Novel oral composition

Abstract

To provide a composition described below.SOLUTION: The present invention relates to a solid oral composition for targeted release in an intestine of a mammal, comprising a core and a coating completely surrounding the core, where the core comprises an entrapped material to be released in the intestine, where the coating or a part of the coating comprises a first component and a second component, where the first component is resistant to the environment in the stomach of a mammal and the second component enzymatically digests the first component when subjected to the more basic environment of the intestine compared to the more acidic environment of the stomach.SELECTED DRAWING: None

Description

Technical Field

[0001] Technical Field The present invention relates to solid oral compositions for targeted release in the intestine of mammals. Furthermore, the present invention relates to solid oral compositions for various uses, such as use as a pharmaceutical, use as a dietary supplement, or use as a tracer. Furthermore, the present invention relates to the use of a pair of components for preparing a coating for a solid oral dosage form.

Background Art

[0002] Background Art Oral administration of pharmaceutical active ingredients is often the selected route of administration because it is easier, more convenient, generally painless, and has a higher patient adherence compared to other means of administration.

[0003] Other important biologically active compounds can be administered to patients in various ways, including, for example, the oral route. Administering highly sensitive small molecule therapeutics via the oral route, not only proteins and peptides, is a challenge that has been pursued for many years. The challenges include, but are not limited to, digestive enzymes, the strongly acidic environment of the stomach, the components of pancreatic juice, and bile system secretions. Due to these challenges, when sensitive active pharmaceutical ingredients are orally administered, unreliable bioavailability may result. Furthermore, the composition and concentration of gastrointestinal (GI) components are not uniform but vary within segments of the digestive tract. Some of the challenges of peptides, proteins, and other sensitive substances in the digestive tract are shown in FIG. 1.

Summary of the Invention

Problems to be Solved by the Invention

[0004] One skilled in the art will understand that, in order to enhance efficiency and bioavailability, the dosage form needs to administer the active agent (captured material) and any necessary excipients chemically and physically to the part of the gastrointestinal tract that is most suitable for the absorption of its active ingredient. An enteric coating capable of providing appropriate bioavailability of such administered proteins, peptides and small molecules is required. **Means for Solving the Problems**

[0005] Summary of the Invention In a first aspect, the present invention relates to the following composition: A solid oral composition for targeted release in the intestine of a mammal, comprising a core and a coating completely surrounding the core, moreover, the core contains the captured material to be released in the intestine, moreover, the coating or a part of the coating contains a first component and a second component, moreover, the first component is resistant to the environment in the stomach of a mammal, and the second component enzymatically digests the first component when exposed to the more basic environment of the intestine compared to the more acidic environment of the stomach. The above composition.

[0006] In a second aspect, the present invention relates to the following composition: A solid oral composition for targeted release in the intestine of a mammal, comprising a core and a coating completely surrounding the core, moreover, the core contains the captured material to be released in the intestine, and the coating or a part of the coating is adapted to digest / self-perforate in the intestine, moreover, the coating contains a first component and a second component, moreover, the first component is resistant to the environment in the stomach of a mammal, and the second component enzymatically digests the first component when exposed to the more basic environment of the intestine compared to the more acidic environment of the stomach. The above composition.

[0007] Typically, the coating consists essentially of a first component and a second component.

[0008] In one embodiment, the intestine is selected from the small intestine, large intestine, duodenum, ileum, jejunum, and colon.

[0009] In a further embodiment, the coating is adapted to resist destruction from the environment within the mammalian stomach.

[0010] In yet another embodiment, the coating prevents release of the captured material within the mammalian stomach.

[0011] In a further embodiment, the coating protects the captured material within the mammalian stomach.

[0012] In yet another embodiment, the coating is adapted to release the captured material within the mammalian intestine.

[0013] As noted above, the coating comprises a pair of components, and in particular the pair of components are in contact with each other within the coating. When the coating consists of two components, such components are in contact with each other without an intermediate layer, as detailed herein, such that they are ready to initiate a reaction within the intestine.

[0014] In yet another embodiment, the first component is resistant to the environment within the mammalian stomach, and the second component enzymatically digests the first component when exposed to the more basic environment of the intestine as compared to the more acidic environment of the stomach.

[0015] In a further embodiment, the digestive activity of the second component is inhibited within the environment of the mammalian stomach.

[0016] In yet another embodiment, the mammal is selected from animals that have little or no ability to digest dietary fiber such as cellulose, e.g., humans, monkeys, pigs, dogs, humanoid apes, rodents, and cats.

[0017] In a further embodiment, the captured material is a protein, enzyme, polypeptide, oligopeptide, peptide, deoxyribonucleic acid (DNA), ribonucleic acid (RNA), small organic molecule less than 900 Da, or any prodrug. One of these materials is a dietary supplement, or a microbial culture, or a microbial additive, or a vaccine. Further embodiments of the captured material are selected from: a) protein, human growth hormone (hGH), calcitonin, insulin, GLP-1 analog, GLP-1 b) peptide, octreotide c) oral vaccine, oral cholera vaccine, Mycoplasma hyopneumoniae oral vaccine, live bacterial cells as a live attenuated vaccine, live cell culture d) organic small molecule 200 < MW < 900 g / mol, desmopressin, vasopressin, cyclosporine, ranitidine, diclofenac, ketoprofen, amifostine, omeprazole, gemcitabine, domperidone, paclitaxel, cinnarizine, donepezil, leucovorin, raloxifene, indomethacin, dextromethorphan, nizatidine, peptide Val-Leu-Pro-Val-pro-Arg (VLPVPR), flurbiprofen, mebendazole, thymidine, zolpidem tartrate, loratidine, venlafaxine, tamsulosin, urapidil, prednisolone, miconazole, diltiazem, ambroxol, captopril, acyclovir, cimetidine, metoprolol, griseofulvin, atazanavir, ibuprofen, azithromycin, lercanidipine, sulfacetamide, azelastine, didanosine, chloricromene, oxymatrine, acarbose, propranolol, alfuzosin, stavudine, lobenzarit, genistein, verapamil, terbinafine, lornoxicam, clotrimazole.

[0018] In yet another embodiment, the first component and the second component are mixed.

[0019] In a further embodiment, the first component and the second component are in different layers, the first component is in the outer layer, and the second component is in the inner layer around the core.

[0020] In yet another embodiment, the pair of the first component and the second component is selected from dietary fibers such as cellulose and cellulase, pectin and pectin-degrading enzyme, hemicellulose and hemicellulase, lignin and lignin-degrading enzyme, fructan and fructan-degrading enzyme, and lipid and lipase.

[0021] In a further embodiment, the pair of the first component and the second component is selected from structurally ordered cellulose I such as bacterial cellulose or its derivatives, and cellulases such as cellulase (EC3.2.1.4) (endocellulase) and cellobiase (EC3.2.1.21) (beta-glucosidase) and 1,4-beta-cellobiosidase (EC3.2.1.91) (exocellulase). Further usable cellulases are cellulose 1,4-beta-cellobiosidase (reducing end) (EC3.2.1.176) (exocellulase), as well as cellulase complexes and their mixtures.

[0022] As used herein, the expression "cellulase" has the meaning understood by those skilled in the art and is understood to encompass all cellulases such as endocellulase, exocellulase, cellulase complex, beta-glucosidase, and their mixtures.

[0023] In yet another embodiment, the first component is cellulose, and the second component is a cellulase selected from one or more of endocellulase, exocellulase, and beta-glucosidase. Preferably, the first component includes structurally ordered cellulose I such as bacterial cellulose, and the second component includes endocellulase. Typically, a cellulase such as endocellulase has a cellulose-binding domain and is active against bacterial cellulose.

[0024] In a further embodiment, the first component is cellulose and the second component is a cellulase complex.

[0025] In yet another embodiment, the second component is enzymatically active and digests the first component in the environment of the mammalian intestine. Typically, the second component has maximum enzymatic activity in the pH range of pH 3 to 12, such as from pH 3.5 to 9.5, or from pH 3.0 to 9.0, or from pH 4.0 to 9.0.

[0026] In a further embodiment, the composition is in the form of a tablet or capsule or other type of solid oral dosage form.

[0027] In a third aspect, the present invention relates to a composition according to any one of the first or second aspects or the above embodiments for use as a pharmaceutical. In certain embodiments, the pharmaceutical is in the form of a microbial culture.

[0028] In a fourth aspect, the present invention relates to a composition according to any one of the first or second aspects or the above embodiments for use as a dietary supplement.

[0029] In a fifth aspect, the present invention relates to a composition according to any one of the first or second aspects or the above embodiments for use as a tracer. In a further aspect, the present invention relates to the use of a pair of components for preparing a coating for a solid oral dosage form, wherein the coating is degraded when subjected to a pH change from a lower pH to a higher pH, the first component by the second component is inhibited at a lower pH, and the second component, when exposed to a higher pH, digests the first component. BRIEF DESCRIPTION OF THE DRAWINGS

[0030]

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DETAILED DESCRIPTION OF THE INVENTION

[0031] Description of the Invention The present invention relates to a solid oral composition for targeted release in the intestine of a mammal. The solid oral composition can be in any form known to those skilled in the art, in particular tablets or capsules, and can be administered to a mammal via the oral route. In one embodiment, the oral composition is a tablet. In another embodiment, the oral composition is a capsule. The mammal can be any mammal such as a human.

[0032] As used herein, the term "mammal" means, but is not limited to, animals such as humans, dogs, cats, pigs, monkeys, human apes, rodents, etc. The term "mammal with little or no ability to digest cellulose" means a human, dog, cat, pig, monkey, human ape, rodent and other animals with little or no ability to digest cellulose. Mammals such as cows, oxen, horses, goats, sheep, deer, etc., which inherently have a digestive system with the ability to digest cellulose polymers, do not benefit from the present invention when the coating contains cellulose.

[0033] The solid oral composition for targeted release in the intestine of a mammal such as a human refers to the design of the solid composition described in detail below, which enables accurate sensing when the composition reaches the intestine that is the target, and thus targeted release.

[0034] The solid composition includes a core, provided that the core itself does not affect the stability of the coating. The core can include a solution, a suspension, or can be a solid core. Since the core is surrounded by a coating that defines an outer solid layer, the overall composition is called a solid composition. The core contains a material that should be released into the intestine when the coating or a part of the coating is dissolved or broken down and is confined (captured). The captured material can be any material suitable for release in the intestine, not limited to drugs, nutrients, supplements, microorganisms, vaccines, radio transmitters, devices for measuring parameters in the intestine, etc. The coating or a part of the coating is adapted to be digested in the intestine. This means that the coating can consist of different coatings, such as a part that is digested to release the captured material and another part that remains intact, or the entire coating should be digested or perforated in the intestine to release the captured material. The intestine includes different elements such as the small intestine, duodenum, ileum, jejunum, and the large intestine consisting of different elements of the colon. Each of these elements is intended to be the subject of embodiments in combination with aspects and embodiments of the present invention.

[0035] Preferably, the coating is adapted to resist destruction from the environment within the mammalian stomach, such that release of the captured material does not occur in the stomach. The coating may itself be composed of two or more elements, where one enzymatically digests the other in the intestine but not in the stomach. Thus, the coating prevents release of the captured material in the mammalian stomach and / or the coating protects the captured material in the mammalian stomach. When the coating is said to be adapted to release the material captured in the mammalian intestine, it refers to the composition of the coating that is destroyed by enzymatic digestion in the intestine. Such a coating is composed of two or more components and, according to a preferred embodiment of the invention, the coating comprises a pair of components. A pair of components means two components, such components differing in that one must digest the other in order to be used as the coating according to the invention and moreover, the coating or a part of the coating is adapted to be digested in the intestine.

[0036] The first component is resistant to the environment within the mammalian stomach and the second component digests the first component when exposed to the more basic environment of the intestine as compared to the more acidic environment of the stomach. In this regard, the mammalian is preferably an animal that has little or no ability to digest cellulose, such as, for example, a human, monkey, pig, dog, great ape, rodent and cat. In a preferred embodiment, the mammalian is a human. The reference to the first and second components is only to indicate that the two components are different and not to indicate how the coating is made or the order thereof. Preferably, the second component digests the first component by having digestive activity that is inhibited in the environment within the mammalian stomach. If not inhibited in the stomach environment, the second component can be compensated for by adding an additional coating that covers the solid oral composition of the invention, but this may be a less practical solution.

[0037] One way to produce a coating for use in accordance with the present invention is the preparation of a pair of components. The first component of the coating composition for use in the present invention can be produced, for example, by first generating a bacterial cellulose (BC) cuticle by microbial fermentation and then purifying the BC. This procedure may include an alkali treatment step. Next, a second component, such as cellulase, can be produced by microbial fermentation, chemical synthesis, or other means, and then purified, for example, by affinity chromatography, whereby the cellulase is purified. Thereafter, the cellulase is made in a liquid formulation (formulation) and injected into the BC cuticle (e.g., at a pH or other conditions where the cellulase is inactive). The cuticle is dried to obtain a BC sheet that is impermeable to molecules with MW>200Da containing cellulase (CX). A core (containing the captured material to be released in the intestine) is embedded in the BC / CX sheet and sealed with a suitable component. An overview of the coating manufacturing process is shown in Figure 2.

[0038] The captured material can be anything suitable for release in the intestine, such as a compound for use as a drug.

[0039] In further embodiments, the captured material is a drug. In yet another embodiment, the captured material is a dietary supplement. In further embodiments, the captured material is a microbial culture. In yet another embodiment, the captured material is a microbial additive. In further embodiments, the captured material is a vaccine.

[0040] Further embodiments of the drug are selected from one or more of a protein, an enzyme, a polypeptide, an oligopeptide, a peptide, deoxyribonucleic acid (DNA), ribonucleic acid (RNA), a small organic molecule less than 900Da, or a prodrug of any one of these materials, all of which are considered individual embodiments and can be the subject of one or more claims with respect to any one of the aspects and embodiments described herein.

[0041] Further embodiments of the captured material are selected from one or more of the following. a) Proteins, human growth hormone (hGH), calcitonin, insulin, GLP-1 analogs, GLP-1, b) Peptides, octreotide, c) Oral vaccines, oral cholera vaccine, Mycoplasma hyopneumoniae oral vaccine, live bacterial cells as attenuated vaccines, d) Organic small molecules 200 < MW < 900 g / mol, desmopressin, vasopressin, cyclosporine, ranitidine, diclofenac, ketoprofen, amifostine, omeprazole, gemcitabine, domperidone, paclitaxel, sinnalidine, donepezil, leucovorin, raloxifene, indomethacin, dextromethorphan, nizatidine, peptide Val-Leu-Pro-Val-pro-Arg (VLPVPR), flurbiprofen, mebendazole, thymidine, zolpidem tartrate, loratidine, venlafaxine, tamsulosin, urapidil, prednisolone, miconazole, diltiazem, ambroxol, captopril, acyclovir, cimetidine, metoprolol, griseofulvin, atazanavir, ibuprofen, azithromycin, lercanidipine, sulfacetamide, azelastine, didanosine, chloricromen, oxymetazoline, acarbose, propranolol, alfuzosin, stibudine, lobenzarit, genistein, verapamil, terbinafine, lornoxicam, clotrimazole. Each of the compounds or vaccines is considered an individual embodiment and can be the subject of one or more claims with respect to any one of the aspects and embodiments described herein.

[0042] Pairs of components can be mixed or made into separate layers. As long as the two components are in contact with each other, other ways of making a coating consisting of the two components are contemplated by the present invention. For example, a first component and a second component are mixed. Alternatively, the first component and the second component are in different layers, such as two layers where the first component is in the outer layer and the second component is in the inner layer around the core.

[0043] In yet another embodiment, the pair of the first component and the second component are a dietary fiber and an enzyme that digests the dietary fiber. In a further embodiment, the pair of the first component and the second component are cellulose and cellulase. In a further embodiment, the pair of the first component and the second component are pectin and pectinase. In yet another embodiment, the pair of the first component and the second component are hemicellulose and hemicellulase. In a further embodiment, the pair of the first component and the second component are lignin and ligninase. In yet another embodiment, the pair of the first component and the second component are fructan and fructanase. In a further embodiment, the pair of the first component and the second component are lipid and lipase.

[0044] When the pair of the first component and the second component are cellulose and cellulase, preferably, the first component and the second component are selected from structurally ordered cellulose I and cellulase. The most abundant type of natural cellulose found in nature is called cellulose I [6,7,8]. Structurally ordered cellulose I is preferably bacterial cellulose or a derivative thereof, and the cellulase is preferably selected from the group consisting of cellulase (EC3.2.1.4) (endocellulase), cellobiase (EC3.2.1.21) (beta-glucosidase), 1,4-beta-cellobiosidase (EC3.2.1.91) (exocellulase), cellulose 1,4-beta-cellobiosidase (reducing end) (EC3.2.1.176) (exocellulase), as well as cellulase complexes and mixtures thereof.

[0045] As used interchangeably herein, the terms "structurally ordered cellulose I" or "native cellulose" refer to unbranched polymers containing any number of eight or more D-glucose units linked by β-1,4 glycosidic bonds.

[0046] In yet another embodiment, the second component is enzymatically active and digests the first component in the environment within the mammalian intestine. In particular, the second component has maximum enzymatic activity in the pH range of 3 to 12, such as from pH 3.5 to 9.5, or from 3.0 to 9.0, or from 4.0 to 9.0.

[0047] Furthermore, the present invention relates to a solid oral composition for targeted release in the mammalian intestine, comprising a core and a coating completely surrounding the core, the core containing the captured material to be released in the intestine, and the coating or a part of the coating being adapted to be digested in the intestine for use as a pharmaceutical. Each of the above-described embodiments related to the first aspect is also applicable to this particular mode of use.

[0048] Furthermore, the present invention relates to a solid oral composition for targeted release in the mammalian intestine, comprising a core and a coating completely surrounding the core, the core containing the captured material to be released in the intestine, the coating or a part of the coating being adapted to be digested in the intestine, the coating comprising a first component and a second component, the first component being resistant to the environment within the mammalian stomach, and the second component enzymatically digesting the first component when exposed to the more basic environment of the intestine as compared to the more acidic environment of the stomach for use as a dietary supplement. Each of the above-described embodiments related to the first aspect is also applicable to this particular mode of use.

[0049] Furthermore, the present invention relates to a solid oral composition for targeted release in the intestine of a mammal, comprising a core and a coating that completely surrounds the core, the core containing the captured material to be released in the intestine, the coating or a part of the coating being adapted to be digested in the intestine, the coating comprising a first component and a second component, the first component being resistant to the environment in the stomach of a mammal, and the second component being adapted to enzymatically digest the first component when exposed to the more basic environment of the intestine as compared to the more acidic environment of the stomach for use as a tracer. Each of the above embodiments related to the first aspect is also applicable to this particular mode of use.

[0050] In a further aspect, the present invention relates to the use of a pair of components for preparing a coating for a solid oral dosage form, the coating being decomposed when subjected to a pH change from a lower pH to a higher pH, the first component being adapted to be resistant to digestion at a lower pH, and the second component being adapted to digest the first component when exposed to a higher pH. The coating can optionally be used to surround a solid oral dosage form or cover a part of a solid oral dosage form. Typically, the solid oral dosage form is a tablet, a capsule or a granule. Usually, in the intestine, the lower pH is in the range of 1.0 to 4.5 and the higher pH is in the range of 4.5 to 8.5. The preparation of a coating according to this further aspect that can preserve the coating for later use is also contemplated by this aspect of the present invention. The coating can be used in the setup of a test system to verify the appropriate pair and amounts and ratios of the components used.

[0051] In a further aspect, the present invention relates to a composition comprising a pair of components, wherein a) the first component is resistant to the environment i) similar to the stomach of a mammal or ii) in the stomach of a mammal, and b) the second component is adapted to enzymatically digest the first component when exposed to i) the more basic environment of the intestine or ii) the more basic environment similar to the intestine as compared to the more acidic environment of the stomach or a more acidic environment similar to the stomach.

[0052] The above embodiments refer to any one of the aspects described herein (such as "composition", "pharmaceutical composition", "composition for use as a medicament", or "compound for use in a method"), and any one, and should be considered to refer to one of the embodiments described herein, unless the embodiment is specifically stated to relate to a particular aspect or side of the present invention.

[0053] All references, including publications, patent applications, and patents cited herein, are hereby incorporated by reference in their entirety to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

[0054] All headings and subheadings are used herein for convenience only and should not be construed as limiting the invention in any way.

[0055] Any combination of the above elements in all possible variations is included in the present invention unless otherwise indicated herein or clearly contradicted by the context.

[0056] The terms "a", "an", "the", and similar referents used in the context of describing the present invention should be construed to include both the singular and the plural unless otherwise indicated herein or clearly contradicted by the context.

[0057] The term "and / or" used herein is intended to mean both alternatives and each alternative individually. For example, the expression "xxx and / or yyy" means "xxx and yyy; xxx; or yyy", and all three alternatives are the subject of separate embodiments.

[0058] The recitation of a range of values herein is merely intended to serve as a simplified method of referring individually to each individual value that falls within the range, and each individual value is incorporated into the specification as if it were recited individually. Unless otherwise specified, all exact values provided herein represent corresponding approximate values (e.g., all exact exemplary values provided for a particular factor or measurement can be considered to also provide corresponding approximate measurements modified by "about" where appropriate).

[0059] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by the context.

[0060] The use of any examples, or of exemplary language (e.g., "such as") provided herein is merely intended to better illuminate the invention and does not impose a limitation on the scope of the invention unless otherwise indicated. No language in the specification should be construed as indicating any non-essential element of the invention as being essential to the practice of the invention unless explicitly stated otherwise.

[0061] The citation and incorporation of patent documents herein is for convenience only and does not reflect any opinion as to the validity, patentability, and / or practicability of such patent documents.

[0062] The description herein of any aspect or embodiment of the invention using terms such as "comprising", "having", "including", or "containing" with respect to one or more elements is intended to support similar aspects or embodiments of the invention that "consist of", "consist essentially of", or "substantially contain" that particular element or elements, unless otherwise specified or clearly contradicted by the context (e.g., a composition described herein as including a particular element should also be understood to describe a composition consisting of that element unless otherwise specified or clearly contradicted by the context).

[0063] The present invention includes all modifications and equivalents of the subject matter presented in the aspects or claims herein, to the maximum extent permitted by applicable law.

[0064] The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of protection. The features disclosed in the foregoing description and the following examples can be materials for realizing the present invention in its various forms, both separately and in any combination thereof.

[0065] Experimental Procedure Abbreviations

Table 0

[0066] Methods and Results Physiological parameters were extracted from the literature for human gastrointestinal pH and transit time. From these parameters, a semi-physiological model of gastrointestinal pH was synthesized and validated against the literature data. Furthermore, biochemical parameters of cellulase, which has maximum activity near neutral pH and strongly inhibits activity at acidic pH, were extracted from the Brenda bioinformatics database [9] and the literature [10, 11, 12]. From these data, a semi-biochemical model of the pH-dependence of cellulase activity was synthesized and validated against the literature data. By combining these two models, a semi-physiological model of cumulative cellulase activity was synthesized and used to perform simulations of cellulase passing through the human gastrointestinal tract.

[0067] Results: The two synthetic models predicted the literature data appropriately. In the simulation, it was shown that cellulase activity was strongly inhibited when cellulase passed through the stomach and was activated when it entered the small intestine. Furthermore, in the simulation, it was shown that even with a physiologically very long gastric transit time and a physiologically very short small intestine transit time, the cumulative activity (cumulative cellulose degradation) occurring during gastric transit was negligible compared to the cumulative activity (cumulative cellulose degradation) occurring during small intestine transit. This indicates that there is a robust design space for cellulose-cellulase-based coatings that protect the captured material during gastric transit and open holes in the intestine.

[0068] The enteric coating presented here is a method of firmly protecting the captured material during gastric transit and firmly releasing the material into the intestine by a self-perforating mechanism.

[0069] Results Cellulases with maximum activity in the pH range of 5.5 - 8.0 and with activity up to 25% of the maximum activity (%ma) in an acidic environment (pH < 4.0) were identified in the Brenda Bioinformatics database and in the literature [9, 10, 11, 12], and biochemical property data from these cellulases were used to synthesize a model (A1(pH)) that predicts the relative cellulase activity as a function of pH.

Number

[0070] The synthesized activity function A1(pH) models a cellulase with maximum activity at pH 6.5.

[0071] A graphical representation of the relative activity as a function of pH is shown in Figure 3. The model was validated against the literature data by overlaying the synthesized A1(pH) activity function with the activity data from the cellulases identified in the literature [10, 11, 12].

[0072] The model of the pH(t) of the human gastrointestinal system was synthesized by combining physiological data from the literature [1, 2]. A model of the change in gastric pH (pHs(t)) over time after a meal in healthy young men and women was extracted from study [1].

Number

[0073] The model of the pH in the small intestine being a constant pH = 6.1 is based on study [2]. T S represents the gastric transit time, and T I represents the intestinal transit time, then a model pH(t) is obtained that predicts the surrounding human gastrointestinal pH environment when the capsule / captured material passes through the intestine. Figure 1 shows a graphical representation of the synthetic model A1(pH) that predicts relative cellulase activity as a function of pH.

Number

[0074] The model pH(t) is plotted on top of the physiological data of the human stomach and intestine and appropriately predicts the data on the pH of the healthy human gastrointestinal tract found in the literature [1, 2]. Figure 4 shows a graphical representation of the model that predicts the human gastrointestinal pH(t) where the gastric transit time T S is 127 minutes and the short intestinal transit time T I is 162 minutes.

[0075] By combining the model (A1(pH)) that predicts relative cellulase activity as a function of pH with the model that predicts human gastrointestinal pH(t), and by constructing two functions, a model of relative cellulase activity in the digestive tract was obtained:

Number

[0076] A model for predicting the cumulative activity of a self-perforating material where the first component is cellulose and the second component is cellulase is obtained by integrating the relative activity function A1(pH(t)) / 100 with respect to time. The median gastric transit time T S is 60 minutes, and the median small intestine transit time T I is 275 minutes, and a graphical representation of the cumulative activity of the self-perforating material is shown in Figure 6.

[0077] For the calculation of cumulative activity, relative units of maximum activity (mma) are used. The mma unit represents the cumulative cellulase activity as corresponding to the reaction minutes when the reaction is carried out under optimal conditions (such as the optimal reaction pH at pH 6.5 for the model cellulase described in A1(pH), for example). · The basic unit 1 mma is the enzymatic turnover of β-1,4-glycosidic bonds at the maximum enzyme activity per minute. · The mma unit is related to a specific number of active sites, for example, the amount of cellulose, and a specific number of 1-4 glycosidic bonds, for example, the amount of cellulose. · The mma unit is specific to an individual cellulase and an individual cellulose substrate.

[0078] Using the mma unit, the cumulative cellulase activity under various reaction conditions such as reaction time, temperature, pH, cofactor concentration, inhibitor concentration, etc. can be compared. The mma unit is convenient for product design and can be used as a manufacturing specification for designing materials that self-perforate within a specific range of cumulative cellulase activity.

[0079] Example 1 Using the model A1(pH(t)) / 100 of the performance of the self-perforating material in the gastrointestinal system, the activity accumulated in the self-perforating material when passing through the human digestive tract under various physiological conditions was studied. Five studies were conducted to investigate the characteristics of a self-perforating material in which the first component is cellulose and the second component is cellulase with the activity function A1(pH) under different gastric emptying times and small intestine transit times.

[0080] The gastric transit time was 60 minutes and the small intestine transit time was 275 minutes The median of the typical gastric emptying time was found to be 60 minutes in the literature [3,4,5], and the median of the intestinal transit time was found to be 275 minutes in the literature [3,4,5]. The graphical representation of the cumulative cellulose hydrolysis predicted by the model using these gastric emptying and small intestine transit times is shown in Figure 6. Figure 6 shows a model for predicting the cumulative activity of the self-perforating material in the gastrointestinal system. Input parameters: gastric transit time T of 60 minutes S and small intestine transit time T of 275 minutes I .

[0081] The model of the cumulative activity in the digestive tract shows that a self-perforating material designed to withstand a cumulative activity exceeding 17 mma protects the captured material from the gastric environment at a gastric emptying time (time for the stomach to empty) up to 60 minutes. Furthermore, a self-perforating material designed to be digested with a cumulative activity less than 290 mma releases the captured material into the human small intestine when given a small intestine transit time of 275 minutes. Therefore, a self-perforating material designed to be digested by a cumulative activity in the range of 17 - 290 mma releases the captured material at typical median gastric transit time and small intestine transit time.

[0082] The gastric transit time was 5 minutes and the small intestine transit time was 162 minutes Typical short gastric emptying times are known from the literature to be 5 minutes [3,4,5], and typical short intestinal transit times are known from the literature [3,4,5] to be 162 minutes. The graphical representation of the cumulative cellulose hydrolysis predicted by the model using these gastric emptying and small intestine transit times is shown in Figure 7. Figure 7 shows a model for predicting the cumulative activity of a gastrointestinal self-perforating material. Input parameters: gastric transit time T of 5 minutes S and small intestine transit time T of 162 minutes I .

[0083] The model of the cumulative activity of the gastrointestinal tract shows that a self-perforating material designed to withstand a cumulative activity exceeding 5 mma protects the material captured from the environment in the human stomach with a gastric emptying time of up to 5 minutes. Furthermore, when designed to be digested with a cumulative activity of less than 165 mma, when given a small intestine transit time of 162 minutes, the captured material is released into the human small intestine. Thus, a self-perforating material designed to be digested by a cumulative activity in the range of 5 - 165 mma releases the captured material with typical short gastric and small intestine transit times.

[0084] The gastric transit time was 337 minutes and the small intestine transit time was 162 minutes Typical long gastric emptying times are known from the literature to be 337 minutes [3,4,5], and typical short intestinal transit times are known from the literature [3,4,5] to be 162 minutes. The graphical representation of the cumulative cellulose hydrolysis predicted by the model using these gastric emptying and small intestine transit times is shown in Figure 8. Figure 8 shows a model that predicts the cumulative activity of a gastrointestinal self-perforating material using the input parameters: gastric transit time T of 337 minutes S ; small intestine transit time T of 162 minutes I and shows a model that predicts the cumulative activity of a gastrointestinal self-perforating material using these parameters.

[0085] The model of the cumulative activity of the digestive tract shows that a self-perforating material designed to withstand a cumulative activity exceeding 17 mma protects the captured material from the environment in the human stomach with a gastric emptying time of up to 337 minutes. Further, when designed to be digested with a cumulative activity of less than 178 mma, the captured material is given a small intestine transit time of 162 minutes and released into the human small intestine. Therefore, a self-perforating material designed to be digested by a cumulative activity in the range of 17 - 178 mma releases the captured material with a typical long gastric transit time and a short small intestine transit time.

[0086] A gastric transit time of 5 minutes and a small intestine transit time of 669 minutes It has been found in the literature that a typical short gastric emptying time is 5 minutes [3, 4, 5], and a typical long intestinal transit time is 669 minutes in the literature [3, 4, 5]. A graphical representation of the predicted cumulative cellulose hydrolysis by a model using these gastric emptying and small intestine transit times is shown in Figure 9. Figure 9 shows a model for predicting the cumulative activity of a gastrointestinal self-perforating material. Input parameters: gastric transit time T of 5 minutes S and small intestine transit time T of 669 minutes I .

[0087] The model of the cumulative activity of the digestive tract shows that a self-perforating material designed to withstand a cumulative activity exceeding 5 mma protects the captured material from the environment in the human stomach with a gastric emptying time of up to 5 minutes. Further, a self-perforating material designed to be digested with a cumulative activity of less than 668 mma releases the captured material into the human small intestine when the small intestine transit time is 669 minutes. Therefore, a self-perforating material designed to be digested by a cumulative activity in the range of 5 - 668 mma releases the captured material with a typical long gastric transit time and a short small intestine transit time.

[0088] The gastric transit time was 337 minutes and the small intestine transit time was 669 minutes A typical long gastric emptying time was found to be 337 minutes [3,4,5] in the literature, and a typical long intestinal transit time was 669 minutes in the literature [3,4,5]. The graphical representation of the cumulative cellulose hydrolysis predicted by the model using these gastric emptying and small intestine transit times is shown in Figure 10. Figure 10 shows a model for predicting the cumulative activity of self-perforating materials in the gastrointestinal system. Input parameters: gastric transit time T S is 337 minutes, and the small intestine transit time T I is 669 minutes.

[0089] The model of the cumulative activity of the gastrointestinal tract shows that a self-perforating material designed to withstand a cumulative activity exceeding 17 mma protects the captured material from the environment in the human stomach with a gastric emptying time up to 337 minutes. Furthermore, a self-perforating material designed to be digested with a cumulative activity less than 681 mma releases the captured material into the human small intestine when given a small intestine transit time of 669 minutes. Therefore, a self-perforating material designed to be digested by a cumulative activity in the range of 17 - 681 mma releases the captured material with a typical long gastric transit time and a long small intestine transit time.

[0090] In the five studies of Example 1, all combinations of typical short and long gastric emptying times and typical short and long intestinal transit times were studied. A self-perforating material with the first component being cellulose and the second component being cellulase of the activation function A1(pH) can protect the captured material from the environment in the human stomach and be designed to release the captured material into the human small intestine in any of the above considered cases when the material is designed with a cumulative activity specification in the window of 17 mma to 165 mma.

[0091] Example 2 The model A1(pH(t)) / 100 for predicting the performance of self-perforating materials in the gastrointestinal system was modified to study the performance of self-perforating materials in the human gastrointestinal tract when given the post-meal invasion time T PM for coating. The equation for pH variation is as follows.

Equation

[0092] Using the obtained model, after the diet intrusion, T PM = 60 minutes, the coating was applied, and the cumulative activity was examined when the gastric transit time T S was considered to be 30 minutes. The figure is shown in FIG. 11. FIG. 11 shows that after the diet intrusion, T PM = 60 minutes, the gastric transit time T S is 30 minutes, and the small intestine transit time T S is 275 minutes, showing the activity accumulated in the self-perforating material of the human gastrointestinal tract.

[0093] When the coating is given a 60-minute post-meal intrusion, the cellulase activity is very low due to the acidic environment. This is reflected in the predicted cumulative activity of 0mma in the stomach. When the coating material enters the small intestine, the cellulase activity increases, initiating the destruction of the coating and supporting the release of the captured material. The intrusion of the coating at the post-meal delay time significantly reduces the cumulative activity in the stomach compared to when the coating is intruded with the diet. Therefore, the design space of the coating is significantly increased.

[0094] Example 3 The effect of using cellulase enzyme at other optimal pHs on the cumulative activity in the gastrointestinal tract was studied.

[0095] The model for predicting the performance of the self-perforating material of the gastrointestinal system was changed to A2(pH(t)) / 100, and the performance of the cellulose-cellulase self-perforating material in the human digestive tract was predicted when cellulase shows maximum activity at pH OPT A2(pH) models a cellulase enzyme with similar characteristics to those of the cellulase characteristics described by model A1(pH), but the enzyme is optimal at pH OPT

Number

[0096] ​Using A2(pH), the cumulative activity of an enzyme with maximum activity at a pH equal to 3.5 was studied. The figure is shown in Figure 12. Figure 12 shows the pH described by the function A2(pH(t)) / 100 OPT and depicts the cumulative activity diagram of an enzyme with maximum activity at pH = 3.5. OPT

[0097] Using A2(pH), the cumulative activity of an enzyme with maximum activity at a pH equal to 9.0 was studied. The figure is shown in Figure 13. Figure 13 shows the pH described by the function A2(pH(t)) / 100 OPT and depicts the cumulative activity diagram of an enzyme with maximum activity at pH = 9.0. OPT

[0098] In a composition containing cellulase with maximum activity at pH 3.5, the cumulative activity in the stomach becomes almost zero and levels off as the gastric transit time increases (Figure 12). A composition containing an enzyme with maximum activity at pH 3.5 can protect the captured material in the stomach if the coating material is designed to release the captured material in the range of 100 mma to 118 mma. However, such a composition containing an enzyme with maximum activity at pH 3.5 may require the application of a coating after the entry of food in order to obtain a robust design space (a strong design space) for releasing the captured material into the small intestine.

[0099] When the coating material is designed to release the captured material in the range of 0.1 mma to 7.8 mma, a composition containing an enzyme with maximum activity at pH 9.0 can protect the captured material in the stomach. Using such a composition, a very robust design space for releasing the captured material into the intestine can be obtained.

[0100] A composition containing an enzyme with maximum activity above pH 9.0 will only protect the captured material in the stomach and improve the ability of the material to release the captured material into the intestine.

[0101] Compositions containing cellulase enzymes having an enzymatic optimum in the range of at least pH 3.0 to 12.0, such as from 3.5 to 9.0, can function as a second component in self-perforating materials and can support the protection of the captured material in the stomach and its release in the small intestine.

[0102] Example 4 The aim of this experiment was to investigate the influence of the BC membrane thickness (measured as specific mass mg / cm 2 and pH on the diffusion of model compounds through the membrane.

[0103] Wet BC membranes from cultures of Komagataebacter xylinus were compressed to remove moisture and then lyophilized (3 days, -99 °C; 0.049 mbar). Membranes with a mass per area of 3.3 mg / cm 2 and 13.9 mg / cm 2 (thickness) were obtained. Sulforhodamine B (SRB) (MW 558.7 g / mol) was used as a model compound. The time-dependent diffusion of SRB through the BC membrane was investigated in a diffusion cell at pH 2 and pH 6.5. The diffusion cell consisted of a donor chamber where the model compound was placed at the start of the study and a receptor chamber where the model compound could migrate. The membrane under investigation was placed between the two chambers.

[0104] The donor chamber was filled with a 2 mg / mL SRB solution in 0.01 M HCl (pH 2) or PBS (pH 6.5). The membrane under study was placed on top of the donor chamber. The study was started when the receptor chamber was filled with 0.01 M HCl (pH 2) or PBS (pH 6.5) corresponding to the pH of the donor chamber. Samples were taken from the receptor chamber after 0 h, 1 h, 1.5 h, 2 h, 4 h, and 6 h, and the concentration of SRB was measured at OD 565 nm. The results are shown in Tables 1 and 2.

[0105]

Table 1

[0106]

Table 2

[0107] The results in Table 1 show that when diffusing through the BC membrane at pH 2 with a loading of 3.3 mg / cm 2 , the SRB concentration in the receptor chamber is 66.8 μg / ml after 2 hours, and when diffusing through the BC membrane at pH 2 with a loading of 13.9 mg / cm 2 , the SRB concentration in the receptor chamber is 4.6 μg / ml after 2 hours. When the SRB concentration in the receptor chamber is equal to the SRB concentration in the donor chamber, the diffusion reaches equilibrium. The diffusion cell used in this study shows diffusion equilibrium around an SRB concentration of 1100 μg / ml. The concentrations of 66.8 μg / ml and 4.6 μg / ml achieved after 2 hours at pH 2 correspond to approximately 6% (membrane 3.3 mg / cm 2 ) and 0.5% (membrane 13.9 mg / cm 2 ) of the maximum SRB diffusion. Two hours at pH 2 corresponds to a typical maximum gastric transit time and a typical gastric pH. It can be concluded that bacterial cellulose can hold and protect the captured material during gastric transit. The results in Table 2 show that the BC membrane requires a second component to accelerate the release of the captured substance in order to hold and protect the captured substance at pH 6.5 (corresponding to the intestinal pH). Diffusion through the membrane depends on the membrane thickness.

[0108] Example 5 The purpose of this experiment was to determine the effect of pH on the activity of the cellulase complex introduced into the bacterial cellulose membrane.

[0109] The wet BC membrane was obtained from a culture of Komagataebacter xylinus and compressed to remove water. A cellulase complex solution (100 μl) of cellulase 1.5L from T. reesei (Novozymes, DK) was added to the BC membrane and incubated to adsorb the enzyme onto the BC fibers (15 minutes at 0 °C). The membrane injected with the cellulase complex was lyophilized (3 days, -99 °C; 0.049 mbar). In the formulation without the injection of cellulase, the specific gravity of the BC membrane was 3.1 mg / cm 2 was.

[0110] The digestive activity of the cellulase complex injected into the BC membrane was examined at pH 2 and pH 6.5. The study was initiated by incubating the membrane at pH 2 and 6.5 (6.7 ml of 0.01 M HCl (pH 2) or PBS (pH 6.5) respectively). Samples were taken at 0 h, 1 h, 1.5 h, 2 h, 4 h, and 6 h of cellulose digestion and the reducing sugars were analyzed by the DNS method of Miller

[13] . The results are shown in Table 3.

[0111]

Table 3

[0112] The results show that the cellulase complex introduced into the cellulose membrane, lyophilized, and then rehydrated can bring about the digestion of the cellulose membrane. This shows the effectiveness of the two-component coating manufacturing process shown in Figure 2. At pH 2 corresponding to the gastric environment, the cellulase activity, and thus cellulose digestion, is inhibited and stops after 1 hour. At pH 6.5 corresponding to the intestinal environment, the BC membrane is digested.

[0113] Example 6 The purpose of this experiment was to determine the effect of pH on the activity of the combination of cellulases introduced into the bacterial cellulose membrane.

[0114] The wet BC membrane was obtained from a culture of Komagataebacter xylinus and compressed to remove water. The 8:8:3:6 combination of cellulases was prepared from two endocellulases from Thermobifida fusca and Clostridium cellulolyticum (EC: 3.2.1.4 from families 6A and 9G, respectively) and two exocellulases from Podospora anserina and Thermo-bifida usca (EC: 3.2.1.91 family 6A and EC: 3.2.1.176 family 48A). The enzymes have optimal activity in the pH range of 5.0 to 9.0, have a cellulose-binding domain, and have crystalline cellulose as a substrate. All enzymes were produced by heterologous expression followed by purification (NZYTec, Portugal).

[0115] The cellulase combination solution (415 μl) was added to the compressed BC membrane and incubated to adsorb the enzyme to the BC fibers (15 minutes at 0 °C). The BC membrane was lyophilized (3 days, -99 °C; 0.049 mbar). In the formulation without cellulase injection, the specific gravity of the BC membrane was 7.2 mg / cm 2 It was.

[0116] The activity study was initiated by incubating the lyophilized BC membrane injected with the cellulase combination at pH 2 and 6.5 (6.7 ml of 0.01 M HCl (pH 2) or PBS (pH 6.5), respectively). Samples were taken at 0, 1, 1.5, 2, 4, and 6 hours of digestion, and the production of reducing sugars was measured by the method of Miller

[13] . The results are shown in Table 4.

[0117]

Table 4

[0118] The results indicate that a combination of cellulase introduced into the cellulose membrane, lyophilized, and then rehydrated can effect the digestion of the BC cellulose membrane. This further demonstrates the effectiveness of the two-component coating manufacturing process shown in Figure 2. At pH 2 corresponding to the gastric environment, the activity is strongly inhibited and no activity can be detected. At pH 6.5 corresponding to the intestinal environment, the BC membrane is digested.

[0119] Example 7 The purpose of this experiment was to show the diffusion of model compounds through the BC membrane (component 1) digested by the introduced cellulase (component 2).

[0120] The wet BC membrane was obtained from a culture of Komagataebacter xylinus and compressed to remove water. A cellulase complex solution (100 μl) of 1.5 L of cellulase from T. reesei (Novozymes, DK) was added to the BC membrane and incubated to adsorb the enzyme onto the BC fibers (15 minutes at 0 °C). The BC membrane injected with the cellulase complex was lyophilized (3 days, -99 °C; 0.049 mbar). In the formulation without the injection of cellulase, the specific gravity of the BC membrane was 7.3 mg / cm 2 Sulforhodamine B (SRB) (MW 558.7 g / mol) was used as the model compound. The time-dependent diffusion of SRB through the BC membrane was investigated in diffusion cells at pH 2 and pH 6.5. The donor chamber of the diffusion cell was filled with a 2.9 mL solution of 2 mg / mL SRB at pH 2 or pH 6.5. The membrane to be studied was placed on top of the donor chamber. The study was initiated when the receptor chamber was filled with 0.01 M HCl (pH 2) or PBS (pH 6.5) corresponding to the pH of the donor chamber. The diffusion cell was placed at 50 °C. Samples were taken from the receptor chamber at 0 h, 1 h, 2 h, 3 h, 4 h, and 6 h, and the concentration of SRB was measured at OD 565 nm. The results are shown in Table 5.

[0121]

Table 5

[0122] The results show that the diffusion of the model compound through the BC membrane digested by the injected cellulase complex is constant at a lower rate at pH 2 and at a higher rate at pH 6.5. The results illustrate the use of a pair of components for preparing the coating (where 1) the coating is digested when exposed to a higher pH but not at a lower pH, 2) the first component (exemplified here by bacterial cellulose) is not digested by natural digestion in the gastrointestinal system, and 3) the second component (exemplified here by cellulase) digests the first component when exposed to a higher pH in the intestine but not when exposed to a lower pH in the stomach). Thus, the BC membrane coating prevents the release of the model compound under typical conditions found in the stomach (pH 2) and promotes the release of the model compound under typical conditions found in the mammalian intestine (pH 6.5).

[0123] Conclusion Based on the presented studies, the described coating materials enable the protection of the captured material in the stomach of mammals such as humans and enable release in the intestine. Combining Examples 1 to 3 shows the high robustness of the design space and enables a wide range of coating specifications. Combining Examples 4 to 7 shows the technical feasibility of the described coating materials. In connection with the present invention, the following content is further disclosed. [1] A solid oral composition for targeted release in the intestine of a mammal, comprising a core and a coating that completely surrounds the core, Moreover, the core contains the captured material to be released in the intestine, Moreover, the coating or a part of the coating contains a first component and a second component, Moreover, the first component is resistant to the environment in the stomach of a mammal, and the second component enzymatically digests the first component when exposed to the more basic environment of the intestine compared to the more acidic environment of the stomach, Said composition. [2] The composition according to [1], wherein the coating is adapted to resist destruction from the environment in the stomach of a mammal. [3] The composition according to any one of [1] to [2], wherein the coating prevents the release of the captured material in the stomach of a mammal. [4] The composition according to any one of [1] to [3], wherein the coating protects the captured material in the stomach of a mammal. [5] The composition according to any one of [1] to [4], wherein the coating is adapted to release the captured material in the intestine of a mammal. [6] The composition according to any one of [1] to [5], wherein the digestive activity of the second component is inhibited in the environment in the stomach of a mammal. [7] The composition according to any one of [1] to [6], wherein the mammal is selected from animals with little or no ability to digest cellulose, such as humans, monkeys, pigs, dogs, human apes, rodents, and cats. [8] The composition according to any one of [1] to [7], wherein the captured material is a pharmaceutical, such as a protein, an enzyme, a polypeptide, an oligopeptide, a peptide, deoxyribonucleic acid (DNA), ribonucleic acid (RNA), a small organic molecule less than 900 Da, or a prodrug of any of these materials, a dietary supplement, or a microbial culture, or a microbial additive, or a vaccine. [9] The composition according to any one of [1] to [8], wherein the first component and the second component are mixed.

[10] The composition according to any one of [1] to [9], wherein the first component and the second component are in different layers, the first component is in the outer layer, and the second component is in the inner layer around the core.

[11] The composition according to any one of [1] to

[10] , wherein the pair of the first component and the second component is selected from cellulose and cellulase, pectin and pectin-degrading enzyme, hemicellulose and hemicellulase, lignin and lignin-degrading enzyme, fructan and fructan-degrading enzyme, and lipid and lipase.

[12] The composition according to any one of [1] to

[11] , wherein the pair of the first component and the second component is selected from structurally ordered cellulose I such as bacterial cellulose or its derivative, and cellulase (EC3.2.1.4) (endocellulase), cellobiase (EC3.2.1.21) (beta-glucosidase), 1,4-beta-cellobiosidase (EC3.2.1.91) (exocellulase), cellulose 1,4-beta-cellobiosidase (reducing end) (EC3.2.1.176) (exocellulase), and cellulase such as cellulase complex and their mixtures.

[13] The composition according to any one of [1] to

[12] , wherein the second component is enzymatically active and digests the first component in the environment of the mammalian intestine.

[14] The composition according to

[13] , wherein the second component has maximum enzyme activity in the pH range of 3 to 12, such as from pH 3.5 to 9.5, or from 3.0 to 9.0, or from 4.0 to 9.0.

[15] The composition according to any one of [1] to

[14] , wherein the intestine is selected from the small intestine, large intestine, duodenum, ileum, jejunum, and colon.

[16] The composition according to any one of [1] to

[15] , wherein the composition is in the form of a tablet or capsule or other type of solid oral dosage form.

[17] The composition according to any one of [1] to

[16] for use as a pharmaceutical.

[18] The composition according to any one of [1] to

[16] for use as a dietary supplement.

[19] The composition according to any one of [1] to

[16] for use as a tracer.

[20] Use of a pair of components for preparing a coating for a solid oral dosage form, wherein the coating is degraded when exposed to a pH change from a lower pH to a higher pH, and wherein at a lower pH, digestion of a first component by a second component is inhibited, and when exposed to a higher pH, the second component digests the first component.

[21] The composition according to any one of [1] to

[20] , wherein the captured material is selected from the following: e) proteins, human growth hormone (hGH), calcitonin, insulin, GLP-1 analogs, GLP-1 f) peptides, octreotide g) oral vaccines, oral cholera vaccine, Mycoplasma hyopneumoniae oral vaccine, live bacterial cells as attenuated vaccines, live cell cultures h) organic small molecules 200 < MW < 900 g / mol, desmopressin, vasopressin, cyclosporine, ranitidine, diclofenac, ketoprofen, amifostine, omeprazole, gemcitabine, domperidone, paclitaxel, cinacalcet, donepezil, leucovorin, raloxifene, indomethacin, dextromethorphan, nizatidine, peptide Val-Leu-Pro-Val-pro-Arg (VLPVPR), flurbiprofen, mebendazole, thymidine, zolpidem tartrate, loratadine, venlafaxine, tamsulosin, urapidil, prednisolone, miconazole, diltiazem, ambroxol, captopril, acyclovir, cimetidine, metoprolol, griseofulvin, atazanavir, ibuprofen, azithromycin, lercanidipine, sulfacetamide, azelastine, didanosine, chloricromene, oxymetazoline, acarbose, propranolol, alfuzosin, stibudine, robenzarit, genistein, verapamil, terbinafine, lornoxicam, clotrimazole.

[0124]

Table 6

Claims

1. 1. A solid oral composition for targeted release in the intestine of a mammal, comprising a core and a coating completely surrounding the core, Moreover, the core contains the entrapped material to be released in the intestine, Moreover, the coating or a portion of the coating comprises a first component and a second component, Moreover, the first component is selected from structurally ordered cellulose I, which is insoluble in water and is resistant to the environment in the mammalian stomach; and the second component is selected from cellulases and cellulase complexes and mixtures thereof that enzymatically digest the first component when exposed to the more basic environment of the intestine compared to the more acidic environment of the stomach; Moreover, the digestive activity of the second component is inhibited in the mammalian stomach environment. The composition described above.

2. The composition of claim 1 , wherein the coating is adapted to resist destruction from the environment in a mammalian stomach.

3. The composition of any one of claims 1 to 2, wherein the coating prevents release of the entrapped material in the mammalian stomach.

4. The composition of any one of claims 1 to 3, wherein the coating protects the entrapped material in the mammalian stomach.

5. The composition of any one of claims 1 to 4, wherein the coating is adapted to release the entrapped material in the intestine of a mammal.

6. The composition according to any one of claims 1 to 5, wherein the mammal is selected from animals that have little or no ability to digest cellulose and is selected from humans, monkeys, pigs, dogs, apes, rodents and cats.

7. 7. The composition of any one of claims 1 to 6, wherein the entrapped material is a pharmaceutical agent and is selected from a protein, an enzyme, a polypeptide, an oligopeptide, a peptide, deoxyribonucleic acid (DNA), ribonucleic acid (RNA), a small organic molecule less than 900 Da, or a prodrug of any of these materials, a nutritional supplement, or a microbial culture, or a microbial additive, or a vaccine.

8. The composition of any one of claims 1 to 7, wherein the first component and the second component are mixed.

9. The composition of any one of claims 1 to 8, wherein the first component and the second component are in different layers, the first component being in an outer layer and the second component being in an inner layer around a core.

10. 10. The composition according to any one of claims 1 to 9, wherein the pair of first and second components is selected from a structurally ordered cellulose I selected from bacterial cellulose or its derivatives, and a cellulase selected from cellulase (EC 3.2.1.4) (endocellulase), celluviase (EC 3.2.1.21) (beta-glucosidase), 1,4-beta-cellobiosidase (EC 3.2.1.91) (exocellulase), cellulose 1,4-beta-cellobiosidase (reducing end) (EC 3.2.1.176) (exocellulase) and cellulase complexes and mixtures thereof.

11. The composition of any one of claims 1 to 10, wherein the second component is enzymatically active and digests the first component in the mammalian intestinal environment.

12. 12. The composition of claim 11, wherein the second component has maximum enzymatic activity in the range of pH 3 to 12, such as pH 3.5 to 9.5, or 3.0 to 9.0, or 4.0 to 9.

0.

13. The composition of any one of claims 1 to 12, wherein the intestine is selected from the small intestine, the large intestine, the duodenum, the ileum, the jejunum, and the colon.

14. The composition of any one of claims 1 to 13, wherein the composition is a tablet or capsule or other type of solid oral dosage form.

15. A composition according to any one of claims 1 to 14 for use as a medicament.

16. A composition according to any one of claims 1 to 14 for use as a dietary supplement.

17. A composition according to any one of claims 1 to 14 for use as a tracing agent.

18. 1. Use of a pair of components to prepare a coating for a solid oral dosage form, wherein the coating degrades when exposed to a pH change from a lower pH to a higher pH, and at the lower pH, the second component inhibits digestion of the first component, and when exposed to a higher pH, the second component digests the first component, Moreover, the first component is selected from structurally ordered cellulose I, which is insoluble in water; the second component is selected from cellulases and cellulase complexes and mixtures thereof that enzymatically digest the first component when exposed to the more basic environment of the intestine compared to the more acidic environment of the stomach; Moreover, the digestive activity of the second component is inhibited in the mammalian stomach environment. The above uses.

19. The composition of any one of claims 1 to 17, wherein the entrapped material is selected from: a) Proteins, human growth hormone (hGH), calcitonin, insulin, GLP-1 analogs, GLP-1 b) The peptide Octreotide c) Oral vaccines, oral cholera vaccine, oral Mycoplasma hyopneumoniae vaccine, live bacterial cells as attenuated vaccines, live cell cultures d) Organic small molecules 200<MW<900 g / mol, desmopressin, vasopressin, cyclosporine, ranitidine, diclofenac, ketoprofen, amifostine, omeprazole, gemcitabine, domperidone, paclitaxel, cinnarizine, donepezil, leucovorin, raloxifene, indomethacin, dextromethorphan, nizatidine, peptide Val-Leu-Pro-Val-pro-Arg (VLPVPR), flurbiprofen, mebendazole, thymidine, zolpidem tartrate, loratidine , venlafaxine, tamsulosin, urapidil, prednisolone, miconazole, diltiazem, ambroxil, captopril, acyclovir, cimetidine, metoprolol, griseofulvin, atazanavir, ibuprofen, azithromycin, lercanidipine, sulfacetamide, azelastine, zidovudine, cloricromene, oxymatrine, acarbose, propranolol, alfuzosin, stavudine, lobenzarit, genistein, verapamil, terbinafine, lornoxicam, clotrimazole.

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