WO2019106626A1

WO2019106626A1 - Composition for oral administration, the use of the composition in prevention and treatment of mucositis, and a method of treatment of mucositis

Info

Publication number: WO2019106626A1
Application number: PCT/IB2018/059525
Authority: WO
Inventors: Agata LEWANDOWSKA
Original assignee: Lewandowska Agata
Priority date: 2017-12-01
Filing date: 2018-11-30
Publication date: 2019-06-06
Also published as: PL423673A1

Abstract

The invention relates to a composition for oral administration, the use of the composition for prevention and treatment of mucositis, and the method of treating mucositis using this composition in patients before and after the systemic treatment.

Description

COMPOSITION FOR ORAL ADMINISTRATION, THE USE OF THE COMPOSITION IN PREVENTION AND TREATMENT OF MUCOSITIS, AND A

METHOD OF TREATMENT OF MUCOSITIS

Field of the invention

The present invention relates to a composition for oral administration, the use of such composition to prevent and treatment of mucositis (intestinal mucosa toxic damage) and the method of treatment of mucositis using said composition in patients before and after the systemic treatment. The composition is useful for preventing the occurrence of mucositis in patients before and after the systemic treatment, for example in patients after the chemotherapy. Using nutrient ingredients contained in the composition administrated orally before the systemic treatment which is carried out by using chemotherapy is intended to prevent malabsorption, and after the end of the treatment - to treat gastrointestinal complications related to absorption and digestion disorders.

Background of the invention

Stability and proper functioning of intestinal mucosa depends on many factors. These factors are genetic predisposition, environmental conditions and associated with them modifiable and unmodifiable risk factors, intestinal microflora composition, immune system activity and intestinal barrier condition (squamous epithelium belonging to rapidly dividing cells). In the case of healthy individuals it is normal bacterial flora supplied through foods rich in fiber, or containing alive bacterial cultures, that provides the basic source of energy for enterocytes. Intestinal barrier is preserved due to many layers of epithelium (including the presence of proteins typical for tight junctions) and the cooperation of the immune and lymphatic systems, which are intended to recognize pathogens and to not allow for their passage through the intestinal wall. The entire system located in the mucous membrane of the digestive tract forms the GALT system ( gut-associated lymphoid tissue).

Neoplasm (especially of malignant nature) is the process of uncontrolled proliferation of various type of cells. Specifically at the advanced stage such proliferation is usually accompanied with tumor angiogenesis and transfer of cell clones (genetically identical) via blood vessels to other distant organs. As a result of the migration of cell clones new metastases arise. Uncontrolled by the physiological mechanisms cells proliferation leads to damage of primary organ and adjacent organs. The essential role in the neoplasmatic process plays the inflammation induced by the immune system as a consequence of existing disease. Intensification of synthesis of acute-phase proteins in the liver and production of pro- inflammatory factors by cells of the immune system determinate the result of such state. Their increased and persistent amount in plasma inhibits the hunger and satiety regulation center located in the hypothalamus, resulting in eating disorders frequently manifested in anorexia. Generalized inflammation also plays an important role in the development of disorders of basic metabolic processes. In the pathways of carbohydrate metabolism anaerobic glycolysis and gluconeogenesis are intensified and the insulin resistance of peripheral tissues also increases. Disorders in fat metabolism are primarily increasing in the rate of lipolysis and simultaneously limiting of liponeogenesis. In the protein metabolism however the proteolysis of skeletal muscle proteins is increased. Amino acids released in this process, among others are used for the production of glucose de novo (gluconeogenesis), the production of cancer- causing proteins and production of acute-phase proteins; the excessive amount of which leads to eating disorders as mentioned above. The use of the systemic treatment leads to damage of successive layers of squamous epithelium (intestinal mucosa toxic damage), paralysis of the immune and lymphatic systems - including neutropenia, i.e. to damage of the entire GALT system.

The described above processes and phenomena are the reason why patients with damaged mucous membrane of digestive tract ( mucositis of various degrees) after the systemic treatment exhibit low level of tolerance of energy-protein nutrient ingredients. The most frequently manifested symptoms of such intolerance are bloating, belly rumbling, putrescent gasses, up to diarrhea.

As a result of intensification of mentioned above metabolic processes and due to stimulation of the immune system during the disease the body reseves are used and the need for nutrient ingredients increased.

Moreover the systemic treatment often leads to inflammation. Inflammation is a physiological reaction associated with the activation of the immune system in response to the development of neoplasm disease or autoimmune disease. Inflammation also occurs in the case of injury (tissue disintegration) and as a consequence of taking certain medicines. Besides cytokines substances that directly participate in inflammatory reactions are reactive oxygen species (ROS); which damage cellular structures, particularly those related to the cell nucleus and genetic material. As a consequence of administering chemotherapeutic drugs, such as cytarabine (examples of other drugs of this type are given in Table 1 below, in which the side effects of chemotherapeutics negatively affecting the nutritional status are presented), which [drugs] base their action on generating large amounts of ROS among others, and this in turn leads to damage and to disintegration of cancerous cells but healthy cells are also damaged. These are mainly rapidly dividing cells; and among others there are epithelial cells of mucous membranes of the digestive tract.

Table 1

In order to prevent damages caused by ROS and for restoring the antioxidant system efficiency after the treatment it is necessary for individuals in need to take up those compounds which participate in reactions of this system.

Such compounds which supplementation is necessary are selenium, zinc, being cofactors of antioxidant enzymes, glutathione and vitamins C and E, carotenoids and flavonoids, being substances derived from food. The requirement of taking several different from mentioned above compounds is supported by multi-level action of the antioxidant system and their complementation.

Due to its impact on immune system activity selenium deficiency causes the reduction in body responses to bacterial and viral infections, decrease in T lymphocytes activity, macrophages and NK cells, as well as makes disorder in prostaglandins and immunoglobulins synthesis.

Zinc deficiency disturbs the chemotaxis process, functions of NK cells and the ability of macrophages to phagocytosis. The lack of zinc is also associated with the reduction in total amount of B lymphocytes.

Vitamin D which receptors are inter alia on macrophages, monocytes, dendritic cells or active T and B lymphocytes, has an ability to modulate the immune response towards suppression, whereas vitamin A plays an important role in the processes of maturation and differentiation immune system cells.

One of the most important function of vitamin C is the participation in the immune response process triggered by tissue damage, and this affects the mitosis and monocytes migration to the wound site as well as the transformation into macrophages in the inflammatory phase of healing.

Healthy individuals with documented deficiencies of iron, zinc, folic acid, vitamin B12 and choline are diagnosed with increased risk of DNA damage and reduced ability to repair it. Moreover low level of zinc in the body leads to disturbance in DNA repair processes, and after compensation of the deficiency they returns to their normal state.

Furthermore also low intake of the oral diet caused by decreased appetite and/or bothersome symptoms from the gastrointestinal tract causes that during the treatment period the demand for nutrient ingredients is not completely covered.

During the systemic treatment a majority of patients also suffer from depression and anxiety associated with their health condition. Many recent works, inter alia Ewelina Gulas et al. „Can microbiology affect psychiatry? A link between gut microbiota and psychiatric disorders” Psychiatr. Pol. ONLINE FIRST Nr 91: 1-17 indicates that there is a connection between depressed mood and the quality and quantity of bacterial flora producing GABA (aminobutyric acid) among others. In healthy humans GABA - gamma-aminobutyric acid is produced by commensal bacteria - and the whole produced amount acts as a neurotransmitter. Deficiencies in commensal flora causes the deficiencies in GABA synthesis. Too low level of this biogenic neurotransmiter contributes to excessive stimulation of the intestinal system (disorders in intestinal peristalsis - sudden diarrheas - very evident in patients with irritable bowel syndrome for which too low level of GABA acid were also detected, and makes disorder in the amount of naturally produced short-chain fatty acids due to disturbances in the intestinal microflora). Too low biogenic synthesis of this acid promotes mood lowering, nervousness, increases anxiety. For the population of patients with mucositis after chemotherapy the commensal flora producing this acid is damaged, moreover the diet does not contain substances that stimulate the growth of desired bacteria population. Additionally the mucous membrane is chemically damaged by cytostatics and is characterized by disturbed integrity and this makes it impossible to administer the selected strains which would synthetize both GABA acid as well as short-chain fatty acids, particularly butyric acid.

Qualitative malnutrition resulting from persistent damage of intestinal barrier and an inability to rebuild it, affects adversely on the result of the systemic treatment in oncology. Patients reduced nutritional status is associated with lower tolerance to the systemic treatment and higher risk of septic complications (decrease in lymphocyte production, bacterial translocation - (lack of the integrity of mucous membrane) from the intestines to bloodstream) or cachexia syndrome.

Therefore for many years numerous studies has been carried out to develop such formulations which could be useful in the treatment and/or improvement of the condition of individuals suffering from the deficiencies described above, particularly for individuals after the systemic treatment.

State of the art

Various preparations of compositions to be orally administered intended to maintain a proper microbiotic ecosystem in the body are known in the art, as well as numerous additives /supplements/ for enteral administration intended to keep in good condition or to restore the intestinal barrier are known.

For example, the patent specification EP 1638418 discloses an amino acid based supplement intended to maintain a proper microbiotic ecosystem in the body. The nutritional composition disclosed in this patent specification is intended for use in the restoration and in the prevention in healthy [microbiota] and for providing proper microbiota to an individual which may be an animal, including human; and such supplement contains a source of protein, a source of carbohydrates, a source of fats and is supplemented with threonine, serine, proline and cysteine in amounts effective in promotion of growth and equilibrium of microbiota. The composition provides serine in an amount of 0,07 to 0,35 g/kg of the body weight/day; proline in an amount of 0,07 to 0,3 g/kg of the body weight/day; threonine in an amount of 0,04 to 0,20 g/kg of the body weight/day and cysteine in an amount of 0,03 to 0,15 g/kg of the body weight/day.

Polish patent PL202031 discloses a supplement to be administered enterally and the use of components of this supplement for the preparation of such supplement to be administered enterally to maintain in a good condition or to restore the intestinal barrier in critically or chronically ill and malnourished patients. This supplement contains glutamine, antioxidants and fatty acids and has total daily energy value up to 4185 kJ (1000 kcal); and in each case based on a daily dose as a solution it comprises: a) glutamine and/or substances being convertible into glutamine selected from the group consisting of glutamine esters, glutamine amides, N-alkylated glutamines, glutamine salts, keto precursors of glutamine or short-chain glutamine-containing peptides in an amount in a range of 15 to 70 g, but in case of substances being convertible into glutamine given amounts are based on the glutamine participation; b) at least two representatives of the group belonging to the class of antioxidants selected from the group consisting of vitamins, amino acids, amino acid derivatives, amino sulfonic acids, trace elements, polyphenols and carotenoids; and c) short-chain fatty acids having two to five carbon atoms and/or salts or esters taken as substances being convertible into short-chain fatty acids having two to five carbon atoms in an amount in a range of 0,5 to 10 g, but in case of substances being convertible into short-chain fatty acids given amount are based on the short- chain fatty acids participation. This supplement is intended for enteral administration only and it is not possible to administer it through the oral route. Moreover the precursor for synthesis of gamma amino butyric acid is glutamine - and currently it is not recommended as an amino acid for this group of patients, because it can enter many metabolic pathways, including those using blood cancer cells and other solid tumors. Thus, its administration as a GABA precursor in mucositis is not recommended.

Known from the state of the art compositions however do not solve the problem of supporting (aiding) proper intestinal barrier system, particularly in individuals exhibiting symptoms of mucositis.

Inventors of the present invention have surprisingly found that damaged cells of squamous epithelium, even in case of supplying a large amount of protein, fats, carbohydrates, have a limited ability to regeneration due to the low energy supply to those cells.

The only appropriate way to prevent and/or to minimize the intestinal barrier damage introduced before and after the systemic treatment will lead by maintaining a proper condition of the intestinal mucosa and a GALT system, to rapid return of normal digestion and absorption process and further to the proper nutritional status.

Moreover known in the state of the art compositions frequently are an energetic-protein nutrients (oral supplements nutrition), containing aside from protein and fats also alive probiotic bacteria cultures; and the administration of which, especially in the case of deficiency of intestinal barrier function (proliferation of pathogenic flora) may lead to bacterial translocation and sepsis, as well as to induce the symptoms of intolerance such as bloating, diarrhea and putrescent gases, painful intestinal cramps. These nutrient ingredients are characterized by high osmolarity of the mixture and in this group of patients it causes increased severity of diarrhea instead of nutrition.

Thus, an administration of composition enriched in probiotic substances is reasonable in case when an individual to whom such composition is administered, has no recognised deficiency of intestinal barrier function, particularly in individuals exhibiting the symptoms of mucositis, and who are not under the systemic treatment.

Inventor of the present invention surprisingly has come to a conclusion that the malnutrition found in individuals with diagnosed neoplasm disease is caused not only by too low supply of energy, macronutrients (carbohydrates, proteins, fats) and micronutrients (vitamins, mineral ingredients) but at the large extent it is also associated with intestinal barrier damage (mucositis = intestinal mucosa toxic damage), which is responsible for a proper digestion and food absorption as indicated above. The result of such damage is a reduction in amount of nutrient ingredients provided to the body; what in turn leads to fast or slowly growing malnutrition and impaired functioning of all body systems, depending on the degree of intestinal failure.

Inventor of the present invention surprisingly found that the process of regeneration may be initiated and conducted properly only after providing main source of energy for enterocytes, colonocytes (cells of gastrointestinal mucosa) which is in particular butyric acid administered in a pure form or in a form of precursor substances.

Thus, one of the objects of the present invention is to provide a composition enabling to come to the regeneration of the normal intestinal microflora producing short-chain fatty acids by itself, and which, according to the inventor it is only achievable when the intestinal barrier function is maintained; and when it is possible to consume essential substrates necessary to produce those acids - i.e. complex carbohydrates and fiber. However, these substrates can be consumed only when their digestion and absorption is possible, and this depends on the degree of enterocytes reconstitution and liver and pancreas function.

another problem which has to be solved noticed by the present inventor has is the prevention of ROS induced damages and the restoration of efficiency of the antioxidant system after the treatment, since it is necessary to ingest those components that participate in reactions of this system.

Known from the state of the art compositions do not respond to this demand since they do not contain substrate providing energy used directly for intestinal cells reconstruction, what, in the light of the inventor’s findings it is of importance in restoring the proper digestion and absorption process. Without such restoration supplying antioxidants or single amino acids even in large amounts will not be sufficient for fast regeneration of the body after the systemic treatment.

Besides preventing or minimizing intestinal barrier damage the object of the present invention is also to promote antioxidant system of the body being a part of immune system, so also the GALT system.

As a result of using chemotherapeutic drugs during the course of the systemic treatment arises the problem of significant depletion of the resources of many nutrient ingredients used in synthesis of substances sharing immune reactions which is noticed in individuals under the chemotherapeutic s treatment. Moreover low intake of the oral diet caused by decreased appetite and/or bothersome symptoms from the gastrointestinal tract, results in that a demand for nutrient ingredients is not completely covered during the chemotherapeutic treatment.

Besides preventing or minimizing intestinal barrier damage and promoting antioxidant system of the body being a part of immune system, another object of the present invention is to improve the patient’s mood and to reduce intestinal cramps caused by GABA deficiencies.

From the state of the art it is known that in case of GABA deficiencies there is a possibility of seeking a proper bacterial flora and nowadays even [it may be made] through the fecal transplantation from non-related donor. Unfortunately in the case of onco- haematological patients with the toxic damage of intestinal mucosa it is not possible to administer living intestinal flora (even the most carefully selected) into the intestinal lumen due to high risk of bacterial translocation, and afterwards sepsis, which at this time threatens death for patients. The effects of GABA deficiencies are repeated in patients receiving known preparations intestinal cramps, decreased mood, increased aggravation, aggression and increased pain.

Therefore, there is a need to provide to an individual these compounds in increased amounts both before starting the treatment, and when the resources of the body are lowered at this stage of disease, as well as after the end of the treatment in order to restore the body resources lost during the systemic treatment.

Inventor of the present invention addressed above mentioned problems and developed a special formula of a composition to be administered to the individual in order to prevent and/or treat of mucositis after the systemic treatment.

Inventor of the present invention surprisingly found that the saturation with antioxidant substances of an individual in need thereof will reduce the risk of mucositis development, inter alia by neutralization of reactive oxygen species, and will improve the prognosis for further treatment.

With this knowledge the present inventor has shown that many patients undergoing the systemic treatment have significant deficiencies in above mentioned nutrient ingredients, mainly selenium, zinc, and vitamin B12, already at the diagnostic stage. The inventor has also showed that it is highly desirable to use antioxidant compounds at the preparatory stage of the treatment in order to prevent gastrointestinal mucosal membrane cells damage caused by ROS excess.

Inventor of the present invention has also noticed that when the GABA is administered orally in its pure form in an aqueous solution then digestive enzymes affect it. This way a part of administered gamma aminobutyric acid brakes down to free butyric acid and becomes its additional source. The remaining part of GABA which is not break down by digestive enzymes [still] acts as neurotransmitter, and this is beneficial because it gives the reduction in increased intestinal peristalsis - intestinal cramps; and also has a relaxing effect on the digestive tract mucosa.

Summary of the invention

The subject of the present invention is a composition for oral administration to an individual in need thereof, for prevention and treatment of mucositis, containing butyric acid and/or substances being butyric acid precursors suitable to be converted into butyric acid, antioxidants and omega-3 fatty acids, the composition comprising, based on a daily dose:

•butyric acid and/or substances being butyric acid precursors suitable to be converted into butyric acid, preferably butyric acid salts, in an amount of the range of 100 - 499 mg per day, preferably in a dose of about 200 - 300 mg, more preferably about 250 mg per day, in case of substances being butyric acid precursors based on the butyric acid participation,

•antioxidants, preferably being representatives of the group of tocopherols, ascorbic acid, carotenoids, zinc and selenium compounds in the form of their inorganic and organic pharmaceutically acceptable derivatives,

• polyunsaturated fatty acids of the group omega-3 in an amount of the range of 900 - 2000 mg, containing docosahexaenoic acid in an amount of the range of 20-30% of the contents of all omega-3 fatty acids and eicosapentaenoic acid in an amount of the range of 10- 20% of the contents of all omega-3 fatty acids, and these acids are of plant and/or mixed animal-plant origin.

Administration of the composition as described above, particularly [administration] of a butyric acid addresses the problem of the lack of adequate amount of energy supplied to enterocytes, and due to this a regeneration [process] can be initiated and performed properly.

Preferably substances being butyric acid precursors suitable to be converted into butyric acid are substances selected form the group consisting of zinc butyrate, tributyrin and/or gamma-aminobutyric acid, preferably it is zinc butyrate or a combination of zinc butyrate and gamma-aminobutyric acid.

Preferably the composition is characterized in that polyunsaturated fatty acids of the group omega-3 are of plant origin in an amount of the range of 900 - 2000 mg per day, preferably in a dose of about 1000 mg, and they comprise about 273 mg EPA, about 179 mg DHA in a daily portion.

Preferably an individual is an individual under the systemic treatment and the prevention of mucositis is based on improving of the intestinal barrier function.

Preferably an individual is an individual with recognised symptoms of mucositis, and the treatment is based on improving of the intestinal barrier function manifested by reducing symptoms of mucositis.

Preferably the composition is in the form of a powder to be dissolved.

Preferably the composition comprises a combination of antioxidants comprising vitamin C, vitamin E, b-carotene, selenium and zinc.

Preferably as an antioxidants the composition comprises vitamin C in an amount of 250 - 750 mg, vitamin E in an amount of the range of 24 - 48 mg, b-carotene in an amount of the range of 9,6 - 19,2 mg, selenium in an amount of the range of 220 - 750 pg, zinc in the amount of the range of 20 - 40 mg in a daily portion. Preferably the composition contains vitamin C in an amount of about 250 mg in a daily portion and the individual is a paediatric patient.

Preferably the composition contains vitamin C in an amount of about 750 mg in a daily portion and the individual is an adult patient.

Preferably the composition is free of iron and copper.

Preferably the composition additionally comprises B group vitamins, such as Bl, B2, B3, B5, B6, B7, B12, folic acid in an amount which is twice, preferably three times [bigger] of the recommended dietary allowance (RDA).

Preferably the composition additionally comprises magnesium preferably in an amount of 40 mg, calcium preferably in an amount of 250 mg and vitamin K2 preferably in an amount of 60 pg.

The subject of the invention is also the use of the composition as defined above, as the only separate regenerating composition for oral administration to individuals in need, particularly to individuals preparing for the systemic treatment, individuals who had received systemic treatment, individuals exhibiting symptoms of mucositis, individuals exhibiting intolerance to ordinary enteral food preparations for special medical purposes.

Preferably the composition as defined above is administered as a single daily dose.

Preferably the composition as defined above is administered in two to three, preferably in two doses per day, cumulatively not exceeding the daily dose of the composition.

The subject of the invention is also the use of the composition as defined above as an additive /supplement/ to a protein preparation dedicated to patients with high risk of malnutrition, malnourished or with cachexia, as an additive /supplement/ to other multicomponent oral nutritional preparations - ONS for improving their nutritional values in the group of individuals under the systemic treatment, or as an additive /supplement/ to infant milk and follow-on milk for improving their nutritional values in the group of paediatric individuals exhibiting symptoms of mucositis.

The subject of the invention is also a method of treatment of the individual in need, particularly an individual preparing for the systemic treatment, individual, who had received systemic treatment, individual exhibiting symptoms of mucositis, or individual exhibiting intolerance to ordinary enteral food preparations for special medical purposes, and such method is characterized in that it comprises the step of administering the composition as defined above. Preferably the method of treatment relates to the individual in need, particularly an individual preparing for the systemic treatment, and is characterized in that at the step of administration of the composition it is administered as a single daily dose.

Preferably the method of treatment relates to the individual in need, particularly an individual who had received systemic treatment, individual exhibiting symptoms of mucositis, or individual exhibiting intolerance to ordinary enteral food preparations for special medical purposes, and is characterized in that at the step of administration of the composition as defined above it is administered in two to three, preferably in two doses per day cumulatively not exceeding the daily dose of the composition.

The composition comprising a) butyric acid in its pure form, as well as its salts and esters and substances being suitable to convert into butyric acid in the digestive tract (in an amount of the range of 100 - 499 mg per day, preferably about 200 - 300 mg, preferably about 250 mg), b) polyunsaturated fatty acids of plant origin in the form of a powder - the plant source is preferred (also possible is an animal origin - fish) and animal origin including fish -providing 273 mg EPA, 179 mg DHA in a daily portion, c) compounds being a part of the antioxidant system including: zinc, selenium, magnesium, ascorbic acid, folic acid, B group vitamins including Bl, B2, B3, B4, B5, B6 and B12, addresses all the problems mentioned above.

Daily dose of vitamin C and E, b-carotene, zinc and selenium should be not less than twice RDA (recommended dietary allowance) for such compounds, preferably three times RDA for such compounds, and this will allow to provide these compounds [at the amount covering] the current requirements of the body, and will allow to regenerate the structures damaged by the treatment and to obtain restoration of the body reserves.

Compounds that have been selected for the composition are vitamins C and E, b- carotene, zinc and selenium, and their consumption should be increased in the period of before and after the systemic treatment. The amount of vitamin C should be of the range of 250 - 750 mg per day, vitamin E - 24 - 48 mg per day, zinc - 20 - 40 mg per day, selenium - 110 - 220 pg per day.

The supply of vitamins from the group of carotenoids -during the period of the systemic treatment also requires an increase, and it is reflected in the therapeutic composition as an increased amount of b-carotene of the range of 9,6 - 19,2 mg per day.

A combination of antioxidant compounds in the form of a combination of vitamin C, vitamin E, b-carotene, selenium and zinc shows a synergistic effect. The invention relates to the contents of the composition, which is made of substrates for the proper course of processes being a part of the antioxidant and immune system, as well as serving as a direct source of energy for enterocytes, which aims to support the intestinal barrier system - preventing or minimizing its damage by maintaining the intestinal mucosa in a proper condition before starting the treatment and quick return to a proper state after the end of systemic treatment.

Proper nutrition of mucosa and submucosa cells, especially enterocytes responsible for nutrient ingredients absorption, will be associated with lower risk of developing intestinal barrier damage, and thus will give greater chance to maintain digestive processes and absorption of nutrient ingredients at the level sufficient to provide all nutrient ingredients at recommended levels.

The smaller intestinal barrier system damage due to systemic treatment, the better state of all elements of this system before starting the treatment, while in case of damage the supply of essential nutrient ingredients will intensify the regeneration [process] of the elements of intestinal barrier system to a level that ensure providing nutrient ingredients in amounts needed to replenish reserves lost as a consequence of disease.

Both the supply of nutrient ingredients before starting as well as after the end of the systemic treatment will reduce the risk of intestinal barrier system damage, and in turn will have an influence on reducing the risk of developing of malnutrition in patients taking cytoreductive drugs or others previously mentioned.

The gist of the invention is a combined administration of butyric acid in tolerated in this group of patients amounts of the range of 100 - 499 mg per day, preferably about 200 - 300 mg, preferably 250 mg, together with omega-3 acids of plant origin. The administration of both a direct energy source for intestinal epithelial cells which is butyric acid and unsaturated omega-3 fatty acids has a synergistic effect. Such composition will have influence on the improvement of the functionality of mucosal cells - sealing, reduction of inflammation, proper signal transmission, transport of nutrient ingredients or production of various substances, such as brush border enzymes or protective mucus, and this will contribute to the reduction of the risk of infections and improvement of digestion and absorption.

Preferably the preparation is administered in the form of the composition discussed in Table 5, where simultaneous administration of butyric acid from two different chemical compounds together with acids EPA, DHA and antioxidants is provided. Preferred administration of butyric acid in two biological forms of compounds in the form of two compounds zinc butyrate salt and in the form of gamma-aminobutyric acid GABA causes that we get a double-action preparation. Zinc butyrate salts are the source of free butyric acid. This salt will break down under the action of hydrochloric acid, but the absorption of butyric acid is possible only in the alkaline environment - in downstream segments of the gastrointestinal tract. In turn GABA - gamma-aminobutyric acid is produced in healthy human body by commensal bacteria - the entire amount raised in the gut of healthy body plays the role of neurotransmitter. The situation changes when it is administered orally in its pure form in an aqueous solution. In such situation it is affected by digestive enzymes. Thus a part of administered amount of gamma-aminobutyric acid breaks down into free butyric acid and becomes an additional source of this acid. The remaining part of GABA which is not breaking down by the digestive enzymes acts as neurotransmitter; and this is beneficial since it reduces increased intestinal peristalsis - intestinal cramps. Due the fact that the majority of patients suffer from depression and anxiety associated with their health condition, and many recent works indicate on the relation with the quality and quantity of microbial flora, which among others produces GABA, the administration of GABA has additional advantages in terms of improving mood and stimulating appetite.

Addition of antioxidant compounds will effect on the reduction of damage caused by ROS activity which can arise during systemic treatment as well as on supplementation of body reserves. The addition of GABA will reduce intestinal cramps and at the same time it will be a source of butyric acid. Focusing on aforementioned aspects related to the regeneration and protection of the digestive tract mucosa will ultimately affect lowering the risk of malnutrition and faster improvement of patients health after the systemic treatment, reduction of the risk of death from cachexia and bacterial translocation.

Composition which is the object of the present invention contains nutrient ingredients that promote regeneration of damaged intestinal mucosa cells and regeneration of body reserves of selected micronutrients.

The composition does not provide macronutrients in the diet and it is dictated by the need to adjust the supply of micronutrients irrespective of supply of the energy or simple sugars, what is particularly important in patients with overweight and obesity and glucose metabolism disturbances.

The need for prophylaxis and rapid control of inflammation in systemic treated patients caused that the composition has been supplemented with omega-3 fatty acids in the range of 500-2000 mg per day, preferably 1000 mg per day.

Due to more favourable organoleptic characteristics in production of the composition omega-3 fatty acids of plant origin or the mixture of plant and animal sources (fish) should be used. Administration of omega-3 fatty acids of animal origin in the form of composition for oral administration in patients under the systemic treatment is difficult due to unpleasant repulsive odour. Since people with diminished appetite are particularly sensitive to taste attributes of administered compositions, it is proposed to use omega-3 fatty acids of animal origin.

Polyunsaturated fatty acids are one of the cell membrane constituents and are substrates useful for the production of immunomodulatory compounds (prostaglandins, eicosanoids) and compounds affecting blood clotting (thromboxanes). A high intake of omega-3 fatty acids (especially eicosapentaenoic acid - EPA and docosahexaenoic acid - DHA) causes suppression of inflammation, lowering platelet aggregation and improve the transmission of intercellular signals that affect the level of synthesis and release of cytokines, interleukin and interferon.

The inventor of the presented invention has noted that administration of antioxidants in high doses but orally will not negatively affect the cytostatic concentration within 72 hours after the end of intravenous infusion.

In the case of paediatric patients with acute lymphoblastic leukemia, after the end of the treatment in the blood plasma selenium and glutathione peroxidase levels are lowered and are compensated by higher levels of vitamin E. The use of high doses of selenium during and after the chemotherapy may favourably reduce hematotoxicity and nephrotoxicity associated with the use of cisplatin without reducing the effectiveness of the therapy.

In the case of Hodgkin’s lymphoma administering the sodium selenate promotes better response to the treatment and increases average survival time of an individual.

Intracellular concentrations of these mineral ingredients in the immune system cells indicate an increased demand for selenium, while the levels of zinc and copper are reduced. On the contrary however observed intracellular concentrations of these components determined in the immune system cells indicate an increased demand for selenium, while the levels of zinc and copper are reduced.

Disorders of intracellular concentrations of mineral ingredients observed in onco- haematological patients are probably due to intense enzymatic rearrangements, for example in the synthesis of antioxidant enzymes whose cofactors are mentioned components, whereas plasma concentrations result from deteriorated nutritional status of such patients.

In the blood plasma of patients with lung tumors significantly lower levels of lutein, zeaxanthin, a-carotene, b-carotene, lycopene, retinol and a-tocopherol are observed and those compounds have antioxidant activity, they participate in the proper functioning of the eye, as well as reduce DNA damages.

The problem noticed and addressed by the inventor of the present invention is also the need to supplement an individual who received systemic treatment but does not require additional energy supply from sources other than natural food products, what happens in the case of overweight and obese individual and individual with glucose metabolism disturbances, and who due to the limitations resulting from this loads should not take an additional portion of simple sugars. According to the inventors opinion in this situations the protein supply should be achieved by natural methods using high-protein food products and/or foods for special medical purposes containing in their composition only protein having proper amino acid profile dedicated to patient under the systemic treatment.

Due to a small amount of data concerning the loss of individual amino acids in patients under the systemic treatment, it seems reasonable to supplement them regardless of administration of the composition; since this will allow to supply only essential amino acids and to adjust the dose to such patient’s current needs.

Nutritional status [of the patient] is an important prognostic factor in oncology and onco-haematology. Malnourished patients and patients with cachexia, both in qualitative and quantitative terms, have lower tolerance for the systemic treatment. In such individuals metabolic complications are observed four times more often, and the regeneration and healing processes are disturbed and prolonged in time, and this increases the risk of sepsis and death. Therefore it is important to prevent malnutrition by preparing the digestive tract mucosa for higher ROS concentrations and less availability of energy and building substrates, as well as quick restoration of the digestive tract functionality after the treatment.

Food digestion and absorption of nutrient ingredients takes place through the digestive tract and this way of nutrition - oral route - is also preferred for patients under the systemic treatment due to the preservation of physiological processes and intestinal mucosa integrity (enterocyte nutrition), the maintenance of normal intestinal microflora (dysbiosis preventing), the reduction of infection risk and lower therapy costs. Among patients treated with high-dose chemotherapy it is not possible to establish a false access to gastrointestinal tract since it is associated with a high risk of developing pressure sores in the gastrointestinal tract. However, parenteral access is associated with the risk of catheter-associated infections, impracticality of the home-mode treatment or one-day hospitalization, as well as it is a high-cost method.

Definitions Unless otherwise stated, the terms used herein have the meaning commonly understood by person skilled in the art.

The term individual means a mammal, preferably a human child, an adult or elderly person, and the most preferably an adult who can consume the composition on his own via the oral route, without using a false access to gastrointestinal tract.

An individual under the systemic treatment means a mammal, preferably a human child, an adult or elderly person, and the most preferably an adult who receive the systemic treatment.

An individual in need of administration of the oral composition means an individual who is preparing to the systemic treatment, an individual who had received systemic treatment, an individual exhibiting symptoms of mucositis (intestinal mucosa toxic damage ), and/or an individual exhibiting intolerance to ordinary enteral food preparations for special medical purposes.

An individual in need of components participating in the reactions in the antioxidant system, in the context of the present invention means any individual who has been shown to need supplementation to improve the functionality of the antioxidant system, particularly an individual preparing for the systemic treatment, an individual who has received systemic treatment, an individual exhibiting symptoms of mucositis, an individual exhibiting intolerance to ordinary enteral food preparations for special medical purposes.

Multicomponent oral nutritional preparation - ONS (oral supplements nutrition) i.e. an oral food preparation for special medical purposes, in the context of the present invention means a nutritional composition containing macronutrients and micronutrients administered to fortify the energy-protein diet.

The patient is an individual during the preparation for diagnosis, who is diagnosed and who is under the treatment. In this specification terms patient and individual are used interchangeable.

The term pharmaceutically acceptable derivative refers to a substance that does not cause significant organism irritation and do not effect on the biological activity of administered composition.

The term short-chain fatty acids should be understood [as concerning to] carboxylic acids having two to five, preferably two to four carbon atoms. Examples thereof are acetic acid, propionic acid, a-methylopropionic acid, pentanoic acid (valeric acid) and particularly it is butyric acid. The term substances being convertible into short-chain fatty acid is understood as [concerning to] compounds which contain short-chain fatty acids having two to five carbon atoms which are released by metabolic activities in an amount and of the range from an amount of the range of 100 - 499 mg per day, whereas in case of substances that convert into short-chain fatty acids those amounts refer to short-chain fatty acids participation. Examples of such substances are short-chain fatty acid salts or esters and amino derivatives such as GABA. Preferably the salt is zinc butyrate. Preferably precursor substances are administered in combination zinc butyrate + GABA. The esters may be derived from monohydric or polyhydric alcohols. Examples of esters are methyl or ethyl esters, phospholipids or in particular glycerol esters. Esters of polyhydric alcohols besides short-chain fatty acids may also contain medium- and long-chain fatty acids. Preferably in the case of esters of polyhydric alcohols with different fatty acids all the acid moieties are derived from short-chain fatty acids. Glycerol esters of short-chain fatty acids are preferred, and tributyrin /= glycerol triester of butyric acid / is particularly preferred. In the case of substances being convertible into short-chain fatty acid stated amounts are based on participation of such acid in the substance.

Further immunonutrients or pharmaconutrients optionally included in the additive /supplement/ are depending on each outline of the disease and they are food components contained in concentrations higher than recommended daily dose RDA (Recommended Dietary Allowances) counting on the whole supply of food administered orally. RDA (, recommended dietary allowance , approved in 1944) - means the reference daily intake and was used in the United States and Canada. Reference daily intake is a value based on statistical data from the population of the given country or region and regards: the distribution of real consumption of given component in a population depending on age, physical activity and sex of residents; identified nutrient deficiencies and health status of given population; scientific findings regarding maximum permitted values of such nutrients as, for example vitamins and mineral ingredients that are credibly recognized as safe for healthy people. Because it is not possible to objectively set one norm for the whole population the set values are only of reference (reference value) and serve primarily for practical purposes, for example in food production or mass nutrition meeting the nutritional requirements and recommendations of an average healthy adult person having correct weight and normal level of physical activity. Demand for macro- and micronutrients in a diet in case of disease increases about 2-3 times in relation to demand for healthy person. The term free radical in the context of the present invention means an atom or molecule capable of independent existence with one or several unpaired electrons on its valence shell (e.g. H₂0₂- hydrogen peroxide, 0₂- superoxide radical, OH - hydroxyl radical). A molecule without an electron becomes a free radical, and series of such transformations lead to the formation of oxidation-reduction chain reaction. In normal conditions there is a balance between oxidants and antioxidants in the body. An increase of production of free radicals or a decrease in antioxidant activity causes the imbalance at the equilibrium concerning the direction of oxidation reaction and this is called oxidative stress. At first free radicals oxidize fatty acids (lipids) of skin cell membranes, structural proteins, especially collagen and enzymatic proteins. The main consequences of oxidative stress are: inactivation of some proteins, increased adenine nucleotide catabolism, increase rate of lipid peroxidation, mitochondria damage, reduction of ATP and glutathione levels, disorder of intracellular calcium homeostasis (Ca²⁺), increased permeability and depolarization of the cell membrane, DNA damage, breakdown of red blood cells, change in antigenic properties of cells. Oxidative stress occurs in the etiopathogenesis of many diseases i.a. cancers and autoimmune diseases.

In the context of the present invention antioxidants mean a stock of various reducing compounds (antioxidants), such as for example ascorbic acid, carotenoids, dihydrolipoic acid which under normal conditions are at disposal of our body to fight off oxidative stress. However also trace elements such as selenium and zinc may act as antioxidants. During prevention or the systemic treatment of mucositis, to which individuals may undergo, these intrinsic antioxidants are not sufficient to catch free radicals formed in high concentrations or to bind them as early as there are formed. As the result in the frame of generalized inflammation the pathological picture of systemic inflammatory disease even intensifies. Therefore, putting the calculated amount of antioxidant at the disposal shows how should one counteract to the action of free radicals and oxidative damage caused by them. It is also known that during the removal of free radicals in the body antioxidants depend on each other in a synergistic manner regarding their regeneration by creating an antioxidative spiral. Thus, for example vitamin C, vitamin E, gluthation and NADP are oxidized and after reduction they recover their active action again. This type of antioxidative spiral is also based on interaction of vitamin C and E, selenium and zinc. Because of the complementary antioxidant activity of the various resources it is reasonable to add at least two from aforementioned antioxidants, preferably more, but in particular a combination of vitamin C and E, b-carotene and trace elements selenium and zinc should be added to the supplement /additive/ according to the invention besides both other important ingredients (short-chain fatty acids or substances from which they may be obtained). Examples of antioxidants are vitamins with antioxidant properties such as vitamin C or vitamin E; trace elements with antioxidant properties such as selenium or zinc; polyphenols and carotenoids, preferably b-carotene.

The intestinal barrier consist of intestinal bacteria, epithelium and immune cells. In the context of the present invention the intestinal barrier includes not only epithelial layers of intestinal mucous membranes, but also microflora, peristalsis, mucus production and local immune defence, as components of„gut associated lymphoid tissue” (GALT). The intestinal barrier represents the first line of defence against potentially penetration of pathogens and toxins - referred to as relocation. It performs the following functions:

• Protective - it protects against toxins and pathogens from the external environment;

• Absorptive - it is involved in digestion, absorption of nutrient ingredients, fluids and electrolytes from food and in fermentation of fiber to compounds that intestinal bacteria eat;

• Immunological - it secretes corresponding antibodies and minimizes the risk of infections;

• Transmitting - it is involved in transmission of signals to other cells and organs.

Bacterial flora plays the key role in maintaining health. The correct intestinal microflora is necessary for the proper functioning not only the gastrointestinal tract but the entire organism.

In the context of the present invention malnutrition means a condition resulting from the lack of absorption, or from the lack of consuming nutritional substances leading to changes in the body composition, to physical and mental impairment of the body’s function, and adversely affect the results of treatment of underlying disease. In particular, in the context of the present invention malnutrition means cachexia-anorexia cancer related syndrome (CACS) and it is a complex metabolic process characterized by generalized inflammation, impaired appetite, intensification of catabolic processes and inhibition of anabolism. As a result of this process skeletal muscle cells break down along with the systematic consumption of energy reserves from adipose tissue. The frequency of this syndrome is high - it is diagnosed in 50- 80% of oncological and haematological patients depending on the type and metabolic activity of the cancer according to ESPEN.

In the context of the present invention a paediatric patient with regard to humans means an individual of the age up to 18 years.

An adult patient is an individual over the age of 18 years. In the context of the present invention cachexia syndrome means qualitative and quantitative cachexia resulting from generalized and persistent for a long time inflammation state in patient’s body.

In the context of the present invention the intestinal barrier system means interaction of various elements present in the gastrointestinal tract which in correct condition allow the proper course of digestive processes and subsequent nutrient ingredients absorption, at the same time they protect the body against harmful components. These elements are the intestinal mucosa (epithelium, lamina propria), submucosa (containing blood vessels, lymphatic vessels - GALT system, nerve fibers) and commensal bacterial microflora.

In the context of the present invention the intestinal barrier function improvement means minimization of symptoms of mucositis manifested in the form of abdominal pain, bloating, belly rumbling, putrescent gasses, diarrhea.

In the context of the present invention intestinal barrier function improvement means ensuring proper number of layers of the intestinal epithelium and restoring the normal physiological structure of the mucous membrane.

In the context of the present invention mucositis is understood as the mucosal barrier damage caused by the toxic activity of drugs and excess of reactive oxygen species, located in the oral cavity ( oral mucositis - OM) or in stomach and intestines ( gastrointestinal musositis - GIM ), as well as other symptoms associated with impaired functioning of the intestinal barrier system, i.e. neutropenic enteritis, persistent nausea and vomiting, Graft- Versus-Host Disease, bacterial overgrowth, as well as persistent and transient intolerances, characterized by specific gastroenterological symptoms resulted directly or indirectly from effects of the drugs as well as the disease itself.

In the context of the present invention the systemic treatment means any treatment using medicaments that are toxic to squamous epithelium and other cells being a part of intestinal barrier of the gastrointestinal tract, particularly cytoreductive drugs (see Table 1) used in oncology, onco-haematology, haematology, dermatology, rheumatology or autoimmune diseases, as well as broad-spectrum of antibiotics and up-to-date drugs in the field of molecular engineering (see Table 2) for which it is known and/or alleged that after the use of them squamous epithelium and/or the intestinal barrier are impaired.

In the context of the present invention drugs obtained by molecular engineering (biochemistry, immunology, molecular biology, genetics and biotechnology) means all monoclonal antibodies, kinase inhibitors and the like. Drugs from this group inhibit the cascade of inflammation at a level of production or neutralization of proinflammatory factors, for example TNF-alpha or interleukin 1. Due to the participation of these factors in the intestinal microflora immunological tolerance processes, which make the part of the GALT system, drugs obtained through molecular engineering cause the triggering of inadequate reaction to the presence of commensal microflora bacteria or pathogenic bacteria and this increases the risk of mucositis.

Table 2

In the context of the present invention protein preparation means a preparation for fortifying a diet of an individual having recognised lack of muscle mass.

In the context of the present invention a patient at high risk of malnutrition means an individual preparing for the systemic treatment, an individual who had received systemic treatment, an individual exhibiting symptoms of mucositis, or individual exhibiting intolerance to ordinary enteral food preparations for special medical purposes.

In the context of the present invention a patient with cachexia means an individual with low muscle and fat mass.

The invention is further described by the following examples.

Examples of the embodiments of the invention Compositions as described in Tables 3-8 were prepared.

Composition A is intended for use in women with ovarian cancer, Composition B is intended for use in individuals with psoriasis, composition C is intended for use in individuals with acute myeloid leukemia, Composition E is intended for use in individuals with acute lymphoblastic leukemia, Composition F is intended for use in individuals with large B-cell lymphoma, Composition D is intended for use in individuals with multiple myeloma.

Table 3

Table 4

Table 5

Table 6

Table 7

Table 8

Example 1

The whole mixture having the composition as presented in Table 3 was applied to the female patient with ovarian cancer stage IIIC.

The patient, aged 69, after bilateral adnexectomy and after 2 lines of the systemic treatment. Currently qualified for the third-line of the systemic treatment due to recurrence.

During the first-line treatment and after the surgical intervention patient’s body weight was 46 kg, 154 cm tall (usual body weight 63 kg), [so the] weight reduction during first three months from the beginning of systemic and surgical treatment was about 10 kg. Systemic treatment as the first-line treatment was carried out according to the scheme: carboplatin, paclitaxel.

The patient had many gastrointestinal problems. After the infusion of chemotherapy agents nausea and decreased appetite (anorexia) persisted for about 10 days. After consumption of foods containing animal protein and complex carbohydrates, the abdominal pain, putrescent gases, loose stools occurred. After consumption of fats both of animal and plant origin, the patient reported steatorrhea, tenesmus and defecatory urgency and defecation after about 15-30 minutes after intake of fats containing products. The patient also reported: dry mouth, shortages of saliva and changes in its consistency to a very thick, making swallowing difficult. With each subsequent administration of the systemic treatment the symptoms aggravated. The patient completed I course of nutritional treatment with a body weight of 39 kg. She obtained remission for about 13 months at the same time receiving maintenance treatment with humanized monoclonal antibody - Avastin.

At the time of disease-free interval (when the tumor markers maintained a stable trend and no progression in imagination examinations was found) the patient gained weight of 5 kg. Symptoms of fat and proteins of animal origin intolerance manifested as gastrointestinal issues have been partially remitted. The second-line of the systemic treatment according to carboplatin, paclitaxel regimen was given after about 14 months. Patient’s condition in terms of ability to intake, digest and absorption was very similar. Nutritional status of the patient was evaluated by Scored Patient- Generated Individualive Global Assessment (PG-SGA) sheet as cachexia, and the quality of life was evaluated by the EORTC questionnaire with QLQ-OV28 unit dedicated to patients with ovarian tumors. Initially nutritional treatment by multicomponent preparations available on the market of the oral type preparations for special medical purposes was applied according to the indications for nutritional treatment in oncology ESPEN and POLSPEN. This type of procedure was not tolerated by patient due to the occurrence of bloating abdominal pain, nausea, and subsequently loose stools. The nutritional treatment procedure had been changed to monocomponent preparations such as protein nutrients for diet fortification. This procedure was not tolerated by the patient for 14 days after each infusion of chemotherapy. After this time, the patient began to tolerate the preparation but without therapeutic effect even after increasing a dose. The therapeutic effect is considered as an inhibition of weight loss which after about 21 days should tend to increase.

After finding another recurrence and qualifying patient for the third-line treatment according to carboplatin + liposomal doxorubicin regimen, it was proposed to administer to the patient a composition according to the invention (Composition A as described in Table 3) with the intention to prepare gastrointestinal mucosa for such type of treatment, as well as to reduce the time of acute side effects. The compositions were administered 21 days before start the first course of the systemic treatment. The preparation was administered in a form of a powder to be dissolved in homogenous and heterogeneous solutions. The best tolerated by the patient administration covered taking the mixture in 3 equal portions during the day. During the course of the systemic treatment in the form of intravenous infusions, said composition was not administered. After the end of the course of drugs and until the drugs has been completely removed from the body, said composition was not administered. After this time oral administering of said composition was restarted. This procedure was carried out throughout the entire third-line treatment. The beneficial effects of applying the composition could be observed in the form of shortening the duration of the acute symptoms of mucositis. Although during each line of the treatment the same dose of carboplatin which is toxic to mucous membranes and marrow cells was administered the shortening of a duration of acute gastrointestinal complications was observed only during the III line of treatment, and it was shortened to 3 days. This effect was also independent on administration of antiemetic drugs and other drugs aimed at the prevention of gastrointestinal disorders which were included during each line of the treatment form the lOth day of drug administration. The beneficial effect of applying the composition was the lack of food intolerances that has occurred during the I and II line of treatment - and these intolerances were related to dairy products, proteins of animal origin and high-fat products. During the third line of the treatment, the patient’s appetite was the same, the body weight was not reduced and there was no drastic decline in physical performance - the patient felt so physically fit that she performed daily life activities. During previous lines of treatment it keep on

The results of the questionnaires used has showed an improvement in both nutritional state and the quality of life particularly in terms of gastroenterological problems.

Example 2

The composition according to the invention as shown in Table 4 was applied to the male patient, aged 42, with the severe psoriasis [being under] the systemic treatment by means of methotrexate in a dose of 12,5 mg 1 time per week. During this period of time the patient took folic acid preparation in a dose of 5 mg 6 times per week. The duration of treatment was 8 months. During the first 3 months patient did not experience any side effects. From about 4 month of applying a treatment symptoms of general weakness, decline in respiratory function, non-specific bloating and belly rumbling occurred. In subsequent months fat intolerance in the form of steatorrhea followed. In the 7th month of treatment there was a reduction of scalp hair, as well as the severity of food intolerances in the form of bloating and chronic diarrhea, increased putrescent gases. The patient was subjected to a treatment by a gastroenterologist according to the scheme metronidazole 3 times a day 2 tablets for a 7 days alternating with a large amount of probiotics. This treatment gave a subjective feeling of improvement in the efficiency of the gastrointestinal tract in the form of reduction of diarrhea. After 13 months of a treatment with methotrexate the treatment was modified due to liver enzymes increased. Cyclosporine was applied. After a month the treatment was discontinued due to acute abdominal pain, bloating, diarrhea, increase in blood pressure. The patient was pre-qualified for biological treatment. Unfortunately the symptoms of mild mucositis persisted despite discontinuation of the systemic treatment. Nutritional status of the patient was assessed by the PG-SGA sheet and a quality of life assessment sheet dedicated to the assessment of patients with psoriasis. The nutritional status was evaluated as threatened by qualitative and quantitative malnutrition (because of diarrhea and intestinal mucosa barrier damage, proliferation of pathogenic flora). The quality of the patient’s life was very low in terms of basic social activities, for example embarrassment at the pool, in intimate situations, what affected patient’s libido negatively. Frequent diarrhea limiting and determining [patient’s] behaviour at work as well as during leisure time also had a negative impact on the quality of his life.

It has been proposed to administer the composition of the invention (Composition B as described in Table 4). A liquid formulation was administered twice a day. After about 10 days of use patient reported silencing previously intensified peristalsis and reducing the amount and the nature of gases to more physiological. After 45 days of using said mixture the nutritional status and the quality of life were re-evaluated. Normalization of nutritional status parameters was obtained and recorded - the nutritional status was assessed as normal. The quality of life have improved in terms of stress reduction associated with normal functioning of gastrointestinal tract.

Example 3

The composition may be administered as a prophylaxis of mucositis in individuals prior to the hematopoietic stem cell transplantation procedure in the following algorithm: the composition (Composition A as described in Table 3) should be administered 21 days before starting the procedure; the preparation should be given in a form of a powder to be dissolved in homogenous and heterogeneous solutions. The mixture is best tolerated when is taken in 3 equal portions a day.

Example 4

Method of treatment by orally administering the composition in the following regimen.

In patients with neoplasm disease during the systemic treatment administering the Composition A as described in Table 3 in a daily dose. The whole composition should be dissolved in water or other liquid or semi-liquid product at a temperature not exceeding 20 degrees Celsius. The solvent for the composition cannot be chemically preserved carbonated beverages.

Consuming within no longer than 2 hours after reconstitution. The composition can be dissolved in batches of about 15 g and dissolved in about 200 ml of bottled water. Preferably the composition is administered about 7 days before the systemic treatment and the most preferably 21 days before the first dose of the systemic treatment.

Then an interval for the chemotherapy infusion and its entire removal from the body, i.e. usually 72 hours [should be preserved]. Continuation of the administration of the composition every day in the whole daily dose until the end of treatment [should be preserved]. [Administering] in two or three portions per day in a batch of about 10-15 g of the whole composition. Time of the continuously administering is 90 days at maximum. After this time the levels of selenium and zinc in patient’s blood should be controlled. In patients during the systemic treatment of autoimmune diseases Composition B as described in Table 4 in a daily dose should be administered. The whole composition should be dissolved in water or other liquid or semi-liquid product at a temperature not exceeding 20 degrees Celsius. The solvent for the composition cannot be chemically preserved carbonated beverages.

Consuming within no longer than 2 hours after reconstitution. The composition can be dissolved in batches of about 10-15 g and dissolved in about 200 ml bottled water.

Administration of the composition every day in the whole daily dose until the end of treatment [should be preserved]. Administering the composition in two or three portions per day in a batch of about 10-15 g of the whole composition. Time of the continuously administering is 90 days at maximum. After this time the levels of selenium and zinc in patient’s blood should be controlled.

Example 5

Two patients with AML (acute myeloid leukemia) who have completed the first-line treatment with daunorubicin administered for 3 days and cytosine arabinoside (cytarabine) administered for 7 days. The patients were under the age of 60, one woman and one man. After the end of chemotherapeutic treatment the patients did not have severe symptoms of mucositis, but experienced frequent food intolerances especially concerning products containing dietary fiber, animal fat and had difficulties in animal protein digestion. They reported frequent putrescent gases, and bloating after consuming that kind of food. These problems negatively influenced on the possibility and willingness to eat thus limiting the recovery after the end of the first-line treatment.

After the end of the chemotherapeutic treatment regenerating mixture (Composition C) as described in Table 5 was administered for 90 days (3 months). After the chemotherapy treatment there was a 5 days interval. Composition C was administered orally in 250 ml of low- sodium non-carbonated water.

After the first 30 days patients experienced marked reduction in above mentioned symptoms. Moreover they increased the amount of home food intake by 30% of volume. There was a marked improvement in digestion and absorption. The body weight reduction rate was inhibited. After 2 months of use [of the composition] the symptoms of mucositis were almost unnoticeable.

Then [they] started to introduce raw fruits and vegetables to the diet with good tolerance. The woman gained 2 kg and the man gained 1 kg. After 3 months of use [of the composition] both patients reported no symptoms of digestive or absorption disorders and weight gain (fat- free body mass and body fat mass) 1 kg in woman and 1,2 kg in man.

The quality of patients life relative to the evaluation made before the use of preparation was significantly increased. The quality of life was assessed using QLQ EORTC sheets dedicated to this particular disease * https://qol.eortc.org/

Example 6

Two men and one woman with the diagnosis of acute lymphoblastic leukemia. Male patients received treatment with fludarabine, cytarabine and mitoxantrone. The woman also received treatment with fludarabine, cytarabine and mitoxantrone - 6 courses. Both in woman and men since the 4th chemotherapy course food intolerances with varying intensity have appeared and persisted until the end of chemotherapy courses. Temporarily patients have experienced diarrhea but with negative cultures towards Clostridium Difficile. The symptoms of digestive and intestinal absorption disorders (mucositis- toxicological and chemical mucosal damage) persisted also after the end of cytoreductive treatment. These symptoms were loose stools alternating with constipation, putrescent gases, bloating and abdominal cramps after consumption majority of product groups as well as without consuming food at night. Products with the lowest degree of tolerance were: vegetables, raw fruits and meat, even cooked. These were the symptoms of gastrointestinal tract mucosa damage - mucositis.

During the first-line of nutritional treatment sodium butyrate (available on the market preparation Debutir) was used according to the administration recommendations as follows: 1 capsule 2 times a day in line with the manufacturer instruction. This corresponded to 240 mg of pure butyric acid per day in a form of sodium salt. Since there was no clinical effect after 14 days a formulation containing omega-3 of fish origin in the encapsulated form was introduced to the treatment. After the first month of the treatment there was no clinical effect and there was even an increase in dyspeptic symptoms - heartburn and belching with fish oil aftertaste. Moreover patients suffered from increased gastric acid secretion (occurrence of heartburn), disgust, feeling of fullness in the stomach and increased putrescent gases after ingestion of tablets with fish oil. Moreover the preparation containing omega-3 acids (containing EPA and DHA acids) of animal origin - fish - was too difficult to digest and absorption for chemically damaged mucosa. The use of only sodium butyrate was reinstated. During the 3 months of using according to the manufacturer’s instructions there was no therapeutic result and aggravation of diarrhea episodes [was marked]. It might have been caused by the fact that the preparation contained fully hydrogenated palm oil which could irritate toxic-damaged mucosa. It should be noticed that mucositis also negatively affect the production of intestinal enzymes: intestinal protease, amylase, saccharase, lactase, and this could be the reason for the intolerance of a preparation containing hydrogenated palm oil in this group of patients. Hydrogenated palm oil can be also a source of not recommended substances such as trans-fat. Its supply is minimized in the healthy population feeding while in the population of ill people it should be eliminated. When the above mentioned preparations were administered the increased mucositis symptoms instead of intended effect occurred, and as a consequence the reduction of body weight, acceleration of the rate of patient’s cachexia - in average 0,7 kg per week. It should be also noticed that the preparation contains only one salt - sodium butyrate as a gastro-resistance capsule and additionally sodium butyrate is also encapsulated in microcapsule. Sodium (Na) is not recommended for enteral administration in mucositis, but rather parenterally because it may exacerbate diarrhea episodes. According to the guidelines of the Multinational Association of Supportive Care in Cancer (MASCC) in cooperation with International Society of Oral Oncology (ISOO) zinc should be supplemented chronically as a prophylaxis of mucositis during the marrow transplantation procedure to patients with the highest risk of mucositis occurrence at stage 4/

Example 6A

Due to progressive patient’s cachexia as described in Example 6 caused by the lack of idiopathic mucosal healing gastrointestinal tract mucosa after the end of the treatment with Debutir and compositions described above in Example 6; the regenerating mixture with composition as presented in Table 7 (Composition E) was used for the nutritional treatment.

7 days interval was made in administration of sodium butyrate and omega-3 acids of fish origin. Composition E was administered orally in 250 ml low-sodium non-carbonated water.

The mixture was used for 3 months with monitoring of patient’s condition every 30 days. After the first 30 days patient reported significant decrease in intestinal cramps, decreased putrescent gases and general increase in appetite. After 60 days patient reported a lack of diarrhea episodes, lack of putrescent gases, increased food intake (decreased feeling of fast fullness after meal) and inhibition of weight loss - stabilization of the body weight [was marked]. After 90 days of the treatment patient reported a lack of mucositis symptoms and weight gains of 2 kg. Only after 3 months of using the mixture patients began to include raw products (vegetables and fruits) containing soluble and insoluble fiber in their diet. The quality of patient’s life was significantly improved in relation to the evaluation made before introducing the preparation *. The quality of life was assessed by QLQ EORTC sheets dedicated to this disease * https://qol.eortc.org/ Example 7

Two female patients under the age of 30 with the diagnosis of large B-cell lymphoma received treatment according to the scheme: Etoposide + Prednisone + Vincristine + Cyclophos-phamide + Doxorubicin + Rituximab. After the end of this line of treatment the symptoms of mild mucositis persisted for about 3 months, and with no tendency to reduction or self-extinguish over time after the end of chemotherapy. Patients reported digestion and absorption disorders of products containing soluble and insoluble fiber. Both patients had a tendency to reduce the body weight by 0,5 kg per week. Patients did not have diarrhea resulting from bacterial infection - it was confirmed by the negative culture of pathogenic bacteria. However loose stools and putrescent gases after every meal occurred.

The product ONS - IMPAC ORAL containing among others amino acids and antioxidants, nucleotides, was orally administered. The preparation was used for 30 days. The result of such supplementation was not significant in the aspect of the intestinal mucosa regeneration - symptoms persisted.

Example 7A

Due to lack of desired effect in the aspect of efficiency of intestinal mucosa barrier after the nutritional treatment described in Example 7, the patients described in Example 7 after the end of previous treatment were treated with the composition as described in Table 8 (Composition F). The composition was administered by oral route dissolved in 250 ml of low- sodium non-carbonated water. They began to use the mixture considering the 7 days interval since the non-application of IMPACT ORAL preparation.

Both patients used the mixture for 3 months. After the first month the number of loose stools was decreased by 50%, after the 2nd month bloating and putrescent gases let up. During the third month the patients did not reported problems described before introducing the mixture according to Table 8. After the 2^nd month the patient’s weight reduction was inhibited and after the 3rd month they started to slowly gain weight - 0,5 kg every 14 days. After 3 months the mixture was put away since the patients could introduce and consume without the symptoms of diarrhea and dyspepsia products from all food groups. The quality of patient’ s life was significantly improved in relation to the evaluation made before introducing the preparation *. The quality of life was assessed by QLQ EORTC sheets dedicated to this disease * https://qol.eortc.org/

Example 8

Two female patients with the diagnosis of multiple myeloma: a woman over the age of 65 after the treatment according to the scheme: Bortezomib, Cyclophosphamide and Dexamethazone; and a woman over the age of 65 after the treatment according to the scheme: Bortezomib, Melphalan, Prednisone. Both women after ending these lines of treatment had symptoms of chronic mucositis which persisted for about 3 months with no tendency to reduction or self-extinguishing over time after the end of chemotherapy. Patients reported digestion and absorption disorders of products containing soluble and insoluble fiber. Due to the low nutrition level and further plans to prepare to the autologous graft procedure a mixture as described in Table 6 (Composition D) was used. Both women have received the mixture for 3 months. After 2 months complete remission of the above mentioned symptoms was achieved. Treatment was continued for the third month maintaining the remission and intestinal regeneration. All groups of food products were tolerated by the patients, even products rich in insoluble fiber no longer caused the symptoms of mucositis. The quality of patient’ s life was significantly improved in relation to the evaluation made before introducing the preparation *. The quality of life was assessed by QLQ EORTC sheets dedicated to this disease * https://qol.eortc.org/

Example 9

Patient under the age of 55 with the diagnosis of multiple myeloma after many lines of the treatment according to following schemes: Vincristine, Doxorubicin, Dexamethazone, then Cyclophos-phamide, Talidomid, Dexamethazone, then Bortezomib, Melphalan, Prednisone, then Melphalan, then Lenalidomide. All of them were used during four years. The treatment was completed with autologous graft. After the autologous graft the patient was diagnosed with chronic mucositis and diabetes and second stage of renal failure. The symptoms of mucositis persisted a year after the treatment completion. The body weight was stable although the patient was chronically using a steroid therapy and this resulted in swellings and glucose metabolism pathways damage (increased lipogenesis, decreased synthesis of muscle tissue) - [this gave the masking effect of symptoms of cachexia i.e. loose of body weight] .

Due to the use of multiple lines of treatment and prolonged mucositis a mixture as described in Table 6 (composition D) was used for 3 months. The treatment started about 14 months after the end of the last lines of cytoreductive treatment. The composition was administered by oral route dissolved in 250 ml of low-sodium non-carbonated water.

After the first 30 days the reduction of the symptoms was in the range of 20% only. After 2 months the reduction of the symptoms was noticeable for the patient in the range of about 50% - the number of diarrhea during day and night, the improvement of digestion and absorption. After only 3 months there was a significant improvement in the reduction of the symptoms of mucositis (bloating, loose stools, food intolerance). There was no improvement in terms of increase of non-fat mass (muscle mass). This may be caused by the long-term use of various chemotherapy regimens and this caused chronical damage of the intestinal mucosa followed by healing and scarring. The scarring - adhesions within mucosa thereby the absorption area decreases. In addition the steroid therapy, increased lipogenesis and the decrease of anabolic processes

Claims

1. A composition for oral administration to an individual in need thereof, for prevention and treatment of mucositis, which comprises butyric acid and/or substances being butyric acid precursors suitable to be converted into butyric acid, antioxidants and omega-3 fatty acids, the composition comprising, based on a daily dose:

•butyric acid and/or substances being butyric acid precursors suitable to be converted into butyric acid, preferably butyric acid salts, in an amount of the range of 100 - 499 mg per day, preferably in a dose of about 200 - 300 mgin case of substances being butyric acid precursors based on the butyric acid participation,

2. The composition according to claim 1, characterized in that substances being butyric acid precursors suitable to be converted into butyric acid are selected from the group consisting of zinc butyrate, tributyrin and/or gamma-aminobutyric acid, preferably zinc butyrate or a combination of zinc butyrate and gamma-aminobutyric acid.

3. The composition according to claim 1 or 2, characterized in that polyunsaturated fatty acids of the group omega-3 are of plant origin in an amount in the range of 900 - 2000 mg per day, preferably in a dose of 1000 mg, and they comprise 273 mg EPA, 179 mg DHA in a daily portion.

4. The composition according to any one of the claims 1-3, wherein the individual is an individual under the systemic treatment, and the prevention of mucositis is based on the intestinal barrier function improvement.

5. The composition according to any one of the claims 1-4, wherein the individual is an individual with symptoms of mucositis, and the treatment is based on improving of the intestinal barrier function manifested by the reduction of symptoms of mucositis.

6. The composition according to any one of the claims 1-5, characterized in that it is in the form of a powder to be dissolved.

7. The composition according to any one of the claims 1-6, characterized in that it comprises a combination of antioxidants comprising vitamin C, vitamin E, b-carotene, selenium and zinc.

8. The composition according to any one of the claims 1-7, characterized in that as antioxidants it comprises vitamin C in an amount of 250-750 mg, vitamin E in an amount of range of 24-48 mg, b-carotene in an amount of the range of 9,6-19,2 mg, selenium in an amount of the range of 220-750 pg, zinc in the amount of the range of 20-40 mg in a daily portion.

9. The composition according to claim 8, characterized in that it contains vitamin C in an amount of 250 mg in a daily portion, and an individual is a paediatric patient.

10. The composition according to claim 8, characterized in that it contains vitamin C in an amount of 750 mg in a daily portion, and an individual is an adult patient.

11. The composition according to any one of claims 1-10, characterized in that it is free from iron and copper.

12. The composition according to any of claims 1-11, characterized in that additionally contains B group vitamins, such as Bl, B2, B3, B5, B6, B7, B12, folic acid in an amount twice, preferably three times of the recommended dietary allowance RDA.

13. The composition according to any one of claims 1-12, characterized in that additionally contains magnesium preferably in an amount of 40 mg, calcium preferably in an amount of 250 mg, and vitamin K2 preferably in an amount of 60 pg.

14. The use of the composition as defined in any one of claims 1-13, as the separate regenerating composition for oral administration to individuals in need, particularly to individuals preparing for the systemic treatment, individuals, who had received systemic treatment, individuals exhibiting symptoms of mucositis, individuals exhibiting intolerance to ordinary enteral food preparations for special medical purposes.

15. The use of the composition as defined in any one of claims 1-14, characterized in that the composition as defined in claims 1-13 is administered as a single daily dose.

16. The use of the composition as defined in any one of claims 1-13, characterized in that the composition is administered in two to three, preferably in two doses per day cumulatively not exceeding the daily dose of the composition.

17. The use of the composition as defined in any one of claims 1-13, as an additive to a protein preparation dedicated to patients at a high risk of malnutrition, malnourished or with cachexia.

18. The use of the composition as defined in any one of claims 1-13, as an additive to a multicomponent oral nutritional preparations - ONS for improving their nutritional values in the group of individuals under the systemic treatment.

19. The use of the composition as defined in any one of claims 1-13, as an additive to infant milk and follow-on milk for improving their nutritional values in the group of paediatric individuals exhibiting symptoms of mucositis.

20. A method of treatment of an individual in need thereof, particularly an individual preparing for the systemic treatment, individual who have received systemic treatment, individual exhibiting symptoms of mucositis, individual exhibiting intolerance to ordinary enteral food preparations for special medical purposes, characterized in that it comprises a step of administering of the composition as defined in any one of claims 1-13.

21. A method of treatment according to claim 20 of an individual in need thereof, particularly an individual preparing for systemic treatment, characterized in that in the step of administering of the composition, a composition as defined in any one of claims 1-13 is administered as a single daily dose.

22. A method of treatment according to claim 19 of an individual in need thereof, particularly an individual who have received systemic treatment, individual exhibiting symptoms of mucositis, individual exhibiting intolerance to ordinary enteral food preparations for special medical purposes, characterized in that in the step of administering of the composition, a composition as defined in any one of claims 1-13, is administered in two to three, preferably in two doses per day cumulatively not exceeding the daily dose of the composition.