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    • 专利摘要:
    pharmaceutical composition containing nicotinic acid and/or nicotinamide and/or tryptophan, and its use. the present invention relates to a new pharmaceutical composition that contains nicotinic acid, nicotinamide, tryptophan or related compounds to positively influence the intestinal microbiota. in certain embodiments, the pharmaceutical composition is partially or fully delivered to the small intestine or large intestine.
    公开号:BR112014030835B1
    申请号:R112014030835-7
    申请日:2013-06-14
    公开日:2022-01-11
    发明作者:Georg Waetzig；Dirk Seegert
    申请人:Conaris Research Institute Ag；
    IPC主号:
    专利说明:

    FIELD OF THE INVENTION
    [001] The present invention relates to a new pharmaceutical composition that contains nicotinic acid and/or nicotinamide and/or tryptophan to positively influence the intestinal microbiota, wherein the pharmaceutical composition is specifically released (e.g., selectively released) in the intestine. small and/or large intestine. BACKGROUND
    [002] Many inflammatory bowel wall diseases are caused or influenced by changes in the gut microbiota and/or a diminished interaction between the gut microbiota and the intestines. Such intestinal inflammations occur in humans, eg inflammatory bowel diseases (IBD) such as Crohn's disease or ulcerative colitis, but also in other mammals (eg chronic idiopathic colitis in dogs). These diseases are based on complex immune processes that are not fully understood. However, changes in, and impaired interactions of, the gut microbiota can also be causative factors in a number of other diseases. Examples include atopic diseases such as atopic eczema, allergic conditions, or asthma (see, for example, Bisgaard et al. 2011, J. Allergy Clin. Immunol. 128:646 ; Iebba et al 2011, Dig. Dis. 29:531 ; ; Abrahamsson et al. 2012, J. Allergy Clin. Immunol. 129:434; Candela et al. 2012, BMC Microbiol. 12:95; Olszak et al. 2012, Science 336:489), as well as metabolic diseases, with a inflammatory component, such as arteriosclerosis with resultant coronary heart disease, obesity, or diabetes (Ott et al. 2006, Circulation 113:929; Koren et al. 2011, PNAS 108 Suppl 1: 4592; for comments see César et al. 2010, J. Intern. Med. 268: 320; and Vrise et al. 2010, Diabetologia 53:606 ).
    [003] Although the relationship between the gut microbiota and various diseases is known, it has not been understood how to influence the microbiota in a way that has a positive impact on associated diseases.
    [004] Nicotinic acid (niacin, vitamin B3), nicotinamide (nicotinic acid amide), and/or L-tryptophan have been used for the therapy of niacin deficiency diseases (eg, pellagra) for decades. Pellagra is known to be accompanied by intestinal inflammation, which is ameliorated after administration of niacin, where the therapeutic principle is the elimination of the vitamin deficiency causing intestinal inflammation (Segal et al. 1986, Int J. Colorectal Dis. 1: 238; and Clayton et al. 1991, Eur J. Pediatr. 150: 498).
    [005] Nicotinic acid is also known to have a health-promoting effect on blood cholesterol lipoproteins (HDL/LDL ratio and LDL vesicle size; Wahlberg et al. 1990, J. Intern. Med. 228: 151; Semente et al. 1993, Atherosclerosis 101:61; Elam et al. 2000, JAMA 284:1263; McKenney et al. 2001, Am J. Cardiol. 88: 270 ). SUMMARY OF THE INVENTION
    [006] The objective of the present invention is to provide new forms of treatments for the therapy and/or prophylaxis of diseases in humans and animals associated with alterations in the intestinal microbiota and/or an impaired interaction between the intestinal microbiota and the intestines.
    [007] According to the invention, the above problem is solved by a pharmaceutical composition that contains nicotinic acid, nicotinamide, tryptophan or another compound described herein, which is believed to positively influence the intestinal microbiota. In preferred embodiments, nicotinic acid and/or nicotinamide and/or tryptophan are administered to locally influence the intestinal mucosa and intestinal microbiota. For example, the active substance is formulated to be selectively administered to the terminal ileum or colon where the intestinal microbiota to be modified is located. Other active substances that can be converted to nicotinic acid and/or nicotinamide and/or tryptophan in an animal organism (e.g., a human body) are also contemplated by the present invention.
    [008] Therefore, pharmaceutical compositions are provided containing nicotinic acid (niacin, vitamin B3) and/or nicotinamide and/or tryptophan. These three substances act individually or in combination (combination of two or three) with each other in an anti-inflammatory and/or beneficial way on the microbiota in the small intestine and/or large intestine. The composition is suitable for oral administration with controlled and/or slow release of the active ingredient during for specific local or topical efficacy in the terminal ileum and/or colon. Examples of conditions treated include the therapy or prophylaxis of inflammatory diseases of the small intestine, inflammatory diseases of the large intestine, prophylaxis of colon carcinoma, and therapy or prophylaxis of other diseases that result from changes in the intestinal microbiota and/or an impaired interaction between the intestinal microbiota and the intestines. The composition is also suitable for (neo)rectal administration to the colon or pouch for local and/or topical therapy of inflammatory diseases of the large intestine or pouchitis.
    [009] The invention also includes methods of treating one or more of the diseases and conditions described herein with a pharmaceutical composition described herein. Furthermore, the invention provides the use of a pharmaceutical composition described herein in the manufacture of a medicament for the treatment of one or more of the diseases and conditions described herein. BRIEF DESCRIPTION OF THE DRAWINGS
    [0010] Figure 1 shows prevention of SDS enhancement in ACE-2 deficient mice by nicotinamide or tryptophan. Top column: Colon histopathology (hematoxylin eosin colored on day 10 after DSS administration; bar: 100 μm (a)), percent weight loss (b) and diarrhea score (c) of ACE2-normal mice challenged with DSS (ACE2+/y) and ACE2-deficient (ACE2/y) mice that received vehicle or nicotinamide (NAM) in their drinking water. NAM administration started three days before DSS administration. Lower column: colon histopathology (hematoxylin and eosin on day 7 after DSS challenge; bar: 100 μm (d)), percent weight loss (e) and colonic crypt damage (f) in ACE2- normals challenged with DSS (ACE2+/y) and ACE2 deficient mice (ACE2/y) that received either a normal diet (control) or a tryptophan-dipeptide (Trp+) diet.
    [0011] All values are mean values with standard error of 3-10 mice per group.*: P < 0.05; ** Or ##: P < 0.01.
    [0012] Figure 2 shows the development of Crohn's Disease Activity Index (CDAI) in three patients from week (without) 0 to week 4 while administering nicotinamide (2 x 600 mg daily).
    [0013] Figure 3 shows the histological scores of the colonic mucosa of mice challenged with dextran sodium sulfate (DSS)-induced colitis and treated with nicotinamide (NAM) by gavage in water or a controlled-release mini-pill formulation. NAM mixed in the diet or 5-aminosalicylic acid by gavage as a suspension in 0.5% methylcellulose.
    [0014] Figure 4 shows disease activity index (DAI) data from mice challenged with dextran sodium sulfate (DSS)-induced colitis and treated with (1) nicotinamide (NAM) by water gavage, or ( 2) control granules mixed into the diet, or (3) a controlled release granules formulation of NAM mixed into the diet in three doses, or (4) a controlled release granules formulation of 5-aminosalicylic acid (5-ASA granules) ) mixed in the diet. *, P<0.05 vs. control granules; **, P < 0.01 versus control beads; *** P < 0.001 vs control beads; ###, P<0.001 vs same dose of NAM in water.
    [0015] Figure 5 shows the myeloperoxidase (MPO) content of colon tissue homogenates from mice challenged with dextran sodium sulfate (DSS)-induced colitis and treated with (1) nicotinamide (NAM) by gavage in water, or (2) control granules mixed into the diet, or (3) a controlled-release granules formulation of NAM mixed into the diet in three doses, or (4) a controlled-release granules formulation of 5-aminosalicylic acid (granules 5 -ASA) mixed in the diet. *, P<0.05 vs. control granules; ***, P<0.001 vs. control granules.
    [0016] Figure 6 shows the relative abundance of the main phylobacteria Bacteroides and Firmicutes in stool samples from 5 to 8 mice per group, before and after 12 days of a diet deficient in tryptophan, nicotinic acid or nicotinamide (Trp-free diet). /Nia/NAM). The Trp/Nia/NAM-free diet contained (1) control granules without NAM or 5-aminosalicylic acid (5-ASA), (2) a controlled-release granule formulation of NAM mixed into the diet in three doses, or ( 3) a controlled release formulation of 5-aminosalicylic acid granules (5-ASA granules) mixed in the diet.
    [0017] Figure 7 shows the percentage similarity analyzes (SIMPER) of the microbiota composition in stool samples from 5 to 8 mice per group, before and after 12 days of a diet deficient in tryptophan, nicotinic acid or nicotinamide (diet free of Trp/Nia/NAM). The Trp/Nia/NAM-free diet contained (1) control granules without NAM or 5-aminosalicylic acid (5-ASA), or (2) a controlled-release granule formulation of NAM mixed into the diet in three doses, or (3) a formulation of controlled release granules of 5-aminosalicylic acid (5-ASA granules) mixed in the diet. The expansion of unclassified Bacteroidales and Bacteroidales of the genus Paraprevotella is visualized by the dashed portions of the columns. DETAILED DESCRIPTION
    [0018] The core of the present invention is a pharmaceutical composition comprising one, two or more active substance(s) selected from nicotinic acid; nicotinamide; tryptophan; a compound that converts in the body of an animal (e.g., a human body) to nicotinic acid, nicotinamide or tryptophan; nicotinamide adenine dinucleotide (NAD); nicotinamide adenine dinucleotide phosphate (NADP); an intermediate in the biosynthesis of NAD or NADP; and a tryptophan dipeptide, for positively influencing the gut microbiota, wherein the pharmaceutical composition is designed for a slow release so that it releases (e.g., partially release, selectively release) in the lower small intestine, colon, or both.
    [0019] The inventors have found that nicotinic acid and/or anicotinamide and/or tryptophan have an anti-inflammatory effect by influencing the intestinal microbiota (the totality of all microorganisms in the intestines, in particular bacteria), in which they alter the pattern of antimicrobial peptide secretion in the intestines. The altered gut microbiota after administration of a pharmaceutical composition according to the invention has a minor inflammation promoting effect or is anti-inflammatory, thus causing and/or supporting a clear reduction in the symptoms of IBD, such as the disease Crohn's disease or ulcerative colitis, in humans or other mammals (eg, chronic idiopathic colitis in dogs). Furthermore, it has been shown for the first time here that pharmaceutical compositions that deliver at least part of their active substance to the affected area of the gastrointestinal tract have significantly better efficacy than a pharmaceutical composition that is largely absorbed before reaching the affected area.
    [0020] Thus, as used herein, "positively influencing the gut microbiota" refers to bringing about a change in the gut microbiota that has a positive impact on health, especially in one or more of the diseases and conditions described herein. For example, positive impacts are associated with reducing the number of pathogenic bacteria, reducing the ratio of pathogenic to beneficial bacteria, increasing the diversity of the microbiota, reducing the amount of inflammation that the microbiota induces in the intestines, and, in part or completely, reversing pathological changes in the enterotype of the microbiota (eg, enterotypes associated with Bacteroides, Prevotella and Ruminococcus). Bacteria generally considered to be pathogens in inflammatory bowel diseases include, for example, Enterobacteriaceae (e.g. Escherichia coli) with invasive properties or virulence factors, Desulfovibrio spp. and Fusobacterium spp producing sulfide with invasive properties. Bacteria generally considered to be beneficial include species of the genera Lactobacillus, Bifidobacterium and Faecalibacterium, such as L. casei, L. plantarum and F. prausnitzii. For a more recent look at the gut microbiota in inflammatory bowel disease, see Manichanh et al. 2012, Nat. Rev. Gastroenterol. Hepatol. 9: 599.
    [0021] Hashimoto et al. (Nature 2012, 487: 477), published after the priority date of this application and the contents of which are incorporated herein by reference, provide additional evidence regarding the invention described herein. Hashimoto et al. demonstrated that the malabsorption of tryptophan in mice leads to a significant increase in the severity of colitis induced by the irritating sodium dextran sulfate (DSS). Dietary supplementation of tryptophan or nicotinamide prevented this increase in colitis. Hashimoto et al. demonstrated that the increased susceptibility to severe colitis was due to an altered gut microbiota, which, when transplanted into other mice, also increased the severity of colitis in recipients. The detrimental change in the gut microbiota was due to strongly reduced amounts of certain antimicrobial peptides (AMPs), especially alpha-defensins, whose expression in terminal ileal epithelial cells was largely controlled by mTOR signaling induced by tryptophan or nicotinamide.
    [0022] Because chronic intestinal inflammation strongly increases the risk of developing colon carcinoma (for a review see, e.g., Ullman & Itzkowitz 2011, Gastroenterology 140: 1807), a use of the composition according to the invention is also prophylaxis of colon carcinoma in the case of chronic or recurrent intestinal inflammation.
    [0023] Therapeutic intervention by establishing or restoring a normal intestinal microbiota or by supplementing beneficial bacteria has been effective in several disease models and in the respective human diseases. For example, Olszak et al. (Science 2012, 336: 489) recently demonstrated that the pathological accumulation of invariant natural killer T cells in diseased organs in germ-free murine models of IBD or asthma can be prevented by colonizing newborn mice with normal microbiota. In different diseases, studies have shown beneficial effects of certain pre, pro or symbiotics. For example, lactobacilli can reduce blood cholesterol levels in obesity, but the mechanism is still not entirely clear (reviewed by César et al. 2010, J. Intern. Med. 268:320). In inflammatory bowel diseases, some probiotics such as VSL #3 (a mixture of Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantil, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus paracasei, Lactobacillus delbrueckii ssp. bulgaricus and Streptococcus thermophilus) have been used successfully in a limited number of clinical studies. It appears that supplementation of at least several strains of bacteria is generally required to provide significant therapeutic benefit. A recent example of the spectacular efficacy of a complex bacterial intervention is the successful use of stool transplants against Clostridium difficile (van Nood et al. 2013, New Engl. J. Med 368:407).
    [0024] As pathological changes in the gut microbiota can also play a causal role in numerous other diseases arising from atopic disorders, as well as in metabolic diseases with an inflammatory component, the therapy and/or prophylaxis of such diseases is also within the scope of the invention. In particular, the following diseases are examples of such indications:
    [0025] - Skin: allergy, atopic eczema, psoriasis;
    [0026] - Lung: cystic fibrosis, asthma, COPD;
    [0027] - Vessels: coronary heart disease, arteriosclerosis, atherosclerosis;
    [0028] - Endocrine system: diabetes, adiposity.
    [0029] The inventive, specific, topical use of nicotinic acid and/or nicotinamide and/or tryptophan (and related active substances) to locally influence the intestinal mucosa and intestinal microbiota, intestinal inflammations, and direct therapy of the intestinal mucosa result from the insights described here to the previously unknown and unexpected role of these compounds. This use differs significantly from conventional uses of active substances, where these substances are absorbed and supposedly act systemically. Because of their novel anti-inflammatory effect and/or their effect on modifying the intestinal microbiota, nicotinic acid and/or nicotinamide and/or tryptophan (and the other compounds described here) are therefore suitable as substances. active for the treatment of inflammatory diseases of the small intestine and/or large intestine. Particular conditions include the treatment of intestinal inflammation, the prophylaxis of colon carcinoma, and the therapy or prophylaxis of other diseases that result from changes in the intestinal microbiota and/or an impaired interaction between the intestinal microbiota and the intestines. Preferably, these active substances are used in a pharmacological formulation that protects as much of the active substance as possible from being absorbed by the body in the upper small intestine and instead effects a release (e.g. controlled release and/or slow release) to the terminal ileum or colon where the intestinal microbiota to be modified is located (eg active substance is selectively released into the terminal ileum and/or colon).
    [0030] In particular, the active substances described here are therefore suitable for use in topically-released (e.g. controlled and/or slow-release) drugs for the therapy of Crohn's disease, ulcerative colitis, pouchitis, other chronic diseases of the large intestine or inflammation of the large intestine, fecal diversion colitis, infectious enteritis, antibiotic-associated diarrhea, such as C. difficile-associated diarrhea, infectious colitis, diverticulitis, and inflammation that is formed by irradiation, by antibiotics , by chemotherapeutic agents, by pharmaceuticals or by chemicals, as well as for the prophylaxis of colon carcinoma and for the therapy or prophylaxis of other diseases that result from alterations in the intestinal microbiota and/or impaired interaction between an intestinal microbiota and the intestines.
    [0031] The claimed substances are equally useful for the therapy or prophylaxis of diseases of similar origin in both humans and other mammals, in particular domestic and useful animals. Examples of such animals are dogs, cats, horses, camels or cows without objective restriction.
    [0032] The active substances, ie nicotinic acid and/or nicotinamide and/or tryptophan, can be used in any form available on the market, eg produced by Merck KgaA. Tryptophan can be used as a single amino acid or dipeptide, for example as a Gly-Trp dipeptide.
    [0033] In addition to nicotinic acid, nicotinamide and tryptophan, other related compounds can be used in the invention described herein as active substances. For example, compounds that convert to one of these agents (e.g., by hydrolysis, metabolism) in the human or animal body are suitable, such as nicotinic acid esters. In addition, intermediates in the synthesis of nicotinamide adenine dinucleotide (NAD) or NAD phosphate (NADP), such as N-formylkynurenine, L-kynurenine, 3-hydroxy-L-kynurenine, 3-hydroxyanthranilate, 2-amino-3-carboxymuconate semialdehyde, quinolinate and D-ribonucleotide beta-nicotinate can be used. Other examples include NAD and NADP.
    [0034] Pharmaceutical compositions containing nicotinic acid and/or nicotinamide and/or tryptophan (or one of the other substances described above) can be administered orally with a slow release of the active substance or also through a rectal mode of application (e.g. e.g. enemas or suppositories). The delivery site of the active substance is preferably the lower portions of the small intestine and/or colon to inhibit inflammatory processes, and thus fundamentally differs from modes of application that - for example, for the therapy of pellagra - seek maximum absorption and metabolism in the body and thus a systemic effect. Furthermore, the mode of administration according to the invention and the dose according to the invention minimize the likelihood of the occurrence of side effects, for example as described in connection with the systemic administration of nicotinic acid.
    [0035] As used herein, the "lower small intestine" is the second half of the small intestine and the "terminal ileum" is the second half of the ileum.
    [0036] In this regard, the present invention also comprises combination preparations, such as combinations of nicotinic acid and/or nicotinamide with acetylsalicylic acid and/or prostaglandin D2 antagonists, such as laropiprant, which reduce typical acid side effects. nicotinic. The composition and dosage of such combinations are known to one skilled in the art. Furthermore, the use of nicotinamide instead of nicotinic acid, which is preferred according to the invention, minimizes the likelihood of side effects occurring.
    [0037] To produce orally administered formulations of an active substance that has an anti-inflammatory and/or modifying effect on the intestinal microbiota in the terminal ileum and/or colon it is thus advantageous and innovative to use controlled and/or slow modes of release. In contrast to conventional (in some cases also slow) modes of delivery for optimal supplementation, for example in the case of pellagra, certain embodiments of the present invention partially or substantially prevent absorption in the stomach and upper portions of the small intestine.
    [0038] In order to treat Crohn's disease or ulcerative colitis, oral and/or rectal (eg enema) modes of application are suitable. In order to treat pouchitis, in the case of ulcerative colitis, rectal application (eg, with an enema) is preferred. It can also be supported by an oral administration of the oral formulations described above, for example, slow release preparations. For symptomatic therapy of any other form of colitis, both oral and rectal applications may be chosen for therapeutic modification of the gut microbiota. Oral application is preferred for the prophylaxis of colon carcinoma, in particular in the case of ulcerative colitis, and for the therapy and/or prophylaxis of other diseases which partially or substantially result from alterations in the intestinal microbiota and/or an impaired interaction between the intestinal microbiota and the intestines.
    [0039] For oral administration, particular dosage forms that control and/or delay the release of the active substance due to special galenics (called controlled-release, slow-release or slow-release forms) are particularly suitable. Such dosage forms can be plain tablets and also coated tablets, for example film tablets or dragees. Tablets are usually round or biconvex. Oblong tablet shapes, which allow the tablet to be separated, are also possible. In addition, granules, spheroids, pellets or microcapsules are possible, which are filled into sachets or capsules, if applicable.
    [0040] The term "slow release" preferably refers to a pharmaceutical formulation that releases the active ingredients after a delay period. In certain embodiments, the delay is sufficient for at least a portion of the active substances in a formulation for delivery to the lower small intestine (eg, the terminal ileum) and/or colon.
    [0041] The term "controlled release" preferably refers to a pharmaceutical formulation or component thereof that releases, or delivers, one or more active ingredients over an extended period of time. In certain embodiments, the time period is sufficient for at least a portion of the active substances in a formulation for delivery to the lower small intestine (eg, the terminal ileum) and/or colon.
    [0042] The delay is advantageously achieved, for example, by coatings that are resistant to gastric juice and dissolve as a function of pH, by means of microcellulose and/or multi-matrix technologies (MMX), using different vehicle matrices, or a combination of these techniques. Examples include film coatings that contain acrylic and/or methacrylate polymers in various controlled and/or slow release blends. For example, the active substance(s) can be contained in a conventional matrix of cellulose or microcrystalline gelatin, or with MMX technology, which is coated with a material, which provides the slow release of active substance(s). It is preferred to introduce an active substance into large-volume capsules (eg gelatin with a content of 0.68 ml) which are coated using known methods. Suitable coating agents are waxes and water-insoluble polymers such as polymethacrylates (e.g. the Eudragit® product portfolio, in particular Eudragit® S and Eudragit® L, Evonik Industries AG, Essen, Germany ) and water-insoluble celluloses (eg methyl cellulose, ethyl cellulose). If applicable, water-soluble polymers (e.g. polyvinylpyrrolidone), water-soluble celluloses (e.g. hydroxypropylmethylcellulose or hydroxypropylcellulose), polysorbate 80, polyethylene glycol (PEG), lactose or mannitol may also be used. be contained in the coating material.
    [0043] For example, a combination of Eudragit®S and L compounds (e.g. Eudragit® L/S 100) effects a controlled release of the active substances according to the invention at a pH> 6.4, which occurs in the terminal ileum. Other uses of Eudragit® preparations and mixtures (compounds L, S, and R) are also conceivable for the packaging of an active substance, and therefore a topical use in selected portions of the entire gastrointestinal tract can be achieved. by controlled release at certain pH values.
    [0044] The pharmaceutical composition may also contain other pharmaceutical excipient substances, such as binders, fillers, glidants, lubricants and flow-regulating agents. The compounds according to the invention can be formulated, where appropriate, with the most active substances and with conventional excipients in pharmaceutical compositions, for example, talc, acacia, lactose, starch, magnesium stearate, cocoa butter, - aqueous and non-aqueous agents, lipid components of animal or vegetable origin, paraffin derivatives, glycols (in particular polyethylene glycol), various plasticizers, dispersants, emulsifiers and/or preservatives.
    [0045] In order to produce enemas or suppositories for rectal application, preparations of an active substance can be dissolved in a suitable solvent and subsequently processed into enemas or suppositories according to known pharmaceutical methods.
    [0046] The active substance content in the finished dosage form ranges from 1 to 3000 mg, preferably 100 to 1000 mg in the case of oral administration; enemas and/or suppositories may contain an amount of 10 mg to 5000 mg of the active substance. Depending on the intensity and severity of the inflammatory disease, the dosage forms are administered once or several times a day or in another dosage regimen to be chosen by a physician.
    [0047] As used herein, the terms "treatment", "treating" and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of, a disease or disorder, or one or more of its symptoms. , as described here. In some modalities, treatment may be given after one or more symptoms have developed. In other modalities, treatment may be given in the absence of symptoms. For example, treatment may be given to a susceptible individual prior to the onset of symptoms (eg, as a function of a history of symptoms and/or as a function of genetic factors or other susceptibilities). Treatment can also be continued after symptoms have disappeared, for example to prevent or delay their recurrence.
    [0048] As used herein, the terms "prophylaxis" and "prevent" refer to delaying the onset of a disease or reducing the likelihood of developing a disease or disorder or one or more of its symptoms, compared to a population untreated control.
    [0049] Another aspect of the invention described herein is the effective use of the claimed drugs in the genetic and/or microbiological database and the specific needs of each individual to be treated. New insights into the genetic predisposition of individuals to all types of diseases (in particular also diseases where the interaction between the gut microbiota and the intestines is impaired) and into pharmacogenetics indicate that evidence-based personalized medicine, including genetic analyzes of relevant risk and also genes encoding, for example, cell surface receptors, transport proteins, metabolism enzymes or signal transduction proteins, which interact with the drug and/or its metabolites and/or its downstream effectors, can contribute information and improvements with respect to the type of use, mode of application, time(s) of use, dose and/or dosing regimen of the drugs described herein. Individuals who may benefit from this personalized treatment include those with reduced serum tryptophan, altered B0AT1 expression (eg, in gut epithelial cells), and B0AT1 polymorphisms. This applies analogously to the analysis of the gut microbiota, particularly when a stool sample indicates a change in the microbiota. The present invention therefore also comprises the use of genetic and/or microbiological testing methods suitable for identifying individuals particularly sensitive to the drugs according to the invention and/or adapting the use of drugs according to the invention to individual circumstances. This also comprises expressing the use of different substances (nicotinic acid and/or nicotinamide and/or tryptophan) in different modes of administration depending on the microbiological and genetic properties of the individual. For these purposes, it is possible to use suitable laboratory tests and/or test kits and also measurement methods, devices and/or kits to be employed by a physician, user and/or patient, for example, to take samples of feces or analyzing appropriate parameters in blood, urine or other body fluids. EXAMPLES
    [0050] There are varying possibilities to advantageously develop, and further develop, the teaching of the present invention. For this purpose, reference is made to the examples below which describe the invention in a representative manner. Example 1:
    [0051] New and unpublished findings at the time the priority application was filed, once published as Hashimoto et al. (Nature 2012, 487: 477), support the teachings of the present invention and are briefly described here for the purpose of illustration: It is known that the expression of the neutral amino acid transporter B0AT1 (which transports tryptophan) on the surface of intestinal epithelial cells is linked to the presence of angiotensin-converting enzyme 2 (ACE2) ( Kowalczuk et al. 2008, FASEB J. 22:2880; Camargo et al. 2009, Gastroenterology 136:872 .). The defective ACE2 results in an amino acid deficiency disease (so-called Hartnup disease), whose disease pattern is similar to pellagra and which can be treated by an increased supply of tryptophan and nicotinamide. A mouse model has already shown that mice lacking ACE2 function (genotype: Ace2-/y) suffered from artificially induced intestinal inflammations substantially stronger than mice with normal genotype (Ace2 +/y) when they were given the sulfate substance. dextran sodium (DSS). Interestingly, it was possible to reduce this effect by prophylactic and permanent administration of nicotinamide (NAM) or by fed tryptophan dipeptides (which are absorbed through a transporter other than B0AT1, which is not available in the present document) to the value of genetically modified mice. normal. Follow-up data are summarized in Figure 1 and support, with respect to content, the results and claims of the present invention for use in humans and animals from the perspective of a mouse model. Example 2:
    [0052] In order to analyze the change in gut microbiota when nicotinamide is given, genomic DNA is isolated from stool samples according to the prior art and quantified, and the variable region of the bacterial 16-S-rRNA gene is amplified, where the amplicons are provided with appropriate tags for the purpose of identification. Following high throughput pyrosequencing of the amplicons, all sequences obtained are quality-controlled and analyzed by multi-step sequence comparison with curated bacterial DNA sequence databases. Differences from representative cross-sections obtained from the gut microbiota in stool samples from treated and untreated subjects are correlated and evaluated with the subjects' observed and measured disease symptoms and relevant genetic factors.
    [0053] Figure 2 shows the development of the Crohn's disease activity index (CDAI), that is, the disease activity calculated according to a recognized pattern from different disease parameters of three patients suffering from Crohn's disease and were treated with conventionally formulated high-dose nicotinamide for 4 weeks (2 x 600 mg daily). A CDAI value <150 is equivalent to remission. All three patients suffering from Crohn's disease showed a clear response to the administration of nicotinamide, two of them achieved remission within the period of therapy.
    [0054] The underlying mechanism and beneficial effects of nicotinamide described by Hashimoto et al. 2012 (Nature 487: 477) for the murine colitis model (see Example 1) match the clinical improvement of human Crohn's disease patients in response to nicotinamide supplementation seen in this example. Example 3:
    [0055] It was surprisingly found that although the expression of ACE2 in the intestinal mucosa of patients suffering from Crohn's disease and ulcerative colitis did not differ significantly from the values in healthy subjects (data not shown), the expression of B0AT1 in inflamed portions of the mucosa was reduced very strongly and in a statistically significant way (P value <0.05) (see table 1). Furthermore, control samples from patients suffering from intestinal inflammations of different genesis (called disease specificity controls) did not show significant deviation from hospitalized normal people (NH). This argues against a general non-specific deficiency disease or amino acid deficiency, and for the specific effects of nicotinic acid, nicotinamide and/or tryptophan (and related compounds) in the treatment of IBD, the effects of which have recently been observed in the present invention. Table 1: B0AT1 mRNA expression relative to baseline (from samples of hospitalized normal controls, HN, i.e. patients without intestinal inflammation)

    [0056] The tryptophan transporter deficiency seen in IBD patients seen in this example corresponds to the situation in mice with exacerbated colitis due to tryptophan transporter deficiency (Hashimoto et al. 2012, Nature 487:477; see Example 1). Example 4:
    [0057] In order to characterize the advantage of controlled-release formulations for targeted delivery of nicotinamide to the intestinal epithelium, a proof-of-concept study was conducted in a mouse model of dextran sodium sulfate (DSS) colitis. Colitis DSS is a standardized colitis model for evaluating candidate drug efficacy for human inflammatory bowel disease. As a control in the normally effective treatment in DSS colitis, 5-aminosalicylic acid (5-ASA) was used. 5-ASA is nearly insoluble at physiological pH and therefore was administered as a suspension in 0.5% methylcellulose.
    [0058] Due to species-specific differences in the gastrointestinal tract, in terms of length, passage time, and pH medium, the controlled-release formulations were adapted to the organism that was treated. Based on murine gastrointestinal tract parameters (Koopman et al. 1978, Lab Anim 12:223; McConnell et al. 2008, J. Pharm Pharmacol 60:63), a murine-specific formulation was produced for the proof study. -of-concept in mice.
    [0059] Controlled-release mini tablets were produced with a blended powder of 99% NAM and 1% magnesium stearate (both from Caelo, Hilden, Germany) as a lubricant. After mixing, the powder was characterized in terms of powder flow (angle of repose; <35°) and size distribution (laser diffraction; main particle fraction: 100-200 μm) to ensure good powder flow. Mini-tablets were then produced on a rotary press and coated with a Kollidon SR 30 D water-insoluble polymer film (BASF, Ludwigshafen, Germany) to control the release of NAM by diffusing NAM through the film. The coating formulation was as follows: Kollicoat SR 20 D (49.9%), glycerol monostearate 60 (0.743%), propylene glycol (0.743%), iron oxide red (0.4%), polysorbate 80 (0.314 %) and water ad 100%.
    [0060] Glycerol monostearate 60 (Caelo) was heated with half the water to 80°C and emulsified with an Ultraturrax (IKA, Staufen, Germany). Subsequently, red iron oxide (Caelo) was added and dispersed for another 5 minutes (first compartment). Polysorbate 80 (Caelo), propylene glycol (Caelo) and polymer dispersions were combined in a second compartment and stirred with a magnetic stirrer. The cold emulsion (<30°C) from the first compartment was combined with the polymer dispersion from the second compartment, and the remaining water was added. The dispersion was stirred for 1 h before filtration (<500 µm). The mini-tablets were coated in a fluid bed apparatus (Mycrolab, Hüttlin, Schopfheim, Germany) with a batch size of 50 g with a liquid feed rate of about 1 mL/min and a spray pressure of 0 .7 bar. Prior to spraying, the tablets were preheated by a volume flow of 8 m3 at 45°C. During spraying, the volume flow was increased to 16 m3 at 45°C. A product temperature of about 38° C was observed. After spraying, the tablets were fluidized with 16 m3 for a further 10 min at 45°C during curing. In the final step of the process, the heating was turned off and the tablet bed was cooled to <30°C to prevent sticking. Tablets were coated at 6.2 ± 0.04 mg/cm 2 . Drug release was determined in a paddle apparatus (DT6, Erweka, Heusenstamm, Germany) according to Ph. Eur. at 50 rpm. Phosphate buffer (pH 4) was used as the dissolution medium because a slightly acidic gastrointestinal fluid of about this pH is expected in mice (McConnell et al. 2008, J. Pharm. Pharmacol. 60:63-70). Drug concentration was determined by UV absorption at 262 nm. The uncoated tablets showed instant drug release due to the tiny size of the tablets and the high water solubility of nicotinamide. Using the Kollidon SR coating, drug delivery was optimized to cover target areas in the small intestine of mice (time delay of at least 15 min, drug release constant over 3 h). The mini-tablets were mixed homogeneously with the tryptophan/niacin-free diet powder, pellets approximately 2 cm in length and 1 cm in diameter were formed with a minimum amount of sterile water, frozen in single-use aliquots at - 20°C for storage and freshly thawed daily to feed the mice.
    [0061] Male C57BL/6J mice (specific pathogen free; Taconic Europe, Ry, Denmark) were enrolled at the trial site at 6-7 weeks of age and acclimatized for 2 weeks. The diet during the acclimatization phase was Altromin 1324, produced by Altromin (Lage, Germany). After 2 weeks of acclimatization, the diet was changed to a custom-made diet without tryptophan or nicotinic acid or nicotinamide (Trp/Nia/NAM-free diet), which was manufactured by Ssniff (Soest, Germany). On the day of the diet change, the treatment regimen began as specified below. Both the Trp/Nia/NAM-free diet and the treatment were administered until the mice were sacrificed. After 12 days on a Trp/Nia/NAM-free diet, mice were challenged with 1.5% DSS (MP Biomedicals, Illkirch, France) in drinking water for 4 days and then sacrificed.
    [0062] The treatment regimen was carried out with four groups of 10 mice each, which were treated as follows:
    [0063] Group 1: daily oral gavage of 0.25 mL of vehicle (sterile water).
    [0064] Group 2: daily oral gavage of 0.25 mL of nicotinamide (Cat No. 4488 Caelo.) solution in sterile water (6 mg/mL; final dose: about 60 mg/kg of body weight).
    [0065] Group 3: NAM controlled-release mini-tablets evenly dispersed in the diet (final dose: about 60 mg/kg body weight, based on a food intake of 2.5 g per mouse per day).
    [0066] Group 4: daily oral gavage of 0.25 ml of 5-aminosalicylic acid (5-ASA; Cat No. A3537, Sigma-Aldrich, Brondby, Denmark) suspended in 0.5% methylcellulose (Cat. No. M7140, Sigma-Aldrich) at a concentration of 15 mg/ml (final dose: about 150 mg/kg body weight).
    [0067] Dose solutions were freshly prepared from the same stock solutions every day immediately prior to administration.
    [0068] Immediately before changing the diet, before induction of DSS colitis and before sacrifice, fresh stool samples equivalent to two fecal pellets were collected from each animal for microbiome analysis. Stool samples were immediately frozen in liquid nitrogen and stored at -80°C. Immediate freezing was performed to maintain relationships between different bacteria with different growth characteristics under environmental conditions.
    [0069] Immediately after the animals were sacrificed, the colon was washed with 0.9% saline and "swiss roll" samples were prepared (Moolenbeek and Ruitenberg 1981: Lab. Anim. 15:57). Briefly, the clean colon was opened longitudinally, wrapped with the villi facing out, and the resulting roll was fixed in formaldehyde and embedded in paraffin according to standard procedures. The "swiss roll" preparation allows long-gitudinal and quantitative histological evaluation of the entire colonic mucosa on the same slice slide. Sections were stained with hematoxylin-eosin according to standard procedures. Samples were evaluated by two independent, blinded investigators and scored according to the following three-parameter system:
    [0070] Severity of inflammation: 0, rare inflammatory cells nalamina; 1, increased number of granulocytes in the lamina propria, submucosal edema; 2, confluence of inflammatory cells extending into the submucosa; 3, Transmural extent of the inflammatory infiltrate.
    [0071] Crypt Damage: 0, crypts intact; 1, loss of a basal third; 2, loss of basal two-thirds; 3, loss of all crypt; 4, epithelial surface change with erosion; 5, confluent erosion.
    [0072] Ulceration: 0, no ulcers; 1, 1 or 2 foci of ulcerations; 2, 3 or 4 ulceration foci; 3, confluent or extensive ulceration.
    [0073] The maximum histological score was 3 + 5 + 3 = 11.
    [0074] Blind histological evaluation of whole colonic mucosa was chosen as a difficult parameter for a therapeutic effect of the claimed NAM formulations.
    [0075] The scores of the four groups are shown in Figure 3, expressed as means and standard deviations. Only optimally preserved and prepared colon samples and sections were used (number of animals represented in parentheses in the following text). The scores were as follows:
    [0076] Group 1 (water control): 6.25 ± 1.39 (n = 8);
    [0077] Group 2 (NAM in water): 5.14 ± 1.07 (n = 7);
    [0078] Group 3 (NAM controlled release tablets): 3.38 ± 0.92 (n = 8);
    [0079] Group 4 (5-ASA): 6.50 ± 1.60 (n = 8).
    [0080] Considering that NAM in drinking water induced only a trend decrease in histological inflammation score relative to water control (p = 0.1), a highly significant difference was observed both between NAM controlled release tablets and the water control group (p<0.001) and, importantly, also between NAM in water and controlled release of NAM (p<0.01). Interestingly, the 5-ASA control treatment (which improves normal DSS colitis and is widely used for the therapy of inflammatory bowel disease in humans) was not able to improve DSS colitis in the absence of tryptophan or niacin (Figure 3). . These results support the concept of the present invention that the beneficial effects on NAM in the gut microbiota and colitis are not optimally harnessed by systemic delivery via oral gavage, but by controlled release formulations in the gut, and that the primary effect of NAM is in the local environment in the gut. Example 5:
    [0081] To further characterize controlled-release formulations for targeted delivery of nicotinamide to the intestinal epithelium, a second proof-of-concept study was conducted in a mouse model of dextran sodium sulfate (DSS) colitis. In this second and largest proof-of-concept study, a controlled-release granule formulation for NAM was tested at three different doses. As a normally effective treatment control in DSS colitis, controlled-release granules containing 5-amino-salicylic acid (5-ASA granules; PENTASA, Ferring Pharmaceuticals, Saint-Prex, Switzerland) were used.
    [0082] The controlled release formulation for NAM is a granulate of 25% nicotinamide, 70% calcium phosphate dibasic and 5% Povidone K30. The average particle size was 234 μm. The granulate was subsequently film coated with ethylcellulose 7 to achieve a weight gain of 30% and an average particle size of 640 µm. Filtration removed particles smaller than 355 μm. Control granules replaced NAM with an equivalent amount of dibasic calcium phosphate.
    [0083] Male C57BL/6J mice (specific pathogen free; Charles River Laboratories, Saint-Germain-sur-l'Arbresle, France) were enrolled at the trial site at > 12 weeks of age and acclimated for 1.5 months, in order to enrich and stabilize its microbiota. The diet during the acclimatization phase was the A4 diet, produced by SAFE (Scientific animal Food and Engineering, Augy, France). After acclimatization, the diet was changed to a custom-made diet without tryptophan or nicotinic acid or nicotinamide (Trp/Nia/NAM-free diet), which was manufactured by Ssniff (Soest, Germany). The Trp/Nia/NAM-free diet was supplied as a powder, which was used to prepare food pellets without granules, control granules without NAM or 5-ASA, NAM granules or 5-ASA granules. The granules were dispersed homogeneously in the diet. Food pellets of about 2 cm in length and 1 cm in diameter were formed with a minimal amount of sterile water, frozen in single-use aliquots at -20°C for storage and thawed daily to feed the mice. The granule content of the food pellets was defined as follows with a calculation basis of 30 g of body weight and a daily food intake of 3 g.
    [0084] 5-ASA granules (5-ASA target dose: 150 mg/kg body weight; 5-ASA content: 52%): 4.5 mg of 5-ASA required in 3 g of food; 8.65 mg of granules needed in 3 g of food; 2.88 g of granules added per kg of feed. Fixed doses for the other granules were calculated in an analogous manner.
    [0085] NAM granules (target doses of NAM: 30, 60 or 120mg/kg body weight; NAM content: 19.1%): for 30 mg/kg of NAM, 1.57 g of granules per kg of foods; for 60 mg/kg of NAM, 3.14 g of granules per kg of feed; for 120 mg/kg of NAM, 6.28 g of granules per kg of feed.
    [0086] Control granules were added to food in the same proportion as 120 mg/kg dose group NAM granules, ie 6.28 g granules per kg of food.
    [0087] On the day the diet was changed to a Trp/Nia/NAM-free diet with or without granules, the oral gavage treatment regimen was initiated for groups 1 and 2 as specified below. Both the Trp/Nia/NAM-free diet with or without granules and the treatment were administered by gavage until the mice were sacrificed. After 12 days on a Trp/Nia/NAM-free diet, mice were challenged with 1.5% DSS (TDB Consultancy, Uppsala, Sweden) in the drinking water for five days and sacrificed after a further two days, during which they were supplied with normal drinking water.
    [0088] The treatment regimen was carried out with seven groups of 10 mice each, which were treated as follows:
    [0089] Group 1: daily oral gavage of 0.1 mL of vehicle (sterile water).
    [0090] Group 2: daily oral gavage of 0.1 mL of NAM solution (Sigma-Aldrich, Brondby, Denmark) in sterile water (18 mg/mL; final dose: about 60 mg/kg of body weight).
    [0091] Group 3: diet control granules (granule content corresponding to group 6).
    [0092] Group 4: NAM granules in the diet (final dose: 30 mg/kg body weight).
    [0093] Group 5: NAM granules in the diet (final dose: 60 mg/kg of body weight).
    [0094] Group 6: NAM granules in the diet (final dose: 120 mg/kg of body weight).
    [0095] Group 7: 5-ASA granules in the diet (final dose: 150 mg/kg of body weight).
    [0096] Dose solutions were freshly prepared from the same stock solutions every day immediately prior to administration.
    [0097] Immediately before changing the diet, before induction of DSS colitis and before sacrifice, fresh stool samples equivalent to two fecal pellets were collected from each animal for microbiome analysis. Stool samples were immediately frozen in liquid nitrogen and stored at -80°C. Immediate freezing was performed to maintain the proportions between different bacteria with different growth characteristics under environmental conditions.
    [0098] From the start of the DSS challenge, the mice were monitored daily for their general health status and the parameters relevant to the disease activity index (DAI), ie diarrhea and visible fecal blood. After sacrifice, a macroscopic classification of colon inflammation was performed. DAI was calculated according to Melgar et al. 2005 (Am J. Physiol. Gastrointest. Liver Physiol. 288:G1328), which has a theoretical maximum of 9. The DAI data summarized in Table 2 and Figure 4 show that, similar to the data in Example 4, NAM in water showed only a non-significant trend towards improvement in this experimental setup, whereas the controlled release formulation of NAM (NAM granules) caused a highly significant and dose-dependent reduction of DAI. It is important to note that the NAM granule group receiving 60 mg/kg NAM had a significantly lower DAI than the group receiving 60 mg/kg NAM in water (Table 2). 5-ASA granules exhibited a non-significant trend towards therapeutic efficacy.Table 2: Disease activity index (DAI) data and its statistical evaluation.

    [0099] The amount of myeloperoxidase (MPO), an enzyme contained in granulocyte, neutrophil and polymorphonuclear granules, is a quantitative tissue marker for neutrophil recruitment and allows indirectly to quantify acute colonic inflammation mediated by neutrophils in DSS colitis.
    [00100] To assay the MPO content of murine colon tissue, representative colon tissue samples were analyzed with the Hycult MPO Mouse ELISA Kit (No. HK210; Hycult Biotech; CliniSciences, Nanterre, France) according to the manufacturer's recommendations.
    [00101] While NAM in water showed only a non-significant trend towards MPO reduction, a significant decrease in MPO levels was observed in the groups of mice that received NAM granules at doses of 60 and 120 mg/kg, which again indicates a significant therapeutic effect of NAM only when administered as a controlled-release formulation (Table 3, Figure 5).Table 3: Quantification and statistical analysis of myeloperoxidase (MPO) levels in the colon.
    Example 6:
    [00102] As the results of the two animal studies described in Examples 4 and 5 suggested a significant therapeutic effect of controlled release formulations of NAM, the intestinal microbiota of mice from the study described in Example 5 was analyzed with exactly the same methodology and machinery (16SrDNA phylogenies and 454 marker sequencing) as described by Hashimoto et al. 2012 (Nature 487:477). Of the five groups that received controlled-release granules (groups 3-7), eight animals had been selected in a blinded fashion before analyzing the disease parameters described in Example 5. Stool samples from all these mice before the nutritional intervention (normal, non-colitogenic flora as a reference point) and after 12 days of Trp/Nia/NAM-free diet (immediately before DSS challenge, see Example 5) were compared.
    [00103] Figure 6 shows that 12 days of a Trp/Nia/NAM-free diet led to a dramatic switch from the dominant phylum of Bacteroides to Firmicutes. This could, in part, and in a dose-dependent manner, be prevented by controlled-release NAM granules. Controlled-release 5-ASA granules showed a trend in the same direction (Figure 6). In addition, more detailed percentage similarity analyzes (SIMPER) of the groups of bacteria showed that controlled release of NAM induced an expansion of unclassified Bacteroidales and Bacteroidales of the genus Paraprevotella (Figure 7; dashed portions of the columns).
    [00104] Beneficial symbionts of the order Bacteroidales belong to the genera predominantly represented in the gut of mammals and are important for nutrient processing because they hydrolyze dietary polysaccharides and convert them into short-chain fatty acids (SCFAs), which can be utilized by the host . The genomes most homologous to those found in the Bacteroidales group expanding under treatment with controlled-release NAM granules belonged to these SCFA producers. Of particular relevance, the prevalence of these beneficial symbionts and the resulting levels of intestinal SCFAs are reduced in human inflammatory bowel diseases (Frank et al. 2007, Proc. Natl. Acad. Sci. USA 104:13780). Expansion of such microbiota by pre- or probiotics, as well as their SCFA products, have been shown to be therapeutically effective in rodent DSS colitis (Osman et al. 2006, BMC Gastroenterol 28; 6:31; Maslowski et al. 2009; , Nature 461:1282). Furthermore, Bacteroidales have been shown to secrete immunomodulatory carbohydrate (polysaccharide A) structures that can suppress the inflammatory response (Mazmanian et al. 2008, Nature 453:620).
    [00105] In summary, the controlled release of NAM into the gut leads to a dose-dependent increase in beneficial microbiota and reduces colitis.
    [00106] The above examples serve to explain the invention, but are not intended to limit the scope.
    权利要求:
    Claims (13)
    [0001]
    1. Composition, characterized in that it comprises an active substance selected from nicotinic acid, nicotinic acid esters, nicotinamide, tryptophan, a tryptophan dipeptide or a combination thereof, wherein the composition is formulated for oral administration with slow release and /or controlled, and wherein said composition delivers the active substance for topical efficacy to the terminal ileum, the colon, or both, where the intestinal microbiota to be modified is located.
    [0002]
    2. Composition according to claim 1, characterized in that it is formulated for oral administration, with slow release of the active ingredient(s) for specific local effectiveness in the terminal ileum and/or colon .
    [0003]
    3. Composition according to claim 1, characterized in that it is formulated for oral administration with controlled release of the active ingredient(s) for specific local efficacy in the terminal ileum and/or colon.
    [0004]
    4. Composition according to any one of claims 1 to 3, characterized in that it comprises nicotinamide.
    [0005]
    5. Composition according to any one of claims 1 to 4, characterized in that it is formulated for oral administration with slow or controlled release of the active substance - for use in the therapy or prophylaxis of inflammatory diseases of the small intestine and/or diseases of the large intestine and/or in the prophylaxis of colon carcinoma and/or for use in the therapy or prophylaxis of diseases by altering the intestinal microbiota to have less of an inflammation promoting effect or to be anti-inflammatory, and/or for use in the treatment and/or prophylaxis of pathological changes in the intestinal microbiota;- for use in the cause of a change in the intestinal microbiota that has a positive impact on health by reducing the number of pathogenic bacteria, and/or reducing the ratio of pathogenic bacteria to bacteria beneficial effects, and/or increasing the diversity of the microbiota, and/or reducing the amount of inflammation that the microbiota induces in the intestines, and/or reversing partial or complete of pathological changes in the enterotype of the microbiota.
    [0006]
    6. Composition according to any one of claims 1 to 5, characterized in that it is formulated for selective release of the active substance for topical efficacy in the terminal ileum, colon or both, where the microbiota to be modified is located.
    [0007]
    7. Composition according to any one of claims 1 to 6, characterized in that it is formulated for oral application with an active substance content of 1 to 3000 mg per finished dosage form.
    [0008]
    8. Composition according to any one of claims 1 to 7, characterized in that acetylsalicylic acid and/or prostaglandin D2 antagonists are contained in addition to nicotinic acid and/or nicotinamide.
    [0009]
    9. Composition according to any one of claims 1 to 8, characterized in that it is (a) for use in the therapy or prophylaxis of inflammatory bowel disease, (b) for use in the therapy or prophylaxis of colon carcinoma, or (c) for use in the therapy or prophylaxis of diseases arising from atopic disorders and/or metabolic diseases with an inflammatory component, and/or selected from the group consisting of skin allergy, atopic eczema, psoriasis, cystic fibrosis, asthma, COPD, coronary heart disease, arteriosclerosis, atherosclerosis, diabetes and adiposity.
    [0010]
    10. Composition according to claim 9, characterized in that it is for use in the therapy or prophylaxis of inflammatory bowel disease.
    [0011]
    11. Composition according to any one of claims 1 to 10, characterized in that it comprises tryptophan dipeptide.
    [0012]
    12. A composition according to any one of claims 1 to 11, characterized in that it is for use in the cause of an alteration in the intestinal microbiota that has a positive impact on health by reducing the number of pathogenic bacteria, and /or reducing the proportion of pathogenic to beneficial bacteria, and/or increasing the diversity of the microbiota, and/or reducing the amount of inflammation that the microbiota induces in the intestines, and/or partially or completely reversing pathological changes in the enterotype from the microbiota; and/or for use in the therapy or prophylaxis of diseases by altering the gut microbiota to have less of an inflammation-promoting or anti-inflammatory effect; and/or for use in the treatment and/or prophylaxis of pathological changes in the intestinal microbiota.
    [0013]
    13. Use of the composition, as defined in any one of claims 1 to 12, characterized in that it is for the preparation of a medicament to treat one or more diseases and conditions selected from inflammatory diseases of the small intestine, inflammatory diseases of the large intestine, colon carcinoma, diseases that have intestinal microbiota with an inflammation-promoting effect, and pathological changes in the intestinal microbiota.
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    法律状态:
    2018-03-06| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2018-03-13| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2018-03-20| B06I| Publication of requirement cancelled [chapter 6.9 patent gazette]|Free format text: ANULADA A PUBLICACAO CODIGO 6.6.1 NA RPI NO 2462 DE 13/03/2018 POR TER SIDO INDEVIDA. |
    2018-06-05| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|
    2020-04-28| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|
    2020-05-05| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2021-07-13| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|
    2021-11-03| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2022-01-11| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 14/06/2013, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    DE102012011890.2|2012-06-15|
    DE102012011890|2012-06-15|
    PCT/EP2013/062363|WO2013186355A1|2012-06-15|2013-06-14|A pharmaceutical composition containing nicotinic acid and/or nicotinamide and/or tryptophan for positively influencing the intestinal microbiota|
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