AU2017279782A1

AU2017279782A1 - Compositions for gastrointestinal disease

Info

Publication number: AU2017279782A1
Application number: AU2017279782A
Authority: AU
Inventors: Waldemar Krzewski; Piotr Pietrzak
Original assignee: Biolek Sp zoo
Current assignee: Biolek Sp zoo
Priority date: 2017-12-22
Filing date: 2017-12-22
Publication date: 2019-07-11
Also published as: KR20190076809A

Abstract

The invention relates to compositions comprising acylglycerols and an acceptable butyrate salt encapsulated therein, and their use in the dietary management, prevention or treatment of gastrointestinal diseases or disorders.

Description

Compositions for gastrointestinal disease

Technical Field

The invention relates to compositions comprising acylglycerols and an acceptable butyrate salt encapsulated therein. The invention also relates to 5 capsules with core formulations comprising the above compositions, and uses of the compositions and capsules in the dietary management, prevention or treatment of gastrointestinal diseases or disorders.

Throughout this disclosure, various publications are referred to by first author and year of publication. Full citations for these publications, in the 10 order they appear in the application, are presented in a References section immediately before the claims.

Background

Butyric acid is a member of the short chain fatty acid (SCFA) group of compounds, which are the chief source of anions in the colon of humans.

Butyric acid is the main end product of bacterial fermentation of dietary fibre in the colon. After dissociation, the butyrate anion is absorbed by enteric cells which use it as a source of energy.

Butyric acid salts, such as sodium butyrate, are therefore important for gastrointestinal health. Apart from its role as an energy donor to the enteric 20 cells of the intestinal mucosa; sodium butyrate helps regulate fluid transport through mucosa and helps regulate the motility of the gastrointestinal tract; it helps cell regeneration; it is important in regulating bacterial composition and it exerts an anti-inflammatory effect [W. Tarnowski et al. 2011].

A wide spectrum of gastrointestinal diseases or disorders are linked to 25 deficiencies in SCFAs or the impairment of SCFA metabolism.

Representative diseases or disorders linked with a deficiency in butyrate or

2017279782 22 Dec 2017 impairment in butyrate metabolism include intestinal infections, diarrhoea, ulcerative colitis, inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) [R. B. Canani et al. 2011],

The administration of butyrate has the potential in the dietary management, prevention or treatment of this wide spectrum of gastrointestinal diseases or disorders and others such as Crohn’s disease [A. Di Sabatino et al. 2005] and diverticulitis [L. Krokowicz et al. 2014], Combination butyrate therapies have also been reported [W. Tarnowski et al. 2011]. However, existing oral butyrate compositions have little benefit if they are immediately absorbed in 10 the mouth, esophagus and/or stomach of the gastrointestinal tract or are only absorbed in the small intestine and do not reach the colon. Existing oral compositions also have extremely poor palatability due to the unpleasant taste and obnoxious odor of butyric acid [R. B. Canani et al. 2011],

The present invention is based, in part, on the design and development of 15 compositions comprising acylglycerols and an acceptable butyrate salt encapsulated therein with specific morphology and fatty acid composition such that the acylglycerols substantially protect the butyrate to allow for controlled release in the gastrointestinal tract of a human subject. Surprisingly, it has been found that the acylglycerols substantially protect the 20 butyrate to allow for gradual release along the entire length of the small intestine and large intestine of a human subject. This gradual release provides an improvement in the prevention or treatment of gastrointestinal diseases or disorders in patients by oral administration of butyrate. Also, as the butyrate is protected by acylglycerols, the oral compositions disclosed 25 herein have improved palatability.

Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present

2017279782 22 Dec 2017 disclosure as it existed before the priority date of each claim of this application.

Summary

According to a first aspect, there is provided a composition comprising acylglycerols and an acceptable butyrate salt encapsulated therein, wherein the composition is in the form of a microgranule having a closed structure whereby:

butyrate particles are coated by the acylglycerols; and the microgranule is substantially spherical; and the microgranule has a substantially smooth external surface, and wherein the acylglycerols are composed of fatty acids selected from the group comprising of: C12 (about 0.1%); C14 (about 1.2 %); C16 (about 61%); C18 (about 37 %); and C20 and longer (about 0.6 %).

According to a second aspect, there is provided a capsule comprising:

(A) a core formulation, wherein the core formulation comprises a composition according to the first aspect;

and (B) a coating formulation, wherein the coating formulation comprises at least one acceptable excipient.

According to a third aspect, there is provided a method for the dietary management, prevention or treatment of a gastrointestinal disease or disorder

2017279782 22 Dec 2017 in a human subject, the method comprising administering to the human subject a composition according to the first aspect.

According to a fourth aspect, there is provided a method for the dietary management, prevention or treatment of a gastrointestinal disease or disorder in a human subject, the method comprising orally administering to the human subject a capsule according to the second aspect.

According to a fifth aspect, there is provided use of a composition according to the first aspect in the controlled release of an acceptable butyrate salt in the gastrointestinal tract of a human subject to whom the composition has been orally administered.

According to a sixth aspect, there is provided use of a composition according to the first aspect in the dietary management, prevention or treatment of a gastrointestinal disease or disorder.

According to a seventh aspect, there is provided use of a composition according to the first aspect in the preparation of a medicament for the dietary management, prevention or treatment of a gastrointestinal disease or disorder.

Definitions

Unless otherwise defined herein, scientific and technical terms used in connection with the present application shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. Thus, as used in this specification and the appended claims, the singular forms “a”, “an” and “the” include plural referents unless the context clearly indicates otherwise. For example, reference to “a microgranule” includes a plurality of microgranules.

2017279782 22 Dec 2017

With regards to the definitions provided herein, unless stated otherwise, or implicit from context, the defined terms and phrases include the provided meanings. Unless explicitly stated otherwise, or apparent from context, the terms and phrases below do not exclude the meaning that the term or phrase 5 has acquired by a person skilled in the relevant art. The definitions are provided to aid in describing particular embodiments, and are not intended to limit the claimed invention, because the scope of the invention is limited only by the claims.

Throughout the present specification, various aspects and components of the 10 invention can be presented in a range format. The range format is included for convenience and should not be interpreted as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range, unless specifically 15 indicated. For example, description of a range such as from 1 to 5 should be considered to have specifically disclosed sub-ranges such as from 1 to 2, from 1 to 3, from 1 to 4, from 2 to 3, from 2 to 4, from 2 to 5, from 3 to 4 etc., as well as individual and partial numbers within the recited range, for example, 1, 2, 3, 4, and 5. This applies regardless of the breadth of the 20 disclosed range. Where specific values are required, these will be indicated in the specification.

As used herein, and unless otherwise specified, the term about, when used in connection with doses, amounts or concentrations, such as weight percent (wt %) of ingredients of a composition or a dosage form, means a 25 dose, amount, or weight percent that would be recognized by those of ordinary skill in the art to provide an effect equivalent to that obtained from the specified dose, amount, concentration. For illustration, the term “about” contemplates a dose, amount, or concentration within (i.e. ± ) 30%, 20%, 15% of the specified dose, amount or concentration.

2017279782 22 Dec 2017

The term “acceptable excipient includes excipients or agents such as solvents, diluents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like that are physiologically compatible and are not deleterious to a compound as 5 described herein or use thereof. The use of such agents to prepare compositions of pharmaceutically active substances is well known in the art (see, for example Remington: The Science and Practice of Pharmacy, 21st Edition; Lippincott Williams & Wilkins: Philadelphia, PA, 2005).

The term “acceptable salt(s) include(s), but are not limited to, inorganic acid 10 salts such as hydrochloride, hydrobromide, sulfate, phosphate and the like;

organic acid salts such as formate, acetate, trifluoroacetate, maleate, tartrate and the like; sulfonates such as methanesulfonate, benzenesulfonate, ptoluenesulfonate and the like; amino acid salts such as arginate, asparaginate, glutamate and the like; metal salts such as sodium salt, potassium salt, 15 cesium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; and organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, discyclohexylamine salt, Ν,Ν'-dibenzylethylenediamine salt and the like.

Base salts include, but are not limited to, those formed with pharmaceutically 20 acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, zinc, ammonium, alkylammonium such as salts formed from triethylamine, alkoxyammonium such as those formed with ethanolamine and salts formed from ethylenediamine, choline or amino acids such as arginine, lysine or histidine.

In particular, the term “acceptable butyrate salt” or the term “butyrate” refers to acceptable salts of butyric acid. Acceptable salts of butyric acid include, but are not limited to, sodium and calcium salts of butyric acid or sodium butyrate and calcium butyrate respectively.

2017279782 22 Dec 2017

General information on types of acceptable salts and their formation is known to those skilled in the art and is as described in general texts such as “Handbook of Pharmaceutical salts” P.H.Stahl, C.G.Wermuth, 1^st edition, 2002, Wiley-VCH.

As used herein, the term “acylglycerols” encompasses mono-, di-, triacylglycerols or mixtures thereof. It would be recognised that acylglycerols are esters formed from glycerol and fatty acids.

The terms administration of and or administering a compound should be understood to mean providing a compound of the invention to the individual 10 in need of treatment.

The term composition as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

Throughout this specification the word comprise, or variations such as comprises or comprising, will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

As used herein, a “subject” is a recipients of the compositions disclosed herein. The term is interchangeable with the terms “patient” and “individual”. A “subject” has presented a clinical manifestation of a particular symptom or symptoms suggesting the need for treatment, who is treated preventatively or prophylactically for a condition, or who has been diagnosed with a condition to be treated. The present invention is directed to a “subject” who is a human. The human can be male or female.

2017279782 22 Dec 2017

As used herein, the terms “preventing”, “prevent” or “prevention” and variations thereof, refer to clinical intervention designed to avert the development of a course of clinical pathology.

As used herein, the terms treating, treat or treatment and variations thereof, refer to clinical intervention designed to alter the natural course of the subject during the course of clinical pathology. Desirable effects of treatment include decreasing the rate of disease progression, ameliorating or palliating the disease state, and remission or improved prognosis. A subject is successfully treated, for example, if one or more of the above treatment 10 outcomes is achieved.

As used herein, the term prophylactically effective refers to the amount of drug or the rate of drug administration needed to produce the desired preventive result. A therapeutically effective amount is at least the minimum concentration or amount required to effect a measurable improvement of a particular disease or disorder (e.g., irritable bowel syndrome).

A prophylactically/therapeutically effective amount herein may vary according to factors such as the disease state, gastrointestinal health, age, sex, and weight of the patient, and the ability of the butyrate compositions of 20 the present disclosure to elicit a desired response in the individual. A prophylactically/therapeutically effective amount is also one in which any toxic or detrimental effects of the butyrate are outweighed by the therapeutically beneficial effects

Brief Description of Drawings

Figure 1 and Figure 2 depict representative images of the composition described in Example 1. The images show that the composition is in the form of a microgranule having a “closed” structure whereby: butyrate

2017279782 22 Dec 2017 particles (visible as discrete black spots in the images) are coated by acylglycerols; the micro granule is substantially spherical; and the microgranule has a substantially smooth external surface.

Figure 3 and Figure 4 depict representative images of the composition described in Example 4, which is a comparative example. The images show that the comparative composition is in the form of particles having an “open” structure whereby the particles are irregular with a jagged surface.

Specific embodiments of the disclosure are described below. It will be appreciated that these embodiments are illustrative and not restrictive.

Description of Embodiments

Disclosed herein is a composition comprising acylglycerols and an acceptable butyrate salt encapsulated therein, wherein the composition is in the form of a microgranule having a closed structure whereby:

butyrate particles are coated by the acylglycerols; and the microgranule is substantially spherical; and the microgranule has a substantially smooth external surface, and wherein the acylglycerols are composed of fatty acids selected from the group comprising of: C12 (about 0.1%); C14 (about 1.2 %);

C16 (about 61%); C18 (about 37 %); and C20 and longer (about 0.6 20 %).

Preferably, the closed structure is assessed by microscopy. The microgranule preferably has a diameter in the range of about 539 to about 763 pm as measured using microscopy. Preferably, the microgranule has a diameter of about 651 pm as measured using microscopy.

2017279782 22 Dec 2017

Preferably, the acyglycerols are isolated from a fraction of natural plant oil. The natural plant oil is preferably palm oil. Preferably, the acylglyerols are of a grade produced in accordance with specifications for human food production.

Preferably, the composition is such that the acylglycerols substantially protect the butyrate to allow for controlled release in the gastrointestinal tract of a human subject to whom the composition has been orally administered.

Preferably, the composition is such that the acylglycerols substantially protects the butyrate from immediate release in the gastrointestinal tract of a 10 human subject to whom the composition has been orally administered.

Preferably, the composition is such that the acylglycerols substantially protects the butyrate from release in the mouth, esophagus or stomach controlled of a human subject to whom the composition has been orally administered.

Preferably, the composition is such that the acylglycerols substantially protect the butyrate to allow for release in the small intestine and/or large intestine of a human subject to whom the composition has been orally administered.

Preferably, the composition is such that the acylglycerols substantially 20 protect the butyrate to allow for release along the small intestine and large intestine of a human subject to whom the composition has been orally administered.

Preferably, the composition is such that the acylglycerols substantially protect the butyrate to allow for release along the entire length of the small 25 intestine and large intestine of a human subject to whom the composition has been orally administered.

2017279782 22 Dec 2017

Preferably, the composition is such that the acylglycerols substantially protect the butyrate to allow for gradual release along the entire length of the small intestine and large intestine of a human subject to whom the composition has been orally administered.

Preferably, the concentration of butyrate released in the stomach is negligible. The concentration of butyrate released in the stomach is preferably measured as not more than 2 % following the in vitro digestion protocol described herein. Preferably, the concentration of butyrate released in the duodenum is preferably measured as 29 ± 5% following the in vitro 10 digestion protocol described herein. The concentration of butyrate released in the large intestine is preferably measured as 22 ± 5% following the in vitro digestion protocol described herein.

Preferably, the amount of butyrate in the composition is in the range of about 20 wt% to 50 wt%. Preferably, the amount of butyrate in the composition is 15 in the range of about 20 wt% to 40 wt%. Preferably, the amount of butyrate in the composition is in the range of about 20 wt% to 30 wt%. Preferably, the amount of butyrate in the composition is about 50 wt%. Preferably, the amount of butyrate in the composition is about 40 wt%. Preferably, the amount of butyrate in the composition is about 30 wt%. Preferably, the 20 amount of butyrate in the composition is about 20 wt%.

Preferably, the butyrate is selected from the group consisting of: the sodium butyrate salt and the calcium butyrate salt. The butyrate is preferably sodium butyrate. Preferably, the sodium butyrate is crystalline. The crystalline sodium butyrate is preferably a grade produced in accordance with 25 specifications for human food production.

Preferably, the composition further comprises at least one acceptable excipient. The composition is preferably in a form suitable for oral administration to a human subject. Preferably, the composition is in a form

2017279782 22 Dec 2017 selected from a capsule and a tablet. The composition is preferably in the form of a capsule.

Also disclosed herein is a capsule comprising:

(A) a core formulation, wherein the core formulation comprises a composition as disclosed herein;

Preferably, the capsule comprises a core formulation, wherein:

(A) the core formulation comprises:

(a) the acceptable butyrate salt present in an amount of 150 mg, wherein the acceptable butyrate salt is sodium buyrate;

(b) the acylglycerols present in an amount of 350 mg, the acylglycerols is isolated from a fraction of natural palm oil;

and (B) the coating formulation comprises:

(i) hydroxypropylmethyl cellulose present in an amount of 93.2 mg;

(ii) titanium dioxide present in an amount of 1.8 mg.

Preferably, the microgranule has a diameter of about 651 μπι as measured using microscopy.

2017279782 22 Dec 2017

Preferably, the capsule has a shelf-life of about two years when stored in a closed container, in a dry place at a temperature of 15-25 °C protected from the light.

Preferably, the sodium butyrate is substantially protected to allow for 5 controlled release in the gastrointestinal tract of a human subject to whom the composition has been orally administered.

Preferably, the sodium butyrate is substantially protected from immediate release in the gastrointestinal tract of a human subject to whom the capsule has been orally administered.

Preferably, the sodium butyrate is substantially protected from release in the mouth, esophagus or stomach of a human subject to whom the capsule has been orally administered.

Preferably, the sodium butyrate is substantially protected to allow for gradual release along the entire length of the small intestine and large intestine of a 15 human subject to whom the capsule has been orally administered.

Preferably, the concentration of butyrate released in the stomach is negligible. The concentration of butyrate released in the stomach is preferably measured as not more than 2 % following the in vitro digestion protocol described herein. Preferably, the concentration of butyrate released 20 in the duodenum is preferably measured as 29 ± 5% following the in vitro digestion protocol described herein. The concentration of butyrate released in the large intestine is preferably measured as 22 ± 5% following the in vitro digestion protocol described herein.

Also disclosed herein is a method for the dietary management, prevention or 25 treatment of a gastrointestinal disease or disorder in a human subject, the method comprising administering to the human subject a composition as disclosed herein.

2017279782 22 Dec 2017

Preferably, the administration is by oral administration.

Also disclosed herein is a method for the dietary management, prevention or treatment a gastrointestinal disease or disorder in a human subject, the method comprising orally administering to the human subject a capsule as 5 disclosed herein.

Preferably, the gastrointestinal disease or disorder is selected from the group consisting of:

a gastrointestinal disease or disorder associated with a short chain fatty acid deficit;

a gastrointestinal disease or disorder which is an intestinal flora disease or disorder;

an intestinal inflammation or a gastric mucosal inflammation;

an intestinal infection;

diarrhoea;

diverticulitis;

ulcerative colitis;

Crohn’s disease;

inflammatory bowel disease (IBD); and irritable bowel syndrome (IBS).

Preferably, the gastrointestinal disease or disorder is IBS.

2017279782 22 Dec 2017

Preferably, the short chain fatty acid deficit is a deficit in butyric acid. The intestinal inflammation or a gastric mucosal inflammation is preferably a non-specific intestinal inflammation. Preferably, the intestinal infection or diarrhoea is following antibiotic treatment.

Preferably, the dietary management, prevention or treatment is used in combination with one or more agents suitable for the dietary management, prevention or treatment of a gastrointestinal disease or disorder. The one or more agents suitable for the dietary management, prevention or treatment of a gastrointestinal disease or disorder is preferably selected from rifaximin;

trimebutine; or mebeverine.

Preferably, a dosage of one capsule twice daily is administered to an adult subject. The dosage of one capsule twice daily is preferably administered to the adult subject for at least three months.

Preferably, a dosage of one capsule daily is administered to a child subject 15 over at least seven years of age. The dosage of one capsule daily is preferably administered to the child subject for at least six weeks.

According to a fifth aspect, there is provided use of a composition according to the first aspect in the controlled release of an acceptable butyrate salt in the gastrointestinal tract of a human subject to whom the composition has 20 been orally administered.

2017279782 22 Dec 2017

Preferably, the medicament is formulated for oral administration. The medicament is preferably formulated as a capsule.

an intestinal inflammation or a gastric mucosal inflammation;

an intestinal infection;

diarrhoea;

diverticulitis;

ulcerative colitis;

Crohn’s disease;

inflammatory bowel disease (IBD); and irritable bowel syndrome (IBS).

Preferably, the gastrointestinal disease or disorder is IBS.

Preferably, the short chain fatty acid deficit is a deficit in butyric acid. The intestinal inflammation or a gastric mucosal inflammation is preferably a

2017279782 22 Dec 2017 non-specific intestinal inflammation. Preferably, the intestinal infection or diarrhoea is following antibiotic treatment.

Preferably, the dietary management, prevention or treatment is used in combination with one or more agents suitable for treating or preventing a 5 gastrointestinal disease or disorder. The one or more agents suitable for the dietary management, treatment or prevention of a gastrointestinal disease or disorder is preferably selected from rifaximin; trimebutine; or mebeverine.

It would be recognised that in the disclosed methods and uses that when other therapeutic agents are employed in combination with the substances of 10 the present disclosure, e.g. compositions or capsules they may be used for example in amounts as noted in the Physician Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.

Preferably, a dosage of one capsule twice daily is administered to an adult subject. The dosage of one capsule twice daily is preferably administered to 15 the adult subject for at least three months.

Preferably, a dosage of one capsule daily is administered to a child subject over at least seven years of age. The dosage of one capsule daily is preferably administered to the child subject for at least six weeks.

It would be understood that in the disclosed methods and uses that the dosage 20 may be adjusted accordingly for heavier or lighter weighted individuals.

Preferably, administration to the subject is by dosing in a treatment regimen once daily or thrice weekly. The treatment regimen may be adapted according to the severity of the gastrointestinal disease or disorder experienced by the subject. In some instances where a patient is 25 experiencing high level of gastrointestinal distress it may be desirable to increase the preventative or therapeutic loading of the butyrate composition as quickly as possible. This may necessitate, for example, the administration of a higher dose.

2017279782 22 Dec 2017

It would be understood, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the age, body weight, general health, gastrointestinal health, sex, diet, mode and time of administration, drug combination, the severity of 5 the particular condition, and the host undergoing therapy.

Example Embodiments

1. A composition comprising acylglycerols and an acceptable butyrate salt encapsulated therein, wherein the composition is in the form of a microgranule having a closed structure whereby:

C16 (about 61%); C18 (about 37 %); and C20 and longer (about 0.6

%).

2. The composition according to example embodiment 1, wherein the closed structure is assessed by microscopy.

3. The composition according to example embodiment 2, wherein the microgranule has a diameter in the range of about 539 pm to about

763 pm as measured using microscopy.

2017279782 22 Dec 2017

4. The composition according to example embodiment 3, wherein the microgranule has a diameter of about 651 gm as measured using microscopy.

5. The composition according to any one of example embodiments 1 to

4, wherein the acyglycerols are isolated from a fraction of natural plant oil.

6. The composition according to example embodiment 5, wherein the natural plant oil is palm oil.

7. The composition according to any one of example embodiments 1 to

6, wherein the composition is such that the acylglycerols substantially protect the butyrate to allow for controlled release in the gastrointestinal tract of a human subject to whom the composition has been orally administered.

8. The composition according to example embodiment 7, wherein the composition is such that the acylglycerols substantially protect the butyrate from immediate release in the gastrointestinal tract of a human subject to whom the composition has been orally administered.

9. The composition according to example embodiment 8, wherein the composition is such that the acylglycerols substantially protect the butyrate from release in the mouth, esophagus or stomach controlled of a human subject to whom the composition has been orally administered.

10. The composition according to example embodiment 9, wherein the composition is such that the acylglycerols substantially protect the butyrate to allow for release in the small intestine and/or large

2017279782 22 Dec 2017 intestine of a human subject to whom the composition has been orally administered.

11. The composition according to example embodiment 10, wherein the composition is such that the acylglycerols substantially protect the butyrate to allow for release along the small intestine and large intestine of a human subject to whom the composition has been orally administered.

12. The composition according to example embodiment 11, wherein the composition is such that the acylglycerols substantially protect the butyrate to allow for release along the entire length of the small intestine and large intestine of a human subject to whom the composition has been orally administered.

13. The composition according to example embodiment 12, wherein the composition is such that the acylglycerols substantially protect the butyrate to allow for gradual release along the entire length of the small intestine and large intestine of a human subject to whom the composition has been orally administered.

14. The composition according to example embodiment 7, wherein the concentration of butyrate released in the stomach is measured as not more than 2 % following the in vitro digestion protocol described herein.

15. The composition according to example embodiment 7, wherein the concentration of butyrate released in the duodenum is measured as 29 ± 5 % following the in vitro digestion protocol described herein.

2017279782 22 Dec 2017

16. The composition according to example embodiment 7, wherein the concentration of butyrate released in the large intestine is measured as 22 ± 5 % following the in vitro digestion protocol described herein.

17. The composition according to any one of example embodiments 1 to

16, wherein the amount of butyrate in the composition is in the range of about 20 wt% to 50 wt%.

18. The composition according to example embodiment 17, wherein the amount of butyrate in the composition is about 30 wt%.

19. The composition according to any one of example embodiments 1 to

18, wherein the butyrate is sodium butyrate.

20. The composition according to any one of example embodiments 1 to 19 further comprising at least one acceptable excipient.

21. The composition according to example embodiment 20 in a form suitable for oral administration to a human subject.

22. The composition according to example embodiment 21, wherein the composition is in a form selected from a capsule and a tablet.

23. The composition according to example embodiment 22, wherein the composition is in the form of a capsule.

24. A capsule comprising:

(A) a core formulation, wherein the core formulation comprises a composition according to example embodiment 1;

and

2017279782 22 Dec 2017 (B) a coating formulation, wherein the coating formulation comprises at least one acceptable excipient.

25. The capsule according to example embodiment 24, wherein:

(A) the core formulation comprises:

and (B) the coating formulation comprises:

(i) hydroxypropylmethyl cellulose present in an amount of 93.2 mg;

(ii) titanium dioxide present in an amount of 1.8 mg.

26. The capsule according to example embodiment 25, wherein the microgranule has a diameter of about 651 gm as measured using microscopy.

27. The capsule according to any one of example embodiments 24 to 36 which has a shelf-life of about two years when stored in a closed container, in a dry place at a temperature of 15-25 °C protected from the light.

28. The capsule according to any one of example embodiments 24 to 27, wherein the sodium butyrate is substantially protected to allow for

2017279782 22 Dec 2017 controlled release in the gastrointestinal tract of a human subject to whom the composition has been orally administered.

29. The capsule according to example embodiment 28, wherein the sodium butyrate is substantially protected from immediate release in 5 the gastrointestinal tract of a human subject to whom the capsule has been orally administered.

30. The capsule according to example embodiment 29, wherein the sodium butyrate is substantially protected from release in the mouth, esophagus or stomach of a human subject to whom the capsule has been orally administered.

31. The capsule according to example embodiment 30, wherein the sodium butyrate is substantially protected to allow for gradual release along the entire length of the small intestine and large intestine of a human subject to whom the capsule has been orally administered.

32. The capsule according to example embodiment 28, wherein the concentration of butyrate released in the stomach is measured as not more than 2 % following the in vitro digestion protocol described herein.

33. The capsule according to example embodiment 28, wherein the concentration of butyrate released in the duodenum is measured as 29 ±5% following the in vitro digestion protocol described herein.

34. The capsule according to example embodiment 28, wherein the concentration of butyrate released in the large intestine is measured as 22 ± 5% following the in vitro digestion protocol described herein.

2017279782 22 Dec 2017

35. A method for the dietary management, prevention or treatment of a gastrointestinal disease or disorder in a human subject, the method comprising administering to the human subject a composition according to any one of example embodiments 1 to 23.

36. The method according to example embodiment 35, wherein the administration is by oral administration.

37. A method for the dietary management, prevention or treatment of a gastrointestinal disease or disorder in a human subject, the method comprising orally administering to the human subject a capsule according to any one of example embodiments 24 to 34.

38. The method according to any one of example embodiments 35 to 37, wherein the gastrointestinal disease or disorder is selected from the group consisting of:

a gastrointestinal disease or disorder associated with a short chain 15 fatty acid deficit;

an intestinal inflammation or a gastric mucosal inflammation;

an intestinal infection;

diarrhoea;

diverticulitis;

ulcerative colitis;

2017279782 22 Dec 2017

Crohn’s disease;

inflammatory bowel disease (IBD); and irritable bowel syndrome (IBS).

39. The method according to example embodiment 38, wherein the gastrointestinal disease or disorder is IBS.

40. The method according to example embodiment 38, wherein the short chain fatty acid deficit is a deficit in butyric acid.

41. The method according to example embodiment 38, wherein the intestinal inflammation or a gastric mucosal inflammation is a non-specific intestinal inflammation.

42. The method according to example embodiment 38, wherein the intestinal infection or diarrhoea is following antibiotic treatment.

43. The method according to any one of example embodiments 35 to 42, wherein the dietary management, prevention or treatment is used in combination with one or more agents suitable for the dietary management, prevention or treatment of a gastrointestinal disease or 20 disorder.

44. The method according to example embodiment 43, wherein the one or more agents suitable for the dietary management, treatment or prevention of a gastrointestinal disease or disorder is selected from rifaximin;

trimebutine; or mebeverine.

2017279782 22 Dec 2017

45. The method according to any one of example embodiments 37 to 44, wherein a dosage of one capsule twice daily is administered to an adult subject.

46. The method according to example embodiment 45, wherein the dosage of one capsule twice daily is administered to the adult subject for at least three months.

47. The method according to any one of example embodiments 37 to 44, wherein a dosage of one capsule daily is administered to a child subject over at least seven years of age.

48. The method according to example embodiment 47, wherein the dosage of one capsule daily is administered to the child subject for at least six weeks.

49. Use of a composition according to any one of example embodiments 1 to 23 in the controlled release of an acceptable butyrate salt in the gastrointestinal tract of a human subject to whom the composition has been orally administered.

50. Use of a composition according to any one of example embodiments 1 to 23 in the dietary management, prevention or treatment of a gastrointestinal disease or disorder.

51. Use of a composition according to any one of example embodiments 1 to 23 in the preparation of a medicament for the dietary management, prevention or treatment of a gastrointestinal disease or disorder.

2017279782 22 Dec 2017

52. The use according to example embodiment 51, wherein the medicament is formulated for oral administration.

53. The use according to example embodiment 52, wherein the medicament is formulated as a capsule.

54. The use according to any one of example embodiments to 53, wherein the gastrointestinal disease or disorder is selected from the group consisting of:

an intestinal inflammation or a gastric mucosal inflammation;

an intestinal infection;

diarrhoea;

diverticulitis;

ulcerative colitis;

Crohn’s disease;

inflammatory bowel disease (IBD); and irritable bowel syndrome (IBS).

2017279782 22 Dec 2017

55. The use according to example embodiment 54, wherein the gastrointestinal disease or disorder is IBS.

56. The use according to example embodiment 54, wherein the short chain fatty acid deficit is a deficit in butyric acid.

57. The use according to example embodiment 54, wherein the intestinal inflammation or a gastric mucosal inflammation is a non-specific intestinal inflammation.

58. The use according to example embodiment 54, wherein the intestinal infection or diarrhoea is following antibiotic treatment.

59. The use according to any one of example embodiments 51 to 58, wherein the dietary management, prevention or treatment is used in combination with one or more agents suitable for the dietary management, treatment or prevention of a gastrointestinal disease or disorder.

60. The use according to example embodiment 59, wherein the one or more agents suitable for the dietary management, treatment or prevention of a gastrointestinal disease or disorder is selected from rifaximin;

trimebutine; or mebeverine.

61. The method according to any one of example embodiment 53 to 60, wherein a dosage of one capsule twice daily is administered to an adult subject.

2017279782 22 Dec 2017

62. The use according to example embodiment 61, wherein the dosage of one capsule twice daily is administered to the adult subject for at least three months.

63. The use according to any one of example embodiments

53 to 60, wherein a dosage of one capsule daily is administered to a child subject over at least seven years of age.

64. The use according to example embodiment 63, wherein the dosage of one capsule daily is administered to the child subject for at least six weeks.

Examples

Example 1 - Acylglycerols and butyrate composition

A composition of the present disclosure may be prepared by a mixing process, and then a microencapsulation process using spray-cooling. The 15 mixing and microencapsulation are well known techniques.

Crystalline sodium butyrate and palm oil acylglycerols with a specific fatty acid composition are weighed.

The purity of sodium butyrate and the fatty acid composition of the acylglycerols may be determined and verified using routine analyses. The 20 acylglycerols of the composition are composed of fatty acids selected from the group comprising of: C12 (about 0.1%); C14 (about 1.2 %); C16 (about 61%); C18 (about 37 %); and C20 and longer (about 0.6 %).

Butyrate and acylgylcerols ingredients are weighed and thoroughly mixed.

Mixing is carried in the sequence of:

2017279782 22 Dec 2017

1) palm oil acylglycerols; and then

2) sodium butyrate.

As the person skilled in the art would recognise, the desired morphology of the composition can be effected by systemic variation of parameters of the microencapsulation process. For example, heating and cooling and pressure used in spray-cooling can be modified to ensure the desired morphology is obtained. The type of spray-cooling system may also be changed to effect production of the desired morphology. After spray-cooling to give the desired microencapsulated product, sieving, analysis and microscopic assessment can take place.

Figure 1 and Figure 2 depict representative images of the prepared composition. The images show that the composition is in the form of a microgranule with the desired morphology, i.e., a microgranule having a “closed” structure whereby: butyrate particles (visible as discrete black spots 15 in the images) are coated by acylglycerols; the microgranule is substantially speherical; and the microgranule has a substantially smooth external surface.

The diameter of the microgranules is in the range of about 539 μηι to about 763 μιη. That is, the microgranules have a diameter of 651 + 112 μηι (where 112 μηι is the standard deviation).

Analysis of the sodium butyrate content in the microgranulated product can also be undertaken. The wt% of sodium butyrate is in the range of about 20 wt% to 50 wt%. More particularly, the wt% of sodium butyrate is about 30 wt%.

Example 2 - in vitro digestion

2017279782 22 Dec 2017

The in vitro study of Example 2 examines digestion of a composition of the type disclosed in Example 1 and, as such, the release of butyrate. The study is predictive for in vivo release of butyrate along the gastrointestinal tract of a human subject to whom the composition has been orally administered.

The in vitro digestion was carried out according to the method described in the Boisen digestion method (S. Boisen and J. A. Fernandez, 1997) with modifications.

In vitro digestion was performed in three stages:

Phase I

Intended to mimic the stomach environment • 10 ml of 0.2 M HC1 were added to the sample (1 g) and then pH was adjusted to 2.0.

• 1 ml freshly prepared solution containing 25 mg pepsin was added to the mixture obtained from the step above.

• The mixture was incubated at 38 °C for 1 hour.

• After an hour of incubation, 1.5 ml of the solution from each sample was taken to determine the amount (% concentration) of released butyric acid.

Phase II

Reflects the condition of the duodenum ml of phosphate buffer (0.2 M, pH 6.8) + 5 ml of 0.6 M NaOH were added to the mixture obtained in Phase I. The pH was adjusted to 6.8 with 1 M HC1 or 1 M NaOH.

2017279782 22 Dec 2017 • 1 ml solution containing 100 mg pancreatin was added and incubated again at 38 °C for 4 hours. Pancreatin interacts with the acylglycerols carrier/matrix of the sample as it exhibits lipolytic activity.

· After the incubation, 1.5 ml of the solution was taken to determine the butyric acid concentration and undigested microgranules were taken for further examination in Phase III.

Phase III

Reflects the conditions of the bowel and colon · 10 mL of 0.2 M EDTA (pH 6.8) was added to the mixtures formed in Phase I and II.

• Then 1 ml of solution containing the enzyme mixture of cellulase, arabinase, xylanase, pectinase and β-glucanase was added.

• Incubated again at 39 °C for 6 hours.

· After the incubation, 1.5 ml of the mixture from each of the samples and the remaining undigested microgranules were taken

The release of butyrate in water incubated at 37 - 38 °C was also measured.

The concentration of butyric acid was determined by HPLC analysis. Measurement of pH was carried out using the Mettler Toledo pH Meter 20 System.

Results

The butyrate content in the granulated composition mass before digestion was determined to be 30.8 wt%.

Table 2 shows the results for the in vitro digestion study by way of the 25 concentration of butyric acid released from the granulated composition mass.

2017279782 22 Dec 2017

Table 2. Butyric acid released from granulated composition mass

	Butyrate ion concentration after digestion [%]
Phase	Granulated mass
Water	0.56
Phase I	1.70
Phase II	28.8
Phase III	21.7

Note: The results are based on the obtained samples.

Example 3 - Capsule formulation

The composition of Example 1 may be formulated as the core in a capsule for oral administration to a human subject as a dietary food for preventing or treating gastrointestinal diseases or disorders. An example capsule formulation is shown below in Table 3. The formulation is made from four ingredients. Information on the function and amount of each ingredient is provided.

Table 3 Capsule ingredients

Name of ingredient	Description of ingredient / technological function	Quantity per capsule
Nutrients
Sodium butyrate	Active substance microgranulated with carrier	150 mg
Additives
Palm oil acylglycerols	Carrier/matrix	350 mg
Fatty acid profile
C12-about 0.1 %
C14-about 1.2%
C16 - about 61 %
C18 - about 37 %
C20 - about 0.6 %
HPMC (E464)	Capsule coating	93.2 mg
Titanium dioxide (E-171)	Dye	1.8 mg

2017279782 22 Dec 2017

In the above table, HPMC is hydroxypropylmethylcellulose.

Analysis of the capsule formulation shows it has:

a shelf-life of about two years when stored in a closed container, in a dry 5 place at a temperature of 15-25 °C protected from the light.

Example 4 - comparative formulation

An example of a comparative capsule formulation is shown below in Table 4 which lists the seven capsule ingredients and information on the function and amount of each ingredient.

Table 4 Comparative capsule ingredients

Name of ingredient	Description of ingredient / technological function (amount)
Nutrients
Sodium butyrate	Active substance (150 mg)
Additives
Hydrogenated plant triglyceride	Carrier/matrix (350 mg)
Fatty acid profile
C12; C14; C16; C18; C20
Calcium sulphate	Filling agent
Calcium carbonate	Filling agent
Food gelatine	Capsule coating
E171	Colouring agent
E172	Colouring agent

Figure 3 and Figure 4 depict representative images of the acylglycerols:sodium butyrate composition described in Example 4. The images show that the comparative composition is in the form of microgranules having an “open” structure whereby the granules are irregular with a jagged surface. Butyrate particles are both on the surface of the granules and coated by the acylgylcerols. Figure 3 shows that the diameter of the microgranules is in the range of about 892.92 pm to about 1377.45

2017279782 22 Dec 2017 μπι. Figure 4 shows that the diameter of the microgranules is in the range of about 461.28 gm to about 902.59 gm and that the calculated area is in the range of about 138,692.33 gm² to 532,896.82 gm².

It would be appreciated that the “closed” structure possessed by the composition of the present disclosure improves the palatability of the composition to a human subject.

The composition of the present disclosure comprises acylglycerols and an acceptable butyrate salt encapsulated therein. As shown in Figure 1 and Figure 2 the butyrate particles are coated by the acylglycerols.

In contrast, as shown in Figure 3 and Figure 4 the butyrate particles of the comparative composition are both on the surface of the granules and coated by the acylglycerols.

Palability problems with existing butyrate compositions and the comparative composition of Example 4 are caused by butyric acid which has an unpleasant taste and obnoxious odor. Due to the “closed” structure of the disclosed composition, these problems are reduced.

It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the above-described embodiments, without departing from the broad general scope of the present disclosure.

The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

References

W. Tarnowski, K. Borycka-Kiciak A. Kiciak, J. Friediger, A. Cienciala, R. Zabielski “Outcome of treatment with butyric acid in

2017279782 22 Dec 2017 irritable bowel syndrome - preliminary report” Gastroenterologia Praktyczna, 2011: 1(8),43-48.

R. B. Canani, M. Di Costanzo, L. leone, M. Pedata, R. Meli, A. Calignano “Potential beneficial effects of butyrate in intestinal and extraintestinal diseases” World J Gastroenterol, 2011: 17(12), 1519-1528.

A. Di Sabatino, R. Morera, R. Ciccocioppo, P. Cazzola, S. Gotti, F. P. Tinozzi, S. Tinozzi, G. R. Corazza “Oral butyrate for mildly to moderately active Crohn's disease” Aliment Pharmacol Ther. 2005: 22(9), 789-94.

L. Krokowicz, Z, Stojcev, B. F. Kaczmarek, W. Kociemba, E. Kaczmarek, J.

Walkowiak, P. Krokowicsz, M. Drews, T. Banasiewicz “Microencapsulated sodium butyrate administered to patients with diverticulosis decreases incidence of diverticulitis - a prospective randomized study” Int. J. Colorectal Dis. 2014: 29, 387-393.

S. Boisen and J. A. Fernandez “Prediction of the total tract digestibility of energy in feedstuffs and pig diets by in vitro analyses” Animal Feed Science and Technology 1997: 68(3-4), 1997, 2777-286.

2017279782 22 Dec 2017

Claims

5 butyrate particles are coated by the acylglycerols; and the microgranule is substantially spherical; and the microgranule has a substantially smooth external surface, and wherein the acylglycerols are composed of fatty acids selected from the group comprising of: C12 (about 0.1%); C14 (about 1.2

10 %); C16 (about 61%); C18 (about 37 %); and C20 and longer (about 0.6 %).

2. The composition according to claim 1, wherein the closed structure is assessed by microscopy.

3. The composition according to claim 2, wherein the micro granule

15 has a diameter in the range of about 539 to about 763 μιη as measured using microscopy.

4. The composition according to claim 3, wherein the microgranule has a diameter of about 651 μιη as measured using microscopy.

5. The composition according to any one of claims 1 to 4, wherein the

20 acyglycerols are isolated from a fraction of natural plant oil.

6. The composition according to claim 5, wherein the natural plant oil is palm oil.

2017279782 22 Dec 2017

7. The composition according to any one of claims 1 to 6, wherein the composition is such that the acylglycerols substantially protect the butyrate to allow for controlled release in the gastrointestinal tract of a human subject to whom the composition has been orally

5 administered.

8. The composition according to claim 7, wherein the composition is such that the acylglycerols substantially protect the butyrate from immediate release in the gastrointestinal tract of a human subject to whom the composition has been orally administered.

10 9. The composition according to claim 8, wherein the composition is such that the acylglycerols substantially protect the butyrate from release in the mouth, esophagus or stomach controlled of a human subject to whom the composition has been orally administered.

10. The composition according to claim 9, wherein the composition is

15 such that the acyl glycerols substantially protect the butyrate to allow for release in the small intestine and/or large intestine of a human subject to whom the composition has been orally administered.

11. The composition according to claim 10, wherein the composition is

20 such that the acylglycerols substantially protect the butyrate to allow for release along the small intestine and large intestine of a human subject to whom the composition has been orally administered.

12. The composition according to claim 11, wherein the composition is

25 such that the acylglycerols substantially protect the butyrate to allow for release along the entire length of the small intestine and

2017279782 22 Dec 2017 large intestine of a human subject to whom the composition has been orally administered.

13. The composition according to claim 12, wherein the composition is such that the acylglycerols substantially protect the butyrate to

5 allow for gradual release along the entire length of the small intestine and large intestine of a human subject to whom the composition has been orally administered.

14. The composition according to claim 7, wherein the concentration of butyrate released in the stomach is measured as not more than 2 %

10 following the in vitro digestion protocol described herein.

15. The composition according to claim 7, wherein the concentration of butyrate released in the duodenum is measured as 29 ± 5 % following the in vitro digestion protocol described herein.

16. The composition according to claim 7, wherein the concentration of

15 butyrate released in the large intestine is measured as 22 ± 5% following the in vitro digestion protocol described herein.

17. The composition according to any one of claims 1 to 16, wherein the amount of butyrate in the composition is in the range of about 20 wt% to 50 wt%.

20

18. The composition according to claim 17, wherein the amount of butyrate in the composition is about 30 wt%.

19. The composition according to any one of claims 1 to 18, wherein the butyrate is sodium butyrate.

20. The composition according to any one of claims 1 to 19 further

25 comprising at least one acceptable excipient.

2017279782 22 Dec 2017

21. The composition according to claim 20 in a form suitable for oral administration to a human subject.

22. The composition according to claim 21, wherein the composition is in a form selected from a capsule and a tablet.

5

23. The composition according to claim 22, wherein the composition is in the form of a capsule.

24. A capsule comprising:

(A) a core formulation, wherein the core formulation comprises a composition according to claim 1;

10 and (B) a coating formulation, wherein the coating formulation comprises at least one acceptable excipient.

25. The capsule according to claim 24, wherein:

(A) the core formulation comprises:

15 (a) the acceptable butyrate salt present in an amount of 150 mg, wherein the acceptable butyrate salt is sodium buyrate;

and (B) the coating formulation comprises:

2017279782 22 Dec 2017 (i) hydroxypropylmethyl cellulose present in an amount of 93.2 mg;

(ii) titanium dioxide present in an amount of 1.8 mg.

26. The capsule according to claim 25, wherein the microgranule has a

5 diameter of about 651 μηι as measured using microscopy.

27. The capsule according to any one of claims 24 to 26 which has a shelf-life of about two years when stored in a closed container, in a dry place at a temperature of 15-25 °C protected from the light.

28. The capsule according to any one of claims 24 to 27, wherein the

10 sodium butyrate is substantially protected to allow for controlled release in the gastrointestinal tract of a human subject to whom the composition has been orally administered.

29. The capsule according to claim 28, wherein the sodium butyrate is substantially protected from immediate release in the

15 gastrointestinal tract of a human subject to whom the capsule has been orally administered.

30. The capsule according to claim 29, wherein the sodium butyrate is substantially protected from release in the mouth, esophagus or stomach controlled of a human subject to whom the capsule has

20 been orally administered.

31. The capsule according to claim 30, wherein the sodium butyrate is substantially protected to allow for gradual release along the entire length of the small intestine and large intestine of a human subject to whom the capsule has been orally administered.

2017279782 22 Dec 2017

32. The capsule according to claim 28, wherein the concentration of butyrate released in the stomach is measured as not more than 2 % following the in vitro digestion protocol described herein.

33. The capsule according to claim 28, wherein the concentration of

5 butyrate released in the duodenum is measured as 29 ± 5 % following the in vitro digestion protocol described herein.

34. The capsule according to claim 28, wherein the concentration of butyrate released in the large intestine is measured as 22 ± 5% following the in vitro digestion protocol described herein.

10

35. A method for the dietary management, prevention or treatment of a a gastrointestinal disease or disorder in a human subject, the method comprising administering to the human subject a composition according to any one of claims 1 to 23.

36. The method according to claim 35, wherein the administration is by

15 oral administration.

37. A method for the dietary management, prevention or treatment of a gastrointestinal disease or disorder in a human subject, the method comprising orally administering to the human subject a capsule according to any one of claims 24 to 34.

20

38. The method according to any one of claims 35 to 37, wherein the gastrointestinal disease or disorder is selected from the group consisting of:

2017279782 22 Dec 2017 a gastrointestinal disease or disorder which is an intestinal flora disease or disorder;

an intestinal inflammation or a gastric mucosal inflammation;

an intestinal infection;

5 diarrhoea;

diverticulitis;

ulcerative colitis;

Crohn’s disease;

inflammatory bowel disease (IBD); and

10 irritable bowel syndrome (IBS).

39. The method according to claim 38, wherein the gastrointestinal disease or disorder is IBS.

40. The method according to claim 38, wherein the short chain fatty acid deficit is a deficit in butyric acid.

15

41. The method according to claim 38, wherein the intestinal inflammation or a gastric mucosal inflammation is a non-specific intestinal inflammation.

42. The method according to claim 38, wherein the intestinal infection or diarrhoea is following antibiotic treatment.

2017279782 22 Dec 2017

43. The method according to any one of claims 35 to 43, wherein the dietary management, prevention or treatment is used in combination with one or more agents suitable for the dietary management, prevention or treatment of a gastrointestinal disease or disorder.

5

44. The method according to claim 43, wherein the one or more agents suitable for the dietary management, treatment or prevention of a gastrointestinal disease or disorder is selected from rifaximin; trimebutine; or mebeverine.

45. The method according to any one of claims 37 to 44, wherein a

10 dosage of one capsule twice daily is administered to an adult subject.

46. The method according to claim 45, wherein the dosage of one capsule twice daily is administered to the adult subject for at least three months.

15

47. The method according to any one of claims 37 to 44, wherein a dosage of one capsule daily is administered to a child subject over at least seven years of age.

48. The method according to claim 47, wherein the dosage of one capsule daily is administered to the child subject for at least six

20 weeks.

49. Use of a composition according to any one of claims 1 to 23 in the controlled release of an acceptable butyrate salt in the gastrointestinal tract of a human subject to whom the composition has been orally administered.

2017279782 22 Dec 2017

50. Use of a composition according to any one of claims 1 to 23 in the dietary management, prevention or treatment of a gastrointestinal disease or disorder.

51. Use of a composition according to any one of claims 1 to 23 in the

5 preparation of a medicament for the dietary management, prevention or treatment of a gastrointestinal disease or disorder.

52. The use according to claim 51, wherein the medicament is formulated for oral administration.

53. The use according to claim 52, wherein the medicament is

10 formulated as a capsule.

54. The use according to any one of claims 51 to 53, wherein the gastrointestinal disease or disorder is selected from the group consisting of:

an intestinal inflammation or a gastric mucosal inflammation;

an intestinal infection;

20 diarrhoea;

diverticulitis;

ulcerative colitis;

2017279782 22 Dec 2017

Crohn’s disease;

inflammatory bowel disease (IBD); and irritable bowel syndrome (IBS).

55. The use according to claim 54, wherein the gastrointestinal disease

5 or disorder is IBS.

56. The use according to claim 54, wherein the short chain fatty acid deficit is a deficit in butyric acid.

57. The use according to claim 54, wherein the intestinal inflammation or a gastric mucosal inflammation is a non-specific intestinal

10 inflammation.

58. The use according to claim 54, wherein the intestinal infection or diarrhoea is following antibiotic treatment.

59. The use according to any one of claims 51 to 58, wherein the dietary management, prevention or treatment is used in combination

15 with one or more agents suitable for the dietary management, treatment or prevention of a gastrointestinal disease or disorder.

60. The use according to claim 59, wherein the one or more agents suitable for the dietary management, treatment or prevention of a gastrointestinal disease or disorder is selected from rifaximin;

20 trimebutine; or mebeverine.

61. The method according to any one of claims 53 to 60, wherein a dosage of one capsule twice daily is administered to an adult subject.

2017279782 22 Dec 2017

62.

63.

64.

The use according to claim 61, wherein the dosage of one capsule twice daily is administered to the adult subject for at least three months.

The use according to any one of claims 53 to 60, wherein a dosage of one capsule daily is administered to a child subject over at least seven years of age.

The use according to claim 63, wherein the dosage of one capsule daily is administered to the child subject for at least six weeks.