Veterinary non-antibiotic antimicrobial compositions

Abstract

A veterinary composition comprising a therapeutically effective amount of a zeolite and at least one member of the Lactobacilli genus, and at least one veterinary acceptable excipient is provided. The

Description

[1] The present invention relates to a veterinary non-antibiotic composition, new uses and methods of medical treatment or prophylaxis. In particular the present invention relates to a veterinary non-antibiotic antimicrobial composition. More in particular, the present invention relates to a veterinary non-antibiotic antimicrobial composition comprising a zeolite and at least one member of the Lactobacilli genus for the treatment or prophylaxis of a disease or a condition associated with or caused by Helicobacter spp such as Helicobacter pylori. INTRODUCTION [2] Infectious diseases including bacterial infections continue to be a serious veterinary health problem worldwide. The Gram negative (-ve) microorganism Helicobacter pylori was first cultivated in 1982 and since then it has become apparent that many related species can often be found in animals. These Helicobacter species (Helicobacter spp) are generally classified according to their ability to invade and colonise gastric or enterohepatic tissues or animals. Colonisation of gastric mucosa appears to be most prevalent in the surface mucus layer and within the gastric glands and parietal cells. [31 Gastric Helicobacter spp are widely distributed in mammalian hosts and are many cases could cause an inflammatory response. Similarly, enterohepatic Helicobacter spp are also a diverse group of microorganisms which can be found in the intestinal tract and the liver of mammals and birds. They are frequently linked with inflammation or malignant transformation in immunocompetent hosts and with more severe clinical disease in immunocompromised or otherwise stressed animals. |41 The primary disorder, which occurs after animal colonisation with H. pylori, is chronic active gastritis. This condition can be observed in all H. pylori-positive animals. The intragastric distribution and severity of this chronic inflammatory process depend on a variety of factors, such as characteristics of the colonizing strain, host genetics and immune response, diet, and the level of acid production. H. pylori-mduceA ulcer disease, gastric cancer, and lymphoma are all complications of this chronic inflammation; ulcer disease and gastric cancer in particular occur in those animals and at those sites with die most severe inflammation (Kusters, Johannes G et al, “Pathogenesis of Helicobacter pylori infection.” Clinical microbiology reviews vol. 19,3 (2006): 449-90. doi:10.1128 / CMR.00054-05). |5| More than 100% of healthy dogs, cats and pigs are positive for Helicobacter infection with similar infection rates being reported for example for vomiting or ill dogs and cats (Blois, M., 2022 Helicobacter infection in small animals, MSD Manuel, Veterinary Manual, Taillieu, M., et al., 2022 Gastric Helicobacter species associated with dogs, cats and pigs: significance for public and animal health, Veterinary Research, 53, No: 42). [6] Treatment of Helicobacter pylori infection remains an acute challenge. Combination therapy, including antibiotics and acid suppressants, is recommended for treatment of Helicobacter infections. The lack of knowledge regarding the pathogenicity of Helicobacter infections in animals makes treatment decisions difficult and complex with largely indefinite outcomes. Hpylori infections in people are treated with double or triple antimicrobial agent therapy plus an acid secretory inhibitor (eg. clarithromycin, amoxicillin, bismuth, and ranitidine) for 2 weeks, and similar therapeutic approaches have been used in veterinary medicine. |7| Currently, the role of Helicobacter as a causative agent of gastritis and other associated conditions in most animals is not entirely unclear. It has been recommended that treatment decisions of animals should be based on laboratory test confirmation of presence of Helicobacter, in combination with appropriate clinical signs and / or in some cases confirmed gastric lesions. In many veterinary studies, Helicobacter infections have been difficult to eradicate following current treatment. The recommended treatment regimens for animals include use of antibiotics such as amoxicillin or tetracycline, metronidazole, bismuth subsalicylate, and a proton pump inhibitor (eg, omeprazole) or for instance H2- receptor blocker (eg. famotidine) for 2-3 weeks. Other treatment combinations of omeprazole and azithromycin or clarithromycin have been described and also used with limited success rate. Although many treated animals with the above combinations do not experience long term eradication of Helicobacter infection when retested, the frequency of vomiting and gastric lesions showed some albeit limited improvement. [8] However, these treatment regimens have inherent drawbacks and frequently, especially when used indiscriminately across animal husbandly’ which may not exhibit any clinical symptoms, promote further increases in antimicrobial resistance and induce gut microbiota dysbiosis because of the empiric use of multiple antibiotics. Antibiotic resistance has been ranked as one of the top 10 threats to global public health by the World Health Organisation. [9] Unless treated effectively, an infection by H. pylori would usually persist indefinitely, manifesting as other seemingly unrelated disorders and diseases. 110] Despite the efforts to find effective treatments against Helicobacter spp., reports on specific and successful therapies with low resistance and desired efficiency are rare if not absent. [111 Thus, currently, there are no effective non-antibiotic treatments against the Helicobacter spp in animals. There are also no efficacious treatments which can be widespread and accepted as a long-term animal-friendly treatment standards of Helicobacter spp., absent the associated detrimental effects described above.

[12] Therefore, there is a pressing need for developing not only effective treatments against Helicobacter spp. in animals but also treatment which can be widely adopted in veterinary medicine, lacks toxicity and avoids the unfettered reliance on antibiotics in animal husbandry. SUMMARY 113] The present invention relates to a veterinary non-antibiotic antimicrobial composition, new uses and methods of medical treatment or prophylaxis of animals.

[14] Specifically, the present invention relates to a veterinary non-antibiotic antimicrobial composition comprising a zeolite and at least one member of the Lactobacilli genus for the treatment of a condition or disease associated with or caused by Helicobacter spp in an animal.

[15] In one aspect of the present invention, there is provided a veterinary antimicrobial composition comprising a zeolite and at least one member of the Lactobacilli genus and at least one veterinary acceptable excipient.

[16] In one further aspect of the present invention there is provides a veterinary antimicrobial composition comprising a zeolite and at least one member of the Lactobacilli genus and at least one veterinary acceptable excipient, for use in the treatment of medical conditions associated with Helicobacter, in an animal.

[17] In some embodiments of the present invention of the present invention, the veterinary composition further comprises at least one animal based palatant and / or at least one non-animal based palatant. 118] In some further embodiments of the present invention, the veterinary acceptable excipient is selected from a disintegrant, binder, humectant, lubricant, glidant, and flavor modifier; and wherein the nonanimal based palatant is yeast.

[19] In some further embodiments of the present invention, the veterinary acceptable disintegrant is an analogue of providone, sodium starch glycolate, or mixture thereof.

[20] In some further embodiments of the present invention, the disintegrant is a mixture of an analogue of an analogue of providone and sodium starch glycolate, and combined are in the amount of about 10w / w% to about 15w / w% of the total weight of the composition.

[21] In some further embodiments of the present invention, the veterinary acceptable binder comprises polyethylene glycol, a gum, or mixture thereof. In some further embodiments, the polyethylene glycol is polyethylene glycol 3350 and the gum is xanthan gum and wherein the mixture of polyethylene glycol and the gum comprises about 5w / w% to about 7w / w% of the total weight of the composition. In some further of the present invention, veterinary acceptable humectant is glycerol in the amount of about 10w / w% to about 15w / w% of the total weight of the veterinary composition.

[22] In some further embodiments of the present invention, the veterinary acceptable lubricant is a mixture of magnesium stearate and glycerol monostearate and wherein the composition comprises about lw / w% to about 3w / w% of a glidant and about 0.4w / w% to about 0.6w / w% of a flavour modifier. 123] In some embodiments of the present invention, there is provided an antimicrobial composition wherein the zeolite is naturally occurring or synthetic.

[24] In some embodiments of the present invention, there is provided a veterinary antimicrobial composition wherein the zeolite is zeolite clinoptilolite (ZC).

[25] In some embodiments of the present invention, there is provided a veterinary antimicrobial composition wherein the zeolite is activated zeolite clinoptilolite (aZC), preferably double activated zeolite clinoptilolite (aZC).

[26] In some embodiments of the present invention, there is provided a veterinary antimicrobial composition wherein the at least one member of the Lactobacilli genus is selected from the group consisting of Lactobacillus reuteri, Lactobacillus delbrueckii, Lactobacillus rhamnosus, Lactobacillus casei, Lactobacillus acidophilus, Lacticaseibacillus paracasei, Lactiplantibacillus plantarum, Levilactobacillus brevis, Ligilactobacillus salivarius, Limosilactobacillus fermentum, Lactobacillus bulgaricus, Lactobacillus crispatus, Lactobacillus helveticus and Lactobacillus johnsonii. [271 In some embodiments of the present invention, there is provided a veterinary antimicrobial composition wherein the at least one member of the Lactobacilli genus is Lactobacillus reuteri.

[28] In some embodiments of the present invention, there is provided a veterinary antimicrobial composition wherein the Lactobacillus reuteri is Lactobacillus reuteri DSM17648.

[29] In some embodiments of the present invention, there is provided a veterinary antimicrobial composition wherein the vertebrate is administered with a therapeutically effective amount of the veterinary antimicrobial composition.

[30] In some embodiments of the present invention, there is provided a veterinary antimicrobial composition wherein the therapeutically effective amount is achieved by a regimen of administration of the zeolite and the at least one member of the Lactobacilli genus.

[31] In some embodiments of the present invention, there is provided a veterinary antimicrobial composition wherein the regimen comprises one or more types of administration of the zeolite and the at least one member of the Lactobacilli genus. In some embodiments of the present invention, the regimen of administration of the veterinary antimicrobial composition is suitable for peroral, rectal, topical, enteral, vaginal, buccal, orthotopic, intratracheal, intralesional, endoscopical, transmucosal, sublingual, intestinal administration and combinations thereof.

[32] In some embodiments of the present invention, the regimen of administration of the veterinaiy antimicrobial composition is suitable for peroral. 133] In some embodiments of the present invention, there is provided a veterinary antimicrobial wherein the at least one member of the Lactobacilli genus is viable.

[34] In some embodiments of the present invention, there is provided a veterinary antimicrobial composition wherein the antimicrobial composition further comprises biologically active substances or minerals such as calcium carbonate, magnesium carbonate, vitamins, such as D and E. pharmaceutically acceptable carriers, additives and adjuvants, as well as antimicrobial chitin, such as chitosan and alphaketoglutarate, citrate and lactate.

[35] In some embodiments of the present invention, there is provided a veterinary antimicrobial composition wherein the regimen of administration of the zeolite and the at least one member of the Lactobacilli genus, is suitable for peroral administration or gastric administration.

[36] In some embodiments of the present invention, there is provided a veterinary antimicrobial composition wherein the composition comprises, activated zeolite clinoptilolite (aZC), Lactobacillus reuteri DSM17648, calcium carbonate and magnesium carbonate.

[37] In some embodiments of the present invention, there is provided a veterinary antimicrobial composition wherein the disease or condition is associated with Helicobacter pylori.

[38] In some embodiments of the present invention, there is provided a veterinary antimicrobial composition for use in the treatment, alleviation or prophylaxis in an animal.

[39] In some embodiments of the present invention, there is provided a veterinary antimicrobial composition wherein the animal is selected from a companion animal and livestock.

[40] In some embodiments of the present invention, there is provided a veterinary composition, wherein the companion animal is a dog (canine), cat (feline), and horse (equine), and wherein the livestock is pig, goat, sheep, and cattle.

[41] In some embodiments of the present invention, there is provided a veterinary composition, wherein the animal is deer, ferret, guinea pig, rabbit and zoo animal.

[42] In some embodiments of the present invention, there is provided a veterinary antimicrobial composition wherein the antimicrobial composition leads to a reduction of one or more markers in a animal.

[43] In some embodiments of the present invention, there is provided a veterinary antimicrobial composition wherein the marker is a predictive marker selected from the group consisting of urea, gastric ammonia, acid reflux, bloating and urease activity.

[44] In some embodiments of the present invention, there is provided a veterinary antimicrobial composition wherein the predictive marker is gastric ammonia.

[45] In some embodiments of the present invention, there is provided a veterinary antimicrobial composition wherein the antimicrobial composition leads to reduction of gastric ammonia levels in a vertebrate infected by Helicobacter pylori.

[46] In some embodiments of the present invention, there is provided a veterinary antimicrobial composition wherein the reduction of gastric ammonia is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% or greater compared to placebo.

[47] In some embodiments of the present invention, there is provided a veterinary antimicrobial composition wherein the reduction of gastric ammonia is at least 0.1, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5,4,4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10-fold or greater compared to placebo. |48] In some embodiments, there is provided a veterinary antimicrobial composition wherein the reduction of the predictive marker is statistically significant compared to a placebo.

[49] In some embodiments, there is provided a veterinary antimicrobial composition wherein the reduction of gastric ammonia marker levels in an animal infected with Helicobacter pylori is statistically significant.

[50] In some embodiments, there is provided a veterinary antimicrobial composition wherein the antimicrobial composition leads to a statistically significant clinical improvement in an animal infected with Helicobacter pylori. [511 In an aspect of the present invention there is provided a use of a veterinary antimicrobial composition for the preparation or manufacture of a pharmaceutical formulation for separate, combined, sequential or concomitant administration designed for the treatment, alleviation or prophylaxis of GIT disease or disorder, gastritis, gastric ulcer, duodenal ulcer, gastric cancer, cholestatic disorders, liver disfunction, duodenal cancer, in need of such treatment, alleviation or prophylaxis in an animal.

[52] In some embodiments, the present invention is directed a use of a veterinary antimicrobial composition wherein the pharmaceutical formulation is in a form suitable for administering a dose of the antimicrobial composition in a dose or as divided doses or sub-doses administered at appropriate intervals per day.

[53] In some embodiments, the present invention is directed a use of a veterinary’ antimicrobial composition wherein the pharmaceutical formulation in administered as one, two, three, four or more doses or sub-doses per day or per administration.

[54] In some embodiments, the present invention is directed a use of a veterinary antimicrobial composition wherein the pharmaceutical formulation comprises from 107 to 109 CFU / g of Lactobacillus reuteri DSM17648 and zeolite, wherein the zeolite is present in an amount of at least 50 mg gram of the formulation.

[55] In some embodiments, the present invention is directed a use of a veterinary’ antimicrobial composition wherein the pharmaceutical formulation further comprises calcium carbonate and magnesium carbonate, wherein the calcium carbonate and magnesium carbonate are each present in an amount of at least 0.5 mg / gram of the formulation.

[56] In some embodiments, the present invention is directed a use of an antimicrobial composition w’herein the dose of the veterinary antimicrobial composition is formulated as a palatable capsule, lyophilizate, liquid, pill, freeze-chy powder, tablet, caplet, soft chewable or gel.

[57] In some embodiments, the present invention is directed a use of an antimicrobial composition wherein the treatment leads to complete remission of the disease or disorder caused by or associated with Helicobacter spp infection.

[58] The present inventors surprisingly and unexpectedly observed that the veterinary non-antibiotic antimicrobial composition of the present invention was effective at inactivating and treating Helicobacter pylori infection in animals while established antibiotic therapies which rely on antibiotics, failed to do so.

[59] In particular, the present inventors surprisingly and unexpectedly observed that the nonantibiotic veterinary’ antimicrobial composition of the present invention was effective at inactivating and treating Helicobacter pylori infection by reducing predictive markers such as urea, gastric ammonia, acid reflux, bloating and urease activity, while antibiotic based therapies failed.

[60] More in particular, the present inventors surprisingly and unexpectedly observed that the nonantibiotic veterinary antimicrobial composition of the present invention can be safely used to treat companion animals and livestock, thereby effectively eliminating the fear of increase of antibiotic resistance in Helicobacter pylori. BRIEF DESCRIPTION OF THE DRAWINGS |61] FIG. 1 In vitro urea and ammonia reduction assays using veterinary antimicrobial compositions of the present invention. [621 FIG. 2 In vivo animal test data. DETAILED DESCRIPTION

[63] Throughout this disclosure, various scientific publications, patents and published patent specifications are referenced by an identifying citation. The disclosures of these publications, patents and published patent specifications are hereby incorporated by reference into the present disclosure to more fully describe the state of the art to which this disclosure pertains.

[64] As used herein, certain terms may have the following defined meanings.

[65] As used in the specification and the claims, the singular form "‘a,” “an” and “the” include singular and plural references unless the context clearly dictates otherwise. For example, the term “zeolite” includes a silicate containing substance with affinity for ammonia (NH4+). In the context of the present invention, a zeolite substance may be microporous or mesoporous silicate, known as a molecular sieve, which is granular or powdered for separate, combined or concomitant administration designed for the treatment, alleviation or prophylaxis of GIT disease or disorder, gastritis, gastric ulcer, duodenal ulcer, gastric cancer, cholestatic disorders, liver disfunction, duodenal cancer, in an animal in need of such treatment, with at least one member of the Lactobacilli genus, once daily, or for several days, weeks, months or years, or more than once daily for days to years, and at least one veterinary acceptable excipient.

[66] As used herein the term, “substance” refers to zeolite, a veterinary acceptable excipient, pharmaceutical agents, a palatant, therapeutically active ingredients and / or mineral salts such as for example calcium carbonate and / or magnesium carbonate and combinations thereof.

[67] As used herein the term “antimicrobial” refers to destroying, killing or inhibiting the growth of microorganisms and especially pathogenic microorganisms such as pathogenic bacteria for example Helicobacter spp, in an animal or in vitro.

[68] As used herein, the term “veterinary acceptable excipient” refers to tolerated by animals at least one binder, disintegrant, lubricant, glidant, humectant, antioxidant, flavour modifier and colorant.

[69] As used herein, the term "veterinary acceptable” unless otherwise indicated, refers to a substance or composition is compatible chemically and / or toxicologically, with the other ingredients comprising a formulation, composition, and / or the animal being treated therewith.

[70] As used herein, the term “palatant” refers to a substance which aid or mask the flavour or scent and aim to assist the uptake of the veterinary composition of the present invention by the animal where the palatant can be animal based palatant and / or a non-animal based palatant. In some embodiments, the palatant in an amount of about 55w / w% to about 70w / w% of the total weight of the veterinary composition of the present invention. Artificial palatants are chemically synthesized compounds that are used to flavour the veterinary composition of the present invention and can be formulated with the same chemical compounds found in natural palatants. Most artificial flavours are specific and often complex mixtures of singular naturally occurring flavour compounds to either imitate or enhance a natural flavour. A natural palatant is defined as the essential oil, oleoresin, essence or extract, protein hydrolysate, distillate, or any product of roasting, heating or cnzymolysis. which contains the flavouring constituents derived from a spice, fruit or fruit juice, vegetable or vegetable juice, edible yeast (active and inactive), herb, bark, bud, root, leaf or any other edible portions of a plant, meat, seafood, poultry, eggs, dairy products, or fermentation products thereof; and can include sweeteners like sucrose; whose primary function in food is flavouring rather than nutritional. Natural palatants include chicken, turkey, beef, pork, lamb, fish, egg, cheese, seafood, vegetable and vegetable matter, yeast (e.g., brewer’s yeast) and mixtures thereof. Yeast extracts are also included in the natural flavours. Flavour (taste) modifiers, for example sodium chloride, potassium chloride, are also construed herein as a palatant. Natural meat palatants can be obtained from meat, meat products, organ meat, yeast extracts, vegetable matter, and mixtures thereof. For example, an oral veterinary composition medication might include animal product-based flavourings such as dried or powdered meat and meat parts such as beef, pork, chicken, turkey, fish, and lamb; organ meats such as liver and kidney; meat meals, bone meals and ground bone; and animal-derived food such as casein, milk (which may include dry forms and lowered fat forms, such as dry skim milk), yogurt, gelatin, cheese and egg (collectively, "animal origin flavourings") may be utilized. The natural products may or may not be sterilized by heat or other types of radiation, e.g., gamma-radiation. The preferred palatant for the stable, palatable, chewable composition is a natural animal based palatant. The composition of the invention comprises or contains at least two palatants in the amount of about 55w / w% to about 70w / w% of the total weight of veterinary composition of the present invention. The composition comprises or contains at least one animal based palatant in the amount of about 45w / w% to about 55w / w% of the total weight of the veterinary composition of the present invention. The preferred animal based palatant is in the amount of about 46w / w% to about 52w / w% of the total weight of the veterinary composition of the present invention. The preferred animal based palatant is in the amount of about 48w / w% to 50w / w% of the total weight of the veterinary composition of the present invention. The preferred animal based palatant is derived from organ meat. The preferred organ meat is derived from pork liver. The preferred animal based palatant is pork liver powder. The composition comprises or contains about 10w / w% to about 15w / w% of the total weight of the veterinary composition of the present invention of a non-animal based palatant; and preferably about llw / w / % to about 14w / w% of the total weight veterinary composition of the present invention. [71 ] Preferably, the non-animal based palatant is yeast. The preferred yeast is Brewer’s yeast. The composition also comprises or contains about 0.4w / w% to about 0.6w / w% of the total weight of the veterinary composition of the present invention of a flavour modifier. The preferred flavor modifier is sodium chloride. The composition comprises or contains about 48w / w% to about 50w / w% of the total weight of the veterinary composition of the present invention of an animal based palatant; about 11 w / w% to about 14w w% of a non-animal based palatant, and wherein the w / w% are based on the total weight of the veterinary’ composition of the present invention.

[72] As used herein the abbreviation “(w / w)” means percent by weight, as calculated based on the weight of the component and the total weight of the composition, formulation or tablet. Generally, the terms used in this application are well known to persons of skill in the art.

[73] As used herein the term “Binder” means agents which increase in cohesiveness to the composition, thereby providing the necessary- bonding to form a cohesive mass. Non-limiting examples of veterinary acceptable binders include, but are not limited to: microcrystalline cellulose, carboxymethyl cellulose, sodium carboxy methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone (e.g., povidone (Kollidon 25, 30, and 90) and co povidone (Kollidon VA 64), polyethylene glycol (PEG), acacia, com syrup solids, tragacanth gum, xanthan gum, gelatin, carnauba wax, alginate, and mixtures thereof. Polyethylene glycol (PEG) is a polyether compound with many applications, from industrial manufacturing to medicine. PEG is also known as polyethylene oxide (PEG) or polyoxyethylene (POE), depending on its molecular weight. The structure of PEG is commonly expressed as H(OCH;CH2)nOH. where n is an integer >3. PEG’s are prepared by polymerization of ethylene oxide and are commercially available over a wide range of molecular weights from 300 g / mol to 10,000,000 g / mol. PEG’S are commercially available. A PEG with an n of 9 has an average weight of about 400 daltons (g / mole) and is conveniently labeled as PEG 400. Similarly, a PEG with an n of 45 has an average weight of about 2000 daltons and is conveniently labeled as PEG 2000. PEG 3350 is a PEG with a molecular weight of 3350 g / mol. It is commonly used in the pharmaceutical and veterinary industry. The composition of the invention comprises or contains about 5w / w% to about 7w / w% of the total weight of the tablet of at least one binder. In some embodiments, the binding agent for the veterinary composition of the invention is PEG 3350. The veterinary composition further comprises or contains at least one binder that is a gum selected from the group consisting of tragacanth gum, xanthan gum, arabic gum, cellulose gum, guar gum, locust bean gum, or a mixture thereof; and preferably xanthan gum, in the amount of about 0.3w / w% to about 0.7w / w% of the total weight of the tablet, preferably, about 0.4w / w% to about 0.6w / w% of the total weight of the tablet, and more preferably about 0.5w / w% of the total weight of the tablet. In some embodiments, the veterinary composition comprises or contains about 5w / w% to about 6w / w% of the total weight of the tablet of PEG 3350.

[74] The veterinary composition of the present invention comprises or contains at least one veterinary acceptable excipient that is a disintegrant, thereby providing a means for the dosage form to expand and dissolve more readily when wet and / or break apart while being chewed. Non-exclusive examples of veterinary acceptable disintegrants include: starch including pregelatinized and modified starches, microcn stallinc cellulose, methyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose sodium, crospovidone, magnesium aluminum silicate, guar gum, alginic acid, sodium alginate, calcium alginate, chitosan, croscarmellose sodium, sodium starch glycolate, and the like, and mixtures thereof. In some embodiments, the disintegrant is selected from the group consisting of starch, carboxymethyl cellulose sodium, crospovidone, croscarmellose sodium, and sodium starch glycolate, and mixtures thereof. In some embodiments, the disintegrants are sodium starch glycolate and crospovidone, or a mixture thereof. In some embodiments, the disintegrant is a mixture of crospovidone and sodium starch glycolate. In some embodiments, the amount of disintegrant in the veterinary composition is about 8w / w% to about 18w / w% of the total weight of the veterinary composition. In some embodiments, the amount of disintegrant in the veterinary composition is about 10w / w% to about 15w / w% of the total weight of the veterinary composition.

[75] The veterinary composition of the present invention comprises or contains at least one veterinary acceptable excipient that is a humectant. Humectants are considered hygroscopic in that they impart moisture to the composition. Non-limiting examples of humectants for the composition include, but are not limited to: glycerin (glycerol), hyaluronic acid, sorbitol, urea, alpha hydroxy acids, sugars, lactic acid, propylene glycol, glyceiy1 triacetate, lithium chloride, polyols like sorbitol, xylitol and maltitol, polymeric polyols like polydextrose, natural extracts like quillaia, hexadecyl, myristyl, isodecyl and isopropyl esters of adipic, lactic, oleic, stearic, isostearic, myristic and linoleic acids, as well as many of their corresponding alcohol esters (e.g. sodium isostearoyl-2-lactylate, sodium capryl lactylate). The preferred humectant is glycerol and is in the amount of about 10w / w% to about 15w / w% of the total weight of the veterinary composition. [76| The veterinary composition of the present invention comprises or contains at least one veterinary acceptable excipient that is a lubricant. Lubricants are used to enhance product flow by reducing inter-particulate friction and to prevent compositional ingredients from clumping together and from sticking to the tablet punches. Lubricants also ensure that tablet formation and ejection can occur with low friction between the tablet and die wall. Non-limiting examples of lubricants include: talc, magnesium stearate, glyceryl monostearate, boric acid, sodium benzoate, sodium olete, sodium acetate, sodium lauryl sulfate, magnesium lauryl sulfate, and mixtures thereof. Preferred lubricants include talc, magnesium stearate, and glyceryl monostearate. In some embodiments, the lubricants are magnesium stearate, glycerol monostearate, and mixtures thereof. In some embodiments, the veterinary composition comprises glycerol monostearate and magnesium stearate as lubricants in the amount of about 1 w / w% to about 2w / w% of the total weight of the veterinary composition of the present invention.

[77] The veterinary composition of the present invention comprises or contains at least one veterinary acceptable excipient that is a glidant. Glidants are used to promote powder flow by reducing interparticle friction and cohesion. These are used in combination with lubricants as they have no ability to reduce die wall friction. Examples include fumed silica, colloidal silicon dioxide, talc, and magnesium carbonate. In some embodiments, the glidant is colloidal silicon dioxide and is in the amount of about lw / w% to about 3w / w% of the total weight of the tablet. In some embodiments, the amount of glidant in the composition is about 1.5w / w% to about 2.5w / w% of the total weight of the veterinary composition. |78] All numbers or numerals as used herein that indicate for example amounts, ratios of materials or substances, physical properties of materials or substance, and / or use are to be understood as modified or qualified by the term "about," except as otherwise explicitly indicated. |79] As used herein, the term "about" includes the recited number or number and + / - 10% from the recited numeral or number. By way of non-limiting example, the term "about ten (10)" would encompass nine (9) to eleven (11) or 9-11. 180] As used herein the terms “Animal” and “veterinary” are used interchangeably and unless otherwise indicated, refers to a vertebrate animal that is non-human, which are members of the taxonomic class Animalia. Non-exclusive examples of animal include companion animals and livestock. Non-exclusive examples of a companion animal include: dog (canine), cat (feline), and horse (equine). Preferred companion animals are dog and cat. More preferred is dog. Non-exclusive examples of livestock include: pig, goat, sheep, and cattle. The term also refers to other animals, for example, deer, ferret, guinea pig, rabbit, zoo animals (e.g., bear, large cats, camel, kangaroo, and the like). In some embodiment, the animal is in need of or has been a target of observation or experiment of, treatment or prevention of Helicobacter spp infection. Preferably, an animal is in need of or has been the object of observation or experiment of, treatment or prevention of Helicobacter spp infection such as Helicobacter canis, Helicobacter felis, Helicobacter heilmannii, Helicobacter mustelae, Helicobacter bizzozeronii, Helicobacter acinonyx, Helicobacter fenneliae, Helicobacter rappini, Helicobacter hepaticus, Helicobacter pullorum, Helicobacter bills, Helicobacter rodentium, Helicobacter trogontum, Helicobacter cinaedi, Helicobacter muridarum, Helicobacterpametensis, Helicobacter cholecyctus and Helicobacter pylori infection. Preferably, an animal is in need of or has been the object of observation or experiment of, treatment or prevention of Helicobacter pylori infection. In some embodiment of the present invention, the disease or condition is associated with or caused by Helicobacter canis.

[81] As used herein, the term “companion animal species” refers to an animal suitable to be a companion to humans. In some embodiments, a companion animal species is a small mammal, such as a canine, feline, dog, cat, horse, rabbit, ferret, guinea pig, sheep, rodent, etc.

[82] As used herein the term “symptom” refers to for example vomiting, gastritis, weight loss, peptic ulcers, hair loss, gastric neoplasia, lymphoma, fever, GI disease, hormonal imbalance, associated with or caused by Helicobacter spp.

[83] As used herein the term “condition” unless otherwise indicated, refers to for example vomiting, hyperammonemia, gastric ulcer, associated with or caused by Helicobacter spp. hyperammonemia,

[84] As used herein the term “at least one”, unless otherwise indicated, refers to one or more ingredients or agents of the composition of the present invention. By way of example, at least one Lactic acid bacteria means one member Lactic acid bacteria, it also refers to 2 species of Lactic acid bacteria, it also refers to 3 species of Lactic acid bacteria, it also refers to 4 species Lactic acid bacteria, or more species of Lactic acid bacteria; at least one zeolite means one type of zeolite, it also means 2 different types of zeolites, 3 different types of zeolites, 4 different types zeolites, or more; a veterinary acceptable excipient means one excipient; it also refers to 2 excipients, 3 excipients, 4 excipients, and more excipients.

[85] As used herein the term “Composition of the invention”, “composition” or “vctcrinaiy composition”, unless otherwise indicated, refers to a veterinary composition intended for administration to an animal. [86| As used herein, the term “treatment” or “treating” refers to an amelioration, prophylaxis, or reversal of a disease or disorder, or of at least one discernible symptom or condition thereof in an animal. It is also contemplated that die treatment, as described herein throughout and based on data, leads to one or more of clinical improvement, reduction in the severity of a symptom or disease and reduction in one or more marker in an animal. In some embodiments, “treatment” or “treating” refers to an amelioration, prophylaxis, or reversal of at least one measurable physical parameter related to the disease or disorder being treated, not necessarily discernible in or by the animal. In some embodiments, “treatment” or “treating” refers to inhibiting or slowing the progression of a disease, disorder or condition, either physically, e.g., stabilisation of a discernible symptom, physiologically, e.g., stabilisation of a physical parameter, or both. In some embodiments, “treatment” leads to partial or complete remission of the disease or disorder. In some embodiments, “treatment” leads to clinical improvement in an animal infected with or affected by Helicobacter spp such as Helicobacter pylori. In some embodiments, “treatment” leads to reduction in the severity of disease in an animal infected with or affected by Helicobacter spp such as Helicobacter pylori. In some embodiments, “treatment” leads to reduction in bacterial load in an animal infected with or affected by Helicobacter spp such as Helicobacter pylori. Without wishing to be bound by theory7, elevated blood levels of different markers such as inflammatory markers, CBC markers and predictive markers have been associated with disease state or condition associated w\\.b Helicobacter spp such as Helicobacter pylori. Thus, in some embodiments of the present invention, the predictive markers are selected from the group consisting of the marker is a predictive marker selected from the group consisting of urea, gastric ammonia, acid reflux, bloating and urease activity. In some embodiments, the predictive marker is gastric ammonia. In some embodiments of the present invention, the treatment leads to reduction of one or more predictive markers selected from the group consisting of urea, gastric ammonia, acid reflux, bloating and mease activity. In some embodiments of the present invention, the treatment leads to reduction of the predictive marker gastric ammonia. In some embodiments of the present invention, the treatment leads to reduction or alleviation of hyperammonemia. H. pylori is strongly urease positive. Its ability to split urea within 30 seconds distinguishes it from other Helicobacter species. Bacteriology - Identification | ID 26 | Issue no: 3 | Issue date: 03.07.15 | Page: 18 of 27. UK Standards for Microbiology Investigations | Issued by the Standards Unit, Public Health England.

[87] The present invention relates to a new composition and uses of the veterinary composition in treatment methods that alleviate, abrogate, or otherwise reduce or cure any one or more symptoms caused by or associated with a Helicobacter spp such as Helicobacter pylori infection. Specifically, the invention relates to a new veterinary composition and uses of the veterinary composition in treatment of Helicobacter spp such as Helicobacter pylori infected animals. In some embodiments, the treatment leads to substantial cure of a disease or disorder caused by or associated with Helicobacter spp such as Helicobacter pylori infection. In some embodiments, the invention relates to a new composition and uses of the composition as palliation of Helicobacter spp such as Helicobacter pylori infected animal.

[88] The present inventors surprisingly and unexpectedly found that the non-antibiotic antimicrobial composition of the present invention was effective at inactivating and treating Helicobacter pylori infection while established antibiotic therapies which rely on antibiotics, failed to do so. In particular, the present inventors surprisingly and unexpectedly observed that the non-antibiotic antimicrobial composition of the present invention was effective at inactivating and treating Helicobacter pylori infection by reducing predictive markers such as urea, gastric ammonia, acid reflux, bloating and urease activity, while antibiotic based therapies failed for example due to antibiotic resistance.

[89] As used herein, the term “non-antibiotic” refers to not using, relying on or containing an antibiotic. In some embodiments, the composition of the present invention does not use, rely on or contain an antibiotic. |90] As used herein the term “antibiotic” refers to an antibacterial substance (such as penicillin, cephalosporin, metronidazole, clarithromycin, furazolidone, amoxicillin, tetracycline, ciprofloxacin, levofloxacin) that is used to treat or prevent infections by killing or inhibiting the growth of bacteria in or on the animal, that is administered orally, topically, or by injection, and that is isolated from cultures of certain microorganisms (such as fungi) or is of semi-synthetic or synthetic origin. Currently, a standard triple therapy consisting of two antibiotics and a proton-pump inhibitor have been proposed as the first-line regimen. Alternatively, bismuth-containing quadruple treatment, sequential treatment or a non-bismuth quadruple treatment (concomitant) are also used in current treatment therapy. Levofloxacin containing triple treatment are recommended as rescue treatment for infection of H. pylori after defeat of first-line therapy. However, due to a rapid acquisition of antibiotic resistance drastically reducing the effectiveness of any antibiotic regimens inevitably leading to acute and long-term suffering with concomitant and often unpredictable side effects for the affected animal. It is known that H. pylori is becoming increasingly resistant to metronidazole and clarithromycin. Bacteriology - Identification | ID 26 | Issue no: 3 | Issue date: 03.07.15 | Page: 10 of 27. UK Standards for Microbiology Investigations | Issued by the Standards Unit, Public Health England.

[91] As contemplated in the context of the present invention, an antibiotic can be used to treat or prevent Helicobacter spp infection such as Helicobacter pylori infection. In some embodiments, the Helicobacter spp, such as Helicobacter canis, Helicobacter felis, Helicobacter heilmannii, Helicobacter mustelae, Helicobacter bizzozeronii, Helicobacter acinonyx, Helicobacter femeliae, Helicobacter rappini, Helicobacter hepaticus, Helicobacter pullorum, Helicobacter bilis, Helicobacter rodentium, Helicobacter trogontum, Helicobacter cinaedi, Helicobacter muridarum, Helicobacter pametensis, Helicobacter cholecyctus and Helicobacter pylori is resistant to antibiotic treatment. In some embodiments Helicobacter pylori is resistant to antibiotic treatment.

[92] As used herein the term “administration’’ should be understood to encompass for example peroral, intravenous, parenteral, inhalation, pulmonary rectal, nasal, topical, intravesical, intrathecal, enteral, intralymphatic, intracavital, vaginal, transurethral, intradermal, aural, intramammary, buccal, orthotopic, intratracheal, intralesional, percutaneous, endoscopical, transmucosal, sublingual, intestinal administration and combinations thereof. In some embodiments, the regimen of administration of the antimicrobial composition is suitable for peroral, rectal, topical, enteral, vaginal, buccal, orthotopic, intratracheal, intralesional, endoscopical, transmucosal, sublingual, intestinal administration and combinations thereof. In some embodiments, the regimen of administration of the antimicrobial composition or formulation is peroral. |93] In some embodiment, the zeolite is a silicate containing substance with affinity for ammonia (NH4+). In some embodiments, the zeolite is synthetic zeolite with affinity for ammonia (NH4+). As used herein, “synthetic zeolite” refers to a zeolite manufactured or synthesized by one or more chemical reactions involving breaking and / or making chemical bonds. Physicochemical properties and features of zeolites include for example different size pores, channels and ion exchange capacity. The channels are filled with water and with exchangeable cations to balance negative charges in the zeolite structural framework. As a consequence of the highly porous structure and the substitution, clinoptilolite and other zeolites have significant cation exchange capacities (CEC), on the order of 100 to 300 cmol of charge per kg. As with most zeolites, however, exchange selectivity is restricted by channel size. Larger ions may be selectively excluded. These “ion sieving” properties of zeolites are important properties exploited in a number of industrial and other uses. In the presence of ammonium rich liquids, NH4+-N is exchanged with the cations present in the framework.

[94] In some embodiments, there is provided an antimicrobial composition wherein the zeolite is zeolite clinoptilolite (ZC). In some embodiments, there is provided an antimicrobial composition wherein the zeolite clinoptilolite comprises Clinoptilolite-K, Clinoptilolite-Na and Clinoptilolite-Ca. In some embodiments, there is provided an antimicrobial composition wherein the zeolite is activated zeolite clinoptilolite (aZC). In some embodiment, there is provided an antimicrobial composition wherein activated zeolite clinoptilolite (aZC) is double activated zeolite clinoptilolite (aZC). The clinoptilolite series comprises three known species: Clinoptilolite-K, Clinoptilolite-Na, Clinoptilolite-Ca named after their dominant chemical element constituent namely K+, Na+ and Ca++. These chemical element constituents are exchanged during cation exchange in favour of for example heavy metals, toxins, mycotoxins and ammonia as present in the environment, such as the GIT, displaying higher chemical affinity for zeolite clinoptilolite such as Clinoptilolite-K, Clinoptilolite-Na and Clinoptilolite-Ca. [951 In some embodiment the Activated Zeolite Clinoptilolite is Tribomechanically Activated Zeolite Clinoptilolite. 196] In some embodiment the Tribomechanically Activated Zeolite Clinoptilolite is (TMAZ®). It would be known by the skilled person that the chemical formula of SiO2, 65.0-71.3%; AI2O3, 11.5-13.1%; CaO 27-5.2%; K2O,2.2-3.4%; Fe2O3, 07-1.9%; MgO, 0 6-1.2%; Na2O, 0.2-1.3%; TiO2, 0.1-0.3%; Si / Al ratio, 4.8-5.4.

[97] It would be understood by the skilled person that the empirical formula of zeolite can be (Ca, K2, Na2, Mg)4Ai8Si4o096 x 24H2O with specific molecular mass, 2.2-2.5 g / cm3; porosity 32-40%; effective pore diameter, 0.4 nm or greater such as 0.5 nm, 0.75 nm, 1 nm, 1.5 nm, 2 nm, 10 nm, 25 nm, 50 nm 100 nm, 150 nm, 250 nm, 0.5 pm or grater diameter.

[98] In some embodiments the zeolite displays Ion-exchange capacity: 1.2-1.5 mol / kg; Ca2+, 0.64-0.98 mol / kg; Mg2+, 0.06-0.19 mol / kg; K+, 0.22-0.45 mol / kg; Na+, 0.01-0.19 mol / kg lon-exchanging selectivity Cs>NH4 +>Pb2+>K+>Na+>Mg2+>Ba2+>Cu2+>Zn2+.

[99] In some embodiments, the chemicals or toxins absorbed by zeolite comprise NH3, hydrocarbons C1-C4, CO2, H2S, SO2, NOx, aldehydes.

[100] Preferably, as contemplated within the context of the compositions or formulations of the present invention, zeolite is nontoxic. In some embodiment zeolite is generally recognized as safe (GRAS) according to US Code of Federal Regulations (21 CFR 182, Subpart C).

[101] It is proposed that the antimicrobial composition and uses of the composition in treatment methods are able to alleviate, abrogate, or otherwise reduce or cure any one or more symptoms caused by or associated with a Helicobacter spp such as Helicobacter pylori infection by restoring the natural acid pH levels in the GIT of the animal.

[102] It is proposed that the mineral salts in the composition of the present invention such as for example calcium carbonate and magnesium carbonate, further extend or contribute to the ion exchange capability of the zeolite, thereby affording an enhancement in the absorption and / or neutralisation of ammonium such as ammonium in the GIT.

[103] As used herein, “palliation” refers to any form of medical care or treatment that concentrates on reducing the severity of the symptoms of a disease or slows its progress rather than providing a cure. It aims at improving quality of life, and particularly at reducing or eliminating pain. The definition specifically focuses on the general unavailability of a cure in that it emphasizes the active total care of animal whose disease is not responsive to curative treatment.

[104] Without wishing to be bound by theory, a disease or condition in animal associated with or caused by Helicobacter spp infection such as Helicobacter canis, Helicobacter fells. Helicobacter heilmannii, Helicobacter mustelae, Helicobacter bizzozeronii, Helicobacter acinonyx, Helicobacter fenneliae, Helicobacter rappini, Helicobacter hepaticus, Helicobacter pullorum, Helicobacter bills, Helicobacter rodentium, Helicobacter trogontum, Helicobacter cinaedi, Helicobacter muridarum, Helicobacter pametensis, Helicobacter cholecyctus and Helicobacter pylori infection is characterised with increased levels or higher than normal levels of urea, gastric ammonia, acid reflux, bloating and mease activity. Gastric Helicobacter spp infection has been reported to be associated with hyerammonemia. H. pylori, H. bizzozeroni, H cynogastricus, H. salomonis, H suis, H. bilis, H heilmannii are urease positive. Bacteriology - Identification | ID 26 | Issue no: 3 | Issue date: 03.07.15 | Page: 21 of 27. UK Standards for Microbiology Investigations | Issued by the Standards Unit, Public Health England.

[105] As used herein the term “hyerammonemia” or other terms used to indicate higher than normal levels of ammonia is meant higher levels than normal, where normal is a specified laboratory's normal range as determined for blood from non-diseased, healthy animal, using an analytical technique-of-choice for that laboratory that performed the assay (which could be venous blood, arterial blood, or some fraction of whole blood including plasma or serum) and processed according to the laboratoiy's procedure specifying whether it should be placed immediately on ice, the timeframe in which it is to be delivered to the laboratory, using the specified preservative, if any. 1106] Lactic acid bacteria, especially Lactobacillus, are the most commonly used microorganisms as probiotics - “Generally Recognized As Safe” (GRAS). Acidity, presence of ammonia, bile salts, and pancreatic enzymes in the gastrointestinal tract (GIT) are some of the major stresses that an orally taken probiotic experiences in the GIT. Apart from being able to survive, a probiotic strain of the present invention also has to be able to adhere to and subsequently colonize (at least temporarily) the intestinal tract. Since the GIT is a dynamic environment, the flow of the gut digesta may wash out any bacterium not attached to the intestinal mucosa. Thus, probiotic strains with adherent ability are more likely to have an increased opportunity to colonize the GIT and provide beneficial effects. In some embodiments, the Lactobacillus is able to withstand, preferably remain active or biochemically effective, at elevated levels of gastric ammonia observed with Helicobacter spp infection such as Helicobacter pylori infection. [107| Different methods of producing probiotic s have been described and are well documented. Some of these methods describe producing mixed microbial cultures in liquid growth medium. The production of such mixed cultures is greatly challenged by microbial competition among the diverse populations in the culture medium. One way of producing mixed microbial cultures is to separately propagate the different strains and to afterwards combine the propagated strains in the desired ratio.

[108] Other methods of propagating probiotics focus on the quorum sensing capabilities of microorganisms, particularly bacteria such as lactic acid bacteria. Lactic acid bacteria, due to the metabolic stress they experience, increase the release of different antimicrobial metabolites. In particular, a combination of metabolic stress and quorum sensing capabilities of the microorganisms, maximise the release of different antimicrobial metabolites (WO2020 / 177858). |109] In the context of the present invention, the at least one member of the Lactobacilli genus is produced using methods known in the art. In some embodiments, the at least one member of the Lactobacilli genus is produced using methods known in the art.

[110] In some embodiments, the al least one member of the Lactobacilli genus is propagated or produced using a combination of metabolic stress and quorum sensing capabilities of the at least one member of the Lactobacilli genus. [1111 In some embodiments, the at least one member of the Lactobacilli genus is selected from the group consisting of Lactobacillus reuteri. Lactobacillus delbrueckii, Lactobacillus rhamnosus, Lactobacillus casei, Lactobacillus acidophilus, Lacticaseibacillus paracasei, Lactiplantibacillus plantarum, Levilactobacillus brevis, Ligilactobacillus salivarius, Limosilactobacillus fermentum, Lactobacillus bulgaricus, Lactobacillus crispatus, Lactobacillus helveticus and Lactobacillus johnsonii. In some embodiment, the at least one member of the Lactobacilli genus is selected from the group consisting of Lactobacillus reuteri, Lactobacillus delbrueckii, Lactobacillus rhamnosus, Lactobacillus casei, Lactobacillus acidophilus, Lacticaseibacillus paracasei, Lactiplantibacillus plantarum, Levilactobacillus brevis, Ligilactobacillus salivarius, Limosilactobacillus fermentum, Lactobacillus bulgaricus, Lactobacillus crispatus, Lactobacillus helveticus and Lactobacillus johnsonii is propagated or produced using a combination of metabolic stress and quorum sensing capabilities of the at least one member of Lactobacillus reuteri, Lactobacillus delbrueckii, Lactobacillus rhamnosus, Lactobacillus casei, Lactobacillus acidophilus, Lacticaseibacillus paracasei, Lactiplantibacillus plantarum, Levilactobacillus brevis, Ligilactobacillus salivarius, Limosilactobacillus fermentum, Lactobacillus bulgaricus, Lactobacillus crispatus, Lactobacillus helveticus and Lactobacillus johnsonii. In some embodiment, the at least one member of the Lactobacilli genus is selected from the group consisting of Lactobacillus reuteri, Lactobacillus delbrueckii, Lactobacillus rhamnosus, Lactobacillus casei, Lactobacillus acidophilus, Lacticaseibacillus paracasei, Lactiplantibacillus plantarum, Levilactobacillus brevis, Ligilactobacillus salivarius, Limosilactobacillus fermentum. Lactobacillus bulgaricus, Lactobacillus crispatus. Lactobacillus helveticus and Lactobacillus johnsonii.

[112] In some embodiments, the at least one member of the Lactobacilli genus is Lactobacillus reuteri. In some embodiments, the at least one member of Lactobacillus reuteri is Lactobacillus reuteri DSM17648.

[113] In some embodiments, Lactobacillus reuteri DSM17648 is produced or propagated using a combination of metabolic stress and the quorum sensing capabilities of Lactobacillus reuteri DSM17648. [H4] The antimicrobial metabolites can be toxic to pathogenic microorganisms such as bacterial pathogens. In some embodiments, the composition or formulation of the present invention comprises antimicrobial metabolites which are toxic to Helicobacter spp such as Helicobacter pylori.

[115] In some embodiments, the at least one member of the Lactobacilli genus of the composition of the present invention is lyophilised. In some embodiments, the at least one member of the Lactobacilli genus of the composition of the present invention is freeze dried. In some embodiments the at least one member of the Lactobacilli genus of the composition of the present invention is viable.

[116] As used in the present invention, a therapeutically effective amount of the veterinary composition comprising of the present invention can be delivered to a patient as part of a regimen.

[117] In some embodiments, there is provided a veterinary antimicrobial composition wherein the regimen comprises one or more types of administration of the zeolite and the at least one member of the Lactobacilli genus. In some embodiments, the regimen of administration of the antimicrobial composition is suitable for peroral, rectal, topical, enteral, vaginal, buccal, orthotopic, intratracheal, intralesional, endoscopical, transmucosal, sublingual, intestinal administration and combinations thereof. In some embodiments, the antimicrobial composition is suitable for peroral administration.

[118] As used herein the term “regimen” refers to a plan or a set of rules of different possible routs or modes of administration, preferably to achieve a therapeutically effective amount of the veterinary antimicrobial composition of the present invention in an animal. It would be known to those of skill in the art that different regimens may be employed in the context of the present invention.

[119] As used herein the term “administration” should be understood to encompass for example peroral, rectal, topical, enteral, vaginal, buccal, orthotopic, intratracheal, intralesional, endoscopical, transmucosal, sublingual, intestinal administration and combinations thereof.

[120] Peroral Administration: The composition of the invention can be formulated to take the form of tablets or capsules prepared by conventional means with one or more pharmaceutically acceptable carriers (e.g., excipients such as binding agents, fillers, lubricants and disintegrants). The inventors found that the composition may be conveniently administered to an animal by the peroral route, particularly in the form of a tablet or capsule (e.g. a tablet). In some embodiments, the particular dosage regimes contemplated in the invention are particularly suited to oral administration in the form of a tablet or capsule that is formulated such that the release of compounds used in the invention e.g. zeolite, and the at least one member of the Lactobacilli genus, calcium carbonate and magnesium carbonate. The term “modified” or "modified release" as used herein in relation to the composition according to the invention or as used in any other context means release, which is not immediate release and is taken to encompass controlled release, sustained release, prolonged release, timed release, retarded release, extended release and delayed release.

[121] Controlled-Release Administration: Controlled-release (or sustained- release) preparations can be formulated to extend the activity of a substance and reduce dosage frequency. Controlled-release preparations can also be used to affect the time of onset of action or other characteristics, such as blood levels of the substance, and consequently affect the occurrence of any side effects.

[122] Controlled-release preparations can be designed to initially release an amount of a substance that produces the desired therapeutic effect, and gradually and continually release other amounts of the substance to maintain the level of therapeutic effect over an extended period of time. In order to maintain a near-constant level of a substance in the body, the substance can be released from the dosage fonn at a rate that will replace the amount of the composition of the present invention being metabolised and / or excreted from the body. The controlled-release can be stimulated by various inducers, e.g., change in pH, change in temperature, enzymes, water, and / or other physiological conditions or molecules such as ammonia. H23] Controlled-release systems can include, for example, an infusion pump which can be used to administer the composition in a manner similar to that used for delivering insulin or chemotherapy to the body generally, or to specific organs or tumours. Typically, using such a system, the veterinary composition is administered in combination with a biodegradable, biocompatible polymeric implant that releases the composition over a controlled period of time at a selected site. Example polymeric materials include polyanhydrides, polyorthoesters, polyglycolic acid, polylactic acid, polyethylene vinyl acetate, and copolymers and combinations thereof. In addition, a controlled release system can be placed in proximity of a therapeutic target such as a GIT ulcer, thus requiring only a fraction of a peroral dosage.

[124] Veterinary compositions of the invention can be administered by other controlled-release means or delivery devices that are well known to those of skill in the art. These include, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or the like, or a combination of any of the above to provide the desired release profile in varying proportions. Other methods of controlled-release delivery of the composition or formulation of the invention will be known to the skilled person and are within the scope of the invention. It will be appreciated by those skilled in the art that the amount of the different constituents of the composition of the invention required in the present uses and methods will vary with the nature or severity of the condition being treated, the age, weight, pre-existing medical treatments, and the overall condition of the animal.

[125] In some embodiments, there is provided an antimicrobial composition wherein the antimicrobial composition further comprises biologically active substances or minerals such as calcium carbonate, magnesium carbonate, vitamins, such as D and E, pharmaceutically acceptable carriers, additives and adjuvants, as well as antimicrobial chitin, such as chitosan and alpha-ketoglutarate, citrate and lactate.

[126] In some embodiments, there is provided a veterinary antimicrobial composition wherein the regimen of administration of the zeolite and the at least one member of the Lactobacilli genus, is suitable for peroral administration or gastric administration.

[127] In some embodiments, there is provided a veterinary antimicrobial composition wherein the composition comprises, activated zeolite clinoptilolite (aZC), Lactobacillus reuteri DSM17648, calcium carbonate and magnesium carbonate.

[128] In some embodiments, there is provided a veterinary antimicrobial composition wherein the antimicrobial composition leads to a reduction of one or more markers.

[129] In some embodiments, there is provided a veterinary antimicrobial composition wherein the marker is a predictive marker selected from the group consisting of urea, gastric ammonia, acid reflux, bloating and urease activity. [130| In some embodiments, there is provided a veterinary antimicrobial composition wherein the predictive marker is gastric ammonia.

[131] In some embodiments, there is provided a veterinary antimicrobial composition wherein the antimicrobial composition leads to reduction of gastric ammonia levels in a vertebrate infected by Helicobacter pylori.

[132] In some embodiments, there is provided a veterinary antimicrobial composition wherein the reduction of gastric ammonia is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% or greater compared to placebo. [ 133] In some embodiments, there is provided an antimicrobial composition wherein the reduction of gastric ammonia is at least 0.1, 0.25, 0.5, 1, 1.5,2,2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9,9.5, or 10-fold or greater compared to placebo.

[134] In some embodiments, there is provided a veterinary antimicrobial composition wherein the reduction of the predictive marker is statistically significant compared to a placebo.

[135] In some embodiments, there is provided a veterinaiy antimicrobial composition wherein the reduction of gastric ammonia marker levels in an animal infected with Helicobacter pylori is statistically significant. In some embodiments, there is provided an antimicrobial composition wherein the antimicrobial composition leads to a statistically significant clinical improvement in an animal infected with Helicobacter pylori.

[136] The term “regression” may be used interchangeably with the terms, “reduction”, “decrease” or “reduce” a disease or disorder, bacterial load, or of at least one discernible symptom or marker caused by or associated with Helicobacter spp such as Helicobacter pylori infection. In some embodiments, the reduction is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% or greater compared to control or placebo. In some embodiments the reduction is at least 0.1, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10-fold or greater compared to control or placebo. In some embodiments the regression or reduction is statistically significant. In some embodiments the effectiveness or the treatment of the present invention is assessed by a quantify ing step. In some embodiments, regression is assessed by a quantifying step. In further embodiments, the quantifying step is performed on a sample. In further embodiments, the quantifying step is performed by an immunoassay. In some embodiments, the sample is one of a plasma sample, blood sample, sputum sample, lavage, synovial fluid, or combinations thereof.

[137] In some embodiments, regression refers to a disease or disorder, or at least one discernible symptom caused by or associated with Helicobacter spp such as Helicobacter pylori infection. In some embodiments, regression is used to provide an indication of the extent by which, for example, disease, disorder or symptom is altered in terms of, for example, frequency of occurrence, intensity and severity. In some embodiments, regression means make less, bring down, lower or lessen, for example, fever in the treated animal. In some embodiments, reduction means make less, bring down, lower or lessen, the bacterial load in the treated patient. In some embodiments, the present treatment leads to an accelerated or faster reduction in the bacterial load in the treated patient compared to a placebo. In some embodiments, the reduction of the bacterial load is statistically significant. 1138] As used herein, the term “significant” when referring to for example reducing, enhancing, remission, amelioration, prophylaxis, or reversal, that is statistically significant, not due to chance alone, which has a p-value of 0.05 or less. In particular, the term “significant” can have a p-value of less than 0.05, 0.04, 0.03, 0.01, 0.005, 0.001, etc., when referring to for example reducing, enhancing, remission, amelioration, prophylaxis, or reversal of disease, disorder or symptom caused by or associated with Helicobacter spp such as Helicobacter pylori infection, for example when compared with the level or frequency of occurrence of implantation or pregnancy in one or more non-treated patients or when compared to the level or frequency of occurrence of implantation or pregnancy in the same patient observed at an earlier time point (e. g. comparison with a "base line" level or placebo). Those of skill in the relevant art would be familiar with different statistical calculation approaches, examples include, t-test, z-test, sample test, O’Brien-Fleming method for normally distributed data etc.

[139] In some embodiments the significant reducing, enhancing, remission, amelioration, prophylaxis, or reversal, refers to statistically significant reduction, enhancement, remission, amelioration, prophylaxis, or reversal of disease, disorder or symptom caused by or associated with Helicobacter spp such as Helicobacter pylori infection in an animal.

[140] In an aspect of the present invention there is provided a use of a veterinary antimicrobial composition for the preparation or manufacture of a pharmaceutical formulation for separate, combined or concomitant administration designed for the treatment, alleviation or prophylaxis of GIT disease or disorder, gastritis, gastric ulcer, duodenal ulcer, gastric cancer, duodenal cancer in vertebrates, including mammals and birds, in need of such treatment, alleviation or prophylaxis.

[141] Without wishing to be bound by thcoiy. the inventors have hypothesised that the animal naturally creates more gastric acid to combat H. pylori in an inflammatory response. The animal also recognises when this acid becomes too high it needs buffered so uses stores of calcium and magnesium to achieve this, over time too much acid and depleted stores of magnesium and calcium create many other ailments alongside the gastric disorders created by the auto immune response and colonisation of the H. pylori. Using the non-antibiotic antibacterial compositions of the present invention were not only able to effectively show experimentally reduction of ammonia and urea levels in affected animal, but also show complete elimination of the pathogen H. pylori thereby alleviating and / or preventing any H. pylori linked symptoms, diseases and conditions.

[142] In some embodiments, the present invention is directed a use of an antimicrobial composition wherein the pharmaceutical formulation is in a form suitable for administering a dose of the antimicrobial composition in a dose or as divided doses or sub-doses administered at appropriate intervals per day.

[143] In some embodiments, the present invention is directed a use of an antimicrobial composition wherein the pharmaceutical formulation in administered as one, two, three, four or more doses or sub-doses per day or per administration.

[144] In some embodiments, the present invention is directed a use of an antimicrobial composition wherein the pharmaceutical formulation comprises from 107 to IO9 CFU / g of Lactobacillus reuteri DSM17648 and zeolite, wherein the zeolite is present in an amount of at least 50 mg / gram of the formulation. 1145] In some embodiments, the zeolite will typically be in the range of about 0.1 to 2000 mg / kg of body weight, about 0.15 to 1750 mg / kg of body weight, about 0.2 to 1700 mg / kg of body weight, about 0.3 to 1500 mg / kg of body weight, about 0.5 to 1250 mg / kg of body weight, about 1 to 1000 mg / kg of body weight, about 2 to 900 mg / kg of body weight, about 3 to 800 mg / kg of body weight, about 4 to 700 mg / kg of body weight, about 5 to 600 mg / kg of body weight, about 10 to 500 mg / kg of body weight, administered as one, two, three, four or more doses or sub-doses per day or per administration. In some embodiments, the dose is 400 mg / kg of body weight administered as one, two, three, four or more doses or sub-doses per day or per administration.

[146] In some embodiments, the present invention is directed a use of an antimicrobial composition wherein the pharmaceutical formulation further comprises calcium carbonate and magnesium carbonate, wherein the calcium carbonate and magnesium carbonate are each present in an amount of at least 0.5 mg / gram of the composition or the formulation. 1147] In some embodiments, the calcium carbonate and magnesium carbonate will typically be in the range of about 0.1 to 200 mg / kg of body weight, about 0.15 to 150 mg / kg of body weight, about 0.2 to 120 mg / kg of body weight, about 0.3 to 100 mg / kg of body weight, about 0.5 to 75 mg / kg of body weight, about 1 to 50 mg / kg of body weight, about 2 to 40 mg / kg of body weight, about 3 to 30 mg / kg of body weight, about 4 to 20 mg / kg of body weight, about 5 to 10 mg / kg of body weight, administered as one, two, three, four or more doses or sub-doses per day or per administration.

[148] In some embodiments, the present invention is directed a use of a veterinary antimicrobial composition wherein the dose of the antimicrobial composition is formulated as a palatable capsule, lyophilizate, liquid, pill, freeze-chy powder, tablet, caplet, soft chewable or gel.

[149] In some embodiments, the present invention is directed a use of a veterinary antimicrobial composition wherein the treatment leads to complete remission of the disease or disorder caused by or associated with Helicobacter spp infection.

[150] In some embodiments, the veterinary composition contains about 1010 cells / ml of the at least one member of the Lactobacilli genus. In some embodiments, the inoculated aqueous medium contains about 109 cells / ml of the at least one member of the Lactobacilli genus. In some embodiments, the inoculated aqueous medium contains about cells / ml of the at least one member of the Lactobacilli genus. In some embodiments, the inoculated aqueous medium contains about IO7 cells / ml of the at least one member of the Lactobacilli genus. In some embodiments, the inoculated aqueous medium contains about cells / ml of the at least one member of the Lactobacilli genus. In some embodiments, the inoculated aqueous medium contains about 105 cells / ml of the at least one member of the Lactobacilli genus.

[151] In some embodiments, there is provided a veterinary antimicrobial composition wherein the at least one member of the Lactobacilli genus is viable.

[152] The skilled person would know that viability of microbial cells can be assessed or estimated using colony-forming units per millilitre (CFU / mL) in case of a liquid being tested or grams (CFU / g) if a solid material is tested.

[153] In some embodiments, where the at least one member of the Lactobacilli genus composition is a liquid, the concentration of the viable cells can be estimated via colony-forming units per millilitre (CFU / mL or growth medium). In some embodiments, the concentration of the viable cells in the composition is from 0.5 million to 1 billion CFU / mL, 0.5 million to 500 million CFU / mL, 0.5 million to 400 million CFU / mL, 0.5 million to 300 million CFU / mL, 0.5 million to 200 million CFU / mL, 0.5 million to 150 million CFU / mL, 0.5 million to 125 million CFU / mL, 0.5 million to 100 million CFU / mL, 0.5 million to 75 million CFU / mL, 0.5 million to 50 million CFU / mL, 0.5 million to 10 million CFU / mL, 0.5 million to 5 million CFU / mL, 0.5 million to 1 million CFU / mL, 1 million to 1 billion CFU / mL, 1 million to 500 million CFU / mL, 1 million to 400 million CFU / mL, 1 million to 300 million CFU / mL, 1 million to 200 million CFU / mL, 1 million to 150 million CFU / mL, 1 million to 125 million CFU / mL, 1 million to 100 million CFU / mL, 1 million to 75 million CFU / mL, 1 million to 50 million CFU / mL, 1 million to 10 million CFU / mL, 1 million to 5 million CFU / mL, 5 million to 1 billion CFU / mL, 5 million to 500 million CFU / mL, 5 million to 400 million CFU / mL, 5 million to 300 million CFU / mL, 5 million to 200 million CFU / mL, 5 million to 150 million CFU / mL, 5 million to 125 million CFU / mL, 5 million to 100 million CFU / mL, 5 million to 75 million CFU / mL, 5 million to 50 million CFU / mL, 5 million to 10 million CFU / mL, 10 million to I billion CFU / mL, 10 million to 500 million CFU / mL, 10 million to 400 million CFU / mL, 10 million to 300 million CFU / mL, 10 million to 200 million CFU / mL, 10 million to 150 million CFU / mL, 10 million to 125 million CFU / mL, 10 million to 100 million CFU / mL, 10 million to 75 million CFU / mL, 10 million to 50 million CFU / mL, 50 million to 1 billion CFU / mL, 50 million to 500 million CFU / mL, 50 million to 400 million CFU / mL, 50 million to 300 million CFU / mL, 50 million to 200 million CFU / mL, 50 million to 150 million CFU / mL, 50 million to 125 million CFU / mL, 50 million to 100 million CFU / mL, 50 million to 75 million CFU / mL, 100 million to I billion CFU / mL, 100 million to 500 million CFU / mL, 100 million to 400 million CFU / mL, 100 million to 300 million CFU / mL, 100 million to 200 million CFU / mL, 100 million to 150 million CFU / mL, 100 million to 125 million CFU / mL, 125 million to 1 billion CFU / mL, 125 million to 500 million CFU / mL, 125 million to 400 million CFU / mL, 125 million to 300 million CFU / mL, 125 million to 200 million CFU / mL, 125 million to 150 million CFU / mL, 150 million to 1 billion CFU / mL, 150 million to 500 million CFU / mL, 150 million to 400 million CFU / mL, 150 million to 300 million CFU / mL, 150 million to 200 million CFU / mL, 200 million to 1 billion CFU / mL, 200 million to 500 million CFU / mL, 200 million to 400 million CFU / mL, 200 million to 300 million CFU / mL, 300 million to 1 billion CFU / mL, 300 million to 500 million CFU / mL, 300 million to 400 million CFU / mL, 400 million to I billion CFU / mL, 400 million to 500 million CFU / mL, or 500 million to 1 billion CFU / mL or more such as 10 billion CFU / ml. 1154] In some embodiments, where the composition is a solid, the concentration of the viable at least one member of the Lactobacilli genus cells can be estimated via colony-forming units per gram (CFU / g). In some embodiments, the concentration of the at least one member of the Lactobacilli genus is from 0.5 million to 1 billion CFU / g, 0.5 million to 500 million CFU / g, 0.5 million to 400 million CFU / g, 0.5 million to 300 million CFU / g, 0.5 million to 200 million CFU / g, 0.5 million to 150 million CFU / g, 0.5 million to 125 million CFU / g, 0.5 million to 100 million CFU / g, 0.5 million to 75 million CFU / g, 0.5 million to 50 million CFU / g, 0.5 million to 10 million CFU / g, 0.5 million to 5 million CFU / g, 0.5 million to I million CFU / g, 1 million to I billion CFU / g, I million to 500 million CFU / g, I million to 400 million CFU / g, I million to 300 million CFU / g, 1 million to 200 million CFU / g, 1 million to 150 million CFU / g, 1 million to 125 million CFU / g, 1 million to 100 million CFU / g, 1 million to 75 million CFU / g, 1 million to 50 million CFU / g, 1 million to 10 million CFU / g, 1 million to 5 million CFU / g, 5 million to 1 billion CFU / g, 5 million to 500 million CFU / g, 5 million to 400 million CFU / g, 5 million to 300 million CFU / g, 5 million to 200 million CFU / g, 5 million to 150 million CFU / g, 5 million to 125 million CFU / g, 5 million to 100 million CFU / g, 5 million to 75 million CFU / g, 5 million to 50 million CFU / g, 5 million to 10 million CFU / g, 10 million to 1 billion CFU / g, 10 million to 500 million CFU / g, 10 million to 400 million CFU / g, 10 million to 300 million CFU / g, 10 million to 200 million CFU / g, 10 million to 150 million CFU / g, 10 million to 125 million CFU / g, 10 million to 100 million CFU / g, 10 million to 75 million CFU / g, 10 million to 50 million CFU / g, 50 million to 1 billion CFU / g, 50 million to 500 million CFU / g, 50 million to 400 million CFU / g, 50 million to 300 million CFU / g, 50 million to 200 million CFU / g, 50 million to 150 million CFU / g, 50 million to 125 million CFU / g, 50 million to 100 million CFU / g, 50 million to 75 million CFU / g, 100 million to 1 billion CFU / g, 100 million to 500 million CFU / g, 100 million to 400 million CFU / g, 100 million to 300 million CFU / g, 100 million to 200 million CFU / g, 100 million to 150 million CFU / g, 100 million to 125 million CFU / g, 125 million to 1 billion CFU / g, 125 million to 500 million CFU / g, 125 million to 400 million CFU / g, 125 million to 300 million CFU / g, 125 million to 200 million CFU / g, 125 million to 150 million CFU / g, 150 million to 1 billion CFU / g, 150 million to 500 million CFU / g, 150 million to 400 million CFU / g, 150 million to 300 million CFU / g, 150 million to 200 million CFU / g, 200 million to 1 billion CFU / g, 200 million to 500 million CFU / g, 200 million to 400 million CFU / g, 200 million to 300 million CFU / g, 300 million to 1 billion CFU / g, 300 million to 500 million CFU / g, 300 million to 400 million CFU / g, 400 million to 1 billion CFU / g, 400 million to 500 million CFU / g, or 500 million to 1 billion CFU / g, or more such as 10 billion CFU / ml.

[155] In some embodiments, the present invention is directed a use of the veterinary antimicrobial composition wherein the pharmaceutical formulation comprises from 107 to IO9 CFU / g of Lactobacillus reuteri DSMI7648 and zeolite, wherein the zeolite is present in an amount of at least 50 mg gram of the formulation.

[156] In some embodiments, the present invention is directed a use of the veterinary antimicrobial composition wherein the pharmaceutical formulation further comprises calcium carbonate and magnesium carbonate, wherein the calcium carbonate and magnesium carbonate are each present in an amount of at least 0.5 mg / gram of the formulation.

[157] In some embodiments, the present invention is directed a use of the veterinary antimicrobial composition wherein the dose of the antimicrobial composition is formulated as a palatable capsule, lyophilizate, liquid, pill, freeze-dry powder, tablet, caplet, soft chewable or gel.

[158] In some embodiments, the present invention is directed a use of the veterinary antimicrobial composition wherein the treatment leads to complete remission of the disease or disorder caused by or associated with Helicobacter spp infection. Quorum sensing 1159] Without wishing to be bound by theoiy, quorum sensing is generally considered to represent a response to fluctuations in cell-population density. Quorum sensing microorganisms for instance bacteria, produce and release chemical signal molecules called autoinducers that increase in concentration as a function of cell density. The detection of a minimal threshold stimulatory concentration of an autoinducer leads to an alteration in gene expression. Microorganism such as Gram-positive and Gram-negative bacteria use quorum sensing communication circuits to regulate a diverse array of physiological activities. These processes include symbiosis, virulence, competence, conjugation, antibiotic production, motility, sporulation, and biofilm formation. In general, Gram-negative bacteria use acylated homoserine lactones as autoinducers, and Grampositive bacteria use processed oligo-peptides to communicate. Recent advances in the field indicate that cellcell communication via autoinducers occurs both within and between bacterial species.

[160] A desirable level of antimicrobial metabolites can depend on the preferred subsequent uses of the antimicrobial composition.

[161] In some embodiments the desirable level of antimicrobial metabolites is at the peak of log phase.

[162] In some embodiments the growth or propagation of the antimicrobial culture is substantially reduced or stopped upon reaching the peak of log phase.

[163] The term “substantially reduce” as used herein, refers to a sufficiently high degree of reduction between a numeric value and a reference numeric value such that one of skill in the art would consider the difference between the two values to be of statistical significance within the context of the biological characteristic measured by said values. In some embodiments, the substantially reduced numeric values is reduced by greater than about any one of 10%, 15% 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 100% compared to the reference value.

[164] In some embodiments the antimicrobial metabolites can be toxic to pathogenic microorganisms such as bacterial pathogens. As used herein the term “toxic” refers to a toxin or other microbial substance or metabolite which induces an immune response especially the production of antibodies or peptides.

[165] In various embodiments, the propagated veterinary antimicrobial culture can be useful for the treatment of animal diseases caused by microorganisms such as bacteria through the inhibition of the bacterial quorum sensing cascade rendering the pathogen avirulent. Such diseases include endocarditis, respiratory and pulmonary infections (preferably in immunocompromised patients), bacteraemia, skin conditions, vagina, colon, central nervous system infections, ear infections including external otitis, eye infections, bone and joint infections, urinary tract infections, gastrointestinal infections and skin and soft tissue infections including wound infections, pyoderma and atopic dermatitis which all can be triggered by Helicobacter spp such as Helicobacter pylori.

[166] In some embodiments the propagated antimicrobial culture is lyophilised. As used herein the term “lyophilised” means preserving the propagated antimicrobial culture by freezing it very quickly and then subjecting it to a vacuum or sublimation to remove the ice. In some embodiments, the lyophilised antimicrobial culture is preserved long-term. In some embodiment the lyophilised antimicrobial culture comprises viable microbial cells. In some embodiment, lyophilisation can be used to prepare a dosage form that is to be reconstituted for injection.

[167] In some embodiments the lyophilised antimicrobial culture is a lyophilised veterinary antimicrobial composition.

[168] In some embodiments the lyophilised veterinary antimicrobial culture is a lyophilised antibacterial composition. In some embodiments the lyophilised antibacterial composition comprises zelotite and at least one member of the Lactobacilli genus is Lactobacillus reuteri. In some embodiments, the lyophilised antimicrobial composition comprises a zelotite and Lactobacillus reuteri DSM17648. In some embodiments, the lyophilised antimicrobial composition comprises a zelotite, Lactobacillus reuteri DSM17648 and a mineral salt. In some embodiments, the lyophilised antimicrobial composition comprises a zelotite, Lactobacillus reuteri DSMI7648, calcium carbonate and magnesium carbonate.

[169] In some embodiments there is provided a propagated antimicrobial culture combined with one or more pharmaceutically acceptable ingredients. In some embodiments there is provided a propagated antimicrobial culture combined with one or more pharmaceutically acceptable excipients or additive.

[170] In some embodiments the pharmaceutical compositions comprise the antimicrobial agent. In some embodiments the pharmaceutical compositions comprised the antibacterial agent.

[171] Thus, the present invention also relates to compositions including pharmaceutical compositions comprising a therapeutically effective amount of a propagated antimicrobial culture, for example a lyophilised culture, as mentioned herein. As used herein a propagated antimicrobial culture, for example a lyophilised culture, will be therapeutically effective if it is able to affect the target microorganism concentration.

[172] Preferably, a propagated antimicrobial culture, for example a lyophilised culture or formulation, will be therapeutically effective if it is able to affect the target microorganism concentration where it is able to treat or prevent a microorganism related disease such as bacteria-related disease or disorder in an animal after the composition, for example a lyophilised composition, has been administered to an animal. In some embodiments the disease or disorder is associated with a pathogen. 1173] In some embodiments, the pathogen is Helicobacter spp. In some embodiments the pathogen is selected from the group comprising Helicobacter canis, Helicobacter felis, Helicobacter heilmannii, Helicobacter mustelae, Helicobacter bizzozeronii, Helicobacter acinonyx, Helicobacter fenneliae, Helicobacter rappini, Helicobacter hepaticus, Helicobacter pullorum, Helicobacter bilis, Helicobacter rodentium, Helicobacter trogontum, Helicobacter cinaedi, Helicobacter muridarum, Helicobacter pametensis, Helicobacter cholecyctus and Helicobacter pylori. [174| In some embodiment of the present invention, the disease or condition is associated with or caused by Helicobacter canis.

[175] In some embodiments, the pathogen is Helicobacter pylori.

[176] In a further embodiment, the propagated antimicrobial culture, for example a lyophilised culture of the present invention can be administered directly to animals, preferably to mammals, and in particular to animals as veterinary non-antibiotic antibiotics per se, as mixtures with one another or in the form of pharmaceutical preparations which allow enteral or parenteral use and which as active constituent contain an effective dose of the propagated antimicrobial culture, for example a lyophilised culture, in addition to customary pharmaceutical excipients and additives.

[177] As mentioned above, in addition to the propagated antimicrobial culture, the culture can contain further customary, usually inert carrier materials, additives or excipients. Thus, the culture can also contain additives or adjuvants commonly used for instance in galenic formulations, such as, e.g., fillers, extenders, disintegrants, binders, glidants, wetting agents, stabilizers, emulsifiers, preservatives, sweetening agents, colorants, flavourings or aromatisers, buffer substances, and furthermore solvents or solubilizers or agents for achieving a depot effect, as well as salts for modifying the osmotic pressure, coating agents or antioxidants. They can also contain two or more cultures and also other therapeutically active substances such as antivirals, antifungals or antibiotics.

[178] Thus, the cultures of the present invention can be used alone, in combination with other compounds of this invention or in combination with other active compounds, for example with active ingredients already known for the treatment of the afore mentioned diseases, whereby in the latter case a favourable additive effect is noticed. 1179] In another aspect, the present invention provides a process of preparing a product selected from food products, beverages, nutritional products, nutraceuticals and animal feed, the process comprising combining one or more ingredients with a propagated antimicrobial culture.

[180] In some embodiment, the propagated antimicrobial culture products can incorporate inert, inorganic or organic excipients.

[181] In some embodiments, to prepare pills, tablets, coated tablets and hard gelatine capsules, e.g., lactose, com starch or derivatives thereof, talc, stearic acid or its salts, etc. can be used. Excipients for soft gelatine capsules and suppositories are, e.g., fats, waxes, semi-solid and liquid polyols, natural or hardened oils etc. Suitable excipients for the production of solutions and syrups are, e.g., water, alcohol, sucrose, invert sugar, glucose, polyols etc. MATERIALS AND MRETHODS 1182] L Growth and laboratory maintenanre of H. pylori

[183] Different microbiological techniques and methods of maintaining and growing H. pylori would be known to the skilled person. An example of such laboratory techniques which have been employed in the present invention can be found in following link:

[184]     2. TEST FOR UREASE OUTPUT

[185] Urease activity assay kit (Sigma Aldrich)

[186] The urease test identifies those organisms that are capable of hydrolyzing urea to produce ammonia and carbon dioxide. It is primarily used io distinguish urease-positive Proteeae from other Enterobacteriaceae.

[187] Method 1

[188] The ureolytic activity assay with the M9U medium is capable of screening cell-based and cell-free urease activity'. Urea-containing growth medium and method for continuous real-time monitoring and screening of mease activity from both bacterial cells and pure mease in a plate reader setup. The defined M9-based mea (M9U) medium was found to be more sensitive and suitable for a plate reader setup than both Christensen's urea broth (CUB) and Stuart's mea broth (SUB), which are established and well-known complex urea media that formed the principle foundation of M9U. Furthermore, the urease activity measmements using the M9U medium in our plate reader-based method allow reliable high-throughput screening of mease inhibitors.

[189] Development of a M9-based mea medium (M9U) for sensitive and real-time monitoring of ureolytic activity of bacteria and cell-free mease Jens Jakob Sigmdarson, Simon Svane, Henrik Karring:

[190] Method 2

[191] Our assay is a robust cellular model to test, directly in the immediate cellular environment, urease inhibitors. The efficacy of a co-expressed peptide to affect the interaction between UreF and UreD, two accessory proteins necessary for urease activation, was observed. This event involves a process that occms through folding upon binding, pointing to the importance of intrinsically disordered hot spots in protein interfaces. [ 192] Targeting Helicobacter pylori mease activity and matmation: In-cell high-throughput approach for drug discovery CinziaTarsia, AlbertoDanielli, FrancescaFlorini, PaoloCinelli, StefanoCiurli, Barbara Zambelli. |193] Two media ty pcs are commonly used to detect mease activity-.

[194] Christensen’s mea agar is used to detect urease activity- in a variety of microorganisms. Stuart’s urea broth is used primarily for the differentiation of Proteus species. For Christensen’s urea agar, urease production is indicated by a bright pink (fuchsia) color on the slant that may extend into the butt after 1-6 hours of incubation.

[195] The culture medium will remain a yellowish colour if the organism is mease negative.

[196] For Stuart’s urea broth, urease production is indicated by a bright pink (fuchsia) colour throughout the broth. [197'|    TEST FOR AMMONIA - EXAMPLE PREDICTIVE MARKER

[198] Ammonium test kit Quantofix (Sigma Aldrich) Ammonia Assay Kit (Sigma Aldrich).

[199] Four solutions with the following concentrations: 50, 100, 300, and 500 mg L-l N-NH4+ were prepared from the standard solution of ammonium chloride at concentration of 1 g L-l These solutions were subjected to the pH analysis performed with the potentiometric method.

[200] Samples of 1, 2 g &3g of clinoptilolite were weighed and 100 ml of N-NH4+ solutions were added. The prepared samples were shaken for 30, 60 and 180 minutes and after that the pH was measured. Next, the samples were filtered in order to determine the concentration of ammoniacal nitrogen.

[201] Each solution was prepared in triplicates.

[202] The ammonium concentration of the aqueous phase was determined by the standard distillation method. Prior to the determination of ammoniacal nitrogen the filtered samples were subjected to distillation (BUCHI 323) and the concentration of N-NH4+ was determined using spectrophotometer (Hach). |203] FIGURE 1 describes an in vitro urea and ammonia reduction assays data using the antimicrobial compositions of the invention (composition B).

[204] Fixed Bed Ion Exchange Column Studies In order to test the feasibility of natural Zeolite-Stilbite as an adsorbent for the removal of nitrate from groundwater, a continuous mode of application was studied in a glass column (60 cm x 0.8 cm).

[205] Natural ZeoliteStilbite was suspended in distilled water for about 10 minutes and was then used for column studies, glass wool was kept at the bottom of the column to avoid the losses of sorbent with the flow of nitrate solution. Then the sorbents was transferred onto the glass wool in the column. Nitrate solution was fed into the column at the flow rate of 10 ml / min using a peristaltic pump. Journal of Water Resource and Hydraulic Engineering Dec. 2014, Vol.b, Iss. 4, PP. 74-80 - 77 - determine exhaustive capacity7, 50-ml fractions of the effluent were collected from the bottom of the column.

[206] The process was continued until the amount of nitrate in the effluent was the same as that in the feed. PH was measured using pH meter (Elico Instruments model LI-107). The effect of pH was studied in the pH range 2 to 7 by adjusting pH of nitrate solutions using dilute HCL and NaOH solutions.

[207] The effect of flow rate was studied with different flow rate between 1 to 5 mL per min. by using peristaltic pump. The effect of different initial concentration was studied with different concentration nitrate solution in the range between 40 to 240 mg / L. [208| After each service cycle of the exchange, a regeneration cycle took place with the solution of sodium nitrate with the concentration of 30 g / L, by passing the solution from the top of the column through the fixed bed of Zeolite. The regeneration process was stopped when the nitrate ion concentration in the effluent became.

[209] AMMONIA EXCHANGE CAPACITY (AEC), OPTIMISATION 1210] The inhibitory7 effect of Ca2+on NH4+exchange efficiency was fitted to the competitive inhibition Monod model with half-saturation rate constant of 134.7 mg L-L Ca2 addition reduced the NH4+ removal rate and lengthened the exchange equilibrium time of zeolite. |211] Periodic precipitation of Ca2+ in the form of calcium carbonate from the used regenerant maintained the removal efficiency of NH4+ commendably by alleviating inhibition effect of Ca and extended the working life of zeolite.

[212] Compared to Bohart-Adams model and Thomas model, the Dose-Response model could predict the breakthrough curve well, and the fitted parameter further confirmed that NaClO-NaCl regeneration with periodic Ca2+ removal is an effective method to maintain efficient NH4+ from wastewater by zeolite. EXAMPLES |213] H. pylori infection is associated with elevated levels of ammonia and / or urea which allow members of the pathogen to survive and thrive in a higher pH as may be found in the GIT of animals.

[214] Removing or reducing the levels of ammonia and / or urea may adversely affect the survival of H. pylori if exposed to physiologically normal gastric acid conditions. The ability of the antimicrobial composition of the present invention to remove or reduce ammonia and / or urea levels that Helicobacter spp.. for example, Helicobacter pylori produce was tested.

[215] Lactobacillus L. reuteri a Gram positive (+ve) bacteria aggregates to the exposed H. pylori and with the active mineral salts such as calcium carbonate and / or magnesium carbonate help remove the pathogen from an animal.

[216] The carbonates help to ease stomach discomfort and contribute to rebalance the natural action of the stomach of an animal. |217] Lactobacillius L. reuteri can survive the normal gastric acid conditions of the stomach populating the microbiota much more favourably.

[218] If an animal suffers with the following symptoms of H. pylori-, bloating, abdominal pain worse when stomach is empty, nausea, shortness of breath, vomiting, acid reflux, high ammonia / ammonium levels, ulcers, gastritis, gastric cancer, black tarry stool. [219| Example - antimicrobial composition A used in to treat H. pylori pathogen infection: • 3.5g double activated Zeolite Clinoptilolite • at least one veterinary acceptable excipient • 1 Obillion viable organisms L. reuteri DSM17648 culture. Example - antimicrobial composition B used in tests to treat H. pylori pathogen infection: • 2g calcium carbonate • 2g magnesium carbonate • 3.5g double activated Zeolite Clinoptilolite • ~lg to 5g of at least one veterinaiy acceptable excipient (sodium starch glycolate or an analogue of providone), • 10 billion viable organisms L. reuteri DSM17648 culture. Example - antimicrobial composition C for treating acid reflux and bloating associated with H pylori infection: • 1.5g double activated Zeolite Clinoptilolite • at least one veterinary acceptable excipient • 5 billion viable organisms L. reuteri DSM17648 culture. Example - antimicrobial composition D for treating acid reflux and bloating associated with H. pylori infection: • 1g calcium carbonate • 1g magnesium carbonate • 1.5g double activated Zeolite Clinoptilolite • at least one veterinary acceptable excipient • 5 billion viable organisms L. reuteri DSM17648 culture. Antimicrobial composition A, B, C or D can be employed in a regimen for treating H. pylori pathogen infection in a animal. • Sachet of powder such as lyophilised culture of the antimicrobial composition of choice -dissolved in water • at least one veterinary acceptable excipient • Liquid suspension in lactulose • Tablet format Veterinary antimicrobial composition A, B, C or D employed in a regimen for treating H. pylori pathogen infection in an animal. • Sachet of powder such as lyophilised culture of the antimicrobial composition of choice -dissolved in water; • Liquid suspension in lactulose Composition and Physicochemical Properties of the Tribomechanically Activated Zeolite Clinoptilolite (TMAZ®). Examples of the at least one veterinary acceptable excipient are provided in the description. For completeness, the veterinary acceptable excipient of anyone of the veterinary antimicrobial composition A, B, C or D can be selected from at least one tolerated by animals binder, disintegrant, lubricant, glidant, humectant, antioxidant, flavour modifier and colorant. Chemical composition SiO2, 65.0-71.3%; A12O3, 11.5-13.1%; CaO 2.7-5.2%; K2O, 2.2-3.4%; Fe2O3, 0.7-1.9%; MgO, 0.6-1.2%; Na2O, 0.2-1.3%; TiO2, 0.1-0.3%; Si / Al ratio, 4.8-5.4. Empirical formula (Ca,K2,Na2,Mg)4AlsSuo096 x 24H2O • Physicomechanical properties Specific mass, 2.2-2.5 g / cm3; porosity, 32-40%; effective pore diameter, 0.4 nm • Ion-exchanging capacity Total exchange capacity, 1.2-1.5 mol / kg; Ca2+, 0.64-0.98 mol / kg; Mg2+, 0.06-0.19 mol / kg; K+, 0.22-0.45 mol / kg; Na+, 0.01-0.19 mol / kg Ion-exchanging selectivity Cs>NH4+>Pb2+>K+>Na+>Mg2+>Ba2+>Cu2+>Zn2+ Chemicals absorbed NH3, hydrocarbons C1-C4, CO2, H2S, SO2, NOX, aldehydes. • Toxicity Nontoxic; generally recognized as safe (GRAS) according to US Code of Federal Regulations (21 CFR 182, Subpart C). Effective in vivo testing on animals such as sheep - FIG. 2 No previous symptoms were reported with the animals (sheep flock) such as vomiting, weight loss or wool loss. Blood tests and a series of at least six (6) B12 injections were administered as a loading dose within 2 weeks. Following the identification of an H. pylori infection in a stool test, animal can be prescribed veterinary protocol triple therapy; amoxicillin 500mg, Clarithromycin 500mg, lansoprazole 30mg, to be taken for 7 days. Upon completion of the prescribed standard of care for treatment of H. pylori infection antibiotic course and re-tested the stool sample a month later. However, the test results remained positive with no discernible improvement of the symptoms. The animal was treated using combined calcium carbonate, magnesium carbonate, Zeolite Clinoptilolite, sodium starch glycolate and L. reuteri for 5 days (veterinary antimicrobial composition B as detailed above). Effective regimen or course for administration and treatment for H. pylori - duration of regimen 5 days. Upon completion of the regimen, the test results for H. pylori were negative. It is hypothesised that the animal naturally creates more acid to combat Helicobacter spp such as H. pylori in an inflammatory response. The animal also recognises that when the acid levels become too high it needs buffering by deploying the assistance of stores of calcium and magnesium to achieve this. However, over time, for instance, weeks, months or ever years of persistent Helicobacter spp such as H. pylori infection, too much acid and depleted stores of magnesium and calcium may lead to other ailments and concomitant symptoms, alongside the gastric disorders potentially caused by the auto immune response and colonisation from the pathogen. Using the non-antibiotic veterinary antibacterial compositions of the present invention the inventors were not only able to effectively reduce ammonia and urea levels but also in vivo in a patient eliminate H. pylori but are able to prevent associated symptoms, diseases or conditions which are linked to or associated with Helicobacter spp such as H. pylori infection.

[220] The disclosure illustratively described herein can suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising’', “including, “containing”, etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the disclosure claimed. * * *

Claims

1. A veterinary composition comprising:a. therapeutically effective amount of a zeolite and at least one member of the Lactobacilli genus; andb. at least one veterinary acceptable excipient.

2. A veterinary7 composition according to claim 1, wherein the composition further comprises at least one animal based palatant and / or at least one non-animal based palatant.

3. A veterinary composition according to anyone of claims 1 or 2, wherein the at least one veterinary acceptable excipient is selected from a disintegrant, binder, humectant, lubricant, glidant, and flavour modifier; and wherein the non-animal based palatant is yeast.

4. A veterinary composition according to claim 3, wherein the veterinary acceptable disintegrant is an analogue of providone, sodium starch glycolate, or mixture thereof.

5. A veterinary7 composition according to claim 4, wherein the disintegrant is a mixture of an analogue of an analogue of providone and sodium starch glycolate, and combined are in the amount of about 10w / w% to about 15w / w% of the total weight of the composition.

6. A veterinary composition according to claim 3, wherein the veterinary acceptable binder comprises polyethylene glycol, a gum, or mixture thereof.

7. A veterinary composition according to claim 6, wherein the polyethylene glycol is polyethylene glycol 3350 and the gum is xanthan gum and wherein the mixture of polyethylene glycol and the gum comprises about 5w / w% to about 7w / w% of the total weight of the composition.

8. A veterinary composition according to claim 3, wherein the veterinary acceptable humectant is glycerol in the amount of about 10w / w% to about 15w / w% of the total weight of the veterinary composition.

9. A veterinary composition according to claim 3, wherein the veterinary' acceptable lubricant is a mixture of magnesium stearate and glycerol monostearate and wherein the composition comprises about 1 w / w% to about 3w / w% of a glidant and about 0.4w / w% to about 0.6w / w% of a flavour modifier.

10. A veterinary' composition according to anyone of the preceding claims, wherein the zeolite is naturally occurring or synthetic.

11. A veterinary composition according to claim 10, wherein the zeolite is zeolite clinoptilolite (ZC).

12. A veterinary composition according to anyone of claims 10 or 11, wherein the zeolite is activated zeolite clinoptilolite (aZC), preferably double activated zeolite clinoptilolite (aZC).

13. A veterinary' composition according to anyone of the preceding claims, wherein the at least one member of the Lactobacilli genus is selected from the group consisting of Lactobacillus reuteri. Lactobacillus delbrueckii, Lactobacillus rhamnosus, Lactobacillus casei, Lactobacillus acidophilus, Lacticaseibacillusparacasei, Lactiplantibacillus plantarum, Levilactobacillus brevis, Ligilactobacillus salivarius, Limosilactobacillus fermentum, Lactobacillus bulgaricus, Lactobacillus crispatus, Lactobacillus helveticus and Lactobacillus johnsonii.

14. A veterinary composition according to claim 13, wherein the at least one member of the Lactobacilli genus is Lactobacillus reuteri.

15. A veterinary composition according to anyone of claims 13 or 14, wherein the Lactobacillus reuteri is Lactobacillus reuteri DSM17648.

16. A veterinary composition according to anyone of the preceding claims, wherein the animal is administered with a therapeutically effective amount of the veterinary composition.

17. A veterinary’ composition according to claim 16, wherein the therapeutically effective amount is achieved by a regimen of administration of the zeolite and the at least one member of the Lactobacilli genus.

18. A veterinary composition according to claim 17, wherein the regimen comprises one or more types of administration of the zeolite and the at least one member of the Lactobacilli genus.

19. A veterinary composition according anyone of the preceding claims, wherein the at least one member of the Lactobacilli genus is viable.

20. A veterinary7 composition according to claim 19, wherein the composition comprises from 107 to 109 CFU / g of Lactobacillus reuteri DSM17648 and zeolite, wherein the zeolite is present in an amount of at least 50 mg / gram of the formulation.

21. A veterinary composition according to anyone of the preceding claims, wherein the veterinary composition further comprises biologically active substances or minerals such as calcium carbonate, magnesium carbonate, vitamins, such as D and E, pharmaceutically acceptable carriers, additives and adjuvants, as well as antimicrobial chitin, such as chitosan and alpha-ketoglutarate, citrate and lactate.

22. A veterinary' composition according to anyone of claims 17 to 21, wherein the regimen of administration is suitable for peroral administration or gastric administration.

23. A veterinary composition according to anyone of the preceding claims, wherein the veterinary composition comprises, activated zeolite clinoptilolite (aZC), Lactobacillus reuteri DSM17648, calcium carbonate and magnesium carbonate.

24. A veterinary composition according to anyone of the preceding claims, wherein the veterinary composition leads to a reduction of one or more markers in an animal.

25. A veterinary' composition according to claim 24, wherein the marker is a predictive marker selected from the group consisting of urea, gastric ammonia, acid reflux, bloating and urease activity.

26. A veterinary composition according to anyone of claims 24 or 25, wherein the predictive marker is gastric ammonia.

27. A veterinary composition according to according to claim 26, wherein the antimicrobial composition leads to reduction of gastric ammonia levels in an animal infected by Helicobacter pylori.

28. A veterinary' composition according to anyone of claims 24 to Tl, wherein the reduction of the marker is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% or greater compared to placebo.

29. A veterinary composition according any one of claims 24 or 27, wherein the reduction of the marker is at least 0.1, 0.25, 0.5,1, 1.5, 2, 2.5, 3, 3.5,4,4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5,9, 9.5, or 10-fold or greater compared to placebo.

30. A veterinary composition according to any one of claims 24 to 30, wherein the reduction of the marker is statistically significant compared to a placebo.

31. A veterinary composition according to claim 30, wherein the reduction of the marker levels in an animal infected with Helicobacter pylori is statistically significant.

32. A veterinary composition according to anyone of the preceding claims, wherein the antimicrobial composition leads to a statistically significant clinical improvement in an animal infected with Helicobacter pylori.

33. A veterinary composition according to anyone of claims 1 to 32, for use in the treatment of a condition associated with Helicobacter spp.

34. A veterinary composition for use according to claim 33, for use in treating an animal with a condition associated with Helicobacter pylori.

35. A veterinary composition for use according to claim 34, wherein the animal is selected from a companion animal and livestock.

36. A veterinary composition for use according to anyone of claims 33 to 35, wherein the companion animal is a dog (canine), cat (feline), and horse (equine), and wherein the livestock is pig, goat, sheep, and cattle.

37. A veterinary composition for use according to anyone of claims 33 to 35, wherein the animal is deer, ferret, guinea pig, rabbit and zoo animal.

38. A use of a veterinary composition according to anyone of claims 1 to 32, for the manufacture of a pharmaceutical formulation for separate, combined, sequential or concomitant administration designed for the treatment, alleviation or prophylaxis of GIT disease or disorder, gastritis, gastric ulcer, duodenal ulcer, gastric cancer, cholestatic disorders, liver disfunction, duodenal cancer, in need of such treatment, alleviation or prophylaxis in an animal.

39. A use according to claim 38, wherein the pharmaceutical formulation is in a form suitable for administering a dose of the veterinary composition in a dose or as divided doses or sub-doses administered at appropriate intervals per day.

40. A use according to claim 39, wherein the pharmaceutical formulation in administered as one, two, three, four or more doses or sub-doses per day or per administration.

41. A use according to anyone of claims 38 to 40, wherein the pharmaceutical formulation comprises from 107 to 109 CFU / g of Lactobacillus reuteri DSM17648 and zeolite, wherein the zeolite is present in an amount of at least 50 mg / gram of the formulation.

42. A use according to anyone of claims 38 to 41, wherein the pharmaceutical formulation comprises from 107 to 109 CFU / g of lactobacillus reuteri DSM17648 and zeolite wherein the pharmaceutical formulation further comprises calcium carbonate and magnesium carbonate, wherein the calcium carbonate and magnesium carbonate are each present in an amount of at least 0.5 mg / gram of the formulation.

43. A use according to anyone of claims 38 to 42, wherein the dose of the veterinary composition is formulated as a palatable capsule, lyophilizate, liquid, pill, freeze-dry powder, tablet, caplet, soft chewable or gel.30

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