AU2019279974A1 - Compositions and methods for treating certain gastrointestinal disorders - Google Patents

Abstract

The present invention provides Medications which are useful in treating or ameliorating the symptoms or adverse effects associated with a functional or a biochemical gastrointestinal disorder in an animal subject. The subject may be a human or a non-human 5 animal. The Medications of the invention comprise therapeutically active ingredients of natural origin, and include one or more of the following: (a) Curcumin; (b) L-Glutamine; .0 (c) Quercetin; (d) Glucosamine; (e) Aloe vera; (f) An edible essential oil; (g) Powder derived from the inner bark of Slippery Elm (Umus rubra); .5 (h) Guar Gum; and (i) Pectin. Methods of preparing and using the Medications in order to treat various functional and/or biochemical disorders of the gastrointestinal tract and associated symptoms in animal subjects, are also disclosed. Also disclosed are methods of improving the concentration of 20 beneficial bacteria in the gastrointestinal tract in an afflicted subject, by treating the subject with a Medication according to the invention.

Description

P/00/011 Regulation 3.2

Australia

Patents Act 1990

ORIGINAL COMPLETE SPECIFICATION STANDARD PATENT

Names of Applicants: Nutrition Care Pharmaceuticals Pty Ltd (ACN613457293)and Ausnutria Dairy (China) Co., Ltd Title of Invention: 'Compositions and methods for treating certain gastrointestinal disorders'

The following is a full description of this invention, including the best method known to the Applicants of performing the invention:

Compositions and methods for treating certain gastrointestinal disorders

Field of the Invention

The present invention relates to the treatment of certain gastrointestinal disorders in animals. It has particular, although not exclusive, application to the treatment of gastrointestinal disorders in mammalian subjects, and especially, in humans. Accordingly, and while not detracting from the scope of the numerous applications to which the invention may be put, the background to the invention will be discussed by way of background in the following comments with particular reference to its application to mammals (and especially, to humans).

Background to the Invention

In many animals (and most notably, in mammals, and especially humans), the gastrointestinal tract is essentially a hollow muscular tube which communicates between the subject's mouth and the anus. In most such animals, the gastrointestinal tract serves two primary functions. First, in many species, it serves as an animal's means of ingesting, digesting and absorbing nutrients. Secondly, and at the same time, the gastrointestinal tract expels waste materials left over from the digestive process. Maintaining good gastrointestinal health throughout life is therefore essential. If either of these basic functions of a subject's gastrointestinal function is disturbed, the resultant consequences for the subject's wellbeing can be serious.

There are several major categories of disorders which can adversely impact on gastrointestinal function. Gastrointestinal disorders can be characterized broadly as:

(a) Structural disorders; (b) Biochemical disorders; and (c) Functional disorders.

Structural disorders - as their name implies - are caused by structural or anatomical irregularities of the gastrointestinal tract. The present invention is not concerned however with treating this category of such disorders. Rather, the invention is concerned instead with the treatment of certain functional or biochemical disorders of the gut.

Biochemical disorders of the gastrointestinal tract are those where abnormal function of the tract can be attributed to a specific biochemical stimulus, such as (for example) an allergen, or intolerance to a substance contained in food, such as lactose.

Functional disorders of the gastrointestinal tract are a group of idiopathic disorders of normal tract function. They are characterised by gastrointestinal symptoms related to any combination of the following features:

(a) motility disturbance (b) visceral hypersensitivity (c) altered mucosal and immune function (d) altered gut microbiota, and (e) altered central nervous system processing.

(Reference: Parkman HP and Doma S. "Importance of gastrointestinal motility disorders", Practical Gastroenterology, September 2006).

In this context, the use of the term "functional" refers to impairment of one or more of the following:

(1) normal motility of the gastrointestinal tract; (2) sensitivity of nerves in the gastrointestinal tract; or (3) the ways in which the central nervous system controls (1) or (2).

(Reference: Dalton, Christine: "What is a functional GI disorder?" (2017) a publication of the University of North Carolina Center for Functional GI & Motility Disorders, University of North Carolina School of Medicine, published at https://www.med.unc.edu/ibs/files/2017/1O/What-is-Functional-GI.pdf) The impairment to normal function observed in afflicted subjects is typically chronic or recurrent.

Motility for this purpose may be defined as the muscular activity of the gastrointestinal tract. In normal subjects, gut motility is characterised by a process known as peristalsis, which is an orderly and coordinated sequence of contractions of the muscular structures that form key parts of the gastrointestinal tract, in a direction from the "upper" regions of the tract (ie, those closest to the subject's mouth) to the "lower" regions (ie, those at or near the anus). In normal subjects, the process of peristalsis therefore operates to move substances which the subject ingests orally, to lower regions of the tract, so that digestive metabolic processes may be performed on those substances via specific anatomical structures located along the tract, and so that in turn, the subject may absorb desired nutrients, and at the same time, process waste materials for removal from its body.

In subjects who suffer from a functional gastrointestinal tract disorder, these processes are typically disrupted. The degree of the disruption is typically such that instead of there being an orderly co-ordinated sequence of muscular contractions, an afflicted individual instead suffers from spasms of the gut musculature. The spasms can be very rapid, very slow and/or disorganised. Such spasms typically cause the subject to suffer discomfort, and (not uncommonly) pain.

In some affected individuals, one or more of the subject's nerves that innervate or supply a part of the gastrointestinal tract may be abnormally sensitised to stimuli (including for example, even normal stimuli such as the presence of food in the tract). In some such subjects, even normal muscular contractions of the tract can trigger discomfort or pain through actuation of signalling in abnormally sensitised nerves.

In yet other afflicted subjects, the normal processes of communication between the gut and the brain are impaired. The communications between the brain and the gut that regulate normal gut function are known to be bi-directional (this is called the "brain gut axis"). Disturbances observed in functional gastrointestinal disorders in the normal bi-directional neuronal communications of the tract are sometimes referred to collectively as "brain-gut dysfunction". This condition causes or contributes to the symptoms of discomfort and pain that afflicted subjects experience.

In a given subject, the underlying cause of a functional gastrointestinal disorder may be any one of the three mechanisms mentioned earlier, or combinations or two or more of them. As indicated earlier, functional gastrointestinal disorders are generally regarded as being idiopathic conditions. Hence, in many instances, in view of the current state of medical science, the ultimate cause of the particular condition is not readily discernible, and the condition presents as having developed spontaneously. Much about the pathophysiology of these orders presently remains unknown. Taken together, these considerations mean that diagnosing and treating afflicted individuals can present particular challenges to clinicians. The risk of misdiagnosis is high, and the consequences of misdiagnosis or inappropriate treatment can therefore be serious.

Functional gastrointestinal disorders are characterised by symptoms which cannot be explained by reference to identifiable structural or biochemical markers. Traditionally then, they have been diagnosed by reference solely or predominantly to the symptoms of dysfunction which prevail in the afflicted individual. Accordingly, functional gastrointestinal disorders have generally considered to be diagnoses of exclusion, meaning that they could only be diagnosed after objectively identifiable diseases or conditions were ruled out. However, in 1988, a group of clinicians and researchers met in order to clarify and establish stricter criteria for the diagnosis of these disorders. The criteria (known as the "Rome Criteria") are now in their fourth revision (as of 2016).

According to the Rome IV criteria, there are approximately 20 conditions which currently are recognized as being functional gastrointestinal disorders. These conditions affect millions of people of all ages around the world. One of the most commonly encountered of these conditions is Irritable Bowel Syndrome (or "lBS"). IBS is characterised by symptoms which can include: • bloating

" cramping

• diarrhea

" constipation (often alternating with diarrhea)

• intolerance to certain foods,

" fatigue and difficulty sleeping, and

• anxiety and depression.

J IBS often impacts severely on the lives of afflicted sufferers. The symptoms associated with IBS and other functional gastrointestinal disorders can cause discomfort, ranging from inconvenience to physical pain, as well as personal distress. For those with severe IBS symptoms the disorder can be debilitating, leaving them unable to participate fully in life activities and work.

IBS is particularly prevalent in many communities around the world. A meta review published in 2012 estimated that the pooled prevalence of IBS across the 82 studies reviewed (and covering a total of 260,960 subjects) was 11.2% of the total populations surveyed (Reference: Lovell, RM and Ford, AC "Global Prevalence of and Risk Factors for Irritable Bowel Syndrome: A Meta-analysis" Clinical Gastroenterology and Hepatology (2012) Volume 10, Issue 7, pp 712-721 [July 2012]). More recent studies on the prevalence of the condition estimate that IBS may affect between 16 and 26% of the population (Reference: Drossman, D "Functional Gastrointestinal Disorders: History, Pathophysiology, Clinical Features, and Rome IV" Gastroenterology (2016) Volume 160, Issue 6, pp 1282 to 1279). It has also been estimated in the past that the human health care cost of IBS to the United States alone lies in the realm of billions of Dollars per annum. For example, in a paper published as far back as in 1995 (Talley et al, Gastroenterology 109, pp 1736-1741 (1995)), it was estimated that the health care cost of IBS in the human population the United States was then US$8 Billion per year.

Given that of the known gastrointestinal disorders, IBS alone is so prevalent, that the condition can impact so adversely on the life of an afflicted sufferer, and that it imposes such significant health care (and indeed, consequential) costs on modern society, it would be highly desirable to have effective treatments for such disorders. Modification of an individual's lifestyle and diet are amongst the tools available to modern medicine in the quest to treat such disorders, but many sufferers find it difficult to comply with prescribed lifestyle or dietary modifications, especially over an extended period. The known treatments also include medications, but for the most part, the known medications used are often synthetic pharmaceuticals whose efficacy can vary significantly from one patient to the next. In addition, in modern society, some of the compliance problems associated with the use of traditional medications may be attributable to a sector of the patient population preferring to avoid taking synthetic pharmaceuticals, especially over an extended time frame.

In order to ensure greater effectiveness of treatment, there is hence a need for a method of treating functional or biochemical gastrointestinal disorders which involves administering medications that comprise therapeutically active ingredients of natural origin as the active agents. There is thus correspondingly a need for medications that are useful in treating such disorders, and which comprise therapeutically active ingredients of natural origin as active agents, as well as methods by which such medications can be manufactured, especially in large quantities. The present invention therefore aims to address these needs.

Summary of the Invention

The present therefore invention generally provides Medications which are useful in treating or ameliorating the symptoms or adverse effects associated with a functional or a biochemical gastrointestinal disorder in an animal subject. The animal subjects that may be treated in accordance with the present invention include: (a) mammals;

(b) birds;

(c) fish;

(d) reptiles; and

(e) amphibians.

In some embodiments of the invention, the animal subject is a mammal. In particular embodiments, the animal subject is a human. In other embodiments however, the subject may be any other non-human animal that has a gastrointestinal tract. The invention therefore can generally be used in both human and veterinary medicine in order to treat functional or biochemical gastrointestinal disorders in animal subjects of all the kinds mentioned earlier.

The invention may be used generally to treat either adult or immature animal subjects. Accordingly, the invention may be used in order to treat not only adult subjects, but also to treat young and old subjects. The invention can therefore be used in, amongst other applications, neonatal and geriatric care.

It is to be understood that wherever appearing in this specification, the terms "subject", "animal subject" and "patient" are used interchangeably, and mean the same thing.

The functional or a biochemical gastrointestinal disorders that may be treated by using Medications according to the invention include the following:

(a) any functional gastrointestinal disorder as defined in the Rome IV Classification as published in 2016 (the text and content of which is expressly incorporated into this specification by reference, as if set expressly set out in it); and (b) any biochemical gastrointestinal disorder.

In either case, the disorders may be of either the upper or the lower region of the gastrointestinal tract.

In embodiments of the invention, the functional gastrointestinal disorders which may be treated include the following: (1) esophageal disorders;

(2) gastroduodenal disorders;

(3) bowel disorders;

(4) centrally mediated disorders of gastrointestinal pain;

(5) childhood functional gastrointestinal disorders (neonatal/toddler);

(6) childhood functional gastrointestinal disorders (child / adolescent); (7) anorectal disorders;

(8) functional abdominal pain disorders; and

(9) gallbladder and Sphincter of Oddi disorders.

In particular embodiments of the invention, the functional gastrointestinal disorders amenable to treatment in accordance with the invention include: (A) Reflux hypersensitivity;

(B) Irritable Bowel Syndrome;

(C) Functional; dyspepsia;

(D) Gastro Esophageal Reflux Disorder ("GERD");

(E) Belching, nausea and vomiting disorders;

(F) Functional chest pain and heartburn;

(G) Functional constipation;

(H) Functional diarrhea;

(1) Functional abdominal bloating/distension;

(J) Centrally mediated abdominal pain syndrome;

(K) Faecal incontinence;

(L) Infant Colic;

(M) Enteritis (inflammation of the small intestine);

(N) Gastritis (inflammation of the lining of the stomach); and

(0) Leaky Gut Syndrome.

Biochemical gastrointestinal disorders that may be treated in accordance with the invention include:

(a) intolerance to specific substances contained in foods; and

(b) intolerance to orally administered medications.

Such disorders include lactose intolerance, and intolerance to specific orally ingested allergens.

The symptoms of gastrointestinal disorders which may be treated in accordance with the present invention include the following: (a) chest pain;

(b) heartburn;

(c) reflux and reflux hypersensitivity;

(d) indigestion and impaired digestion;

(e) bloating;

(f) abdominal distension;

(g) belching;

(h)nausea;

(i) vomiting;

(j) flatulence;

(k) constipation;

(I) diarrhea;

(m) fecal incontinence;

(n) urgent need to defecate; and

(o) abdominal discomfort or pain.

In accordance with the present invention, Medications suitable for treating the disorders and conditions previously mentioned include one or more therapeutically active ingredients of natural origin, optionally formulated in combination with one or more conventional formulation ingredients. Examples of conventional formulation ingredients include, but are not limited to, carriers, gelling agents, stabilizers, solvents, excipients, solubilisers, binders, buffers, preservatives, emulsification agents, bulking agents, lubricants, suspending agents, disintegrating agents, flavours, sweeteners, antioxidants, isotonic agents, and combinations thereof.

In embodiments of the invention, the therapeutically active ingredients of natural origin include one or more of the following:

(a) Curcumin;

(b) L-Glutamine;

(c) Quercetin;

(d) Glucosamine;

(e) Aloe vera;

(f) An edible essential oil;

(g) Powder derived from the inner bark of Slippery Elm (Ulmus rubra);

(h)GuarGum;and

(i) Pectin.

Preferably, the Curcumin is derived from Turmeric (Cucurmalonga).

Quercetin is a plant flavonol of the flavonoid group of polyphenols. It is found in numerous fruits, vegetables, leaves, and grains. Common foods that contain this substance in appreciable quantities include red onions and kale. The substance as used in the Medications according to the invention is preferably derived from the dried flower buds of the Japanese Pagoda Tree (Sophorajaponica).

Preferably, Glucosamine (an amino-sugar) as used in Medications made in accordance with the invention, is derived from shellfish or crustaceans, such as lobster, crab, prawns and/or shrimp. In some preferred forms of Medications made in accordance with the invention, Glucosamine is present as Glucosamine Hydrochloride.

Preferably, the Aloe vera component of such Medications takes the form of, or is derived from Aloe vera fresh leaf. It is particularly preferred that the fresh leaf used is at least substantially devoid of Aloe plant material derived from latex or rind.

Preferably, the edible essential oil is a Peppermint Oil, being the essential oil derived from Peppermint (Mentha piperita).

Preferably, the Guar Gum as used in Medications made in accordance with the invention, is obtained by grinding the endosperms of seeds of the Cluster Bean plant (Cyamopsis tetragonolobus (L.) Taub).

Pectins are a family of complex polysaccharides that contain 1,4-linked a-D galactosyluronic acid residues. They provide prebiotic fibres in formulations of the Medication. Pectins suitable for making Medications according to the present invention. are found in many plants and fruits. The pectins used in Medications made in accordance with the invention are preferably derived from citrus fruits. In particularly preferred embodiments, they are derived from dilute acid extracts of the inner portion of the rind of citrus fruits.

In preferred forms of this aspect of the invention, a pharmaceutically acceptable preparation or formulation for treating a functional or biochemical gastrointestinal disorder would contain a combination containing all of the therapeutically active ingredients (a) to (j) listed above. In some preferred forms, the pharmaceutically acceptable preparation or formulation optionally also includes Sodium Diphosphate.

Medications made in accordance with the present invention may be prepared or formulated in any of a number of different ways so as to be suitable for administration to the subject. In embodiments of the present invention, such Medications could take the form of edible powders, capsules, tablets, liquids or gels containing one or more of the therapeutically active ingredients (a) to (j) listed above, as well as, optionally - in some embodiments - Sodium Diphosphate.

In one generally preferred form of this aspect of the invention, a Medication made in accordance with the present invention would be formulated as an edible powder containing one or more of the therapeutically active ingredients (a) to (j) listed above. Such an edible powder could either be ingested directly by the subject (for example, by eating a quantity of the powder), or incorporated into another food (for example, by dissolving it in a beverage or by including it in the batter for a baked foodstuff). In particularly preferred versions of these embodiments of the invention, such a powdered formulation would contain all of the therapeutically active ingredients (a) to (j). In one preferred version of that embodiment, such a formulation would contain all of the therapeutically active ingredients (a) to (j), as well as Sodium Diphosphate in about the following amounts per (or in each) kilogram of the finished product:

(a) Curcumin - 1.276 g;

(b) L-Glutamine - 500 g;

(c) Quercetin - 40 g;

(d) Glucosamine Hydrochloride - 83.01 g;

(e) Aloe vera fresh leaf - 100 g;

(f) Peppermint oil - 600 mg;

(g) Slippery Elm inner bark powder - 100 g;

(h)GuarGum-20g;

(i) Pectin - 20 g; and

(k) Sodium Diphosphate (Dibasic Sodium Phosphate) - 52 g.

In some preferred forms of the invention, a Medication made in accordance with the present invention would be formulated such as to deliver a daily dose of the following therapeutically active ingredients to the patient:

(1) L-Glutamine - 0.3 to 30 grams;

(2) Quercetin - 0.06 to 1.5 grams; and

(3) Glucosamine Hydrochloride - 0.5 to 2.0 grams.

The invention further generally provides a substance that comprises one or more of the following therapeutically active ingredients:

(a) Curcumin;

(b) L-Glutamine;

(c) Quercetin;

(d) Glucosamine;

(e) Aloe vera;

(f) An edible essential oil;

(g) Powder derived from the inner bark of Slippery Elm (Ulmus rubra);

(h) Guar Gum; and

(i) Pectin.

for or when used in the manufacture of a medicament for the treatment of a functional or biochemical gastrointestinal disorder of the kinds previously described.

Preferably, in this aspect of the invention, the Aloe vera component of such a medicament takes the form of, or is derived from Aloe vera fresh leaf.

Preferably, in the medicament, the edible essential oil is a Peppermint Oil, being the essential oil derived from Peppermint (Mentha piperita).

In some preferred forms, substances in accordance with the invention also include Sodium Diphosphate.

In one generally preferred form of this aspect of the invention, the substance would contain all of the therapeutically active ingredients (a) to (). In a particularly preferred version of that embodiment, the substance would contain all of the therapeutically active ingredients (a) to (j) in about the following amounts per (or in each) kilogram of the finished medicament:

(a) Curcumin - 1.276 g;

(b) L-Glutamine - 500 g;

(c) Quercetin - 40 g;

(d) Glucosamine Hydrochloride - 83.01 g

(e) Aloe vera fresh leaf - 100 g;

(f) Peppermint oil - 600 mg;

(g) Slippery Elm inner bark powder - 100 g;

(h) Guar Gum - 20 g;

(i) Pectin - 20 g; as well as:

(k) Sodium Diphosphate (Dibasic Sodium Phosphate) - 52 g.

The present invention further generally provides a method of treating a functional or biochemical gastrointestinal disorder of the kinds previously described, the method comprising the step of administering to a patient in need of such treatment, a Medication that comprises an effective dose of one or more of the following therapeutically active ingredients:

(a) Curcumin;

(b) L-Glutamine;

(c) Quercetin;

(d) Glucosamine;

(e) Aloe vera;

(f) An edible essential oil;

(g) Powder derived from the inner bark of Slippery Elm (Ulmus rubra);

(h) Guar Gum; and

(i) Pectin.

Preferably, in the method of this aspect of the invention, the patient is a human being.

In some preferred forms of this aspect of the invention, the Medications administered to the patient also include Sodium Diphosphate.

In one generally preferred form of this aspect of the invention, the Medication would contain all of the therapeutically active ingredients (a) to (). In a particularly preferred version of that embodiment, the Medication would contain all of the therapeutically active ingredients (a) to (j) in about the following amounts per (or in each) kilogram of the finished Medication:

(a) Curcumin - 1.276 g;

(b) L-Glutamine - 500 g;

(c) Quercetin - 40 g;

(d) Glucosamine Hydrochloride - 83.01 g

(e) Aloe vera fresh leaf - 100 g;

(f) Peppermint oil - 600 mg;

(g) Slippery Elm inner bark powder - 100 g;

(h) Guar Gum - 20 g;

(i) Pectin - 20 g; as well as:

(k) Sodium Diphosphate (Dibasic Sodium Phosphate) - 52 g.

In another generally preferred form of this aspect of the invention, the method would comprise administering to the patient, a Medication formulated as an edible powder containing one or more of the therapeutically active ingredients (a) to (j) listed above. As previously described, such an edible powder could either be ingested directly by the subject (for example, by eating a quantity of the powder), or incorporated into another food (for example, by dissolving it in a beverage or by including it in the batter for a baked foodstuff). In other preferred embodiments of the invention, the Medication could be administered by incorporating a suitable quantity or dose of the Medication in another pharmaceutically acceptable delivery vehicle, such as a tablet, a capsule or caplet, a chewable tablet, gel, capsule or caplet, a rapidly dissolving tablet, gel, capsule or caplet, or a sustained or delayed release version of any of these delivery devices. Ordinary persons of skill in the field of pharmaceutical formulation would readily appreciate that in practice, Medications in accordance with the invention could be formulated for administration to intended animal subjects in these or in many other ways, and that all such modes of administration are specifically included within the scope of the present invention.

In particularly preferred versions of these embodiments of the invention, such a powdered formulation would contain all of the therapeutically active ingredients (a) to (j). In a particularly preferred version of that embodiment, such a formulation would contain all of the therapeutically active ingredients (a) to (k) in about the following amounts per (or in each) kilogram of the finished product:

(a) Curcumin - 1.276 g;

(b) L-Glutamine - 500 g;

(c) Quercetin - 40 g;

(d) Glucosamine Hydrochloride - 83.01 g;

(e) Aloe vera fresh leaf - 100 g;

(f) Peppermint oil - 600 mg;

(g) Slippery Elm inner bark powder - 100 g;

(h) Guar Gum - 20 g;

(i) Pectin - 20 g; and

(k) Sodium Diphosphate (Dibasic Sodium Phosphate) - 52 g.

In this method of treatment aspect of the invention, a Medication formulated as such an edible powder would be administered to a human patient as a 5 gram dose. In any period of 24 hours, an adult patient would be administered a maximum dose of no more than 15 grams of the powdered formulation.

Where the patient is not an adult, the dosage per day is preferably as follows:

(a) For a patient aged 12 years or older - up to the recommended daily prescribed dose (although of course, desirably, the dose for a given patient will be recommended by a health care professional);

(b) For a patient aged between 5 and 12 years- up to one-half of the recommended and maximum adult daily dose;

(c) For a patient aged between 2 and 5 years- up to one-third of the recommended and maximum adult daily dose; and

(d) In the case of a child aged under 2 years, as directed by a physician or other health care professional.

Preferably, the method of treatment optionally involves co-administering a probiotic substance to the patient. Preferred probiotic substances for this purpose include preparations or formulations that contain bacterial species selected from the Bacteroides genus and/or the phylum Firmicutes. Particularly preferred probiotic bacterial species for this purpose include Bifidobacteria and Lactobacillus bacterial species. In some preferred forms of this aspect of the invention, the step of co administering the probiotic substance to the patient is commenced before the step of administering the Medication to the patient.

The present invention further generally provides a method of increasing the concentration of one or more beneficial bacterial species in the gastrointestinal tract of a patient afflicted by a functional or biochemical gastrointestinal disorder of the kinds previously described, the method comprising the step of administering to the patient, a Medication that comprises an effective dose of one or more of the following therapeutically active ingredients:

(a) Curcumin;

(b) L-Glutamine;

(c) Quercetin;

(d) Glucosamine;bifo

(e) Aloe vera;

(f) An edible essential oil;

(g) Powder derived from the inner bark of Slippery Elm (Ulmus rubra);

(h) Guar Gum; and

(i) Pectin.

In one generally preferred form of this aspect of the invention, the Medication would contain all of the therapeutically active ingredients (a) to (). In a particularly preferred version of that embodiment, the Medication would contain all of the therapeutically active ingredients (a) to (j) in about the following amounts per (or in each) kilogram of the finished Medication:

(a) Curcumin - 1.276 g;

(b) L-Glutamine - 500 g;

(c) Quercetin - 40 g;

(d) Glucosamine Hydrochloride - 83.01 g

(e) Aloe vera fresh leaf - 100 g;

(f) Peppermint oil - 600 mg;

(g) Slippery Elm inner bark powder - 100 g;

(h) Guar Gum - 20 g;

(i) Pectin - 20 g; as well as:

(k) Sodium Diphosphate (Dibasic Sodium Phosphate) - 52 g.

In another generally preferred form of this aspect of the invention, the method would comprise administering to the patient, a Medication formulated as an edible powder containing one or more of the therapeutically active ingredients (a) to (k) listed above. As previously described, such an edible powder could either be ingested directly by the subject (for example, by eating a quantity of the powder), or incorporated into another food (for example, by dissolving it in a beverage or by including it in the batter for a baked foodstuff). In particularly preferred versions of these embodiments of the invention, such a powdered formulation would contain all of the therapeutically active ingredients (a) to (k). In a particularly preferred version of that embodiment, such a formulation would contain all of the therapeutically active ingredients (a) to (k) in about the following amounts per (or in each) kilogram of the finished product:

(a) Curcumin - 1.276 g;

(b) L-Glutamine - 500 g;

(c) Quercetin - 40 g;

(d) Glucosamine Hydrochloride - 83.01 g;

(e) Aloe vera fresh leaf - 100 g;

(f) Peppermint oil - 600 mg;

(g) Slippery Elm inner bark powder - 100 g;

(h)GuarGum-20g;

(i) Pectin - 20 g; and

(k) Sodium Diphosphate (Dibasic Sodium Phosphate) - 52 g.

In another preferred embodiment of this aspect of the invention, the method comprises the additional step of administering a further probiotic substance to the patient. In one particularly preferred embodiment of this aspect of the invention, the step of administering the probiotic substance to the patient is commenced before commencing the step of administering the Medication to the patient.

In an alternative preferred embodiment of this aspect of the invention, the method the step of administering the probiotic substance to the patient is commenced on or after commencing the step of administering the Medication to the patient.

For the purposes of the present invention, a "probiotic" is any substance which stimulates or promotes the growth of any beneficial microorganism (and especially, bacterial) species of the gastrointestinal flora. Preferred probiotic substances for this purpose include preparations or formulations that contain bacterial species selected from the Bacteroides genus and/or the phylum Firmicutes. Particularly preferred probiotic bacterial species for this purpose include Bifidobacteria and Lactobacillus bacterial species.

Preferably, in this aspect of the invention, a Medication formulated as such an edible powder would be administered to a human patient as a 5 gram dose. In any period of 24 hours, the patient would be administered a maximum dose of no more than 15 grams of the powdered formulation.

It is also to be understood that wherever appearing in this specification, the terms "Medication" and "medicament" are used interchangeably, and mean the same thing.

Detailed description of exemplary embodiments of the Invention

Exemplary embodiments of the Invention will now be described by way of example only in the comments that follow, and with reference to the drawings and tables provided.

Overview of a study performed on adult human patients with gastrointestinal symptoms

The following comments and information describe and report the results of a study conducted in Melbourne, Australia, of the impact of a Medication formulated by or on behalf of the Applicant, on certain gastrointestinal symptoms in a sample population of 50 adult volunteer subjects. The study was conducted on behalf of the Applicant by National Institute of Integrative Medicine Ltd (Australian Company Number 095 139 209) (the latter entity having assigned all the intellectual property rights in the conduct of and the results of the study to the Applicant).

Volunteers for the study were recruited by advertisements, through the use of social media, and via the National Institute of Integrative Medicine's web site.

The Medication

The Medication administered to participants in the study was manufactured in Australia or on behalf of the Applicant, and each 5 gram sachet of the medication contained the following ingredients:

Ingredient Quantity present

Curcuma longa rhizome as Cumerone@ 30.37 mg

Containing curcuminoids 6.074 mg

Containing curcumin 4.25 mg

Glutamine 2.5 g

Quercetin 200 mg Glucosar ne hydrochloride (from 500 mg Shellfish)3 (Equivalent to Glucosamine): 415.05 mg

Aloe vera (inner leaf / gel without 500 mg latex & rind) Equivalent to Aloe vera leaf fresh

Equivalent to Aloe polysaccharides 187.5 mg

Equivalent to Aloin (as barbaloin) 0.02 mcg

Ulmus rubra (Slippery Elm) Bark Powder 500 mg Guar Gum 100 mg

Pectin 100 mg Peppermint oil 3 mg

Sodium phosphate 250 mg

On a per kilogram basis, the Medication therefore had the following composition

(a) Curcumin - 1.276 g;

(b) L-Glutamine - 500 g;

(c) Quercetin - 40 g;

(d) Glucosamine Hydrochloride - 83.01 g

(e) Aloe vera fresh leaf - 100 g;

(f) Peppermint oil - 600 mg;

(g) Slippery Elm inner bark powder - 100 g;

(h) Guar Gum - 20 g;

(i) Pectin - 20 g; and

(k) Sodium Diphosphate (Dibasic Sodium Phosphate) - 52 g.

The Medication was provided to patients in powdered form in sachets containing 5 grams of the Medication. At the inception of the study, participants were given guidance on how to take the Medication. It was suggested that a preferred form was to take the Medication with warm water. Other methods of oral administration (eg, to take the medication with food or with beverages other than water, were also options available to the participants.

Participants

A total of 50 adult participants with gastrointestinal symptoms were enrolled to take part in the study, after an initial 66 to 100 volunteers were screened. The participants enrolled had either upper or lower gastrointestinal tract symptoms (or both).

Some of the key characteristics of the participants are summarised in the following comments.

The mean age of the enrolled participants was 50yrs (female 76%).

The participants were grouped into those that manifested with upper gastrointestinal tract (GI) issues (n=32, 74%) and lower GI issues (n=42, 97%), with most participants (n = 31, 72%) experiencing both.

Preliminary evaluation of the participants at recruitment revealed the following:

Table 1

GI Symptoms: Bloating (76%) Other symptoms: Fatigue (60%) Heartburn/reflux (50%) Anxiety (54%) Constipation (52%) Bad-breath Diarrhea (48%) Mouth-ulcers Nausea (48%) Rashes (30%)

Key aspects of these data are represented graphically in Fig 1.

Study Methodology

After enrolment, the study involved assessing certain parameters of the gastrointestinal health of the enrolled participants over a period of approximately 16 weeks. The assessments were performed at 4 stages, as follows:

(1) At a first visit (Visit 1) at the commencement of the study;

(2) At a second visit (Visit 2), that took place at 3-4 weeks after Visit 1;

(3) At a third visit (Visit 3) that took place 4 weeks after Visit 2;

(4) At a fourth visit (Visit 4) that took place 4 weeks after Visit 3.

After this schedule was completed, the data obtained from the study were compiled and analysed.

The key events that took place at each stage were as follows:

Stage Key events

Visit 1 Certain baseline gastrointestinal health data for each participant were collected, in the manner explained (Commencement below under "Data Collection". and "run-in" stage) The data included the collection of stool samples from each patient, for laboratory analysis.

Visit 2 The participants were divided into 2 "Groups" (namely, "Group 1" and "Group 2"). (3 - 4 weeks after Visit 1) Participants were asked to take 5 grams of the Medication daily during this stage. The Medication was taken each evening over the duration of this stage.

Data for the stage were collected from each participant.

Visit 3 Participants in each Group were asked to take 10 grams of the Medication daily during this stage. The (4 weeks after Medication was taken each evening over the duration Visit 2) of this stage.

Data for the stage were collected from each participant.

Visit 4 Participants in each Group were asked to take 0, 5 or 10 grams of the Medication daily during this stage, (4 weeks after according to individual patient preference. Visit 3) Data for the stage were collected from each participant.

This included the collection of stool samples from each participant at the commencement of this stage.

Blood and urine samples were collected from participants at the end of the stage, for laboratory analysis.

Data Collection

Data were collected from the study in two ways:

(a) Assessments of certain patient gastrointestinal health indicators were collected via individual patient answers to a series of questions contained in clinical questionnaires aimed at addressing the frequency and severity of certain key gastrointestinal symptoms.

The clinical questionnaires used were:

(1) the Leeds Dyspepsia Short Form Questionnaire;

(2) the Bristol-Stool-Chart;

(3) the GERD-Questionnaire, and

(4) the Birmingham-IBS-Symptom- Questionnaire.

Although these questionnaires would be familiar to persons of skill in the field of the invention, for the sake of ensuring full disclosure, exemplary details of the questionnaires can be found either in this specification, and/or at the following web sites:

(1) the Leeds Dyspepsia Short Form Questionnaire - at the address:

https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2036.2006.03233.x

(2) the Bristol-Stool-Chart;

https://www.continence.com.au

(3) the GERD-Questionnaire, and

http://www.journalofmas.com/articles/2018/14/3/images/JMinAccessSurg_2018 14_3_213_214880_sm7.pdf

(4) the Birmingham-IBS-Symptom- Questionnaire:

https://bmcgastroenterol.biomedcentral.com/articles/10.1186/1471-230X-8-30

Full details of each of these exemplary source materials are incorporated into this specification by reference, as if they were specifically set out in this document.

(b) Furthermore, gut microbiota, intestinal permeability, inflammatory markers, and H- pylori infection were assessed by using standard laboratory techniques, the nature of which would readily be apprehended by persons of skill in the field of the invention.

Statistical analysis of data collected

Where required, data collected from the study were subjected to statistical analysis in accordance with accepted and conventional biostatistical methodologies. These included the use of the Paired T-Test and the Chi-squared test. (Fort an example of a reference, see: Colquhoun, D, Lectures on Biostatistics (Oxford University Press, 1971). The Birmingham-IBS-Symptom Questionnaire Data were analysed using the methodology outlined in Roalfe (2008) (Reference: Roalfe, AK, Roberts, LM, and Wilson "Evaluation of the Birmingham-IBS-Symptom-Questionnaire", BMC Gastroenterol (2008) Jul 23 8:30). Certain other data (for example, the data tabulated at Table 33 and shown in Figure 20) were analysed using Fisher's Exact Test (Reference: http://mathworld.wolfram.com/FishersExactTest.html).

Results

Extent of participation by the participants

As previously indicated, at the commencement of the trail, there were 50 participants enrolled.

Ofthese:

• 7 participants (14%) withdrew after Visit 1;

• 43 participants completed the trial;

• Of the participants that completed the trial: • 42 completed the intestinal permeability testing at start and end of study (n=1 failed to complete this test at the end of the study); and • 37 completed the stool testing.

Comparison of the prevalence or severity of certain symptoms observed at four time points in the study

Fig 2 summarises some of the key results observed from the study as a whole, when assessed across the four major time points during the duration of the study.

As can be seen from Fig 2, reductions were observed in all the key symptoms assessed over the duration of the study. In particular, the following reductions were observed:

• Abdominal boating reduced by 55%; • Diarrhea reduced by 75%; • Heartburn/reflux reduced by 78%; and • Fatigue reduced by 32%.

Palatability of the Medication to the participants

Table 2 (below) summarises feedback received from the participants about the palatability of the Medication.

Table 2: Participants' perceptions of Palatability

Response to taste n %

Liked a lot 5 11.6 Liked 19 44.2 Neutral 16 37.2

Totals 43 100

The majority of participants therefore either responded positively or were neutral to the taste of the Medication.

Table 3 (below) sets out data concerning the methods preferred by participants for taking the Medication.

Table: articipants' preferredmethod oftakingtheMedication

Method n%

Warm water 36 83.7 Food 1 2.3 Other 6 14

Totals 43 100

As shown in Table 3, some 83.7% of the participants chose to take the formula with warm water, as recommended at the commencement of the study.

The participants' preferred dosage regimes

As previously indicated, during the Visit 3and Visit 4stages of the study, the participants were asked to take up to 10grams ofthe Medication daily.

Table 4 (below) summarises the results of the acceptability of the 10 gram per day dosage to the participant group.

Table 4

Acceptability of 1sachet (5g)and 2 1sachet(5g) 2 sachets(1Og) sachets (0g)

V e ry E asy ............................................................ 19 4 4 .2 12 27 .9 .

Easy 21 48.8 16 37.2. Sometimes easy, sometimes hard 3 7 1023.3 Hard 0 0 49.3 Very Hard 0 0 1 2.3

Totals 43 100 43 100

As will be apparent from Table 4:

• Almost all participants found taking 1 sachet either "easy" or "very easy"; and

• The acceptability of 2 sachets ranged from very easy to very hard - with the highest number of participants scoring this in the "easy" category.

[The next page is page 29].

Compliance by the participants with the study's dosage regimes

This parameter is summarised in Table 5 (shown below).

Table 5: Compliance (%) amongst the total participants with dosage regimes

Study stage and n Percentage of Other observations dose participants complying with the dose in the month (%)

Visit 2 (5 grams) 43 90.8

Visit 3 (10 grams) 39 89.5 3 participants took 5 grams;

1 participant took 0 grams

Visit 4

5 grams 13 10 grams 28 0 grams 2

Table 6: The choice of dosage regime adopted by Participants at Visit 4, and their reasons for doing so

The results for these parameters are summarised in table 6 (below).

Table 6

10 grams 5 grams 0 grams 5 grams 0 grams

Number of 28 10 1 3 1 participants

Reasons Significant * Improvement •Disliked •Harder •Disliked given for improveme s in upper GI taste and stools, taste and adopting the nt in upper symptoms texture straining to texture dose GI pass stools, *Looser symptoms * Harder feeling bowel stools, constipated, motions Loose and straining to less regular mushy pass stools, bowel stools were feeling motions, firming up constipated, abdominal less regular bloating More bowel frequent motions •Disliked and regular taste and bowel texture motions

Table 7: Incidence of unwanted effects

The results for this parameter are summarised in Table 7 (below).

Table 7

Exacerbation of symptoms Month and Dose

Type Month 1 Month 2 Month 3 (Visit 2) (Visit 3) (Visit 4) Daily dose 5 gram dose 10 gram dose Dose of 0, 5 or 10 grams None 21 21 35 Bloating 5 1 1 Incomplete evacuation/ Harder 6 14 3 stools / Constipation Urgent / Loose / Diarrhea 5 2 2 Reflux/Indigestion 4 1 0 Other 2 4 2

As will be apparent from reading Table 7:

• The number of participants experiencing side effects declined from Month 1 to Month 3; and

• The number of participants who experienced harder stools, incomplete evacuation and constipation increased in Month 2 at the higher dose of 10 grams.

Table 8: Incidence of unwanted effects in the participant group with both upper and lower GI symptoms The results for these parameters are shown in Table 8 (below):

Table 8

Unwanted effects: Upper G1 & Lower G1 participants (n = 32)

Unwanted effect Month 1 Month 2 Month 3 (Visit 2) (Visit 3) (Visit 4) Daily dose 5 grams 10 grams 0, 5 or 10 grams None 16 19 25 Bloating 3 0 1 Incomplete/Harder/Constipation 5 11 3 Urgent/Loose/Diarrhea 3 0 1 Reflux/Indigestion 4 0 0 Other 1 2 2

As will be evident from Table 8:

• Unwanted effects in participants experiencing both upper and lower symptoms reduced significantly from Month 1 to Month 3 of the study;

• At the daily dose of 10 grams in Month 2, the number of participants experiencing harder stools, incomplete evacuation or constipation increased; and

• No reflux/indigestion side effects were observed in Months 2 or 3.

Table 9: Incidence of unwanted effects in the participant group with both upper and lower GI symptoms, by the dose chosen in Month 3 of the Study

The results for these parameters are shown in Table 9 (below):

Table 9

Unwanted effects: Upper & Lower participants (n = 32) in Month 3 by choice of dosage Unwanted effects Og 5g log None 0 6 19

Bloating 0 0 1 Incomplete/Harder/Constipation 0 1 2 Urgent/Loose/Diarrhea 0 0 1 Reflux/Indigestion 0 0 0 Other 0 1 1

By way of summary:

• These results show that In general, more participants with both upper and lower symptoms chose the 10 gram dosage; and

• No reflux/indigestion side effects were observed in Month 3.

Table 10: Unwanted effects in participants with lower GI issues

For all intents and purposes, virtually all participants (97% of the sample population studied) had experienced lower GI issues at the commencement of the study.

Table 10 (below) summarises the impact of the Medication on those issues throughout the duration of the study.

Table 10

Unwanted effects in the lower GI participant population

Baseline stool Month 1: Month Month 3: Month Month 3: consistency 5g 2:lOg ChoiceOg 3: Choice (n=43) (n=39) (n=2) Choice log 5g (n=28) (n=13) Normal stool None 6 5 0 2 0 Bloating 0 0 0 0 6 Incomplete/Harder/Constipation 2 3 0 0 2 Urgent/Loose/Diarrhea 0 0 0 0 0 Reflux/Indigestion 1 0 0 0 0 Other 1 2 0 0 0

Soft None 5 5 1 3 5 Bloating 0 0 0 0 1 Incomplete/Harder/Constipation 2 3 0 0 0 Urgent/Loose/Diarrhea 4 1 1 0 0 Reflux/Indigestion 1 0 0 0 0 Other 0 1 0 0 1

Hard None 10 11 0 6 12 Bloating 5 0 0 0 0 Incomplete/Harder/Constipation 2 6 0 1 0 Urgent/Loose/Diarrhea 1 0 0 0 1 Reflux/Indigestion 2 1 0 0 0 Other 1 1 0 1 0

Other general observations reported by participants or which emerged from the study

The following additional observations or comments emerged from the study:

• The Medication was generally well tolerated by participants; • The impact of the Medication on upper gastrointestinal symptoms was observed generally to be more rapid than with lower GI symptoms; • A number of the participants reported that during the study, they were able to reduce the extent of their use of other medications (in particular, anti-reflux medication and laxatives); • A number of participants reported that after taking the Medication, they found that they were able to introduce foods into their diet which had previously been triggers for gastrointestinal symptoms. The food triggers that participants had been able to introduce into their diet included gluten, carbohydrates, FODMAPs (namely, fermentable oligo-, di-, mono-saccharides and polyols), and acidic/spicy foods. Some participants found that they either had less severe symptoms in response to such food triggers than before the study, and in some instances, participants found that they had no symptoms; and • The 1Og/day dose of the Medication was generally found to be more likely to induce constipation than 5g/day. This is a useful finding for subjects who suffer from loose stools, but conversely, the dose of the medication administered may need to be taken into account in relation to subjects suffering from constipation/ hard stools.

The impact of the Medication on participants' responses to food triggers

Table 11 (which appears in Fig 3 of the accompanying drawings) sets out data showing the impact of the Medication on food triggers in the participants.

In summary, the data in Table 11 show:

• An overall improvement of between 18 to 57% in participants' ability to tolerate trigger foods;

SA 52% improvement in the ability of participants who had tolerance issues to this food, in tolerating it;

SA significant improvement (>40%) in the tolerance of participants to foods that cause GERD (notably, these are citrus foods, acidic foods, caffeine and spicy foods; and

SA significant improvement (47%) in the tolerance of patients who previously had issues tolerating casein.

The impact of the Medication on the tolerance of participants with upper GI symptoms

Table 12 (which appears in Fig 4 of the accompanying drawings) sets out the impact of the Medication on the tolerance of participants with upper GI symptoms, to the food triggers studied. It is to be noted that all but one of the participants also had lower GI symptoms.

In summary, the data in Table 12 show:

SA 16 to 50% improvement amongst participants, in their tolerance to FODMAP trigger foods; and

• An improvement of >40% in the response of participants to trigger foods for GERD.

[The next page is page 35].

Changes observed in participants' tolerance levels to food triggers, based on the dose of the Medication

Table 13 (which appears in Fig 5 of the accompanying drawings) sets out the results observed when assessing this parameter.

In summary:

• The dose of 10 grams per day was found to be more effective overall; and

• The 10 grams per day dose of the Medication was more effective in participants who had issues with acidic foods, fatty foods, caffeine, spicy foods or alcohol.

Impact of the Medication on the use of other medicines or supplements to relieve upper or lower GI symptoms

The data for this aspect of the study are set out in Table 14.1 (which in turn, appears as Fig 6 of the accompanying drawings).

Details of the changes in the medicines or supplements used to relieve upper GI symptoms

The data for this aspect of the study are set out in Table 14.2 (which in turn, appears as Fig 7 of the accompanying drawings).

In summary, these data show that by the end of the study, there had been a reduction of 40% in the number of participants who used other medicines or supplements to relieve their upper GI symptoms.

Table 14.3: Details of the changes in the medicines or supplements used to relieve lower GI symptoms

The data for this aspect of the study are set out in Table 14.3 (which in turn, appears as Fig 8 of the accompanying drawings).

The laxatives used included Soda bicarb, Nomacol fibre granules, Colozone (Mg laxative), Herbalax, Metamucil fibre capsules, Nulax, Celery juice, Coloxil, Intestinal Movement Formula.

In summary: No change was found in the number of participants with lower GI symptoms taking medicines or supplements to relieve those symptoms.

Results from Questionnaires

LEEDs Dyspepsia Questionnaire (upper GI symptoms)

Total participants with upper gastrointestinal symptoms: N=32

Method of analysis: Within subject comparison of LEEDs Questionnaire answers, by repeated measure t-test.

Table 15.1 - LEEDs 1. Baseline vs Control (run-in-phase)

The data for this aspect of the study are set out in Table 15.1 (which in turn, appears as Fig 9 of the accompanying drawings).

Table 15.2 - LEEDs 2. Baseline vs 12 weeks = Change after treatment with the Medication

The data for this aspect of the study are set out in Table 15.2 (which in turn, appears as Fig 10 of the accompanying drawings).

In summary:

The Medication significantly reduced upper GI symptoms (including indigestion, heartburn, regurgitation and nausea) (p<0.001)

Figure 11: Graphical representation of Leeds Questionnaire Scores

The data for this aspect of the study are represented graphically in Fig 11 of the accompanying drawings).

Figure 12: Sample of a LEEDs Questionnaire

A sample of the LEEDs Questionnaire used in the study is depicted in Fig 12 of the accompanying drawings.

GERD Questionnaire - (upper GI symptoms) Frequency of upper GI symptoms

As indicated earlier, a sample of this Questionnaire can be found on the Internet, at the following World Wide Web address:

http://www.journalofmas.com/articles/2018/14/3/images/JMinAccessSurg_2018_14_3_213 214880_sm7.pdf.

Total participants with upper gastrointestinal symptoms: N=32.

Method of analysis: Within subject comparison of answers to the GERD Questionnaire by repeated t-test.

Table 16.1 - GERD 1. Baseline vs Control (run-in-phase)

The results for this aspect of the study are set out in Table 16.1, (which in turn, appears as Fig 13 of the accompanying drawings).

Table 16.2 - GERD 2. Baseline vs 12 weeks = Change after treatment with the Medication

The results for this aspect of the study are set out in Table 16.2, (which in turn, appears as Fig 14 of the accompanying drawings).

In summary:

• The Medication significantly reduced the frequency and severity of upper GI symptoms,

• including indigestion, heartburn, regurgitation, nausea and associated quality of sleep issues (p<0.001).

GERD frequency and days measurements

These data are set out in Fig 15 of the accompanying drawings, which includes (and depicts as "Table 1" in Fig 15, a sample GERDQ Questionnaire).

[The next page is page No 38].

GERD Quality of Life (QoL) Questionnaire and GERD HQoL - (Upper GI Symptoms)

The results for this aspect of the study are set out in Table 17.1 (below):

Table 17.1- GERD QoL 1. Baseline vs Control (run-in-phase) Questionnaire Measure N Control Meant Baseline Mean Difference p-value SE ±SE Mean±SE GERD QoL Daily activity 32 47.07 ± 5.06 42.77 4.81 4.30 ±2.81 p = 0.138 Treatment 11 63.63 ± 9.61 56.06 11.01 7.58 ±8.66 p = 0.402 Effect (Subgroup on PPI) Diet 32 48.95 ±6.71 52.08 5.70 3.13 ±5.06 p 0.54 Psych 32 56.25 ±6.35 47.65 6.31 8.59 ±4.68 p =0.076 Wellbeing Overall score 11 62.74 ±7.50 76.04 10.07 13.30 9.98 p =0.21 (subgroup on PPI) Adjusted 32 50.76 ±5.44 47.50 ±4.90 3.25 3.38 p =0.34 Overall Score* Gerd HQoL TotalScore 32 20.19 ±2.72 18.50 ±2.25 1.69 1.59 P =0.30

Notes to Table 17.1:

Total participants with upper gastrointestinal symptoms: N=32;

Subgroup: Participants on meds (PPI) only (n=11) - GERD QoL - Treatment effect;

Method of analysis: Within subject comparison of the answers to the GERD repeated measure t-test. QoL and GERD HQoL Questionnaires by Table 17.2 - GERD QoL 2. Baseline vs 12 weeks = Change after treatment with the Medication

Questionnaire Measure N Control Mean ± Baseline Mean Difference p-value SE ±SE Mean±SE GERD QoL Daily activity 32 42.77 ±4.81 17.68 ± 3.60 25.09 ±3.72 p < 0.001 Treatment 11 56.06± 41.67 ±8.84 14.39 ±8.71 p = 0.129# Effect 11.01 (Subgroup on PPI) Diet 32 52.08 ±5.70 33.07 ±6.27 19.01±4.27 p < 0.001 Psych 32 47.65 ± 6.31 19.14 ±5.14 28.51 ±5.62 p <0.001 Wellbeing

Overall score 11 76.04 32.59 ±6.60 43.44 ±7.74 p < 0.001# (subgroup on 10.07 PPI) Adjusted 32 47.50 ±4.90 23.29 ±4.45 24.21 ±3.64 p < 0.001 Overall Score* Gerd HQoL Total Score 32 18.50 ± 2.25 8.63 ± 1.62 9.88 ± 1.85 p < 0.001

Legend to Tables 17.1 and 17.2:

Bold p-values are indicative of statistical significance (p < 0.05). Treatment effect (TE) was only analysed for participants taking medication (n=11, PPI). The Overall Score as per GERD QoL original questionnaire was calculated for (n=11 on PPI) = DA+TE +D +PW) / 4

* The adjusted overall score was calculated for all participants with upper symptoms (n=32) (DA+DI+PW) / 3 # 8/11 took PPI daily/regularly before the study, 3/11 occasionally; 60% (n=5 out of 8) of participants taking PPI's daily at the start of the study, reported no longer requiring daily PPs after the Medication intervention.

The data from Tables 17.1 and 17.2 are depicted graphically in Fig 16 of the accompanying drawings.

In summary:

S The Medication significantly improved the Quality of Life in participants with upper symptoms, including daily activities, diet, and psychological wellbeing (p<0.001), and associated Health Related Quality of Life (GERD- HQoL, p<0.001).

Fig 7: Examples of the GERD QoL and GERD HQoL Questionnaires

Examples of these are depicted in Fig 17 of the accompanying drawings.

Birmingham - Irritable Bowel Syndrome (IBS) - Q (Lower GI Symptoms)

Total participants with lower gastrointestinal symptoms: N=42

Note: One participant was excluded from this analysis, as the participant concerned had only upper GI symptoms.

Method of analysis: Within subject comparison of the results of the Birmingham IBS Q by repeated measure t-test.

Table 18.1: Birmingham IBS 1. Baseline vs Control (run-in-phase) n=42 (Analysis as per Roalfe (2008))

The results for this aspect of the study are set out in Fig 18.1 of the accompanying drawings.

Note: Most patients reporting constipation (N=7) at visit 1 were taking laxatives/herbs during the run- in =control phase, thus reducing the number reporting constipation at baseline (v2) to n=3.

Table 18.2: Birmingham IBS Symptom - Score: Baseline vs Control (run-in-phase) n=42 (Analysis as per Roalfe (2008))

The results for this aspect of the study are set out in Fig 18.2 of the accompanying drawings.

Note: Most patients reporting constipation (N=7) at visit 1 were taking laxatives during the run- in =control phase, thus reducing the number reporting constipation at baseline (v2) to n=3.

Table 18.3: Birmingham IBS Symptom - Number of Days: Baseline vs 12 weeks= Change after treatment with the Medication

The results for this aspect of the study are set out in Fig 18.3 of the accompanying drawings.

Bold p-values shown in Table 18.3 are indicative of statistical significance (p < 0.05).

Table 18.4: Birmingham IBS Symptom Score: Baseline vs 12 weeks = Change after treatment with the Medication

The results for this aspect of the study are set out in Fig 18.4 of the accompanying drawings.

In summary:

• The Medication significantly improved frequency (days) and severity (score) of lower GI symptoms, including diarrhea, and overall pain (p<0.001).

Constipation improved in a small number of patients (n=3) reporting constipation at baseline (p=0.047).

Figure 19 - Birmingham Day Differences

These data are represented graphically in Fig 19 of the accompanying drawings.

Figure 20 - Birmingham Scores Questionnaire

These data are represented graphically in Fig 20 of the accompanying drawings.

Birmingham lower GI Symptoms Questionnaire

These data analyse the results obtained from various subgroups in the study. Each subgroup includes solely participants with the particular symptom.

Table 19: Birmingham Days: Control vs Baseline

Questionnaire Measure N Control Baseline Difference p-value Mean±SE Mean±SE Mean ±SE Birmingham Constipation 34 6.44 ± 0.69 4.24 ±0.75 2.19 ±0.66 p = 0.02 days Diarrhea 37 6.02 ± 0.86 5.94 ±0.84 0.087 p = 0.89 0.60 Abdominal 39 7.53 ±0.86 7.94 ±0.88 0.42 ±0.70 p = 0.56 pain Troublesome 34 4.60 ± 0.45 4.94 ±0.37 0.35 ±0.41 p = 0.41 Flatulence

Table 20: Birmingham Days: Baseline vs 12 weeks

Questionnaire Measure N Control Baseline Difference p-value Mean±SE Mean±SE Mean±SE Birmingham Constipation 34 4.24 ± 0.75 2.97 ±0.76 1.28 ±0.60 p = 0.04 days Diarrhea 37 5.94 ± 0.84 2.31 ±0.47 3.62 ±0.81 p < 0.001

Abdominal 39 7.94 ± 0.88 2.14 ±0.49 5.79 ±0.79 p < 0.001 pain Troublesome 34 4.94 ±0.37 1.38 ±0.36 3.57 ±0.52 p < 0.001 Flatulence

Table 21: Birmingham Score: Control v Baseline

Questionnaire Measure N Control Baseline Difference p-value Mean ± SE Mean SE Mean SE Birmingham Constipation 34 7.82 ±0.70 6.88 0.59 0.94 0.51 p = 0.07 days Diarrhea 37 8.16 ± 0.73 7.78 0.72 0.38 0.60 p = 0.53

Abdominal 39 8.12 ±0.57 7.97 0.51 0.15 0.51 p = 0.76 pain Troublesome 34 4.09 ±0.18 4.24 0.13 0.147 ±0.18 p= 0.42 Flatulence

Table 22: Birmingham Score: Baseline v 12 weeks

Questionnaire Measure N Baseline 12 wks Difference %Change p-value Mean ± SE Mean SE Mean SE reduction Birmingham Constipation 34 6.88 ±0.59 4.12 0.70 2.76 0.66 -40% p< days 0.001 Diarrhea 37 7.78 ±0.72 4.43 0.60 3.35 0.62 -43% p< 0.001 Abdominal 39 7.97 ±0.51 3.05 0.46 4.92 0.51 -62% p< p 0.001 Troubleso 34 4.24 ±0.13 1.79 0.30 2.44 0.35 -58% p< me 0.001 Flatul

Figure 21: Birmingham Scores Questionnaire

Fig 21 depicts graphically, analysis of the results obtained from four participant subgroups.

[The next page is page No 43].

Figure 22: Birmingham Score Subgroup Analysis

Fig 22 depicts graphically, analysis of the Birmingham Score results across four participant subgroups.

In summary:

• Three-quarters of the participants experienced a combination of specific GI symptoms.

• 77% (n=33 out of 42) suffered constipation and abdominal pain at baseline.

• 83% (n=35) suffered diarrhea and abdominal pain at baseline.

• 71% (n=30) suffered constipation and flatulence at baseline.

• 76% (n=32) suffered diarrhea and flatulence at baseline.

• The Medication significantly reduced the frequency and severity by 40-60% of lower GI symptoms, such as constipation (40%), diarrhea (43%), abdominal pain (62%), and troublesome flatulence (58%) in participants with these symptoms at beginning of the study (p<0.0001).

Figure 23: Example of Birmingham IBS Questionnaire

Fig 23 depicts an example of a Birmingham Score Questionnaire for IBS.

Reference: Roalfe AK, Roberts LM,Wilson S. Evaluation of the Birmingham IBS symptom questionnaire. BMC Gastroenterology 2008;8:30.

[The next page is page No 44].

Irritable Bowel Syndrome - Quality of Life (IBS-QoL) (Lower GI Symptoms)

Total participants with lower gastrointestinal symptoms: N=42

Note: 1 participant was excluded from the analyses of lower GI symptoms as that participant had only upper symptoms.

Method of analysis: Within subjects comparison of Irritable Bowel Syndrome QoL by repeated measure t-test.

Table 23: IBS-QoL 1. Baseline vs Control (run-in-phase)

Table 23

Questionnaire Measure N Control Meant Baseline Difference p-value SE Mean ± SE Mean ± SE IBS QoL Emotional 42 9.62 ±0.88 9.41 ±1.00 0.21 ±0.49 p = 0.67 Mental 42 8.81 ±0.83 9.07 ±0.96 0.26 ±0.49 p = 0.60 Health Sleep 42 4.98 ±0.71 4.09 ±0.644 0.88 ±0.64 p = 0.17 Energy 42 5.74 ±0.52 5.90 ±0.55 0.17 ±0.33 p = 0.62 Physical 42 4.90 ±0.76 4.21 ±0.74 0.69 ±0.76 p = 0.37 Function Diet 42 7.31 ±0.54 7.52 ±0.64 0.21 ±0.43 p = 0.62 Social Role 42 8.74 ±0.72 7.97 ±0.76 0.76 ±0.40 p = 0.06 Physical Role 42 6.81 ±0.99 6.50 ±1.00 0.31 ±0.53 p = 0.56 TotalScore 42 56.90 ±4.60 51.95 ±4.68 4.95 ±1.87 p = 0.012

Bold p-values are indicative of statistical significance (p<0.05).

[The next page is page No 45].

Table 24: Baseline vs 12 weeks =Change after intervention

Table 24

Questionnaire Measure N Baseline Mean Week 12 Mean Difference p-value ±SE ±SE Mean ± SE IBSQoL Emotional 42 9.41 ±1.00 3.00 ±0.78 6.40 ±0.85 p<0.001 Mental 42 9.07 ±0.96 2.48 ±0.74 6.60 ±0.81 P<0.001 Health Sleep 42 4.09 0.644 0.74 ±0.33 3.36 ±0.60 p<0.001 Energy 42 5.90 0.55 1.79 ±0.43 4.11 ±0.53 p<0.001 Physical 42 4.21 0.74 1.38 ± 0.47 2.83 ±0.73 p < 0.001 Function Diet 42 7.52 0.64 3.64 ±0.56 3.88 ±0.63 p < 0.001 Social Role 42 7.97 0.76 3.40 ±0.68 4.57 ±0.67 p<0.001 Physical 42 6.50 1.00 2.00 ±0.63 4.50 ±0.79 p<0.001 Role TotalScore 42 51.95 4.68 18.43 ±4.13 33.52 ±3.86 p<0.001

Note: Bold p-values are indicative of statistical significance (p < 0.05).

In summary:

The Medication significantly improved lower symptoms associated Quality of Life, including emotional and mental health and wellbeing, sleep, energy, physical functioning, diet and social interactions (p<0.001).

Figure 24: IBS Qol Score Difference

The data for this aspect of the study are represented graphically in Fig 24 of the accompanying drawings.

Figure 25: Example of Revised IBSQoL An example of this appears at Fig 25 of the accompanying drawings.

[The next page is page 46].

Bristol Stool Chart

Table 25: Bristol Stool Chart 1: Number of participants with each stool type (n=43)

Table 25

Type 1: Type 2: Type 3: Like Type 4: Like Type 5: Soft Type 6: Type 7: Hard Sausag a sausage a sausage blobs with Fluffy Watery, Lumps e- with cracks orsnake clear cut pieces with no solid shaped edges ragged pieces

Control 3 4 14 10 4 8 0

Baseline 1 2 15 13 5 7 0

12 Weeks 1 10 12 18 1 1 0

Figure 26: Bristol Stool Chart 1: Number of participants with each stool type (n=43) The data set out in Table 25 are represented graphically in Fig 26 of the accompanying drawings.

In summary:

• The Medication improved stool consistency towards the ideal type 4, and harder stools (types 3 and 2); • The number of participants with loose/ diarrhoea-like stools significantly reduced, due to the fibre ingredients, such as Pectin, in the Medication (p<0.001); • The Medication significantly improved stool frequency and regularity towards the ideal 1-2 times per day; and • A daily dose of 1og/day of the Medication was more likely to induce constipation that a dose of 5g/day.

[The next page is page No 47].

Table 26: Bristol Stool Chart 2: Number of participants and average frequency of passing stools (n=43)

Table 26

Number of >2 times per 1-2 times per Every second 1-3 days per Days day day day week (Ideal)

Control 6 25(58%) 6 2 Baseline 4 33(76%) 5 1

12 weeks 5 34(79%) 3 1

3 Figure 27

The data set out in Table 26 are represented graphically in Fig 27 of the accompanying drawings.

Figure 28: An Example of the Bristol Stool Chart

An example of this appears at Fig 28 of the accompanying drawings.

Reference: Lewis S, Heaton K. Stool form scale as a useful guide to intestinal transit time Scandinavian J Gastroenterology 1997;32:920-4

Analysis of the Bristol Stool Chart Results by Repeated Measures t-test '5 Table 27: Bristol Stool Chart by Stool Consistency: Control vs Baseline

Stooltype Visit n Mean ± SE Mean Difference p- value ± SE Normal Control 1 4.00 ± 0 0.50 0.37 p = 0.21 Baseline 1 4.50 ±0.37 Soft Control 1 5.67 ± 0.14 0.917 0.26 p = 0.05 baseline 1 4.75 ±0.31 Hard control 2 2.52 ±0.16 0.667 0.26 p = 0.019 baseline 2 3.19 ±0.20

Legend to Table 27: Normal, optimal value = 4 -0 Values below 4 are indicative of harder stools. Values over 4 are indicative of softer, waterier stools.

Table 28: Bristol Stool Chart by Stool Consistency Baseline vs Week 12

Stool Visit n Mean ± SE Mean Difference p- value type ±SE Normal baseline 10 4.50 ±0.37 1.00 ±0.47 p = 0.063 12 weeks 10 3.50 ±0.40 Soft baseline 12 4.75 ±0.31 1.42 ±0.34 p = 0.001 12 weeks 12 3.33 ±0.23 Hard baseline 21 3.19 ± 0.20 0.095 ±0.32 ns 12 weeks 21 3.10 ±0.22

Legend to Table 28: Normal, optimal value = 4 Values below 4 are indicative of harder stools. 3 Values over 4 are indicative of softer, waterier stools.

In summary:

• The results show a significant change towards the normal stool type in the soft stool group;

• The Medication had the most beneficial impact on the soft stool group.

Analysis of pain experienced by the participants

Pain Scales - VAS (n=43)

Method of analysis: Within-subject comparison of the Pain VAS by repeated measure t-test by group (upper GI symptoms or lower GI symptoms)

The impact of the Medication on pain experienced by the participants was measured by using a Visual Analog Scale ("VAS") for pain measurement.

[The next page is page No 49].

Table 28A: Analysis of pain experienced by the participants Pain Scales - VAS (n=43)

The data for this aspect of the study are set out in Table 28A (below).

Table 28A

Questionnaire Measure N Baseline 12 week score Difference p-value

Pain VAS Upper GI 13 5.08 ±0.69 2.62 ±0.95 2.46 ±1.33 p = 0.088 Uppergroup Pain Lower GI 24 4.23 ±0.54 1.97 ±0.42 2.25 ±0.59 p = 0.001 pain Other Pain 24 5.08±0.39 2.49 ±0.43 2.59 ±0.64 p<0.001

(Reference: McCormack, JM, Horne, DJ and Sheather, S,

"Clinical applications of visual analogue scales: a critical review"

Psychol Med (1988): 18, 1007-1019).

Note: Only participants who experienced pain are included in the tables and figures. Some participants experienced several types of pain. Some participants did not report any pain.

The numbers of participants who experienced one or more types of pain were as follows:

N= 5 3 types of pain N= 6 2 types of pain (upper & lower) N = 13 1 type of pain

[The next page is page No 50].

Upper GI Symptom Group (n=32):

Table 29: Pain VAS (Score 0-10): Baseline vs Control (run-in-phase, n=32)

The data for this aspect of the study are set out in Table 29 (below).

Table 29

Questionnaire Measure N Control Baseline Difference p-value Mean±SE Mean±SE Mean±SE Pain VAS UpperGI 13 6.81± 0.58 5.08 ±0.69 1.73 ±0.74 p =0.038 Uppergroup Pain Lower GI 24 4.62 ±0.38 4.23 ±0.54 0.40 ±0.52 p =0.45 pain Other Pain 24 4.76 ±0.44 5.08 ±0.39 0.33 ±0.46 p =0.49

Table 30: Pain VAS: Baseline vs 12 weeks = Change after Treatment with the Medication (n=32)

The data for this aspect of the study are set out in Table 30 (below).

Table 30

Questionnaire Measure N Baseline 12 Week Difference p-value Score Pain VAS Upper UpperGI 13 5.08 ±0.69 2.62 ±0.95 2.46 ±1.33 p = 0.088 Group pain Lower GI 24 4.23 ±0.54 1.97 ±0.42 2.25 ±0.59 p = 0.001 pain Other pain 24 5.08 ±0.39 2.49 ±0.43 2.59 ±0.64 p<0.001

Figure 29: Pain Severity (Upper GI Symptoms)

The data for this aspect of the study are represented graphically in Fig 29 of the accompanying drawings.

Summary: • Participants who experienced upper GI symptoms demonstrated a significant reduction in upper abdominal, lower abdominal and other pain following treatment with the Medication in the study.

Lower GI Symptoms Group (n=42):

Table 31: Pain VAS: Baseline vs Control (run-in-phase) The data for this aspect of the study are set out in Table 31 (below).

Table 31

Questionnaire Measure N Control Baseline Difference p-value Mean ± SE Mean ± SE Mean ± SE Pain VAS UpperGI 12 6.71 ±0.62 5.08 ±0.75 1.73 ±0.74 p = 0.64 lowergroup Pain Lower GI 30 4.71 ±0.35 4.38 ±0.49 0.33 ±0.49 p = 0.50 pain Other Pain 31 4.72 ± 0.36 4.75 ± 0.39 0.03 ± 0.47 p = 0.95

Table 32: Pain VAS: Baseline vs 12 weeks after the Medication

The data for this aspect of the study are set out in Table 32 (below).

Table 32

Questionnaire Measure N Baseline 12 weeks Difference p-value Mean ± SE Mean ± SE Mean ± SE Pain VAS UpperGi 12 5.08 ±0.75 2.25 ±0.95 1.80 ±0.79 p = 0.065# Lowergroup Pain Lower GI 30 4.38 ±0.49 1.58 ±0.36 2.80 ±0.56 p < 0.001* pain Other Pain 31 4.75 ±0.39 2.81 ±0.43 1.93 ±0.63 p = 0.00 4

* Legend to Table 32:

* = Statistical significance # Upper pain: borderline significant difference between baseline and 12 weeks (0.065), likely due to small numbers (n=12).

Figure 30: Pain Severity (Lower GI Symptom Group)

The data for this aspect of the study are represented graphically in Fig 30 of the accompanying drawings.

In Summary:

• Participants experiencing lower GI symptoms demonstrated a significant reduction in upper abdominal, lower abdominal and other pain following treatment with the medication during the study.

• There were no significant reductions in pain severity between the control and baseline between any of the measures.

Other Symptoms (n=43) relevant to gastrointestinal disturbances

The data for certain other symptoms relevant to gastrointestinal disturbances experienced by the participants during the study are set out in Table 33, which appears at Fig 31 of the accompanying drawings.

Figure 20: Change in Other Symptoms - Medical Treatment Trial

The data for this aspect of the study are represented graphically in Fig 32 of the accompanying drawings.

As indicated in Fig 32:

* Statistical analysis methodologies applied: Chi-Square analysis and Fisher's Exact Test with two-tailed p-values using www.graphpad.com;and

* p<0.05

In Summary:

• The Medication generally reduced the incidence of other GI-related symptoms, such as mouth ulcers, bad breath and rashes, with a significant lesser number of participants feeling constantly tired, or nervous (p<0.05).

Intestinal Permeability - Leaky Gut Report

Table 34: Leaky Gut - Intestinal Permeability Test (urine) - Baseline Test

Table 34

Participants (n) Mean (SD) Range Comment

Lactulose 43 1.31 (0.67) % Normal: 0 - All above Recovery 0.3% normal range

Mannitol 43 35.04 (13.3) % Normal: 9.5- N=8 (18.6%) in Recovery 25% normal range

N=35 (81.4%) above normal range

Lactulose/Mannitol 43 0.040 (0.02) Normal: 0-0.035 N=21 (48.8%) in

Ratio (LMR) normal range

N= 22 (51.2%) above normal range

Leaky Gut: Baseline - summary:

• All participants (n=43) had intestinal permeability or • About 80% (n=35) had intestinal hyperpermeability (high Lactulose and Mannitol • About half of the participants had an elevated Lactulose/Mannitol Ratio which suggests size of the gut mucosa has increased, allowing larger, possibly antigenic molecules to enter the blood

Table 35: Leaky Gut Baseline (v1), 12 weeks (v5) and change

The data for this aspect of the study are set out in Table 35 (below).

Table 35

Descriptive Statistics N Minimum Maximum Mean Std. Deviation viLactuloseRecovery 42 .41 3.34 1.3288 .67106 vi Mannitol Recovery 42 12.51 77.59 34.9674 13.41417 vi LM ratio 42 .012 .111 .04114 .022725 v5 Lactulose Recovery 42 .22 1.57 .5869 .36022 v5 MannitolRecovery 42 13.00 41.92 26.1179 7.46940 v5 LM ratio 42 .011 .054 .02202 .010522 v51_Lactulose change 42 -3.11 .82 -.7419 .73055 v51 Mannitol change 42 -43.41 16.49 -8.8495 13.16274 v51_LMratio-change 42 -.08 .01 -.0191 .02306

Legend to Table 35:

Normal ranges:

Lactulose Recovery: 0-0.3 % - the lower the lactulose recovery, the better

Mannitol Recovery: 9.5-25%

LM ratio: 0-0.035 - the lower the LM Ratio the better.

N=42 (Note: One participant did not perform the test at the end of study; n=31 lower symptoms)

Analysis:

• Lactulose Recovery: mean (v1->v5)= 1.33 %(above normal range)-> 0.59

% (slightly above normal)

• v51 mean change - 0.74 % (more than 50% change to the better)

• Mannitol Recovery: mean (vl->v5) = 35% (above normal range) -> 26.1

% (slightly above normal)

• v51 mean change - 8.8 %, change to the better, improvement

• LM ratio: mean (vl->v5) = 0.04 (above normal range) -> 0.22 % (within normal)

• v51 mean change - 0.02, change to the better, improvement

Figure 33: lactulose recovery data

The data for this aspect of the study are represented graphically in Fig 33 of the accompanying drawings.

As indicated in Fig 33, the data shown were analysed using the Chi-square test: P= 0.0258.

In Summary:

• Lactose recovery - all above normal at V1.

e v5 result: 6/42 (14%) achieved normal levels after Medical treatment

[The next page is page No 55].

Figures 34 and 35: Individual Lactulose levels & percentage change over time

The data for this aspect of the study are represented graphically in Fig 34 and Fig 35 of the accompanying drawings.

[The next page is page No 56].

Figure 36: Mannitol Recovery

The data for this aspect of the study are represented graphically in Fig 36 of the accompanying drawings.

The following observations are made about the data:

• *Statistical analysis was performed via the Chi-square test: P= 0.0046; • V1: N=7 (16%) within normal range -> v5: n=20 (48%, half) within normal range after treatment with the Medication; • N=35 (84%) above normal range -> v5: n=22 (42%) above the normal range; • Comparison of the number of participants above the normal range at v1 vs v5 by Chi-square Test; and • There was a significantly larger number of participants in the normal range for Mannitol Recovery after the treatment with the Medication than before (p = 0.003), indicating healing of leaky gut and a healthier gut membrane after the treatment.

Figure 37: Individual Mannitol Levels & Percentage Change Over Time

The data for this aspect of the study are represented graphically in Fig 37 of the accompanying drawings.

Lactulose-Mannitol ("LM") Ratio

With reference to Fig 38, the following observations are made concerning the data gathered from this aspect of the study:

SV1: normal n=21 (50%), above range n=21 (50%);

• V5: normal n=36 (86%), above n=6 (14%);

SV1 -> v5 normal 50-86%, 36% improved to normal.

[The next page is page No 57].

Summary of individual changes in the LM Ratio:

p The LM ratio improved for all but one participant, with high LM levels (above normal range, group 2, n=21) at baseline.

• The one participant in group 2 with an increase in LM ratio chose to have no medical treatment (Og) in month 3.; and

• All participants with LM ratios in the normal range at baseline (group 1) remained in this category;

• Chi-square Test: P= 0.0009.

[The next page is page No 58].

Figure 39: Individual LM Ratio percentage change 0-12 weeks by Group LM ratio

The data for this aspect of the study are represented graphically in Fig 39 of the accompanying drawings.

Comparison of means for Leaky Gut Studies - paired t-Test

The comparisons are set out in Table 35A (below).

Table 35A

Paired Samples Statistics Mean N Std. Deviation Std. Error Mean v1_LactuloseRecovery 1.3288 42 .67106 .10355 v5 Lactulose Recovery .5869 42 .36022 .05558 v1_Mannitol Recovery 34.9674 42 13.41417 2.06985 v5 Mannitol Recovery 26.1179 42 7.46940 1.15255 v1 LM ratio .04114 42 .022725 .003507 v5 LM ratio .02202 42 .010522 .001624

Table 36 (below) sets out data for certain Leaky Gut studies, showing the changes observed after medical treatment.

Table 36: Leaky Gut: Baseline vs 12 weeks - Change after medical treatment

excl n=2 (Og/day dosage)

Measure N Baseline Mean 12 Weeks Difference % change p-value Lactulose 40 1.33 ±0.11 0.55 ±0.05 0.78 0.11 59% p < 0.001 Recover Mannitol 40 35.4 ±2.14 26.0 ±1.17 9.43 2.0 27% p<0.001 Recovery LM Ratio 40 0.04 0.004 0.03 0.001 0.02 0.004 50% p <0.001

By dose Dose/day Measure N Baseline 12 Weeks Difference % change p-value Mean ± SE Mean ± SE Mean ± SE 5g Lactulose 13 1.27 ±0.16 0.54 ±0.28 0.72 ±0.16 57% p = 0.001 Recovery log 27 1.37 ±0.14 0.56 ±0.07 0.81 ±0.15 59% p <0.001 5g Mannitol 13 37.8 ±4.93 27.4 ±2.14 10.39 4.45 28% p=0.038 Recovery log 27 34.3 ±2.15 25.3 ±1.40 8.97 2.18 26% p <0.001 5g LM Ratio 13 0.04 ±0.007 0.02 ±0.002 0.02 ±0.007 50% p=0.02 log 27 0.04 ±0.004 0.02 ±0.002 0.02 ±0.004 50% p <0.001

By PPI PPI yes/no Measure N Baseline 12 Weeks Difference % change p-value Mean±SE Mean±SE Mean±SE PPI use Lactulose 11 1.21 ±0.16 0.56 ±0.11 0.65 ±0.19 54% p = 0.007 Recovery

PPIuse Mannitol 11 34.7 ±3.38 26.8 ±1.84 7.95 ±3.47 23% p = 0.045 Recovery

PPI use LM Ratio 11 0.04 ±0.005 0.02 ±0.004 0.02 ±0.005 50% p=0.007

Notes: Normal ranges: Lactulose Recovery: 0-0.3 %; Mannitol Recovery: 9.5-25%; LM ratio: 0-0.035

PPi = Proton Pump inhibitor

In Summary:

) The Medication significantly improved intestinal permeability, including Lactulose by 59%, Mannitol Recovery by 27%, and Lactulose/Mannitol Ratio by 50% (p<0.001).

• The dosage of the Medication did not change the outcome appreciably.

• Individuals on PPIs had a slightly smaller but still significantly positive improvement in intestinal permeability, including Lactulose Recovery by 54%, Mannitol Recovery by 23%, and Lactulose/Mannitol Ratio by 50%.

[The next page is page No 60].

Figures 40 (a) - (b): Leaky Gut by Dosage - Individual Graphs Lactulose Recovery by Dosage

The data for this aspect of the study are represented graphically in Fig 40 (a) and (b) of the accompanying drawings.

Figures 41 (a) - (b): Mannitol Recovery by Dosage

The data for this aspect of the study are represented graphically in Figs 41 (a) and (b) of the accompanying drawings.

Figures 42 (a) - (b): LMratio by dosage - Individual Graphs

The data for this aspect of the study are represented graphically in Figs 42 (a) and (b) of the accompanying drawings.

Figures 43 (a) - (c): Leaky Gut by PPI Intake - Individual Graphs

The data for this aspect of the study are represented graphically in Fig 43 (a) to (c) of the accompanying drawings.

Figures 44 and 45 - Leaky Gut Change by BASELINE Stool Consistency

The data for this aspect of the study are represented graphically in Fig 44 and 45 of the accompanying drawings.

In Summary: Percentage change within group:

The Medication significantly improved Lactulose Recovery for 33% of participants with normal stools, and 14% of participants with hard stool/constipation-type (p=0.0001), while there was no change in the group with soft stool / diarrhea-type. Lactulose Recovery remained above the reference range for leaky gut for all participants with soft stools.

[The next page is page No 61].

Figures 46 and 47 - Mannitol recovery change by stool consistency

The data for this aspect of the study are represented graphically in Fig 46 and Fig 47 of the accompanying drawings.

In Summary:

• The Medication significantly improved Mannitol Recovery for 45% of participants with normal stools, and 43% of participants with hard stools/constipation-type (p=0.0001), while there was no change in the group with soft stool/ diarrhea-type; and

SA third of participants (33%) with soft stool had Mannitol Recovery values within the normal range at baseline and at 12 weeks.

Figures 48 and 49 - LM Ratio change by stool consistency

The data for this aspect of the study are represented graphically in Fig 48 and Fig 49 of the accompanying drawings.

In Summary:

• The Medication significantly improved Lactulose/Mannitol Ratio for 44% of participants with normal stool, and 33% of participants with soft stool/ diarrhea-type, and 33% of participants with hard stool/constipation-type (all groups: p=0.0001);

All participants (100%) with normal stool, 90% with hard stool, and 66% with soft stool had normal LM Ratio levels, indicating a recovery from leaky gut, after taking the Medication for 3 months.

Cytokine Report - Inflammatory Marker Levels

Some key parameters for this aspect of the study were:

Total participants analysed: N=43

Time points: v1 = between enrolment and baseline; v4 = between 8 and 12 weeks (end of study)

Method of Analysis: Within-subject comparison of Cytokine levels measured by repeated measure t-test.

The data for this aspect of the study are set out in Table 37, which appears in Fig 50 of the accompanying drawings, and in Fig 51.

Summary of some observations from the results of this aspect of the study:

• Inflammatory marker levels in all participants were within or close to normal range.

• No significant changes in IL1P, IL6, and TNFa were observed.

> Interleukin 1b change: small reduction - 0.0674 - all (v1 and v4) within normal range

> IL6 change: small reduction -0.0140 - all (v1 and v4) within normal range

> TNFa: v1 & v4 very similar - only slight increase, only slightly above range of 14 (highest 17); V1 n=3 above range -> 2/3 stayed above range, 1 reduced, 1 increased, 4 different people above range.

• Further investigations into the slightly larger but not significant changes in IL8 revealed several confounding factors. The exclusion of n=6 participants with elevated IL8 levels revealed a smaller non-significant change in IL8 levels.

IL8 (interleukin 8) Level measurements (Excluding n=6 (change increase to >40 pg/mi, above range))

Some observations from the results of this aspect of the study:

1) ID 50 v41 change = 85.20, v4 = 94: had vertigo at time of blood draw (possibly due to a viral influence); IL 8 is implicated in viral infections (Bosch, I et al, J Virol. 2002 Jun; 76 (11):5588-97);

2) ID 26: v41_change = 68.20, started body building training during trial, IL8 increase implicated after exercise

(Frydelund-Larsen L, Penkowa M, Akerstrom T, Zankari A, Nielsen S, et al. (2007). "Exercise induces interleukin-8 receptor (CXCR2) expression in human skeletal muscle", Experimental Physiology Vol. 92, No. 1 (January 2007), pp. 233-40.);

3) ID 21: v41_lL8_change = 47.30, taken PPI proton pump inhibitors before blood test, PPI increase IL8 production from gastric cells (Handa, 0 et al, /nflamm Res. 2006 Nov; 55 (11):476-80);

4) ID 24: v41_lL8_change = 46.90, started food trigger challenges during trial, had a bad flare up for 4 days prior to blood test;

5) ID 22: v41_lL8_change = 44.00, had a UTI infection the month before blood test, just stopped antibiotics, IL8 early marker for bacterial infection (Hirao, Y et al., "Interleukin 8 - An early marker for bacterial infection", Laboratory Medicine, Volume 31, Issue 1, January 2000, Pages 39-44);

6) ID 2: v41-IL8_change = 43.50, had angular chelates (mouth edge sores), IL8 increase implicated in inflammatory skin conditions, such as psoriasis (Kondo S et al, "L-8 gene expression and production in human keratinocytes and their modulation by UVB" JInvest Dermatol. 1993 Nov; 101 (5):690-4).

Table 38 - Cytokine Analysis by Group (Upper / Lower GI Symptoms)

The data for this aspect of the study are set out in Table 38, which appears in Fig 52 of the accompanying drawings.

Summary:

• Cytokine analysis by group (upper/lower symptoms) and by dosage (results not shown) (Og, 5g, 1Og) did not reveal any significant differences between the groups.

• Other than IL8 changes (due to complicating factors), no meaningful changes were observed.

• Normal acute fluctuations of inflammatory markers were expected.

• The Medication does not influence inflammatory markers (in either direction), meaning it is safe because it doesn't cause inflammation.

Microbial Analysis Report (all n = 37)

The data for this aspect of the study are set out in Tables 39 (a) and (b) and Tables 40 (a) and (b) (below), which set out the Relative Abundance CFU/g (colony-forming units per gram) - change over baseline to 12 weeks (v4- v1):

Tables 39 (a) - (b)

Bacteroidetes Phylum N Mean Std. Deviation

v41_Bac1_change 37 280189189.2 807513393.0

Bacterioides-Prevotella group

v41_Bac2_change 37 494270270.3 4972303343.0 Bacterioides vulgatus

v41_Bac3_change 37 60978378.38 147075778.2

Barnesiella spp

v41_Bac4_change 37 23502702.7 80202055.55 Odoribacter spp

v41_Bac5_change 37 1209189.189 8244917.08

Prevotella spp

V41_sumBac-change 37 860149729.7 5455944081.0

Total Bacterioidetes phylum

Firmicutes Phylum N Mean Std. Deviation

v41Firm1_change 37 1646486.486 12721424.67

Anaerotruncuscolihominis

v41_Firm2_change 37 139027.020 518990.4054

Butyrivibrio crossotus

v41_Firm3_change 37 947378378.4 4520966940.0

Clostridium spp

v41_Firm4_change 37 4816216.216 20765675.92

Coprococcus eutactus

v41_Firm5_change 37 816972973.0 3563494559.0 Faecalibacterium prausnitzii

v41_Firm6_change 37 215405405.4000 1827978672.0

Lactobacillus spp

v41_Firm7_change 37 54078378.380 158809612.0

Pseudoflavonifractor spp

v41_Firm8_change 37 505702702.700 1714215546.0

Roseburia spp v41_Firm9_change 37 5632432.432 76946348.75

Ruminococcusspp

v41_Firm1Ochange 37 4586216.216 14449033.1

Veillonella spp

v41_sumFirm-change Total 37 2556358216.0 9362021650.C

Firmicute phylum

Tables 40 (a) - (c)

ActinobacteriaPhylum N Mean Std. Deviation

v41_Actinolchange 37 -74324324.320 763879755.4

Bifidobacterium spp

v41_Actino2_change 37 -2789189.1890 69444677.36 Bifidlobacteriumnlongumn

v41_Actino3_change 37 106378378.4000 436467216.0 Collinsella aerofaciens

v41_sumActinochange 37 29264864.86 1140080357.0

Total Actinobacteria phylum

Proteobacteria Phylum N Mean Std. Deviation

v41_Proteol-change 37 1966378.378 12664416.41 Desulfovibrio piger

v41_Proteo2_change 37 3333243.243 58902755.03 Escherichia coi

v41_Proteo3_change 37 812972.973 13448609.98 Oxalobacter formigenes

v41_sumProteo_change 37 6112594.595 70628367.26

Total Proteobacteria phylum

Euryarchaeota, Fusabacteria, Verrucomicrobia Phylum N Mean Std. Deviation

v41_methanobrevichange 37 6937567.568 59543865.22 Methanobrevibacter smithil

v41_Fusobac-change 37 22524.3243 47322.842 Fusobacterium spp

v41_Akkermansiachange 37 1119459.459 6976722.386

Akkermansiamuciniphila

Figure 53: Change in microbial profile after 12 week program with the Medication (n=37)

The data for this aspect of the study are represented graphically in Fig 53 of the accompanying drawings.

Summary - Microbiota Changes (n=37):

• Mean Bacteriodetes, Firmicutes and Proteobacteria bacterial mass (RA) increased over time.

• Mean Bifidobacteria bacterial mass (relative abundance) decreased over time.

• Bifidobacteria and Lactobacilli are standard probiotics. In this study, participants were asked to stop their probiotic intake before the commencement of treatment (so as to take the Medication) one month after the baseline stool test.

Observations on the results depicted in Fig 53:

Bacterioides vulgatus:

• Unlike other colonic Bacteroides species, B. vulgatus is not a versatile utilizer of polysaccharides. The only types of polysaccharide that support rapid growth and high growth yields by all strains are the starches amylose and amylopectin.

• B.vulgatus is the only sequenced Bacteroidetes species that possesses a gene coding for a xylanase. It has the largest and most complete set of enzymes that target pectin.

http://bacmap.wishartlab.com/organisms/533

• Pectin is included in the Medication.

Clostridium spp:

• While Clostridium spp have a bad reputation (e.g. Clostridium difficile, Clostridium botulism), not all Clostridia bacteria are detrimental to gut health.

• The study by Stefka et al (2014) in mice, found that a common gut bacteria called Clostridia helps prevent sensitization to food allergens. In fact, immune responses to food allergens were reversed once Clostridia bacteria were put back into the mice.

• Another common type of gut bacterium, Bacteroides, did not have this effect, suggesting Clostridia may have a unique role in this regard.

S The study found, that Clostridia colonization activates innate immune genes in intestinal epithelial cells.

Reference: Stefka, Andrew T., et al. "Commensal bacteria protect against food allergen sensitization." Proceedings of the National Academy of Sciences 111.36 (2014): 13145-13150.

Faecalibacterium prausnitzii:

• Faecalibacterium prausnitzii might have been influenced by the fibre-rich cellulose in the placebo capsules. Cellulose, generally regarded as inert, may have been food for growth for bacterial species thriving on dietary fibre, such as the Firmicute Butyrivibria crossus.

References:

Chung WSF, Walker AW, Louis P, Parkhill J, Vermeiren J, Bosscher D, et al. Modulation of the human gut microbiota by dietary fibres occurs at the species level. BMC Biology 2016;14:3; and

Flint HJ, Scott KP, Duncan SH, Louis P, Forano E. Microbialdegradation of complex carbohydrates in the gut. Gut Microbes 2012;3:289-306

Lactobacillus spp:

• Lactobacillus bacteria, increased by the prebiotic aged garlic extract, are generally regarded as beneficial.

Reference: Slavin J. Fiber and prebiotics: mechanisms and health benefits. Nutrients 2013; 5:1417-35.

Roseburia spp:

• The genus Roseburia consists of obligate Gram-positive anaerobic bacteria that are slightly curved, rod-shaped and motile by means of multiple subterminal flagellae. It includes five species: Roseburia intestinalis, R. hominis, R. inulinivorans, R. faecis and R. cecicola.

Gut Roseburia spp. metabolize dietary components that stimulate their proliferation and metabolic activities. They are part of commensal bacteria producing short-chain fatty acids, especially butyrates, affecting colonic motility, immunity maintenance and anti-inflammatory properties.

References:

https://www.ncbi.nlm.nih.gov/pubmed/28139139Tamanai-Shacoori Z et al.

Roseburia spp.: a marker of health? Future Microbiol. 2017 Feb;12:157-170. doi: 10.2217/fmb-2016-0130.

[The next page is page No 70].

Subgroup Analysis: Microbial change in participants by reference to whether a probiotic was previously taken

Figure 54 of the accompanying drawings depicts the results of a test to determine the gut flora profiles of participants from the Baseline Stool test performed before treatment with the Medication commenced. In the results shown, 19 of the participants had previously taken a probiotic, and 11 participants had not.

Summary - Probiotics:

• Orange (Firm6 = Lactobacilli) + dark grey+black (Actinol+2 = Bifidobacteria)

• Seem to increase in group previously taking probiotics

• Slight decrease in group not having previously taken probiotics

• Conclusion: The Medication promotes the growth of existing beneficial bacteria introduced through previous intake of probiotics.

[The next page is Page No 71].

Figure 55: Microbial change by Dosage at 12 weeks (end of study)

The data for this aspect of the study are represented graphically in Fig 55 of the accompanying drawings.

Main change in 5g subgroup (n=13):

Green: Bac2 - Bacterioides vulgatus - increase in CFU/g (not in 10g group) Grey: Firm3 - Clostridium spp - increase Dark green: Firm5 - Faecalibacillus prausnitzii - increase Orange: Firm6 - Lactobacillus spp - increase (not in 10g group) Light blue: Fusobac - Fusobacterium spp - increase (not in 10g group)

Main change in 10g subgroup (n=28):

Grey: Firm3 - Clostridium spp - increase (less than 5g group) Dark green: Firm5 - Faecalibacillus prausnitzii- increase (less than 5g group) GreyBlue: Firm8 = Roseburia - increase (not in 5g group)

Conclusions about the impact of the dose of the Medication on promotion of gut flora growth

The optimum result appears to have been achieved by using the 5g/day dose.

More growth across a larger variety of species was observed at that dosage level, than at the other two levels tested.

Comparison in Gut Flora Profiles - Group-upper symptoms (reflux, upper abdominal pain, stomach) vs group-lower symptoms (lower abdominal symptoms, IBS).

Figure 56: Change in Flora Profile in Group Upper

The data for this aspect of the study are represented graphically and in tabular form in Fig 56 of the accompanying drawings.

Summary by Group (Upper vs Lower GI):

• Three-quarters (77%; n=20/26) of the participants with upper & lower symptoms chose to take 1Og of the Medication.

SA third (36%, n=4/11) of the participants with only lower symptoms chose to take 1Og of the Medication, half (45%) chose 5g, and n=2 (20%) chose Og.

Conclusions:

A dosage of 1Og/day of the Medication would appear to be more beneficial for upper GI symptoms, while 5g of the Medication appears to be sufficient to benefit lower GI symptoms.

Figure 57: Microbial Profile at Baseline by Consistency of Stool (Hard/Soft/Normal)

The data for this aspect of the study are represented graphically in Fig 57 of the accompanying drawings.

Figure 58: Microbial Change 0-12 Weeks by Stool Consistency at Baseline

The data for this aspect of the study are represented graphically in Fig 58 of the accompanyingdrawings.

Summary:

• The Microbial profile was similar at baseline across all 3 groups of stool consistency.

Microbial change over time

Summary:

• While the Medication generally improved microbial profile by increasing relative abundance/bacterial number in participants with normal or hard stool consistency, bacterial number decreased over time in those participants experiencing soft/diarrhea-type stools.

• One possible explanation for this result is that in the group with soft stool, due to the shorter transit time of food and the medication, bacteria have less time to feed and grow/multiply.

• There is a marked difference specifically in the following groups of bacterial species:

[The next page is page No 73].

Figures 59 (a) - (b): Microbial Change by Stool Consistency & whether a Participant took a PPI Medicine

The data for this aspect of the study are represented graphically in Fig 59 (a) and (b) of the accompanying drawings.

Summary:

• PPI use appears to influence bacterial growth.

• While the Medication generally improved microbial profile by increasing rekative abundance/bacterial number in participants not taking PPIs (group no PPI, n=32), bacterial number decreased over time in the group on PPI (n=11).

Overall conclusions

These data strongly support the conclusion that the Medication has a number of beneficial effects in subjects who are afflicted with any one or more of a broad variety of gastrointestinal problems, including those of idiopathic origin (such as Irritable Bowel Syndrome). The Medication can therefore be used to treat many such symptoms, and a broad array of gastrointestinal conditions.

[The next page is page No 74].

Interpretation of this specification

It will therefore be understood that the invention could take many forms and be put to many different uses. All such forms and uses are embodied within the spirit and scope of the invention, which is to be understood as not being limited to the particular details of the embodiments discussed above, but which extends to each novel feature and combination of features disclosed in or evident from this specification. All of these different combinations constitute various alternative embodiments of the invention.

It will also be understood that the term "comprises" (or its grammatical variants), wherever used in this specification, is equivalent in meaning to the term "includes" and should not be taken as excluding the presence of other elements or features. Further, wherever used in this specification, the term "includes" is not a term of limitation, and is not be taken as excluding the presence of other elements or features.

It is further to be understood that any discussion in this specification of background or prior art documents, devices, acts, information, knowledge or use ('Background Information') is included solely to explain the context of the invention. Any discussion of any such Background Information is therefore not be taken as an admission in any jurisdiction that any such Background Information constitutes prior art, part of the prior art base or the common general knowledge in the field of the invention on or before the earliest priority date or any priority date which the present application claims.

It is also to be understood that wherever in this specification, reference is made to any external document or recorded source of information, then the entire content of that document or the information contained in the recorded source of information is expressly incorporated by reference into this specification verbatim, as if that information was specifically set out in it.

Claims (1)

1. THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:

   1. A method of increasing the concentration of one or more beneficial bacterial species in the gastrointestinal tract of an animal subject afflicted by a functional or biochemical gastrointestinal disorder, the method comprising the step of administering to the patient, a pharmaceutical substance that comprises an effective dose of one or more of the following therapeutically active ingredients:

   (a) Curcumin;

   (b) L-Glutamine;

   .0 (c) Quercetin;

   (d) Glucosamine;bifo

   (e) Aloe vera;

   (f) an edible essential oil;

   (g) powder derived from the inner bark of Slippery Elm (Ulmus rubra);

   .5 (h) Guar Gum; and

   (i) Pectin.

   2. A method as claimed in claim 1, in which the functional or biochemical gastrointestinal disorder is:

   (a) a functional gastrointestinal disorder of the kind defined in the Rome IV Classification as published in 2016; or

   (b) a biochemical gastrointestinal disorder.

   3. A method as claimed in either of claim 1 or claim 2, in which the functional or biochemical gastrointestinal disorder is a disorder of either:

   (a) an upper or

   (b) a lower region of the gastrointestinal tract.

   4. A method as claimed in claim 3, in which the disorder is a functional gastrointestinal disorder.

   5. A method as claimed in claim 4, in which the functional gastrointestinal disorder is one of the following:

   (a) an esophageal disorder;

   (b) a gastroduodenal disorder;

   (c) a bowel disorder;

   (d) a centrally mediated disorder of gastrointestinal pain;

   .0 (e) a childhood functional gastrointestinal disorder;

   (f) a functional gastrointestinal disorders affecting a subject that is either a child or an adolescent;

   (g) an anorectal disorder;

   (h) a functional abdominal pain disorder;

   .5 (i) a gallbladder disorder; and

   (j) a Sphincter of Oddi disorder.

   6. A method as claimed in either of claim 3 or claim 4, in which the method is used to treat one or more of the following conditions or symptoms in the animal subject:

   (a) Reflux hypersensitivity;

   (b) Irritable Bowel Syndrome;

   (c) Functional; dyspepsia;

   (d) Gastro Esophageal Reflux Disorder ("GERD");

   (e) Belching, nausea and vomiting disorders;

   (f) Functional chest pain and heartburn;

   (g) Functional constipation;

   (H) Functional diarrhea;

   (I) Functional abdominal bloating/distension;

   (J) Centrally mediated abdominal pain syndrome;

   (K) Faecal incontinence;

   (L) Infant Colic;

   (M) Enteritis (inflammation of the small intestine);

   (N) Gastritis (inflammation of the lining of the stomach); and

   .0 (0) Leaky Gut Syndrome.

   7. A method as claimed in claim 3, in which the disorder is a biochemical gastrointestinal disorder.

   8. A method as claimed in claim 7, in which the biochemical gastrointestinal disorder comprises:

   .5 (a) intolerance to one or more specific substances contained in food; or

   (b) intolerance to one or more orally administered medications.

   9. A method as claimed in claim 8, in which the intolerance is one to:

   (a) lactose intolerance; or

   (b) an orally ingested allergen.

   10. A method as claimed in any one of the preceding claims, in which the method is used to treat any one or more of the following symptoms in the animal subject:

   (a) chest pain;

   (b) heartburn;

   (c) reflux or reflux hypersensitivity;

   (d) indigestion or impaired digestion;

   (e) bloating;

   (f) abdominal distension;

   (g) belching;

   (h)nausea;

   (i) vomiting;

   (j) flatulence;

   (k) constipation;

   (I) diarrhea;

   .0 (m) fecal incontinence;

   (n) urgent need to defecate; or

   (o) abdominal discomfort or pain.

   15. A method as claimed in any one of claims 1 to 14, in which the method comprises the additional step of co-administering a probiotic substance or .5 formulation to the animal subject.

   16. A method as claimed in claim 15, in which the step of co-administering the probiotic substance or formulation to the animal subject is commenced prior to the administration of the pharmaceutical substance or formulation of claim 1.

   17. A method as claimed in claim 15, in which the step of co-administering the probiotic substance or formulation to the animal subject occurs concomitantly with or during at least a part of the time when a pharmaceutical substance or formulation of claim 1 is administered to the animal subject.

   18. A method as claimed in claim 15, in which the step of co-administering the probiotic substance or formulation to the animal subject is commenced after commencing the administration of a pharmaceutical substance or formulation of claim 1 to the animal subject.

   19. A method as claimed in any one of claims 15 to 18, in which the probiotic substance or formulation comprises one or more bacterial species selected from the Bacteroides genus and/or the phylum Firmicutes.

   20. A method as claimed in any one of claims 15 to 18, in which the probiotic substance or formulation comprises one or more bacterial species from the genus Bifidibacterium.

   21. A method as claimed in any one of claims 15 to 18, in which the probiotic substance or formulation comprises one or more bacterial species from the genus Lactobacillus.

   .o 22. A method as claimed in any one of the preceding claims, in which the pharmaceutical substance of claim 1 additionally comprises Sodium Diphosphate.

   23. A method as claimed in any one of the preceding claims, in which the pharmaceutical substance of claim 1 comprises, in combination, all of the .s therapeutically active ingredients (a) to (i) of claim 1.

   24. A method as claimed in claim 23, in which the method comprises administering to the animal subject, a medicament in which all of the therapeutically active ingredients (a) to (j) of claim 1 are present in about the following amounts per (or in each) kilogram of the finished medicament:

   (a) Curcumin - 1.276 g;

   (b) L-Glutamine - 500 g;

   (c) Quercetin - 40 g;

   (d) Glucosamine Hydrochloride - 83.01 g

   (e) Aloe vera fresh leaf - 100 g;

   (f) Peppermint oil - 600 mg;

   (g) Slippery Elm inner bark powder - 100 g;

   (h) Guar Gum - 20 g;

   (i) Pectin - 20 g; as well as:

   (k) Sodium Diphosphate (Dibasic Sodium Phosphate) - 52 g.

   25. A method as claimed claim 24, in which the medicament is administered orally to the animal subject.

   26. A method as claimed in claim 25, in which the medicament is in the form of an edible powder.

   27. A method as claimed in claim 26, in which the edible powder is:

   (a) dissolved in a solvent so as to produce a beverage;

   .0 (b) incorporated in a food substance,

   for ingestion by the animal subject.

   28. A method as claimed in either of Claims 25 or 26, in which the medicament is comprised within an edible:

   (a) tablet; .5 (b) chewable tablet;

   (c) gel;

   (d) capsule; or

   (e) caplet.

   29. A method as claimed in any one of claims 25 to 28, in which the animal subject is a human, and the medicament is administered in one or more doses of up to 5 grams per dose.

   30. A method as claimed in claim 29, in which the maximum dose of the medicament administered to the animal subject in any period of 24 hours is 15 grams.

   31. A method as claimed in any one of the preceding claims, in which the animal subject is:

   (a) a mammal;

   (b) a bird;

   (c) a fish;

   (d) a reptile; or

   (e) an amphibian.

   32. A method as claimed in claim 31, in which the animal subject is a mammal.

   33. A method as claimed in claim 32, in which the mammal is a human.

   .o 34. A method as claimed in either of claim 31 or claim 32, in which the animal subject is:

   (a) a mammal other than a human;

   (b) a bird;

   (c) a fish;

   .5 (d) a reptile; or

   (e) an amphibian.

   35. A pharmaceutical substance or formulation when used in a method as claimed in any one of clams 1 to 34, the pharmaceutical substance or formulation comprising, in combination, all of the therapeutically active ingredients (a) to (i) of claim 1, in further combination with one or more pharmaceutically acceptable formulation ingredients.

   36. A pharmaceutical substance or formulation as claimed in claim 35, in which the one or more pharmaceutically acceptable formulation ingredients are selected from the group comprising carriers, gelling agents, stabilizers, solvents, excipients, solubilisers, binders, buffers, preservatives, emulsification agents, bulking agents, lubricants, suspending agents, disintegrating agents, flavours, sweeteners, antioxidants, isotonic agents, and combinations thereof.

   Dated: 11 December 2019

   Nutrition Care Pharmaceuticals Pty Ltd (Australian Company Number 613 457 293)

   Ausnutria Dairy (China) Co., Ltd

   By their Patent Attorneys o KNIGHTSBRIDGE PATENT ATTORNEYS