Capsule for delivering carrier system containing topically acting payload to intestinal tract of mammal

Abstract

The present invention relates to a capsule comprising an effervescent pair for targeted delivery of an active agent to the gastrointestinal tract.

Description

Technical Field

[0001] This invention relates to a capsule comprising effervescent pairs for targeted delivery of a carrier system for transporting a payload to the small and / or large intestine of mammals. Background Technology

[0002] In many cases, it is necessary to apply the active agent topically to the small intestine and / or large intestine. Inflammatory bowel diseases (IBD), such as Crohn's disease and ulcerative colitis, are one such case.

[0003] Even in healthy subjects without any diagnosed gastrointestinal conditions, it may be desirable to inoculate the entire inner surface of the large intestine with bacteria (probiotics) or spray it with a nutritional supplement for gut microbiota. In this case, the motivation may be to achieve a healthier gut microbiota, provide energy substrates for intestinal cells, and / or protect intestinal cells from oxidative stress.

[0004] Some oral formulations for delivering active agents consist of capsules with an enteric coating, which ensures the capsule remains intact before reaching the desired site in the gastrointestinal tract. For agents intended to exert systemic action, actual drug absorption is likely to occur within a small surface area around the site of capsule dissolution. However, for agents intended to exert local action, maximizing the exposed surface area of ​​the active agent is crucial. Furthermore, depending on the specific circumstances, it may be necessary to maintain the capsule's release kinetics independent of the carrier system used for the active agent. Summary of the Invention

[0005] This disclosure relates to a capsule for delivering a carrier system containing a locally acting payload into the mammalian intestine. This disclosure relates to a discovery that a carrier system comprising appropriate proportions of microparticles (micropellets) and an effervescent agent enables repeatable delayed release of the locally acting active ingredient, thereby providing localized treatment over an expanded surface area.

[0006] The first aspect of this disclosure relates to a composition for oral administration of an active agent, the composition comprising: a. Particles with a size of 100µm to 2000µm, said particles comprising a polymer and an active agent. b. Effervescent reagent, The w / w ratio of the microparticles to the effervescent reagent is between 7:1 and 1.5:1, and the composition is encapsulated.

[0007] A second aspect of this disclosure relates to an oral administration composition of an active agent, which is used as a medicament, the composition comprising: a. Particles with a size of 100µm to 2000µm, said particles comprising a polymer and an active agent. b. Effervescent reagent, The w / w ratio of the microparticles to the effervescent reagent is between 7:1 and 1.5:1, and the composition is encapsulated.

[0008] A third aspect of this disclosure relates to a composition for treating inflammatory bowel disease and / or inflammatory-induced colorectal tumors and / or cancer, wherein the active agent comprises or is composed of insulin or an analogue thereof.

[0009] A fourth aspect of this disclosure relates to a method for preparing the composition, the method comprising: a. Mix the polymer with an activator, and optionally with a lubricant; b. Extruding microparticles containing at least one polymer and having a size of 100 to 2000 µm and optionally rounding them; c. Mix the microparticles with the surfactant and effervescent reagent to obtain a mixture; d. Encapsulate the mixture. Thus, the composition according to this disclosure is obtained.

[0010] A fifth aspect of this disclosure relates to a method of manufacturing a composition, the method comprising: a. Suspend the polymer, surfactant, and optional lubricant in a solvent; b. Stir until the solvent evaporates, collect and wash the particles containing at least one polymer and with a size of 100 to 2000 µm; c. The microparticles are mixed with the surfactant and effervescent reagent to obtain a mixture; d. Encapsulate the mixture. Thus, the composition according to this disclosure is obtained. Attached Figure Description

[0011] Figure 1 Excipients are used in capsules to promote disintegration (gelatin capsules). i: microparticles, ii: microparticles + citric acid + bicarbonate, iii: microparticles + MgCl2. A . A. t=0. B. t=3 min standing. C. t=6 min additional standing, then 4 min of track shaking. D. t=0. i: Particles, ii: Particles + citric acid + bicarbonate, iii: Particles + MgCl2. E. The track is rocked for 1.5 minutes. F. An additional 4 minutes of track rocking is performed.

[0012] Figure 2 The application of excipients in capsules to promote disintegration (hydroxypropyl methylcellulose (HPMC) capsules). A. t=0. i: microparticles, ii: microparticles + citric acid + bicarbonate, iii: microparticles + MgCl2. B. Let it stand for 2.5 minutes. C. Perform an additional 5 minutes of track shaking.

[0013] Figure 3 Release studies of capsules (regular, exothermic, and effervescent) (gelatin capsules). Microparticles: 1% insulin, 99% microcrystalline cellulose (MCC). Capsules: Coni-Snap®, size 5. Regular: 50 mg microparticles. Effervescent (labeled in the legend as +citric acid and bicarbonate): 50 mg microparticles + 40 mg citric acid + bicarbonate. Exothermic (labeled in the legend as MgCl2): 50 mg microparticles + 40 mg MgCl2. A. Insulin release from the microspheres within 24 hours. B. Figure 3 A magnified view of a portion of A, showing insulin release in the first 6 hours.

[0014] Figure 4 Excipients are applied in capsules to promote disintegration. HPMC capsules with different amounts of effervescent powder are used. A. t=0. i: 225 mg microparticles, 45 mg effervescent powder (5:1). ii: 180 mg microparticles, 90 mg effervescent powder (2:1). iii: 135 mg microparticles, 135 mg effervescent powder (1:1). B. Stand: 1.5 min, track shaking: 3 min. C. Additional track shaking: 2 min. D. Additional track shaking: 4 min.

[0015] Figure 5 Excipients are applied in the capsules to promote disintegration. HPMC capsules with different microsphere sizes. A. Different microsphere sizes: 250-400 μm (iii), 400-710 μm (ii), 710-1000 μm (i). B. Standing: 2 min, track shaking: 1 min. C. Additional track shaking: 3 min. D. Additional track shaking: 1 min.

[0016] Figure 6 Excipients are applied in the capsules to promote disintegration. HPMC capsules with different microsphere sizes. A. Different microsphere sizes: 400-700 μm, 700-1000 μm. B. Standing: 2.5 min, track shaking: 2 min. C. Additional track shaking: 1 min.

[0017] Figure 7 Excipients were applied to the capsules to promote disintegration. HPMC capsules: coated S 100 (4) vs. uncoated (3). pH: 7.3 (PBS). A. Coated microspheres (Eudragit S 100, right) and uncoated microspheres (left). B. Orbital shaking: 8 min. C. Additional orbital shaking: 4 min.

[0018] Figure 8 Particulate release studies. A. Insulin release from particulates (MCC:mannitol (2:1) / insulin, MCC:mannitol (5:1) / insulin, and MCC / insulin (mannitol-free)) over 24 hours. B. Figure 8 A magnified view of a section. C. MCC: mannitol (5:1) / insulin microparticles at t=0 and 1.5 hours, respectively.

[0019] Figure 9 Release curves of various APIs. A. Sodium butyrate, B. Caffeine, C. Insulin, D. Infliximab. MCC: Microcrystalline cellulose.

[0020] Figure 10 A. Butyrate release curves for different microcapsule coatings, namely uncoated, 5% RL, 8% RL, and 8% RL+12% RS. B. Butyrate release from microcapsules coated with 8% RL+12% RS, these microcapsules were either encapsulated in HPMC capsules (capsule + effervescent powder) or were free microcapsules (bulk).

[0021] Figure 11 The mitigating effect of carrier properties: commercial celllets (stearate-free) vs. microcapsules (stearate-containing)

[0022] Figure 12 Microsphere coverage area. The area of ​​the circle covered after 15 minutes, with or without effervescent powder. Compare the diameter of the circle surrounding the microspheres released after 15 minutes.

[0023] Figure 13 Effect of effervescent pair dosage. Added effervescent pair: citric acid and sodium bicarbonate (molar ratio 3:1). Effervescent pair dosages: 0 mg, 20 mg, 45 mg, 90 mg. Microsphere dosage remained constant at 225 mg. Invention Details

[0025] definition

[0026] For the purposes of this invention, the following terms may be considered substantially equivalent to "sustained release": continuous release, controlled release, delayed release, depot, gradual release, long-term release, programmed release, prolonged release, proportionate release, protracted release, repository, retard, slow release, spaced release, timecoat, timed release, delayed action, extended action, layered-time action, long-acting, prolonged action, repeated action, slowing acting, sustained action, sustained-action medications, and extended release. For a further discussion of these terms, see Lesczek Krowczynski, Extended-Release Dosage Forms, 1987 (CRC Press, Inc.).

[0027] Sustained-release or controlled-release means that the therapeutic bioactive agent will not be released sporadically from the sustained-release material in an unpredictable manner, nor will it be "burst-released" from the sustained-release material upon exposure to a biological environment (also referred to herein as first-order kinetics) unless intentionally intended to be so. However, the term "sustainable-release" as used herein does not exclude "burst-release phenomena" associated with deployment. According to some exemplary embodiments of this specification, an initial burst release of at least one therapeutic bioactive agent may be required, followed by a more gradual release. The release rate may be steady-state (often referred to as "timed release" or zero-order kinetics), meaning that at least one therapeutic bioactive agent is released in a uniform amount over a predetermined time (with or without an initial burst-release phase), or it may be a gradient release. Gradient release refers to the change in the concentration of the therapeutic bioactive agent released from the sustained-release material over time.

[0028] As used herein, “enteric coating” is a material, such as one or more polymeric materials, that encapsulates a therapeutic agent into a dosage form or granules. Typically, most or all of the enteric coating material dissolves before the therapeutic agent is released from the dosage form, thereby achieving delayed dissolution of the therapeutic agent in the intestine. For a discussion of enteric coatings, see, for example, Loyd, V. Allen, Remington: The Science and Practice of Pharmacy, 21st ed., (Pharmaceutical Press, 2005); and PJ Tarcha, Polymers for Controlled Drug Delivery, Chapter 3, CRC Press, 1991. Methods of applying enteric coatings to pharmaceutical compositions are well known in the art and include, for example, U.S. Patent Publication No. 2006 / 0045822.

[0029] As used in this article, the terms "effervescent couple," "effervescent reagents," and "effervescent powder" refer to a pair of pharmaceutically acceptable excipients, one of which is basic and the other is acidic. The basic component releases carbon dioxide upon contact with the acidic component and water.

[0030] As used herein, the term "treatment" refers to the management and care of a patient in order to combat a condition, disease, or symptom. This term is intended to encompass comprehensive treatment of a given condition that a patient has or is suspected of having, such as the administration of an active compound for the purpose of: alleviating or reducing symptoms or complications; delaying the progression of the condition, disease, or symptom; curing or eliminating the condition, disease, or symptom; and / or preventing the condition, disease, or symptom. "Preventing" should be understood as the management and care of a patient to prevent, reduce, or delay the development of a condition, disease, or symptom, including the administration of an active compound to prevent or reduce the risk of symptoms or complications. Therefore, treatment can be preventative. Patients to be treated are preferably mammals, particularly humans. Patients to be treated can be of different ages.

[0031] Inflammatory bowel disease (IBD) is a group of inflammatory conditions affecting the colon and small intestine. The main types of IBD are Crohn's disease and ulcerative colitis (UC). Other types of IBD are much less common, such as collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behcet's disease, indeterminate colitis, left-sided colitis, and noninfective colitis.

[0032] For the treatment or prevention of inflammatory bowel disease (IBD) such as Crohn's disease and ulcerative colitis, the active agent can be locally acting insulin or its analogues, or a monoclonal antibody that acts locally against tumor necrosis factor α.

[0033] Inflammation-induced colorectal tumors and / or cancers are colorectal tumors and / or cancers that occur in subjects with or suspected of having IBD. Inflammation-induced colorectal tumors and / or cancers appear to have different etiologies, carcinogenic pathways, and clinical courses than their sporadic counterparts. Therefore, different treatment approaches may be necessary.

[0034] As used in this article, “unit” or “unit of insulin” or “U” or “IU” is defined as the bioequivalence of 34.7 μg of pure crystalline insulin, which is also equivalent to 6 μmol (assuming the molecular weight of insulin is considered to be 5800 Da). This corresponds to the insulin unit in the old United States Pharmacopeia, where one unit (U) of insulin was defined as the amount required to reduce the blood glucose concentration in a fasting rabbit to 45 mg / dl (2.5 mmol / L).

[0035] As used in this disclosure, "local administration" refers to delivering a composition to a specific "local" area of ​​the body of a subject in need, whereby it acts locally at the site of administration. Specifically, this disclosure relates to delivery to the intestines of mammals, such as the small intestine, large intestine, or colon. In this disclosure, the term "local administration" means administration that is not systemic but rather limited to the site of release of the active agent. It refers to administration with little or no systemic effect. An example of local administration could be the administration of insulin or an analogue thereof to the intestines, such as the large intestine. Administration of the compositions of this disclosure containing insulin as an active ingredient will ensure that insulin acts locally within the intestines without affecting systemic blood glucose levels.

[0036] The small intestine (also called the small bowel) is a specialized tubular structure located between the stomach and the large intestine, which absorbs nutrients from food. It is about 5.5 meters long and is divided into three parts: the duodenum, the jejunum, and the ileum.

[0037] The large intestine (also called the large bowel) is the last part of the gastrointestinal tract in the digestive system of vertebrates. It includes the cecum, colon, rectum, and anal canal. The large intestine is about 1.5 meters long, accounting for about one-fifth of the total length of the gastrointestinal tract. It is the main part of the digestive system responsible for absorbing water from indigestible food residue.

[0038] As used herein, the term "prebiotic" or "prebiotic nutrient" refers to an indigestible food component that, upon ingestion, exerts a beneficial effect on the host by selectively stimulating the growth and / or activity of one or a limited number of bacteria in the gastrointestinal tract. Prebiotics can be selected from fructooligosaccharides, glucose oligosaccharides, galactooligosaccharides, polydextrose, isomaltooligosaccharides, xylooligosaccharides, polydextrose, and lactulose.

[0039] As used herein, the term "probiotics" refers to microorganisms or processed compositions of microorganisms that have a beneficial effect on the host. As used herein, "probiotics" also includes bacteria, bacterial homogenates, bacterial proteins, bacterial extracts, bacterial supernatants, and mixtures thereof, which exert a beneficial effect on the host when administered in therapeutic doses. Therefore, yeasts, molds, and bacteria may be included. Non-limiting examples of probiotics used herein include strains of the genera *Bifidiobacterium*, *Lactobacillus*, and *Enterococcus*.

[0040] As used herein, the term “subject” refers to an individual of the mammalian species disclosed herein. “Patient” refers to a subject who has, is suspected of having, or has been diagnosed with a specific condition.

[0041] Composition

[0042] The compositions disclosed herein are used to deliver a carrier system with a locally acting payload into the intestine of a mammal.

[0043] In one embodiment, the carrier system of this disclosure comprises an active agent embedded in microparticles. In one embodiment, the microparticles are microspheres. In one embodiment, the microparticles are loaded into the carrier system. In one embodiment, the microparticles are loaded into the carrier system together with an effervescent reagent. In one embodiment, the carrier system is encapsulated. In one embodiment, the carrier system is contained in a capsule.

[0044] In one embodiment, the composition disclosed herein comprises: a. Particles with a size of 100µm to 2000µm, said particles comprising a polymer and an active agent. b. Effervescent reagent, The w / w ratio of the microparticles to the effervescent reagent is between 7:1 and 1.5:1, and the composition is encapsulated.

[0045] In one embodiment, the composition disclosed herein comprises: a. Particles with a size of 100µm to 2000µm, said particles comprising a polymer and an active agent. b. Effervescent reagent, The w / w ratio of the microparticles to the effervescent reagent is between 7:1 and 3:1, and the composition is encapsulated.

[0046] Effervescent reagent

[0047] Generating effervescent gases has been proposed as a means to promote the disintegration of capsules and tablets. However, to date, even in the presence of effervescent gases, the hydration and subsequent disintegration of capsules with capsule walls composed of polymer networks of proteins (e.g., gelatin) or polysaccharides (e.g., cellulose) remains a lengthy process.

[0048] The inventors of this disclosure have demonstrated that generating effervescent gas and combining it with particles of sufficient size is an effective means of promoting the disintegration of the encapsulated carrier system, thereby effectively releasing the active agent and increasing coverage.

[0049] The inventors of this disclosure have demonstrated that incorporating effervescent reagents and microparticles into capsules is an effective strategy that both accelerates capsule rupture and increases the microparticle coverage area (Examples 2 and 11). Furthermore, the inventors have demonstrated that this disclosure can effectively deliver small molecule drugs, antibodies, peptides, and tracers (Example 8).

[0050] The inventors of this disclosure have also demonstrated that the ratio of effervescent reagent to microparticles (microcapsules) (Example 4) and the size of the microparticles (Example 5) are important for the capsule rupture time.

[0051] The inventors have surprisingly discovered that when the w / w ratio of the amount of microparticles with a size of 100µm to 2000µm to the amount of effervescent reagent is between 7:1 and 1.5:1, the capsules rupture faster and the microparticles are released more quickly compared to other ratios containing a higher proportion of effervescent reagent (e.g., a microparticle to effervescent reagent ratio of 1:1).

[0052] The inventors have demonstrated that larger microparticles (710-1000 µm) accelerate capsule rupture more efficiently than smaller microparticles (250-400 µm and 400-710 µm). This makes it possible to manufacture different capsules, each filled with microspheres of either large or small diameter. When two such capsules are ingested (each containing either a large-diameter or small-diameter microsphere), this results in the capsules rupturing in a predictable manner at different anatomical locations within the intestine. Thus, the capsule filled with the large-diameter microsphere ruptures first, while the capsule filled with the small-diameter microsphere ruptures later. In this way, a larger surface area is covered in a predictable manner.

[0053] The inventors of this disclosure have demonstrated that the presence of effervescent reagents not only accelerates capsule rupture but also improves insulin release (Example 3).

[0054] Ideally, effervescent gas production is initiated when the carrier system reaches its intended location in the intestine. One method to achieve this is to use enteric coating combined with an encapsulation layer. Once the enteric coating dissolves, water can penetrate the encapsulation material, dissolve the effervescent reagent, and initiate the release of effervescent gas. Subsequently, the effervescent gas promotes the rapid disintegration of the encapsulated carrier system, thereby dispersing the microparticles onto the mucosa.

[0055] The inventors of this disclosure have demonstrated that enteric coating (Eudragit® S) prolongs the time it takes for capsules to rupture at pH 7.3.

[0056] In one embodiment, the effervescent gas is generated by an effervescent agent. In one embodiment, the effervescent agent is an effervescent pair. In one embodiment, the effervescent pair is a pair of pharmaceutically acceptable excipients, one of which is a basic component and the other is an acidic component. In one embodiment, carbon dioxide is released when the basic component comes into contact with the acidic component and water. In one embodiment, the effervescent agent produces carbon dioxide upon contact with water.

[0057] In one embodiment, the effervescent agent comes into contact with water when the encapsulation layer ruptures. In one embodiment, the effervescent agent is activated when the encapsulation layer ruptures. In one embodiment, effervescent gas is generated when the encapsulation material ruptures. In one embodiment, the effervescent gas acts as a propellant. In one embodiment, the effervescent gas promotes the rapid disintegration of the encapsulated carrier system. In one embodiment, the generated effervescent gas effectively releases the microparticles containing the active agent. In one embodiment, the generated effervescent gas can increase the coverage of the targeted intestinal surface. In one embodiment, the effervescent agent helps achieve efficient coverage of the intestinal surface. In one embodiment, the microparticles gradually release the embedded active agent into the intestinal mucosa.

[0058] In one embodiment, the effervescent reagent is an effervescent pair comprising or composed of the following substances: a. Bases, such as bases selected from sodium bicarbonate, potassium bicarbonate, and sodium carbonate, and b. Acids, such as those selected from citric acid, maleic acid and tartaric acid.

[0059] In one embodiment, the effervescent reagent comprises or is composed of an acid and a base, wherein the molar ratio is 1 mol acid to 1 to 6 mol base, for example, the molar ratio is 1 mol acid to 1 mol base, for example, the molar ratio is 1 mol acid to 2 mol base, for example, the molar ratio is 1 mol acid to 3 mol base, for example, the molar ratio is 1 mol acid to 4 mol base, for example, the molar ratio is 1 mol acid to 5 mol base, for example, the molar ratio is 1 mol acid to 6 mol base.

[0060] In one embodiment, the effervescent reagent comprises or is composed of citric acid and bicarbonate, with a molar ratio of 1 mol citric acid to 1 to 6 mol sodium bicarbonate, for example, a molar ratio of 1 mol citric acid to 1 mol sodium bicarbonate, for example, a molar ratio of 1 mol citric acid to 2 mol sodium bicarbonate, for example, a molar ratio of 1 mol citric acid to 3 mol sodium bicarbonate, for example, a molar ratio of 1 mol citric acid to 4 mol sodium bicarbonate, for example, a molar ratio of 1 mol citric acid to 5 mol sodium bicarbonate, for example, a molar ratio of 1 mol citric acid to 6 mol sodium bicarbonate.

[0061] In one embodiment, the effervescent reagent comprises or consists of citric acid and bicarbonate in a molar ratio of 1 mol citric acid to 3 mol sodium bicarbonate. The molar ratio of 1 mol citric acid to 3 mol sodium bicarbonate corresponds to a w / w ratio of 1:1.3 for citric acid to sodium bicarbonate.

[0062] In one embodiment, the effervescent reagent comprises citric acid and bicarbonate in a w / w ratio of 1:1.3 (citric acid to sodium bicarbonate) or is composed of the same.

[0063] In one embodiment, the effervescent reagent comprises or consists of a base and an acid, with a molar ratio of 1 mol base to 1 to 6 mol acid, for example, a molar ratio of 1 mol base to 1 mol acid, a molar ratio of 1 mol base to 2 mol acid, a molar ratio of 1 mol base to 3 mol acid, a molar ratio of 1 mol base to 4 mol acid, a molar ratio of 1 mol base to 5 mol acid, or a molar ratio of 1 mol base to 6 mol acid.

[0064] In one embodiment, the effervescent reagent comprises or is composed of sodium bicarbonate and citric acid in a molar ratio of 1 mol sodium bicarbonate to 1 to 4 mol citric acid, for example, a molar ratio of 1 mol sodium bicarbonate to 1 mol citric acid, for example, a molar ratio of 1 mol sodium bicarbonate to 2 mol citric acid, for example, a molar ratio of 1 mol sodium bicarbonate to 3 mol citric acid, for example, a molar ratio of 1 mol sodium bicarbonate to 4 mol citric acid.

[0065] The molar ratio of 3 mol sodium bicarbonate to 1 mol citric acid corresponds to a w / w ratio of sodium bicarbonate to citric acid of 1:0.77.

[0066] In one embodiment, the effervescent reagent comprises or consists of a bicarbonate and citric acid in a w / w ratio of 1 sodium bicarbonate to 0.77 citric acid.

[0067] In one embodiment, the ratio of microparticles to effervescent reagent is between 6:1 and 4:1, for example, about 5:1.

[0068] In one embodiment, the ratio of microparticles to effervescent reagent is between 7:1 and 1.5:1, for example between 6:1 and 4:1, for example 1.6:1, for example 2.5:1, for example 3:1, for example 5:1.

[0069] In one embodiment, the ratio of microparticles to effervescent reagent is between 7:1 and 3:1.

[0070] particle

[0071] The terms “microparticles” and “micropellets” used in this article are interchangeable.

[0072] In one embodiment, the microparticles of this disclosure comprise a polymer and an active agent. In one embodiment, the microparticles further comprise one or more diluents. In one embodiment, the microparticles further comprise one or more additives. In one embodiment, the microparticles further comprise one or more coatings.

[0073] The release kinetics of microparticles, particularly the dissolution rate of active ingredients from microparticles, are influenced by the composition of the microparticles.

[0074] polymer

[0075] In one embodiment, the particles of this disclosure comprise a polymer. In one embodiment, the polymer is a sustained-release polymer. In one embodiment, the particles comprise a polymer material. In one embodiment, the polymer material is a sustained-release polymer.

[0076] In one embodiment, the polymer is selected from microcrystalline cellulose (MCC), acrylic polymers such as Eudragit RL (CAS No.: 51822-44-7) and Eudragit RS (CAS No.: 33434-24-1), polyethylene oxide, starch, starch derivatives, alginate, pullullan, stearin, povidone, povidone derivatives, natural gums, gelatin, chitosan, polyvinyl alcohol, and combinations thereof.

[0077] EUDRAGIT® RL and EUDRAGIT® RS are acrylic resins comprising copolymers of acrylates and methacrylates, with a low content of quaternary ammonium groups (Eudragit RL: 10% quaternary ammonium groups, Eudragit RS: 5% quaternary ammonium groups, Santos et al., 2021). The ammonium groups, present as salts, impart membrane permeability. EUDRAGIT® RL and EUDRAGIT® RS are free-permeable (RL) and micro-permeable (RS), respectively, and their permeability is pH-independent. The polymers swell in water and digestive fluids in a pH-independent manner. In the swollen state, they are permeable to both water and dissolved active compounds.

[0078] Eudragit RL is a low-permeability polymer comprising poly(ethyl acrylate, methyl methacrylate, and a small amount (10%) of quaternary ammonium-containing methacrylates). Because Eudragit RL can control drug release rates by adjusting its permeability, it is commonly used in sustained-release formulations. Furthermore, drug release can be tailored by adjusting the ratio of Eudragit RL to other polymers or excipients in the formulation. Eudragit RL is insoluble in the gastrointestinal tract but swells and becomes permeable in an aqueous environment.

[0079] Eudragit® RS is a standard permeable polymer with a composition similar to Eudragit® RL, both being polymers containing poly(ethyl acrylate, methyl methacrylate, and a small amount (5%) of quaternary ammonium methacrylate). Eudragit RL is typically used in sustained-release formulations. Because Eudragit RS has a lower quaternary ammonium group content than Eudragit RL, its permeability is also lower. This means that drug release from Eudragit RS may be slower than from Eudragit RL. Eudragit RS is insoluble in the gastrointestinal tract but swells and becomes permeable in an aqueous environment.

[0080] The CAS number for the monomer Eudragit RS (ethyl propionate; methyl 2-methylpropionate; trimethyl-[2-(2-methylpropion-2-enoyloxy)ethyl]ammonium; chloride) is 33434-24-1. The monomer Eudragit RL ( N , N-II The CAS number for methyl methylamine (2-methylprop-2-enoic acid) is 51822-44-7.

[0081] Starch is a polymeric carbohydrate composed of many glucose units linked by glycosidic bonds. Starch includes amylose, amylopectin, and maltodextrin, including digestible maltodextrin and resistant maltodextrin. Starch derivatives include modified starches such as dextrin, acid-treated starch, alkali-treated starch, starch acetate, and bleached starch.

[0082] Alginate is a naturally occurring linear copolymer composed of mannuronate and guluronate. Alginates include alginate, alginate derivatives (such as amphiphilic alginate derivatives derived with hydrophilic moieties (e.g., alkyl chains), and alginate compositions, including combinations of alginate and chitosan (Wang et al, 2016).

[0083] Povidone (polyvinylpyrrolidone, PVP) is a synthetic polymer used in the pharmaceutical industry as a vehicle for dispersing and suspending drugs. It also acts as a disintegrant and tablet binder. The molecular formula of povidone is (C6H9NO). n Because povidone formulations are soluble in both water and oil solvents, they are widely used in the pharmaceutical industry. Povidone derivatives include crospovidone (PVPP) and copovidone.

[0084] In one embodiment, the concentration of the polymer in the particles is 94% to 98.9% (w / w), for example, 97% to 98% (w / w). In another embodiment, the concentration of the polymer in the particles is 75% to 99% (w / w), for example, 80% to 99% (w / w), for example, 82% to 99% (w / w), for example, 84% to 99% (w / w), for example, 86% to 99% (w / w), for example, 88% to 99% (w / w), for example, 90% to 99% (w / w), for example, 91% to 99% (w / w), for example, 92% to 99% (w / w), for example, 93% to 99% (w / w), for example, 94% to 99% (w / w), for example, 95% to 99% (w / w), for example, 96% to 99% (w / w), for example, 97% to 99% (w / w), for example, 98% to 99% (w / w).

[0085] In one embodiment, the concentration of the polymer in the particles is 75% to 80% (w / w), for example 80% to 85% (w / w), for example 85% to 90% (w / w), for example 90% to 95% (w / w), for example 95% to 99% (w / w).

[0086] In one embodiment, the concentration of polymer in the microparticles is 97.5%.

[0087] In one embodiment, the particles comprise one or more polymers.

[0088] In one embodiment, the one or more polymers are selected from or comprise the group consisting of: microcrystalline cellulose (MCC), acrylic polymers such as Eudragit RL (CAS No.: 51822-44-7) and Eudragit RS (CAS No.: 33434-24-1), polyethylene oxide, starch, starch derivatives, alginate, povidone derivatives, natural gums, gelatin, chitosan, polyvinyl alcohol, and combinations thereof.

[0089] In one embodiment, the concentration of microcrystalline cellulose (MCC) in the microparticles is 94% to 98.9% (w / w), for example, 97% to 98% (w / w). In another embodiment, the concentration of the polymer in the microparticles is 75% to 99% (w / w), for example, 80% to 99% (w / w), for example, 82% to 99% (w / w), for example, 84% to 99% (w / w), for example, 86% to 99% (w / w), for example, 88% to 99% (w / w), for example, 90% to 99% (w / w), for example, 91% to 99% (w / w), for example, 92% to 99% (w / w), for example, 93% to 99% (w / w), for example, 94% to 99% (w / w), for example, 95% to 99% (w / w), for example, 96% to 99% (w / w), for example, 97% to 99% (w / w), for example, 98% to 99% (w / w).

[0090] In one embodiment, the concentration of microcrystalline cellulose (MCC) in the microparticles is 97.5%.

[0091] In one embodiment, the microparticles comprise two polymers, such as polymers A and B, wherein the ratio of polymers A and B is at least 1:1, such as 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, or 8:1.

[0092] In one embodiment, the microparticles comprise two polymers, such as polymers A and B, wherein the ratio of polymers A and B is at least 1:1, such as 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, or 1:10.

[0093] In one embodiment, the microparticles comprise microcrystalline cellulose and Eudragit® RL.

[0094] In one embodiment, the microparticles comprise microcrystalline cellulose and Eudragit® RL in a ratio of at least 3:1, such as 4:1, 5:1, 6:1, 7:1, or 8:1.

[0095] In one embodiment, the microparticles comprise microcrystalline cellulose and Eudragit® RL in a ratio of 4:1.

[0096] In one embodiment, the microparticles comprise 78.16% microcrystalline cellulose, 19.54% Eudragit RL, 1.3% insulin, and 1.0% magnesium stearate.

[0097] diluent

[0098] The kinetics of particles, and especially the dissolution rate of active ingredients from particles, are influenced by the particle composition.

[0099] One strategy to control the dissolution rate is to exchange some of the insoluble microcrystalline cellulose with a soluble diluent.

[0100] The inventors of this disclosure have demonstrated (Example 7) that a higher ratio of insoluble polymer to soluble diluent results in a higher release rate of the active ingredient. Furthermore, the inventors of this disclosure have also demonstrated (Example 7) that a higher ratio of insoluble polymer to soluble diluent results in a faster release rate of the active ingredient.

[0101] In one embodiment, the microparticles contain a diluent. In one embodiment, the diluent is selected from lactose, dicalcium phosphate, starch, and sugar alcohols (such as mannitol, xylitol, and sorbitol) and combinations thereof.

[0102] In one implementation, the diluent is mannitol.

[0103] Example 7 demonstrates that microparticles prepared from MCC release 80% of insulin within 24 hours. Furthermore, it demonstrates that insulin release is even faster if the microparticles also contain a soluble diluent (e.g., mannitol). It shows that a 2:1 ratio of MCC to mannitol results in the release of 80% of insulin within 1 hour and 90% within 6 hours; microparticles containing a 5:1 ratio of MCC to mannitol release 80% of insulin within 4 hours and 90% within 6 hours. Finally, Example 7 demonstrates that microparticles containing mannitol as a diluent exhibit complete insulin release within 24 hours.

[0104] In one embodiment, the microparticles comprise microcrystalline cellulose and mannitol in a ratio of 2:1 (w / w) to 6:1 (w / w), for example, a ratio of 5:1 (w / w).

[0105] This disclosure indicates that a method for controlling the release rate of the active ingredient and the total amount of active ingredient released can be the ratio of polymer to diluent. This disclosure indicates that a higher diluent ratio can lead to a faster release of the active ingredient. Furthermore, this disclosure also indicates that a higher diluent ratio can lead to a faster release of the active ingredient.

[0106] additive

[0107] In one implementation, the microparticles contain one or more additives.

[0108] Additives can be lubricants, adhesives, disintegrants, plasticizers, flow aids, surfactants, colorants, flavorings, antioxidants, and preservatives.

[0109] In one embodiment, the microparticles contain one or more additives, such as lubricants, binders, disintegrants, plasticizers, flow aids, surfactants, colorants, flavorings, antioxidants, and preservatives.

[0110] In one implementation, the microparticles are manufactured using an extrusion process. If the microparticles are produced using an extrusion process, it may be advantageous to add additives such as lubricants.

[0111] In one implementation, the particles also contain a lubricant.

[0112] In one embodiment, the lubricant is selected from magnesium stearate, stearic acid, and talc, and / or combinations thereof.

[0113] In one embodiment, the concentration of the additive in the microparticles is 0.1% to 2% (w / w), for example, about 1% (w / w).

[0114] Preparation of microparticles

[0115] The microparticles disclosed herein can be prepared by any standard method known in the art. Examples of microparticle preparation methods include extrusion and solvent evaporation.

[0116] In one embodiment, the microparticles are prepared by extrusion. In one embodiment, extrusion includes the steps of mixing components, extrusion, spheronization, and drying. In one embodiment, extrusion is performed using a Celeva Multi laboratory extruder. In one embodiment, extrusion is performed using a Celeva Multi laboratory extruder equipped with a mixer / granulator. In one embodiment, the Celeva Multi laboratory extruder is also equipped with a spheronization mill. In one embodiment, the microparticles are manufactured using the extrusion method described in Example 1. For more information on extrusion methods, please refer to the review by Muley et al., 2016.

[0117] In one embodiment, the microparticles comprise a polymer, an activator, and a lubricant. In one embodiment, the polymer is a slow-release polymer. In one embodiment, the slow-release polymer is one or more polymers, such as Eudragit® RL, Eudragit® RS, microcrystalline cellulose, and / or polyethylene oxide. In one embodiment, the lubricant is magnesium stearate, stearic acid, and talc, or a combination thereof.

[0118] In one embodiment, the microparticles are prepared by solvent evaporation. In one embodiment, the solvent evaporation is performed using a solvent evaporation apparatus. In one embodiment, the solvent evaporation includes the steps of suspending the surfactant and polymer in a suitable solvent and stirring until the solvent has evaporated. In one embodiment, the polymer is a sustained-release polymer as defined in other parts of this application. In one embodiment, the solvent is an organic solvent. In one embodiment, the solvent is a low-boiling-point organic solvent. In one embodiment, the solvent is acetone.

[0119] The choice of method for preparing microparticles can depend on the desired particle size or shape. Generally, microparticles prepared by solvent evaporation are smaller than those prepared by extrusion. In one embodiment, the microparticles are spherical. In another embodiment, the microparticles are pellets.

[0120] In one embodiment, the particle size is 100µm to 2000µm, for example 150µm to 2000µm, for example 200µm to 2000µm, for example 250µm to 2000µm, for example 300µm to 2000µm, for example 350µm to 2000µm, for example 400µm to 2000µm, for example 245µm to 2000µm, for example 500µm to 2000µm, 550µm to 2000µm, for example 600µm to 2000µm, for example 650µm to 2000µm, for example 700µm to 2000µm. 000µm, for example, dimensions from 700µm to 2000µm, for example, dimensions from 700µm to 1900µm, for example, dimensions from 700µm to 1000µm, for example, dimensions from 700µm to 1100µm, for example, dimensions from 800µm to 2000µm, for example, dimensions from 900µm to 2000µm, for example, dimensions from 1000µm to 2000µm, for example, dimensions from 1200µm to 2000µm, for example, dimensions from 1300µm to 2000µm, for example, dimensions from 1400µm to 2000µm, for example, dimensions from 1500µm to 2000µm.

[0121] In one embodiment, the particle size is from 150µm to 2000µm, for example, from 150µm to 1500µm, for example, from 150µm to 1000µm, for example, from 150µm to 800µm, for example, from 150µm to 700µm, for example, from 150µm to 600µm, for example, from 200µm to 600µm.

[0122] In one embodiment, the particle size is from 250µm to 1000µm, for example from 250µm to 400µm, for example from 400µm to 700µm, for example from 700µm to 1000µm.

[0123] Typically, microparticles prepared by solvent evaporation are smaller than those prepared by extrusion. Conversely, microparticles prepared by extrusion are typically larger than those prepared by solvent evaporation.

[0124] In one embodiment, the particle size prepared by solvent evaporation is 250 to 400 µm.

[0125] In one embodiment, the size of the microparticles prepared by extrusion is 400 to 1000 µm, for example 400 to 710 µm, for example 710 to 1000 µm.

[0126] The microparticles disclosed in this article, with sizes ranging from 150µm to 2000µm, cannot penetrate the intestinal mucosa, thus ensuring local therapeutic and local effects of the active agent.

[0127] As demonstrated in Example 5, the capsule rupture time and particle release rate are related to particle size. Therefore, those skilled in the art will select one size or a combination of sizes based on the desired release rate.

[0128] Coating

[0129] The compositions disclosed herein are used to deliver a carrier system with a locally acting payload into the intestine of a mammal.

[0130] In one embodiment, the composition disclosed herein further comprises at least one coating layer.

[0131] Coating can be performed using any coating method known in the art by spraying a coating solution onto the microcapsules. An example of a suitable method is the Mini-Glatt fluidized bed coating system or the FC-LAB Micro FLO-COATER® system.

[0132] Examples of suitable coatings include poly(ethyl acrylate, methyl methacrylate, 2-trimethylammonium ethyl methacrylate chloride, 10% quaternary ammonium group) (Eudragit RL) and poly(ethyl acrylate, methyl methacrylate, 2-trimethylammonium ethyl methacrylate chloride, 5% quaternary ammonium group) (Eudragit RS).

[0133] In one embodiment, at least one coating layer covers the microparticles. Adding a coating to the microparticles allows for delayed release from the microparticles, and may further prolong the delayed release already provided by the capsule coating. Examples of coated microparticles are given in the embodiments of WO2020 / 115277A1.

[0134] In one embodiment, at least one coating layer covering the microparticles is an enteric coating.

[0135] In one embodiment, the microparticles of this disclosure are coated in at least one coating layer.

[0136] In one embodiment, the microparticles of the present disclosure are coated with at least one enteric coating.

[0137] In one embodiment, the microparticles are coated with Eudragit RL. In one embodiment, the microparticles are coated with Eudragit RS. In one embodiment, the microparticles are coated with a mixture of Eudragit RL and Eudragit RS. In one embodiment, the microparticles are coated with both Eudragit RL and Eudragit RS. In one embodiment, the microparticles are first coated with a layer of Eudragit RL, and then with a layer of Eudragit RS.

[0138] Coating increases the weight of the microspheres.

[0139] In one embodiment, the theoretical weight gain introduced by coating is at least 2%, for example 4%, for example 6%, for example 8%, for example 10%, for example 12%, for example 14%, for example 20%, for example 25%. In one embodiment, the theoretical weight gain introduced by coating with Eudragit RL is at least 2%, for example 4%, for example 6%, for example 8%, for example 10%, for example 12%, for example 14%, for example 20%. In one embodiment, the theoretical weight gain introduced by coating with Eudragit RS is at least 2%, for example 4%, for example 6%, for example 8%, for example 10%, for example 12%, for example 14%, for example 20%.

[0140] In one implementation, the release of the active ingredient is delayed.

[0141] In one embodiment, the release of the active ingredient is delayed by 5 minutes, for example, 15 minutes, for example, 30 minutes, for example, 1 hour. In another embodiment, the release of the active ingredient is delayed by 15 minutes, for example, 30 minutes, for example, 1 hour, for example, 2 hours, for example, 3 hours, for example, 4 hours, for example, 5 hours.

[0142] In one embodiment, the microparticles of this disclosure are coated with at least one enteric coating to delay the release of the active ingredient. In one embodiment, at least one coating layer covering the microparticles is a pH-sensitive coating, such as a coating that dissolves at pH 5.5 or higher, a coating that dissolves at pH 5.5 to 8, a coating that dissolves at pH 6 or higher, or a coating that dissolves at pH 7 or higher.

[0143] In one embodiment, at least one coating layer covering the microparticles is Eudragit® S 100 (CAS No.: 25086-15-1).

[0144] The coating material may be the same as the material described in the "Coating" section below.

[0145] Active ingredients

[0146] The compositions of the present invention allow for the administration of a variety of active ingredients, including biological agents, small molecule drugs, and tracers.

[0147] In one embodiment, the active agent is selected from biological agents, therapeutic peptides, small molecule drugs, bacteria, probiotics, prebiotics, bacteriophages, and natural products.

[0148] In one embodiment, the natural product is bilberry extract. In another embodiment, the natural product is butyric acid or butyrate / ester, such as a salt of butyric acid and / or an ester of butyric acid, such as sodium butyrate.

[0149] In one embodiment, the active agent is a biological agent, such as a biological agent selected from monoclonal antibodies, proteins or peptides or derivatives thereof.

[0150] In one implementation, the active agent is a therapeutic antibody, such as adalimumab, golimumab, or infliximab.

[0151] In one implementation, the active agent is a therapeutic peptide.

[0152] In one embodiment, the active agent is a biotherapeutic peptide, such as a biotherapeutic peptide selected from proteases, peptidases, disaccharides, oligosaccharides, lipases, growth factors, extracellular matrix proteins such as laminin, collagen, glycosaminoglycans, proteoglycans, mucins, and analogues.

[0153] In one implementation, the active agent is a small molecule, such as caffeine.

[0154] In one implementation, the active agent is a tracer molecule, such as caffeine.

[0155] In one implementation, the active agent is a small molecule drug, such as sodium butyrate.

[0156] In one embodiment, the concentration of the active agent in the composition is up to 4% (w / w), for example up to 3.5% (w / w), for example up to 3% (w / w), for example up to 2.5% (w / w), for example up to 2% (w / w), for example up to 1.5% (w / w), for example up to 1.3% (w / w).

[0157] In one embodiment, the active agent is insulin or an analogue thereof. In one embodiment, the insulin analogue is selected from insulin aspart, insulin lispro, insulin glutathione, insulin glargine, insulin detemir, and insulin degludec. In one embodiment, the insulin analogue is an insulin derivative.

[0158] Encapsulation

[0159] In one embodiment, the composition of this disclosure is encapsulated in an encapsulation layer.

[0160] In one embodiment, the encapsulating layer comprises an encapsulating polymer selected from: gelatin, alginate, alginate derivatives, cellulose, methacrylic acid copolymers (e.g., Eudragit® L100 (CAS No.: 25086-15-1), Eudragit® S 100 (CAS No.: 25086-15-1), Eudragit® L-30D (CAS No.: 100218-76-6 or 25212-88-8), Eudragit® FS 30D (CAS No.: 26936-24-3) and Eudragit® L100-55 (CAS No.: 25212-88-8)), cellulose acetate phthalate, cellulose trimellitate, polyvinyl acetate phthalate, hydroxyethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, or shellac, or an aqueous dispersion thereof. In one embodiment, the encapsulation layer is an edible biopolymer, such as starch, carrageenan, pullulan, stearin, cellulose, or chitin.

[0161] An example of an encapsulation layer is alginate, which has been used in combination with chitosan for microencapsulation of icariin to achieve colon targeting and treat colitis in rat models (Wang et al. 2016).

[0162] In one embodiment, the encapsulation layer is alginate.

[0163] Coating

[0164] The compositions disclosed herein are used to deliver a carrier system with a locally acting payload into the intestine of a mammal.

[0165] To ensure delivery to the mammalian intestine, the carrier system can be coated.

[0166] Coating materials for targeted release after oral administration of solid dosage forms, particularly those targeting release in the ileum or large intestine, are known in the art. They can be further subdivided into coating materials that disintegrate above a specific pH, coating materials that disintegrate after a specific time in the gastrointestinal tract, and coating materials that disintegrate due to enzymatic triggering specific to the microflora of a particular region of the gut. For example, Bansal et al. (Polim. Med. 2014, 44, 2, 109-118) reviewed these three different categories of coating materials targeting the large intestine. These uses of such coating materials are described, for example, in WO 2007 / 122374 A2, WO 01 / 76562 A1, WO 03 / 068196 A1, WO 2008 / 135090 A1, and GB2367002 A.

[0167] In one embodiment, the carrier system is coated with an enteric coating. The enteric coating may be selected to dissolve only under specific conditions (e.g., regarding pH or the presence of a large number of bacteria). Thus, when the specified conditions are met, the enteric coating dissolves, the carrier system ruptures, and microparticles containing the active agent are released.

[0168] The dissolution of the coating and the rupture of the capsule depend on the nature of the enteric coating. The dissolution process itself is time-dependent and can be relatively long (several hours), for example, for coatings designed to dissolve in the large intestine. To improve the anatomical targeting precision of drugs intended for local intestinal therapy, a more abrupt capsule rupture is desirable as the drug approaches or has just entered the target intestinal segment.

[0169] For targeted delivery to the mammalian intestine via oral administration, the delivery system must pass through the stomach. Gastric juice has a low pH, typically around 1.5 to 3.5. To facilitate targeted delivery through the stomach, it may be advantageous to protect the carrier system in a way that prevents it from dissolving in the stomach. One strategy could be to coat the carrier system with at least one layer of coating that will not dissolve before reaching the intestine.

[0170] In one embodiment, the composition disclosed herein further comprises at least one coating layer.

[0171] In one embodiment, the composition disclosed herein further comprises at least one coating layer covering the encapsulation layer.

[0172] In one embodiment, the at least one coating layer is an enteric coating.

[0173] In one embodiment, the composition disclosed herein further comprises at least one coating layer, such as two coating layers, such as three coating layers, which cover the encapsulation layer.

[0174] The pH of the proximal small intestine is usually 6-7, while the pH of the distal small intestine and the beginning of the colon is usually 7-7.5.

[0175] For targeted delivery to the small intestine, the coating should dissolve at pH > 6. For targeted delivery to the colon, dissolution should occur at pH > 7.0.

[0176] In one embodiment, the composition disclosed herein is used for delivery into the small intestine.

[0177] In one embodiment, the composition of this disclosure is coated with a coating that allows release into the small intestine. In one embodiment, the coating dissolves at pH > 6.

[0178] In one embodiment, the composition of this disclosure is intended for delivery to the large intestine. In one embodiment, the composition of this disclosure is coated with a coating that allows release into the large intestine. In one embodiment, the coating dissolves at a pH > 7.

[0179] In one embodiment, the composition of this disclosure is intended for delivery to the colon. In one embodiment, the composition of this disclosure is coated with a coating that allows release into the colon. In one embodiment, the coating dissolves at pH > 7.

[0180] An example of a polymer that can be used for targeted delivery to the mammalian gut is Eudragit® S. Eudragit® S is a pH-sensitive polymer comprising a copolymer of methacrylic acid and methyl methacrylate (in a 1:2 ratio). Eudragit® S is used for enteric coating to protect the coating material from the acidic environment of the stomach. Eudragit® S dissolves at pH values ​​above 7, which are typically found in the distal small intestine and colon, making Eudragit® S suitable for targeted drug release in these areas. The formal name of Eudragit® S is poly(methacrylic acid-co-methyl methacrylate copolymer (1:2)). The CAS number for Eudragit® S is 25086-15-1.

[0181] In one embodiment, at least one coating layer is a pH-sensitive coating, such as a coating that dissolves at pH 5.5 or higher, a coating that dissolves at pH 5.5 to 8, a coating that dissolves at pH 6 or higher, or a coating that dissolves at pH 7 or higher.

[0182] In one embodiment, at least one coating layer is an enteric coating.

[0183] In one embodiment, at least one coating layer is a coating that dissolves under conditions in the mammalian gut (e.g., conditions in the primate gut).

[0184] In one embodiment, at least one coating layer is a coating that dissolves under conditions in the mammalian small intestine (e.g., conditions in the human small intestine).

[0185] In one embodiment, at least one coating layer is a coating that dissolves under conditions in the mammalian large intestine (e.g., conditions in the human large intestine).

[0186] Use as a medicine

[0187] In one embodiment, the composition disclosed herein is used as a medicine.

[0188] In one embodiment, the composition of this disclosure is administered to a subject in need.

[0189] In one embodiment, the composition does not cause cell proliferation in the small intestine.

[0190] In one embodiment, the compositions disclosed herein are used for topical treatment.

[0191] In one embodiment, the composition does not promote the penetration of biological tissues or biological barriers.

[0192] In one embodiment, the composition does not promote the penetration of biological barriers such as the gastrointestinal barrier or the gastrointestinal mucosa.

[0193] In one embodiment, the compositions disclosed herein are used for local treatment of the intestines (e.g., the small intestine and / or large intestine).

[0194] In one embodiment, the active ingredient is insulin or an analogue thereof.

[0195] In one embodiment, the active ingredient is an antibody or its functional fragment and derivative that is specific to tumor necrosis factor α (TNFa).

[0196] In one implementation, insulin has low or no systemic effects.

[0197] In one implementation scheme, insulin does not affect systemic blood glucose levels.

[0198] Modified release

[0199] In one embodiment, the composition disclosed herein is a modified release composition.

[0200] Several factors affect the release rate of the active ingredient from the compositions disclosed herein. Strategies to improve the release rate of the compositions disclosed herein include coating the microparticles and introducing a soluble diluent into the microparticles.

[0201] In one embodiment, the composition of this disclosure releases the active agent at least 1 hour after application, for example at least 2 hours after application, for example at least 3 hours after application, for example at least 4 hours after application, for example 6 to 8 hours after application, for example 10 to 20 hours after application.

[0202] In one embodiment, the composition disclosed herein is a prolonged release composition.

[0203] Delivery of drug compounds

[0204] In one embodiment, the compositions of this disclosure are used for a method of delivering a pharmaceutical compound to the intestine. In one embodiment, the compositions of this disclosure are used for a method of repairing the colonic mucosa of a subject who has or is suspected of having inflammatory bowel disease, wherein the active agent comprises or is composed of insulin or an analogue thereof.

[0205] In one embodiment, the compositions disclosed herein are used to prevent or repair the colonic mucosa of a subject who has or is suspected of having inflammatory-induced colorectal tumors and / or cancer, wherein the active agent comprises or is composed of insulin or an analogue thereof.

[0206] In one implementation, the insulin analogue is selected from insulin aspart, insulin lispro, insulin glutares, insulin glargine, insulin detemir, and insulin degludec.

[0207] In one embodiment, the composition comprises 100 IU to 1000 IU of insulin or its analogues, such as 200 IU to 1000 IU of insulin or its analogues, such as 300 IU to 1000 IU of insulin or its analogues, such as 400 IU to 1000 IU of insulin or its analogues, such as 500 IU to 1000 IU of insulin or its analogues, such as 600 IU to 1000 IU of insulin or its analogues, such as 700 IU to 1000 IU of insulin or its analogues, such as 800 IU to 1000 IU of insulin or its analogues.

[0208] In one embodiment, the composition comprises 1 mg to 35 g of insulin or an analogue thereof, such as 3 mg to 35 g of insulin, such as 10 mg to 35 g of insulin or an analogue thereof, such as 50 mg to 35 g of insulin or an analogue thereof, such as 100 mg to 35 g of insulin or an analogue thereof, such as 1 g to 35 g of insulin or an analogue thereof, such as 10 g to 35 g of insulin or an analogue thereof, such as 20 g to 35 g of insulin or an analogue thereof.

[0209] In one embodiment, the insulin or its analogues are insulin with a total daily insulin dose of 100 IU to 1000 IU, such as 200 IU to 1000 IU, such as 300 IU to 1000 IU, such as 400 IU to 1000 IU, such as 500 IU to 1000 IU, such as 600 IU to 1000 IU, such as 700 IU to 1000 IU, such as 800 IU to 1000 IU.

[0210] In one embodiment, the composition of this disclosure releases the active agent in the intestine of an individual in need.

[0211] In one embodiment, the composition of this disclosure releases the active agent in the small intestine of the individual in need.

[0212] In one embodiment, the composition of this disclosure releases the active agent in the large intestine (e.g., colon) of an individual in need.

[0213] Inflammatory bowel disease

[0214] Crohn's disease and ulcerative colitis are two types of inflammatory bowel disease (IBD), both of which tend to develop in early adulthood, although they can actually begin at any age, starting in early childhood. Despite their well-defined clinical presentations, including diarrhea, abdominal pain, and, in ulcerative colitis, perianal bleeding, diagnosis is often delayed. Crohn's disease can affect the entire digestive tract transmurally, from the mouth to the anus, while ulcerative colitis primarily affects the colonic mucosa. Extraintestinal clinical manifestations in the joints, eyes, and skin further complete the clinical picture; these extraintestinal manifestations can occur before the bowel disease develops.

[0215] In one embodiment, the composition of this disclosure is used for the treatment or prevention of inflammatory bowel disease and / or inflammatory-induced colorectal tumors and / or cancer, wherein the active agent comprises or is composed of insulin or an analogue thereof.

[0216] Inflammatory bowel disease (IBD) is very common, with a prevalence of up to 1 in 198 (ulcerative colitis) and 1 in 310 (Crohn's disease). It can affect both young and old people, and once diagnosed, IBD is a chronic condition characterized by alternating periods of inflammatory flare-ups with acute symptoms and asymptomatic remission. In the long term, ulcerative colitis (UC), in particular, is a known risk factor for colorectal tumors and cancers. Crohn's disease and ulcerative colitis are two types of inflammatory bowel disease (IBD), both of which tend to develop in early adulthood, but can actually begin at any age from early childhood. Despite their obvious clinical presentations, including diarrhea, abdominal pain, and perianal bleeding in ulcerative colitis, their diagnosis is often delayed. Crohn's disease can affect the entire digestive tract transmurally, from the mouth to the anus, while ulcerative colitis primarily affects the colonic mucosa.

[0217] In one implementation, inflammatory bowel disease is selected from: ulcerative colitis, diverted colitis, Behcet's disease, undifferentiated colitis, left colitis, microscopic colitis (such as collagenous colitis or lymphocytic colitis), Crohn's disease, non-infectious colitis, pouchitis, immunotherapy-related colitis, and immune-checkpoint-induced colitis.

[0218] Subjects with or suspected of having IBD typically experience a disease phase (during which IBD symptoms appear) and a remission phase (during which no symptoms appear). After the remission phase, symptoms may reappear, i.e., a relapse or recurrence occurs.

[0219] In one embodiment, this disclosure relates to a composition comprising a therapeutically effective amount of insulin or a pharmaceutically acceptable salt thereof, for the treatment of inflammatory bowel disease, wherein the composition is administered to a subject in need. In some embodiments of this disclosure, the inflammatory bowel disease is selected from ulcerative colitis, microscopic colitis (e.g., collagenous colitis or lymphocytic colitis), diverted colitis, Behçet's disease, undifferentiated colitis, left-sided colitis, non-infectious colitis, Crohn's disease, and pouchitis.

[0220] Ileal pouch inflammation refers to inflammation of the ileal pouch (an artificial rectum surgically reconstructed from ileal tissue in patients who have undergone colectomy). Ileal pouches are created in the management of patients with ulcerative colitis, undifferentiated colitis, familial adenomatous polyposis (FAP), or in some cases, other types of colitis. Subjects with ileal pouch inflammation typically present with symptoms associated with IBD, particularly bloody diarrhea, severe cramps, and abdominal pain.

[0221] Ulcerative colitis typically extends continuously upwards from the rectum to the colon. Based on the extent of involvement (depending on the distance the disease extends into the colon), the disease can be classified as: (a) distal colitis, which includes proctitis, proctosigmoiditis, and left-sided colitis; and (b) extensive colitis, which includes pancolitis. For the purposes of this disclosure, the term "ulcerative colitis" refers to any form of the disease itself, particularly the forms mentioned above.

[0222] Inflammation-induced colorectal tumors and / or cancer

[0223] Inflammation-induced colorectal tumors, also known as colitis-associated cancer (CAC), are a subtype of colorectal cancer associated with IBD. They are difficult to treat and have a high mortality rate.

[0224] In one embodiment, the compositions disclosed herein are used in a method of treating or preventing cancer.

[0225] With the widespread use of immune checkpoint inhibitors in the treatment of various types of cancer, immune-related adverse events are becoming increasingly common. Immunotherapy-induced colitis is one example of an immune-related adverse event.

[0226] In one implementation, immunotherapy-related colitis is immunotherapy-induced colitis.

[0227] In one embodiment, a composition comprising insulin or an analogue thereof is used to treat immunotherapy-associated colitis.

[0228] In one embodiment, a composition comprising insulin or an analogue thereof is used to treat immunotherapy-induced colitis.

[0229] In some embodiments of this disclosure, the composition is administered to a subject who has been diagnosed with inflammatory bowel disease and / or inflammatory-induced colorectal tumors and / or cancer.

[0230] One aspect of this disclosure relates to a method of treating inflammatory bowel disease in a subject of need, the method comprising administering a composition disclosed herein containing a therapeutically effective amount of insulin or a pharmaceutically acceptable salt thereof.

[0231] Skin cancer

[0232] Inflammatory bowel disease (IBD) is a chronic autoimmune disease associated with an increased risk of skin cancer. Proposed mechanisms contributing to skin cancer susceptibility in IBD patients include chronic inflammation, cellular damage, and underlying immune dysfunction leading to alterations in tumor surveillance. It has been shown that immunosuppressant use in IBD patients increases the risk of skin cancer by 4–7 times, and approximately half of IBD patients use these medications within 5 years of diagnosis.

[0233] In one embodiment, the composition is used to prevent skin cancer. In one embodiment, the composition is used to reduce the risk of developing skin cancer. In one embodiment, the skin cancer is nonmelanoma skin cancer (NMSC) or melanoma.

[0234] Delivery of probiotics and / or prebiotics

[0235] Even healthy subjects without a diagnosed gastrointestinal condition may wish to inoculate the entire inner surface of the large intestine with bacteria (probiotics) or spray with nutritional supplements for gut microbiota (prebiotics). Motivations are varied, such as to achieve a healthier gut microbiota, provide energy substrates for intestinal cells, and / or protect intestinal cells from oxidative stress damage.

[0236] In one embodiment, the compositions disclosed herein relate to a dietary supplement.

[0237] In one implementation, the active ingredient in the dietary supplement is a prebiotic nutrient.

[0238] In one embodiment, the composition of this disclosure is used for oral administration of an active agent, wherein the active agent is a prebiotic.

[0239] Prebiotic nutrients are indigestible food components that, when ingested, exert beneficial effects on the host by selectively stimulating the growth and / or activity of bacteria in the gastrointestinal tract. Non-limiting examples of prebiotic nutrients include butyrate and bilberry extract, as well as dietary fiber such as fructooligosaccharides, glucose oligosaccharides, galactooligosaccharides, polydextrose, isomaltooligosaccharides, xylooligosaccharides, polydextrose, and lactulose.

[0240] In one implementation, the active ingredient in the dietary supplement is probiotics.

[0241] In one embodiment, the composition of this disclosure is used for oral administration of an active agent, wherein the active agent is a probiotic.

[0242] Probiotics are live microorganisms designed to maintain or improve the gut microbiota. Examples of probiotics include yeasts, molds, and bacteria. Non-limiting examples of probiotics include strains of Bifidobacterium, Lactobacillus, and Enterococcus.

[0243] In one embodiment, the compositions of this disclosure are used for oral administration of a dietary supplement to a subject.

[0244] In one embodiment, the composition of this disclosure is used for a method of delivering a dietary supplement into the intestine of a subject.

[0245] In one embodiment, the composition disclosed herein is used for a method of delivering probiotics into the intestine of a subject.

[0246] In one embodiment, the composition disclosed herein is used for a method of delivering prebiotics to the intestines of a subject.

[0247] For example, prebiotics may include sodium butyrate and / or bilberry extract.

[0248] application

[0249] In one implementation, the composition is administered to the individual in need up to four times a day, for example up to three times a day, for example up to two times a day, for example up to once a day, for example up to once every 48 hours.

[0250] In one embodiment, the composition is a capsule.

[0251] In one implementation, a capsule may be administered to an individual in need up to four times a day, for example up to three times a day, for example up to two times a day, for example up to once a day, for example up to once every 48 hours.

[0252] In one implementation, one or more capsules may be administered to an individual in need up to four times a day, such as up to three times a day, such as up to two times a day, such as up to once a day, such as up to once every 48 hours.

[0253] In one implementation, one or more capsules are administered once daily to an individual in need.

[0254] In one implementation, one or more capsules are administered once daily to an individual in need.

[0255] In one implementation, two capsules are administered to the individual in need once a day.

[0256] In one implementation, three capsules are administered to the individual in need once a day.

[0257] In one embodiment, the composition is applied in the morning. In another embodiment, the composition is applied at night.

[0258] In one embodiment, the composition of this disclosure is administered to an individual in need three times a day, such as twice a day, once a day, or every other day.

[0259] In one embodiment, the composition is applied to an individual in need for a period of at least 3 weeks, such as at least 4 weeks, such as at least 5 weeks, such as at least 6 weeks, such as at least 7 weeks, such as for life.

[0260] In one embodiment, the composition comprises insulin or an analogue thereof, and is administered to an individual in need during remission of inflammatory bowel disease and / or inflammation-induced colorectal tumors and / or cancer, for a period of 3 weeks to 3 months, for example 3 weeks to 4 months, for example 3 weeks to 5 months, for example 3 weeks to 6 months, for example 3 weeks to 7 months, for example 3 weeks to 8 months, for example 3 weeks to 9 months, for example 3 weeks to 10 months, for example 3 weeks to 11 months, for example 3 weeks to 12 months, for example 3 weeks to 18 months, for example 3 weeks to 24 months.

[0261] In one embodiment of this disclosure, the active ingredient is insulin or an analogue thereof.

[0262] In one embodiment, a composition comprising insulin or an analogue thereof is administered to a subject who has or is suspected of having inflammatory bowel disease and / or inflammatory-induced colorectal tumors and / or cancer during the acute phase and / or recurrence of the disease.

[0263] In one embodiment, a composition comprising insulin or an analogue thereof is administered to a subject who has or is suspected of having inflammatory bowel disease and / or inflammatory-induced colorectal tumors and / or cancer during the acute phase and / or recurrence of the disease.

[0264] In one embodiment, a composition comprising insulin or an analogue thereof is administered to a subject who has or is suspected of having inflammatory bowel disease and / or inflammatory-induced colorectal tumors and / or cancer during a period of disease remission.

[0265] In one implementation, a composition comprising insulin or an analogue thereof is administered to a subject who has or is suspected of having inflammatory bowel disease during the acute phase and / or recurrence of the disease.

[0266] In one implementation, a composition comprising insulin or an analogue thereof is administered to a subject who has or is suspected of having inflammatory bowel disease during a period of disease remission.

[0267] In one implementation, a composition comprising insulin or an analogue thereof is administered to a subject who has or is suspected of having inflammatory-induced colorectal tumors and / or cancer during the acute phase and / or recurrence of the disease.

[0268] In one implementation, a composition comprising insulin or an analogue thereof is administered to a subject who has or is suspected of having the disease during a period of disease remission.

[0269] In one embodiment, a composition comprising insulin or an analogue thereof is administered to a subject who has or is suspected of having mild to moderate ulcerative colitis.

[0270] In one implementation, a composition comprising insulin or an analogue thereof is administered to a subject who has or is suspected of having mild to moderate ulcerative colitis during the acute phase and / or recurrence of the disease.

[0271] In one implementation, a composition comprising insulin or an analogue thereof is administered to a subject who has or is suspected of having mild to moderate ulcerative colitis during a period of disease remission.

[0272] In one embodiment, a composition comprising insulin or an analogue thereof is administered to a subject in need, wherein the subject presents with one or more of the following symptoms: abdominal pain, vomiting, chronic diarrhea, rectal bleeding, severe internal colic / muscle spasm in the pelvic region, weight loss, deep geographic and creeping ulcers, continuous ulcers, transmural inflammation, mucosal inflammation, stricture, granulomas found on biopsy (e.g., non-necrotizing non-pericardial crypt granulomas), elevated fecal calprotectin levels, anemia, thrombocytosis, histological findings of rectal tissue abnormalities, fistulas or abscesses in any segment of the gastrointestinal tract, or toxic megacolon.

[0273] In one embodiment, a composition comprising insulin or an analogue thereof is administered to a subject who has been diagnosed with inflammatory bowel disease and / or inflammatory-induced colorectal tumors and / or cancer.

[0274] manufacture

[0275] In one embodiment, the composition of this disclosure is manufactured by a method comprising: a. Mix the polymer with an activator, and optionally with a lubricant; b. Extruding microparticles containing at least one polymer and having a size of 100 to 2000 µm, and optionally rounding them; c. The microparticles are mixed with the surfactant and effervescent reagent to obtain a mixture; d. Seal the mixture. The composition disclosed herein is thus obtained.

[0276] In one embodiment, the microparticles are manufactured using the method described in Example 1. In another embodiment, the microparticles are manufactured using the extrusion method described in Example 1.

[0277] In one embodiment, the composition of this disclosure is manufactured by a method comprising: a. Suspend the polymer, surfactant, and optional lubricant in a solvent; b. Stir until the solvent has evaporated, collect and wash the particles containing at least one polymer and with a size of 100 to 2000 µm; c. The microparticles are mixed with the surfactant and effervescent reagent to obtain a mixture; d. Seal the mixture. The composition disclosed herein is thus obtained.

[0278] In one embodiment, the microparticles, polymers, surfactants, and effervescent agents used in the manufacture are as defined in other parts of the specification.

[0279] In one embodiment, a method of manufacturing the composition disclosed herein further includes adding at least one coating layer, wherein the at least one coating layer is defined as in other parts of the specification.

[0280] Example

[0281] Example 1. Preparation of microparticles and analysis of insulin release and capsule rupture.

[0282] Materials and Methods : Material ： Recombinant human insulin (Bioton SA), recombinant monoclonal antibody against tumor necrosis factor α (infliximab; Sigma), Celllets (IPC Process-Center), caffeine (AppliChem), microcrystalline cellulose (MCC, Avicel PH-101), magnesium stearate (MS), MgCl2, NaHCO3, citric acid, sodium butyrate (Sigma).

[0283] Insulin microspheres

[0284] Dissolve insulin (80 mg) in 5.3 mL of 10 mM HCl. Mix magnesium stearate (50 mg) with 1.625 g of MCC in a mortar. After proper mixing, add another 1.625 g of MCC and mix further, then add another 1.625 g of MCC and mix again. Wet the powder mixture with 5.0 mL of insulin solution slowly to achieve a liquid addition of 1.0 mL / g. Extrude the uniformly moistened insulin-containing powder mixture using a Caleva Multi Lab instrument with a 1 mm die and an extrusion speed of 300-500 RPM. Refeed the extrudate into the extruder until it reaches a suitable compaction state. Immediately spheronize the final, still moistened extrudate at 3000 RPM for 5 min and dry the pellets under vacuum overnight.

[0285] The composition after drying is: insulin 75 mg (1.5%), MCC: 4875 mg (97.5%), MS: 50 mg (1.0%).

[0286] The microspheres are sieved through relevant pore sizes, and fractions from 250 µm to 1400 µm are collected. In some cases, mannitol is mixed with the MCC / MS mixture before being added to the insulin solution. In these cases, mannitol is added to the MCC / MS mixture, for example, at an MCC to mannitol ratio of 2:1 and 5:1, without altering the composition of insulin % and MS % in the MCC / MS mixture.

[0287] Sodium butyrate microspheres

[0288] Equal amounts (w / w) of MCC and sodium butyrate were mixed with 1% magnesium stearate, extruded, then spheroidized (as described above for insulin) and sieved to obtain microspheres with a size of approximately 1000 µm. The microspheres were further coated with poly(ethyl acrylate, methyl methacrylate, 2-trimethylammonium ethyl methacrylate chloride, 10% quaternary ammonium group) (Eudragit RL) (theoretical weight gain 8%), and then further coated with poly(ethyl acrylate, methyl methacrylate, 2-trimethylammonium ethyl methacrylate chloride, 5% quaternary ammonium group) (Eudragit RS) (theoretical weight gain 12%). Coating was performed using FC-LAB MicroFLO-COATER®.

[0289] Caffeine microcapsules

[0290] MCC and caffeine were mixed in a 4:1 ratio, and then 1% magnesium stearate was added. Microspheres were prepared by extrusion / spheronization (as described above for insulin), with a target microsphere size of 1000 µm.

[0291] Infliximab microparticles

[0292] Infliximab was purchased from Sigma and mixed with MCC at a ratio of 1:1000, followed by the addition of 1.23% magnesium stearate. Microspheres were prepared by extrusion / spheronization (as described above for insulin), with a target microsphere size of 1000 µm.

[0293] HMPC and gelatin capsules were filled with microspheres, sodium bicarbonate, and citric acid and then sealed. Effervescent formulations were mixed at a 1:3 molar ratio (citric acid to NaHCO3). For enteric coating, capsules were impregnated in a 10% (w / v) solution of poly(methacrylic acid-co-methyl methacrylate copolymer (1:2)) (also sold under the trade name Eudragit® S 100) in isopropanol:water (98:2 v / v). The capsule caps were first immersed in the coating solution and allowed to dry before immersing the capsule bodies. The impregnation process was repeated to ensure coating integrity.

[0294] Analysis of insulin release from the microspheres: Microparticles were placed in glass tubes and separated by a grid. Phosphate-buffered saline (PBS, pH 7.0) was injected into the tubes, and a magnetic rod was placed above the grid to prevent direct contact between the rod and the separated microparticles (Knopp et al., 2022). The system was placed in a magnetic stirrer. The buffer was sampled periodically, and the amount of intact insulin in the samples was quantitatively analyzed by HPLC.

[0295] Capsule rupture analysis

[0296] Fill petri dishes with PBS (pH 7.4) and add one capsule to each dish. Place three petri dishes at a time on a heated rotating platform. Mount a GoPro camera above the platform and record the entire experiment. Set the platform temperature to 37°C. After adding the capsules (one per petri dish), the experiment begins with a static incubation period 1 (1.5 to 3 minutes, depending on the experiment) without any shaking, followed by starting the rotating platform (approximately 15-20 rpm). The experiment ends when all capsules rupture and release the microspheres.

[0297] Example 2. Effervescent reagents increased the area covered by microspheres after gelatin capsules ruptured.

[0298] Gelatin capsules (No. 2) were filled with microspheres containing insulin microcrystalline cellulose. Additionally, MgCl2 was added to some capsules as an exothermic agent, expected to accelerate the dissolution of the gelatin capsules. Alternatively, a citric acid and sodium bicarbonate (NaHCO3) effervescent pair in a molar ratio of 1:3 was added. The capsules were placed in petri dishes on a heated rotating platform. Static incubation for 3 minutes resulted in hydration and rupture of all three types of capsules (control, NaHCO3 / citric acid, MgCl2), with no difference in the time required for capsule rupture. Figure 1 B). To simulate intestinal peristalsis, incubation continued for 4 minutes with gentle rocking. This resulted in ( Figure 1 (C) A significant difference was observed between capsules containing effervescent pairs and those containing MgCl2, indicating a larger area covered by the microspheres. Furthermore, by gently tilting the culture dish manually after the orbital shaking ended, it was observed that microspheres from the control capsules and the MgCl2-containing capsules adhered more firmly to the hydrated gelatin mesh compared to those released from capsules containing effervescent pairs. Based on this preliminary experiment, the following experimental design was adopted to continue the experiment, starting with a short settling period followed by a longer period of gentle orbital shaking.

[0299] In subsequent experiments, HPMC capsules were used instead of gelatin capsules. HPMC capsules hydrated more slowly than gelatin capsules. After 2.5 minutes of static incubation, all three types of capsules (control (i), NaHCO3-) showed improved hydration rates. 3 / Citric acid (ii) and MgCl2 (iii) remained intact, and no microsphere release was observed. Figure 2 B). Bubbles were visible in the capsules containing NaHCO3 / citric acid. Further 5-minute orbital shaking incubation resulted only in the capsules containing NaHCO3 / citric acid rupturing and releasing microspheres (B). Figure 2 C). The released microspheres covered most of the culture dish. The other two types of capsules remained intact, and no microspheres were observed to be released from these capsules.

[0300] Example 3. Effervescence does not affect insulin release.

[0301] The effects of citric acid and sodium bicarbonate effervescent agents, or MgCl2 exothermic agents, on insulin release from microcrystalline cellulose pellets were investigated. Figure 3 As can be seen from the HPLC analysis, effervescence has no effect on the percentage of insulin release. Conversely, the addition of MgCl2 leads to a decrease in the percentage of insulin release. Figure 3 A, 3B).

[0302] Example 4. Determining the optimal ratio of effervescent pairs to microcapsules in HPMC .

[0303] The effect of varying the effervescent pair ratio on the rupture time of HPMC capsules was investigated. A 5:1 w / w ratio between the amount of microparticles (710µm-1000µm in size) and the amount of effervescent pair was found to be optimal. This 5:1 ratio resulted in the fastest capsule rupture and microparticle release compared to other ratios tested (2:1 and 1:1). This was not due to incomplete dissolution of the effervescent pair, as the 1:1 ratio using 135 mg of effervescent pair produced the highest amount of CO2 bubbles. Therefore, despite the high CO2 production at the 1:1 ratio, the capsule rupture efficiency was inferior compared to using only 45 mg of effervescent pair (5:1 ratio). Figure 4This was further confirmed in more quantitative experiments. Figure 13 The time to first release of the microcapsules was measured as a function of the amount of effervescent pair added (citric acid and sodium bicarbonate; molar ratio 3:1). In this experiment, the amount of microcapsules was kept constant at 225 mg. Adding 20 mg of effervescent pair did not significantly differ the time to first release from the microcapsules compared to capsules without effervescent pair. Adding 45 mg of effervescent pair significantly shortened the time to first release, but increasing the amount of effervescent pair to 90 mg did not significantly shorten the time to first release compared to adding 45 mg of effervescent pair.

[0304] Example 5. Compared to smaller microsphere sizes, larger microsphere sizes accelerate capsule rupture more efficiently.

[0305] Microspheres of different sizes (710µm–1000µm, 400µm–710µm, and 250µm–400µm) and effervescent pairs (NaHCO3 and citric acid) were filled into HPMC capsules. The weight of the microspheres and the amount of effervescent pairs were kept constant. After incubation on a heated rotating table for 2 minutes, gentle rocking was performed. After rocking for 1 minute (i.e., a total incubation time of 3 minutes), the capsules with the largest microsphere diameter ruptured and began to release the microspheres. Figure 5 B). Capsules with medium-sized pellets (400µm–710µm) ruptured after 3 minutes of further orbital shaking (total 6 minutes). Figure 5 C), while capsules with the smallest pellet size begin to release after further orbital shaking for 1 minute (after a total incubation time of 7 minutes). Figure 5 D). Using products with 400-700 respectively m and 700-1000 The experiment was repeated with two different microsphere sizes (m). Figure 6 The results were similar, namely, capsules with microspheres of the largest diameter ruptured earlier than capsules with microspheres of the smaller diameter.

[0306] Example 6. Ejection of microspheres from capsules coated with poly(methacrylate-co-methyl methacrylate copolymer (1:2)) (Eudragit® S100) enteric coating.

[0307] HPMC capsules coated with enteric-coated poly(methacrylic acid-co-methyl methacrylate copolymer (1:2)) dissolved more slowly at pH 7.3 than uncoated HPMC capsules. Figure 7 B). However, by adding effervescent pairs and incubating for 10-12 minutes, the microspheres were observed to be actively ejected from the capsule along with CO2 bubbles. Figure 7 C).

[0308] The capsules tested contained 180 mg of microspheres (400-710 μm) and 90 mg of effervescent pair (citric acid: sodium bicarbonate, molar ratio 1:3).

[0309] Example 7. Recovery rate study.

[0310] Recovery studies were conducted on three different types of microparticles: MCC:mannitol (2:1) / insulin, MCC:mannitol (5:1) / insulin, and MCC / insulin. Recovery studies were performed by agitating the microparticles in the release medium.

[0311] MCC / insulin microparticles (microparticles composed of MCC and insulin) release 60% of insulin within 6 hours and 80% of insulin within 24 hours. Figure 8 MCC:mannitol (2:1) / insulin microparticles (microparticles composed of MCC, mannitol, and insulin) released 80% of insulin within 1 hour and 90% within 6 hours. MCC:mannitol (5:1) / insulin microparticles (microparticles composed of MCC, mannitol, and insulin) released 80% of insulin within 4 hours and 90% within 6 hours. MCC:mannitol (5:1) / insulin microparticles showed complete insulin release within 24 hours.

[0312] Example 8. Testing of components that can be used in this invention.

[0313] Sodium butyrate

[0314] Commercial Use: Sodium butyrate is sold to retail consumers as a nutritional supplement compound. The product is available in enteric-coated capsules and granules.

[0315] Analysis of the manufactured microspheres: In PBS buffer at pH 7.0, microspheres coated with Eudragit RS (poly(ethyl acrylate, methyl methacrylate, 2-trimethylammonium ethyl methacrylate chloride, 5% quaternary ammonium group) released 50% sodium butyrate after one hour. Figure 9 A).

[0316] caffeine

[0317] Commercial Uses: Caffeine is a natural extract from coffee beans. It is present in coffee and is also added as an additive to soft drinks. Caffeine is also sold in tablet form. In medical and pharmaceutical research, caffeine can be used as a tracer in experiments measuring the release of water-soluble compounds from orally administered tablets and capsules.

[0318] Analysis of the manufactured microspheres: 50% caffeine was released after 20 min in PBS buffer at pH 7.0. Figure 9 B).

[0319] insulin

[0320] Commercial Use: Insulin is a drug approved for the treatment of diabetes. Insulin is available in solution form and can be administered intravenously or subcutaneously. Insulin has also been developed as a local treatment for inflammatory bowel disease.

[0321] Analysis of the manufactured microspheres: 50% insulin was released after 2 hours in PBS buffer. Figure 9 C).

[0322] Infliximab

[0323] Commercial use. Infliximab is a brand name for a monoclonal antibody that binds to tumor necrosis factor-α (TNF-α). Infliximab is an approved drug administered intravenously to patients to suppress inflammation in certain autoimmune diseases, such as rheumatoid arthritis and inflammatory bowel disease.

[0324] Analysis of the manufactured microspheres: After 1 hour in PBS buffer, 40% of the infliximab antibody was released. After 1 hour, the release continued in a nearly linear manner until 80% was released after 32 hours of incubation. Figure 9 D).

[0325] Example 9. Effect of sodium butyrate on coating

[0326] A) For example, 275 mg of sodium butyrate / MCC microspheres (in a 1:1 ratio) can be filled into capsule #2. The release of sodium butyrate from uncoated microspheres is rapid. Figure 10 A) 85% is released within 6 minutes. The maximum recovery rate of sodium butyrate is 90%.

[0327] To achieve delayed release of sodium butyrate compatible with local treatment, microspheres were first coated with poly(ethyl acrylate, methyl methacrylate, 2-trimethylammonium ethyl methacrylate chloride, 10% quaternary ammonium group) (Eudragit RL) (theoretical weight gain 8%), and then further coated with poly(ethyl acrylate, methyl methacrylate, 2-trimethylammonium ethyl methacrylate chloride, 5% quaternary ammonium group) (Eudragit RS) (theoretical weight gain 12%). Microspheres coated with both Eudragit RL and Eudragit RS polymers exhibited delayed release curves of sodium butyrate after 90 minutes. The delayed-release coating with poly(ethyl acrylate, methyl methacrylate, 2-trimethylammonium ethyl methacrylate chloride, 10% quaternary ammonium group) (Eudragit RL) itself did not produce microspheres with delayed-release properties, as this coating only slightly shifted compared to uncoated microspheres. 。

[0328] B) Sodium butyrate release profiles for microspheres manufactured using the double-coated method (Example 9A) were tested, either as bulk microspheres or as microspheres filled into capsules along with an effervescent pair of citric acid and sodium bicarbonate (molar ratio 3:1). Release profiles of microspheres in capsules ( Figure 10 B) The capsule shifted to the right by approximately 15 minutes. Therefore, the encapsulation delayed the release of sodium butyrate from the microspheres until capsule rupture occurred. No signs of premature leakage of sodium butyrate from the capsules were observed; the capsules described in this experiment were unencapsulated HPMC capsules. In our experiments, such capsules typically detach the first microsphere after 4–5 minutes when containing effervescent pairs simultaneously.

[0329] Example 10. Adding effervescent agents to capsules reduced the influence of the microparticle-carrier chemical composition on release kinetics.

[0330] In the release study, capsules filled with commercially available microcrystalline cellulose microspheres (350 µm) without a flow aid, or capsules filled with internally prepared microcrystalline cellulose microspheres (350 µm) with an added flow aid (stearate), were tested, and the time to first release of the microspheres was measured. Figure 11 Without the addition of an effervescent pair, a significant difference was observed in the initial release time of microcapsules between MCC microcapsules (detached after approximately 6 minutes) and MCC+stearate microcapsules (released after approximately 9 minutes). The addition of the effervescent pair (citric acid and sodium bicarbonate, molar ratio 3:1) shortened the initial release time for both microcapsule types. Furthermore, no significant difference in microcapsule release time was observed in the presence of the effervescent pair. Therefore, the addition of the effervescent pair provides release kinetics independent of the carrier material composition.

[0331] Example 11. Area covered by microspheres as a function of time

[0332] A) HPMC capsules filled with 350µm diameter MCC microspheres and with or without added citric acid and sodium bicarbonate (3:1 molar ratio) were tracked by video recording for 15 minutes.

[0333] After 5 minutes, it was clear that adding effervescent pairs resulted in more consistent microsphere release, as all three capsules with effervescent pairs released between 39 and 70 microspheres. Without effervescent pairs, one capsule released no microspheres after 5 minutes, another released very few (10), and the last capsule released 50 microspheres. Due to the high variability, the average difference in the number of microspheres released was not statistically significant.

[0334] B) After 15 minutes of incubation, all capsules released microspheres. To quantify the coverage area, circles were drawn around the microsphere clouds using the selection tool in Adobe Photoshop. The drawn circles contained 90% of the released microspheres, thus excluding individual microspheres that had moved away from the main microsphere cloud as outliers. The area of ​​the circles was then measured (in pixels). Adding effervescent pairs resulted in a 40% increase in the covered surface area. Figure 12 B, p<0.05, unpaired t-test). Without effervescent pairs in the capsules, the average circle area was 5487 pixels, while with effervescent pairs added, the average circle area was 7670 pixels.

[0335] References

[0336] Bansal V, Malviya R, Malaviya T, Sharma PK. Novel prospective incolon specific drug delivery system. Polim Med. 2014;44(2):109-118.

[0337] Knopp, MM; Kiil-Nielsen, NK; Masser, AE; Staaf, M. Introducing a Novel Biorelevant In Vitro Dissolution Method for the Assessment of Nicotine Release from Oral Tobacco-Derived Nicotine (OTDN) and Snus Products. Separations 2022, 9, 52.

[0338] Lesczek Krowczynski, Extended-Release Dosage Forms, 1987 (CRC Press,Inc.)

[0339] Loyd, V. Allen, Remington: The Science and Practice of Pharmacy,Twenty-first Ed., (Pharmaceutical Press, 2005; P.J. Tarcha, Polymers forControlled Drug Delivery, Chapter 3, CRC Press, 1991.

[0340] Sagar Muley, Tanaji Nandgude, Sushilkumar Poddar,: Extrusion–spheronization a promising pelletization technique: In-depth review, AsianJournal of Pharmaceutical Sciences, Volume 11, Issue 6, 2016, Pages 684-699.

[0341] Santos, J., da Silva, G.S., Velho, M.C., Beck, R.C.R.: Eudragit®: AVersatile

[0342] Family of Polymers for Hot Melt Extrusion and 3D Printing Processesin Pharmaceutics. Pharmaceutics, 2021, 13, 1424.

[0343] Wang QS, Wang GF, Zhou J, Gao LN, Cui YL. Colon targeted oral drugdelivery system based on alginate-chitosan microspheres loaded with icariinin the treatment of ulcerative colitis. Int J Pharm. 2016 Dec 30;515(1-2):176-185GB 2367002 A

[0344] US 2006 / 045822 A1; WO 2001 / 76562 A1; WO 2003 / 068196 A1;WO 2007 / 122374A2;

[0345] WO 2008 / 135090 A1; WO 2020 / 115277 A1。

Claims

1. A composition for oral administration of an active agent, the composition comprising... a. Particles with a size of 100µm to 2000µm, said particles comprising a polymer and an active agent. b. Effervescent reagent, The w / w ratio of the microparticles to the effervescent reagent is between 7:1 and 1.5:1, and the composition is encapsulated.

2. The composition according to claim 1, wherein the composition is a modified release composition.

3. The composition according to claim 2, wherein the composition releases the active agent at least 1 hour after application, for example at least 2 hours after application, for example at least 3 hours after application, for example at least 4 hours after application, for example 6 to 8 hours after application, for example 10 to 20 hours after application.

4. The composition according to any one of the preceding claims, wherein the size of the particles is from 150µm to 2000µm, for example, from 150µm to 1500µm, for example, from 150µm to 1000µm, for example, from 150µm to 800µm, for example, from 150µm to 700µm, for example, from 150µm to 600µm, for example, from 200µm to 600µm.

5. The composition according to any one of the preceding claims, wherein the particle size is 100µm to 2000µm, for example 150µm to 2000µm, for example 200µm to 2000µm, for example 250µm to 2000µm, for example 300µm to 2000µm, for example 350µm to 2000µm, for example 400µm to 2000µm, for example 245µm to 2000µm, for example 500µm to 2000µm, 550µm to 2000µm, for example 600µm to 2000µm, for example 650µm to 2000µm, for example 650µm to 2000µm, for example 60 ... The size ranges from 700µm to 2000µm, for example, the size ranges from 700µm to 2000µm, for example, the size ranges from 700µm to 1900µm, for example, the size ranges from 700µm to 1000µm, for example, the size ranges from 700µm to 1100µm, for example, the size ranges from 800µm to 2000µm, for example, the size ranges from 900µm to 2000µm, for example, the size ranges from 1000µm to 2000µm, for example, the size ranges from 1200µm to 2000µm, for example, the size ranges from 1300µm to 2000µm, for example, the size ranges from 1400µm to 2000µm, for example, the size ranges from 1500µm to 2000µm.

6. The composition according to any one of the preceding claims, wherein the particle size is from 250µm to 1000µm.

7. The composition according to any one of the preceding claims, wherein the effervescent agent is an effervescent pair comprising or composed of the following: a. Bases, such as those selected from sodium bicarbonate, potassium bicarbonate, and sodium carbonate. b. Acids, such as those selected from citric acid, maleic acid and tartaric acid.

8. The composition according to any one of the preceding claims, wherein the effervescent reagent comprises or is composed of citric acid and bicarbonate in a molar ratio of 1 mole of citric acid to 3 moles of sodium bicarbonate.

9. The composition according to any one of the preceding claims, wherein the ratio of the microparticles to the effervescent reagent is between 7:1 and 1.5:1, for example between 6:1 and 4:1, for example 1.6:1, for example 2.5:1, for example 3:1, for example 5:

1.

10. The composition according to any one of the preceding claims, wherein the ratio of microparticles to effervescent reagent is between 7:1 and 3:

1.

11. The composition according to any one of the preceding claims, wherein the ratio of the microparticles to the effervescent reagent is between 6:1 and 4:1, for example, about 3:

1.

12. The composition according to any one of the preceding claims, wherein the size of the microparticles is from 710µm to 1000µm, wherein the effervescent agent is citric acid and sodium bicarbonate, and wherein the ratio of microparticles to effervescent agent is 5:

1.

13. The composition according to any one of the preceding claims, wherein the polymer is selected from microcrystalline cellulose, acrylic polymers such as Eudragit® RL and Eudragit® RS, polyethylene oxide, starches such as amylose, amylopectin and maltodextrin, starch derivatives such as dextrin, acid-treated starch, alkali-treated starch, acetic acid starch, bleached starch, alginates, pullulan, stearyl glucan, povidone derivatives such as crospovidone (PVPP) and copovidone, natural gums, gelatin, chitosan, polyvinyl alcohol and combinations thereof.

14. The composition according to any one of the preceding claims, wherein the concentration of the polymer in the microparticles is 94% to 98.9% (w / w), for example 97% to 98% (w / w).

15. The composition according to any one of the preceding claims, wherein the particles comprise a diluent, such as a diluent selected from lactose, dicalcium phosphate, starch, and sugar alcohols such as mannitol, xylitol, and sorbitol, and combinations thereof.

16. The composition according to any one of the preceding claims, wherein the microparticles comprise microcrystalline cellulose and mannitol in a ratio of 2:1 (w / w) to 6:1 (w / w), for example, a ratio of 5:1 (w / w).

17. The composition according to any one of the preceding claims, wherein the microparticles comprise microcrystalline cellulose and Eudragit® RL in a ratio of 4:

1.

18. The composition according to any one of the preceding claims, wherein the microparticles comprise one or more additives.

19. The composition according to any one of the preceding claims, wherein the concentration of the additive in the microparticles is 0.1% to 2% (w / w), for example about 1% (w / w).

20. The composition according to any one of the preceding claims, wherein the microparticles comprise a lubricant, such as a lubricant selected from magnesium stearate, stearic acid, and talc and combinations thereof.

21. The composition according to any one of the preceding claims, wherein the active agent is selected from biological agents, therapeutic peptides, small molecule drugs, bacteria, probiotics, prebiotics, bacteriophages, and natural products.

22. The composition according to any one of the preceding claims, wherein the active agent is a biotherapeutic peptide, such as a biotherapeutic peptide selected from proteases, peptidases, disaccharidases, oligosaccharides, lipases, growth factors, extracellular matrix proteins such as laminin, collagen, glycosaminoglycans, proteoglycans, mucins and analogues.

23. The composition according to any one of the preceding claims, wherein the active agent is a biological agent, such as a biological agent selected from, for example, monoclonal antibodies, vaccines, and modified or unmodified mRNA having vaccine properties.

24. The composition according to any one of the preceding claims, wherein the active agent is a therapeutic peptide.

25. The composition according to any one of the preceding claims, wherein the active agent is a therapeutic peptide, such as insulin or an analogue thereof.

26. The composition according to any one of the preceding claims, wherein the active agent is insulin or an analogue thereof, such as an analogue selected from insulin aspart, insulin lispro, insulin glutares, insulin glargine, insulin detemir, and insulin degludec.

27. The composition according to any one of the preceding claims, wherein the active agent is a therapeutic antibody, such as adalimumab, golimumab, or infliximab.

28. The composition according to any one of the preceding claims, wherein the active agent is a small molecule drug, such as sodium butyrate.

29. The composition according to any one of the preceding claims, wherein the active agent is a tracer molecule, such as caffeine.

30. The composition according to any one of the preceding claims, wherein the active agent is a small molecule, such as caffeine.

31. The composition according to any one of the preceding claims, wherein the concentration of the active agent in the composition is at most 6% (w / w), for example at most 5% (w / w), for example at most 4% (w / w), for example at most 3.5% (w / w), for example at most 3% (w / w), for example at most 2.5% (w / w), for example at most 2% (w / w), for example at most 1.5% (w / w), for example at most 1.3% (w / w), for example at most 1% (w / w), for example at most 0.5% (w / w).

32. The composition according to any one of the preceding claims, wherein the composition is encapsulated in an encapsulation layer.

33. The composition according to any one of the preceding claims, wherein the encapsulating layer comprises an encapsulating polymer selected from: gelatin, cellulose, methacrylic acid copolymers such as Eudragit® L100 (CAS No.: 25086-15-1), Eudragit® S100 (CAS No.: 25086-15-1), Eudragit® L-30D (CAS No.: 100218-76-6 or 25212-88-8), Eudragit® FS 30D (CAS No.: 26936-24-3), and Eudragit® L100-55 (CAS No.: 25212-88-8), cellulose acetate phthalate, cellulose trimellitate phthalate, polyvinyl acetate phthalate, hydroxyethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, chitosan, pullulan, stearin, alginate, alginate derivatives or shellac, or an aqueous dispersion thereof.

34. The composition according to any one of the preceding claims, wherein the composition further comprises at least one coating layer.

35. The composition according to any one of the preceding claims, wherein at least one coating layer covers the microparticles.

36. The composition according to any one of the preceding claims, wherein at least one coating layer is an enteric coating, such as Eudragit® S 100.

37. The composition according to any one of the preceding claims, wherein at least one coating layer covers the encapsulating layer.

38. The composition according to any one of the preceding claims, wherein at least one coating layer is a pH-sensitive coating, such as a coating that dissolves at pH 5.5 or higher, such as a coating that dissolves at pH 5.5 to 8, such as a coating that dissolves at pH 6 or higher, such as a coating that dissolves at pH 7 or higher.

39. The composition according to any one of the preceding claims, wherein at least one coating layer is an enteric coating.

40. The composition according to any one of the preceding claims, wherein at least one coating layer is a coating that dissolves under conditions present in the mammalian intestine, such as in the primate intestine.

41. The composition according to any one of the preceding claims, wherein at least one coating layer is a coating that dissolves under conditions present in the mammalian large intestine, such as in the human large intestine.

42. The composition according to any one of the preceding claims, wherein at least one coating layer is an alginate or an alginate derivative.

43. The composition according to any one of the preceding claims, wherein at least one coating layer covers the microparticles.

44. The composition according to any one of the preceding claims, wherein at least one coating layer covering the microparticles is Eudragit RL.

45. The composition according to any one of the preceding claims, wherein at least one coating layer covering the microparticles is Eudragit RS.

46. ​​The composition according to any one of the preceding claims, wherein at least one coating layer covering the microparticles is a mixture of Eudragit RL and Eudragit RS.

47. The composition according to any one of the preceding claims, wherein the microparticles are coated with one or more layers of Eudragit RL and one or more layers of Eudragit RS.

48. The composition according to any one of the preceding claims, wherein the theoretical weight gain introduced by at least one coating layer covering the microparticles is at least 2%, for example 4%, for example 6%, for example 8%, for example 10%, for example 12%, for example 14%, for example 20%, for example 25%.

49. The composition according to any one of the preceding claims, wherein the theoretical weight gain introduced by the Eudragit RL coating layer is at least 2%, for example 4%, for example 6%, for example 8%, for example 10%, for example 12%, for example 14%, for example 20%.

50. The composition according to any one of the preceding claims, wherein the theoretical weight gain introduced by the Eudragit RS coating layer is at least 2%, for example 4%, for example 6%, for example 8%, for example 10%, for example 12%, for example 14%, for example 20%.

51. The composition according to any one of the preceding claims, wherein at least one coating layer is an enteric coating that dissolves under conditions present in the mammalian intestine, such as under conditions present in the human small intestine and / or colon.

52. The composition according to any one of the preceding claims, wherein the microparticles are produced by extrusion and spheroidization, or by solvent evaporation.

53. The composition according to any one of the preceding claims, wherein the particles are spherical.

54. A method for manufacturing the composition according to any one of the preceding claims, the method comprising: a. Mix the polymer with an activator, and optionally with a lubricant; b. Extruding microparticles comprising at least one polymer and having a size of 100 to 2000 µm and optionally rounding the microparticles; c. Mix the microparticles with the surfactant and effervescent reagent to obtain a mixture; d. Seal the mixture. Thus, the composition according to any one of claims 1 to 53 is obtained.

55. A method for manufacturing the composition according to any one of the preceding claims, the method comprising: a. Suspend the polymer, surfactant, and optional lubricant in a solvent; b. Stir until the solvent has evaporated, collect and wash the particles containing at least one polymer and with a size of 100 to 2000 µm; c. Mix the microparticles with the surfactant and effervescent reagent to obtain a mixture; d. Seal the mixture. Thus, the composition according to any one of claims 1 to 53 is obtained.

56. The method according to claims 54 and 55, wherein the microparticles, polymers, surfactants, and effervescent agents are as defined in any one of claims 7 to 12.

57. The method according to any one of claims 54 to 56, further comprising adding at least one coating layer, wherein the at least one coating layer is defined as in any one of claims 34 to 51.

58. The method of claim 55, wherein the solvent is an organic solvent, such as a low-boiling-point organic solvent, such as acetone.

59. The composition according to any one of the preceding claims, used as a medicine.

60. The composition for use according to claim 59, wherein the composition is applied to an individual in need.

61. The composition for use according to any one of claims 59 and 60, wherein the composition releases the active agent in the intestine of the individual in need.

62. The composition for use according to any one of claims 59 to 61, wherein the composition releases the active agent in the small intestine of the individual in need.

63. The composition for use according to any one of claims 59 to 62, wherein the composition releases the active agent in the large intestine, for example, in the colon, of the individual in need.

64. The composition according to any one of claims 1 to 53, for treating inflammatory bowel disease and / or inflammatory-induced colorectal tumors and / or cancer, wherein the active agent comprises or is composed of insulin or an analogue thereof.

65. The composition according to any one of claims 1 to 53, for repairing the colonic mucosa of a subject suffering from or suspected of suffering from inflammatory bowel disease and / or inflammatory-induced colorectal tumors and / or cancer, wherein the active agent comprises or is composed of insulin or an analogue thereof.

66. The composition for use according to any one of claims 64 and 65, wherein the composition comprises 100 IU to 1000 IU, for example 200 IU to 1000 IU, for example 300 IU to 1000 IU, for example 400 IU to 1000 IU, for example 500 IU to 1000 IU, for example 600 IU to 1000 IU, for example 700 IU to 1000 IU, for example 800 IU to 1000 IU, or an analogue of insulin.

67. The composition for use according to any one of claims 64 to 66, wherein the composition comprises 1 mg to 35 g of insulin or an analogue thereof, for example 3 mg to 35 g of insulin, for example 10 mg to 35 g of insulin or an analogue thereof, for example 50 mg to 35 g of insulin or an analogue thereof, for example 100 mg to 35 g of insulin or an analogue thereof, for example 1 g to 35 g of insulin or an analogue thereof, for example 10 g to 35 g of insulin or an analogue thereof, for example 20 g to 35 g of insulin or an analogue thereof.

68. The composition for use according to any one of claims 64 to 67, wherein the total daily insulin dose is 100 IU to 1000 IU, for example 200 IU to 1000 IU, for example 300 IU to 1000 IU, for example 400 IU to 1000 IU, for example 500 IU to 1000 IU, for example 600 IU to 1000 IU, for example 700 IU to 1000 IU, for example 800 IU to 1000 IU, or an insulin or analogue thereof.

69. The composition for use according to any one of claims 64 to 68, wherein the composition is applied to the individual in need at most four times a day, for example at most three times a day, for example at most two times a day, for example at most once a day, for example at most once every 48 hours.

70. The composition for use according to any one of claims 64 to 69, wherein the composition is applied to the individual in need three times a day, for example twice a day, for example once a day, for example every other day.

71. The composition for use according to any one of claims 64 to 70, wherein the composition is applied to an individual in need for a period of at least 3 weeks, for example, at least 4 weeks, for example, at least 5 weeks, for example, at least 6 weeks, for example, at least 7 weeks, for example, for example, for life.

72. The composition according to any one of claims 64 to 71, wherein the composition is administered to an individual in need during remission of inflammatory bowel disease and / or inflammation-induced colorectal tumors and / or cancer for a period of 3 weeks to 3 months, for example 3 weeks to 4 months, for example 3 weeks to 5 months, for example 3 weeks to 6 months, for example 3 weeks to 7 months, for example 3 weeks to 8 months, for example 3 weeks to 9 months, for example 3 weeks to 10 months, for example 3 weeks to 11 months, for example 3 weeks to 12 months, for example 3 weeks to 18 months, for example 3 weeks to 24 months.

73. The composition for use according to any one of claims 64 to 72, wherein the inflammatory bowel disease is selected from ulcerative colitis, diverted colitis, Behcet's disease, undifferentiated colitis, left-sided colitis, microscopic colitis such as collagenous colitis or lymphocytic colitis, Crohn's disease, non-infectious colitis, pouchitis, and immunotherapy-associated colitis.

74. The composition according to any one of claims 64 to 73, wherein the composition is administered during the acute phase and / or recurrence of the disease to a subject who has or is suspected of having inflammatory bowel disease and / or inflammatory-induced colorectal tumors and / or cancer.

75. The composition according to any one of claims 64 to 74, wherein the composition is administered during disease remission to a subject who has or is suspected of having inflammatory bowel disease and / or inflammatory-induced colorectal tumors and / or cancer.

76. The composition according to any one of claims 64 to 75, wherein the composition is administered to a subject who has or is suspected of having inflammatory bowel disease during the acute phase and / or relapse of the disease.

77. The composition according to any one of claims 64 to 76, wherein the composition is administered to a subject who has or is suspected of having inflammatory bowel disease during a disease remission period.

78. The composition according to any one of claims 64 to 77, wherein the composition is administered to a subject who has or is suspected of having inflammatory-induced colorectal tumors and / or cancer during the acute phase and / or recurrence of the disease.

79. The composition according to any one of claims 64 to 78, wherein the composition is administered to a subject who has or is suspected of having the disease during a disease remission period.

80. The composition according to any one of claims 64 to 79, wherein the composition is administered to a subject who has or is suspected of having mild to moderate ulcerative colitis.

81. The composition according to any one of claims 64 to 80, wherein the composition is administered to a subject who has or is suspected of having mild to moderate ulcerative colitis during the acute phase and / or recurrence of the disease.

82. The composition according to any one of claims 64 to 81, wherein the composition is administered during disease remission to a subject who has or is suspected of having mild to moderate ulcerative colitis.

83. The composition according to any one of claims 64 to 82, wherein the composition is administered to a subject in need, wherein the subject presents with one or more of the following symptoms: abdominal pain, vomiting, chronic diarrhea, rectal bleeding, severe internal colic / muscle spasm in the pelvic region, weight loss, deep geographic and creeping ulcers, continuous ulcers, transmural inflammation, mucosal inflammation, stricture, granulomas found on biopsy (e.g., non-necrotizing non-pericardial crypt granulomas), elevated fecal calprotectin levels, anemia, thrombocytosis, histological findings of rectal tissue abnormalities, fistulas or abscesses in any segment of the gastrointestinal tract, toxic megacolon.

84. The composition according to any one of claims 64 to 83, wherein the composition is administered to a subject who has been diagnosed with inflammatory bowel disease and / or inflammatory-induced colorectal tumors and / or cancer.

85. The composition for use according to any one of claims 64 to 84, wherein the composition does not cause cell proliferation in the small intestine.

86. The composition for use according to any one of claims 64 to 85, wherein the insulin has low or no systemic effect.

87. The composition for use according to any one of claims 64 to 86, wherein insulin does not affect systemic blood glucose levels.

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