural formula 21 The structural formula of group C in Formula 2 is shown in Structural Formula 22. Structural formula twenty-two, Z is selected from , and One of them, R4 is selected from hydrogen, hydrocarbon group, carboxyl group or ester group, R is selected from hydrogen or hydrocarbon group, h and k are each independent integers from 0 to 3, and w is an integer from 1 to 3.

7. The gastrointestinal mucosal polymer according to claim 6, characterized in that, The structural formulas of the C groups mentioned in Formulas 1 and 3 are shown in structural formulas 23 to 25. Structure 23, Structure 24, Structure 25 The structural formula of C in Formula 2 is shown in Structural Formulas 26 to 31. Structure 26, Structure 27, Structure 28 Structure 29, Structure 30, Structure 31.

8. The gastrointestinal mucosal polymer according to claim 1, characterized in that, Selected from one of compounds II to III, Compound II Compound III.

9. A gastrointestinal mucosal composition, characterized in that, It includes at least one gastrointestinal mucosal polymer as described in any one of claims 1 to 8 and a pharmaceutically acceptable excipient.

10. The method for preparing the gastrointestinal mucosal polymer according to any one of claims 1 to 8, characterized in that, It is prepared by at least one of reactions one, three, and four. Reaction 1: Using a polyamine polymer containing B as a backbone, grafting compounds containing A and C onto it; Reaction 3: Free radical polymerization reaction involving compounds containing A, B, and C; Reaction 4: Using polysuccinimide or polymaleimide as a backbone, graft compounds containing A, B, and C onto the structure.

11. The method for preparing the gastrointestinal mucosal polymer according to claim 10, characterized in that, The structural formula of the compound containing A is shown in structural formula 32. Structural Formula Thirty-Two Where X is selected from , , and One of them, K is selected from hydrogen or C1~C6 olefin group, x and z are each independently 0 or 1, and x and z are not 0 at the same time, y is an integer from 0 to 3.

12. The method for preparing the gastrointestinal mucosal polymer according to claim 11, characterized in that, The compound containing A is selected from one of compounds one through six. Compound 1, Compound 2, Compound 3 Compound four, compound five, compound six.

13. The method for preparing the gastrointestinal mucosal polymer according to claim 10, characterized in that, The structural formulas of the compounds containing B are shown in structural formulas 33, 34, or 35. Structural Formula 33 Structural Formula 34 Structural Formula Thirty-Five Where Y is selected from , , and In this context, R1, R2, and R3 are each independently selected from H, methyl, ethyl, and propyl; P is selected from hydrogen or a C1-C6 olefinic group; q and r are each independently 0 or 1, and q and r are not simultaneously 0; and p is an integer from 0 to 3. It is represented as an N-containing heterocyclic group in the C2~C7 range.

14. The method for preparing the gastrointestinal mucosal polymer according to claim 10, characterized in that, The compound containing B is selected from one of compounds seven through twelve. Compound 7, Compound 8, Compound 9 Compound 10, Compound 11, Compound 12.

15. The method for preparing the gastrointestinal mucosal polymer according to claim 10, characterized in that, The structural formula of the C-containing compound is shown in structural formula 36. Structural Formula Thirty-Six Z is selected from , and In the formula, Q is selected from hydrogen or an olefinic group of C1 to C6, R4 is selected from hydrogen, hydrocarbon, carboxyl or ester group, R is selected from hydrogen or hydrocarbon group, i and j are each independently 0 or 1, and i and j are not simultaneously 0, and h is an integer from 0 to 3.

16. The method for preparing the gastrointestinal mucosal polymer according to claim 10, characterized in that, The compound containing C is selected from one of compounds thirteen to twenty-one. Compound Thirteen, Compound Fourteen, Compound Fifteen Compound 16, Compound 17, Compound 18 Compound 19, Compound 20, Compound 21.

17. The method for preparing the gastrointestinal mucosal polymer according to claim 10, characterized in that, The structural formula of the polyamine polymer containing B is shown in Formula 4, the structural formula of the polyamine polymer containing A and B is shown in Formula 5, and the structural formula of the polysuccinimide is shown in Formula 6, where n is an integer from 20 to 100. Forms four, five, and six.

18. The use of the gastrointestinal mucosal polymer according to any one of claims 1 to 8 or the gastrointestinal mucosal composition according to claim 9 in the preparation of a medicament for regulating metabolism in obese or diabetic patients.

19. A drug for treating obesity or diabetes, characterized in that, It includes the gastrointestinal mucosal polymer of any one of claims 1 to 8 or the gastrointestinal mucosal composition of claim 9.

20. The medicament for treating obesity or diabetes according to claim 19, characterized in that, Dosage form: liquid, tablet, capsule, or capsule.

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