Mesalazine colon-targeted drug delivery and transfer system as well as preparation method and application of mesalazine colon-targeted drug delivery and transfer system

Abstract

The invention discloses a mesalazine colon-targeted drug delivery transfer system as well as a preparation method and application thereof, and belongs to the technical field of pharmaceutical preparations. The transfer system comprises a mesalazine drug carrier skeleton, an enzyme sensitive component and a pH sensitive coating, the enzyme-sensitive component wraps the outer layer of the mesalazine drug carrier skeleton or is mixed with the mesalazine drug carrier skeleton; the pH-sensitive coating wraps the outer layer of the enzyme-sensitive component or the outer layer of the mixture of the enzyme-sensitive component and the mesalazine drug carrier skeleton. A unique enzyme-sensitive and pH-sensitive double-layer coating technology is adopted, so that enzymatic degradation of mesalazine in a gastric acid environment and the upper section of a small intestine is effectively protected, and early release and whole-body absorption of drugs are remarkably reduced; it is ensured that mesalazine is efficiently and intensively released in the colon environment; the bioavailability of mesalazine in a colon focus is improved, and the local treatment effect is enhanced; the systemic exposure of mesalazine is reduced, and potential systemic adverse reactions are reduced.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, and particularly relates to a mesalazine colon-targeted drug delivery system, its preparation method, and its application. Background Technology

[0002] Inflammatory bowel disease (IBD), especially ulcerative colitis, is a chronic, relapsing disease, with lesions primarily concentrated in the colon. Mesalazine, a first-line drug for treating IBD, works by exerting its anti-inflammatory effect through local action. However, with oral mesalazine formulations, some of the drug is easily absorbed or degraded in the stomach and upper small intestine before reaching the colon, resulting in a lower drug concentration reaching the lesion site and hindering its effectiveness.

[0003] Currently available mesalazine colon-targeted formulations mostly rely on pH-sensitive coatings or sustained-release matrix tablets to achieve targeted release. The original patent uses microparticle coating (three-layer coating), a method that is not only complex in its process but also prone to individual variations in drug release due to differences in preparation or fluctuations in the in vivo environment. Other existing technologies also have shortcomings. For example, CN11258757A involves the preparation of pH-buffered particles and sustained-release tablets, with cumbersome process steps; CN105456223A achieves sustained-release through microparticle technology, which, while possessing some colon-targeting ability, also suffers from complex processes and susceptibility to individual differences; CN105902500B discloses an enteric-coated, targeted, controlled-release mesalazine formulation with a complex technical solution combining multiple mechanisms such as ethyl cellulose diffusion-controlled release, pH sensitivity, and bioadhesion. Although this multi-layered composite system aims to achieve colon-targeting, its process is complex and its controlled-release mechanism has relatively low efficiency. These traditional dosage forms generally suffer from problems such as inaccurate drug release, low drug bioavailability in the colon, and the potential for gastrointestinal side effects from drugs that are not released in a targeted manner, making it difficult to meet clinical treatment needs.

[0004] Therefore, there is an urgent need to develop a mesalazine colon-targeted formulation technology that is more targeted, releases more precisely and stably, has a simpler preparation process, and can effectively reduce individual differences. This technology would address the technical shortcomings of traditional formulations, such as premature release of the drug in the stomach and small intestine, resulting in insufficient local drug concentration, unsatisfactory sustained-release effect, inability to achieve precise colon-targeting, complex formulation processes, and poor batch-to-batch consistency. The goal would be to ensure that the drug can achieve efficient and concentrated release at the lesion site in the colon, thereby further improving the clinical efficacy and safety of mesalazine in the treatment of inflammatory bowel disease. Summary of the Invention

[0005] In view of this, the purpose of this invention is to provide a mesalazine colon-targeted drug delivery system that achieves high-concentration, explosive release of mesalazine locally in the colon, thereby achieving: effective protection of mesalazine from enzymatic degradation in the acidic environment of the stomach and the upper small intestine, significantly reducing premature drug release and systemic absorption; ensuring efficient and concentrated release of mesalazine in the colonic environment; simplifying the production process; improving the bioavailability of mesalazine in colonic lesions, thereby enhancing the local therapeutic effect; and reducing the systemic exposure of mesalazine, thus reducing potential systemic adverse reactions.

[0006] Another object of the present invention is to provide a method for preparing the aforementioned transport system.

[0007] Another object of the present invention is to provide the application of the transport system or the transport system prepared by the preparation method in the preparation of a mesalazine colon-targeted drug.

[0008] Another object of the present invention is to provide a mesalazine colon-targeted drug delivery capsule.

[0009] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides a mesalazine colon-targeted drug delivery system, the delivery system comprising a mesalazine drug carrier backbone, an enzyme-sensitive component, and a pH-sensitive coating; the enzyme-sensitive component is coated on the outer layer of the mesalazine drug carrier backbone or mixed with the mesalazine drug carrier backbone; the pH-sensitive coating is coated on the outer layer of the enzyme-sensitive component or on the outer layer of the mixture of the enzyme-sensitive component and the mesalazine drug carrier backbone.

[0010] Preferably, the mesalazine drug carrier matrix comprises mesalazine and a matrix material; the matrix material comprises any one or more of microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, and polyethylene glycol.

[0011] Preferably, the enzyme-sensitive component includes an enzyme-sensitive material; the enzyme-sensitive material includes any one or more of starch, pectin, dextran, inulin, guar gum, sodium alginate, and xylan.

[0012] Preferably, the pH-sensitive coating comprises a pH-sensitive polymer; the pH-sensitive polymer comprises any one or more of acrylic resins, hydroxypropyl methyl cellulose phthalate, and cellulose acetate.

[0013] The present invention also provides a method for preparing the aforementioned delivery system, the method comprising: mixing mesalazine and a matrix material, and obtaining a mesalazine drug carrier matrix by tableting or granulation; dissolving an enzyme-sensitive material in water to obtain an enzyme-sensitive coating solution, and coating the mesalazine drug carrier matrix to obtain enzyme-sensitive coated particles; dissolving a pH-sensitive polymer in an organic solvent to obtain a pH-sensitive coating solution, and coating the enzyme-sensitive coated particles to obtain a mesalazine colon-targeted drug delivery system; Alternatively, the preparation method includes: mixing mesalazine, a matrix material, and an enzyme-sensitive material; obtaining a mixture of the enzyme-sensitive component and the mesalazine drug carrier matrix using a tableting or granulation method; dissolving a pH-sensitive polymer in an organic solvent to obtain a pH-sensitive coating solution; coating the mixture of the enzyme-sensitive component and the mesalazine drug carrier matrix to obtain a mesalazine colon-targeted drug delivery system.

[0014] Preferably, the weight gain of the enzyme-sensitive coating solution after coating is 5% to 9%.

[0015] Preferably, the weight gain of the pH-sensitive coating solution after coating is 8% to 12%.

[0016] The present invention also provides the application of the transport system described herein or the transport system prepared by the preparation method in the preparation of a mesalazine colon-targeted drug.

[0017] Preferably, the dosage form of the drug includes solid dosage forms; the solid dosage forms include tablets, granules, or capsules.

[0018] The present invention also provides a mesalazine colon-targeted drug delivery capsule, wherein the delivery system or the delivery system prepared by the preparation method is filled into a capsule to obtain the capsule.

[0019] The beneficial effects of this invention are: This invention provides a mesalazine colon-targeted drug delivery system, employing a unique "enzyme-sensitive + pH-sensitive" dual-layer coating technology. The pH-sensitive coating provides protection in the stomach and upper small intestine, while the enzyme-sensitive material functions in the unique microbial enzyme environment of the colon. This effectively protects mesalazine from enzymatic degradation in the acidic environment of the stomach and the upper small intestine, significantly reducing premature drug release and systemic absorption; ensuring efficient and concentrated release of mesalazine in the colonic environment; improving the bioavailability of mesalazine in colonic lesions, thereby enhancing local therapeutic effects; reducing systemic exposure to mesalazine, minimizing potential systemic adverse reactions; and achieving a more stable, reliable drug release mode with smaller individual release variability.

[0020] This invention provides a method for preparing a mesalazine colon-targeted drug delivery system. Instead of using microcapsules as the drug core, it employs drug particles or tablets prepared using traditional solid dosage form techniques such as tableting and granulation as the carrier. This simplifies the preparation process and avoids the stringent requirements on equipment and process parameters inherent in microcapsule coating. The preparation method of this invention offers controllable processes, and the resulting delivery system exhibits precise colon-targeting, high bioavailability, and good industrialization feasibility. Detailed Implementation

[0021] This invention provides a mesalazine colon-targeted drug delivery system, the delivery system comprising a mesalazine drug carrier backbone, an enzyme-sensitive component, and a pH-sensitive coating; the enzyme-sensitive component is coated on the outer layer of the mesalazine drug carrier backbone or mixed with the mesalazine drug carrier backbone; the pH-sensitive coating is coated on the outer layer of the enzyme-sensitive component or on the outer layer of the mixture of the enzyme-sensitive component and the mesalazine drug carrier backbone.

[0022] In this invention, the mesalazine drug carrier matrix preferably includes mesalazine and a matrix material; the matrix material is preferably a hydrophilic or lipophilic polymer; in some embodiments, the matrix material preferably includes any one or more of microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose (CMC-Na), polyvinylpyrrolidone (PVP), and polyethylene glycol (PEG).

[0023] In some embodiments of this invention, the mesalazine drug carrier matrix preferably further includes excipients; the excipients preferably include any one or more of fillers, diluents, binders, disintegrants, and lubricants. In some embodiments, the excipients preferably include any one or more of lactose, microcrystalline cellulose, povidone K30, croscarmellose sodium, croscarmellose, and magnesium stearate. Microcrystalline cellulose not only serves as a matrix material and filler, but its fibrous structure also facilitates particle formation and subsequent disintegration; croscarmellose sodium, as a hyperdisintegrant, can rapidly absorb water and swell after the coating dissolves, promoting rapid particle disintegration and providing a physical basis for the degradation of enzyme-sensitive materials and the explosive release of the drug.

[0024] In this invention, the enzyme-sensitive component preferably comprises an enzyme-sensitive material; the enzyme-sensitive material preferably comprises any one or more of starch, pectin, dextran, inulin, guar gum, sodium alginate, and xylan. This invention selects dextran, pectin, or starch as enzyme-sensitive materials, which are not easily degraded in the upper small intestine, but whose unique chemical bond structures (such as the α-1,6-glycosidic bonds of dextran) can be specifically hydrolyzed by bacterial enzymes specific to the colon. Furthermore, this application abandons the alkalization treatment in the traditional enzyme-sensitive coating process, and through a unique coating sequence of "enzyme-sensitive inner layer → pH-sensitive outer layer," the pH-sensitive outer layer provides protection, thereby eliminating the necessity of alkalization treatment and simplifying the process.

[0025] In some embodiments of the present invention, the enzyme-sensitive component preferably further includes excipients; the excipients preferably include one or more of film-forming agents, sustained-release agents, flow aids, anti-blocking agents, and plasticizers. In some embodiments, the excipients preferably include one or more of hydroxypropyl methylcellulose, talc, and polyethylene glycol.

[0026] In this invention, the pH-sensitive coating preferably comprises a pH-sensitive polymer; the pH-sensitive polymer preferably comprises any one or more of acrylic resins, hydroxypropyl methyl cellulose phthalate, and cellulose acetate phthalate; the acrylic resin preferably comprises an aqueous dispersion of acrylic resins (Eudragit) of the L or S series. In some embodiments, the aqueous dispersion of acrylic resins of the L series preferably comprises Eudragit L100-55; the aqueous dispersion of acrylic resins of the S series preferably comprises Eudragit S100. This invention selects pH-sensitive polymers such as Eudragit S100 or Eudragit L100-55, which dissolve only at specific pH levels, ensuring zero or very low release in the stomach and upper small intestine.

[0027] In some embodiments of this invention, the pH-sensitive coating preferably further includes excipients; the excipients are preferably any one or more of plasticizers, anti-blocking agents, flow aids, emulsifiers, and lubricants. In some embodiments, the excipients preferably include any one or more of diethyl phthalate, talc, triethyl citrate, diethyl phthalate, and polysorbate. The plasticizers such as diethyl phthalate and triethyl citrate selected in this invention can increase the flexibility of the coating film and prevent premature drug leakage due to brittleness during drying or gastrointestinal motility.

[0028] This invention employs a dual-gating mechanism of "pH-sensitive coating + enzyme-sensitive material" rather than a single pH gradient or multi-layer microparticle coating. The pH-sensitive coating provides protection in the stomach and upper small intestine, while the enzyme-sensitive material functions in the unique microbial enzyme environment of the colon, achieving more precise colon-targeted release and realizing a more stable, reliable drug release mode with smaller individual release variability.

[0029] In this invention, the enzyme-sensitive component can be coated as a separate layer onto the mesalazine drug carrier matrix to form a layered structure, or it can be directly mixed with the drug to form a core matrix, creating an invaginated structure. For the layered structure, after the pH-sensitive outer layer dissolves in the small intestine, the inner enzyme-sensitive layer is fully exposed. The colonic enzymes act on this exposed enzyme-sensitive layer relatively uniformly from the outside in. The drug core only begins to disintegrate and release when the enzyme-sensitive layer is degraded to a certain extent. The advantage of this method is stronger release "gating," higher colonic targeting, and extremely low leakage of the drug before the colon. For the invaginated structure, after the pH-sensitive outer layer dissolves, the enzyme-sensitive material and the drug in the drug matrix are simultaneously exposed. The colonic enzymes degrade the enzyme-sensitive material from all accessible surfaces of the matrix. This degradation breaks the integrity of the matrix, allowing for rapid drug release. This method typically results in a faster release rate than the layered structure, enabling a more thorough "burst" release. Furthermore, because an additional coating step is eliminated, the preparation process is relatively simpler.

[0030] The present invention also provides a method for preparing the aforementioned delivery system, the preferred method comprising: mixing mesalazine and a matrix material, and obtaining a mesalazine drug carrier matrix by tableting or granulation; dissolving an enzyme-sensitive material in water to obtain an enzyme-sensitive coating solution, and coating the mesalazine drug carrier matrix to obtain enzyme-sensitive coated particles; dissolving a pH-sensitive polymer in an organic solvent to obtain a pH-sensitive coating solution, and coating the enzyme-sensitive coated particles to obtain a mesalazine colon-targeted drug delivery system; Alternatively, the preparation method preferably includes: mixing mesalazine, a matrix material, and an enzyme-sensitive material; obtaining a mixture of the enzyme-sensitive component and the mesalazine drug carrier matrix using a tableting or granulation method; dissolving a pH-sensitive polymer in an organic solvent to obtain a pH-sensitive coating solution; coating the mixture of the enzyme-sensitive component and the mesalazine drug carrier matrix to obtain a mesalazine colon-targeted drug delivery system.

[0031] In this invention, when the mesalazine and the skeleton material are mixed, or when the mesalazine, the skeleton material and the enzyme-sensitive material are mixed, the mixing method is not particularly limited and can be conventionally selected according to actual needs. In some embodiments, a high-efficiency mixing granulator is used for mixing.

[0032] In this invention, the tableting method and granulation method are not particularly limited and can be conventionally selected according to actual needs. In some embodiments, spray granulation is used for granulation.

[0033] In this invention, after granulation by tableting or granulation, drying is preferably performed. In some embodiments, drying is preferably carried out in a fluidized bed dryer at 60°C until the moisture content is <2%. In other embodiments, drying is preferably carried out in an oven at 60°C until the moisture content is <2%. The dried granules are preferably sieved for granulation, and the mesh size of the sieve is preferably 14 to 18 mesh, for example, 14, 16, or 18 mesh.

[0034] In this invention, excipients are preferably added during the preparation of the mesalazine drug carrier matrix. The amount, method, and timing of the addition of the excipients can be conventionally selected according to actual needs.

[0035] In this invention, the preferred mass-volume percentage of the enzyme-sensitive material in the enzyme-sensitive coating solution is 5% to 15% (w / v, g / mL), for example, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15%. During the preparation of the mesalazine drug carrier matrix, excipients are preferably added. The amount, method, and timing of addition of the excipients can be conventionally selected according to actual needs.

[0036] In some embodiments of this invention, a fluidized bed coating machine is preferably used to spray-coat the mesalazine drug carrier matrix. The inlet air temperature for the spray coating is preferably 60-70°C, for example, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70°C, and the spray rate is preferably 5-12 mL / min, for example, 5, 6, 7, 7.5, 8, 9, 10, 11, or 12 mL / min.

[0037] In this invention, the coating weight gain after coating of the enzyme-sensitive coating solution is preferably 5% to 9%, for example 5%, 6%, 7%, 8% or 9%.

[0038] In this invention, the organic solvent preferably includes an ethanol solution or an acetone-isopropanol mixed solution; in the ethanol solution, the volume ratio of ethanol to water is preferably (7~9.5):1, for example 7:1, 7.5:1, 8:1, 8.5:1, 9:1 or 9.5:1; in the acetone-isopropanol mixed solution, the volume ratio of acetone to isopropanol is preferably 1:(0.5~1.5), for example 1:0.5, 1:1 or 1:1.5.

[0039] In this invention, the mass-volume percentage of pH-sensitive polymer in the pH-sensitive coating solution is preferably 5% to 15% (w / v, g / mL), for example 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% or 15%.

[0040] In some embodiments of this invention, a fluidized bed coating machine is preferably used for spray coating of enzyme-sensitive particles. The inlet air temperature for the spray coating is preferably 40-55°C, for example, 40, 42, 45, 48, 50, 52, or 55°C, and the spray rate is preferably 6-15 mL / min, for example, 6, 7, 7.5, 8, 9, 10, 11, 12, 12.5, 13, 14, or 15 mL / min.

[0041] In this invention, the coating weight gain after coating with the pH-sensitive coating solution is preferably 8% to 12%, for example, 8%, 9%, 10%, 11% or 12%.

[0042] Mesalazine exhibits low solubility and strong pH dependence (almost insoluble in acidic environments, with significantly increased solubility in neutral to weakly alkaline environments), requiring rapid release at high concentrations in the colon to exert its anti-inflammatory effect. Simply relying on pH-sensitive coatings cannot completely solve the leakage problem in the small intestine, nor can it guarantee a burst of release in the colon. Furthermore, traditional sustained-release formulations, even if they deliver the drug to the colon, may not achieve an effective local concentration due to slow release, thus affecting efficacy. This invention, by adding an enzyme-sensitive material beneath the pH-sensitive layer, achieves dual control through "pH gating + enzyme triggering." This mechanism ensures that the drug is protected by the pH-sensitive coating in the small intestine, and upon entering the colon, the pH-sensitive layer dissolves, and the inner enzyme-sensitive layer is degraded by colonic enzymes, thereby achieving rapid and concentrated drug release and overcoming the insufficient targeting problem of single-layer coatings. Meanwhile, this invention overcomes the shortcomings of traditional colon-targeted formulations, which often employ complex micro-pellet coating technologies, resulting in long process flows and extremely stringent requirements for equipment and operating parameters. It utilizes more universal and simpler granulation or tableting technologies as the core drug carrier, avoiding the micro-pellet core. This method not only greatly simplifies the preparation process and lowers the production technology threshold but also significantly improves batch-to-batch consistency and product stability, making it easier to achieve large-scale industrial production. Furthermore, traditional enzyme-sensitive coatings typically require alkalization to promote the precipitation and film formation of enzyme-sensitive materials, maintain their solubility, and prevent premature dissolution in acidic environments. In contrast, this invention employs a two-layer coating structure: an enzyme-sensitive inner layer and a pH-sensitive outer layer. The enzyme-sensitive component is completely encapsulated within the pH-sensitive coating. This unique two-layer structure provides ample protection for the enzyme-sensitive inner layer. Throughout the coating preparation process and in the gastric environment after oral administration, the enzyme-sensitive layer is not directly exposed to acidic or alkaline environments, avoiding complex process steps and achieving more efficient and precise colon-targeted release.

[0043] The present invention also provides the application of the transport system described herein or the transport system prepared by the preparation method in the preparation of a mesalazine colon-targeted drug.

[0044] In this invention, the dosage form of the drug preferably includes solid dosage forms; the solid dosage forms preferably include tablets, granules, or capsules.

[0045] The present invention also provides a mesalazine colon-targeted drug delivery capsule, wherein the delivery system or the delivery system prepared by the preparation method is filled into a capsule to obtain the capsule.

[0046] In this invention, the capsules are preferably No. 0 hard capsules; each capsule preferably contains 250-500mg of mesalazine, for example 250, 300, 350, 400, 450 or 500mg.

[0047] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0048] Unless otherwise specified, the following embodiments are all conventional methods.

[0049] Unless otherwise specified, all materials and reagents used in the following examples are commercially available.

[0050] All the following experiments were conducted in a GMP-compliant laboratory environment, and all instruments and equipment used were calibrated.

[0051] Example 1: Mesalazine pH / enzyme dual-sensitive sustained-release capsules (layered structure) 1. Preparation of the mesalazine drug carrier matrix: Ingredients: 250g mesalazine, 150g lactose, 80g microcrystalline cellulose, 10g povidone K30, 5g croscarmellose sodium; Lactose and microcrystalline cellulose, acting as fillers and diluents, provide appropriate volume and good compressibility, forming a homogeneous powder mixture. Microcrystalline cellulose also serves as a skeletal material, dry binder, and disintegrant; its fibrous structure provides physical structural support and facilitates particle formation and subsequent disintegration in the colon. Povidone K30, acting as a binder in wet granulation, forms polymer chains in an ethanol solution, linking mesalazine and filler particles through intermolecular forces (such as hydrogen bonds) to form dense particles, improving particle flowability and compressibility, and ensuring uniformity of subsequent coating. Crosslinked sodium carboxymethyl cellulose, acting as a superdisintegrant, promotes rapid disintegration of the drug core particles after pH-sensitive coating dissolution through rapid water absorption and swelling, accelerating mesalazine release and ensuring explosive release in the colon.

[0052] Preparation method: Mesalazine, lactose, and microcrystalline cellulose were placed in a high-efficiency mixing granulator (e.g., Glatt GPCG120) and mixed evenly. A 5% w / v, g / mL solution of povidone K30 in ethanol was used as a binder for spray granulation. The wet granules were dried at 60°C in a fluidized bed dryer (e.g., Glatt WSG 30) until the moisture content was <2%. The dried granules were sized by passing them through a 16-mesh sieve (standard sieve, mesh size 1.18 mm). Cross-linked sodium carboxymethyl cellulose was added, and the mixture was mixed for 10 minutes in a V-type mixer (e.g., Dukang Pharma V-Blender) to obtain the mesalazine drug carrier matrix.

[0053] 2. Coating of enzyme-sensitive components: Ingredients: 495g mesalazine drug carrier matrix, 30g dextran, 15g hydroxypropyl methylcellulose E5, 5g talc.

[0054] Among them, dextran, as the main enzyme-sensitive material, has unique α-1,6-glycosidic bonds that are not easily hydrolyzed in the upper part of the human small intestine, but are easily degraded by bacterial enzymes (such as dextranase) in the colon, thus achieving a specific "delayed-triggered" effect on mesalazine release. Hydroxypropyl methylcellulose E5, as a film-forming agent and sustained-release matrix material, has good water solubility and can form a dense coating film with dextran, providing the film's strength and toughness, and playing a certain role in controlling the degradation of dextran, delaying the swelling and excessively rapid disintegration of the enzyme-sensitive layer in a non-colonic environment, ensuring minimal drug release before the colon. Talc, as a flow aid and anti-blocking agent, improves the spray performance of the coating solution and the anti-blocking properties between particles.

[0055] Preparation method: Dextran and hydroxypropyl methylcellulose E5 were dissolved in an appropriate amount of pure water (approximately 10% w / v) and stirred until completely dissolved. Talc was added and stirred to disperse evenly, thus obtaining an enzyme-sensitive coating solution. The mesalazine drug carrier matrix was spray-coated using a fluidized bed coating machine (such as a GlattGPCG 120 equipped with a bottom spray gun). The inlet air temperature was 68℃, the spray rate was 7.5 mL / min, and the coating weight gain was controlled to approximately 5%-7% (monitored by weighing) to obtain enzyme-sensitive coated particles.

[0056] 3. Preparation of pH-sensitive coating: Ingredients: 545g enzyme-sensitive coated granules, 60g Eudragit S100, 6g diethyl phthalate, 3g talc.

[0057] Eudragit S100, as the primary pH-sensitive polymer, contains a large number of carboxyl groups in its molecular structure. It is highly non-ionized in the acidic environment of the stomach (pH < 7.0), making it almost insoluble below pH 7.0, thus perfectly protecting the inner layer structure and mesalazine as it passes through the stomach and most of the small intestine. Only when the ambient pH rises above 7.0 (simulating the environment of the terminal small intestine and colon) do the carboxyl groups begin to ionize, causing the polymer to dissolve and exposing the enzyme-sensitive inner layer. Diethyl phthalate, as a plasticizer, increases the flexibility of the coating film by reducing the intermolecular forces between polymer chains, preventing the coating from cracking during gastrointestinal peristalsis and drying, and ensuring the integrity and stability of the coating layer. Talc, as an anti-blocking agent, reduces particle adhesion during the coating process, ensuring uniform coating.

[0058] Preparation method: Eudragit S100 was dissolved in an appropriate amount of ethanol-water mixture (9:1 v / v) (approximately 15% w / v) and stirred until completely dissolved. Diethyl phthalate and talc were added and dispersed evenly to obtain a pH-sensitive coating solution. The enzyme-sensitive coated particles were spray-coated using a fluidized bed coating machine (such as Glatt GPCG 120) at an inlet air temperature of 48℃ and a spray rate of 10 mL / min. The coating weight gain was controlled to approximately 10%-12% (monitored by weighing) to obtain a mesalazine colon-targeted drug delivery system.

[0059] 4. Capsule filling: Using a semi-automatic or fully automatic capsule filling machine (such as Bosch GKF 700), the coated mesalazine colon-targeted drug delivery system is filled into No. 0 hard capsules, each containing 250mg of mesalazine.

[0060] Example 2: Mesalazine pH-sensitive coated tablets / capsules (containing an enzyme-sensitive invaginated matrix structure) 1. Preparation of mesalazine matrix tablets: Ingredients: 500g mesalazine, 100g starch, 150g microcrystalline cellulose, 20g povidone K30, 5g magnesium stearate.

[0061] In this formulation, starch acts as an enzyme-sensitive component, being degraded by bacterial enzymes (such as amylase) in the colon, thereby promoting tablet disintegration and mesalazine release. Microcrystalline cellulose serves as a matrix material, filler, diluent, and disintegrant, providing tablet volume and hardness, and assisting in starch disintegration under specific conditions, while also exhibiting good compressibility. Povidone K30 acts as a binder, ensuring powder cohesion and tablet formability, and improving tablet hardness. Magnesium stearate acts as a lubricant, forming a thin film on the particle surface through adsorption, reducing friction between the particles and the mold, preventing powder adhesion to the die during compression, and ensuring a smooth tablet surface and easy demolding.

[0062] Preparation method: Mesalazine, starch, and microcrystalline cellulose are mixed evenly and granulated with an aqueous solution of povidone K30 (5% w / v). The wet granules are dried in an oven at 60℃ until the moisture content is <2%. The dried granules are then sized by passing them through a 16-mesh sieve (standard sieve, mesh size 1.18 mm). Magnesium stearate is added, mixed evenly, and compressed into mesalazine matrix tablets, with a tablet weight of approximately 775 mg.

[0063] 2. Preparation of pH-sensitive outer coating: Ingredients: 775g of mesalazine skeleton slices, 70g of Eudragit L100-55, 7g of triethyl citrate, and 3g of talc.

[0064] Eudragit L100-55, a pH-sensitive polymer, begins to dissolve above pH 5.5, ensuring the tablets remain intact in the stomach and pass through the upper small intestine, gradually exposing the starch-containing backbone. Triethyl citrate, as a plasticizer, increases the toughness and elasticity of the coating film, preventing cracking during transportation and storage. Talc, as a flow aid and anti-sticking agent, prevents tablets from sticking together during the coating process.

[0065] Preparation method: Eudragit L100-55 was dissolved in an appropriate amount of ethanol-water mixture (9:1 v / v) (approximately 10% w / v, g / mL), and triethyl citrate and talc were added and dispersed evenly. The mesalazine matrix tablets were spray-coated using a high-efficiency coating machine to form a pH-sensitive outer layer. The inlet air temperature was 52℃, the spray rate was 12.5 mL / min, and the coating weight gain was controlled to approximately 8%-10% (monitored by weighing), thus obtaining a mesalazine colon-targeted drug delivery system.

[0066] 3. Filling capsules: The coated mesalazine colon-targeted drug delivery system is filled into No. 0 hard capsules, each containing 500mg of mesalazine.

[0067] Example 3: Mesalazine double-coated capsules (outer layer pH sensitive, inner layer enzyme sensitive) 1. Preparation of the mesalazine drug carrier matrix: Ingredients: 250g mesalazine, 150g lactose, 10g crospovidone, 10g hydroxypropyl methylcellulose K4M.

[0068] Lactose is used as a filler. Cross-linked povidone, as a superdisintegrant, possesses a highly cross-linked structure that gives it a strong water absorption and swelling capacity. It swells rapidly in aqueous media, causing the particles to disintegrate quickly and thus accelerating drug release. Hydroxypropyl methylcellulose (K4M), as a hydrophilic backbone material, provides a certain viscosity and sustained-release effect. It also serves as an auxiliary binder in dry granulation, increasing particle strength.

[0069] Preparation method: Mesalazine, lactose, crospovidone, and hydroxypropyl methylcellulose K4M were mixed evenly, and then granulated by dry granulation to obtain the mesalazine drug carrier skeleton.

[0070] 2. Coating of enzyme-sensitive components: Ingredients: 420g mesalazine drug carrier matrix, 40g pectin, 10g sodium alginate, 5g polyethylene glycol 6000.

[0071] Pectin and sodium alginate are the main enzyme-sensitive materials. Both are polysaccharides that are specifically degraded in the colon by pectinase and alginate lyase produced by bacteria (such as Bacteroides). The synergistic effect of pectin and sodium alginate provides more stable enzyme-sensitive properties and a more controllable degradation rate, ensuring precise release in the colon. Polyethylene glycol 6000, as a hydrophilic plasticizer and cosolvent, increases the flexibility and permeability of the coating film, while also aiding in the dissolution and dispersion of pectin and sodium alginate in water, improving the uniformity of the coating solution.

[0072] Preparation method: Dissolve pectin and sodium alginate in an appropriate amount of water (approximately 10% w / v), and add polyethylene glycol 6000. Use a fluidized bed coating machine to spray-coat the mesalazine drug carrier matrix to form an enzyme-sensitive inner layer. The inlet air temperature is 62℃, the spray rate is 10 mL / min, and the coating weight gain is controlled to approximately 7%-9%, yielding enzyme-sensitive coated particles.

[0073] 3. Preparation of pH-sensitive coating: Ingredients: 475g enzyme-sensitive coated granules, 50g cellulose acetate phthalate (CAP), 5g diethyl phthalate, 2g polysorbate 80.

[0074] Cellulose acetate (CAP), a pH-sensitive polymer, only begins to dissolve above pH 6.0, ensuring the formulation remains intact in the stomach and begins to dissolve in the mid-small intestine, exposing the inner layer. Diethyl phthalate, as a plasticizer, improves the mechanical strength and elasticity of the coating film, preventing cracking. Polysorbate 80, as an emulsifier and wetting agent, aids in the dispersion and film formation of CAP in organic solvents, while also improving the surface tension of the coating solution, resulting in a smoother and more uniform coating film.

[0075] Preparation method: CAP was dissolved in an appropriate amount of acetone-isopropanol mixture (1:1 v / v) (approximately 10% w / v), and diethyl phthalate and polysorbate 80 were added to prepare a pH-sensitive coating solution. The enzyme-sensitive coated particles were spray-coated using a fluidized bed coating machine to form a pH-sensitive outer layer. The inlet air temperature was 42℃, the spray rate was 7.5 mL / min, and the coating weight gain was controlled to approximately 10%-12%, thus obtaining a mesalazine colon-targeted drug delivery system.

[0076] 4. Filling capsules: The coated mesalazine colon-targeted drug delivery system is filled into No. 0 hard capsules, each containing 250mg of mesalazine.

[0077] Comparative Example 1: Single pH-sensitive coated mesalazine sustained-release capsules (lacking enzyme-sensitive layer) The mesalazine drug carrier backbone is directly coated with pH-sensitive material without containing enzyme-sensitive components.

[0078] 1. The mesalazine drug carrier skeleton was prepared according to the method in Example 1.

[0079] 2. Preparation of pH-sensitive coating: Ingredients: 495g of Mesalazine core granules, 90g of Eudragit S100, 9g of diethyl phthalate, and 5g of talc.

[0080] Preparation method: Eudragit S100 was dissolved in an appropriate amount of ethanol-water mixture (9:1 v / v) (approximately 15% w / v) and stirred until completely dissolved. Diethyl phthalate and talc were added and dispersed evenly to obtain a pH-sensitive coating solution. The mesalazine drug carrier matrix was spray-coated using a fluidized bed coating machine, controlling the coating weight gain to approximately 18%-20%, thus obtaining a mesalazine colon-targeted drug delivery system.

[0081] 3. Filling capsules: The coated mesalazine colon-targeted drug delivery system is filled into No. 0 hard capsules, each containing 250mg of mesalazine.

[0082] Comparative Example 2: Mesalazine sustained-release capsules (hydrophilic matrix tablets) The mesalazine matrix tablets prepared according to Example 2 are prepared without any external coating, and are thus ordinary sustained-release tablets.

[0083] 1. Preparation of mesalazine matrix tablets: Ingredients: 500g mesalazine, 200g hydroxypropyl methylcellulose K100M, 70g lactose, 5g magnesium stearate.

[0084] Preparation method: Mesalazine, hydroxypropyl methylcellulose K100M, and lactose are mixed evenly and granulated using a wet granulation method. The wet granules are dried in an oven at 60℃ until the moisture content is <2%. The dried granules are then sized by passing them through a 16-mesh sieve (standard sieve, mesh size 1.18mm). Magnesium stearate is added, mixed evenly, and then pressed into mesalazine skeleton tablets.

[0085] 2. Filled capsules: The compressed mesalazine matrix tablets are filled into No. 00 hard capsules, each capsule containing 500mg of mesalazine.

[0086] Comparative Example 3: pH-sensitive coated capsules (insufficient amount of enzyme-sensitive component) The preparation method is the same as in Example 1, but the amount of enzyme-sensitive material dextran is significantly reduced.

[0087] 1. The mesalazine drug carrier skeleton was prepared according to the method in Example 1.

[0088] 2. Coating of enzyme-sensitive components: Ingredients: 495g core granules, 5g dextran (Pharmacosmos, Dextran T40), 15g hydroxypropyl methylcellulose E5 (Dow Chemical, Methocel™ E5 Premium LV), 5g talc (Luzenac, Micronized Talc200).

[0089] The preparation method is the same as in Example 1, with the coating weight gain controlled at approximately 1%-2%.

[0090] 3. The preparation of pH-sensitive coating is the same as in Example 1, with the coating weight gain controlled at approximately 10%-12%.

[0091] 4. The filling capsule is the same as in Example 1.

[0092] Comparative Example 4: pH-sensitive coated capsules (insufficient weight gain from pH-sensitive coating) The preparation method is the same as in Example 1, but the weight gain of the pH-sensitive coating is significantly reduced.

[0093] 1. The mesalazine drug carrier skeleton was prepared according to the method in Example 1.

[0094] 2. The coating of the enzyme-sensitive component is the same as in Example 1, with the coating weight gain controlled at approximately 5%-7%.

[0095] 3. Preparation of pH-sensitive coating: Ingredients: 545g enzyme-sensitive coated granules, 20g Eudragit S100 (Evonik Industries), 2g diethyl phthalate (Fisher Scientific), 1g talc (Luzenac, Micronized Talc 200).

[0096] The preparation method is the same as in Example 1, with the coating weight gain controlled at approximately 3%-4%.

[0097] 4. The filling capsule is the same as in Example 1.

[0098] Comparative Example 5: Mesalazine pH / enzyme / pH triple-sensitive sustained-release formulation (pH-sensitive inner layer, enzyme-sensitive middle layer, pH-sensitive outer layer) 1. The mesalazine drug carrier skeleton was prepared according to the method in Example 1.

[0099] 2. First layer pH-sensitive coating: Ingredients: 495g mesalazine drug carrier matrix, 28g Eudragit L100, 2.8g plasticizer (diethyl phthalate), and 1.4g talc. The plasticizer increases the flexibility of the coating film and prevents brittleness; the talc acts as an anti-sticking agent to prevent particles from sticking together during the coating process.

[0100] Preparation method: In a fluidized bed coating machine, the mesalazine drug carrier skeleton was spray-coated with the prepared first-layer pH-sensitive coating solution. The inlet air temperature was 52℃, the spray rate was 12.5mL / min, and the coating weight gain was controlled to be about 6%.

[0101] 3. Second enzyme-sensitive coating (chitosan layer): Raw materials: 524.7g of granules coated with the first layer, 30g of chitosan, 1.5g of glacial acetic acid, and appropriate amounts of ethanol and pure water as solvents. Glacial acetic acid is used to dissolve the chitosan to form the coating solution.

[0102] Preparation method: In a fluidized bed coating machine, the particles coated with the first layer are spray-coated with the prepared second layer enzyme-sensitive coating solution. The inlet air temperature is 68℃, the spray rate is 7.5mL / min, and the coating weight gain is controlled to be about 6%.

[0103] 4. Third layer pH-sensitive coating: Raw materials: 556.2g of granules with a second layer, 32g of Eudragit L100, 3.2g of plasticizer (diethyl phthalate), and 1.6g of talc; plasticizer and talc are used again to ensure the integrity and smoothness of the final coating film.

[0104] Preparation method: In a fluidized bed coating machine, the particles coated with the second layer are spray-coated with a prepared third-layer pH-sensitive coating solution. The inlet air temperature is 62℃, the spray rate is 10mL / min, and the coating weight gain is controlled to be about 6%. The finally coated particles are then thoroughly dried.

[0105] 5. Filling the capsule: Fill the capsule using the same method as in Example 1.

[0106] Test Example 1: In vitro dissolution test Dissolution was determined using a paddle dissolution apparatus, referring to the dissolution determination method in the Chinese Pharmacopoeia, for the capsules of Examples 1, 2, Comparative Examples 1, 2, 3, and 4.

[0107] To simulate the pH changes of drugs in the human gastrointestinal tract, a three-stage continuous dissolution process was set up in the experiment. The dissolution medium, rotation speed, and duration of each stage are as follows: Phase 1 (simulating the gastric environment): using artificial gastric fluid (pH 1.2) as the dissolution medium, rotating at 120 rpm for 2 hours.

[0108] Phase 2 (simulating the small intestinal environment): using artificial small intestinal fluid (pH 6.8) as the dissolution medium, rotating at 120 rpm for 3 hours.

[0109] Phase 3 (simulating the colonic environment): using artificial colonic fluid (pH 7.4, containing porcine cecal enzymes) as the dissolution medium, the rotation speed was 120 rpm, and the time was 7 hours.

[0110] The results are shown in Table 1.

[0111] Table 1 Dissolution data (cumulative release percentage):

[0112] As shown in Table 1, when artificial gastric fluid (pH 1.2) was used as the dissolution medium (0-2h), Examples 1, 2, and Comparative Examples 1 and 3, all containing pH-sensitive coatings, exhibited extremely low drug release (<2%) in gastric fluid. This indicates that the pH-sensitive coating effectively protected mesalazine from gastric acid degradation and premature release. Comparative Example 4, due to insufficient weight gain from the pH-sensitive coating, showed a significantly higher release in gastric fluid than Example 1. This suggests that insufficient pH-sensitive coating leads to premature drug release in the stomach, significantly affecting its protective effect. Comparative Example 2, a conventional sustained-release capsule, released a large amount of drug in gastric fluid. This indicates that conventional sustained-release formulations cannot effectively protect the drug's stability in the stomach, leading to significant drug loss before reaching the target site and increased systemic absorption.

[0113] When artificial intestinal fluid (pH 6.8) was used as the dissolution medium (2-5 h), the drug release in Example 1 remained low. This indicates that although the pH-sensitive coating began to dissolve or swell in the upper small intestine, the enzyme-sensitive inner layer effectively inhibited the rapid release of the drug, ensuring that most of the drug could pass through the small intestine. The cumulative release in Example 2 was slightly higher than that in Example 1. In the layered structure of Example 1, the enzyme-sensitive inner layer, acting as an independent physical barrier, effectively hindered drug release even after the pH-sensitive outer layer dissolved. The drug needed to wait for the enzyme-sensitive layer to hydrate, swell, or even partially degrade before it could begin to be released, thus resulting in less leakage in the small intestine. In the invaginated structure of Example 2, the enzyme-sensitive material (starch) was directly mixed with mesalazine in the matrix. When the pH-sensitive outer layer dissolved, the drug and enzyme-sensitive material in the matrix were simultaneously exposed to the medium. Although starch itself is not easily degraded in the small intestine, the hydration and swelling process of the matrix may cause some mesalazine to be released prematurely, thus resulting in slightly higher leakage in the small intestine. Comparative Example 1 showed a significantly higher drug release than Example 1, indicating that while the single pH-sensitive coating provides protection in the stomach, its dissolution rate in the small intestine may be too rapid, leading to some drug absorption before reaching the colon. Comparative Example 2 showed a sustained, slow release in the small intestinal fluid, with over 75% released by 5 hours, further confirming its non-colon-targeting nature. Comparative Example 3, due to insufficient enzyme-sensitive component, showed a slightly higher release in the small intestinal fluid than Example 1, possibly because the thinner enzyme-sensitive layer reduced its inhibitory effect on drug release. Comparative Example 4 showed a sustained, large release in the small intestinal fluid, with over 70% released by 5 hours, further validating the shortcomings of insufficient pH-sensitive coating.

[0114] When using artificial colonic fluid (pH 7.4, containing porcine cecal enzymes) as the dissolution medium (5-10 h), the drug release rate in Example 1 increased significantly in a short period, rising rapidly from 18.7% at 5.5 h to 45.2% at 6.0 h, and reaching a cumulative release rate of 90.5% at 8 h. This fully demonstrates the synergistic effect of the pH-sensitive coating and enzyme-sensitive inner layer used in this invention, enabling rapid and concentrated drug release under the action of colon-specific enzymes, achieving excellent colon-targeting. Example 2 also exhibited a significant burst release, with the drug release rate increasing rapidly in a short period, ultimately reaching a cumulative release rate of 97.2%. The release rate of Example 1 after entering the colonic fluid was slightly faster than that of Example 2. In the initial stage after entering the colonic fluid (within 0.5 hours), the release rate of Example 1 was slightly faster than that of the invading structure Example 2, because its enzyme-sensitive layer was more directly and fully exposed after the pH-sensitive coating dissolved. Nevertheless, in the long term (after 8 hours), the final cumulative release rates of the two structures were similar, both achieving excellent colon-targeting release effects. Although increased drug release was observed in the colonic fluid of Comparative Example 1, its release rate and cumulative release amount were significantly lower than those of Example 1. At 10 hours, the cumulative release amount was only 70.3%, indicating that the lack of an enzyme-sensitive component and the inability of a single pH-sensitive coating to provide sufficiently rapid and complete drug release in the colon suggests that the drug in Comparative Example 2 still exhibited slow release in the colonic fluid, but given its already substantial release in the stomach and small intestine, its colonic release was largely insignificant, and the release curve was flat, lacking targeting. The release amount in the colonic fluid of Comparative Example 3 was still significantly lower than that of Example 1. Although enzyme-sensitive material was present, insufficient dosage led to reduced enzyme degradation efficiency, failing to achieve the desired explosive release effect. This highlights the importance of the dosage of enzyme-sensitive material in achieving precise explosive release. Although Comparative Example 4 showed a higher release amount in the colonic fluid, its colonic release was largely insignificant due to its already substantial release in the stomach and small intestine, and the release curve was flat, lacking targeting.

[0115] Test Example 2: In vitro dissolution test Using the same method as in Experiment 1, the in vitro dissolution rates of Example 1, Comparative Example 1, Comparative Example 2, and Comparative Example 5 were determined, and the cumulative release percentage (%) at each stage was measured. The results are shown in Table 2.

[0116] Table 2 Dissolution data (cumulative release percentage, average, n=18):

[0117] As shown in Table 2, in the gastric juice (pH 1.2) stage, all samples with pH-sensitive coatings exhibited extremely low drug release (<2%), indicating that they effectively protected mesalazine. This verifies the key role of pH-sensitive materials as the "first gate".

[0118] In the small intestinal fluid stage (pH 6.8), Example 1 showed the lowest drug release (14.3%), indicating that the "pH-sensitive outer layer + enzyme-sensitive inner layer" structure can effectively utilize the gel barrier effect of the inner dextran layer to further delay drug leakage. In contrast, Comparative Example 5 showed a higher release (35.1%), which may be because its three-layer structure, at pH 6.8, allowed some drug to leak through the middle chitosan layer after the first coating dissolved.

[0119] In the colonic fluid (pH 7.4 + enzyme) stage, Example 1 exhibited the highest release rate and total amount, achieving a burst release of mesalazine. This demonstrates that the two-layer coating structure of this invention can achieve more precise and efficient triggered release under the action of colonic enzymes. The release amount of Comparative Example 5 was significantly lower than that of the Sample 1, indicating that its complex three-layer coating structure may have hindered the rapid degradation of the chitosan layer in the colon, leading to incomplete release.

[0120] Experimental Example 3: Simulated Intestinal Transport Experiment (In Vitro) To further verify the colon-targeting properties of the present invention, simulated intestinal transport experiments were conducted using capsules from Example 1 and Comparative Examples 1-4, respectively. By setting different transport time points, the residence time of the drug in the stomach, small intestine and colon was simulated, and the drug release amount at each stage was measured.

[0121] 1. Device: Dynamic simulation of the gastrointestinal system (such as TIM-1 or similar device).

[0122] 2. Simulation conditions: (1) Stomach: pH 1.2, stay for 2 hours.

[0123] (2) Small intestine: pH gradient change from 6.0 to 7.0, stay for 3 hours.

[0124] (3) Colon: pH 7.0-7.5, add fresh fecal homogenate (as a source of colonic enzymes), and let stand for 6 hours.

[0125] 3. Measurement: Samples were taken at the end of each stage to measure the cumulative drug release. The results are shown in Table 3.

[0126] Table 3. Data from simulated intestinal transport experiments (cumulative release percentage):

[0127] As can be seen, in the gastric stage, the release amounts of Example 1, Comparative Examples 1 and 3 were extremely low, further confirming the effective blocking effect of pH-sensitive coating on gastric acid and successfully preventing non-targeted drug release in the stomach. Comparative Example 4 showed significant release due to insufficient coating. Comparative Example 2 showed significant drug release, proving that it could not effectively protect the drug in the stomach.

[0128] In the small intestine stage, Example 1 showed the lowest release level, indicating that its enzyme-sensitive inner layer effectively inhibited premature drug release in the upper small intestine. Comparative Example 1 showed a significantly higher release level in the small intestine, further confirming the potential for excessively rapid release in the small intestine due to its single pH-sensitive coating. Comparative Example 3 experienced a slight increase in premature drug release in the small intestine due to insufficient enzyme-sensitive layer application. Comparative Examples 4 and 2 released most of the drug in this stage.

[0129] In the colonic stage, Example 1 exhibited explosive release, with a cumulative release rate of 95.8%, indicating that the vast majority of the drug was released at the target site in the colon. While Comparative Example 1 also showed release in the colonic stage, the total release was significantly lower than that of Example 1, and the release was insufficient, indicating that its colonic-targeted release efficiency was inferior to that of Example 1. Comparative Example 3 also failed to reach the release level of Example 1 in the colonic stage, further emphasizing the importance of the amount of enzyme-sensitive material for explosive release. Although Comparative Examples 4 and 2 showed high release rates in the colonic stage, considering the large amount of release in the early stages, their actual effective drug concentration in the colon was already very low.

[0130] The comparative experimental data above clearly demonstrate that the colon-targeted drug delivery system proposed in this invention, consisting of a pH-sensitive coating and an enzyme-sensitive material, exhibits significant advantages in both in vitro dissolution and simulated intestinal transport. It effectively protects mesalazine in the stomach and upper small intestine, minimizing premature drug release and absorption, thereby significantly improving the bioavailability of mesalazine. Under the action of bacterial enzymes unique to the colon, mesalazine can be released rapidly and in a concentrated manner, ensuring that mesalazine reaches a high local drug concentration at the site of colonic lesions and enhancing the therapeutic effect; Compared to single pH-sensitive coatings or conventional sustained-release formulations, the design of this invention enables more precise drug delivery to the colon, improving drug targeting and efficacy while reducing systemic adverse reactions.

[0131] These data strongly support the innovation, effectiveness, and practicality of this invention, further highlighting its advantages in the field of mesalazine colon-targeted formulations. This invention differs significantly from existing technologies in terms of its active ingredient (single chemical drug mesalazine), release mechanism (precise triggering by both pH and enzymes), excipient selection and mechanism of action, and preparation process.

[0132] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A mesalazine colon-targeted drug delivery system, characterized in that, The delivery system includes a mesalazine drug carrier backbone, an enzyme-sensitive component, and a pH-sensitive coating; the enzyme-sensitive component is coated on the outer layer of the mesalazine drug carrier backbone or mixed with the mesalazine drug carrier backbone; the pH-sensitive coating is coated on the outer layer of the enzyme-sensitive component or on the outer layer of the mixture of the enzyme-sensitive component and the mesalazine drug carrier backbone.

2. The transfer system according to claim 1, characterized in that, The mesalazine drug carrier matrix includes mesalazine and a matrix material; the matrix material includes any one or more of microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, and polyethylene glycol.

3. The transfer system according to claim 1, characterized in that, The enzyme-sensitive component includes enzyme-sensitive materials; the enzyme-sensitive materials include any one or more of starch, pectin, dextran, inulin, guar gum, sodium alginate, and xylan.

4. The transfer system according to claim 1, characterized in that, The pH-sensitive coating comprises a pH-sensitive polymer; the pH-sensitive polymer comprises any one or more of acrylic resins, hydroxypropyl methyl cellulose phthalate, and cellulose acetate.

5. A method for preparing the transport system according to any one of claims 1 to 4, characterized in that, The preparation method includes: mixing mesalazine and a matrix material, and obtaining a mesalazine drug carrier matrix by tableting or granulation; dissolving an enzyme-sensitive material in water to obtain an enzyme-sensitive coating solution, and coating the mesalazine drug carrier matrix to obtain enzyme-sensitive coated particles; dissolving a pH-sensitive polymer in an organic solvent to obtain a pH-sensitive coating solution, and coating the enzyme-sensitive coated particles to obtain a mesalazine colon-targeted drug delivery system. Alternatively, the preparation method includes: mixing mesalazine, a matrix material, and an enzyme-sensitive material; obtaining a mixture of the enzyme-sensitive component and the mesalazine drug carrier matrix using a tableting or granulation method; dissolving a pH-sensitive polymer in an organic solvent to obtain a pH-sensitive coating solution; coating the mixture of the enzyme-sensitive component and the mesalazine drug carrier matrix to obtain a mesalazine colon-targeted drug delivery system.

6. The preparation method according to claim 5, characterized in that, The weight gain of the enzyme-sensitive coating solution after coating is 5% to 9%.

7. The preparation method according to claim 5, characterized in that, The pH-sensitive coating solution resulted in a coating weight gain of 8% to 12%.

8. The use of the transport system according to any one of claims 1 to 4 or the transport system prepared by the preparation method according to any one of claims 5 to 7 in the preparation of a mesalazine colon-targeted drug.

9. The application according to claim 8, characterized in that, The dosage form of the drug includes solid dosage forms; the solid dosage forms include tablets, granules, or capsules.

10. A mesalazine colon-targeted drug delivery capsule, characterized in that, The transport system according to any one of claims 1 to 4 or the transport system prepared by the preparation method according to any one of claims 5 to 7 is filled into a capsule to obtain a capsule.

Images