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WO2019106626A1 - Composition pour l'administration orale, utilisation de la composition dans la prévention et le traitement de la maladie des muqueuses, et procédé de traitement de la maladie des muqueuses - Google Patents

Composition pour l'administration orale, utilisation de la composition dans la prévention et le traitement de la maladie des muqueuses, et procédé de traitement de la maladie des muqueuses Download PDF

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Publication number
WO2019106626A1
WO2019106626A1 PCT/IB2018/059525 IB2018059525W WO2019106626A1 WO 2019106626 A1 WO2019106626 A1 WO 2019106626A1 IB 2018059525 W IB2018059525 W IB 2018059525W WO 2019106626 A1 WO2019106626 A1 WO 2019106626A1
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Prior art keywords
composition
treatment
individual
amount
mucositis
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PCT/IB2018/059525
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English (en)
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Agata LEWANDOWSKA
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Lewandowska Agata
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Publication of WO2019106626A1 publication Critical patent/WO2019106626A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/01—Hydrocarbons
    • A61K31/015—Hydrocarbons carbocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/25—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids with polyoxyalkylated alcohols, e.g. esters of polyethylene glycol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/18—Antioxidants, e.g. antiradicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • 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.
  • 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).
  • GALT system gut-associated lymphoid tissue
  • Neoplasm 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.
  • Amino acids released in this process 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.
  • 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.
  • ROS reactive oxygen species
  • 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
  • chemotherapeutic drugs 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.
  • 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.
  • 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.
  • vitamin C 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.
  • 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.
  • 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.
  • 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.
  • 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,
  • This supplement is intended for enteral administration only and it is not possible to administer it through the oral route.
  • 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.
  • 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.
  • 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.
  • oral supplements nutrition containing aside from protein and fats also alive probiotic bacteria cultures
  • 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.
  • intestinal barrier damage mucosa toxic damage
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Another object of the present invention is to improve the patient’s mood and to reduce intestinal cramps caused by GABA deficiencies.
  • 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.
  • 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.
  • 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.
  • compositions 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.
  • 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.
  • 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.
  • an individual is an individual under the systemic treatment and the prevention of mucositis is based on improving of the intestinal barrier function.
  • 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.
  • composition is in the form of a powder to be dissolved.
  • the composition comprises a combination of antioxidants comprising vitamin C, vitamin E, b-carotene, selenium and zinc.
  • 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.
  • the composition contains vitamin C in an amount of about 250 mg in a daily portion and the individual is a paediatric patient.
  • the composition contains vitamin C in an amount of about 750 mg in a daily portion and the individual is an adult patient.
  • the composition is free of iron and copper.
  • 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).
  • 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).
  • 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.
  • composition as defined above is administered as a single daily dose.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • composition has been supplemented with omega-3 fatty acids in the range of 500-2000 mg per day, preferably 1000 mg per day.
  • omega-3 fatty acids of plant origin 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).
  • immunomodulatory compounds prostaglandins, eicosanoids
  • thromboxanes blood clotting
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • patient and individual are used interchangeable.
  • 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.
  • 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.
  • 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.
  • esters examples are short-chain fatty acid salts or esters and amino derivatives such as GABA.
  • the salt is zinc butyrate.
  • 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.
  • amounts are based on participation of such acid in the substance.
  • 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 Allowances
  • 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.
  • 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. H 2 0 2 - hydrogen peroxide, 0 2 - 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.
  • 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.
  • free radicals oxidize fatty acids (lipids) of skin cell membranes, structural proteins, especially collagen and enzymatic proteins.
  • Oxidative stress occurs in the etiopathogenesis of many diseases i.a. cancers and autoimmune diseases.
  • 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.
  • antioxidants trace elements such as selenium and zinc may act as antioxidants.
  • these intrinsic antioxidants are not sufficient to catch free radicals formed in high concentrations or to bind them as early as there are formed.
  • 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.
  • antioxidants depend on each other in a synergistic manner regarding their regeneration by creating an antioxidative spiral.
  • 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.
  • 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.
  • 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 confusegut associated lymphoid tissue” (GALT).
  • GALT wholly or not be advantary amylcholine
  • 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:
  • 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.
  • 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.
  • 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.
  • CACS cachexia-anorexia cancer related syndrome
  • a paediatric patient with regard to humans means an individual of the age up to 18 years.
  • cachexia syndrome means qualitative and quantitative cachexia resulting from generalized and persistent for a long time inflammation state in patient’s body.
  • 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 intestinal), submucosa (containing blood vessels, lymphatic vessels - GALT system, nerve fibers) and commensal bacterial microflora.
  • the intestinal barrier function improvement means minimization of symptoms of mucositis manifested in the form of abdominal pain, bloating, belly rumbling, putrescent gasses, diarrhea.
  • intestinal barrier function improvement means ensuring proper number of layers of the intestinal epithelium and restoring the normal physiological structure of the mucous membrane.
  • 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.
  • 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.
  • 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.
  • drugs obtained by molecular engineering 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.
  • protein preparation means a preparation for fortifying a diet of an individual having recognised lack of muscle mass.
  • 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.
  • a patient with cachexia means an individual with low muscle and fat mass.
  • 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.
  • the patient aged 69, after bilateral adnexectomy and after 2 lines of the systemic treatment.
  • composition A as described in Table 3
  • 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.
  • said composition was not administered.
  • 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.
  • 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.
  • previous lines of treatment it keep on
  • 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.
  • 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.
  • 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.
  • 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.
  • composition A 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.
  • the composition can be dissolved in batches of about 15 g and dissolved in about 200 ml of bottled water.
  • 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.
  • the composition can be dissolved in batches of about 10-15 g and dissolved in about 200 ml bottled water.
  • AML acute myeloid leukemia
  • daunorubicin administered for 3 days
  • cytosine arabinoside cytarabine
  • the patients were under the age of 60, one woman and one man.
  • 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.
  • composition C chemotherapeutic treatment regenerating mixture 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.
  • sodium butyrate available on the market preparation Debutir
  • 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.
  • 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.
  • 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.
  • composition E 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.
  • 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
  • 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.
  • 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.
  • 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] .
  • composition D 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.

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Abstract

L'invention concerne une composition pour l'administration orale, l'utilisation de la composition pour la prévention et le traitement de la maladie des muqueuses, et la méthode de traitement de la maladie des muqueuses à l'aide de cette composition chez des patients avant et après le traitement systémique.
PCT/IB2018/059525 2017-12-01 2018-11-30 Composition pour l'administration orale, utilisation de la composition dans la prévention et le traitement de la maladie des muqueuses, et procédé de traitement de la maladie des muqueuses WO2019106626A1 (fr)

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PL423673A PL423673A1 (pl) 2017-12-01 2017-12-01 Kompozycja do podawania doustnego, zastosowanie kompozycji w zapobieganiu i leczeniu mucositis oraz sposób leczenia mucositis

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Cited By (2)

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WO2021160417A1 (fr) * 2020-02-12 2021-08-19 Dsm Ip Assets B.V. Administration directe d'antioxydants dans l'intestin
CN114982970A (zh) * 2022-01-29 2022-09-02 石药集团中诺药业（泰州）有限公司 一种辅助治疗内腔粘膜炎的抗炎营养素含片及其制备方法

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WO2002039978A1 (fr) * 2000-11-17 2002-05-23 Fresenius Kabi Deutschland Gmbh Complement a administrer par voie enterale pour nutrition parenterale ou nutrition enterale/orale partielle dans le cas de maladies critiques ou chroniques et de malnutrition
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WO2002039978A1 (fr) * 2000-11-17 2002-05-23 Fresenius Kabi Deutschland Gmbh Complement a administrer par voie enterale pour nutrition parenterale ou nutrition enterale/orale partielle dans le cas de maladies critiques ou chroniques et de malnutrition
WO2009052106A2 (fr) * 2007-10-14 2009-04-23 University Of Florida Research Foundation Inc. Préparation pour améliorer la fonction gastro-intestinale
WO2012140118A1 (fr) * 2011-04-12 2012-10-18 Nestec S.A. Compositions nutritionnelles comprenant des acides gras à chaîne ramifiée pour cicatrisation des plaies

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021160417A1 (fr) * 2020-02-12 2021-08-19 Dsm Ip Assets B.V. Administration directe d'antioxydants dans l'intestin
JP2023512916A (ja) * 2020-02-12 2023-03-30 ディーエスエム アイピー アセッツ ビー．ブイ． 酸化防止剤の腸への直接的送達
CN114982970A (zh) * 2022-01-29 2022-09-02 石药集团中诺药业（泰州）有限公司 一种辅助治疗内腔粘膜炎的抗炎营养素含片及其制备方法
CN114982970B (zh) * 2022-01-29 2024-02-09 石药集团中诺药业（泰州）有限公司 一种辅助保护内腔粘膜的营养素含片及其制备方法

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