Sugar delayed release compositions and methods of making the same

Abstract

The present invention provides a sugar delayed release composition, the composition comprising a tablet core and a delayed release coating, the tablet core comprising a sugar substance, the delayed release coating comprising at least a barrier layer and an enteric layer, the barrier layer being disposed between the tablet core and the enteric layer, the barrier layer consisting of a hydrophobic polymer, a water-soluble polymer, and optionally a pharmaceutically acceptable carrier, wherein the hydrophobic polymer is ethyl cellulose.

Description

Technical Field

[0001] This application relates to delayed-release products and their preparation methods, specifically to a carbohydrate delayed-release composition and its preparation method. Background Technology

[0002] Nocturnal hypoglycemia is a major challenge in diabetes glycemic management, with its peak incidence concentrated in the late night to early morning (usually between midnight and 4 a.m. the following morning). During this period, patients are asleep, and their autonomic nervous system response is weakened, making it difficult for them to detect hypoglycemia. This not only directly leads to acute risks such as palpitations, coma, and even death, but also triggers reactive hyperglycemia the following day (Somogyi effect) by inducing counter-regulatory hormones, creating a vicious cycle and significantly increasing the risk of long-term complications.

[0003] Currently, measures for preventing and controlling nocturnal hypoglycemia have significant limitations. Regarding interventions, clinically dependent pre-sleep carbohydrate intake (such as biscuits) exhibits significant individual variability, unstable glycemic rise, and complex food composition. Adjusting insulin regimens is a slow trial-and-error process, lacking both precision and reliability. In terms of monitoring and early warning, traditional finger-prick blood glucose testing cannot cover the nighttime blind spot, while alerts from continuous glucose monitoring (CGM) may be ignored during sleep.

[0004] Therefore, developing effective solutions faces a dual technological bottleneck. First, in developing physical intervention products (such as slow-release foods), fast-acting sugars are absorbed too quickly, while commonly used materials for slow release (such as hydrophobic polymers) suffer from poor biodegradability and pH dependence. Furthermore, the sugar raw materials themselves are highly hygroscopic and poorly compressible, leading to unpredictable product effects and insufficient stability. Second, regarding intelligent management pathways, existing technologies lack an effective system capable of integrating real-time data, accurately predicting trends, and implementing closed-loop or intelligent intervention before or during hypoglycemia.

[0005] In summary, existing technologies, whether from the perspective of "end products" or "management systems," cannot meet the urgent clinical needs for safe, accurate, and stable prevention of nocturnal hypoglycemia, and breakthroughs are urgently needed.

[0006] Therefore, there is an urgent need in the field for a new delayed-release carbohydrate composition that can effectively alleviate nocturnal hypoglycemia symptoms in individuals at high risk of diabetes or in diabetic patients. Summary of the Invention

[0007] The purpose of this invention is to alleviate nocturnal hypoglycemia symptoms in individuals at high risk of diabetes or in diabetic patients. Specifically, this invention provides a delayed-release carbohydrate composition that meets the urgent clinical need for safe, precise, and stable prevention of nocturnal hypoglycemia.

[0008] This application provides a carbohydrate-based delayed-release composition comprising a tablet core and a delayed-release coating. The tablet core comprises a carbohydrate substance, and the delayed-release coating comprises at least an isolation layer and an enteric coating layer. The isolation layer is disposed between the tablet core and the enteric coating layer and is composed of a hydrophobic polymer, a water-soluble polymer, and optionally a pharmaceutically acceptable carrier. The hydrophobic polymer is ethyl cellulose.

[0009] In a preferred embodiment, the carbohydrates in the tablet core are selected from: glucose, maltose, lactose, galactose, fructose, mannose, xylose, sucrose, fucose, arabinose, rhamnose, ribose, sorbitol, lactulose, tagatose, maltulose, paraginose, isomaltose, trehalose, sophorose, rutinose, kosperidin, aspergillus niger disodium, laminarin disodium, gentiobiose, pinobiose, gentiodiulose, mannobiose, plantain disodium, xylobiose, sorbitol, lactitol, mannitol, erythritol, or combinations thereof, and the carbohydrate content in the tablet core is 50%-95% by mass. Preferably, the carbohydrate is D-anhydrous glucose.

[0010] In a preferred embodiment, the core further comprises a filler, a disintegrant, a binder, and an anti-adhesion agent, wherein the filler is selected from: mannitol, sorbitol, pregelatinized starch, dextrin, starch, maltodextrin, dicalcium phosphate, calcium carbonate, pregelatinized starch, microcrystalline cellulose, microcrystalline cellulose-lactose complex, or combinations thereof, and the filler has a mass percentage content of 0.1-10% in the core; wherein the disintegrant is selected from: crospovidone, sodium carboxymethyl starch, starch, pregelatinized starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, sodium alginate, hydroxypropyl starch, crospovidone carboxymethyl starch, crospovidone carboxymethyl cellulose, guar gum, or one of these. The disintegrant has a mass percentage content of 0.1-20% in the tablet core, wherein the binder is selected from one or more of the following: hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, starch paste, dextrin, gum arabic, ethyl cellulose, and konjac flour, and the binder has a mass percentage content of 5%-10% in the tablet core, wherein the anti-adhesive is selected from one or more of the following: talc, stearic acid, magnesium stearate, sodium stearate fumarate, polyethylene glycol, magnesium lauryl sulfate, micronized silica, glyceryl monostearate, calcium stearate, and polyoxyethylene stearate, and the anti-adhesive has a mass percentage content of 0.1%-3% in the tablet core.

[0011] In a preferred embodiment, the water-soluble polymer in the isolation layer is selected from one or more of polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol, and povidone. Preferably, the mass ratio of the hydrophobic polymer to the water-soluble polymer is 1:1-1:3, more preferably 1:1.5-1:2.5, and more preferably 1:1.8-1:2.2. Preferably, the water-soluble polymer in the isolation layer is hydroxypropyl methylcellulose with a viscosity of 3-25 mPa·s. Preferably, the weight gain of the isolation layer is 4-8% by weight. Preferably, the mass percentage of the hydrophobic polymer in the isolation layer coating solution is 1%-3%. Preferably, the mass percentage of the water-soluble polymer in the isolation layer coating solution is 3%-5%. Preferably, the optional pharmaceutically acceptable carrier is selected from water, ethanol, or combinations thereof.

[0012] In a preferred embodiment, the enteric coating comprises a film-forming agent, an anti-adhesion agent, and a plasticizer, wherein the plasticizer is selected from one or more of the following: triethyl citrate, triethyl citrate, tributyl citrate, acetylated triethyl citrate, diethyl phthalate, dibutyl phthalate, dimethyl phthalate, glyceryl triacetate, glyceryl monostearate, and dibutyl sebacate; wherein the film-forming agent is a pH-sensitive material selected from: polyacrylic acid resin I, polyacrylic acid resin II, polyacrylic acid resin III, Eudragit L100, Eudragit L100-55, and Eudragit... L30D-55, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate 50, hydroxypropyl methylcellulose phthalate 55, hydroxypropyl methylcellulose acetate succinate, and calcium alginate are selected from one or more of the following: talc, stearic acid, magnesium stearate, sodium stearate fumarate, polyethylene glycol, magnesium lauryl sulfate, micronized silica gel, glyceryl monostearate, calcium stearate, and polyoxyethylene stearate. Preferably, the amount of film-forming agent is 1.5-3.5 parts by weight based on 1 part by weight of the plasticizer, and the amount of anti-sticking agent is 0.3-1.5 parts by weight based on 1 part by weight of the plasticizer. Preferably, the weight ratio of film-forming agent, anti-adhesion agent, and plasticizer is approximately (4-8):(3-5):(2-4), the mass percentage of film-forming agent, anti-adhesion agent, and plasticizer in the enteric coating solution is 5%-15%, and the weight gain of the enteric coating layer is 9%-15%.

[0013] Specifically, this invention provides a delayed-release carbohydrate composition that releases almost no carbohydrates in the first 180 minutes after administration, and releases them almost completely within 240 minutes, thus maintaining normal nighttime blood glucose levels in diabetic patients and preventing nocturnal hypoglycemia. In an acidic medium with a pH not greater than 5.0, the cumulative release rate of the active ingredient in this delayed-release carbohydrate composition is less than 1% within 120 minutes; in a neutral medium with a pH not less than 6.8, the cumulative release rate is no more than 20% within 150 minutes and reaches more than 80% within 240 minutes.

[0014] Preferably, in an acidic medium with a pH value not greater than 5.0, the cumulative release rate of the active ingredient in the delayed-release carbohydrate composition of the present invention is less than 1% within 120 minutes; in a neutral medium with a pH value not less than 6.8, the cumulative release rate is not more than 20% within 180 minutes and reaches more than 80% within 240 minutes.

[0015] More preferably, in an acidic medium with a pH value not greater than 5.0, the cumulative release rate of the active ingredient in the delayed-release sugar composition of the present invention is less than 1% within 120 minutes; in a neutral medium with a pH value not less than 6.8, the cumulative release rate is not more than 20% within 180 minutes and reaches more than 80% within 210 minutes.

[0016] Preferably, in an acidic medium with a pH value not greater than 5.0, the cumulative release rate of the active ingredient in the delayed-release sugar composition of the present invention is less than 1% within 120 minutes; in a neutral medium with a pH value not less than 6.8, the cumulative release rate is not more than 20% within 180 minutes, more than 70% within 210 minutes, and more than 80% within 240 minutes.

[0017] This application also provides a method for preparing a delayed-release carbohydrate composition, the method comprising the following steps: (1) Provide a tablet core containing carbohydrates; (2) Provide at least one isolation layer coating solution, said isolation layer coating solution being composed of a water-soluble polymer, ethyl cellulose and optionally a pharmaceutically acceptable carrier; (3) Coating the tablet cores with at least one release coating solution and drying them to obtain release coated tablet cores; (4) Provide at least one enteric coating solution; and (5) Coat the separator-coated tablet cores with at least one enteric coating solution and dry them.

[0018] This application also provides the use of a combination of water-soluble polymers and ethyl cellulose in the delayed release of carbohydrates. Attached Figure Description

[0019] Figure 1 The dissolution results of the delayed-release carbohydrate composition prepared in Example 2 are shown.

[0020] Figure 2 The dissolution results of the delayed-release carbohydrate composition prepared in Example 4 are shown.

[0021] Figure 3 The dissolution results of the delayed-release carbohydrate composition prepared by formulation C20 are shown.

[0022] Figure 4 The dissolution results of different active substance enteric-coated tablets prepared in Example 6 are shown. Detailed Implementation

[0023] Unless otherwise specified in this specification, the components or their preferred components may be combined to form new technical solutions.

[0024] Unless otherwise specified in this specification, all the embodiments and preferred embodiments mentioned can be combined to form new technical solutions.

[0025] Unless otherwise specified in this specification, all the technical features and preferred features mentioned can be combined to form new technical solutions.

[0026] Unless otherwise specified, the term "a" as used in this specification means "at least one".

[0027] Unless otherwise specified, all tests mentioned in this specification are performed at room temperature.

[0028] Unless otherwise specified, all percentages, parts, etc. in this specification refer to weight.

[0029] The “range” disclosed herein takes the form of a lower limit and an upper limit. It can consist of one or more lower limits and one or more upper limits. A given range is defined by selecting a lower limit and an upper limit. The selected lower and upper limits define the boundaries of the particular range. All ranges that can be defined in this way are inclusive and composable; that is, any lower limit can be combined with any upper limit to form a range.

[0030] In this article, the range defined by "approximately" is usually the range of experimental error. For example, if the experimental error is 0.1, then "approximately 7" means 7 ± 0.1.

[0031] In this document, the term "substantially" means that the deviation of a feature, parameter, or performance from the ideal state or target value does not exceed ±5% of the value of the feature or parameter itself, or when the feature cannot be quantified numerically (e.g., shape, geometric relationship), it means that the difference between the feature and the ideal state is within the conventional manufacturing or measurement tolerances in the relevant technical field, and that the difference does not substantially affect the technical effect to be achieved by the feature.

[0032] This application provides a carbohydrate delayed-release composition comprising a tablet core and a delayed-release coating. The tablet core comprises carbohydrates, and the delayed-release coating comprises at least an isolation layer and an enteric coating. The isolation layer is disposed between the tablet core and the enteric coating, and the isolation layer enables the delayed release of carbohydrates.

[0033] Chip

[0034] In some embodiments of the present invention, the core mainly comprises the following components: carbohydrates and additives selected from the following: fillers, binders, disintegrants and anti-adhesives.

[0035] In some embodiments, the sugars in the core are selected from: D-anhydrous glucose, glucose, D-glucose (or its hydrates, such as monohydrate), fructose, galactose, maltose (maltitol), lactose, sucrose, trehalose, sorbitol, mannitol, erythritol, or combinations thereof, preferably D-anhydrous glucose.

[0036] In some embodiments, the D-anhydrous glucose content in the tablet core is 50%-95% by mass, for example 60%-95%, 70%-90%, or 80-90%.

[0037] In some embodiments, the filler in the core is selected from: mannitol, sorbitol, pregelatinized starch, dextrin, starch, maltodextrin, dicalcium phosphate, calcium carbonate, pregelatinized starch, microcrystalline cellulose, microcrystalline cellulose-lactose complex, or combinations thereof. In other embodiments, the filler is mannitol or microcrystalline cellulose.

[0038] In some embodiments, the filler content in the core is 0.1-10% by mass, for example 0.5-5%, 1.0-2.5%, or 1.0%-2.0%.

[0039] In some embodiments, the disintegrant is selected from one or more of the following: crospovidone, sodium carboxymethyl starch, starch, pregelatinized starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, sodium alginate, hydroxypropyl starch, crospovidone carboxymethyl starch, crospovidone carboxymethyl cellulose, and guar gum. In other embodiments, the disintegrant is crospovidone or crospovidone carboxymethyl cellulose.

[0040] In some embodiments, the disintegrant has a mass percentage content of 0.1-20% in the tablet core, for example 0.5-15%, 1.0-10%, or 2%-10%.

[0041] In some embodiments, the adhesive is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, starch paste, dextrin, gum arabic, ethyl cellulose, and konjac flour. Preferably, the adhesive comprises an inner granule adhesive and an outer granule adhesive. More preferably, the inner granule adhesive is hydroxypropyl methylcellulose, and the outer granule adhesive is ethyl cellulose. In a preferred embodiment, the adhesive accounts for 5%-10% by weight of the core, preferably 7%-9%.

[0042] In a preferred embodiment, the inner particle adhesive accounts for 0.1%-2% of the mass percentage of the core, preferably 0.5%-1.5%.

[0043] In a preferred embodiment, the outer particle adhesive has a mass percentage content of 1%-10% in the core, preferably 5%-9%.

[0044] In a preferred embodiment, the viscosity of the hydroxypropyl methylcellulose is 1-100 mPa·s, preferably 1-50 mPa·s, and more preferably 1-25 mPa·s.

[0045] In one specific implementation, hydroxypropyl methylcellulose (60RT5) or hydroxypropyl methylcellulose (60RT15) is selected as the inner particle binder.

[0046] In one specific embodiment, the hydroxypropyl methylcellulose is added in the form of an aqueous solution, the concentration of which is selected from 2% to 7%, for example, 2%, 3%, 4%, 5%, 6%, 7%, preferably 5%. In a preferred embodiment, the inner particle binder has a mass percentage content of 0.1% to 2% in the core, preferably 0.7% to 1.2%.

[0047] In some embodiments, the anti-adhesion agent is selected from one or more of the following: talc, stearic acid, magnesium stearate, sodium stearate fumarate, polyethylene glycol, magnesium lauryl sulfate, micronized silica gel, glyceryl monostearate, calcium stearate, and polyoxyethylene stearate. Preferably, the anti-adhesion agent is talc or magnesium stearate.

[0048] In a preferred embodiment, the anti-adhesion agent has a mass percentage content of 0.1%-3% in the core, preferably 0.5%-2%.

[0049] In a preferred embodiment, the hardness of the core is in the range of 100N-300N, preferably 140N-240N.

[0050] In a preferred embodiment, the complete release time of the chip core in an acidic medium with a pH not greater than 5.0 is less than 20 minutes, preferably less than 10 minutes.

[0051] Delayed release coating

[0052] In some embodiments of the present invention, the delayed release coating includes at least an isolation layer and an enteric layer.

[0053] In some embodiments, the isolation layer is disposed between the tablet core and the subsequent functional coating layer to form a physical and chemical barrier between the tablet core and the functional coating layer, preventing the migration of components between the layers and avoiding mutual reactions. In some embodiments, the subsequent functional coating layer is an enteric coating layer. The enteric coating layer is able to remain substantially non-releasing of the drug in the acidic environment of the stomach, while selectively dissolving and achieving controlled drug release under specific pH conditions in the intestine, especially in the neutral to weakly alkaline environment of the small intestine.

[0054] In some embodiments, the insulating layer comprises a water-soluble polymer and a hydrophobic polymer. Preferably, the hydrophobic polymer is ethyl cellulose and the water-soluble polymer is hydroxypropyl methyl cellulose.

[0055] In one specific implementation, a mixture of ethyl cellulose and hydroxypropyl methylcellulose (60RT5) or hydroxypropyl methylcellulose (60RT15) is selected as the insulating layer material.

[0056] In some embodiments, the barrier layer is composed of a water-soluble polymer, a hydrophobic polymer, and a solvent. Preferably, the hydrophobic polymer is ethyl cellulose; the water-soluble polymer is hydroxypropyl methyl cellulose. Preferably, the barrier layer does not contain cellulose acetate.

[0057] In some embodiments, the method for preparing the isolation layer includes: dispersing a water-soluble polymer and a hydrophobic polymer in a pharmaceutically acceptable carrier to obtain an isolation layer coating solution, coating the isolation layer coating solution onto the surface of the tablet core, and evaporating all solvents.

[0058] In some embodiments, the mass ratio of the hydrophobic polymer to the water-soluble polymer is 1:1-1:3, preferably 1:1.5-1:2.5, more preferably 1:1.5-1:2, and most preferably 1:1.8-1:2. Within the above ratio range, the delayed-release carbohydrate composition can have the desired hardness and release rate.

[0059] In some embodiments, the hydrophobic polymer is selected from one or more of ethyl cellulose, cellulose acetate, and polyacrylic acid resin of type RL / RS. Preferably, the hydrophobic polymer is selected from ethyl cellulose.

[0060] In some embodiments, the water-soluble polymer is selected from one or more of polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol, and povidone. Preferably, the water-soluble polymer is selected from hydroxypropyl methylcellulose.

[0061] In a preferred embodiment, the viscosity of the hydroxypropyl methylcellulose is 1-100 mPa·s, preferably 3-50 mPa·s, more preferably 3-25 mPa·s, and most preferably 5-15 mPa·s.

[0062] In some embodiments, the barrier layer further comprises a plasticizer. Preferably, the plasticizer is selected from polyethylene glycol and triethyl citrate, and more preferably, the plasticizer is selected from triethyl citrate. In some embodiments, the plasticizer has a mass percentage of 1%-3% in the barrier layer coating solution, preferably 1%-2.5%.

[0063] In some embodiments, the release layer further comprises an anti-adhesion agent. Preferably, the anti-adhesion agent is selected from talc. In some embodiments, the anti-adhesion agent accounts for 1%-3% by mass of the release layer coating liquid, preferably 2-2.5%.

[0064] In a preferred embodiment, the weight gain of the isolation layer is 3%-8%, preferably 4%-8%, and more preferably 5%-7%.

[0065] In a preferred embodiment, the hydrophobic polymer is present in the coating solution of the release layer at a mass percentage of 1%-3%, preferably 1.8%-2.2%.

[0066] In a preferred embodiment, the water-soluble polymer has a mass percentage of 3%-5% in the release layer coating solution, preferably 3.8%-4.2%.

[0067] In some embodiments, the solvent for the release layer coating solution is selected from water or ethanol. Preferably, the solvent for the release layer coating solution is a 90% aqueous ethanol solution.

[0068] In some embodiments of the present invention, the enteric coating mainly comprises the following components: film-forming agent, anti-adhesion agent, and plasticizer.

[0069] In some embodiments, the method for preparing the enteric coating layer includes: dispersing a film-forming agent, an anti-adhesion agent, and a plasticizer in a pharmaceutically acceptable carrier to obtain an enteric coating solution, coating the enteric coating solution onto the surface of the isolation layer, and evaporating all solvents.

[0070] In some embodiments, the plasticizer is selected from one or more of the following: triglyceride, triethyl citrate, tributyl citrate, acetylated triethyl citrate, diethyl phthalate, dibutyl phthalate, dimethyl phthalate, glyceryl triacetate, glyceryl monostearate, and dibutyl sebacate. Preferably, the plasticizer is selected from triglyceride.

[0071] In some embodiments, the film-forming agent of the enteric coating is preferably a pH-sensitive material selected from one or more of polyacrylic resin I, polyacrylic resin II, polyacrylic resin III, Eudragit L100, Eudragit L100-55, Eudragit L30D-55, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate 50, hydroxypropyl methylcellulose phthalate 55, hydroxypropyl methylcellulose acetate succinate, and calcium alginate. Preferably, the pH-sensitive material is polyacrylic resin II.

[0072] In a preferred embodiment, the amount of film-forming agent is 1.5-3.5 parts by weight, preferably 1.5-2 parts by weight, based on 1 part by weight of the plasticizer.

[0073] In some embodiments, the anti-adhesion agent of the enteric coating is selected from one or more of the following: talc, stearic acid, magnesium stearate, sodium stearate fumarate, polyethylene glycol, magnesium lauryl sulfate, micronized silica gel, glyceryl monostearate, calcium stearate, and polyoxyethylene stearate. Preferably, the anti-adhesion agent is talc.

[0074] In a preferred embodiment, the amount of anti-adhesive is 0.3-1.5 parts by weight, preferably 0.9-1.3 parts by weight, based on 1 part by weight of the plasticizer.

[0075] In some embodiments, the weight ratio of film-forming agent, anti-adhesion agent, and plasticizer is about (4-8):(3-5):(2-4), preferably (4-6):(3-4):(2.5-3.5). In other embodiments, the weight ratio of film-forming agent, anti-adhesion agent, and plasticizer is about (4.5-5.5):(3-4):(2.5-3.5). In one specific embodiment, the weight ratio of film-forming agent, anti-adhesion agent, and plasticizer is about 5:3.5:3.

[0076] In some embodiments, the film-forming agent, anti-adhesion agent, and plasticizer in the enteric coating solution have a mass percentage of 5%-15%, preferably 8%-10%.

[0077] In a preferred embodiment, the weight gain of the enteric coating ranges from 9% to 15%, preferably 10% to 12%.

[0078] In a preferred embodiment, the delayed-release carbohydrate composition comprises a core portion and a coating portion. The coating portion of the delayed-release carbohydrate composition comprises 14%-23% by weight of the core portion, preferably 15%-19%.

[0079] Preparation method

[0080] In another aspect, the present invention provides a method for preparing a delayed-release carbohydrate composition, the method comprising the following steps: (1) Provide a tablet core containing carbohydrates; (2) Provide at least one isolation layer coating solution, said isolation layer coating solution being composed of a water-soluble polymer, ethyl cellulose and optionally a pharmaceutically acceptable carrier; (3) Coating the tablet cores with at least one release coating solution and drying them to obtain release coated tablet cores; (4) Provide at least one enteric coating solution; and (5) Coat the separator-coated tablet cores with at least one enteric coating solution and dry them.

[0081] Delayed-release carbohydrate compositions

[0082] The present invention provides a delayed-release carbohydrate composition that releases almost no carbohydrates in the first 180 minutes after administration and releases them almost completely within 240 minutes after administration, thereby maintaining nocturnal blood glucose levels in diabetic patients at normal levels and preventing nocturnal hypoglycemia in diabetic patients.

[0083] In this application, the carbohydrate delayed-release composition has staged release characteristics, including: a gastric retention stage in which the carbohydrate is stable and does not release in gastric juice, a delayed release stage in intestinal juice, and a rapid or complete release stage.

[0084] In some embodiments, the sugar-delayed release composition is placed under acidic conditions for several hours without releasing the contained sugars.

[0085] In a preferred embodiment, the delayed-release carbohydrate composition, under neutral conditions, guarantees no release of carbohydrates for 150 minutes; more preferably, the release onset time can be delayed to 180 minutes. The release onset refers to a dissolution rate of not more than 20%, preferably not more than 10%, even more preferably not more than 5%, and more preferably not more than 1%.

[0086] In a preferred embodiment, the delayed-release carbohydrate composition can be fully released within 240 minutes under neutral conditions; more preferably, it can be fully released within 210 minutes. Full release refers to a dissolution rate of not less than 80%, preferably not less than 90%, even more preferably not less than 95%, and more preferably not less than 99%.

[0087] In a preferred embodiment, the release time (the time from the start of release to complete release) of the carbohydrate delayed-release composition is 30 minutes.

[0088] In a preferred embodiment, in an acidic medium with a pH value not greater than 5.0, the cumulative release of the active ingredient is less than 1% within 120 minutes; in a neutral medium with a pH value not less than 6.8, the cumulative release is not more than 20% within 180 minutes and reaches more than 80% within 240 minutes.

[0089] In a preferred embodiment, in an acidic medium with a pH value not greater than 5.0, the cumulative release of the active ingredient is less than 1% within 120 minutes; in a neutral medium with a pH value not less than 6.8, the cumulative release is not more than 20% within 180 minutes, more than 70% within 210 minutes, and more than 80% within 240 minutes.

[0090] Example

[0091] The present invention will now be described in further detail with reference to embodiments. However, it should be understood that these embodiments are provided for illustrative purposes only and are not intended to limit the scope of the invention.

[0092] The sources of materials used in the embodiments are shown in Table 1 below: Table 1: Material Source Table

[0093] Example 1: Core Preparation

[0094] The glucose tablet cores were prepared according to Table 2, and the specific process is as follows: D-anhydrous glucose and other excipients were passed through a 40-mesh sieve to remove agglomerates. Then, D-anhydrous glucose and mannitol were mixed thoroughly. Next, a soft mass was prepared with the above mixture using a 5% hydroxypropyl methylcellulose (60RT5) aqueous solution. The resulting soft mass was passed through a 24-mesh sieve to form wet granules, and dried at 60±5℃, with a moisture content below 1.5% as the drying endpoint (detected using an infrared moisture analyzer). The dried granules were passed through a 40-mesh sieve again to obtain internal granules with good flowability and uniform particle size. The internal granules were then mixed sequentially with ethyl cellulose, talc, and crospovidone in a specific ratio. Finally, the mixture was compressed using a tablet press to obtain the tablet core.

[0095] Table 2: Tablet Core Formula

[0096] The condition of soft materials and core sheets was determined by visual inspection, weight was measured using an electronic balance, and hardness was measured using a hardness tester. The standards are shown in Table 3.

[0097] Dissolution was determined using the "Method 1 (Basket Method)" in General Chapter 0931 of the Chinese Pharmacopoeia (2020 Edition, Part IV). The dissolution of D-anhydrous glucose was analyzed using an enzymatic method, as detailed below: (1) First method (basket method): 500 mL of dissolution medium (pH 6.8 phosphate buffer (PBS) in this experiment) was used, and the rotation speed was set to 50 rpm and the temperature to 37℃. Samples were taken at time points of 2, 5, 10, 15, 20, 30, 45 and 60 min respectively.

[0098] (2) Enzymatic detection: Samples from the above time points were taken and added to a pre-prepared working solution containing glucose oxidase, peroxidase, 4-aminoantipyrine, and phenol. Simultaneously, reaction tubes containing glucose standards of various concentrations were prepared. All reaction systems were incubated at 37℃ for 5-10 min. After complete color development, the absorbance was measured at 520 nm using an ELISA reader. A standard curve was plotted based on the absorbance values ​​of the standards, and the concentration of D-anhydrous glucose in the samples was then calculated.

[0099] Table 3: Evaluation Criteria for Tablet Core Formulation

[0100] The results of core preparation are shown in Table 4.

[0101] Table 4: Core Evaluation

[0102] The results showed that the tablet core material prepared by this formula exhibited a suitable state of "being able to be clump together by hand and crumble upon touch"; the obtained tablet core had a complete and smooth appearance, uniform color, good appearance after coating, small weight difference, and hardness that met the requirements, and could be completely released in PBS within 10 minutes.

[0103] Example 2: Formulation of isolation layer material

[0104] To further delay the release of D-anhydrous glucose, while ensuring the tablet core remains intact during the coating process and avoiding interaction between the tablet core and the coating layer, this study proposes to design an isolation layer coating on the outside of the tablet core and to optimize and screen the formulation of the isolation layer.

[0105] Material selection example

[0106] The effect of different film-forming materials of the isolation layer on drug release time

[0107] The isolation layer coating solution was prepared according to the prescription in Table 5. The specific process of isolation layer coating is as follows: the film-forming material was weighed according to the prescription amount, added to the coating solution solvent to prepare the isolation layer coating solution, and after being mixed evenly, the core film prepared in Example 1 was coated using a coating machine.

[0108] Table 5: Formulations of film-forming materials for different isolation layers

[0109] After the release liner is coated, the enteric coating is performed according to the method in Formulation C20 of Example 5. Glucose delayed-release tablets are obtained, and the cumulative dissolution rate of the prepared glucose delayed-release tablets is tested.

[0110] The dissolution rate of the coated glucose delayed-release tablets was determined using the "Method 1 (Basket Method)" in General Chapter 0931 of the Chinese Pharmacopoeia (2020 Edition, Part IV). Sampling was performed, and the dissolution rate of anhydrous glucose was analyzed using an enzymatic method. The specific procedures are as follows: (1) Method 1 (basket method): Use 500 mL of dissolution medium, basket speed of 100 rpm, and solution temperature of 37℃. First, use 500 mL of 0.1 M hydrochloric acid solution as the dissolution medium, and take the dissolution solution at 120 min to determine the dissolution rate. Then, transfer the test sample to phosphate buffer (PBS), and use PBS buffer with pH 6.8 as the dissolution medium. Take the dissolution solution at 150 min, 165 min, 180 min, 190 min, 200 min, 210 min, 220 min, 230 min, and 240 min to determine the dissolution rate. The above times refer to the total time of the dissolution test.

[0111] (2) For enzymatic detection, refer to the content described in "Slice Core Preparation".

[0112] Dissolution rates of glucose delayed-release tablets made from different film-forming materials are shown in the table below. Figure 1 See Table 6.

[0113] Table 6: Dissolution of Glucose Delayed-Release Tablets Made with Different Film-Forming Materials

[0114] The results showed that the choice of film-forming material is crucial to drug release time, and the addition of plasticizers and anti-adhesion agents also affects drug dissolution. When using a single water-soluble polymer (Formulation Examples D1, D4-D6) or a pH-dependent polymer (Formulation Examples D2-D3) as the film-forming material, the tablet core began to dissolve at 150 min and was completely released before 240 min. The addition of hydrophobic polymers can delay drug release, but some hydrophobic polymers (Formulation Example D8) result in extremely slow drug release. The addition of excipients such as plasticizers and anti-adhesion agents affects the drug dissolution rate. In the isolation layer, without the addition of plasticizers and anti-adhesion agents (Formulation Example D9), compared with the addition of triethyl citrate (Formulation Example D7), the drug release onset time was delayed and the release rate was significantly increased. In conclusion, hydroxypropyl methylcellulose (60RT5) and ethyl cellulose will be used as film-forming materials for the isolation layer in future studies.

[0115] According to Table 7, a single polymer (hydroxypropyl methylcellulose 60RT4000) or a composite of two polymers (ethyl cellulose and different types of hydroxypropyl methylcellulose) was selected as the release liner coating material for the tablet core. The coating effect of the release liner formed by different film-forming materials was studied, and the differences in coating quality, appearance, and dissolution of glucose delayed-release tablets were further investigated. The specific process for release liner coating is as follows: the film-forming material is weighed according to the formula dosage, added to the coating solvent to prepare the release liner coating solution, mixed evenly, and then the tablet core is coated using a coating machine.

[0116] Table 7: Formulations of film-forming materials for different isolation layers

[0117] After the isolation layer coating, the enteric coating was carried out according to the method of formulation C20 in Example 5 to obtain glucose delayed-release tablets, and the cumulative dissolution rate of the prepared glucose delayed-release tablets was tested.

[0118] The coating conditions of the isolation layer and enteric coating layer, as well as the appearance of the coated tablets, were determined by visual inspection, and the standards are shown in Table 8.

[0119] Table 8: Evaluation Criteria for Prescriptions

[0120] The evaluation results of glucose delayed-release tablets with different film-forming materials for the isolation layer are shown in Table 9.

[0121] Table 9: Evaluation of Film-Forming Materials for Different Isolation Layers

[0122] The results showed that when using a single polymer, hydroxypropyl methylcellulose (60RT 4000) (Formulation G1), the large molecular weight and high viscosity of the coating solution easily clogged the spray gun, resulting in a rough appearance and slow release of the coated tablets. When using a two-polymer composite, Formulations G5 and G6 were prone to spray gun clogging during the coating process, resulting in rough tablets; Formulation G4 showed slight spray gun clogging, but the tablets still had a relatively rough appearance; Formulations G2 and G3 had smooth coating processes and smooth tablet surfaces. Therefore, hydroxypropyl methylcellulose with a viscosity in the range of 5 mPa·s–15 mPa·s performed better. In conclusion, a mixture of ethyl cellulose and hydroxypropyl methylcellulose (60RT5) or hydroxypropyl methylcellulose (60RT15) was selected as a suitable release layer material.

[0123] Ratio of water-soluble polymers to hydrophobic polymers

[0124] A mixture of hydrophobic ethyl cellulose and water-soluble hydroxypropyl methylcellulose possesses both good barrier properties and film-forming toughness. Optimizing the ratio of the two polymers is necessary to achieve ideal drug release performance. Ethyl cellulose and hydroxypropyl methylcellulose (60RT5) were selected as the hydrophobic polymer and water-soluble polymer, respectively, as shown in Formulation Table 10. The isolation layer coating solutions were prepared using ethyl cellulose and hydroxypropyl methylcellulose (60RT5) in ratios of 1:2, 1:1.5, 1:1, 1.5:1, and 2:1, respectively. The isolation layer coating procedure was consistent with that described in the "Material Selection Example".

[0125] Table 10: Formulations with different film-forming material ratios

[0126] The cumulative dissolution rate of the prepared glucose delayed-release tablets was tested, and the evaluation results of glucose delayed-release tablets prepared with different film-forming material ratios are shown in Table 11.

[0127] Table 11: Evaluation of the proportion of different isolation layer film-forming materials

[0128] The results showed that when the proportion of ethyl cellulose in the separator film-forming material increased, the dissolution and release of the prepared glucose delayed-release tablets decreased, failing to meet the requirement of rapid release of the tablet core. When the ratio of ethyl cellulose to hydroxypropyl methylcellulose (60RT5) was 1:1.5-1:2, the tablet core could be completely released within 240 minutes. Therefore, a ratio of ethyl cellulose to hydroxypropyl methylcellulose (60RT5) of 1:1.5-1:2 is the ideal ratio, with 1:2 showing the best effect.

[0129] Example 3: Weight gain ratio of the isolation layer

[0130] An appropriate weight gain range helps maintain stable dissolution behavior; therefore, this study investigated the weight gain range of the release liner. Ethyl cellulose was selected as the hydrophobic polymer, and hydroxypropyl methyl cellulose (60RT5) was selected as the water-soluble polymer, with their ratio controlled at 1:2. As shown in Table 12, weight gain ratios of 3%, 4%, 5%, 6%, 7%, and 8% were selected for release liner coating. The release liner coating procedure was consistent with that described in the "Material Selection Example".

[0131] Table 12: Prescription Table for Weight Gain Ratio of Different Isolation Layers

[0132] The coating condition and appearance were assessed visually, and the evaluation criteria are shown in Table 8. The dissolution of glucose delayed-release tablets followed the method described above. The evaluation results of glucose delayed-release tablets made with different separation layer weight gain ratios are shown in Table 13.

[0133] Table 13: Evaluation of Glucose Delayed-Release Tablets with Different Separation Layer Weight Gain Ratios

[0134] The results showed that increasing the weight gain ratio of the isolation layer could delay the onset of dissolution of glucose delayed-release tablets. When the weight gain ratio was in the range of 5%-8%, the tablets could start to release after 180 minutes and be completely released after 210 minutes. In other words, the product could maintain stable dissolution behavior within this range.

[0135] In summary, the combination of ethyl cellulose and hydroxypropyl methylcellulose (60RT5) (ethyl cellulose: hydroxypropyl methylcellulose (60RT5) = 1:2) to prepare the release coating resulted in a weight gain of 5%-8%. The tablets prepared using this method began to release after 180 minutes and were fully released after 210 minutes, meeting the expected target.

[0136] Example 4: Enteric-coated pH-sensitive material

[0137] Selection of pH-sensitive materials

[0138] Suitable enteric coating materials can protect the tablet core from gastric acid erosion, thereby achieving targeted release and absorption of the drug in the intestine. This study selected common pH-sensitive enteric coating materials—Eudragit L100-55, polyacrylic acid resin II, polyacrylic acid resin III, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose acetate succinate—and prepared the enteric coating solution according to the formulation shown in Table 14. The coating process and the appearance of the coated glucose delayed-release tablets were investigated. The specific enteric coating process was as follows: excipients were weighed according to the formulation dosage, added to the coating solution solvent to prepare the enteric coating solution, mixed evenly, and then coated using a coating machine.

[0139] Table 14: Formulations of different pH-sensitive materials

[0140] The coating and appearance of the glucose delayed-release tablets were evaluated visually, with evaluation criteria referenced in Table 8. Dissolution was performed according to the method described in the "Material Selection Example" section above. The evaluation results of glucose delayed-release tablets made from different pH-sensitive materials are shown in Table 15 and... Figure 2 .

[0141] Table 15: Evaluation of glucose delayed-release tablets with different pH-sensitive materials

[0142] The results showed that Eudragit L100-55 (Formulation C1) had excessively high viscosity, causing multiple nozzle blockages during the coating process, making normal operation impossible, and resulting in flaking on the coating surface. The other formulations could complete the coating, but some experienced minor nozzle blockage and tablet chipping. Using polyacrylic acid resin II (Formulation C2) or a 4:1 mixture of hydroxypropyl methylcellulose phthalate and polyacrylic acid resin III (Formulations C8 and C9) as the enteric coating material could ensure no release of sugars within 180 minutes and complete release within 240 minutes. However, the intra-group deviation in dissolution was large when using triethyl citrate as a plasticizer (Formulation C8), and tablet chipping occurred when using dibutyl sebacate as a plasticizer (Formulation C9). Considering that the formulation of the compound system is more complex than using polyacrylic acid resin II alone, polyacrylic acid resin II was ultimately selected as the enteric coating material, and further optimization will be carried out.

[0143] Enteric coating anti-adhesion agent

[0144] To effectively improve the adhesion phenomenon during the coating process, magnesium stearate and talc, two commonly used anti-adhesion agents, were compared and their dosages were screened, as shown in Table 16. The enteric coating process is the same as described in the "Example of pH Sensitive Material Selection".

[0145] Table 16: Prescriptions of different anti-adhesion agents and their dosages

[0146] The coating and appearance of the glucose delayed-release tablets were evaluated by visual inspection, with the evaluation criteria referenced in Table 8. The dissolution rate followed the method described in the "Material Selection Example" above. The evaluation results of glucose delayed-release tablets made with different anti-adhesives and their dosages are shown in Table 17.

[0147] Table 17: Evaluation of Glucose Delayed-Release Tablets with Different Anti-Adhesion Agents and Doses

[0148] The results showed that when magnesium stearate was used as an anti-sticking agent (formulations C13 and C14), tablet sticking occurred during coating, and the degree of sticking was positively correlated with the amount used. However, when talc was used as an anti-sticking agent (formulations C2, C11, and C12), the clogging of the spray gun during coating was improved with increasing talc content, and the dissolution rate met the requirements. Based on these results, talc was subsequently selected as the anti-sticking agent for further optimization.

[0149] Example of pH-sensitive material dosage

[0150] To reduce the impact of variations in enteric coating weight gain on product dissolution, the amount of pH-sensitive material was reduced. As shown in Table 18, based on the previously determined amount of polyacrylic acid resin II, three reductions were set: 1 / 5 (Formulation Example C15), 2 / 5 (Formulation Example C16), and 1 / 2 (Formulation Example C17) for formulation screening. The enteric coating process was the same as described in "Selection of pH-Sensitive Materials".

[0151] Table 18: Formulations for different pH-sensitive material dosages

[0152] The coating and appearance of glucose delayed-release tablets were evaluated by visual inspection, with the evaluation criteria referenced in Table 8. The dissolution rate followed the method described in the "Material Selection Example" above. The evaluation results of glucose delayed-release tablets made with different amounts of pH-sensitive materials are shown in Table 19.

[0153] Table 19: Evaluation of Glucose Delayed-Release Tablets with Different Amounts of pH-Sensitive Materials

[0154] The results showed that the dissolution rates of formulations C12 and C15-C17 all met the requirements (dissolution began at 180 min, and complete dissolution at 240 min). With decreasing dosage of polyacrylic acid resin II, the intra-group deviation of the dissolution results continuously decreased, and the dissolution stability improved. When the dosage of polyacrylic acid resin II was reduced to 1 / 2, the glucose delayed-release tablets could be completely released at 200 min, with a rapid release process, which basically met the expected target. In summary, the ratio of pH-sensitive material, talc, and triethyl citrate was (4-8):(3-5):(2-4).

[0155] Example 5: Enteric coating weight gain ratio

[0156] The weight gain range of the enteric coating affects the enteric release performance, appearance quality, and batch-to-batch stability of the coated tablets; therefore, the weight gain range of the enteric coating was investigated. As shown in Table 20, the ratio of pH-sensitive material, talc, and triethyl citrate was selected as 5:3.5:3, and the weight gain range was selected from 10% to 15% for the preparation of glucose delayed-release tablets. The enteric coating process was the same as described in the "Example of pH-sensitive material selection".

[0157] Table 20: Prescriptions with different enteric coating weight gain ratios

[0158] The coating, appearance, and dissolution of the glucose delayed-release tablets were all performed according to the methods described in the "Material Selection Example" above. The evaluation results of glucose delayed-release tablets prepared with different enteric coating weight gain ratios are shown in Table 21.

[0159] Table 21: Evaluation of Glucose Delayed-Release Tablets with Different Enteric Coating Weight Gain Ratios

[0160] The results showed that the weight gain of each coating was normal, the appearance of the glucose delayed-release tablets was smooth, uniform, and dense, and the differences within the groups were small, with uniform dissolution. Therefore, dissolution with an enteric coating weight gain between 10% and 15% could meet the release target. Among them, an 11% weight gain (formulation example C20) had a small cumulative release while the complete dissolution time did not exceed 210 min. 11% was the optimal weight gain ratio, and the dissolution curve is shown below. Figure 3 As shown.

[0161] Example 6: Effect of different active pharmaceutical ingredients on dissolution

[0162] To investigate the effect of the same delayed-release formulation on the dissolution performance of different active pharmaceutical ingredients, the dissolution performance of aspirin, salicylic acid, diclofenac sodium, and tolbutamide enteric-coated tablets was studied. Enteric-coated tablets were prepared according to the formulations shown in Table 22.

[0163] Table 22: Prescription information for different active pharmaceutical ingredients

[0164] The coating condition and appearance of enteric-coated tablets were evaluated by visual inspection. Diclofenac sodium tablets showed varying degrees of chipping after the release liner was applied. All other enteric-coated tablets were visually uniform in color, with smooth and intact coating layers and no abnormalities.

[0165] Dissolution testing followed the method described in Example 2, "Material Selection Example," except that the dissolution rate (%) was measured at each time point: 120 min, 160 min, 180 min, 190 min, 200 min, 210 min, 220 min, 230 min, 240 min, and 300 min. Evaluation results for enteric-coated tablets prepared with different active pharmaceutical ingredients are shown below. Figure 4 .

[0166] The results showed that the dissolution performance of A1-A4 (tolbutamide enteric-coated tablets, diclofenac sodium enteric-coated tablets, aspirin enteric-coated tablets, and salicylic acid enteric-coated tablets) differed significantly from that of A5 (glucose delayed-release tablets). At 300 min, the highest dissolution rate was only 52%, and none of them achieved complete release. Furthermore, the dissolution curves of each formulation differed significantly, and even using the same enteric coating system, it was impossible to achieve the same delayed-release target as glucose delayed-release tablets.

Claims

1. A carbohydrate-based delayed-release composition, said composition comprising a tablet core and a delayed-release coating, The tablet core includes an active ingredient, which is a carbohydrate. The delayed-release coating comprises at least an isolation layer and an enteric coating layer, wherein the isolation layer is disposed between the tablet core and the enteric coating layer, and the isolation layer is composed of a hydrophobic polymer, a water-soluble polymer, and optionally a pharmaceutically acceptable carrier. in, The hydrophobic polymer is ethyl cellulose, and the water-soluble polymer is hydroxypropyl methyl cellulose with a viscosity of 3-25 mPa·s. The mass ratio of ethyl cellulose to the water-soluble polymer is 1:1 to 1:

3. Specifically, in an acidic medium with a pH value not greater than 5.0, the cumulative release rate of the active ingredient is less than 1% within 120 minutes; subsequently, in a neutral medium with a pH value not less than 6.8, the cumulative release rate does not exceed 20% within 150 minutes, and reaches more than 80% within 240 minutes.

2. The carbohydrate delayed-release composition according to claim 1, characterized in that, The carbohydrates in the tablet core are selected from: glucose, maltose, lactose, galactose, fructose, mannose, xylose, sucrose, fucose, arabinose, rhamnose, ribose, sorbose, lactulose, tagatose, maltulose, paraginose, isomaltose, trehalose, sophorose, rutinose, kosperidose, aspergillus niger disodium, laminarin disodium, gentiobiose, pinobiose, gentiodiulose, mannobiose, plantain disodium, xylobiose, sorbitol, lactitol, mannitol, erythritol, or combinations thereof, and the carbohydrate content in the tablet core is 50%-95% by mass.

3. The carbohydrate delayed-release composition according to claim 1, characterized in that, The core also contains fillers, disintegrants, adhesives, and anti-adhesion agents. The filler is selected from: mannitol, sorbitol, pregelatinized starch, dextrin, starch, maltodextrin, dicalcium phosphate, calcium carbonate, pregelatinized starch, microcrystalline cellulose, microcrystalline cellulose-lactose complex, or combinations thereof, and the filler has a mass percentage content of 0.1-10% in the core. The disintegrant is selected from one or more of the following: crospovidone, sodium carboxymethyl starch, starch, pregelatinized starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, sodium alginate, hydroxypropyl starch, crospovidone carboxymethyl starch, crospovidone carboxymethyl cellulose, and guar gum. The disintegrant has a mass percentage content of 0.1-20% in the tablet core. The adhesive is selected from one or more of the following: hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, starch paste, dextrin, gum arabic, ethyl cellulose, and konjac flour, and the adhesive accounts for 5%-10% of the mass percentage of the core material. The anti-adhesion agent is selected from one or more of the following: talc, stearic acid, magnesium stearate, sodium stearate fumarate, polyethylene glycol, magnesium lauryl sulfate, micronized silica, glyceryl monostearate, calcium stearate, and polyoxyethylene stearate. The anti-adhesion agent has a mass percentage content of 0.1%-3% in the core.

4. The carbohydrate delayed-release composition according to claim 1, characterized in that, The water-soluble polymer has a viscosity of 5-15 mPa·s. Hydroxypropyl methylcellulose (HMC) for seconds.

5. The carbohydrate delayed-release composition according to claim 1, characterized in that, The mass ratio of ethyl cellulose to water-soluble polymer is 1:1.5 to 1:

2.

6. The carbohydrate delayed-release composition according to claim 1, characterized in that, The weight gain of the isolation layer ranges from 4 to 8 times the weight.

7. The carbohydrate delayed-release composition according to claim 1, characterized in that, The enteric coating includes a film-forming agent, an anti-adhesive agent, and a plasticizer. The plasticizer is selected from one or more of the following: triethyl citrate, triethyl citrate, tributyl citrate, acetylated triethyl citrate, diethyl phthalate, dibutyl phthalate, dimethyl phthalate, glyceryl triacetate, glyceryl monostearate, and dibutyl sebacate. The film-forming agent is a pH-sensitive material selected from one or more of the following: polyacrylic acid resin I, polyacrylic acid resin II, polyacrylic acid resin III, Eudragit L100, Eudragit L100-55, Eudragit L30D-55, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate 50, hydroxypropyl methylcellulose phthalate 55, and calcium alginate. The anti-adhesion agent is selected from one or more of the following: talc, stearic acid, magnesium stearate, sodium stearate fumarate, polyethylene glycol, magnesium lauryl sulfate, micronized silica, glyceryl monostearate, calcium stearate, and polyoxyethylene stearate.

8. The carbohydrate delayed-release composition according to claim 7, characterized in that, Based on 1 part by weight of the plasticizer, the amount of film-forming agent is 1.5-3.5 parts by weight, and based on 1 part by weight of the plasticizer, the amount of anti-adhesive is 0.3-1.5 parts by weight.

9. The carbohydrate delayed-release composition according to claim 7, characterized in that, The weight ratio of film-forming agent, anti-adhesion agent and plasticizer is approximately (4-8):(3-5):(2-4), and the weight gain of the enteric coating is 10%-15%.

10. The carbohydrate delayed-release composition according to any one of claims 1-9, characterized in that, In acidic media with a pH value not exceeding 5.0, the cumulative release rate of the active ingredient is less than 1% within 120 minutes; in acidic media with a pH value not exceeding 5.0, the cumulative release rate of the active ingredient is less than 1%. In a neutral medium of 6.8, the cumulative release rate does not exceed 20% within 180 minutes and reaches more than 80% within 240 minutes.

11. The carbohydrate delayed-release composition according to any one of claims 1-9, characterized in that, In acidic media with a pH value not exceeding 5.0, the cumulative release rate of the active ingredient is less than 1% within 120 minutes; in acidic media with a pH value not exceeding 5.0, the cumulative release rate of the active ingredient is less than 1%. In a neutral medium of 6.8, the cumulative release rate does not exceed 20% within 180 minutes, the cumulative release rate reaches more than 70% within 210 minutes, and the cumulative release rate reaches more than 80% within 240 minutes.

12. A method for preparing the carbohydrate delayed-release composition as described in claim 1, the method comprising the following steps: (1) Provide a tablet core containing carbohydrates; (2) Provide at least one isolation layer coating solution, the isolation layer coating solution comprising a hydrophobic polymer and a water-soluble polymer; (3) Coating the tablet cores with at least one release coating solution and drying them to obtain release coated tablet cores; (4) Provide at least one enteric coating solution; as well as (5) Coat the separator-coated tablet cores with at least one enteric coating solution and dry them.

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