Radix pseudostellariae cyclic peptide B loaded intestinal sticky patch as well as preparation method and application thereof

Abstract

The invention discloses a radix pseudostellariae cyclic peptide B-loaded intestinal mucosa patch as well as a preparation method and application thereof. The preparation method mainly comprises the following steps: self-assembling glycosylated column [6] arene and radix pseudostellariae cyclic peptide B through host-guest interaction to form a host-guest clathrate compound, and loading the host-guest clathrate compound in a mucosa adhesive polymer matrix, the composite patch with intestinal tract targeting and long-acting adhesion functions is prepared through a tape casting technology. The intestinal adhesive patch prepared by the invention can control drug release in an intestinal pH environment, and prolongs the residence time in the intestinal tract by virtue of the mucous membrane adhesion characteristic of the high polymer material, thereby promoting drug absorption. The preparation is simple and convenient in process and good in repeatability, and has industrial amplification potential. A subject-object inclusion-patch delivery double-layer system constructed by the invention can effectively protect the stability of the radix pseudostellariae cyclic peptide B in a complex gastrointestinal tract environment, improve the oral bioavailability of the radix pseudostellariae cyclic peptide B, and provide a novel effective strategy for oral delivery of polypeptide drugs.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to an intestinal adhesive patch loaded with Codonopsis pilosula cyclic peptide B, its preparation method, and its application. Background Technology

[0002] Type 2 diabetes mellitus (T2DM) is a complex metabolic disease characterized by progressive insulin resistance and pancreatic β-cell dysfunction, leading to persistent hyperglycemia. It has become a major global public health problem, often accompanied by microvascular and macrovascular complications such as cardiac and renal impairment and neuropathy, severely impacting patients' quality of life and increasing the medical burden. In Traditional Chinese Medicine (TCM) theory, T2DM falls under the category of "Xiao Ke Bing" (wasting and thirsting disease), and its pathogenesis is often related to Qi and Yin deficiency and spleen dysfunction, as discussed as early as in the *Suwen* (Plain Questions) chapter on "Strange Diseases." Pseudostellariae Radix, a traditional herb for replenishing Qi and generating fluids, is frequently used in the treatment of Xiao Ke Bing. Modern research indicates that *Codonopsis pilosula* contains various active ingredients, including cyclic peptides, polysaccharides, and saponins. Among them, *Heterophyllin B* (HB), a cyclic octapeptide, has shown high affinity for dipeptidyl peptidase-4 (DPP-4) and glucagon-like peptide-1 receptor (GLP-1R) in molecular docking studies, suggesting that it may participate in blood glucose regulation through a dual mechanism of inhibiting DPP-4 enzyme activity and activating GLP-1R signaling, thus possessing good hypoglycemic potential. However, HB suffers from poor water solubility, low membrane permeability, and susceptibility to enzymatic degradation, resulting in low oral bioavailability and rapid elimination in vivo, severely limiting its clinical application. Therefore, developing a delivery system that can effectively improve the solubility, stability, and oral absorption efficiency of HB has become an important issue in promoting the clinical translation of this active ingredient.

[0003] In terms of formulation, oral films (also known as oral patches) are a type of thin-film formulation with a specific shape that can achieve local or systemic drug delivery through mucosal adhesion. Their definition is included in the *Pharmacopoeia of the People's Republic of China*. Oral films typically consist of film-forming materials, plasticizers, drugs, and functional excipients, manufactured through processes such as casting and coating. They offer advantages such as portability, ease of administration, and avoidance of the first-pass effect. Based on different drug release behaviors, they can be divided into two categories: rapidly dissolving films and sustained-release films. The former is suitable for drugs requiring rapid onset of action, while the latter can achieve continuous or controlled release at specific sites through material and structural design. However, conventional oral films still face challenges such as low drug loading, short gastrointestinal retention time, and insufficient enzyme barrier capacity when used with peptide drugs such as hemoglobin (HB), making efficient delivery difficult.

[0004] To prolong the duration of action of hepatitis B (HB) in the intestine and improve its oral bioavailability, it is necessary to develop oral film formulations that combine mucosal adhesion, enzyme barrier protection, and controlled release functions. Summary of the Invention

[0005] Objective: To address the problems of poor stability, low absorption efficiency, and insufficient targeting in existing technologies for oral delivery of peptides, this invention provides an intestinal adhesive patch loaded with Codonopsis pilosula cyclic peptide B, its preparation method, and its applications. This patch possesses intestinal targeting, enzyme protection, and long-lasting adhesion functions, significantly improving the oral bioavailability of hepatitis B (HB).

[0006] Technical solution: To solve the above-mentioned technical problems, the present invention adopts the following technical solution:

[0007] In the first aspect, the present invention provides a method for preparing an intestinal adhesive patch loaded with Codonopsis pilosula cyclic peptide B. The method mainly utilizes glycosylated columnar aromatic hydrocarbons [6] to form a host-guest inclusion complex through host-guest interaction with HB, and loads it into a mucosal adhesive polymer matrix. The composite patch with both intestinal targeting and long-term adhesion functions is prepared by casting molding technology. The method includes the following steps:

[0008] (1) Polysaccharides were used to modify column[6]arene to obtain glycosylated column[6]arene. The glycosylated column[6]arene and Heterophyllin B (HB) were mixed in solution and subjected to ultrasonic self-assembly to obtain host-guest complex solution HB⊂P6-GalNAc. After lyophilization, HB⊂P6-GalNAc lyophilized powder was obtained.

[0009] (2) Carbomer (CP) and hydroxypropyl methylcellulose (HPMC) were mixed in solution to prepare a solution of interpolymer complexes (IPC).

[0010] (3) Mix the above HB⊂P6-GalNAc lyophilized powder, IPC solution and additives to obtain a sustained-release layer solution;

[0011] (4) Prepare a backing layer, lay the sustained-release solution on the backing layer, dry and cut it to obtain HB⊂P6-GalNAc / IPC intestinal adhesive patch, which is the intestinal adhesive patch loaded with Codonopsis pilosula cyclic peptide B.

[0012] As a specific implementation scheme, in step (1), the polysaccharide is selected from one or more of glucose (Glu), mannose (Man), and N-acetylgalactosamine (GalNAc).

[0013] As a specific implementation scheme, in step (1), the molar ratio of the glycosylated column[6] aromatic hydrocarbon to the ginseng cyclic peptide B is (0.5~5):1.

[0014] As a specific implementation plan, in step (1), the conditions for self-assembly are: stirring the solution at a speed of 300~1000 rpm, a temperature of 25~37℃, and a time of 2~12 h.

[0015] As a specific implementation plan, in step (2), the carbomer is selected from CP. 934 CP 940 CP 941 CP 980 CP 1340 CP 2020 One or more of them, preferably CP 940 The mass ratio of CP to HPMC is 9:1 to 1:9 (w / w), preferably 3:1 (w / w).

[0016] As a specific implementation scheme, in step (2), the method of mixing the solution is as follows: using an ethanol solution with a concentration of 0-100% as the dispersion medium, prepare a CP solution and an HPMC solution respectively, slowly add the HPMC solution to the CP solution, adjust the pH to 3-9, and stir for 3-5 hours at a temperature of 25-35℃ to obtain the IPC solution; the concentration of the CP solution is 1-5% (w / v), and the concentration of the HPMC solution is 1-5% (w / v).

[0017] Preferably, the concentration of the ethanol solution is 60%, the pH is 4, and the mixture is stirred at 27°C for 4 hours; the concentration of the CP solution is 3%, and the concentration of the HPMC solution is 3%.

[0018] As a specific implementation plan, in step (3), the mass ratio of the HB⊂P6-GalNAc lyophilized powder, IPC solution and additive is 2:(5-7):(0.1-1.5).

[0019] As a specific implementation plan, in step (4), the method for preparing the backing layer includes: dissolving the film-forming material in an organic solvent, adding an additive, stirring evenly, forming a film, and preparing a waterproof backing layer;

[0020] Preferably, the preparation method further includes preparing a pigment layer solution using pigments and additives, laying it on a waterproof backing layer, and then laying a slow-release layer solution on the backing layer.

[0021] In the above preparation method, the thickness of each film layer is 0.1~0.5 mm, more preferably 1 mm; the drying temperature is 30~60℃, more preferably 48℃. The moisture content of the dried patch is not higher than 8%.

[0022] Secondly, the present invention provides an intestinal adhesive patch loaded with Codonopsis pilosula cyclic peptide B, wherein the intestinal adhesive patch loaded with Codonopsis pilosula cyclic peptide B is prepared by the above-described preparation method.

[0023] Thirdly, the present invention provides the application of the intestinal adhesive patch loaded with Codonopsis pilosula cyclic peptide B in the preparation of hypoglycemic drugs.

[0024] Based on the principle of host-guest molecular self-assembly, this invention utilizes the host-guest interaction between glycosylated columnar aromatic hydrocarbons [6] (P6) and HB to construct a structurally stable inclusion complex system, which is then uniformly dispersed in a mucosal adhesive polymer solution. An intestinal adhesive patch suitable for efficient delivery of peptide drugs is prepared by a casting film process. Specifically, the cavity structure of P6 matches the hydrophobic region of HB, and efficient HB loading is achieved by means of hydrophobic interaction and van der Waals forces. While improving the biocompatibility of the inclusion complex, the exposed glycosyl groups (such as galactose) can specifically recognize lectin receptors (such as galactolectin-3) overexpressed on the surface of intestinal epithelial cells, thereby achieving active targeted delivery of drugs.

[0025] An intestinal patch was developed using carbomer and hydroxypropyl methylcellulose (HPMC) as functional matrices to construct an intramolecular polymeric complex (IPC) material with intelligent phase transition properties. This material maintains structural stability in the acidic environment of the stomach, without significant hydration or swelling. Upon entering the neutral intestinal environment, the adhesive and erosive properties of the IPC are simultaneously activated, allowing it to adhere tightly to the intestinal mucosa surface through hydration and electrostatic interactions, forming a local drug reservoir and significantly prolonging the retention time of the drug HB⊂P6-GalNAc at the intestinal absorption site. The adhesion, swelling rate, and release behavior of different formulation patches in simulated gastrointestinal fluid were systematically evaluated. The results showed that the patch using the IPC constructed from carbomer and HPMC as the matrix exhibited the best adhesion and sustained-release properties in simulated intestinal fluid. Pharmacological results showed that HB significantly improved glycemic homeostasis in T2DM model mice, with its core mechanism of action being the effective alleviation of systemic insulin resistance rather than the stimulation of insulin secretion. This formulation showed superior efficacy compared to metformin, a first-line clinical drug, in reducing glycated hemoglobin and improving insulin sensitivity, demonstrating excellent therapeutic potential. Pharmacokinetic studies showed that the peak plasma concentration (C) of the HB⊂P6-GalNAc / IPC enteric patch group was [missing value]. max ) and the area under the curve (AUC) 0-∞ The relative bioavailability of the free HB group and the HB / IPC group was higher than that of the free HB group and the HB / IPC group, and was 3.3 times that of the free HB group.

[0026] Compared with existing technologies, the intestinal adhesive patch developed in this invention has the following beneficial effects: high drug loading capacity and good encapsulation efficiency; the nanovesicles that self-assemble in water have a particle size of approximately 350 nm; and the system exhibits excellent physical stability and sustained-release performance. This intestinal adhesive patch can control drug release under the intestinal pH environment and prolongs the retention time in the intestine by utilizing the mucosal adhesion properties of polymer materials, thereby promoting drug absorption. Its preparation process is simple, highly reproducible, and easily scaled up for industrial production. The constructed "actively targeted host-guest encapsulation-bioadhesive patch" dual delivery system can synergistically achieve effective protection, intestinal targeting, long-term retention, and absorption promotion of peptide drugs, providing a novel and efficient delivery strategy for oral peptide drugs such as Codonopsis pilosula cyclic peptide B, significantly improving their oral bioavailability.

[0027] Beneficial effects: High drug loading capacity and good encapsulation efficiency; excellent physical stability and sustained-release performance of the system; simple preparation process with high reproducibility, making it easy to achieve industrial-scale production; the constructed "actively targeted host-guest encapsulation-bioadhesive patch" dual delivery system can synergistically achieve effective protection, intestinal targeting, long-term retention and absorption promotion of peptide drugs, providing a novel and efficient delivery strategy for oral peptide drugs such as Codonopsis pilosula cyclic peptide B, and significantly improving their oral bioavailability. Attached Figure Description

[0028] Figure 1 This invention provides the synthetic route and screening method for glycosylated column[6] aromatic hydrocarbons.

[0029] Figure 2 This invention relates to the formation of HPMC / CP complexes and the infrared spectral analysis of IPC structures under different formulation conditions.

[0030] Figure 3 This invention optimizes the preparation process parameters of the intestinal adhesive patch.

[0031] Figure 4 This is a SEM schematic diagram of the intestinal adhesive patch of the present invention.

[0032] Figure 5 This describes the swelling morphology and swelling result of the intestinal adhesive patch of the present invention.

[0033] Figure 6 This study examines the adhesion and in vitro dissolution of the intestinal adhesive patch of the present invention.

[0034] Figure 7 This study examines the stability of the intestinal adhesive patch of the present invention.

[0035] Figure 8 This invention describes the therapeutic effect of the intestinal adhesive patch on a type 2 diabetic mouse model.

[0036] Figure 9This is the drug-time curve of the intestinal adhesive patch of the present invention acting on mice after oral administration. Detailed Implementation

[0037] The invention can be better understood from the following embodiments. However, the descriptions in the embodiments are for illustrative purposes only and should not, and will not, limit the invention as detailed in the claims.

[0038] Example 1 Synthesis of aromatic hydrocarbons with different glycosylation columns [6]

[0039] Experimental method: Refer to Figure 1 The strategy shown was used to prepare three types of glycosylated P6. First, starting with 1,4-bis(2-hydroxyethoxy)benzene, the intermediate 1,4-bis(2-bromoethoxy)benzene was obtained via the Appel reaction, followed by cyclization and azidation to synthesize fully azidated P6 (a). Subsequently, using fully acetylated glucose and mannose as starting materials, propargyl alcohol was glycosylated with boron trifluoride diethyl ether (BF3·Et2O) as a catalyst to prepare β-propargyl glucoside (b, Glu) and α-propargyl mannoside (c, Man), respectively. In addition, α-propargyl-N-acetylgalactosamine (d, GalNAc) was synthesized from N-acetylglucosamine through steps including full acetylation protection, selective deprotection, and Schmidt trichloroacetylimine ester glycosylation. Finally, under copper catalysis, the glycosylation monomer (b–d) was grafted onto the azidated column[6]arene (a) skeleton by copper-catalyzed azid-yne cycloaddition (CuAAC) click reaction, and then the highly water-soluble target glycosylated column[6]arenes P6-Glu (1), P6-Man (2) and P6-GalNAc (3) were obtained by Zemplén deacetylation reaction (NaOMe / MeOH system).

[0040] Experimental results: Characterization results of glycosylated column[6] aromatics are shown in Figure 1 ,according to Figure 1 The A technical route synthesized three highly water-soluble glycosylated column[6] aromatic derivatives: P6-Glu (1), P6-Man (2), and P6-GalNAc (3). The obtained glycosylated column[6] aromatic derivatives were characterized by infrared spectroscopy. Figure 1 B yielded yields of 61%, 64.9%, and 89.7%, respectively.

[0041] Example 2 Screening of aromatic derivatives by glycosylation column [6]

[0042] Experimental method: HB inclusion complexes were prepared by self-assembly. 8.0 mg of HB was accurately weighed and dissolved in 0.4 mL of anhydrous ethanol, and 3.6 mL of ultrapure water was added to prepare a 2 mg / mL HB stock solution. 48.0 mg of P6-Glu, P6-Man or P6-GalNAc was accurately weighed and dissolved in 4 mL of ultrapure water to prepare a 12 mg / mL host molecular solution. The above solutions were ultrasonically treated for 30 min (240 W, 60 Hz) using an ultrasonic instrument (PS-40A, Dongguan Jiekang Ultrasonic Equipment Co., Ltd., Dongguan, China). The HB stock solution was then slowly added dropwise to the glycosylation column [6] aromatic solution under stirring (500 r / min). The ultrasonic treatment was continued for 30 min, and the solution was allowed to stand at room temperature for 12 h to obtain the corresponding inclusion complexes (HB⊂P6-Glu, HB⊂P6-Man, HB⊂P6-GalNAc). The hydrodynamic particle size distribution and polydispersity index (PDI) of each sample were determined by dynamic light scattering (PALS, NanoBrook 90PlusPALS, Brookhaven Instruments, New York, USA) at 25 °C. Each sample was measured in triplicate. All experiments used analytical grade reagents and ultrapure water. The solubility of HB and its host-guest inclusion complexes with Glu, Man, and GalNAc-modified columnar aromatics [6] were further determined by equilibrium solubility method. The simplified steps are as follows: excess HB was added to an aqueous solution of P6-Glu, P6-Man and P6-GalNAc (40 mg / mL each). The mixture was shaken at 37 °C for 48 hours to reach dissolution equilibrium. Subsequently, the suspension was centrifuged at 14000 rpm for 15 minutes to separate the undissolved solids. Carefully remove the obtained supernatant and filter it through a 0.22-micron nylon membrane filter. Dilute the filtrate appropriately with methanol to prevent precipitation, and then immediately determine the concentration of HB by high-performance liquid chromatography (HPLC). Calculate the solubility enhancement factor of each complex relative to pure HB based on the measured concentration. All experiments were repeated three times.

[0043] Experimental results: Dynamic light scattering results show that ( Figure 1C), the average particle sizes of HB⊂P6-Glu, HB⊂P6-Man and HB⊂P6-GalNAc were 520.02 ± 10.43 nm, 324.07 ± 9.65 nm and 344.02 ± 26.08 nm, respectively, and the PDI of all formulations was less than 0.3, indicating that the system had good dispersibility. It is worth noting that in the control group without the addition of HB, the three glycosylated columnar aromatics [6] existed in the form of true solution and no nanoparticles were observed. This indicates that there is a supramolecular interaction between HB and glycosylated columnar aromatics [6]. Further evaluation of their solubilizing effect found that the three columnar aromatics could increase the solubility of HB in water to varying degrees, among which P6-GalNAc increased the solubility of HB by the most 15.2 times ( Figure 1 D), and was therefore selected as the inclusion vector for subsequent research.

[0044] Example 3: Investigating the effect of the CP to HPMC ratio on IPC formation.

[0045] Experimental Methods: Nonionic proton acceptor polymers (such as HPMC) contain hydroxyl and ether groups in their repeating units, allowing them to act as proton acceptors and form interproton polymers (IPCs) via hydrogen bonding with proton donor polymers (such as CP). HPMC solutions of different concentrations (1 mL, 0–3%) were mixed with CP solutions of different concentrations (3 mL, 0–3%) at room temperature to maintain a total polymer concentration of 3% and adjust the pH of the solution to 4. After thorough mixing, the turbidity of the mixed solution was measured using a UV spectrophotometer. The viscosity changes of the IPC solution were quantitatively analyzed using a rotational viscometer (model: NDJ-1) to further evaluate the rheological basis of the IPC solution. The experimental method is as follows: Under isothermal conditions (25 ± 0.1℃), the viscosity of HPMC / CP mixed solutions with different ratios was measured using a rotational viscometer. Place the HPMC / CP mixed solution in a beaker with a diameter of at least 70 mm. Select a suitable rotor and screw it into the connecting screw. Adjust the rotor to align the liquid level mark with the liquid level, level the instrument, and set the rotation speed to 60 rpm. Read the value after the pointer stabilizes. The absolute viscosity (η) is calculated using the following formula: η = K × A, where K is the rotor constant (unit: mPa·s), and A is the pointer reading (deflection angle). Each sample is measured in triplicate, and the average value is taken as the final result. By establishing a correlation model between solution viscosity and polymer interaction strength, the rheological basis of IPC is systematically evaluated.

[0046] Experimental results: Figure 2A shows the changes in turbidity and viscosity of IPC at different ratios of HPMC and CP. The results indicate that as the proportion of HPMC increases, the turbidity of the HPMC and CP solutions first increases and then decreases, with the highest turbidity observed when the CP:HPMC ratio is 3:1 (w / w). Conversely, as the proportion of HPMC increases, the viscosity of the HPMC and CP mixed solution first decreases and then increases, with the lowest viscosity observed when CP:HPMC = 3:1 (w / w). Therefore, in this invention, the CP:HPMC ratio is 3:1 (w / w) in the mixed components.

[0047] Example 4: Investigating the impact of different CP models on IPC formation

[0048] Experimental Methods: To investigate the effects of different polymer chromatographs (CP934, CP940, CP941, CP980, CP1340, CP2020) on IPC formation, HPMC was dissolved in an aqueous solution and mixed with different CP types at a ratio of CP:HPMC = 3:1 (w / w). The total polymer concentration in the sample was kept constant at 3%, and the pH of the solution was adjusted to 4. The turbidity and viscosity of the solution were then examined. This was to screen out CPs that could form IPCs with HPMC, and subsequent experiments were conducted under these conditions.

[0049] Experimental results: Figure 2 B represents the effect of CP molecular weight on IPC formation. The results show that CP 940 The turbidity and viscosity of the HPMC solution changed significantly. Therefore, based on the experimental results, CP is the preferred component in the mixture of this invention. 940 Model number serves as a composite mechanism for IPC.

[0050] Example 5: Example 5 investigated the effect of solution pH on IPC formation.

[0051] Experimental method: To investigate the effect of solution pH on IPC formation, HPMC and CP were used. 940 Dissolve separately in aqueous solution, according to CP 940 HPMC was mixed in a 3:1 (w / w) ratio to fix the total polymer concentration in the sample at 0.3%. The pH of the solution was adjusted to 3, 5, 6, 7, and 9 using HCl and NaOH. The turbidity and viscosity of the solutions obtained at different pH values ​​were observed to analyze the effect of solution pH on IPC formation. The optimal solution pH value was then selected.

[0052] Experimental results: Figure 2C represents the changes in turbidity and viscosity of the solution at different pH values. The results show that when the polymer solution is at pH 4, the HPMC and PAA polymer solutions have lower viscosity and higher turbidity, indicating the formation of a relatively dense complex. As the pH of the solution increases, the viscosity increases, the turbidity decreases, and any potential IPC formation is disrupted. Therefore, based on the experimental results, the pH value of the solution selected for this invention is 4.

[0053] Example 6: Investigating the effect of the dispersion medium on film formation.

[0054] Experimental Methods: This example aims to screen the optimal dispersion medium for preparing film-forming agents. Hydroxypropyl methylcellulose (HPMC) and carbomer (CP) were dissolved in aqueous ethanol solutions of different volume concentrations (0%, 20%, 40%, 60%, 80%, and 100%), with a CP to HPMC mass ratio of 3:1 and a total polymer concentration of 3%. The pH of the system was adjusted to 4.0. The resulting solutions were coated into films, and the optimal dispersion medium was screened by examining the appearance of the film-forming agents.

[0055] Experimental Results: The results showed that the weight and thickness of the samples remained relatively stable under different ethanol concentrations, with weight ranging from 7.0 to 7.5 mg and thickness from 0.073 to 0.079 mm. However, ethanol concentration significantly affected the appearance quality. At 0% and 20% ethanol concentrations, severe pigment migration occurred in the samples. As the concentration increased to 40%-60%, the appearance improved significantly, with the sample prepared at 60% ethanol concentration exhibiting a smooth and flat surface without any pigment migration, representing the optimal condition. However, when the concentration was further increased to 80% and 100%, the samples not only showed uneven thickness but also exhibited miscibility with the pigment layer and backing layer, leading to structural damage. In conclusion, using a 60% ethanol aqueous solution as the dispersion medium can produce an ideal film with a smooth appearance, no pigment migration, and a stable structure.

[0056] Table 1. Appearance characterization of film agents under different dispersion media

[0057]

[0058] Example 7: IPCs Structural Analysis

[0059] Experimental method: HPMC and CP 940 HPMC : CP = 1 : 3 (w / w) was added to a 60% ethanol solution, the pH was adjusted to 4, and then the solution was freeze-dried. The structure of the freeze-dried IPCs powder was analyzed by FTIR spectroscopy.

[0060] Experimental results: Figure 2 D is the infrared spectrum of IPC. The results show that HPMC is at 3469 cm⁻¹.-1 The peak at 1650 cm⁻¹ shows a broad OH stretching peak. -1 The peak at this location is a characteristic OH bend peak, 1100–1000 cm⁻¹. -1 The range corresponds to the COC stretching vibration peak; CP is at 1713 cm⁻¹. -1 A C=O stretching vibration band of the carboxyl group appeared at 1713 cm⁻¹. Characteristic peaks of both the HPMC+CP and IPC systems were present simultaneously; no new peaks were detected, but the absorption intensities differed, with a significant enhancement of the CP characteristic peak in the IPC system. This confirmed the formation of IPCs. Furthermore, at 1713 cm⁻¹... -1 The band moved to 1735 cm -1 This may indicate that IPCs are formed through hydrogen bonding.

[0061] Example 8: Optimization of Drug Release Layer Coating Process

[0062] Experimental Methods: A three-layer microfilm patch was prepared using a layer-by-layer coating method. An EC ethanol solution mixed with a plasticizer (TEC:castor oil = 7.5:1, w / w) was coated onto a PET substrate and dried at 40 ℃ using a small automated drying coating machine (MSK-AFA-IIID, Shenyang Kejing Automatic Instrument Co., Ltd., Shenyang, China) to prepare the backing layer. A pigment layer solution was prepared by mixing 10% HPMC with 0.05% carmine aqueous solution, centrifuged (1000 rpm, 10 min) to remove foam, and then prepared as the pigment layer. An IPC solution was prepared by mixing 3% HPMC with 3% CP940 solution, then mixed with an HB⊂P6-GalNAc inclusion complex solution, and the pH was adjusted to 4. The mixture was then centrifuged (1000 rpm, 10 min) to remove foam, and the drug-loaded adhesive layer was prepared. A three-factor, three-level Box-Behnken design (BBD) combined with response surface methodology (RSM) was adopted to optimize coating height, coating speed, and drying temperature, with blank film appearance, mass per unit area, foldability, and number of bubbles as key quality attributes.

[0063] Experimental Results: By combining the Box-Behnken response surface methodology with experimental design, we optimized the coating process. Figure 3 The results showed that the optimal parameters were a coating speed of 9 mm / s, a temperature of 48℃, and a coating height of 1 mm.

[0064] Example 9 Preparation and characterization of drug-loaded intestinal adhesive patches

[0065] Experimental Methods: Three-layer microfilm patches, HB / IPC enteric adhesive patches and HB⊂P6-GalNAc / IPC enteric adhesive patches, were prepared using a layer-by-layer coating method. EC ethanol solution and plasticizer (TEC:castor oil = 7.5:1, w / w) were coated onto a PET substrate and dried at 40 °C using a small-scale automatic drying coating machine to prepare the backing layer. A mixture of 10% HPMC and 0.05% carmine aqueous solution was used, with TEC added at a ratio of HPMC:TEC of 6:1 and stirred for 4 h. After defoaming by centrifugation at 1000 rpm for 8 min, a pigment layer solution was obtained and laid onto the backing layer. 3% HPMC and 3% CP were used... 940 The solutions are mixed to obtain the IPC solution (prepared according to the above optimal process: CP) 940 The mass ratio of HPMC to ethanol was 3:1 (w / w), the concentration of ethanol solution was 60%, the pH was 4, and the mixture was stirred at 27°C for 4 hours. TEC was added, and after stirring evenly, HB and HB⊂P6-GalNAc lyophilized powder (prepared according to the methods of Examples 1 and 2, wherein the molar ratio of glycosylated column[6] aromatics to Codonopsis pilosula cyclic peptide B was (1:1) was added and mixed. The mass ratio of HB⊂P6-GalNAc lyophilized powder, IPC solution and TEC was 2:6:1, and the mass ratio of HB, IPC solution and TEC was 1:6:1. The pH was adjusted to 4, and the mixture was centrifuged (1000 rpm, 10 min) to remove foam, and HB drug-loaded adhesive layer and HB⊂P6-GalNAc drug-loaded adhesive layer were obtained respectively. According to the optimal film-laying conditions obtained in Example 8, the HB drug-loaded adhesive layer and HB⊂P6-GalNAc drug-loaded adhesive layer were coated at a film-laying speed of 9 At a speed of mm / s, a temperature of 48℃, and a height of 1 mm, the HB / IPC drug-loaded enteric adhesive patch was laid on the dried pigment layer. After drying, it was cut to obtain the HB / IPC drug-loaded enteric adhesive patch and the HB⊂P6-GalNAc / IPC enteric adhesive patch. In addition, the surface morphology of the blank IPC, HB / IPC, and HB⊂P6-GalNAc / IPC patch was studied by differential scanning calorimetry (DSC) using SEM.

[0066] Experimental results: Figure 4 The surface morphology of IPC, HB / IPC, and HB⊂P6-GalNAc / IPC patches was studied using SEM. The results showed that the HB / IPC patch surface exhibited a certain degree of uneven distribution; while no obvious particle or phase separation was observed in the HB⊂P6-GalNAc / IPC group, indicating that HB⊂P6-GalNAc / IPC was uniformly distributed and well dispersed in the patch matrix.

[0067] The drug-loaded intestinal patch prepared in this embodiment was used for characterization and experiments as described below.

[0068] Example 10 Characterization of swelling of intestinal adhesive patches

[0069] Experimental Methods: This embodiment aims to characterize the swelling behavior of different formulations of intestinal adhesive patches to evaluate their potential as drug sustained-release platforms. Circular patches (1 cm in diameter) prepared from HPMC, CP940, HPMC / CP940, IPC, HB / IPC, and HB⊂P6-GalNAc / IPC formulations were placed in a mesh dish containing 100 mL of simulated gastric fluid (SGF, pH 1.2) and incubated for 2 h, then transferred to 100 mL of simulated intestinal fluid (SIF, pH = 6.8). The swelling morphology of the patches was observed and recorded at different time points at 37°C. After the swelling experiment, the patches were removed, surface moisture was absorbed with filter paper, weighed, and the swelling rate was calculated.

[0070] Experimental results: such as Figure 5 As shown in Figure A, we systematically observed and compared the swelling behavior of different formulation micropatches in a simulated gastrointestinal environment. All samples were first incubated in SGF (pH 1.2) for 2 hours, and then transferred to SIF (pH 6.8) for further observation. The results showed that all formulations containing interpolymer complex (IPC) matrices (including IPC matrix alone, HB / IPC loaded with HB, and HB⊂P6-GalNAc / IPC loaded with the targeting complex HB⊂P6-GalNAc) maintained structural stability in SGF without significant swelling. However, when the environment was changed to SIF, these patches rapidly began to swell and maintained an intact gel skeleton structure throughout the observation period without disintegration. In contrast, the control patch with only hydroxypropyl methylcellulose (HPMC) as the matrix showed lower swelling and faster dissolution. Figure 5 Quantitative analysis of the swelling rate of HB further validated the above morphological observations. Data showed that the swelling rates of the IPC, HB / IPC, and HB⊂P6-GalNAc / IPC patches were significantly higher than those of the HPMC control group (P < 0.05). Notably, after loading the drug HB or its targeting complex, the swelling curve of the patch showed no statistically significant difference compared to the unloaded pure IPC matrix patch, indicating that the drug loading process did not alter the inherent swelling properties of the IPC matrix. This experiment confirms that the IPC matrix possesses excellent pH-responsive swelling capacity and good structural integrity. It maintains a low swelling state in the acidic environment of the stomach, which is beneficial for maintaining dosage form integrity and passing through the stomach; after entering the neutral environment of the intestine, it rapidly swells and forms a stable gel network. More importantly, this swelling property is completely preserved after loading the active drug molecule (HB) or its functional complex (HB⊂P6-GalNAc), thus providing an ideal carrier basis for controlled and sustained drug release. Therefore, IPC can be considered as a reliable and ideal matrix material suitable for oral sustained-release administration.

[0071] Example 11: In vitro adhesion strength and adhesion of intestinal adhesive patches.

[0072] Experimental Methods: The adhesion strength and time of the micropatches were evaluated using a modified disintegration apparatus (model ZB-1D, Tianjin Xinzhou Technology Co., Ltd., China). The experimental method followed the previously reported equal-arm balance method. The adhesion strength was determined as follows: One end of the micropatches was fixed to a rubber stopper and incubated with SGF for 2 hours, then incubated with porcine intestinal mucosa moistened with simulated intestinal fluid. Water was continuously and uniformly added to a beaker connected to the other end of the micropatches until the patches detached from the mucosal surface, and the total weight of water added (in grams) was recorded. The mucosal adhesion force (F, unit: N) was calculated using the following formula: F = (Mw × g) / A. Where Mw is the total mass of water required for detachment (kg), and g is the acceleration due to gravity (9.8 m / s²). 2 A is the initial contact area of ​​the patch (m²). 2 )

[0073] A modified disintegration apparatus was used to simulate the adhesion properties of patches in the gastrointestinal environment. The specific procedure was as follows: First, the test patch was placed in a test tube containing SGF (pH 1.2) and incubated in a constant temperature water bath at 37 ± 0.5℃ for 2 h to simulate its residence in the physiological environment of the stomach. Then, the patch was carefully transferred to a glass slide covered with fresh isolated porcine small intestinal mucosa and gently pressed evenly for 30 seconds to ensure full adhesion to the mucosal surface. Next, the glass slide with the patch was vertically fixed in the disintegration apparatus basket containing SIF (pH 6.8). At 37 ± 0.5℃, the instrument was set to reciprocate up and down at a frequency of 30 ± 1 times per minute. Ten intestinal adhesion patches were used in each experiment and attached to the surface of the porcine small intestinal mucosa. Throughout the process, the specific time and number of patches detaching from the mucosal surface were continuously observed and recorded. Each experiment was repeated three times in parallel, and the arithmetic mean of the patch detachment time (x̄ ± SD) was used as the key indicator for evaluating the in vitro adhesion performance of the prescription.

[0074] Experimental results: such as Figure 6 The adhesion performance evaluation results show that the HB⊂P6-GalNAc / IPC formulation exhibits excellent mucosal adhesion ability. In vitro adhesion force testing showed a detachment force of 184.69 ± 14.21 N / m. 2 It was significantly better than other control groups. In the adhesion duration experiment simulating the dynamic environment of the gastrointestinal tract ( Figure 6(B) The formulation maintained stable adhesion under continuous reciprocating motion conditions for 24 hours, demonstrating excellent long-term retention properties. These results collectively indicate that the formulation not only possesses strong initial adhesion but also maintains long-term adhesion in simulated physiological environments, providing crucial experimental evidence for its application as an oral long-acting mucosal adhesion delivery system.

[0075] Example 12: In vitro dissolution study of intestinal adhesive patches.

[0076] Experimental Methods: The in vitro release behavior of HB from HB / IPC and HB⊂P6-GalNAc / IPC patches was determined using Method II (paddle method) of General Chapter 0931, Part IV of the 2020 edition of the Chinese Pharmacopoeia. The specific procedure was as follows: Each prescription patch was fixed in a specially designed stainless steel mesh tray, which was then vertically placed in a dissolution vessel containing 150 mL of SGF (pH 1.2). The distance between the bottom of the paddle and the upper surface of the mesh tray was adjusted to 25 mm. The dissolution experiment was conducted at 37 ± 0.5℃ and a paddle speed of 50 rpm. 1 mL samples were taken at predetermined time points (0.25, 0.5, 1, and 2 h) (with isothermal and equal-volume fresh SGF added simultaneously to maintain the trough conditions). Two hours later, the mesh disk and patch were transferred together to a dissolution vessel containing 150 mL of SIF (pH 6.8) for continued release. Samples of 1 mL were taken at 4, 6, 8, and 12 hours (with an equal volume of fresh SIF added at the same time). All samples were filtered through a 0.22 μm microporous membrane, and the concentration of HB was determined using a validated high-performance liquid chromatography (HPLC) method. The cumulative release rate was calculated.

[0077] Experimental results: Figure 6In vitro drug release studies showed that the HB⊂P6-GalNAc / IPC formulation exhibited pH-responsive two-stage drug release characteristics. In the SGF environment, drug release was extremely limited; the cumulative release rates of the HB / IPC and HB⊂P6-GalNAc / IPC formulations within 2 h were only 10.8 ± 3.14% and 12.77 ± 3.43%, respectively. This is consistent with the non-swelling state of the formulation under acidic conditions. After transfer to the SIF, as the IPC matrix gradually swelled and formed a stable gel network, drug release significantly accelerated. The release process exhibited a clear two-stage kinetic characteristic: a high release rate during 4-8 h in the intestinal fluid environment, followed by a slow, sustained release phase. By the 24-h endpoint, the cumulative release rate of the HB⊂P6-GalNAc / IPC group was 63.54 ± 6.22%, and its release curve was highly synchronized with the swelling process and mucosal adhesion behavior of the formulation in the intestinal environment. Notably, the cumulative release rate of the HB / IPC group under the same conditions was only 48.47 ± 4.73%, indicating that further integration of the targeting inclusion complex into the IPC adhesion matrix not only achieves long-term intestinal retention but also significantly improves the total drug release efficiency through the controlled-release effect of the gel network. This result confirms that the inclusion effect of P6-GalNAc and the gel-controlled-release properties of the IPC matrix have a synergistic effect, jointly promoting the dissolution and release of HB.

[0078] Example 13: Stability study of HB⊂P6-GalNAc / IPC over 90 days

[0079] Experimental Methods: This example aims to evaluate the stability of HB / IPC and HB⊂P6-GalNAc / IPC formulations under long-term storage conditions. Both formulations were stored at -20°C for 90 days, and their physicochemical properties, mechanical properties, and adhesive properties were systematically determined at predetermined time points. The weight, thickness, and surface pH of the patches were determined using a precision balance (ME104e, Mettler Toledo Instruments (Shanghai) Co., Ltd., Shanghai, China) (0.01 mg), a digital micrometer thickness gauge (293MDC-MX, Shanghai Trendow Measurement Tools Co., Ltd., Shanghai, China) (0.001 mm), and a surface pH meter (Beijing No. 00000246, Sartorius Scientific Instruments (Beijing) Co., Ltd., Beijing, China). The number of 180° folds before membrane breakage was recorded to assess folding endurance. After immersing the dried microfilm patch (W0) in PBS (pH 7.4) at 37°C for 4 h, it was removed, the surface moisture was blotted dry with filter paper, and the weight (W0) was measured. t The coefficient of swelling is calculated as (W). t- W0) / W0 calculation. The adhesion properties of the membrane on fresh porcine intestinal mucosa were determined using the equal-arm balance method and a modified disintegration apparatus (ZB-1D intelligent disintegration apparatus, Tianjin Xinzhou Technology Co., Ltd., Tianjin, China). Micromembrane patches moistened with simulated intestinal fluid (SIF) were pressed onto the mucosal surface and kept in contact for 30 s. The time required for the membrane to detach from the vertically fixed mucosa (detachment time) was recorded. Adhesion force (F, N / m²) was calculated by gradually adding water to the connection system and recording the total mass of water added when the patch detached. The formula was: F = (Mw × g) / A, where g is the acceleration due to gravity (9.8 m / s²), and A is the surface area of ​​the membrane (m²). 2 ).

[0080] Experimental results: Stability test results are as follows Figure 7 As shown. Figure 7 The effects of AE (Adaptive Electron Microscopy) on the changes in detachment time, adhesion force, weight, thickness, and swelling coefficient of the two formulations over 90 days were presented. The results showed that after 90 days of storage at -20°C, neither the HB / IPC nor the HB⊂P6-GalNAc / IPC formulations exhibited significant changes in any of the key performance indicators. Specifically, their weight, thickness, surface pH, folding endurance, swelling coefficient, and intestinal mucosal adhesion properties (including detachment time and adhesion force) remained near their initial levels, demonstrating excellent physicochemical and mechanical stability. This indicates that both the HB / IPC and HB⊂P6-GalNAc / IPC formulations possess excellent long-term storage stability at -20°C, and their properties remain stable over 90 days, meeting the storage and application requirements for drug delivery systems.

[0081] Example 14: Hypoglycemic effect of HB-loaded intestinal patch on type II diabetic mice

[0082] Experimental methods: To evaluate the therapeutic effect of the formulation of the present invention on type II diabetes mellitus (T2DM), healthy male C57BL / 6J mice (6-8 weeks old, weighing 20±2 g) were randomly divided into 8 groups (n = 5): (1) normal control group; (2) type 2 diabetes model group; (3) metformin treatment group (100 mg / kg / day, orally); (4) free HB oral group (6 mg / kg / day); (5) free HB intraperitoneal injection group (6 mg / kg / day); (6) HB⊂P6-GalNAc group (6 mg / kg / day, orally); (7) HB / IPC group (6 mg / kg / day, orally); (8) HB⊂P6-GalNAc / IPC group (6 mg / kg / day, orally). In the HB⊂P6-GalNAc group, the prepared HB⊂P6-GalNAc solution was lyophilized, and the lyophilized powder was loaded into mouse-specific capsules for oral administration. Similarly, the HB / IPC group and the HB⊂P6-GalNAc / IPC group received oral administration of micropatches loaded into mouse-specific capsules. Except for the normal control group, all other groups were fed a high-fat diet for 8 weeks combined with intraperitoneal injection of low-dose streptozotocin to induce a type 2 diabetes mellitus (T2DM) model. After successful model establishment (fasting blood glucose >11.1 mmol / L), each group was treated with the corresponding formulation for 4 weeks. During treatment, mouse weight, food intake, water intake, and fasting blood glucose levels were monitored regularly. After treatment, oral glucose tolerance tests and insulin tolerance tests were performed, and blood samples were collected to detect glycated hemoglobin and fasting insulin levels, and the HOMA-IR index was calculated to assess the degree of insulin resistance.

[0083] Experimental Results: After 4 weeks of treatment, compared with the T2DM model group, all treatment groups containing hemoglobin (HB) showed significant improvement in glycemic regulation. Specifically, this was reflected in the results of the oral glucose tolerance test and insulin tolerance test (ORT). Figure 8 (A, 8B) showed that the glucose tolerance and insulin sensitivity of mice in each treatment group were significantly enhanced, and fasting blood glucose levels were significantly reduced. Figure 8 C). In terms of long-term glycemic control, the HB⊂P6-GalNAc / IPC group showed the most significant effect, with its glycated hemoglobin level decreasing by 72.85% compared to the model group, a greater reduction than the metformin group (67.38%). Figure 8 D). Mechanism investigation revealed that while blood glucose levels improved in all treatment groups, fasting insulin levels significantly decreased, with the following reductions: metformin group 47.63%, oral free HB group 29.45%, intraperitoneal injection free HB group 52.67%, HB⊂P6-GalNAc group 42.07%, HB / IPC group 45.06%, and HB⊂P6-GalNAc / IPC group 52.57% ( Figure 7E). This result indicates that the hypoglycemic effect of HB is not achieved by promoting insulin secretion. HOMA-IR analysis further confirms that HB mainly exerts its effect by improving systemic insulin resistance. Among them, the HB⊂P6-GalNAc / IPC group reduced the HOMA-IR index by 4.08 times compared with the model group, which was superior to the metformin group (3.61 times). Figure 8 F). This embodiment demonstrates that the HB⊂P6-GalNAc / IPC intestinal patch formulation of the present invention can significantly improve glycemic homeostasis in T2DM model mice. Its core mechanism of action lies in effectively alleviating systemic insulin resistance, rather than stimulating insulin secretion. This formulation is superior to metformin, a first-line clinical drug, in reducing glycated hemoglobin and improving insulin sensitivity, demonstrating excellent therapeutic potential.

[0084] Example 15 Pharmacokinetic Study of HB⊂P6-GalNAc / IPC

[0085] Methods: Pharmacokinetic characteristics were assessed in healthy male C57BL / 6J mice (6-8 weeks old, weighing 20±2 g). A total of 120 mice were randomly assigned to five experimental groups (n = 45 per group): (1) Free HB (iv); (2) Free HB (po); (3) HB⊂P6-GalNAc group; (4) HB / IPC; (5) HB⊂P6-GalNAc / IPC. In the HB⊂P6-GalNAc group, the prepared HB⊂P6-GalNAc solution was lyophilized, and the lyophilized powder was loaded into mouse-specific capsules for oral administration. Similarly, the HB / IPC and HB⊂P6-GalNAc / IPC groups received oral administration of micropatches loaded into mouse-specific capsules. The dosage was 6 mg / kg (based on HB). Blood was collected from the lateral tail vein of anesthetized mice at 0, 0.5, and 6 h after drug administration; 0.083, 1, and 8 h in subgroup 2; 0.17, 2, and 12 h in subgroup 3; and 0.25, 4, and 24 h in subgroup 4. Immediately after sample collection, plasma was obtained by centrifugation at 1,000 × g for 10 minutes at 4 °C and stored at -80 °C for analysis.

[0086] For LC-MS / MS analysis, 30 μL of plasma sample was taken, and 120 μL of methanol solution containing internal standard was added for protein precipitation. After vortexing and centrifugation, the supernatant was injected into the LC-MS / MS system (detailed chromatographic conditions are provided in the supplementary information). Pharmacokinetic parameters were calculated using WinNonlin software (version 8.2, Certara, USA).

[0087] Experimental Results: Bioavailability of drugs after oral administration is a key indicator for evaluating the efficacy of formulations. This study systematically evaluated the performance of various delivery systems by comparing the pharmacokinetic behavior of orally administered free hemoglobin (HB), intravenously administered free HB, and three oral formulations (HB⊂P6-GalNAc, HB / IPC, and HB⊂P6-GalNAc / IPC) in C57BL / 6 mice. Drug concentration-time curves in the blood of C57BL / 6 mice are shown below. Figure 9 The concentration-time data were analyzed, and the pharmacokinetic parameters obtained from non-compartmental fitting are shown in Table 2. The results indicate that the plasma concentration of free HB after oral administration reached its peak rapidly (C0.05). max It was rapidly cleared after reaching approximately 86.68 ng / mL, indicating limited absorption and rapid metabolism. In contrast, all three formulations significantly improved the pharmacokinetic characteristics of HB: the area under the pharmacokinetic curve (AUC) of HB⊂P6-GalNAc, HB / IPC, and HB⊂P6-GalNAc / IPC were significantly improved. 0-∞ The levels of C in the HB⊂P6-GalNAc / IPC group increased by 1.51 times, 2.78 times, and 2.73 times, respectively; max The HB / IPC group showed the highest half-life (T1 / 2), while the HB / IPC group had the longest, indicating a more prolonged in vivo retention. Correspondingly, the oral absolute bioavailability of the three groups was 3.33 times, 2.56 times, and 1.22 times that of the free HB group, respectively. Notably, both the HB / IPC and HB⊂P6-GalNAc / IPC groups exhibited longer drug retention times, presumably related to the intestinal adhesion patch structure of their IPC components. This structure prolongs drug retention in the intestine, thereby promoting transepithelial absorption and sustained release.

[0088] Table 2. Pharmacokinetic parameters after oral administration of each CIN formulation group (n = 4)

[0089] vs Free HB(po) *

[0090] vs Free HB(iv) #

[0091] vs HB⊂P6-GalNAc (iv) ^

[0092] The embodiments of the present invention have been described in detail above with reference to specific examples. However, the present invention is not limited to the above embodiments. Within the scope of knowledge possessed by those skilled in the art, various changes can be made without departing from the spirit of the present invention.

Claims

1. A method for preparing an intestinal adhesive patch loaded with Codonopsis pilosula cyclic peptide B, characterized in that, Includes the following steps: (1) The column[6]arene was modified with polysaccharide to obtain glycosylated column[6]arene. The glycosylated column[6]arene and Codonopsis pilosula cyclic peptide B were mixed in solution and subjected to ultrasonic self-assembly to obtain host-guest complex solution HB⊂P6-GalNAc. After lyophilization, HB⊂P6-GalNAc lyophilized powder was obtained. (2) Carbomer (CP) and hydroxypropyl methylcellulose (HPMC) were mixed in solution to prepare a polymeric hydrogen-bonded complex (IPC) solution; (3) Mix the above HB⊂P6-GalNAc lyophilized powder, IPC solution and additives to obtain a sustained-release layer solution; (4) Prepare a backing layer, lay the sustained-release solution on the backing layer, dry and cut it to obtain HB⊂P6-GalNAc / IPC intestinal adhesive patch, which is the intestinal adhesive patch loaded with Codonopsis pilosula cyclic peptide B.

2. The method for preparing the intestinal adhesive patch loaded with Codonopsis pilosula cyclic peptide B according to claim 1, characterized in that, In step (1), the polysaccharide is selected from one or more of galactose, mannose, and N-acetylgalactosamine.

3. The method for preparing the intestinal adhesive patch loaded with Codonopsis pilosula cyclic peptide B according to claim 1, characterized in that, In step (1), the molar ratio of the glycosylated column[6] aromatic hydrocarbon to the ginseng cyclic peptide B is (0.5~5):

1.

4. The method for preparing the intestinal adhesive patch loaded with Codonopsis pilosula cyclic peptide B according to claim 1, characterized in that, In step (1), the conditions for self-assembly are: stirring the solution at a speed of 300~1000 rpm, a temperature of 25~37℃, and a time of 2~12 h.

5. The method for preparing the intestinal adhesive patch loaded with Codonopsis pilosula cyclic peptide B according to claim 1, characterized in that, In step (2), the carbomer is selected from CP. 934 CP 940 CP 941 CP 980 CP 1340 CP 2020 One or more of them, preferably CP 940 The CP 940 The mass ratio of HPMC to HPMC is 9:1 to 1:9 (w / w), preferably 3:1 (w / w).

6. The method for preparing the intestinal adhesive patch loaded with Codonopsis pilosula cyclic peptide B according to claim 1, characterized in that, In step (2), the method of mixing the solution is as follows: using a 50-70% ethanol solution as the dispersion medium, prepare CP solution and HPMC solution respectively, slowly add HPMC solution to CP solution, adjust pH to 3-9, stir for 3-5 hours at a temperature of 25-35℃ to obtain IPC solution; the concentration of CP solution is 1-5% (w / v), and the concentration of HPMC solution is 1-5% (w / v).

7. The method for preparing the intestinal adhesive patch loaded with Codonopsis pilosula cyclic peptide B according to claim 1, characterized in that, In step (3), the mass ratio of the HB⊂P6-GalNAc lyophilized powder, IPC solution and additive is 2:(5-7):(0.1-1.5).

8. The method for preparing the intestinal adhesive patch loaded with Codonopsis pilosula cyclic peptide B according to claim 1, characterized in that, In step (5), the method for preparing the backing layer includes: dissolving the film-forming material in an organic solvent, adding an additive, stirring evenly, forming a film, and preparing a waterproof backing layer; Preferably, the preparation method further includes preparing a pigment layer solution using pigments and additives, laying it on a waterproof backing layer, and then laying a slow-release layer solution on the backing layer.

9. An intestinal adhesive patch loaded with Codonopsis pilosula cyclic peptide B, characterized in that, The intestinal adhesive patch loaded with Codonopsis pilosula cyclic peptide B is prepared by the preparation method according to any one of claims 1-8.

10. The use of the intestinal adhesive patch loaded with Codonopsis pilosula cyclic peptide B as described in claim 9 in the preparation of hypoglycemic drugs.

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