Pharmaceutical compositions containing enterokine-releasing substances in multiple dosage forms in combination with gelling agents

Abstract

To provide pharmaceutical compositions for use in improved prevention and treatment of conditions associated with impairment of enterokine release by enteroendocrine cells and amenable to an increase in enterokine release by enteroendocrine cells.SOLUTION: This composition comprises multiple dosage forms, each dosage form comprising a core and an enteric coating; the core comprises at least one compound stimulating enteroendocrine cells to release at least one enterokine; size of each dosage form, with respect to a largest dimension of each dosage form, provides for entry of the dosage forms into an intestine of a subject independent of gastric emptying mechanisms; and the composition further comprises one or more gelling agents.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to pharmaceutical compositions and pharmaceutical products comprising such compositions, wherein the compositions comprise a plurality of dosage forms, each of which comprises a core and an enteric coating; the core comprises at least one compound that stimulates enteroendocrine cells to release at least one enterokine; the size of each dosage form, with respect to its largest dimension, provides for entry of each dosage form into the intestine of a subject independent of gastric emptying mechanisms; and the compositions further comprise one or more gelling agents. The present invention also relates to treating and / or preventing conditions responsive to stimulation of enterokinase release by enteroendocrine cells. [Background technology]

[0002] It has long been recognized that delivery of nutritional substances to the ileum using enteric dosage forms of the nutritional substance results in a feeling of satiety in a mammalian subject (Patent Document 1). More recently, specific delivery of nutritional substances, particularly glucose, to a subject's ileum, particularly delivery of nutritional substances such as glucose in multiple dosage forms (which multiple dosage forms release at least 50% of the administered substance in the subject's ileum), has been suggested for the treatment of metabolic diseases such as type 2 diabetes, metabolic syndrome, insulin resistance, obesity, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic fatty liver disease (NASH) (Patent Documents 2 to 4).

[0003] Co-pending Patent Publication No. 5 relates to a pharmaceutical oral dosage form comprising a core and a pH-sensitive enteric coating. The core comprises at least one compound that stimulates enteroendocrine cells to release at least one enterokine and at least one disintegrant that provides a burst release of the core components when the coating substantially degrades and / or dissolves; and the coating comprises a pH-sensitive polymer selected to substantially dissolve and / or degrade in the jejunum of a subject. Co-pending Patent Publication No. 6 relates to a combination of at least two pharmaceutical oral dosage forms used to prevent and / or treat a condition, disorder, or disease in a subject selected from the group consisting of insulin resistance, type 2 diabetes, non-alcoholic fatty liver disease, non-alcoholic fatty liver disease, microvascular dysfunction, metabolic syndrome, obesity, osteoporosis, neurodegenerative disease, cardiovascular disease, malabsorption conditions, and gastrointestinal dysfunction conditions. The combination comprises at least a first and a second dosage form, each of which comprises a core and a pH-sensitive enteric coating. Each core comprises at least one compound that stimulates enteroendocrine cells to release at least one enterokine and at least one disintegrant that provides a burst release of the core's components when the coating substantially degrades and / or dissolves. Each coating comprises a pH-sensitive polymer selected to substantially dissolve and / or degrade in a selected portion of the subject's small intestine. The first and second dosage forms are formulated so that the first dosage form releases the at least one compound that stimulates enteroendocrine cells to release at least one enterokine in different portions of the subject's small intestine. In contrast, the second dosage form and / or the first and second dosage forms are formulated so that the transit time of the first dosage form through the subject's small intestine is different from the transit time of the second dosage form through the subject's small intestine. The at least one compound that stimulates enteroendocrine cells to release at least one enterokine by the first and second dosage forms can be the same or different. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] U.S. Patent No. 5,753,253 [Patent Document 2] International Publication No. 2010 / 027498 [Patent Document 3] International Publication No. 2012 / 118712 [Patent Document 4] US Patent Application Publication No. 2014 / 0294951 [Patent Document 5] International patent application PCT / EP2019 / 084530 [Patent Document 6] International patent application PCT / EP2019 / 084531 Summary of the Invention [Problem to be solved by the invention]

[0005] The technical problem underlying the present invention is to provide improved means for the prevention and treatment of conditions associated with impaired enterokine release by enteroendocrine cells and / or responsive to increased enterokine release by enteroendocrine cells. [Means for solving the problem]

[0006] The solution to the above technical problem is provided by the embodiments of the present invention disclosed in the claims, this specification and the accompanying drawings.

[0007] In particular, the present invention provides a pharmaceutical composition comprising a plurality of dosage forms, each dosage form comprising a core and an enteric coating, said core comprising at least one compound that stimulates enteroendocrine cells to release at least one enterokine, wherein the size of each dosage form, with respect to its largest dimension, provides for entry of each dosage form into the intestine of a subject independent of gastric emptying mechanisms; and wherein said composition further comprises one or more gelling agents.

[0008] The drawings are shown below. [Brief explanation of the drawings]

[0009] [Figure 1] Figure 1 graphically depicts the time course of GLP-1 blood concentration (pmol / l) measurements in subjects (n=20) from 1 hour before to 10 hours after oral administration of a composition according to the present invention. Data shown are mean values ​​+ / - SEM. DETAILED DESCRIPTION OF THE INVENTION

[0010] A "dosage form" according to the present invention is itself an entity that typically and most preferably represents a pharmaceutical preparation suitable for oral administration to a subject, preferably a human subject. The dosage forms present in the pharmaceutical composition of the present invention are sized, i.e., have a size with respect to their largest dimension, such that when the pharmaceutical composition of the present invention is orally administered to a patient, the dosage forms enter the intestine independently of the gastric emptying mechanism, particularly peristaltic waves, antral contractions, and reduction in stomach size. That is, the dosage forms behave as a liquid with respect to the transition from the stomach to the intestine, particularly the duodenum, the most proximal part of the small intestine.

[0011] Those skilled in the art will understand that the parameters of the dosage forms (particularly the size of the dosage forms, the number of dosage forms in the compositions of the invention, and particularly the number of dosage forms in a unit dose of the compositions of the invention) are interdependent and typically depend on additional parameters (e.g., the specific type and amount of the active pharmacological ingredient (API), particularly the at least one compound that stimulates enteroendocrine cells to release at least one enterokine).

[0012] That is, the size of each dosage form present in the composition of the present invention, in terms of the maximum dimension of each dosage form, is typically about 3 mm or less, preferably about 0.6 mm to about 3.0 mm, more preferably about 0.6 mm to about 2.6 mm, even more preferably about 0.6 mm to about 1.7 mm, and most preferably about 0.8 mm to about 1.2 mm. The dosage forms contained in the composition of the present invention are typically in the form of pellets, beads, or granules, with beads, particularly round beads, being the preferred form.

[0013] The compositions of the present invention comprise a plurality of such dosage forms. The term "plurality of dosage forms" typically means that the composition comprises at least about 1,000, more preferably at least about 2,000, even more preferably at least about 3,000, particularly preferably at least about 5,000, and even more preferably at least about 10,000 dosage forms. A preferred range is about 1,000, about 2,000, about 3,000, or about 5,000, or even about 10,000 to about 20,000, about 30,000, about 40,000, or about 50,000 dosage forms per unit dose of the compositions of the present invention. A particularly preferred range is about 10,000 to about 40,000 dosage forms, with the most preferred compositions of the present invention comprising about 20,000 to about 30,000 dosage forms. For such embodiments in particular, the size of the dosage forms preferably ranges from about 0.6 mm to 1.7 mm, as defined above, and most preferably from about 0.8 mm to about 1.2 mm.

[0014] According to a particularly preferred embodiment of the present invention, the size and number of the multiple dosage forms contained in the pharmaceutical composition of the present invention are controlled as follows: The surface area of ​​the multiple dosage forms in the composition, particularly the surface area of ​​a unit dose of the composition, is selected to cover at least 15%, more preferably at least 20%, and particularly preferably at least about 25% of the target area where at least one active compound defined herein to induce enterokine release interacts with enteroendocrine cells. In this context, it will be understood that the target area is not necessarily limited to the area from which the core of the multiple dosage forms releases the active compound, and preferably is not limited in certain exemplary embodiments of the present invention. The target area of ​​the active compound typically depends on the type of enteroendocrine cell that induces the release of enterokine(s). In a preferred example, L cells, which are preferably induced by the active compound(s) contained in the core of the multiple dosage forms, are present in the small intestine from the duodenum to the ileum in humans, as further outlined below. However, enterokine-releasing capacity, particularly GLP-1-releasing capacity, increases from the proximal to the distal small intestine, particularly due to increased density and differentiation of enteroendocrine cells, and is highest in the terminal ileum. In a preferred embodiment of the present invention, particularly with regard to inducing L cells to release GLP-1 and / or PYY, preferably GLP-1, the enteric coating of the multiple dosage forms is selected to release at least one active compound from the core of the multiple dosage forms in the jejunum, preferably the terminal jejunum, of a subject. The surface area of ​​the multiple dosage forms of the composition of the present invention, preferably a unit dose of the composition, is selected as follows: This surface area is set to occupy about 10% to about 50%, preferably about 15 to about 35%, and more preferably about 20 to about 30% of the target portion of the intestine where the target cells, preferably L cells, have the highest concentration and / or enterokine-releasing capacity (the ileum, particularly the terminal ileum, for L cells). In this context, the term "surface area of ​​the target segment of the intestine" approximates the intestine as a tube with an average diameter of about 0.25 cm and a length of about 60 cm at the terminal ileum.

[0015] The pharmaceutical composition of the present invention further contains at least one gelling agent as an essential component. Gelling agents, also known as thickeners, are gel-forming agents that, when dissolved in a liquid phase as a colloidal mixture, form an internal structure with weak cohesion. Gelling agents are generally organic hydrocolloids or hydrophilic inorganic substances. Representative examples include tragacanth, pectin, starch, carbomer, polysaccharides, gelatin, cellulose derivatives, polyvinyl alcohol clay, and polyethylene glycol (for reviews, see, for example, Kar et al., "Current Developments in Excipient Science," Chapter 2.2.2.5 "Gelling Agents," and R. Tekade (ed.), Basic Fundamentals in Drug Delivery, Academic Press, Cambridge, MA, USA, 2019). As used herein, the term "at least one gelling agent" also includes compositions of one or more gelling agents, optionally in combination with other ingredients.

[0016] Preferred gelling agents, either for use alone or in gelling compositions containing a combination of such gelling agents, include, but are not limited to, modified celluloses (preferably substituted methylcelluloses (e.g., hydroxypropylmethylcellulose (HPMC))), polysaccharides (preferably alginates (e.g., sodium alginate)), and xanthan gum, as well as polyethylene glycols (PEGs) (preferably PEGs having an average molecular weight of about 10,000 Da to about 30,000 Da, more preferably 15,000 Da to about 25,000 Da, and most preferably about 20,000 Da). In preferred embodiments of the present invention, the composition contains two or more gelling agents to fine-tune the properties of the composition, particularly for fine-tuning specific designs of viscosity characteristics, each of which, when contained in or reconstituted with, a preferably pharmaceutically acceptable liquid medium (e.g., water or an aqueous solution), significantly improves the swallowability of the composition during use. Preferred combinations of gelling agents typically contain two, three, or four gelling agents in the form of a gelling composition. Particularly preferred combinations of gelling agents for use in the compositions of the present invention are selected from combinations of modified celluloses, polysaccharides and PEG(s), more preferably one or more of the preferred examples mentioned above.

[0017] The pharmaceutical compositions of the present invention can be provided in various forms. In a preferred embodiment, the pharmaceutical composition of the present invention contains a liquid medium (preferably water or an aqueous solution, more preferably a buffered aqueous solution) such that the multiple dosage forms and one or more gelling agents are present in the liquid medium. In another preferred embodiment of the present invention, at least one gelling agent, or, if at least one gelling agent is present in a gelling composition, the gelling composition and the multiple dosage forms can form a heterogeneous mixture. For use in the latter embodiment of the pharmaceutical composition, a liquid medium as described above and further disclosed herein is preferably added to the composition. For a unit dose of the composition, the volume of liquid is typically selected based on the number and / or size of the multiple dosage forms. For preferred values ​​for multiple dosage forms, the pharmaceutical composition of the dried embodiment is typically mixed with about 5 ml to about 40 ml, preferably about 10 to about 35 ml, and most preferably about 15 to 30 ml of liquid medium.

[0018] To provide stability to the pharmaceutical compositions of the present invention upon oral administration, which typically contain a suitable liquid vehicle for stabilizing the gel or gel-like formulation of the compositions of the present invention in the environment of the mouth, throat, and / or esophagus, the compositions of the present invention also contain one or more pH adjusters (e.g., preferably citric acid, salts of citric acid such as tripotassium citrate monohydrate, adipic acid, sodium bicarbonate, tartaric acid, and combinations thereof). In a further preferred embodiment of the present invention, the one or more pH adjusters may also be included in such gel compositions.

[0019] As used herein, "enterocrine cells" (EECs) refer to cells present in the mucosa of the intestine, particularly the small intestine, of a subject, preferably a human subject, that secrete one or more enterokines upon appropriate triggering by nutritional components. There are several types of enteroendocrine cells that may be addressed by the active compound(s) released by the pharmaceutical compositions of the present invention (for reviews of enteroendocrine cells in the lower gastrointestinal tract, see, for example, Gunawardene et al. (2011) Int. J. Exp. Pathol. 92, 219-231 and Latorre et al. (2017) Neurogastrol. Motil, 28(5), 620-630). Particularly preferred enteroendocrine cells in the context of the present invention are I, K, and L cells, with L cells being the most preferred.

[0020] According to the present invention, "enterokines" are hormones secreted by EECs of the gastrointestinal system. Preferred enterokines are incretins, i.e., hormones that regulate blood glucose levels upon nutritional intake, preferably GLP-1, GLP-2, GIP, and PYY, more preferably GLP-1 and PYY. Other preferred enterokines secreted from EEC(s) via the release of the active compound(s) in the pharmaceutical composition are CCK and neurotensin.

[0021] I cells are primarily found in the proximal small intestine, particularly the lower duodenum and jejunum, and detect nutrients such as amino acids and fatty acids by secreting cholecystokinin (CCK), which not only influences the secretion of bile acids from the gallbladder into the small intestine, but also stimulates the release of digestive secretions from the pancreas.

[0022] K cells are present throughout the small intestine and release GIP (glucose-dependent insulinotropic peptide, also known as gastric inhibitory peptide), which inhibits gastric motility and promotes insulin production and secretion.

[0023] L cells are present throughout the small intestine, i.e., in the duodenum, jejunum, and ileum, and release GLP-1 (glucagon-like peptide 1), GLP-2 (glucagon-like peptide 2), and PYY (peptide YY) in response to various nutrients. L cell concentrations increase in the duodenum, jejunum, and ileum, and GLP-1 release from L cells exhibits a gradient from the proximal to the distal small intestine, with the highest GLP-1 release capacity in the terminal ileum. This gradient is not only a function of increasing L cell number, but also of L cell maturation and differentiation status and GLP-1 production rate, which also increase from the proximal to the distal ileum. GLP-1 is particularly released by L cells located in mucosal crypts and villi. L cells mature from crypts to villi, with GLP-1 release capacity reaching its peak when they reach the top of the villi. L cells also secrete PYY (peptide YY), which is released primarily in the terminal ileum. GLP-1 promotes nutrient-stimulated insulin secretion and inhibits glucagon secretion, gastric emptying, and feeding. GLP-1 also has proliferative, neoplastic, and anti-apoptotic effects on pancreatic β cells. GLP-2, as an enterotrophic peptide, stimulates cell proliferation and inhibits apoptosis in the intestinal crypt compartment, as well as modulating intestinal glucose transport, food intake, gastric acid secretion, and gastric emptying. GLP-2 also improves intestinal barrier function. PYY inhibits gastric motility and increases water and electrolyte absorption in the colon. PYY has also been shown to inhibit pancreatic secretion and reduce appetite. PYY delays gastric emptying, thereby improving the efficiency of postprandial digestion and nutrient absorption.

[0024] EEC(s), particularly L cells, are induced to release enterokines such as GLP-1 and PYY through a variety of mechanisms influenced by one or more active compounds in the pharmaceutical composition of the present invention.

[0025] L cells release GLP-1 and PYY (and also GLP-2; note that GLP-1 and GLP-2 are essentially released together because they share a common mRNA; see, for example, the review by Baggio and Drucker (2004) Best Practice & Research Clinical Endocrinology & Metabolism, 18(4), 531–554) in response to various mechanisms triggered by nutrients and other compounds. One mechanism involves the uptake of carbohydrates, including glucose, via the glucose transporters GLUT2 and / or SGLT1. Other mechanisms rely on binding to specialized G protein-coupled receptors, such as taste receptors, fatty acid receptors, bile acid receptors, peptide receptors, and amino acid receptors.

[0026] These signals, namely glucose transport and binding to G protein-coupled receptors, are usually transduced intracellularly by one or more of three mechanisms (transmembrane calcium influx, intracellular calcium release, and / or intracellular cAMP increase), ultimately leading to the release of enterokines and, in the case of L cells, GLP-1 and PYY.

[0027] Therefore, the active compound(s) that induce enterokine release via EEC are preferably selected from nutrients, and more preferred active compounds include carbohydrates, fatty acids, bile acids, peptides (including oligopeptides, polypeptides, and proteins), amino acids, alcoholamides, and anthocyanins. Fatty acids having 2 to 6 carbon atoms are preferred. Ethanolamides (e.g., oleylethanolamide, anandamide (N-arachidonoylethanolamide, AEA), palmitoylethanolamide, stearylethanolamide, and anandamide derivatives such as prostamides) can also be used as alcoholamide compounds in the oral dosage form of the present invention. A particularly preferred ethanolamide is oleylethanolamide (OEA). A preferred example of a peptide active compound is the protein bovine serum albumin (BSA). Carbohydrates are preferably selected from glucose and sucralose, with glucose being most preferred. In certain preferred embodiments of the present invention, the multiple dosage forms in the pharmaceutical composition contain from about 1% (w / w) to about 99% (w / w), e.g., 60-70% (w / w), of the EEC(s)-inducing active compound, preferably a carbohydrate, most preferably glucose (dextrose). Particularly preferred glucose contents in the core of each dosage form are within the range of from about 5% (w / w) to about 95% (w / w), preferably from about 25% (w / w) to about 75% (w / w), and more preferably from about 40% (w / w) to about 70% (w / w).

[0028] In a preferred embodiment, the active compound that induces EEC-mediated enterokine release is an anthocyanin, more preferably one or more anthocyanins derived from Vaccinium myrtilloides Michx. A particularly preferred anthocyanin for inclusion in the core of the pharmaceutical oral dosage form of the present invention is delphinidin 3-rutinoside.

[0029] In a preferred embodiment of the present invention, one or more of the above active compounds that induce enterokine release by EECs are combined, preferably in a synergistic combination.

[0030] A preferred combination is a combination of a carbohydrate, preferably glucose, with sucralose and / or one or more fatty acids having 2 to 6 carbon atoms and / or oleic acid and / or one or more bile acids and / or one or more alcoholamides (preferably one or more ethanolamides, more preferably oleylethanolamide) and / or one or more peptides (including oligopeptides, polypeptides and proteins (e.g., preferably BSA)) and / or one or more amino acids and / or one or more anthocyanins (preferably delphinidin 3-rutinoside).

[0031] A further preferred combination is a combination of another carbohydrate, preferably sucralose, with glucose and / or one or more fatty acids having 2 to 6 carbon atoms and / or oleic acid and / or one or more bile acids and / or one or more alcoholamides (preferably one or more ethanolamides, more preferably oleylethanolamide) and / or one or more peptides (including oligopeptides, polypeptides and proteins (e.g., preferably BSA)) and / or one or more amino acids and / or one or more anthocyanins (e.g., preferably delphinidin 3-rutinoside).

[0032] Another preferred combination is a combination of a fatty acid having 2 to 6 carbon atoms with one or more carbohydrates (preferably glucose and / or sucralose), and / or oleic acid, and / or one or more bile acids, and / or one or more alcoholamides (preferably one or more ethanolamides, more preferably oleylethanolamide), and / or one or more peptides (including oligopeptides, polypeptides, and proteins (e.g., preferably BSA)), and / or one or more amino acids, and / or one or more anthocyanins (e.g., preferably delphinidin 3-rutinoside).

[0033] According to a further preferred embodiment, the present invention provides a combination of oleic acid with one or more fatty acids having 2 to 6 carbon atoms and / or one or more carbohydrates (preferably glucose and / or sucralose) and / or one or more bile acids and / or one or more alcoholamides (preferably one or more ethanolamides, more preferably oleylethanolamide) and / or one or more peptides (including oligopeptides, polypeptides and proteins (e.g., preferably BSA)) and / or one or more amino acids and / or one or more anthocyanins (e.g., preferably delphinidin 3-rutinoside).

[0034] Further preferred combinations of active compounds are combinations of one or more bile acids with one or more carbohydrates (preferably glucose and / or sucralose) and / or one or more fatty acids having 2 to 6 carbon atoms and / or oleic acid and / or one or more alcoholamides (preferably one or more ethanolamides, more preferably oleylethanolamide) and / or one or more peptides (including oligopeptides, polypeptides and proteins (e.g., preferably BSA)) and / or one or more amino acids and / or one or more anthocyanins (preferably delphinidin 3-rutinoside).

[0035] A further preferred combination of active compounds is a combination of one or more alcoholamides (preferably one or more ethanolamides, more preferably oleylethanolamide) with one or more carbohydrates (preferably sucralose and / or glucose) and / or one or more fatty acids having 2 to 6 carbon atoms and / or oleic acid and / or one or more bile acids and / or one or more peptides (including oligopeptides, polypeptides and proteins (e.g., preferably BSA)) and / or one or more amino acids and / or one or more anthocyanins (e.g., preferably delphinidin 3-rutinoside).

[0036] Other preferred active compound combinations are combinations of one or more peptides (including oligopeptides, polypeptides, and proteins (e.g., preferably BSA)) with one or more carbohydrates (preferably sucralose and / or glucose) and / or one or more fatty acids having 2 to 6 carbon atoms and / or oleic acid and / or one or more bile acids and / or one or more alcoholamides (preferably one or more ethanolamides, more preferably oleylethanolamide) and / or one or more amino acids and / or one or more anthocyanins (e.g., preferably delphinidin 3-rutinoside).

[0037] In another preferred embodiment of the present invention, the core of the multiple dosage forms comprises a combination of one or more amino acids and one or more carbohydrates (preferably sucralose and / or glucose) and / or one or more fatty acids having 2 to 6 carbon atoms and / or oleic acid and / or one or more bile acids and / or one or more ethanolamides (more preferably oleylethanolamide) and / or one or more peptides (including oligopeptides, polypeptides and proteins (e.g., preferably BSA)) and / or one or more anthocyanins (e.g., preferably delphinidin 3-rutinoside).

[0038] A further preferred combination of active compounds in each core of the multiple dosage forms used in the present invention is one or more anthocyanins (preferably delphinidin 3-rutinoside) combined with one or more carbohydrates (preferably sucralose and / or glucose) and / or one or more fatty acids having 2 to 6 carbon atoms and / or oleic acid and / or one or more bile acids and / or one or more alcoholamides (preferably one or more ethanolamides, more preferably oleylethanolamide) and / or one or more peptides (including oligopeptides, polypeptides and proteins (e.g., preferably BSA)) and / or one or more amino acids.

[0039] The active compound(s) within each core portion of the multiple dosage form are preferably further formulated with active ingredients having different functions.

[0040] A preferred example of an additional active ingredient is an EEC maturation agent. As exemplified above for L cells, such maturation agents typically enhance the release capacity of EEC(s) (e.g., L cells) of relevant enterokines, in the case of L cells, GLP-1 and / or PYY and / or GLP-2. Preferred EEC maturation agents, particularly L cell maturation agents, include human milk oligosaccharides (HMOs) and NOTCH signaling inhibitors (e.g., gamma-secretase inhibitors, preferably dibenzazepine). Various HMOs are commercially available (Jennewein Biotechnologie GmbH, Rheinbreitbach, Germany). Examples of preferred HMOs in the context of the present invention include, but are not limited to, 2'-fucosyllactose, 3-fucosyllactose, 6'-sialyllactose, and lacto-N-neotetraose, and mixtures thereof.

[0041] The pharmaceutical composition of the present invention preferably comprises a plurality of oral dosage forms designed to release a burst of active ingredient(s) in a selected target region of the small intestine, preferably the jejunum, more preferably the distal portion of the jejunum, of a subject, preferably a human. To provide a burst release of the components of each core of the plurality of dosage forms, each core of the plurality of dosage forms comprises at least one disintegrant. Disintegrants for use in the present invention are generally known in the art to rapidly swell and dissolve upon contact with a target environment, typically an aqueous environment such as the small intestine of a subject, preferably a human. The disintegrant provides rapid disintegration of the core of the pharmaceutical oral dosage form of the present invention when the core comes into contact with an aqueous medium present in the small intestine of a subject. Preferably, the disintegrant in the plurality of dosage forms of the composition of the present invention is selected so that 70% or more of the core is released within 2 minutes, or 85% or more within 5 minutes, after contact with water or an aqueous medium such as the small intestine of a human subject. Preferred disintegrants in the context of the present invention are cross-linked polyvinylpyrrolidone, cross-linked carboxymethylcellulose, and modified starch. Particularly preferred cross-linked polyvinylpyrrolidones for use in the present invention include polyplasdone, particularly polyplasdone XL, polyplasdone XL-10, and polyplasdone INF-10 (available from Ashland Corporation, Covington, Ky., USA). Other useful disintegrants include, but are not limited to, polyvinylpolypyrrolidone, croscarmellose, carboxymethylcellulose (preferably the sodium salt thereof), and the like.

[0042] The burst release of the core components, particularly the active compound(s) such as glucose, establishes a steep gradient between intracellular and extracellular levels of the respective active compound(s) (preferably glucose, sucralose, ethanolamide, BSA and / or anthocyanins (e.g., delphinidin 3-rutinoside)) in the targeted EEC (preferably L cells) at the release site of the core components.

[0043] Compared with the prior art, in particular WO2010 / 027498A2, WO2012 / 118712A2, and US2014 / 0294951A1, the pharmaceutical compositions of the present invention exhibit a highly improved combination of properties. On the one hand, the pharmaceutical compositions of the present invention improve enterokine release, in particular GLP-1 and / or PYY release, in patients, in particular by combining a highly reproducible and potent enterokine release with very low intra- and inter-patient variability, since each dose of the compositions of the present invention results in a single peak of enterokine (in particular GLP-1) release at a selected time point after oral administration (see in particular Figure 1 of the present application, in comparison with the results obtained with prior art compositions (e.g., those in US2014 / 0294951A1, see Figures 6a-6f)). On the other hand, the combination of multiple dosage forms and gelling agent(s) (preferably present in the gelling composition) allows the pharmaceutical compositions described herein to be very safe formulations consisting of relatively small multiple dosage forms. This formulation, particularly when reconstituted with a liquid medium such as water or an aqueous solution, provides a suspension of multiple dosage forms in a gel or gel-like formulation as disclosed herein, which can be swallowed more easily by a subject in need thereof (e.g., compared to the relatively large capsules or tablets containing 10 g of API (glucose) disclosed in WO2010 / 027498A2 and WO2012 / 118712A2), contributing to improved compliance. Furthermore, the presence of at least one gelling agent prevents the small size of multiple dosage forms from being inhaled by the subject. This is very important from the standpoints of both safety and patient compliance. This is because oral administration of large tablets or capsules containing, for example, 7 to 10 g of glucose to obtain any effect, as taught in WO2010 / 027498A2 and WO2012 / 118712A2, is particularly difficult for children (preferably pediatric patients up to about 6 years of age) and elderly patients (preferably elderly patients in the age range outlined below).Most importantly, subjects preferably treated with the compositions of the present invention (especially those suffering from obesity, insulin resistance, type 2 diabetes mellitus (T2DM), metabolic syndrome, and severe forms of certain viral infections such as COVID-19) are generally elderly, such as subjects at least about 50 years of age, more preferably at least about 55 years of age, and even more preferably at least about 60 years of age. Dysphagia generally exhibits a statistically high incidence, ranging from severe dysphagia and achalasia, and certain formulations of the present invention can be easily and safely ingested by such subjects, even in the presence of dysphagia. This makes it possible to provide a much higher patient compliance rate in the course of treatment, resulting in significantly improved positive outcomes, compared to the prior art.

[0044] Furthermore, it is particularly relevant that the combinations of the present invention, consisting of multiple dosage forms, a gelling agent (preferably present in a gelling composition), and optionally further agents, particularly pH adjusters, have improved viscosity and flow properties on mucosal surfaces, optimizing intake, particularly in elderly and pediatric subjects, whereby the preferred age ranges for subjects in these groups are as set forth above. To further improve the flow properties of the pharmaceutical compositions, the pharmaceutical compositions of the present invention may contain one or more viscosity adjusters (particularly other than gelling agents) and / or one or more flow aids (particularly other than gelling agents), particularly when containing or reconstituted with a liquid medium as disclosed above. Preferred examples of substances useful as viscosity adjusters and / or flow aids include lubricants (e.g., preferably polyhydric alcohols (more preferably glycerol)), colloidal silicon dioxide, and vegetable oils (more preferably one or more vegetable oils selected from olive oil, sunflower seed oil, almond oil, and sesame oil).

[0045] In a preferred embodiment of the present invention, multiple dosage forms preferably release the active compound(s) in the jejunum, preferably the terminal jejunum, of a subject, preferably a human subject, through a specific design of the enteric coating, typically a pH-sensitive coating. Preferably, the coating substantially degrades and / or dissolves in the jejunum, preferably the terminal jejunum. Therefore, the core is released in the jejunum, preferably the terminal jejunum, of a subject by specifically selecting an enteric coating, preferably selected from pH-sensitive polymers that substantially degrade and / or dissolve at a pH value of about 5.5 to about 7.5, preferably about 7.2 to about 7.3. Such pH-sensitive polymers are preferably selected from hydroxypropyl methylcellulose (hereinafter also referred to as "hypromellose") and anionic copolymers of methacrylic acid and methacrylic methacrylate. Most preferably, the pH-sensitive enteric coating containing or consisting of hydroxypropyl methylcellulose is hydroxypropyl methylcellulose acetate succinate. Highly preferred commercial products of this type include AQOAT®, particularly preferred AQOAT®-HF (Shin-Etsu Chemical Co., Ltd., Chiyoda-ku, Japan). In other preferred embodiments of the anionic copolymer type of methacrylic acid and methacrylic methacrylate, various forms of Eudragit® polymers can also be used. Eudragit® is commercially available from Evonik Healthcare & Nutrition GmbH, Essen, Germany. In preferred embodiments, Eudragit® FS30D and / or Eudragit® L30D are used as, or at least as part of, the pH-sensitive polymer(s) of the coating.

[0046] In a further preferred embodiment of the present invention, different coatings can be applied in combination. According to one embodiment, the coating comprises or consists of a combination of hydroxypropyl methylcellulose and an anionic copolymer of methacrylic acid and methacrylic methacrylate. Preferably, the combination of coatings is applied such that a subcoating of one pH-sensitive polymer is applied as a first layer and a coating of a second pH-sensitive polymer is applied as a second layer on top of the first subcoating. For example, a pH-sensitive coating can comprise a first layer of hydroxypropyl methylcellulose or its subcoating and a second layer of an anionic copolymer of methacrylic acid and methacrylic methacrylate applied on top of the first subcoating. In a further preferred embodiment, the coating of the pharmaceutical oral dosage form of the present invention is composed of a coating comprising a first layer (subcoating) comprising or consisting of an anionic polymer of methacrylic acid and methacrylic methacrylate, such as Eudragit®, more preferably Eudragit® FS30D, and a second layer comprising or consisting of hydroxypropyl methylcellulose, such as AQOAT®, more preferably AQOAT®-HF. More preferably, the anionic copolymer of methacrylic acid and methacrylic methacrylate, e.g., Eudragit®, preferably Eudragit® FS30D, is present in an amount less than the hydroxypropyl methylcellulose, such as AQOAT®, more preferably AQOAT®-HF. That is, the thickness of the first layer of this type of combination is less than the thickness of the second layer of this combination. More specifically, the ratio of the amount or thickness of the first layer to the second layer is typically in the range of about 1:10 to about 1:50, and particularly preferably in the range of about 1:20 to about 1:30.

[0047] To further enhance the enterokine release provided by the composition of the present invention, it is preferable to further incorporate an intestinal release-improving agent into multiple dosage forms, particularly the core thereof. This agent is a substance that promotes enterokine release by enteroendocrine cells, which are activated by a compound that stimulates enteroendocrine cells. This releases at least one enterokine, particularly preferably at least one substance that promotes the release of GKLP-1 and / or PYY by L cells. In preferred embodiments of the present invention in which L cells are targeted to release GLP-1, such agents are preferably selected from GLP-1 degradation inhibitors such as DPP-4 inhibitors, substances that enhance L cell maturation (e.g., human milk oligosaccharides, NOTCH signaling inhibitors such as gamma-secretase inhibitors (preferably dibenzazepine)), stimulants, and combinations thereof. A preferred stimulant for use in the present invention is caffeine. An example of a preferred combination of an active compound and a stimulant is glucose and caffeine, with the weight ratio of glucose to caffeine being about 5:1 to about 50:1, preferably about 8:1 to about 40:1. In other embodiments, the preferred combination of glucose and caffeine in the core of the multiple oral dosage forms is about 60 to about 70% (w / w) glucose and about 2 to about 4% (w / w) caffeine, most preferably about 67% (w / w) glucose and about 3.2% (w / w) caffeine, based on the total weight of the core.

[0048] Caffeine or other known substances may also be included to control and monitor the proper release and diffusion of the components of the core of the multiple oral dosage forms contained in the composition of the present invention in the intestinal tract of a subject, preferably a human. The release of the tracer substance from the multiple dosage forms of the pharmaceutical composition in the small intestine can be easily monitored by analytical methods commonly known in the art. In the case of caffeine, blood samples are collected from the subject before and at appropriate time intervals after oral administration of the oral dosage forms. After centrifugation of the blood sample, the caffeine content in the serum fraction of the sample is measured by ELISA using a commercially available test kit (e.g., Caffeine ELISA Kit, BioVision, Milpitas, CA, USA) according to the manufacturer's instructions.

[0049] The form of the pharmaceutical composition of the present invention is preferably further fine-tuned in various ways to further improve targeting of release and induction by EEC(s) in the small intestine of a subject, preferably a human subject. Furthermore, multiple different dosage forms with different release patterns in the small intestine of a subject can be incorporated into the composition of the present invention to act synergistically on the EECs and their enterokine release results in the subject.

[0050] As outlined above, the present invention is directed to specific pharmaceutical compositions comprising a plurality of the preferred dosage forms described above. The dosage forms are small in size, preferably 3 mm or less in maximum dimension, more preferably about 0.6 mm to about 1.7 mm in maximum dimension, and most preferably about 0.8 mm to about 1.2 mm in maximum dimension. As outlined above, such compact dosage forms can conveniently take the form of beads, granules, or pellets. As detailed above, the compact dosage forms of the present invention have the advantage of behaving like a liquid in the subject's stomach. This allows multiple oral dosage forms to rapidly and consistently enter the intestinal tract. Therefore, they are uniformly delivered to a target region, preferably a target burst release region, preferably the subject's jejunum, more preferably the terminal (i.e., distal) portion of the subject's jejunum.

[0051] In addition to the above-mentioned components, the pharmaceutical compositions of the present invention may contain additional components typically found in oral dosage forms such as tablets, capsules, granules, and pellets to provide and / or improve various parameters. Typical additional components for use in the present invention include excipients, carriers, fillers, lubricants, dispersants, plasticizers, humectants, anti-tacking agents, neutralizing agents, colorants, pigments, opacifiers, flavorings, and taste modifiers such as sweeteners. It will be understood that these and other beneficial agents may be included in the multiple dosage forms and / or added to a pharmaceutical composition separate from the multiple dosage forms, e.g., preferably in a gelling composition. Those skilled in the art of formulating pharmaceutical compositions and multiple oral dosage forms can readily identify these and other types of specific compounds and substances, as well as their combinations and amounts. Further guidance can be found in Remington's Pharmaceutical Sciences, 18th Edition, Mack Printing Company, 1990, especially pages 1289-1329.

[0052] A further subject of the present invention is a pharmaceutical product comprising a plurality of dosage forms as defined herein and at least one gelling agent as defined herein, wherein the plurality of dosage forms and the at least one gelling agent are physically separated.

[0053] As described above in relation to the pharmaceutical compositions of the present invention, at least one gelling agent can be present in the gelling composition, which may preferably contain further gelling agents and / or other pharmaceutically acceptable agents, such as, preferably, one or more pH adjusting agents. Preferred examples of pH adjusting agents for use in the present invention have already been outlined above.

[0054] In another embodiment of the present invention, the pharmaceutical product is comprised of a pharmaceutical composition as defined herein and water or an aqueous solution physically separated therefrom. Preferably, the physical separation is achieved by providing the pharmaceutical composition (without the water / aqueous solution) in one container and the water or aqueous solution in a separate, second container. For use, the water or aqueous solution is combined with the pharmaceutical composition in one of the two containers, or in a separate container.

[0055] In a preferred embodiment, the pharmaceutical product further comprises water and / or an aqueous solution physically separated from the plurality of dosage forms and from the at least one gelling agent or gelling composition, respectively.

[0056] "Physical separation" according to the present invention refers to any means by which the dosage forms and one or more gelling agents or gelling compositions are separated from each other. Therefore, they typically do not come into contact with each other until the pharmaceutical product is used by the intended subject. For example, the dosage forms and the gelling agent(s) (gelling composition) can be provided in two separate containers. These, together with appropriate packaging and, more preferably, a pharmaceutical leaflet containing instructions for use, constitute a pharmaceutical product. The product may also contain water or an aqueous solution physically separated from the dosage forms and the gelling agent(s) / gelling composition. Preferably, the water or aqueous solution is provided in a third container.

[0057] In another preferred embodiment of the pharmaceutical product of the present invention, the multiple dosage forms, at least one gelling agent, and optionally the water and / or aqueous solution are provided in a single container comprising at least one compartment containing the multiple dosage forms, at least one compartment containing at least one gelling agent or gelling composition, and optionally at least one compartment containing the water or aqueous solution, wherein said compartments are separated by at least partially removable or preferably destructible physical separating means.

[0058] Removable, preferably partially removable, physical separation means for use in pharmaceutical products are known to those skilled in the art. In one preferred embodiment, the separation means is preferably provided by a rupturable foil between each compartment, which may preferably be embodied as a blister foil commonly used in pharmaceuticals. In a preferred embodiment containing multiple dosage forms, a gelling agent(s) / gelling composition, and water or an aqueous solution, the compartments are provided in a container such that the first, bottom compartment contains a liquid medium and the two upper compartments contain multiple dosage forms. The user then forces the contents of the top compartment through the foil. Thus, the multiple dosage forms and the gelling agent or gelling composition are first mixed and then further pressure is applied to force them through the rupturable separator, preferably the blister foil, into the lower liquid medium compartment. The final pharmaceutical composition is then reconstituted, typically as a gel or gel-like suspension of multiple oral dosage forms, which can be orally administered to a subject in need of treatment, preferably by self-administration.

[0059] In another preferred embodiment, the pharmaceutical product comprises a pharmaceutical composition of the present invention (without water or aqueous solution) and water or aqueous solution, respectively, in a single container with two compartments, where the pharmaceutical composition is provided in one compartment and the water or aqueous solution is provided in the second compartment, respectively. The two compartments are then separated by an at least partially removable, preferably rupturable, physical separator, more preferably a rupturable foil, and particularly preferably a blister foil as outlined above for the three-compartment embodiment. For reconstitution, the user, preferably a subject in need of treatment, at least partially removes the separator between the compartments and preferably presses the pharmaceutical composition (without water / aqueous solution) into the compartment containing the liquid medium, preferably water or aqueous solution, through the blister foil.

[0060] For the pharmaceutical products described herein, the container or compartment containing the multiple dosage forms preferably contains unit doses of the multiple dosage forms for single administration to a subject. Preferred unit doses, particularly the number of multiple dosage forms, are as outlined above.

[0061] The present invention also relates to a method for preparing a pharmaceutical composition as defined and described herein. In one embodiment, the method for preparing the pharmaceutical composition of the present invention comprises combining a plurality of dosage forms, each having a size and / or number as outlined above, with at least one gelling agent or gelling composition. The method preferably further comprises combining the resulting mixture of the plurality of dosage forms and at least one gelling agent or gelling composition with a liquid medium, preferably water or an aqueous solution. In another aspect of the present invention, there is also provided a method for producing the pharmaceutical composition of the present invention, comprising combining a composition comprising a plurality of dosage forms as described above and at least one gelling agent or gelling composition with a liquid medium, preferably water or an aqueous solution. As will be appreciated by those skilled in the art, this method typically results in a gel or gel-like formulation of multiple dosage forms.

[0062] According to the present invention, the water for providing the mixture of the dosage forms and at least one gelling agent or gelling composition in a liquid medium may be tap water or sterile water, respectively. The aqueous solution for this purpose is preferably a buffered or unbuffered saline solution such as physiological sodium chloride solution, Ringer's, lactated Ringer's, etc. The liquid medium can also be selected from other embodiments, such as aqueous solutions with flavors and / or pigments or dyes, or suspensions such as juices (e.g., fruit or vegetable juices), as long as such liquids do not interfere with the formation of a gel or gel-like formulation containing the dosage forms.

[0063] The pharmaceutical compositions and / or pharmaceutical products as defined and described herein are particularly useful for the prevention and / or treatment in subjects suffering from conditions and / or disorders and / or diseases associated with impaired enterokine release by enteroendocrine cells and / or conditions and / or disorders and / or diseases responsive to increased enterokine release by enteroendocrine cells.

[0064] Preferred conditions, disorders or diseases for which the pharmaceutical compositions and / or products of the present invention can be applied to treat and / or prevent are metabolic disorders, vascular disorders, neurodegenerative diseases, skeletal system diseases and digestive system diseases.

[0065] Preferred metabolic disorders are selected from insulin resistance, type 2 diabetes, non-alcoholic fatty liver disease, non-alcoholic fatty liver, metabolic syndrome, hyperlipidemia and obesity.

[0066] In particular, in the context of diabetes, particularly T2DM, and prediabetes, preferably insulin resistance and / or obesity, the therapeutic and / or preventive regimens of the present invention are of great benefit, since the increase in enterokine levels, particularly GLP-1, exerted by administration of the pharmaceutical composition of the present invention is known to have the beneficial effect of increasing the adiponectin / leptin ratio (see, e.g., Unamuno et al. (2019) Nutrients, 11, 2069-2079), which reduces the known inflammation of adipose tissue that frequently occurs in patients with T2DM and / or prediabetes, such as insulin resistance and obesity.

[0067] In contrast to the prior art applications of enterokine-stimulating compositions, the range of indications to which the inventive compositions and / or products, respectively, can be successfully applied is significantly broadened according to the present invention. The present inventors have detected and recognized that enterokines released from enteroendocrine cells, in particular GLP-1 released from L cells, have various effector sites in living organisms, in particular in humans, as indicated in particular by the expression profiles of enterokine receptors, in particular the GLP-1 receptor.

[0068] For example, GLP-1 acts on vascular tissue, particularly exhibiting vasodilatory and myocardial protective effects (see, for example, Ban et al. (2008) Circulation, 117, 2340-2350). Thus, the pharmaceutical composition and / or pharmaceutical product of the present invention can be preferably applied to the treatment and / or prevention of vascular disorders (e.g., preferably microvascular dysfunction, cardiac disease, cerebrovascular disease, and pulmonary vascular disease).

[0069] Pulmonary diseases are preferred targets for treatment and / or prevention according to embodiments of the present invention, since expression of the GLP-1 receptor is highest in the lung. A preferred class of pulmonary vascular diseases is considered to be pulmonary diseases associated with pneumonia, more preferably pneumonia associated with or caused by viral infection, respectively.

[0070] Severe coronavirus infections, particularly those caused by SARS-COV-1, SARS-COV-2, and / or MERS, which cause respiratory pneumonia, are accompanied by significant damage to pulmonary blood vessels. Therefore, the present invention proposes the induction of enterokines, particularly GLP-1, by administering a pharmaceutical composition, particularly by oral administration, e.g., by using a pharmaceutical product as disclosed herein. SARS-COV-2 is a particularly preferred therapeutic target of the present invention, and the administration of the pharmaceutical composition is preferably performed before the onset of COVID-19, or at least before the onset of severe forms of the disease, including the onset of respiratory symptoms such as pneumonia.

[0071] In this context, glucagon-like peptide 1 (GLP-1) is best known as an enteroendocrine hormone that orchestrates insulin release in response to ingested nutrient stimuli (Paternoster et al. (2018) Front. Endocrinol. 9, 1-26). GLP-1 has also emerged as an important homeostatic factor in the cardiovascular system and has important endothelial protective functions (Helmstadter et al. (2020) Arterioscler. Thromb. Vasc. Biol. 40, 145-158; Sun, Y.-H. et al. (2017) Mol. Med. Rep. 16, 929-936). In the lung, GLP-1 strengthens the barrier through upregulation of tight junction proteins in barrier-forming cells. In alveolar type 2 pneumocytes, GLP-1 stimulates surfactant production, which helps minimize fluid accumulation within the alveolar space by reducing surface tension (Vara et al. (2001) Am. J. Respir. Crit. Care Med. 163, 840-846). In endothelial cells, GLP-1 inhibits the expression and activity of tumor necrosis factor (TNF-α)-converting enzyme (TACE) (Ku et al. (2014) Pharmacol. Res. 84, 18-25). Thus, it directly counteracts a key mechanism utilized by SARS-CoV-2 to enhance inflammation and reduce barrier function. Correspondingly, GLP-1 signaling attenuates TACE-dependent shedding of endothelial protein C receptor (EPCR) (Ku et al. (2014) supra). GLP-1 signaling also increases angiotensin-converting enzyme 2 (ACE2) levels in pathological conditions, possibly through decreased ACE2 shedding (Romani-Perez et al. (2015) Endocrinology, 156, 3559-3569).Consistent with this anti-inflammatory role, GLP-1 receptor agonists have several desirable effects: (i) antagonizing NFκB signaling (Helmstadter et al. (2020) supra), (ii) reducing the expression of immune cell adhesion molecules (e.g., ICAM-1 and VCAM-1) on the endothelial cell surface (Helmstadter et al. (2020) supra; Arakawa et al. (2010) Diabetes, 59, 1030-1037), (iii) decreasing immune cell cytokine production (Arakawa et al. (2010) supra), and (iv) attenuating oxidative stress in endothelial cells (Ceriello et al. (2013) Diabetes Care, 36, 2346-2350). Indeed, several risk factors associated with severe COVID-19 (e.g., obesity, diabetes) are also associated with reduced GLP-1 secretion and circulating GLP-1 concentrations.

[0072] Thus, the present invention expands the repertoire of interventions that can bring about the positive therapeutic effects of GLP-1 activity in COVID-19 patients. The high anti-COVID-19 potential of embodiments of the present invention is supported by previous findings that agonistic or supraphysiological levels of innate GLP-1 have been used to elicit desirable effects. However, it is clear that normal postprandial levels of endogenous GLP-1 are sufficient to stimulate nitric oxide production in the forearm, which in turn increases blood flow, microvascular blood volume, and interstitial oxygen uptake in skeletal muscle cells (Chai et al. (2012) Diabetes, 61, 888-896; Dong et al. (2013) Am. J. Physiol.-Endocrinol. Metab., 304, E222-E228).

[0073] A preferred skeletal disease to which embodiments of the present invention are applicable is osteoporosis.

[0074] A further therapeutic aspect of the present invention is based on the known proliferative and anti-apoptotic effects of the enterokines described herein, specifically GLP-1 and GLP-2, on cells of the gastrointestinal tract, particularly the gastrointestinal mucosa (e.g., Sigalet (2012) J. Anim. Sci., 90, 1224-1232; Aw et al. (2017) Asia-Pac. J. Clin. Oncol., 14, 23-31; and Kissow et al. (2012) Cancer Chemother. Pharmacol., 70, 39-48). Administration of the pharmaceutical compositions of the present invention, which may be prepared using pharmaceutical products as disclosed above, can prevent and / or treat malabsorption disorders in affected subjects, as well as treat subjects, particularly human subjects, suffering from disorders, diseases, and / or conditions associated with impaired gastrointestinal function. In particular, preferably in newborns and infants, for irregular gastrointestinal growth, including reduced intestinal length, impaired / reduced formation of the intestinal mucosa and villi, and / or for disorders of the intestinal mucosa, such as mucositis, particularly in tumor and / or cancer patients, preferably as a result of chemotherapy, radiotherapy, infections, etc. This therapeutic aspect of the invention also includes the prevention of the above-mentioned gastrointestinal disorders and diseases.

[0075] As disclosed above, pharmaceutical compositions, particularly pharmaceutical gels or gel-like formulations in multiple dosage forms described herein, are intended for use in patients suffering from metabolic disorders, particularly diseases associated with abnormal energy basal states, such as diabetes and prediabetes, as outlined above. In particular, in such patients, the uptake and transport of conventional oral formulations (especially tablets or capsules containing significant amounts of an active compound, such as glucose) as disclosed in the prior art are often impaired and / or significantly slowed under the following conditions: Helicobacter pylori infection, neuromuscular dysfunction, and gastroparesis (delayed gastric emptying), particularly in elderly patients; diabetes, particularly T2DM, in which up to 50% of diabetic patients suffer from impaired autonomic nerve function, particularly the efferent vagus nerve, which controls peristalsis in the stomach and small intestine. Thus, the pharmaceutical compositions and products of the present invention are particularly useful for treating subjects, particularly humans, in whom one or more of the indications disclosed herein are accompanied by one or more of the comorbid conditions described.

[0076] Therefore, the pharmaceutical composition and / or pharmaceutical product is particularly useful in cases where the above-mentioned symptoms, disorders or diseases are accompanied by at least one symptom selected from the group consisting of dysphagia, dysphagia, achalasia, esophageal peristalsis disorders, gastroparesis and intestinal peristalsis disorders.

[0077] The present invention also relates to a method for treating the above-mentioned conditions, disorders and / or diseases, comprising orally administering to a preferably human subject in need thereof an effective amount of the pharmaceutical composition of the present invention, particularly the formulation of the present invention in multiple dosage forms in a gel or gel-like suspension, wherein the administered pharmaceutical composition preferably results in a substantial increase in the release of GLP-1 and / or GLP-2, particularly the levels of GLP-1 and / or GLP-2, in said subject.

[0078] In certain embodiments, it is also preferred to reconstitute said pharmaceutical composition by combining a pharmaceutical composition comprising multiple dosage forms as outlined herein and at least one gelling agent or gelling composition, each as disclosed above, with a suitable liquid as described herein, preferably by use of a pharmaceutical product as described herein, prior to administration to a subject, preferably by self-administration.

[0079] Generally, administration of the pharmaceutical compositions of the present invention leads to a significant increase in the level of at least one enterokine of interest, preferably GLP-1, GLP-2, GIP, PYY, CCK, and / or neurotensin, particularly preferably GLP-1 and / or GLP-2 and / or PYY, above the respective baseline levels, particularly in the serum / plasma of the treated subject. In a preferred embodiment of the present invention, the level of each enterokine in the subject's plasma / serum is increased by at least about 50%, preferably about 50% to about 200% or even about 300%, compared to the level in the subject's plasma / serum before administration of the pharmaceutical composition of the present invention. The increase in enterokine concentration in the subject's plasma / serum typically occurs within about 2 to about 6 hours after administration of the compositions of the present invention and typically lasts for a period of about 1 to about 5 hours, preferably about 2 to about 4 hours, and most preferably about 3 to about 4 hours.

[0080] According to the present invention, the term "effective amount of a pharmaceutical composition" depends on various factors, such as the specific symptoms, disorders, or diseases to be treated and / or prevented, the age and sex of the subject, and the general condition of the subject. Furthermore, the "effective amount of a pharmaceutical composition" depends on the type of active compound(s) used. Typically, however, the pharmaceutical oral composition of the present invention is preferably administered once daily in one or more unit doses, more preferably while the subject is fasting, particularly preferably at least about 30 minutes, more preferably at least about 45 minutes, and even more preferably at least one hour before the first meal of the day. In a preferred embodiment of the treatment regimen of the present invention, one or more unit doses of the pharmaceutical composition defined herein are orally administered at a time synchronized with the circadian rhythm of the enteroendokine whose release is increased by the pharmaceutical composition of the present invention. For such circadian synchronization of the administration of the pharmaceutical composition of the present invention, it is preferable to further administer one or more unit doses of the pharmaceutical composition at a time period about 2 to about 4 hours before the respective enterokines, particularly GLP-1, reach their circadian maximum in serum or blood. In the case of GLP-1, which is a particularly preferred enterokine for purposes of the present invention, the serum or blood concentration of this enterokine, respectively, reaches a maximum at or around 11:00 a.m. In a preferred embodiment of the present invention, one or more unit doses, particularly for optimal GLP-1 release, are therefore administered between about 7:00 a.m. and about 9:00 a.m. In the context of given time points herein, these time points are understood to refer to the local time zone in which the pharmaceutical composition of the present invention should be administered.

[0081] For glucose as the preferred active compound, an effective amount is preferably orally administered in one or more unit doses of about 0.5 to about 20 g of glucose per day, preferably administered while the subject is fasting, as outlined above. Doses of about 1 to about 15 g per day are more preferred, with particularly preferred regimens being about 5 g to about 12 g, most preferably about 10 g, of glucose per day. The above amounts of active ingredient, preferably glucose, can be administered in one or more unit doses of the pharmaceutical composition, with preferred unit doses being outlined above, particularly with respect to multiple dosage forms. Typical amounts of glucose contained in a unit dose of the pharmaceutical composition of the present invention range from about 0.5 g to about 30 g of glucose, preferably about 5 g to about 20 g of glucose, more preferably about 7 g to 15 g of glucose, e.g., about 10 g of glucose, per unit dose of the composition.

[0082] With regard to the pharmaceutical compositions, uses and methods of treatment of the present invention described above, it is particularly advantageous that the compositions are formulated, particularly in accordance with the size, amount and form of multiple dosage forms, so that at least one compound that stimulates enteroendocrine cells to release enterokines stimulates said cells present in the intestine of a subject, preferably a human, from the jejunum to the ileocecal valve.

[0083] The therapeutic uses and methods of the present invention generally defined above require a combination of different pharmaceutical compositions, each of which comprises multiple dosage forms that exhibit different migration profiles in the gastrointestinal tract of a subject, and / or each of which comprises various compounds that stimulate enteroendocrine cells to release at least one enterokine.For example, one composition comprises multiple dosage forms containing glucose, and another composition comprises multiple dosage forms containing anthocyanins (further combinations of active compounds and specific examples and preferred combinations have already been detailed above).It is also conceivable that a single pharmaceutical composition comprises multiple dosage forms containing different active compounds as described above.A combination of different dosage forms using different active compounds is particularly useful when the various compounds are not easily compatible (e.g., due to their chemical properties) to be included in a single dosage form.

[0084] In another embodiment of this combinatorial approach, the method of treatment of the invention comprises administering a first pharmaceutical composition comprising a plurality of small dosage forms as defined herein, as described herein, and a second pharmaceutical composition comprising one or more oral dosage forms as defined elsewhere herein, the second pharmaceutical composition having a size of 3 mm or more, preferably 3-10 mm, measured based on the largest dimension of the first dosage form, wherein the compounds in the first and second dosage forms that stimulate enteroendocrine cells to release at least one enterokine can be the same or different.

[0085] Of course, it is also possible to administer or use more than two different sizes and / or more than two different active compounds, respectively.

[0086] To prepare multiple dosage forms as described herein, the manufacturing process typically involves the following steps: (a) preparing a mixture comprising at least one compound that stimulates enteroendocrine cells to release at least one enterokine, preferably in combination with at least one disintegrant as defined above; (b) compressing the mixture obtained in step (a); and (c) applying at least one enteric coating to the compressed mixture, preferably wherein the coating comprises at least one pH-sensitive polymer preferably selected to substantially dissolve and / or substantially degrade in the jejunum of the subject; wherein the compressing and coating steps (a) and (b), respectively, are selected to obtain a plurality of dosage forms having sizes as disclosed herein.

[0087] Optionally, the mixture of step (a) and / or at least one coating of step (c) may itself comprise further ingredients as outlined above for the pharmaceutical composition.

[0088] Preferred embodiments of the components defined in steps (a) and (c) have already been described in detail above.

[0089] According to a further preferred embodiment of the preparation process of the present invention, the compression mixture obtained in step (b), i.e. the core component of the pharmaceutical oral dosage form of the present invention, is provided with two or more coatings.

[0090] In a particularly preferred embodiment of this preparation method, a combination of at least two coatings is applied in step (c). Preferably, one pH-sensitive polymer subcoating is applied as a first layer, and a second pH-sensitive polymer coating is applied as a second layer on top of the first subcoating. For example, the pH-sensitive coating may comprise a hydroxypropyl methylcellulose subcoating as a first layer, followed by a second coating comprising or consisting of an anionic copolymer of methacrylic acid and methacrylic methacrylate. In a further preferred embodiment, a first layer (subcoating) comprising or consisting of an anionic polymer of methacrylic acid and methacrylic methacrylate, such as Eudragit®, more preferably Eudragit® FS30D, is applied to the core obtained in step (b), and a second layer comprising or consisting of hydroxypropyl methylcellulose, such as AQOAT®, more preferably AQOAT®-HF, is applied on top of the first layer. More preferably, an anionic copolymer of methacrylic acid and methacrylic methacrylate, such as Eudragit®, preferably Eudragit® FS30D, is applied in a smaller amount than the hydroxypropyl methylcellulose, such as AQOAT®, more preferably AQOAT®-HF, in the second layer. In other words, the thickness of the first layer of this type of combination is thinner than the thickness of the second layer of this combination. More specifically, the ratio of the amounts or thicknesses of the first layer and the second layer is typically in the range of about 1:10 to about 1:50, and particularly preferably in the range of about 1:20 to about 1:30. In a preferred embodiment of the present invention, in step (c), one or more coatings are applied by spray coating.

[0091] To prepare the pharmaceutical composition, the dosage forms are then combined with a gelling agent(s), preferably a gelling composition that includes additional ingredients as outlined above (e.g., one or more formulation aids, preferably selected from pH adjusters, flavorings, taste improvers, lubricants, and pigments).

[0092] The present invention is further illustrated by the following non-limiting examples. [Example]

[0093] Example An exemplary pharmaceutical composition was prepared by mixing the following components (a) and (b): (a) Multiple dosage forms: Eudragit® coated beads approximately 1 mm in diameter with a core containing 40-70% (w / w) glucose and a disintegrant in a carrier material. Total weight of glucose in a unit dose of the composition: 10 g. Number of coated beads: about 20,000 to 30,000. (b) Gelling composition: Gelling agent mixture (polysaccharides, modified cellulose, PEG) (84% (w / w) based on the total weight of the gelling agent composition). pH adjuster fragrance Lubricant pigment

[0094] Before oral administration, the pharmaceutical composition was mixed with 25 ml of water per unit dose.

[0095] The reconstituted composition was orally administered to 20 subjects. Blood GLP-1 levels were measured at the following time points (based on time of oral administration = 0 hours): -1.0 hours, -0.5 hours, 0 hours, 0.5 hours, 1.0 hours, 1.5 hours, 2.0 hours, 2.5 hours, 3.0 hours, 3.5 hours, 4.0 hours, 4.5 hours, 5.0 hours, 5.5 hours, 8.0 hours, and 10.0 hours.

[0096] The results are shown in Figure 1. Compared to prior art approaches, the present pharmaceutical composition produced a significantly more reproducible (less intra- and inter-patient variability) and rapid increase in GLP-1 blood levels (maximum increase of 2.88 + / - 0.46-fold over baseline GLP-1 blood levels at 1.5 hours post-administration), with the increase in GLP-1 over baseline levels at 1.5 hours lasting approximately 4 hours. The rapid increase in GLP-1 blood levels beginning 1.5 hours post-administration is consistent with a burst release of the active compound (here, glucose) in the distal jejunum of the subject, as shown in the following data obtained by Evans et al. (1988) (Gut, 29, 1035-1041):

[0097] [Table 1]

[0098] Applying the data of Evans et al. (1988), burst release of the components of the multiple dosage forms contained in the compositions of the present invention occurred in the jejunum (distal portion) of the subject, where the pH environment was > pH 7.0, particularly about pH 7.3.

Claims

1. 1. A pharmaceutical composition comprising a plurality of dosage forms, each dosage form comprising a core and an enteric coating, the core comprises at least one compound that stimulates enteroendocrine cells to release at least one enterokine, and the size of each dosage form with respect to its largest dimension provides for entry of each dosage form into the intestine of a subject independent of gastric emptying mechanisms; and 10. A pharmaceutical composition, wherein said composition further comprises one or more gelling agents.

2. 2. The composition of claim 1, wherein, with respect to the largest dimension of each dosage form, the size of each dosage form is 3 mm or less, preferably 0.6 mm to 2.6 mm, more preferably 0.6 mm to 1.7 mm, and even more preferably 0.8 mm to 1.2 mm.

3. 3. The composition of claim 2, comprising 10,000 to 40,000 dosage forms.

4. 4. The composition of claim 3, comprising 20,000 to 30,000 dosage forms.

5. 5. The composition of any one of claims 1 to 4, wherein the enteric coating comprises a pH-sensitive polymer selected such that the coating substantially dissolves and / or substantially degrades in the jejunum, preferably the terminal jejunum, of the subject such that the core is released in the jejunum, preferably the terminal jejunum.

6. The composition of claim 5, wherein the pH-sensitive polymer substantially degrades and / or dissolves at a pH value of about 5.5 to about 7.5, preferably about 7.2 to about 7.

3.

7. 7. The composition of claim 5 or 6, wherein the pH-sensitive polymer is selected from the group consisting of hydroxypropyl methylcellulose and anionic copolymers of methacrylic acid and methacrylic methacrylate.

8. 8. The composition of any one of claims 1 to 7, wherein the at least one compound is selected from the group consisting of compounds that stimulate the enteroendocrine cells by a mechanism selected from the group consisting of transport into the cells by a transporter expressed by the cells, and binding to a G protein-coupled receptor expressed by the cells, wherein the transporter is selected from the group consisting of GLUT2 and SGLT1.

9. The composition of claim 8, wherein the G protein-coupled receptor is selected from bile acid receptors, amino acid receptors, peptide receptors, and fatty acid receptors, and taste receptors.

10. 10. The composition of claim 8 or 9, wherein the compound(s) are selected from the group consisting of carbohydrates, fatty acids, bile acids, peptides, amino acids, alcohol amides, and anthocyanins.

11. 11. The composition of claim 10, wherein the core comprises glucose and, optionally, one or more compounds selected from sucralose, fatty acids having 2 to 6 carbon atoms, oleic acid, bile acids, peptides, amino acids, ethanolamides, and anthocyanins.

12. 12. The composition of claim 11, wherein each of the dosage forms has a glucose content of 5% (w / w) to 95% (w / w), preferably 25% (w / w) to 75% (w / w), more preferably 40% (w / w) to 70% (w / w).

13. 13. The composition according to claim 11 or 12, comprising 0.5g to 30g of glucose, preferably 5g to 20g of glucose, more preferably 7g to 15g of glucose per unit dose of the composition.

14. The composition of any one of claims 1 to 13, wherein the enteroendocrine cells are selected from the group consisting of I cells, K cells, and L cells.

15. 15. The composition of any one of claims 1 to 14, wherein the core further comprises a substance that enhances enterokine release by enteroendocrine cells effected by a compound that stimulates the enteroendocrine cells to release at least one enterokine.

16. The composition of claim 15, wherein the substance stimulates the release of GLP-1 and / or PYY by L cells.

17. 17. The composition of claim 16, wherein the substance is caffeine.

18. The composition of any one of claims 1 to 17, wherein the core further comprises an enteroendocrine cell maturation agent.

19. 19. The composition of claim 18, wherein the maturation agent is a human milk oligosaccharide (HMO).

20. 20. The composition of any one of claims 1 to 19, wherein the core comprises at least one disintegrant that provides a burst release of the components of the core from the respective dosage form upon at least partial dissolution and / or degradation of the enteric coating.

21. 21. The composition of any one of claims 1 to 20, wherein the multiple dosage forms and the one or more gelling agents are present in a liquid medium.

22. 22. The composition of claim 21, wherein the liquid medium is water or an aqueous solution.

23. The composition of any one of claims 1 to 22, further comprising one or more pH adjusters.

24. The composition of any one of claims 1 to 20, wherein the one or more gelling agents are present in a gelled composition.

25. 25. The composition of claim 24, wherein the gelling composition comprises one or more pH adjusters.

26. 26. The composition of claim 24 or 25, wherein the gelled composition and the multiple dosage forms form a heterogeneous mixture.

27. 21. A pharmaceutical product comprising a plurality of dosage forms as defined in any one of claims 1 to 20 and at least one gelling agent, wherein said plurality of dosage forms and said at least one gelling agent are physically separated.

28. 28. The product of claim 27, wherein the at least one gelling agent is present in a gelling composition.

29. 30. The product of claim 28, wherein the gelling composition further comprises one or more pH adjusters.

30. 30. The product of any one of claims 27 to 29, further comprising a liquid medium physically separated from said plurality of dosage forms and from said at least one gelling agent or gelling composition.

31. 31. The product of any one of claims 27 to 30, wherein the plurality of dosage forms, the at least one gelling agent, and optionally the liquid medium are provided in a single container comprising at least one compartment containing the plurality of dosage forms, at least one compartment containing the at least one gelling agent or gelling composition, and optionally at least one compartment containing water or an aqueous solution, wherein the compartments are separated by a breakable physical separating means.

32. 27. A pharmaceutical product comprising the composition of any one of claims 24 to 26, which comprises a liquid medium physically separate from said composition.

33. 33. The article of manufacture of claim 32, wherein the composition and the liquid medium are provided in a single container comprising at least one compartment containing the composition and at least one compartment containing the liquid medium, the compartments being separated by a breakable physical separation means.

34. 34. The product of any one of claims 27 to 33, wherein the liquid medium is water or an aqueous solution.

35. A composition according to any one of claims 1 to 26, a product according to any one of claims 27 to 31 or a product according to any one of claims 32 to 34 for use in the prevention and / or treatment in a subject suffering from a condition and / or disorder and / or disease associated with impaired enterokine release by enteroendocrine cells and / or a condition and / or disorder and / or disease responsive to increased enterokine release by enteroendocrine cells.

36. 36. The composition or product for use according to claim 35, wherein the condition, disorder or disease is selected from metabolic disorders, vascular disorders, neurodegenerative disorders, skeletal disorders and gastrointestinal disorders.

37. 37. The composition or product for use according to claim 36, wherein the metabolic disorder is selected from insulin resistance, type 2 diabetes, non-alcoholic fatty liver disease, non-alcoholic fatty liver, metabolic syndrome, hyperlipidemia and obesity.

38. 38. A composition or product for use according to claim 37, wherein the metabolic disorder is associated with inflammation of adipose tissue.

39. 37. The composition or product for use according to claim 36, wherein the vascular disorder is selected from microvascular dysfunction, cardiovascular disease, cerebrovascular disease and pulmonary vascular disease.

40. 40. The composition or product for use according to claim 39, wherein the lung disease is associated with pneumonia.

41. 41. A composition or product for use according to claim 40, wherein the pneumonia is caused by or is associated with a viral infection.

42. 42. The composition or product for use according to claim 41, wherein the viral infection is an infection with a coronavirus that causes respiratory symptoms.

43. 43. The composition or product for use according to claim 41 or 42, wherein the viral infection is an infection by a coronavirus selected from the group consisting of SARS-COV-1, SARS-COV-2 and MERS.

44. 37. A composition or product for use according to claim 36, wherein the skeletal disease is osteoporosis.

45. 37. The composition or product for use according to claim 36, wherein the gastrointestinal disorder is selected from the group consisting of functional gastrointestinal disorders and malabsorptive conditions.

46. 46. ​​The composition or product for use according to any one of claims 35 to 45, wherein the condition, disorder or disease is accompanied by at least one symptom selected from the group consisting of dysphagia, esophageal peristalsis disorders, gastroparesis and intestinal peristalsis disorders.

Images