Compositions comprising nicotinamide, nicotinamide precursors, nicotinamide metabolites, or combinations thereof for preventing or reducing one or more post-acute symptoms of an infectious disease

Abstract

Nicotinamide; nicotinic acid; nicotinic acid esters; tryptophan; tryptophan dipeptides; nicotinamide adenine dinucleotide (NAD); nicotinamide adenine dinucleotide phosphate (NADP); NAD or NA selected from the group consisting of N-formylkynurenine, L-kynurenine, 3-hydroxy-L-kynurenine, 3-hydroxyanthranilate, 2-amino-3-carboxymuconic acid semialdehyde, quinolinate, nicotinic acid mononucleotide (beta-nicotinic acid D-ribonucleotide), and nicotinic acid adenine dinucleotide. A composition for use in preventing and / or reducing one or more post-acute symptoms of an infectious disease comprising an active agent selected from an intermediate in the biosynthesis of DP; nicotinamide riboside; nicotinamide mononucleotide; 1-methylnicotinamide (N-methylnicotinamide); or combinations thereof, formulated to partially or completely release the active agent, preferably nicotinamide, for local replenishment or efficacy in the lower small intestine and / or colon, preferably wherein the pathogen is SARS-CoV-2 and / or the post-acute symptom is PCS.

Description

[Technical field]

[0001] The present invention relates to a composition comprising nicotinamide (niacinamide) or a suitable precursor or metabolite thereof or a combination thereof for use in preventing or reducing post-acute symptoms of infection, preferably long-term symptoms of coronavirus disease 2019 (COVID-19), summarized under the term post-COVID syndrome (PCS). [Background technology]

[0002] The disease course after infection with severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is highly variable, ranging from asymptomatic infection to the development of severe acute respiratory syndrome with hospitalization, eventual need for assisted ventilation and death. Reduced organ function after recovery from acute COVID-19 can persist for weeks to months after the acute phase of infection in patients with both mild and severe disease courses. There are different terms for this syndrome, such as PCS, post-acute COVID syndrome (PACS), post-acute sequelae of SARS-CoV-2 infection (PASC) or "long COVID". In this application, the term PCS is used. Compared to common respiratory viral infections such as influenza, which have similar symptoms (e.g., cough, fever, or fatigue), persistent somatic symptoms are much more common and severe in COVID-19 patients, especially after hospitalization (Marshall 2020, Nature 585:339; Groff et al. 2021, JAMA Netw. Open 4:e2128568; Jiang et al. 2021, JACC Basic Transl. Sci. 6:796).Nevertheless, post-acute symptoms of infectious diseases, such as post-infectious fatigue syndrome, have been described for over 100 years, for example after the Spanish Flu, and for a wide range of viral, bacterial or protozoal pathogens, including, but not limited to, Epstein-Barr virus, Dengue virus, Chikungunya virus, Ebola virus, West Nile virus, Coxiella burnetii, Cryptosporidium hominis and Giardia lamblia (Murray et al. 2014, PloS One 9:e10295; Rehn et al. 2015, BMC Public Health 15:529; Hung et al. 2019, Trends Parasitol. 35:673; Sandler et al. 2021, Open Forum Infect. Dis. 8:ofab440). Persistent somatic symptoms refers to a collective term that subjectively describes bothersome physical symptoms that are present on most days for at least several months after recovery from an illness, regardless of their etiology. Persistent somatic symptoms can be operationalised by repeated measures of the patient's subjective somatic symptom severity, and therefore include other measures of fatigue and distress.

[0003] In COVID-19, the preferred infectious disease of this application, persistence of symptoms or tissue damage beyond the acute phase of the disease is the rule rather than the exception: for example, in a study of COVID-19 patients, 88% of participants had visible lung damage 6 weeks after discharge from the hospital, and in 56% the damage persisted for 12 weeks (Marshall 2020, Nature 585:339). A large meta-analysis showed that "the majority of COVID-19 survivors experienced PASC 6 months after recovery" (Groff et al. 2021, JAMA Netw. Open 4:e2128568). Important symptoms of PCS were fatigue (44% of patients), sleep disturbance (33%), dyspnea (40%), cough (22%), as well as anxiety (34%), depression (32%), and cognitive impairment (15%), and impaired quality of life was reported by 57% of PCS patients (Jennings et al. 2021, J. Clin. Med. 10:8913). Another meta-analysis found that the most frequent persistent symptoms of COVID-19 were fatigue, dyspnea, exercise intolerance, loss of smell and taste, cognitive impairment, headache, and generalized pain (Bahmer et al. 2022, eClinicalMedicine 51:101549). A recent large-scale study in Germany reported that "neurological complaints (61.5%), fatigue (57.1%), and sleep disorders (57.0%) were the most frequent persistent symptoms 6 to 12 months after infection" and developed the PCS score (Bahmer et al. 2022, eClinicalMedicine 51:101549). In this PCS score, 12 long-term symptoms (fatigue, cough / wheezing, neurological complaints, joint / muscle pain, ear-nose-pharyngeal complaints, gastrointestinal complaints, sleep disorders, exercise intolerance, signs of infection, chemosensory loss, chest pain, and skin complaints) are combined with different masses.

[0004] Symptom persistence has also been described in the case of related coronaviruses such as SARS-CoV-1, and has been shown to last for years (Marshall 2020, Nature 585:339). In both cases, symptom persistence is not restricted to hospitalized patients with severe COVID-19 as described above, but occurs in patients with milder disease as well. For example, persistent fatigue after COVID-19 was independent of disease severity in a cohort of 128 patients in Ireland, 52.3% of whom reported persistent fatigue at a median of 10 weeks after initial COVID-19 symptoms (Townsend et al. 2020, PloS ONE 15:e0240784). Also, not all symptoms of PCS or other post-infection related conditions (e.g., cognitive impairment) are predominant or highly common in the acute phase, suggesting that long-term syndromes resulting from such infections may separate disease entities and therefore not necessarily treatable with the same interventions that are effective during the acute phase of infection. Summary of the Invention

[0005] There is therefore a large unmet need for active substances and compositions that are able to prevent or reduce post-acute symptoms of infection (in particular symptoms of PCS) and thereby in particular prevent or reduce the loss of quality of life that is very often reflected in olfactory and / or gustatory disorders, with no or minimal side effects.

[0006] The term vitamin B3 includes nicotinic acid and nicotinamide. In addition to being a precursor of the important ubiquitous coenzyme nicotinamide adenine dinucleotide (NAD) and its phosphorylated derivative nicotinamide adenine dinucleotide phosphate (NADP), nicotinamide is also involved in maintaining energy homeostasis signaling pathways in intestinal epithelial cells and the secretion of antimicrobial peptides from these cells (Hashimoto et al. 2012, Nature 487:477). With regard to maintaining the health and functionality of intestinal epithelial cells and the gut microbiota, nicotinamide has a similar potency to its precursor, the essential amino acid tryptophan (Hashimoto et al. 2012, Nature 487:477). Thus, not only are sufficient amounts of tryptophan or nicotinamide particularly important for food energy metabolism in rapidly replicating cells such as epithelial cells, but nicotinamide supplementation also protects against gut microbiota dysregulation and intestinal inflammation, especially when nicotinamide is delivered locally to the lower small and large intestines where the microbiota is located by appropriate formulations or compositions (Hashimoto et al. 2012, Nature 487:477; Waetzig & Seegert 2013, International Application PCT / EP2013 / 062363; Bettenworth et al. 2014, Mol. Nutr. Food Res. 58:1474; Waetzig & Seegert 2015, International Application PCT / EP2014 / 077637; Waetzig & Seegert 2015, International Application PCT / EP2014 / 077646). It has also been suggested that supplementation with NAD precursors such as nicotinamide may be beneficial in fighting coronavirus infection (Heer et al. 2020, J. Biol. Chem. 295:17986). However, using nicotinamide is not the only obvious choice, as nicotinamide riboside has been suggested to be more effective in raising NAD levels (Bogan-Brown et al. 2021, J. Diet. Suppl., DOI: 10.1080 / 19390211.2021.1881686).Nicotinamide is approved for use in food [Regulation (EC) No 1925 / 2006, amended by Commission Regulation (EC) No 1170 / 2009], in dietary supplements (Directive 2002 / 46 / EC) and in formula foods for infants, infant formulas and foods for certain nutritional purposes (Regulation (EU) No 609 / 2013). Nicotinamide is primarily marketed in the form of dietary supplements, but there is also a prescription nicotinamide drug available for treating vitamin B3 deficiency. Nicotinamide has an excellent safety profile, resulting in a high Tolerable Upper Intake Level (UL) or lifetime Acceptable Daily Intake (ADI) of 12.5 mg / kg / day or 900 mg / day as defined by the European Food Safety Authority (EFSA 2002, SCF / CS / NUT / UPPLEV / 39; EFSA 2014, EFSA J. 12:3759).

[0007] For various types of viruses, such as vaccinia virus (Child et al. 1988, Virus Res. 9:119), human immunodeficiency virus (Murray 2003, Clin. Infect. Dis. 36:453), enterovirus (Moell et al. 2009, J. Med. Virol. 81:1082) or hepatitis B virus (Li et al. 2016, Arch. Virol. 161:621), there is evidence that nicotinamide can reduce viral replication and support the body's acute defense mechanisms. Due to its presumed favorable risk-to-benefit ratio, adequate supplementation of nicotinamide in COVID-19 patients has been recommended due to its antiviral activity and protective effects against lung injury and bacterial pulmonary infection (Shi et al. 2020, Cell Death Differ. 27:1451; Gharote 2020, Ind. J. Med. Sci. 72:25; Zhang et al. 2020, J. Med. Virol. 92:479; Mehmel et al. 2020, Nutrients 12:1616; Shakoor et al. 2021, Maturitas 144:108; Brenner 2022, Nat. Metab. 4:2). Replenishing NAD levels through NAM supplementation may restore antiviral intrinsic immune function and rebalance the maladaptive hyperinflammatory immune response to SARS-CoV-2 infection (Mehmel et al. 2020, Nutrients 12:1616).

[0008] Intestinal uptake of tryptophan, a precursor of nicotinamide, depends on the presence of angiotensin-converting enzyme-2 (ACE2) in the intestinal epithelium (Hashimoto et al. 2012, Nature 487:477). ACE2 is required for SARS-CoV-2 entry into human somatic cells and is expressed at much higher levels in the intestine than in the respiratory epithelium (Mitsuyama et al. 2020, J. Clin. Med. 9:3630). SARS-CoV-2 infection inevitably reduces the cell surface expression of ACE2, which leads to tryptophan malabsorption, gastrointestinal dysbiosis and intestinal inflammatory symptoms (Hashimoto et al. 2012, Nature 487:477; Mitsuyama et al. 2020, J. Clin. Med. 9:3630; Yeoh et al. 2021, Gut 70:698; Vanella et al. 2021, BMC Open Gastroenterol. 8:e000578; Sarkar et al. 2021, Trends Mol. Med. 27:1115). This can be compensated by administration of nicotinamide, the intake of which is independent of ACE2 and which is equally effective in maintaining gut health and a healthy gut microbiota (Hashimoto et al. 2012, Nature 487:477).

[0009] The rationale for evaluating NAD levels in acute COVID-19 has been recently summarized (Brenner 2022, Nat. Metab. 4:2), and the efficacy of nicotinamide in reducing acute symptoms of COVID-19 has been established (Waetzig & Schreiber 2021, International Application PCT / EP2021 / 083138). However, there are no published data on the long-term effects of nicotinamide or related substances in post-acute symptoms of infection (especially PCS). It is important to note that these symptoms are partially different from the acute phase of the respective disease (see above). Thus, the skilled artisan would not necessarily expect that an intervention in an acute infection would also prevent or ameliorate post-acute symptoms. On the other hand, the skilled artisan would expect that an intervention that is effective against one or more symptoms of the acute phase of a disease would also be effective against the same symptoms in the long term, and that an intervention that is not effective in the acute phase would not be effective in the long term.

[0010] Taken together, the state of the art suggests that nicotinamide or related chemicals as active substances in nutritional or pharmaceutical preparations can improve COVID-19 symptoms during the first weeks after infection. However, since the severity of the acute disease course does not necessarily predict illness with post-acute sequelae such as PCS, and since acute and chronic conditions occur at different times (see above), one skilled in the art could not have expected that attenuating symptoms by nicotinamide supplementation during the acute phase of infection (especially COVID-19) would have a long-term beneficial effect on post-acute symptoms (especially PCS) caused by infection. Nor could one expect that a substance such as, for example, nicotinamide or a related active substance would be effective against certain symptoms (e.g., olfactory and / or gustatory disorders) during the acute phase of the disease, but would be highly effective against the same symptoms in the long term. It was therefore an object of the present invention to provide a means for reducing the risk of post-acute symptoms of infectious diseases (especially PCS).In addition, it was an object of the present invention to provide a means for pre- or post-exposure prophylaxis to prevent the manifestation of post-acute symptoms of infectious diseases (especially PCS) in patients who were at risk of infection with a pathogen (especially SARS-CoV-2) or who tested positive for the infection.

[0011] According to the invention, the object is to provide a method for the preparation of a nicotinamide or a nicotinic acid ester, tryptophan, tryptophan dipeptide, nicotinamide adenine dinucleotide (NAD), nicotinamide adenine dinucleotide phosphate (NADP), N-formylkynurenine, L-kynurenine, 3-hydroxy-L-kynurenine, 3-hydroxyanthranilate, 2-amino-3-carboxymuconic acid semialdehyde, quinolinate, nicotinic acid mononucleotide (beta-nicotinic acid D-ribonucleotide), and nicotinic acid adenine dinucleotide. The present invention relates to a composition for use in preventing or reducing one or more post-acute symptoms (particularly PCS) of an infectious disease, comprising an active agent selected from an intermediate in the biosynthesis of NADP; nicotinamide riboside; nicotinamide mononucleotide; 1-methylnicotinamide (N-methylnicotinamide); or a combination thereof, the composition being formulated to partially or completely release the active agent, preferably nicotinamide, for local replenishment or efficacy in the lower small intestine and / or colon, and preferably wherein the pathogen is SARS-CoV-2 and / or the post-acute symptom is PCS.

[0012] Preferably, the compositions of the present invention are formulated for oral administration. The human body is a metaorganism incorporating human cells and many microbial species, especially in the gut microbiota. The sum of all metabolic pathways available from all parts of this metaorganism must be considered as a whole and can be used directly or indirectly by the human body. Tryptophan and nicotinic acid cannot be synthesized de novo by human cells, but can be absorbed in the gastrointestinal tract from a variety of sources. The active substances listed above can be synthesized from these precursors as intermediates in the synthetic pathways leading to NAD or NADP. These substances are therefore considered to be functionally equivalent to the particularly safe and well-characterized NAD(P) precursor nicotinamide. For example, in human nutrition science, the term "niacin equivalent" already indicates the interchangeability of precursor tryptophan and its products nicotinic acid and nicotinamide (collectively referred to as niacin or vitamin B3): approximately 60 mg of tryptophan produces 1 mg of niacin, which is defined as 1 mg niacin equivalent (EFSA Scientific Opinion on dietary reference values ​​for niacin; EFSA Journal 2014; 12:3759). For the sake of brevity, the description and illustration of the present invention will focus on nicotinamide, but will not be restricted to this compound. However, nicotinamide is the most preferred active substance.

[0013] Preferably, the at least one post-acute symptom is a decrease in physical performance (e.g., inability to perform normal activities, decreased movement or decreased physical performance), fatigue, exercise intolerance (e.g., shortness of breath, difficulty breathing or decreased ability to exercise), chemosensory loss (loss of smell or loss of taste), joint pain, muscle pain, chest pain, ear-nose-pharyngeal complaints (e.g., hoarseness, sore throat or runny nose), cough and / or wheezing, gastrointestinal complaints (e.g., abdominal pain, diarrhea, nausea or vomiting), neurological complaints (e.g., The symptom is selected from the group consisting of confusion, dizziness, headache, movement disorder, loss of sensation, numbness, dizziness, tremors, concentration, cognitive or speech deficits), psychological illness (e.g. anxiety, depression, stress or reduced resilience), skin illness (e.g. skin rash, itching or hair loss), signs of infection (e.g. chills, fever, general illness or flu-like symptoms) or sleep disorder (e.g. insomnia, restless sleep), with a particularly preferred selected symptom being olfactory and / or gustatory impairment.

[0014] In the sense of this specification, symptoms may be self-assessed by the patient (e.g. by a medical interview and / or questionnaires and / or a mobile app, in particular with regard to multidimensional parameters of the general state of health such as the ability to perform usual activities) and / or by objective tests and examinations (e.g. by physical examination, e.g. to measure shortness of breath, by electronic monitoring of activity and / or physical parameters and / or by olfactory testing, e.g. to detect and / or quantify olfactory disorders). In case of doubt, the evaluation of the respective symptom is carried out by self-assessment. As will be appreciated by those skilled in the art, in the sense of the present invention, "resolution of symptoms" can occur only if such symptoms were present. As used herein, "resolution of symptoms" means that the symptoms that were present have been completely removed, at least according to the patient's perception.

[0015] According to the present invention, the above-mentioned problems are preferably solved by using nicotinamide or a composition comprising nicotinamide in a supplementation or treatment regimen, as defined in the claims and / or described in more detail herein.It is also within the scope of the present invention to use suitable precursors or metabolites of nicotinamide, alone or in combination, together with or instead of nicotinamide.Nicotinamide is used as a preferred example, although it is not repeated in every case for the sake of brevity. In a preferred embodiment, the composition comprising nicotinamide is formulated to release nicotinamide partially or completely in the lower small intestine and / or colon to beneficially and locally affect the intestinal mucosa and gut microbiota, as described in the following related corresponding patent applications: Waetzig & Seegert 2013, International Application PCT / EP2013 / 062363; Waetzig & Seegert 2015, International Application PCT / EP2014 / 077637; Waetzig & Seegert 2015, International Application PCT / EP2014 / 077646; Schwarz et al., 2017, International Application PCT / EP2017 / 058733. For example, nicotinamide is formulated to be selectively released in the lower small intestine and / or colon, where the gut microbiota is located, for example, at least in part for local efficacy. Thus, there is provided a composition comprising nicotinamide that preferably prevents or reduces one or more symptoms of PCS. [Brief description of the drawings]

[0016] [Figure 1] Figure 1 shows the frequency of olfactory and gustatory disorders at 6-month follow-up in patients in the risk factor population of the COVit-2 study (percentages and 95% confidence intervals). [Diagram 2] FIG. 2 shows a box plot of PCS scores for patients in the risk factor population of the COVit-2 study with more than five predictors for PCS. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] In the futility analysis population (n=402) of the COVit-2 trial (Example 2; Waetzig & Schreiber 2021, International Application PCT / EP2021 / 083138), the use of a combination of immediate release and controlled ileocolonic release nicotinamide surprisingly led to a significant improvement in the decline in the ability to perform normal activities, physical capacity and fatigue during the first weeks after infection in patients with at least one characteristic or underlying medical condition associated with an increased risk of developing severe illness from COVID-19, as well as in patients with significant symptoms of COVID-19. Six months after infection, patients were contacted for a follow-up interview to determine their illness by PCS using an extensive series of questionnaires and tests, including the measurement of antibody levels (Example 2). Data quality control tests were performed on the first 50 patients in each study arm (nicotinamide vs. placebo), revealing surprisingly that nicotinamide supplementation also improved the acute disease trajectory of COVID-19, but reduced symptoms of PCS, even when the same symptoms were not reduced in the acute disease trajectory. In particular, although nicotinamide supplementation resulted in a significant reduction in the frequency of olfactory or gustatory disorders after 6 months, nicotinamide was not appreciably effective in affecting these symptoms during the acute phase of the disease.

[0018] Thus, the core of the invention is the use of the composition of the invention, preferably comprising nicotinamide, in a supplementation or treatment regimen to prevent or reduce one or more post-acute symptoms of an infection (especially PCS), preferably in the form of a composition formulated for oral administration for this use, as defined in the claims and / or described in more detail herein. In particular, the improvement in patients with at least one characteristic or underlying medical condition associated with an increased risk of developing serious illness from an infection (especially COVID-19), as well as at least one characteristic symptom of an infection, is a preferred effect of the invention. The use of the composition of the invention, preferably comprising nicotinamide, as a pre- or post-exposure prophylaxis in cases of risk of infection with a pathogen (especially SARS-CoV-2) or after a positive test and before the onset of disease symptoms, is also preferably within the scope of the invention.

[0019] In addition to the preferred active substance nicotinamide, suitable precursors or metabolites of nicotinamide can be used as active substances in the present invention. For example, compounds that are converted to nicotinamide in the human or animal body (e.g., by hydrolysis or metabolism), such as nicotinic acid or nicotinic acid esters, are suitable. In addition, intermediates in the biosynthesis of nicotinamide adenine dinucleotide (NAD) or NAD phosphate (NADP) starting from tryptophan, such as N-formylkynurenine, L-kynurenine, 3-hydroxy-L-kynurenine, 3-hydroxyanthranilate, 2-amino-3-carboxymuconic acid semialdehyde, quinolinate, nicotinic acid mononucleotide (beta-nicotinic acid D-ribonucleotide), and nicotinic acid adenine dinucleotide, can be used. Further examples include NAD, NADP, nicotinamide riboside, nicotinamide mononucleotide, or the nicotinamide metabolite 1-methylnicotinamide (N-methylnicotinamide). In the case of ACE2 cell surface expression in the intestine, the dipeptide tryptophan as an equivalent to nicotinamide (Hashimoto et al. 2012, Nature 487:477) is also within the scope of the present invention. It is also within the scope of the present invention to use these suitable precursors or metabolites of nicotinamide alone or in combination with or instead of nicotinamide. For the sake of brevity, nicotinamide is used as a preferred example, without repeating it in all cases. In general, the uses disclosed in this invention can be medical or non-medical uses. Medical uses in the present application preferably mean that the compositions used according to the present invention are medicines approved by the respective competent regulatory authorities in the respective countries in which they are used, all other uses being non-medical uses.

[0020] The compositions of the invention are preferably formulated for oral administration to release nicotinamide partially or completely for local supplementation or efficacy in the lower small intestine and / or colon to beneficially and locally affect the intestinal mucosa and gut microbiota as described in the following related corresponding patent applications: Waetzig & Seegert 2013, International Application PCT / EP2013 / 062363; Waetzig & Seegert 2015, International Application PCT / EP2014 / 077637; Waetzig & Seegert 2015, International Application PCT / EP2014 / 077646; Schwarz et al., 2017, International Application PCT / EP2017 / 058733. Preferably, the compositions of the invention are formulated to at least partially selectively release, more preferably at least partially delayed release, nicotinamide for local supplementation or efficacy in the lower small intestine and / or colon where the gut microbiota is located. Preferably, the compositions of the invention are formulated to release nicotinamide at least partially beginning in the latter half of the jejunum. Alternatively, preferably, the compositions of the invention are formulated to release nicotinamide at least partially beginning in the terminal ileum and / or colon. In further preferred embodiments, the release of nicotinamide in both delayed and non-delayed dosage forms is extended by sustained and / or controlled release formulations to achieve higher trough levels and more consistent systemic exposure.

[0021] In the present invention, the terms "formulation" or "composition" or "supplement" or "treatment", particularly the term "composition", have a broad meaning of a pharma- ceutical and / or nutritional and / or physiologically acceptable preparation, composition and / or mode of administration of nicotinamide, including but not limited to a medicine (pharmaceutical preparation), a pharmaceutical product, a nutraceutical, a food for special medical purposes, a dietary supplement, a food ingredient and / or a food. The nature of the composition may vary depending on, for example, the ingredients and excipients, the dose of nicotinamide, the formulation type and other factors. Preferred are dietary supplements, foods for special medical purposes, nutraceuticals and medicines. The compositions of the present invention are preferably formulated for at least partial delayed release of the active agent, preferably nicotinamide, for local supplementation or efficacy in the lower small intestine and / or colon.

[0022] The compositions of the present invention preferably comprise one or more active substance formulations, preferably nicotinamide formulations, for delayed and / or delayed controlled release, which deliver the active substance, preferably nicotinamide, primarily locally to the lower small intestine and / or colon, together with one or more active substance formulations, preferably nicotinamide formulations, for immediate and / or sustained and / or extended release, which deliver the active substance, preferably nicotinamide, primarily systemically to the blood circulation. See below for the definitions of delayed and delayed controlled release. The composition of the present invention preferably contains a combination of two formulation variants of an active substance, preferably nicotinamide, in a specific weight ratio ranging from 1:1 to 1:1000, preferably from 1:1 to 1:100, more preferably from 1:1 to 1:10. Alternatively, the preferred range is from 1:3 to 1:300, more preferably from 1:10 to 1:100. The combination may be in the same or separate dosage forms, which may be administered simultaneously or sequentially. The compositions may be suitable for oral administration with immediate and / or sustained and / or extended release, and may achieve systemic exposure to nicotinamide by delivery to the blood circulation. Preferably, the compositions of the present invention may be suitable for delayed and / or delayed controlled release of nicotinamide for specific local or regional efficacy in the lower small intestine and / or colon.

[0023] As used herein, the terms "preferred" or "preferably" refer to embodiments that may obtain certain benefits under certain circumstances, although other embodiments may be preferred under the same or other circumstances. The recitation of one or more preferred embodiments does not imply the exclusion of other useful embodiments from the scope of the invention. Terms such as "comprises" and variations thereof do not have a limiting meaning in the specification and claims. The citation of several sections of material from a literature does not indicate that the remainder of such document is not relevant or incorporated by reference. Recitation of numerical ranges by one or two endpoints includes all numbers within that range (e.g., "1 to 10" includes 1, 2.4, 4.576, etc., and "less than 1" includes all numbers less than 1). For any method disclosed or referred to herein that includes individual steps, those steps may be performed in any practicable order, and any combination of two or more steps may be performed simultaneously. Any example or list of examples should not be construed as a limiting or exclusive list of any kind.

[0024] As used herein, the term "supplementation" refers to the supplementation of nicotinamide in a patient, particularly a patient with an infection (especially COVID-19). As used herein, the terms "treatment", "treat" and "treating" refer to reversing, reducing or inhibiting the progression of a disease resulting from an infection (especially COVID-19 and / or PCS), or one or more symptoms thereof, by administration of nicotinamide as described herein. Preferably, the supplementation or treatment may be administered after one or more symptoms have developed, or preferred supplementation or treatment may be administered in the absence of symptoms. For example, the supplementation or treatment may be administered to an individual prior to infection (pre-exposure prophylaxis) or to an infected individual prior to the onset of symptoms (post-exposure prophylaxis). The supplementation or treatment may also be continued after the symptoms have resolved, for example to prevent or delay their recurrence. As used herein, "lower small intestine" is the latter part of the small intestine, including the latter part of the jejunum and the ileum. As used herein, "terminal ileum" is the latter part of the ileum.

[0025] As used herein, the term "local efficacy" refers to a local effect in a pharmacodynamic sense, thus implying a local, rather than systemic, target for dietary supplementation or drug therapy. Thus, "local supplementation or efficacy" refers to local supplementation or treatment with nicotinamide specifically or selectively released at a location where, for example, a dietary supplement or drug delivers its direct action effect, and where nicotinamide only produces a reduced or low systemic effect compared to conventional formulations, for example by entering the blood circulation to a lower extent than conventional formulations by immediate and / or sustained and / or extended release. In this respect, the local efficacy of the present invention is also contrasted with enteral (gut) and intravascular / intravenous (injected into the circulatory system) administration. Compared to compositions that aim for high systemic availability and / or exposure, the at least partially local efficacy of the composition may also be characterized by a longer latency time before systemic levels of nicotinamide increase. Such latency of local release can be related to intestinal transit time as known in the art (see, for example, Davis et al. 1986, Gut 27:886; Evans et al. 1988, Gut 29:1035; Kararli 1995, Biopharm. Drug Dispos. 16:351; Sutton 2004, Adv. Drug Deliv. Rev. 56:1383). For example, after variable time of gastric emptying (depending on dosage form and feeding state, ranging from <15 minutes to more than 10 hours), small intestinal transit time is rather constant between 1 and 6 (usually 2 to 4) hours during the study, regardless of formulation (Davis et al. 1986, Gut 27:886). Thus, when in doubt, the latency period in a fasted patient is usually at least 1 hour for a topical formulation, at which time the formulation reaches the lower small intestine and systemic levels of nicotinamide may begin to rise strongly. In the context of the present invention, topical efficacy can also be expressed in terms of a reduction in peak plasma levels of at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or even 95% or more relative to the same amount of nicotinamide administered in an immediate release formulation (e.g., as nicotinamide in a stomach-dissolving capsule) in the same manner and under the same conditions.Since baseline values ​​can vary widely even in the same person, it is preferable to refer the peak level to the respective baseline level immediately before administration. Preferably, the average plasma level of a suitable cohort of people is used for this definition of local efficacy rather than the respective individual levels, which may give very different results (Schwarz et al., 2017, International Application PCT / EP2017 / 058733). Local efficacy is particularly achieved by the compositions of the present invention described herein. In combination preparations that include a nicotinamide formulation for immediate release and / or sustained release and / or extended release that delivers nicotinamide primarily systemically to the blood circulation, together with one or more nicotinamide formulations for delayed release and / or delayed controlled release that deliver nicotinamide primarily locally to the lower small intestine and / or colon, the above reduction in peak level applies only to the delayed release or delayed controlled release formulation, respectively.

[0026] It has been previously established that nicotinamide has a remarkable anti-inflammatory effect by affecting the gut microbiota (the totality of all microorganisms, especially bacteria, in the gut), which is mainly located in the lower small intestine and colon (Waetzig & Seegert 2013, International Application PCT / EP2013 / 062363; Waetzig & Seegert 2015, International Application PCT / EP2014 / 077637; Waetzig & Seegert 2015, International Application PCT / EP2014 / 077646). The mechanism behind this remarkable effect has been shown to involve nicotinamide-induced changes in the secretion patterns of antimicrobial peptides in the gut that support the maintenance and / or regeneration of a normal healthy gut microbiota (Hashimoto et al. 2012, Nature 487:477). Therefore, as used herein, "beneficially affect gut microbiota" means to cause changes in gut microbiota that have beneficial effects on health, particularly on one or more of the diseases and conditions described herein, and / or to maintain a healthy gut microbiota in a preventive environment.For example, beneficial effects can be related to lowering the number of pathogenic bacteria, reducing the ratio of pathogenic bacteria to beneficial bacteria, increasing the diversity of microbiota, increasing the amount of beneficial bacteria, partially or completely reversing pathological changes in enterotypes of microbiota (e.g., enterotypes related to Bacteroides, Prevotella and Ruminococcus), maintaining a healthy endogenous microbiota, and / or maintaining or improving or restoring metabolic pathways and / or their balance in gut microbiota.

[0027] Therefore, preferred according to the invention are compositions of the invention for oral administration with at least partial delayed and / or delayed controlled release of active substance (preferably nicotinamide) for specific local supplementation or efficacy in the lower small intestine and / or colon. More preferably, the composition is formulated for oral administration with at least partial delayed release of active substance for specific local supplementation or efficacy in the lower small intestine and / or colon. In another more preferred variant, the composition is formulated for oral administration with at least partial delayed controlled release of nicotinamide for specific local supplementation or efficacy in the lower small intestine and / or colon. Preferably, nicotinamide is used in dietary and / or pharmacological formulations that protect at least a portion of the nicotinamide from being absorbed into the body in the stomach and / or upper small intestine, e.g., from being absorbed into the circulatory system, and instead provide at least a partial local release (e.g., delayed release and / or delayed controlled release) to the lower small intestine and / or colon.

[0028] In particular, the nicotinamide and the formulations and compositions described herein are therefore suitable for use in medicines, pharmaceuticals, nutraceuticals, foods for special medical purposes, dietary supplements, food ingredients and / or foods for at least partially local release (e.g. delayed release and / or delayed controlled release), and also allow direct nicotinamide supplementation or treatment of the lower small intestine and / or colon, e.g. in situations of prolonged absorption phase due to COVID-19 and / or PCS and its gastrointestinal symptoms, and / or subsequent intestinal exposure. Nicotinamide and the formulations and compositions described herein can be used equally for infectious diseases in both humans and other mammals, particularly domestic and useful animals, examples of such animals are, without objective limitation, dogs, cats, minks, horses, camels, pigs or cattle. Nicotinamide may be used in any form available on the market of suitable nutritional or pharmaceutical quality, for example as provided by common manufacturers and distributors such as DSM, Lonza or Merck.

[0029] Preferably, the compositions of the invention contain a combination of two or more formulation variants of the same dosage form of an active substance, preferably nicotinamide. Preferably, the present invention also relates to nicotinamide combinations and / or compositions, such as immediate release, sustained release, extended release, delayed release and / or delayed controlled release variable dose combinations or fixed dose combinations of nicotinamide. The different release kinetics of such formulations can be used to adjust the degree, duration and kinetics of systemic and local intestinal exposure of nicotinamide. The combinations described herein can be present in the same or separate dosage forms, which can be administered simultaneously or sequentially. The compositions and dosages of such combinations are known to those skilled in the art.

[0030] As used herein, the term "variable dose combination" refers to a combination of two or more formulation variants of nicotinamide in a medicine, pharmaceutical product, nutraceutical product, food for special medical purposes, dietary supplement, food ingredient and / or food, whereby each formulation variant of nicotinamide is applied in the form of a separate composition, for example, two single dosage forms. The separate compositions may be administered simultaneously, sequentially or at separate times according to the dosage regimen. For example, a composition of any suitable dose of immediate release nicotinamide (rapidly absorbed after entering the stomach) may be administered together, sequentially or after a separate composition of any suitable dose of delayed release nicotinamide (partially or completely protected from absorption until reaching the lower small intestine). Thus, two or more different formulations of varying doses of nicotinamide may be combined. These variable dose combinations may use conventionally available compositions of medicine, pharmaceutical product, nutraceutical product, food for special medical purposes, dietary supplement, food ingredient and / or food, or may be achieved by custom polypharmacy combinations by compounding. Immediate, sustained, extended or controlled release formulations for primarily systemic delivery and delayed or delayed controlled release formulations for primarily local intestinal delivery may be administered at different rates and doses depending on the presence and severity of the patient's gastrointestinal symptoms and / or the benefit expected from a prolonged period of absorption due to continued intestinal exposure.

[0031] In contrast to a variable dose combination, a "fixed dose combination," as used herein, is a combination that is a formulation containing two or more formulation variants of nicotinamide, combined as a single dosage form manufactured and dispensed in a fixed respective fixed dose, or as a combination of two or more separate dosage forms representing formulation variants in which a fixed number or amount is supplemented or administered according to the label. Fixed dose combinations primarily refer to mass-produced products with a predetermined combination and respective doses. The total dose of active substance (preferably nicotinamide) used according to the invention can range from 1 to 5000 mg and can be administered as individual or multiple doses and / or once, twice or more times daily. The preferred total dose of active substance according to the invention is in the range of 10 to 4000 mg, more preferably in the range of 100 to 3000 mg.

[0032] As a non-limiting example, a high dose formulation may contain up to 5000 mg of active agent. For example, but not limited to, a high dose formulation may contain a total amount of active agent in the range of 1000-5000 mg, preferably in the range of 1000-4000 mg, more preferably in the range of 1000-3000 mg, such as 2000 mg. As non-limiting examples, low dose formulations can contain up to 1000 mg of active agent, preferably in the range of 1-1000 mg, more preferably in the range of 100-1000 mg of active agent. As a non-limiting example, a standard dose formulation may contain up to 3000 mg of active agent, preferably in the range of 250-2500 mg, more preferably in the range of 500-2000 mg. A specific non-limiting example of a fixed dose high dose formulation includes a combination of 1000 mg immediate release nicotinamide and 1000 mg delayed release and / or delayed controlled release nicotinamide. A specific non-limiting example of a fixed dose standard dose formulation includes a combination of 750 mg immediate release nicotinamide and 750 mg delayed release and / or delayed controlled release nicotinamide. Specific non-limiting examples of fixed dose low dose formulations include a combination of 400 mg or 500 mg immediate release nicotinamide and 400 or 500 mg delayed release and / or delayed controlled release nicotinamide.

[0033] Such compositions according to the invention may, for example, be administered preferably as tablets, pellets or granulates, preferably as microgranulates, if appropriate in a capsule, sachet or stick pack, preferably in a sachet or stick pack. The active substance, preferably nicotinamide, is preferably formulated in the form of tablets, granules, microgranules or pellets. These tablets, granules, microgranules or pellets can be used in single dosage forms or in variable or fixed dose combinations. If different formulation variants of the active substance in the form of tablets, granules, microgranules or pellets are used as described herein, they can be used in the form of any single dietary or pharmaceutical composition, as well as in variable or fixed dose combinations. The granules, microgranules or pellets can be compressed into tablets or packed into capsules, sachets or stick packs, or used as such, as appropriate. To prepare orally administered formulations (e.g., tablets, dragees, capsules, sachets, etc.) of active agents for at least partial release in the lower small intestine and / or colon, it is advantageous to use a delayed mode of release. In contrast to conventional (optionally delayed, but systemically delivered) release modes for optimal supplementation of certain embodiments of the invention, e.g., immediate-release, sustained-release and / or extended-release nicotinamide formulations, such delayed and / or delayed-controlled mode of release (at least) partially or (even) substantially avoids absorption in the stomach and upper part of the small intestine.

[0034] For oral administration, certain dosage forms that at least partially control and / or delay the release of the active substance for a particular galenic formulation are particularly suitable. Such dosage forms can be simple tablets, but also coated tablets, for example film tablets or sugar-coated tablets. Tablets are usually oval, round or biconvex. A particular oval tablet form allows the tablet to be separated and can be preferred. In addition, minitablets, granules, spheroids, pellets or microcapsules are possible (e.g. Liang & Dingari 2017, International Application PCT / US2017 / 028063; Schwarz et al., 2017, International Application PCT / EP2017 / 058733), which are packed in capsules, sachets or stick packs where appropriate. To deliver nicotinamide in a formulation that acts somewhat systemically (e.g., immediate release) and mostly locally in the lower small intestine and / or colon (e.g., delayed and / or delayed controlled release), a combination of different formulations in separate dosage forms and / or multi-layered dosage forms can be used to initially release part of the active substance in the stomach and upper small intestine and another part from, for example, a rapidly disintegrating core (delayed release) or matrix core (delayed controlled release), with or without pH-dependent or microbial-dependent release. Another example is the erosion-based release technology exemplified by the OralogiK™ product portfolio (BDD Pharma).

[0035] The term "delayed release" preferably refers to a formulation or component thereof that releases or delivers an active agent after a delay period, e.g., after degradation of a film coating or other coating due to pH, chemical, enzymatic and / or microbial environment, preferably present in the lower small intestine and / or colon. In some embodiments, the delay is sufficient that at least a portion of the active agent in the formulation is released in the lower small intestine and / or colon. The term "delayed controlled release" preferably refers to a formulation or components thereof that release or deliver an active agent over an extended period of time (time-dependent release) and / or under certain physiological conditions, such as degradation of a coating or matrix due to pH, chemical, enzymatic and / or microbial environment, preferably present in the lower small intestine and / or colon. In some embodiments, the release over a period of time or in accordance with physiological conditions is sufficient that at least a portion of the nicotinamide in the formulation is released in the lower small intestine and / or colon.

[0036] Retardation and / or delayed release and / or delayed controlled release can be advantageously achieved, for example, by coatings that are resistant to gastric juice and dissolve depending on pH, by using different carrier matrix components (e.g., different grades of hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, sodium carboxymethylcellulose, starch, modified starch, pregelatinized starch, gelatin, polyvinylpyrrolidone) or combinations thereof, by other matrix and / or multi-matrix (MMX) technologies, or by combinations of these technologies. Examples include film coatings containing acrylic and / or methacrylate polymers in various mixtures for delayed release. Additional examples include biodegradable polymers and polymer-drug conjugates, coatings and / or matrix agents, such as natural or chemically modified polymers for microbiota-dependent release (reviewed, for example, by Rajpurohit et al. 2010, Indian J. Pharm. Sci. 72:689). For example, the active substance can be contained in a matrix containing the components described above, which is coated with a material that provides delayed release of the active substance. The active substances according to the invention can be administered, for example, in tablets, minitablets, granules, spheroids, pellets, microcapsules or large volume capsules (for example gelatin or hydroxypropylmethylcellulose capsules), which are coated by known methods.Suitable coating agents are water-insoluble waxes, such as carnauba wax, and / or polymers, such as poly(meth)acrylates, for example the entire poly(meth)acrylate product portfolio, trade names Eudraguard® and Eudragit®, offered by Evonik Industries, in particular Eudraguard® protect, Eudraguard® control, Eudraguard® biotic, Eudraguard® natural, Eudragit® L 30 D-55 (aqueous dispersion of anionic polymers with methacrylic acid as functional group), Eudragit® L 100-55 (containing anionic copolymers based on methacrylic acid and ethyl acrylate), Eudragit® L 100 or L 12.5 or S 100 or S 12.5 (anionic copolymer based on methacrylic acid and methyl methacrylate), a combination of Eudragit® S and L compounds, or Eudragit® FS 30 D (aqueous dispersion of anionic copolymer based on methyl acrylate, methyl methacrylate and methacrylic acid), and / or water-insoluble celluloses (e.g. methylcellulose or ethylcellulose). Where appropriate, water-soluble polymers (e.g. polyvinylpyrrolidone), water-soluble celluloses (e.g. hydroxypropylmethylcellulose or hydroxypropylcellulose), emulsifiers and stabilizers (e.g. polysorbate 80), polyethylene glycol (PEG), lactose or mannitol may also be contained in the coating material.

[0037] In a preferred embodiment, the formulations for immediate release and / or sustained release and / or extended release are equipped with taste masking technologies including, for example, the following alone or in combination: - organoleptic methods, such as sweeteners (e.g. sucralose, aspartame, acesulfame potassium, glycerrhizin, cyclamate, lactose, mannitol, saccharin, or sucrose), sugars, flavorings (e.g. mint, peppermint, menthol, sweet cherry, walnut, chocolate, passion fruit, or citrus flavors, e.g. lemon or orange), bitterness blockers (e.g. adenosine monophosphate, dihydrochalcone, ne), sodium chloride, sodium acetate, sodium gluconate, lipoproteins [e.g., consisting of phosphatidic acid and β-lactoglobulin] or phospholipids [e.g., phosphatidic acid, phosphatidylinositol or soy lecithin]), effervescent agents (e.g., carbon dioxide generators), taste modifiers, buffers and / or combinations of other excipients (e.g., zinc sulfate, maltodextrins [e.g., pea maltodextrin] or polyols) are added to the composition or its coating; - single or multi-layer coatings and / or matrix technologies, for example comprising hydrophobic or hydrophilic polymers (e.g. methacrylic acid and methacrylic acid ester copolymers, such as Eudragit® E, E-100, RL 30D, RS 30D, L30D-55 or NE 30D; Eudraguard® protect, natural or control; ethylcellulose; hydroxypropylmethylcellulose; hydroxypropylcellulose; cellulose acetate; croscarmellose; polyvinyl alcohol; polyvinylpyrrolidone (e.g. PVP-K30 or Kollicoat); polyvinyl acetate; shellac; guar gum), lipids (e.g. glyceryl palmitostearate, glyceryl monostearate or glycerol behenate), talc, detergents (e.g. sodium lauryl sulfate or polysorbates, such as polysorbate 80), sugars and / or sweeteners (see above), alone or in combination; - matrix granulation (e.g. with gelling or lipid polymers); - melt, solvent or melt-solvent methods and carriers such as povidone, polyethylene glycols of various molecular weights, hydroxypropylmethylcellulose, urea, mannitol or ethylcellulose; spray drying (e.g. with ethylcellulose, hydroxypropylmethylcellulose; hydroxypropylcellulose or acrylate polymers); solid dispersion using hot melt extrusion (e.g. with ethylcellulose, hydroxypropylmethylcellulose; hydroxypropylcellulose or acrylate polymers), preferably followed by milling or micronization of the extrudate to obtain taste-masked granules or particles, which are preferably then incorporated into a suitable dosage form; - microencapsulation using coating agents listed above (e.g. Wurster fluid bed coating [e.g. with croscarmellose, Eudragit]); - septum; - inclusion complex formation (for example with cyclodextrins, tannic acid, Eudragit® polymers, Eudragit S-100 or chitosan); - ion exchange resins, for example copolymers of styrene, acrylic acid or methacrylic acid with divinylbenzene; - Adsorption (e.g. with silicates, silica gel or bentonite).

[0038] Further non-limiting examples of formulations of dietary supplements according to the invention, as well as food ingredients, are described using maltodextrin-pectin microcapsules and shellac-coated granules (Berg et al. 2012, J. Food Eng. 108:158; Schwarz et al. 2017, PCT / EP2017 / 058733; Theismann et al. 2019, Int. J. Pharm. 564:472). The compositions, e.g. pharmaceutical formulations, medicines, nutritional supplements, foods for special medical purposes, dietary supplements, food ingredients and / or foods, may also contain further excipient substances, such as binders (e.g. methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose / hypromellose, hydroxyethylcellulose, dextrin, maltodextrin, copovidone and / or sodium alginate), fillers (e.g. anhydrous lactose, lactose monohydrate, starch, pregelatinized starch, powdered cellulose, calcium carbonate, magnesium carbonate, anhydrous dibasic calcium phosphate, dibasic calcium phosphate dihydrate, anhydrous calcium sulfate, calcium sulfate dihydrate, tribasic calcium phosphate, sucrose, fructose, anhydrous glucose / dextrose, glucose / dextrose monohydrate, sorbitol, mannitol, maltitol, isomalt and / or xylitol), glidants, lubricants and flow regulators. The nicotinamide according to the invention can, where appropriate, be formulated together with further active substances and excipients customary for dietary or pharmaceutical compositions, such as, for example, talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous and non-aqueous carriers, lipid components of animal or vegetable origin, paraffin derivatives, glycols (in particular polyethylene glycols), various plasticizers, dispersants, emulsifiers and / or preservatives.

[0039] In accordance with the present invention, the compositions are preferably formulated for delayed or delayed controlled release so that a portion of the active substance, preferably nicotinamide, enters the circulation only to a reduced extent, such that the peak plasma level of the active substance, preferably nicotinamide, after administration of the delayed or delayed controlled release formulation is reduced by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% relative to the same amount of active substance, preferably nicotinamide, administered as an immediate release formulation in the same manner and under the same conditions. A further aspect of the invention described herein is the efficient use of the described medicines, pharmaceuticals, nutraceuticals, foods for special medical purposes, dietary supplements, food ingredients and / or foods based on blood and / or urine and / or feces and / or genetic and / or microbiology and / or other biomarkers or data and the specific needs of the individual being treated. In particular, for example, serum levels of tryptophan, nicotinamide and its metabolites can be used to manage supplementation or therapeutic decisions. Evidence-based personalized medicine, including analysis and data of disease course, pathogen variant or strain and / or genetic background (e.g., genes encoding cell surface receptors, transport proteins, metabolic enzymes or signaling proteins that interact with the pathogen, immune response to the pathogen, nicotinamide and / or its metabolites and / or its downstream effectors), can provide information and improvements regarding the type, mode of application, time of use, dosage and / or dosing regime of the medicines, pharmaceuticals, nutraceuticals, foods for special medical purposes, dietary supplements, food ingredients and / or foods described herein. Individuals who may benefit from this individualized treatment include those with disease-specific or non-specific changes in blood and / or plasma and / or serum lipids and / or other biomarkers. This applies equally to the analysis of the gut microbiome, especially when fecal samples indicate changes in the microbiome. The present invention therefore also includes the use of suitable test methods to identify individuals who are particularly sensitive to the medicaments, pharmaceutical products, nutraceuticals, foods for special medical purposes, dietary supplements, food ingredients and / or foods according to the present invention and / or to adapt the use of these and the associated supplementation and / or pharmacological treatments to the individual situation. This also obviously includes the use of different formulation variants or compositions containing active substances or combinations thereof, with different modes of administration depending on the biomarkers of the individual to be supplemented or treated. For these purposes, it is possible to use laboratory tests and / or suitable test kits and even measurement methods, devices and / or kits, which can be adopted by the physician, user and / or patient, for example, to analyze the appropriate parameters in blood, urine or other body fluids or fecal samples.In particular, the present invention also relates to the use of these biomarkers to aid in the selection of patients or subjects for the supplements or treatments described herein, to personalize and adapt the compositions and / or supplements and / or treatments described herein, and / or to determine endpoints and efficacy criteria for the compositions and / or supplements and / or treatments described herein.

[0040] According to the present invention, the composition of the present invention is preferably formulated for use in a once-daily administration. Surprisingly, this dosing regimen showed excellent efficacy (Waetzig & Schreiber 2021, International Application PCT / EP2021 / 083138). The best efficacy was obtained when the composition of the present invention was administered in the morning with breakfast. When administered once a day, a nicotinamide content of 1-5000 mg, preferably 10-4000 mg, more preferably 100-3000 mg per final dosage form is preferred. The compositions of the present invention are also preferably combined with foods, beverages, dietary supplements, foods for special medical purposes, probiotics, prebiotics, synbiotics and / or vitamins, especially those intended to support the recovery of symptoms after the acute phase of infection. Probiotics are live enteric microbial cultures that pass alive through the gastrointestinal tract and beneficially affect the host by improving its gut microbial balance. Prebiotics are non-digestible, selectively fermented food ingredients or supplements that allow specific changes in composition and / or activity of the gastrointestinal microflora that are beneficial to the well-being and health of the host. Examples of prebiotics are resistant starch, fructooligosaccharides, galactooligosaccharides, xylooligosaccharides, polydextrose, lactulose, inulin or soluble fibers (e.g. psyllium husk or acacia fiber). Synbiotics are a combination of probiotics and prebiotics.

[0041] As described above and as can be seen from the examples, the composition of the present invention is highly effective in preventing or reducing one or more symptoms of PCS, preferably olfactory and / or gustatory disorders.Accordingly, the composition of the present invention is preferably used to prevent or reduce one or more post-acute symptoms of infectious diseases, at least one post-acute symptom being selected from the group consisting of reduced physical performance, fatigue, exercise intolerance, chemosensory loss, joint pain, muscle pain, chest pain, ear-nose-pharyngeal disorders, cough, wheezing, gastrointestinal disorders, neurological disorders, psychological disorders, skin disorders, signs of infection, and sleep disorders, and a particularly preferred selected symptom is olfactory and / or gustatory disorders, preferably 6 months or more after the patient has tested positive for an infectious disease. Preferably, this effect is achieved in at least 10%, preferably 15%, more preferably 20%, even more preferably 25%, and most preferably 30% of these patients compared to placebo. Alternatively, or in addition, the effect is preferably achieved in a similar proportion of male and female patients, where similar means + / - 25%, preferably + / - 10%. The compositions of the present invention are preferably used for administration to patients with at least one characteristic or underlying medical condition associated with an increased risk of developing serious illness from an infection (especially COVID-19) and / or post-acute symptoms (especially PCS) (Waetzig & Schreiber 2021, International Application PCT / EP2021 / 083138). Alternatively or additionally, the compositions of the invention are preferably used when treatment and / or supplementation is administered to a patient with at least one characteristic symptom of an infection. For acute COVID-19, such symptoms are preferably selected from the group consisting of cough, fever, taste disorder and loss of taste. EXAMPLES

[0042] There are various possibilities for advantageously developing and further developing the teaching of the present invention, and for this purpose, reference is made to the following examples which are given as representative descriptions of the invention. Example 1: Formulation and product variants (general information for carrying out the invention) (1) Nicotinamide or suitable precursors or metabolites thereof can be administered alone or in combination as tablets or other solid dosage forms such as, for example, granules, pellets or microcapsules described herein, having a core that contains the active agent (preferably nicotinamide) within a matrix for at least partial controlled release (e.g., comprising different grades of hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, sodium carboxymethylcellulose, starch, modified starch, pregelatinized starch, gelatin, polyvinylpyrrolidone, or combinations thereof, or employing other matrix or multi-matrix technologies).

[0043] (2) The core of Example 1(1) can be provided with a coating for delayed release, including a film coating containing acrylic and / or methacrylate polymers in various mixtures for delayed release or biodegradable polymers for microflora-dependent release. Further suitable coating agents are water-insoluble waxes, such as carnauba wax, and / or polymers, such as poly(meth)acrylates, for example the entire poly(meth)acrylate product portfolio under the trade names Eudraguard® and Eudragit® offered by Evonik Industries, in particular Eudraguard® protect, Eudraguard® control, Eudraguard® biotic, Eudragit® natural, Eudragit® L 30 D-55 (aqueous dispersion of anionic polymers with methacrylic acid as functional group), Eudragit® L 100-55 (containing anionic copolymers based on methacrylic acid and ethyl acrylate), Eudragit® L 100 or L 12.5 or S 100 or S 12.5 (anionic copolymer based on methacrylic acid and methyl methacrylate), a combination of Eudragit® S and L compounds, or Eudragit® FS 30 D (aqueous dispersion of anionic copolymer based on methyl acrylate, methyl methacrylate and methacrylic acid), and / or water-insoluble celluloses (e.g. methylcellulose, ethylcellulose). Where appropriate, water-soluble polymers (e.g. polyvinylpyrrolidone), water-soluble celluloses (e.g. hydroxypropylmethylcellulose or hydroxypropylcellulose), emulsifiers and stabilizers (e.g. polysorbate 80), polyethylene glycol (PEG), lactose or mannitol are also contained in the coating material.

[0044] (3) The core of Example 1(1) may be provided with taste masking technology as described in the detailed description, which may comprise, alone or in combination, a single or multi-layer coating comprising, for example, a hydrophobic or hydrophilic polymer (e.g., methacrylic acid and methacrylic acid ester copolymers, such as Eudragit® E, E-100, RL 30D, RS 30D, L30D-55 or NE 30D; Eudraguard® protect, natural or control; ethylcellulose; hydroxypropylmethylcellulose; hydroxypropylcellulose; cellulose acetate; croscarmellose; polyvinyl alcohol; polyvinylpyrrolidone (e.g., PVP-K30 or Kollicoat); polyvinyl acetate; shellac; guar gum), lipids (e.g., glyceryl palmitostearate, glyceryl monostearate or glycerol behenate), talc, detergents (e.g., sodium lauryl sulfate or polysorbates, such as polysorbate 80), sugars and / or sweeteners.

[0045] (4) The core of Example 1(1) may be provided with a coating layer system comprising an inner layer for delayed release in the lower small intestine and / or colon of Example 1(2), a layer of an active agent formulated for immediate release, and an outer layer comprising the taste masking technology described in Example 1(3). (5) Nicotinamide or a suitable precursor or metabolite thereof may be administered alone or in combination as a tablet or other solid dosage form as described herein based on or similar to OralogiK technology (BDD Pharma) or Geoclock technology (Skyepharma) using immediate release, delayed and later pulsed release kinetics as described by the manufacturer.

[0046] (6) Nicotinamide or a suitable precursor or metabolite thereof can be granulated alone or in combination into immediate release pellet, mini-pellet or micro-pellet formulations, of which a fixed or variable portion can be provided with a coating for delayed (e.g. pH-dependent) release and another portion can be provided with a taste-masking coating for immediate release (see Examples 1(1), (2) and (3) for details). The two types of pellets described herein or pellets combining immediate and controlled and / or delayed release properties can be filled in a single sachet, stick pack, sealed lid, bottle lid, capsule or other suitable container, preferably in a fixed ratio, e.g. 2:1 or 1:1, for immediate:delayed release. Alternatively, the two types of pellets can be filled in separate sachets, stick packs or capsules and administered according to the patient's symptoms. In a further option, the pellets can be filled into capsules or incorporated into tablets.

[0047] (7) Nicotinamide or a suitable precursor or metabolite thereof, alone or in combination, may be administered as a tablet or other solid dosage form as described herein having a core containing an active agent, preferably nicotinamide. The core may not have matrix properties for controlled release and may include taste masking technology as described in Example 1(6). (8) Nicotinamide or its suitable precursors or metabolites, alone or in combination, can be administered as tablets or other solid dosage forms as described herein in combination with food, beverages, dietary supplements, foods for special medical purposes, probiotics, prebiotics, synbiotics and / or vitamins. In a preferred embodiment, the pellets are administered together with a beverage or (semi)liquid matrix (e.g., dairy products such as fruit smoothies or liquid yogurt). In a further preferred embodiment, the beverage or (semi)liquid matrix is ​​slightly acidic to prevent degradation of the pH-dependent delayed release coating. In a further preferred embodiment, the solid dosage form of the present invention is administered together with solid or liquid foods for special medical purposes.

[0048] (9) Nicotinamide, nicotinic acid and tryptophan can be administered in combination with tablets or other solid dosage forms as described herein. In a preferred embodiment, such compositions are suitable as medicines or special medical foods for conditions with high demand for NAD precursors. In a further preferred embodiment suitable as dietary supplements or special medical foods, the total amount of niacin equivalents contained in the formulation does not exceed a total amount of 160 mg. For example, 150 mg nicotinamide, 4 mg nicotinic acid and 200 mg tryptophan (3,333 niacin equivalents) are combined, and these dosages reflect the European recommendations of some countries for the addition of said active substances to foods, including dietary supplements. Example 2: Results from the pilot phase of the COVit-2 dietary intervention trial in COVID-19 patients with mild to moderate disease In the monocentric, randomized, double-blind, prospective, placebo-controlled dietary intervention trial COVit-2 (DRKS00021214; NCT04751604), conducted at the Department of Internal Medicine I, University Medical Center Schleswig-Holstein, Campus Kiel (Germany), outpatients with early symptomatic COVID-19 (up to 7 days after the first positive SARS-CoV-2 PCR test) in household isolation were recruited between February 2021 and January 2022. As vaccination against SARS-CoV-2 became more widely available to the public after several hundred patients had already been recruited into the COVit-2 trial, patients who were partially or fully vaccinated were excluded from enrollment, to maintain the same inclusion population and ensure formal comparability of all patients within the study. However, there is no reason or evidence to assume that the effects of targeting the basal metabolism and microbiota of nicotinamide would be different in symptomatic COVID-19 patients with or without previous vaccination.

[0049] For details of the study, see Waetzig & Schreiber 2021, International Application PCT / EP2021 / 083138. Patients were randomized to oral self-administration (once daily in the morning with breakfast for 28 days) of two different nicotinamide tablet combinations (one conventional 500-mg immediate-release nicotinamide tablet and one novel 500-mg controlled ileocolonic release nicotinamide [CICR-NAM] tablet, the latter of which ensures long-term continuous intestinal exposure to nicotinamide) or a matching placebo tablet. The entire study was performed remotely. Patients enrolled online and contacted the study team to check their eligibility and provided written patient information and informed consent forms. After informed consent, patients were asked for baseline data collection (week 0), then at weeks 2, 4 and 6. Baseline information asked included personal and demographic data, smoking status, comorbidities, concomitant administration of dietary supplements or medicines, and COVID-19 symptoms. At weeks 2, 4, and 6, participants were asked about regular intake of study supplements and co-supplements and medications, as well as current COVID-19 symptoms and disease course.

[0050] Approximately 6 months after infection, patients were contacted for a follow-up interview and an extensive series of questionnaires and tests, including the measurement of antibody levels. In addition to the patient interview and the SF-36 (quality of life) and FACIT-F (fatigue) questionnaires, which were also used in the first 6 weeks after starting the dietary intervention (Waetzig & Schreiber 2021, International Application PCT / EP2021 / 083138), the 6-month test group focused specifically on PCS symptoms. A validated olfactory test (University of Pennsylvania Smell Identification Test™; Sensonics / MediSense) was administered to patients and recorded as a patient-reported outcome in a paper questionnaire. Questionnaires on smell and taste ability (including the Self-reported Mini Olfactory Questionnaire, Self-MOQ and Questionnaire of Olfactory Disorders, QOD), breathing (Multidimensional Dyspnea Profile, MDP), mental status (Patient Health Questionnaire Depression, PHQ-8; Generalised Anxiety Disorder 7, GAD-7; Perceived Stress Scale, PSS; Brief Resilience Scale, BRS), sleep quality (Pittsburgh Sleep Quality Index, PSQI) and fatigue (Multidimensional Fatigue Inventory, MFI) were recorded as patient-reported outcomes on paper questionnaires. In addition, a verified cognitive test (Telephone Adaptation of the Modified Mini-Mental State Exam, T3MS) was administered via telephone interview.

[0051] For antibody level measurements, the time between a positive SARS-CoV-2 PCR test and blood sampling for antibody analysis, as well as the interval between one or more subsequent vaccinations against SARS-CoV-2 and blood sampling, if applicable, were recorded. Antibody levels were measured using the AProof Duo Test (Adversis Pharma, now AP Diagnostics; Leipzig, Germany). In this test, dried blood spot samples are rehydrated and analyzed by ELISA to detect antibodies against the nucleocapsid (N) or spike (S) proteins of SARS-CoV-2. Antibodies against the N protein are analyzed to evaluate the immunity that arises only with SARS-CoV-2 infection. After infection with SARS-CoV-2, the level of antibodies against the S protein represents both the effect of infection (in the absence of additional vaccination) or the combined humoral immunity that arises with infection and subsequent vaccination. Between the 6-week observation period after acute infection and at least 6 months of follow-up, many study participants were vaccinated against SARS-CoV-2. Anti-N antibody levels were quantified as a percentage of the signal of a positive control consisting of an anti-N antibody pool from five donors collected at different time points starting 2 weeks after infection confirmed by PCR with SARS-CoV-2. This anti-N antibody pool was diluted in a fixed ratio into negative control medium. Detection was considered negative when less than 20% of the positive control, borderline when 20–30%, and positive when more than 30%. Anti-S antibody protein levels were quantified as binding antibody units per milliliter (BAU / mL; according to the WHO international standard for anti-SARS-CoV-2 immunoglobulins [human] [NIBSC code 20 / 136]). Detection was considered negative when less than 22 BAU / mL, borderline when 22–44 BAU / mL, positive when more than 44 BAU / mL, and positive for neutralizing antibodies when ≥100 BAU / mL.

[0052] Data quality control tests were performed on the first 50 patients in each study arm (nicotinamide vs. placebo) with complete data for each analysis, revealing surprisingly that nicotinamide supplementation did indeed increase levels of both anti-N and anti-S antibodies (Table 1). Borderline values ​​(2-3 per parameter, n=50 each group) are not shown.

[0053] [Table 1] Additionally, the median difference in anti-S antibodies was stronger in patients with at least one characteristic or underlying medical condition associated with increased risk of developing severe COVID-19, i.e., 1,121 BAU / mL (nicotinamide) vs. 692 BAU / mL (placebo).

[0054] Despite the small sample size and partially moderate effect sizes, the effect of PCS on various symptoms was already observed in this pilot population: Patients supplemented with nicotinamide had: - A median PSS score of 24 compared with 28 in the placebo group, indicating less stress (Schneider et al. 2020, Int. J. Clin. Health Psychol. 20:173); - a median PHQ-8 score of 4 compared with 6 in the placebo group, indicating less depression (Kroenke et al. 2009, J. Affect. Disord. 114:163); - A median GAD-7 score of 3 compared with 6 in the placebo group, indicating less anxiety (Spitzer et al. 2006, Arch. Intern. Med. 166:1092); - 2% of patients had severe microsmia / hyposmia (UPSIT score <26) compared with 12% in the placebo group (Doly et al. 1989, Percept. Psychophys. 45:381); - 8% of patients with mild cognitive impairment (T3MS score <89) compared to 12% in the placebo group (Alexopoulos et al. 2006, Fortschr. Neurol. Psychiatr. 74:329), with a slightly stronger signal in patients with at least one characteristic or underlying medical condition associated with an increased risk of developing severe COVID-19, i.e. 10% in the nicotinamide group vs. 21% in the placebo group. Overall, nicotinamide increased anti-SARS-CoV-2 antibody levels and reduced many key PCS symptoms in the first n=50 patients in the COVit-2 trial.

[0055] Example 3: Final Results from the COVit-2 Dietary Intervention Trial in COVID-19 Patients with Mild to Moderate Disease The COVit-2 trial (see Example 2) has been expanded to a total of n=900 randomized patients, including n=500 patients with at least one characteristic or underlying medical condition associated with an increased risk of developing severe disease from COVID-19, the population that would benefit most from nicotinamide supplementation during the acute phase of the disease (Waetzig & Schreiber 2021, International Application PCT / EP2021 / 083138), hereafter referred to as the "risk factor population." Individual symptoms During the acute phase of COVID-19 (up to 7 days after a positive test for SARS-CoV-2) from baseline up to week 6, administration of nicotinamide conferred biologically and statistically significant benefits regarding different parameters of physical performance (mainly at week 2), as shown in an interim analysis of n=402 patients from the COVit-2 trial (Waetzig & Schreiber 2021, International Application PCT / EP2021 / 083138). However, nicotinamide supplementation had no beneficial effect on the olfactory and / or gustatory disorders experienced by some patients, although preliminary data from the pilot trial COVit-1 showed a potential benefit (Waetzig & Schreiber 2021, International Application PCT / EP2021 / 083138). In contrast, in the final analysis of n=500 patients in the risk population (primary analysis population for acute COVID-19 in the COVit-2 trial), there was instead a trend in favor of placebo, as evidenced by the rates of resolved, persistent, or new-onset disability shown in Tables 2 to 5 below.

[0056] Here, the efficacy variables "smell disorder" (yes / no) and "taste disorder" (yes / no) from patient interview represent the broadest and most sensitive approach, as other more specific tests or questionnaires do not capture aspects of smell or taste that are not explicitly asked about and may therefore fail to detect significant differences. In the acute phase of the COVit-2 study, these variables were analyzed using change versus baseline and considered as resolved (symptoms present at baseline but not at week x), persistent (no change compared to baseline) or worsening (symptoms present at week x but not at baseline). The frequency of patients with resolution, persistence or worsening of symptoms for all weeks in the treatment groups was compared using the Cochran-Mantel-Haenszel test. Post-hoc tests for each week were calculated using the Fisher exact test with Benjamini and Hochberg correction for multiple testing. The Woolfe test was performed to test for uniformity of odds ratios over time. In the case of significant p-values ​​for the Woolfe test, the Cochran-Mantel-Haenszel test was not appropriate.

[0057] [Table 2] TIFF2025511241000003.tif28153 [Table 3] [Table 4] TIFF2025511241000006.tif28153 [Table 5]

[0058] Surprisingly, nicotinamide supplementation led to a significant reduction in the frequency of olfactory or gustatory disorders after 6 months (Table 6 and Figure 1), although nicotinamide was not overtly effective in affecting these symptoms during the acute phase of the disease. [Table 6] Focusing on protocol-compliant patients (n=235 for nicotinamide and n=237 for placebo), the P values ​​were further reduced to P=0.039 for anosmia and P=0.016 for taste disorders, respectively. The protocol-compliant population included only patients who did not drop out and were compliant with respect to taking study drug for at least 80% of the acute phases (weeks 0-2 and 2-4), i.e., taking study drug on at least 11 of the 14 days during each study period.

[0059] PCS score Consistent with the overall mild-moderate disease pathway, many patients in the COVit study had absent or mild PCS scores at 6-month follow-up (Bahmer et al. 2022, eClinicalMedicine 51:101549). To characterize relevant subpopulations of the risk factor population defined above who were further at risk for developing PCS, baseline characteristics and symptoms of all available patients (n=425) in the placebo population were used to identify predictors for a PCS score of ≥5 at 6 months with a significance threshold of P<0.05. These predictors were: - Medical history: chronic obstructive pulmonary disease, organ transplant, depression, other chronic diseases, persistent intake of medications; - Symptoms from onset of COVID-19 up to study baseline: wheezing, whistling / wheezing breathing, dizziness, vomiting, conjunctivitis; - At baseline: wheezing, whistling / wheezing breathing, dizziness, conjunctivitis, chills, muscle pain, leg pain, activity limitations (score of 2 on the WHO scale of COVID-19 severity developed in 2020; https: / / apps.who.int / iris / rest / bitstreams / 1266940 / retrieve, last accessed on 20-Mar-2023). To be included in the PCS risk factor population, patients had to have more than five of these predictors at baseline. Surprisingly, nicotinamide was significantly beneficial in this population with respect to the development of PCS (P=0.045; Table 7, Figure 2), although only one symptom (shortness of breath) was positively affected by nicotinamide during the acute phase of the disease (56 of 92 patients treated with nicotinamide recovered at 2 weeks compared with 37 of 90 patients treated with placebo; P=0.012 by Fisher's exact test).

[0060] [Table 7]

[0061] Overall, administration of nicotinamide surprisingly significantly improved olfactory and / or gustatory disorders in all patients in the risk population, as well as PCS in patients at specific risk for PCS, effects that could not be predicted from the effects of nicotinamide in acute COVID-19.

Claims

1. NAD or NA selected from the group consisting of nicotinamide; nicotinic acid; nicotinic acid ester; tryptophan; tryptophan dipeptide; nicotinamide adenine dinucleotide (NAD); nicotinamide adenine dinucleotide phosphate (NADP); N-formylkynurenine, L-kynurenine, 3-hydroxy-L-kynurenine, 3-hydroxyanthranilate, 2-amino-3-carboxymoconate semialdehyde, quinolinate, nicotinic acid mononucleotide (beta-nicotinic acid D-ribonucleotide), and nicotinic acid adenine dinucleotide. A composition for use in preventing and / or reducing one or more post-acute symptoms of an infectious disease, comprising an active substance selected from intermediates in the biosynthesis of DP; nicotinamide riboside; nicotinamide mononucleotide; 1-methylnicotinamide (N-methylnicotinamide); or a combination thereof, wherein the active substance, preferably nicotinamide, is formulated to partially or completely release in the lower small intestine and / or colon for local replenishment or efficacy, and preferably the pathogen is SARS-CoV-2 and / or the post-acute symptom is PCS.

2. The composition according to claim 1, for use as pre-exposure or post-exposure prophylaxis to prevent the onset of post-acute symptoms of an infectious disease in patients who were at risk of infection with a pathogen or who tested positive for infection.

3. The composition according to claim 1 or 2, characterized by comprising one or more active substance preparations for delayed release and / or controlled delayed release, which mainly deliver the active substance, preferably nicotinamide, locally to the lower small intestine and / or colon, and one or more active substance preparations for immediate release and / or sustained release and / or sustained release, which preferably deliver the active substance, preferably nicotinamide, systemically to the blood circulation, together with the nicotinamide preparation.

4. The composition according to claim 1 or 2, characterized by containing a combination of two formulations of an active substance, preferably nicotinamide, in a specific mass ratio in the range of 1:1 to 1:1000.

5. The composition according to claim 1 or 2, characterized by containing a combination of two or more formulation variations of an active substance having the same dosage form, preferably nicotinamide.

6. The composition according to claim 1 or 2, characterized by containing two or more variant or fixed-dose combination drugs of active substances in separate dosage forms, preferably nicotinamide.

7. The composition according to claim 1 or 2, characterized in having an active substance content of 1 to 5,000 mg, preferably 10 to 4,000 mg, more preferably 100 to 3,000 mg, and preferably nicotinamide content per final dose.

8. The composition according to claim 1 or 2, wherein the active substance, preferably nicotinamide, is formulated for delayed or controlled delayed release such that the plasma peak level of the active substance, preferably nicotinamide, after administration of the delayed or controlled delayed release formulation is reduced by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% compared to the same amount of the active substance, preferably nicotinamide, administered as an immediate-release formulation in the same way and under the same conditions, so that only a portion of the active substance, preferably nicotinamide, enters the circulatory system to a low extent.

9. The composition according to claim 1 or 2, for use in administration once a day in the morning with breakfast.

10. The composition according to claim 9, wherein the dose has an active substance content of 1 to 5000 mg, preferably 10 to 4000 mg, more preferably 100 to 3000 mg per final administration form, preferably a nicotinamide content.

11. A composition according to claim 1 or 2 for use in preventing or reducing one or more post-acute symptoms of an infectious disease, wherein at least one post-acute symptom is selected from the group consisting of decreased physical ability, fatigue, exercise intolerance, chemosensory loss, arthralgia, myalgia, chest pain, ear-nose-pharyngeal disease, cough, wheezing, gastrointestinal disease, neurological disease, psychological disorder, skin disease, signs of infection, and sleep disorder, and the symptom particularly preferably selected is olfactory and / or gustatory dysfunction, preferably six months or more after the patient has tested positive for the infection.

12. The composition according to claim 1 or 2, for use in administration to patients having at least one characteristic or underlying medical condition associated with an increased risk of developing a serious illness from infection and / or post-acute symptoms.

13. The composition according to claim 1 or 2, for use in administration to a patient having at least one characteristic symptom of an infectious disease.

14. The composition according to claim 1 or 2, for use in administering to a patient having at least one characteristic symptom of acute COVID-19, preferably a symptom selected from the group consisting of cough, fever, taste disorder, and loss of taste.

15. The composition according to claim 1 or 2, for use in food, beverage, dietary supplement, food for special medical purposes, probiotics, prebiotics, synbiotics and / or vitamins in combination with administration.

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