Colon-releasing dietary supplements as adjuncts in the treatment and prevention of colon disorders caused by suspected or confirmed altered inflammatory patterns and destabilization of the microbiota

Abstract

A colon-release oral tablet, comprising as active ingredients a combination of dried extracts of turmeric, pomegranate and boswellia, said release being ensured by the presence of a combination of sodium alginate and hydroxypropyl methylcellulose in a matrix in which the active ingredients are dispersed. This oral tablet, preferably in the form of a dietary supplement, is used as an adjunct in the treatment and prevention of colon disorders caused by suspected or confirmed changes in the inflammatory status and destabilization of the microbiota.

Description

[Technical field]

[0001] The present invention relates to an oral tablet, particularly in the form of a colon-release food supplement, as a coadjuvant in the treatment and prevention of colon disorders caused by suspected or confirmed altered inflammatory patterns and destabilization of the microbiota. [Background technology]

[0002] According to the Treccani Encyclopedia, inflammation in medicine is a complex reaction event that occurs when the body tissues of higher animals come into contact with harmful agents of different nature. 1 The most frequent outcome of this process is the neutralization of the harmful factor or the containment of the lesion resulting from it. The causes of inflammation can be of a physical, chemical and biological nature, even if some inflammatory diseases are still under investigation with regard to the identification of specific pathogenic factors. The inflammatory response is determined by vascular and cellular events. The clinical events of inflammation have been known since ancient times: fever (calor), redness (rubor), swelling (tumor), pain (dolor) and functional impairment (functio laesa). In this order, they correspond to the obvious events associated with inflammation: blood vessels appear dilated and the local circulation increases (congestion: rubor, calor); plasma (plasma exudation), some formed blood components (representatively granulocytes, lymphocytes, plasma cells, exceptionally red blood cells), which flow out of them (levitation), with the addition of cellular components derived directly from the tissue (histogenic reaction), resulting in swelling of the inflamed area (tumor). 1The latter is deeply painful (dolor) and functionally impaired (functio laesa). Based on the extent to which blood vessels and cells respond to inflammatory stimuli, inflammation can be classified into two main types: acute inflammation, in which vascular events predominate over cellular events (exudation phlogosis), and chronic inflammation, in which cellular events predominate over vascular events (productive phlogosis). Inflammation occurs in all human tissues, with the consequence that it affects all organs and apparatus.

[0003] When inflammatory processes affect the intestinal mucosa, we can observe a very diverse range of clinical diseases (sometimes in mild forms with few symptoms). Among the diseases in which a confirmed or suspected inflammation / hyperimmunity is the focus of the disease or disorder suffered by the patient, we can include, by way of example and not limitation, the various forms of colitis (unclassified colitis, collagen (storage) colitis, drug-induced colitis, nonspecific colitis...), some subclasses of diverticular disease (symptomatic simple diverticular disease SUDD, diverticulitis, segmental colitis SCAD complicated by diverticulosis, irritable colon syndrome IBS...), up to the more severe and debilitating inflammatory bowel diseases IBD (ulcerative proctocolitis RCU, Crohn's disease). An etiological factor that is thought to play a major role in the pathogenesis of intestinal inflammation and that deserves attention is the intestinal microbiota (intestinal flora, intestinal flora). 2 To better explain this, it should be noted that the microbiota is considered by the scientific community as a true «protective organ» of the gastrointestinal system. 2 In this respect, it is often pointed out that the microbiota, among other functions, is able to modulate the local immune system of the intestine, thus controlling all inflammatory processes that may affect the mucosa. The mechanisms that the intestinal microbiota implements to ensure the correct functioning of the intestinal immune system are variable and involve the regulation of many more factors. 2 When the gut microbiota loses its functional integrity, an abnormal activation of the adaptive immune system occurs, which involves the activation of some lymphocyte types of the T helper cell lineage (Th1, Th2, Th17), deregulation of NF-kB factors, hyperactivation of leukocytes, and increased oxidative damage. 3-5Activation of the Th1 and Th17 systems leads to an increase in IL-1, IL-6, IL-8, IL-2, IL-17, TNF-alpha, and IFN-y, known as proinflammatory cytokines, which activate and support inflammation, as well as interact with macrophages and APCs (antigen presenting cells) to amplify their activity and cytokine production. 3-5 Activation of the Th2 system determines the increase in the cytokines IL-5 and IL-13. IL-5 is also a signal that activates natural killer (cells). Leukocyte infiltration into the intestine, if not kept under control, supports and amplifies mucosal inflammation. Leukocytes are indeed attracted by cytokines and chemokines produced by various leukocytes and, once they reach the inflamed tissue, increase the structural damage. 5,6 A commonly measured inflammatory marker to determine intestinal inflammation is fecal calprotectin.

[0004] Calprotectin is a protein belonging to the S100 family, found in large quantities in neutrophil granulocytes, representing 5% of the total protein and 60% of the cytoplasmic protein. It is also found in small amounts in activated monocytes and macrophages. In the presence of inflammatory processes, calprotectin is released after granulation of neutrophil granulocytes. In the case of intestinal inflammation, calprotectin can be detected in the feces. Other blood chemical parameters observed, which are less specific than fecal calprotectin, are ESR and CRP. From a pharmacological point of view, a literature review highlights that many molecules used to treat chronic intestinal inflammation are associated with controlled release technologies with the aim of optimizing their efficiency while at the same time reducing the possibility of side effects typical of these drugs. In 2015, the World Journal of Gastrointestinal Pharmacology and Therapeutics (Bei Ye et al. Mesalazine preparations for the treatment of ulcerative colitis: Are all created equal? ​​World J Gastrointest Pharmacol Ther. 2015 Nov 6;6(4):137-144.) published a review evaluating the differences between the various mesalazine-based formulations found in the literature and highlighting the fact that all the analyzed formulations were provided with modified release technology. This speaks to the scientific interest in such types of release. The following table reports the formulations considered in the review.

[0005] [Table 1]

[0006] This type of essentially pharmacological therapy has significant drawbacks associated with the use of drugs, such as steroids, which have a wide range of undesirable side effects. These are only a small part of the pharmacological therapies proposed by traditional medicine, but besides them, CAM therapies (Complementary and Alternative Medicine) are also actively investigated as therapies to support the treatment of inflammatory diseases, even if the organ in question is the intestine. In this context, there is literature evidence reporting scientific interest in colonic release technologies, even if they are applied to plants (plant extracts). In 2012, the Journal of Pharmacy Research (MK Modasiya et al. / Journal of Pharmacy Research 2012,5(4),2253-2258) published data on some specific technologies applied to curcumin. On the market, there is an oral preparation under the trade name IBIDI® as a disease adjunct in the treatment of colon disorders caused by suspected or confirmed changes in inflammatory patterns and destabilization of the microflora, which contains as active ingredients at least three plants (Boswellia, Turmeric and Punica granatum) dispersed in a hydroxypropyl methylcellulose matrix.

[0007] In fact, curcumin is an active ingredient contained in turmeric (Curcuma longa). It regulates inflammatory processes by inhibiting the expression of several cytokines such as IFN-y, TNF alpha, IL-1 beta and IL-12. Curcumin itself has been shown to be effective in inhibiting the activation of the NF-kB factor, activating the PPAR-y gene, inhibiting the release of COX2, and finally reducing NO levels, which are notoriously high in IBD patients. 7-11 A study conducted in 2013 investigated the synergistic effect between curcumin and antibiotics and the antibacterial effect of curcumin against resistant strains of Staphylococcus aureus. In addition to the significant activity that turmeric showed against 10 resistant strains of Staphylococcus aureus, turmeric also ensured a reduction in the antibiotic MICs for oxacillin (OXI), ampicillin (AMP), ciprofloxacin (CIP), and norfloxacin (NOR), supporting the synergistic effect. 12,13 .

[0008] Boswellia serrata: Boswellia modulates cytokine release, inhibits activation of NF-kB factors, and reduces leukocyte activity, primarily due to its boswellic acid AKBA, inhibiting rolling and endothelial cell adhesion. 14,15 In an in vitro study, the antimicrobial potential of boswellic acids (AKBA, KBA, BA) against 112 bacterial species was analyzed. Pathogenic species commonly present inside the gastrointestinal tract were considered, namely E. fecalis, E. faecium, S. aureus, etc. The MICs obtained for these species showed that the most active boswellic acid in terms of antimicrobial action was 11-keto-beta-boswellic acid (AKBA), E. faecalis -> average MIC 6 μg / ml; E. faecium -> average MIC 6 μg / ml; S. aureus -> average MIC 2 μg / ml. 16 .

[0009] Pomegranate promotes the selective growth of gut bacteria that support the microbiome. Along with its prebiotic effects, pomegranate extract stimulates the microbiome to produce SCFAs (short chain fatty acids), especially the beneficial butyric acid, and promotes the release of urolithins, known endogenous anti-inflammatory agents. 17 .

[0010] Although this type of formulation is a good support for conventional treatments that provide only drug therapy, it has some drawbacks: some of the active ingredients are poorly soluble and / or are almost completely decomposed in the stomach, and it is not certain whether they are released in sufficient amounts in the colon where the inflammatory process occurs.

[0011] The "Handbook of Pharmaceutical Excipients", 6th edition, 2009, Pharmaceutical Press, XP055514625, pages 622-624, describes the properties of alginate and reports that it can be used in matrices to slow the release of active ingredients.

[0012] Similar controlled release properties are described for hydroxypropyl methylcellulose in "Handbook of Pharmaceutical Excipients", February 20, 2009 (2009-02-20), Pharmaceutical Press, XP055325597, ISBN: 978-0-85369-792-3, pages 326-329.

[0013] WO2015 / 087259 A1 discloses tablets containing curcumin dispersed in a matrix of hydroxypropylmethylcellulose, tablets which must always be coated with a gastroresistant film to be effective in treating intestinal inflammatory diseases.

[0014] JOANA TORRES et al.: “European Crohn's and Colitis Organisation Topical Review on Complementary Medicine and Psychotherapy in Inflammatory Bowel Disease”, JOURNAL OF CROHN'S AND COLITIS, vol.13, no.6, March 2019 (2019-03), pp. 673-685, presents the use of several plant extracts to treat inflammatory diseases of the intestine. Table 1 lists a number of plant extracts, including turmeric, boswellia and pomegranate. [Prior art documents] [Patent documents]

[0015] [Patent Document 1] International Patent Application Publication No. 2015 / 087259 A1 [Non-patent literature]

[0016] [Non-Patent Document 1] Bei Ye et al., World J Gastrointest Pharmacol Ther.2015 Nov 6;6(4):137-144 [Non-Patent Document 2] MKModasiya et al. / Journal of Pharmacy Research 2012,5(4),2253-2258 [Non-Patent Document 3] “Handbook of Pharmaceutical Excipients”, 6th edition, 2009, Pharmaceutical Press, XP055514625, pages 622-624 [Non-Patent Document 4] “Handbook of Pharmaceutical Excipients”, February 20, 2009 (2009-02-20), Pharmaceutical Press, XP055325597, ISBN: 978-0-85369-792-3, pages 326-329 [Non-Patent Document 5] JOANA TORRES et al., JOURNAL OF CROHN'S AND COLITIS, vol.13, no.6, March 2019(2019-03), pages 673-685 Summary of the Invention

[0017] Applicants have now found that the problems of background art tablets can be overcome by the tablet subject of the present invention, which, as disclosed more fully below, has better gastrotolerance than the commercially available IBIDI® formulation.

[0018] The object of the present invention is therefore a colonic release oral tablet comprising as active ingredient (active ingredient) a mixture of dry extracts of turmeric, pomegranate and boswellia, said release being ensured by the presence of a combination of sodium alginate and hydroxypropyl methylcellulose in a relational matrix in which said active ingredients are dispersed.

[0019] The tablets are used in particular as an adjunct in the treatment and prevention of colon disorders caused by suspected or confirmed changes in inflammatory patterns and destabilization of the microflora. Applicants have unexpectedly discovered that sodium alginate and hydroxypropyl methylcellulose indeed act synergistically to ensure uniform release rheological properties, which are reproducible and independent of the hydrophilic, lipophilic or amphiphilic nature of the active ingredient being carried. [Brief description of the drawings]

[0020] [Figure 1] Figure 1 reports the results of the test disclosed in Example 2. These are the results after 2, 4 and 5 hours of disintegration tests carried out, respectively, on IBIDI® tablets and on a formulation according to the invention, in particular on tablets whose composition is reported in Example 1. [Diagram 2] Figure 2 instead reports the results of the dissolution test of ellagic acid, disclosed in Example 2. Ellagic acid is the main component contained in pomegranate and thus in the formulation according to the invention. In the figure, the diagram on the left reports the dissolution test of the known IBD formulation, while the diagram on the right reports the release of the formulation according to the invention. [Diagram 3] Figure 3 reports the results of the ex vivo test disclosed in Example 3. These are the results of an ex vivo test carried out on the effectiveness of a tablet according to the invention, in particular the composition of which is reported in Example 1, on a pattern of intestinal cells simulating IBD. [Figure 4A] Figure 4A reports the results of the clinical trial disclosed in Example 4 (fecal calprotectin) at T1 = 3 months and T2 = 6 months, performed on a group of RCU patients (A) who received two tablets per day according to the invention in addition to conventional therapy, compared to a group of patients suffering from the same disease (C) who received only conventional therapy. [Figure 4B]Figure 4B reports the results of the clinical trial disclosed in Example 4 (SIBDQ questionnaire). It reports the results of a clinical trial at T1 = 3 months and T2 = 6 months carried out on a group of RCU patients (A) who received two tablets per day according to the invention in addition to conventional therapy, compared to a group of patients suffering from the same disease (C) who received only conventional therapy. [Figure 4C] Figure 4C reports the results of the clinical trial disclosed in Example 4 (MPS scores) at T1 = 3 months and T2 = 6 months, performed on a group of RCU patients (A) who received two tablets per day according to the invention in addition to conventional therapy, compared to a group of patients suffering from the same disease (C) who received only conventional therapy. [Figure 4D] Figure 4D reports the results of the clinical trial disclosed in Example 4 (VAS scale). It reports the results of the clinical trial at T1 = 3 months and T2 = 6 months carried out on a group of RCU patients (A) who received two tablets per day according to the invention in addition to conventional therapy, compared to a group of patients suffering from the same disease (C) who received only conventional therapy. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] Preferably, sodium alginate and hydroxypropyl methylcellulose are present in a ratio comprised between 1:25 and 1:10, more preferably between 1:20 and 1:15. According to a particularly preferred embodiment, said ratio is 1:19.

[0022] Preferably, to enhance colonic release, the tablet subject of the present invention also contains a dry extract of black pepper. Indeed, black pepper, derived from the fruit of the pepper (Piper nigrum L.) plant, enhances the intestinal uptake of substances that are not readily soluble, such as boswellic acid (http: / / www.cosmofarma.com / wpcontent / uploads / 2017 / 06 / www.cosmofarma.com / Fratter_2.pdf).

[0023] To ensure an increased contact surface between the active substance and the inflamed intestinal epithelium, the product was formulated with excipients that protect its integrity during the passage through the gastric environment and into the first intestinal tract to ensure colonic release of the functional ingredient. To comply with such requirements, the tablet is preferably equipped with a gastro-resistant coating. This is ensured by the presence of shellac in the film. As highlighted in the Summary of the Invention, the integrity of the tablet during the passage through the first intestinal tract is promoted by the presence of sodium alginate and hydroxypropyl methylcellulose in the core. These ingredients facilitate the release of the majority of the active ingredient in the distal part of the intestine by extending the disintegration time. When released in the intestinal secretions, they result in rapid dissolution and hydro-dispersion of the active ingredient (salt of boswellic acid) and (hydro-dispersion of the curcuminoid fraction as a response to the alkaline environment).

[0024] Preferably, in the oral tablet subject of the present invention, the dry extract of turmeric is derived from the rhizome of Curcuma longa L and has a minimum potency of 90%, preferably 95% of curcumin and curcuminoids.

[0025] According to another preferred embodiment, the dry extract of pomegranate is derived from the fruit of the pomegranate (Punica granatum L.) and has a minimum titer of ellagic acid of 20%, preferably 40%. According to a further preferred embodiment, the dry extract of Boswellia is derived from the gum resin of Boswellia serrata Roxb. and has a minimum titer of 30%, preferably 65% ​​of boswellic acids.

[0026] Finally, according to a further preferred embodiment, the black pepper extract possibly present is derived from the fruit of the pepper (Piper nigrum L.) plant and has a minimum titer of 80%, preferably 95% of piperine.

[0027] Preferably, the oral tablet subject of the present invention contains turmeric in an amount of 80-150 mg by weight, more preferably equal to 100 mg, relative to the total weight of the tablet, boswellia in an amount of 150-300 mg, more preferably 200 mg, and dried pomegranate extract in an amount of 200-350 mg by weight, more preferably 250 mg, relative to the total weight of the tablet.

[0028] As mentioned above, when the oral tablet contains black pepper, it is preferably contained in an amount of 1 to 5 mg by weight relative to the total weight of the tablet, more preferably 2 mg. The tablet subjects of the present invention may also possibly contain probiotics, such as Lactobacillus plantarum, Lactobacillus paracasei, and / or postbiotics, including short chain fatty acids (SCFAs) and other active metabolites of the gut microbiota.

[0029] Preferably, said colon disorder caused by suspected or confirmed altered inflammatory patterns and destabilization of the microbiota is preferably selected from colitis selected from unclassifiable colitis, collagenous (storage) colitis, drug-induced colitis and non-specific colitis, diverticular disease selected from symptomatic uncomplicated diverticulosis (SUDD), diverticulitis, segmental colitis with diverticulosis (SCAD), ulcerative proctocolitis (RCU), Crohn's disease, IBS (irritable bowel syndrome).

[0030] Preferably, the tablet according to the invention falls into the category of dietary supplements (food supplements) and is administered twice a day according to a particularly suitable solution. In addition to the ingredients mentioned above, the tablet subject of the present invention may also contain conventional excipients used in the pharmaceutical arts, which are well known to those skilled in the art. Aspects of the invention also include the following. Aspect 1. A colonic release oral tablet comprising as active ingredients dried extracts of turmeric, pomegranate and boswellia, said release being ensured by the presence of a combination of sodium alginate and hydroxypropyl methylcellulose in a relational matrix in which the active ingredients are dispersed. Aspect 2. The oral tablet according to aspect 1, wherein said sodium alginate and said hydroxypropyl methylcellulose are present in said matrix in a weight ratio comprised between 1:25 and 1:10, preferably between 1:20 and 1:15, and more preferably 1:19. Aspect 3. An oral tablet according to any of Aspects 1 or 2, comprising a dry extract of black pepper. Aspect 4. An oral tablet according to any of aspects 1 to 3, wherein the dried turmeric extract is derived from the rhizome of turmeric (Curcuma longa L) and has a minimum titer of 90%, preferably 95% of curcumin and curcuminoids, the dried pomegranate extract is derived from the fruit of pomegranate (Punica granatum L.) and has a minimum titer of 20%, preferably 40% of ellagic acid, and the dried boswellia extract is derived from the gum resin of Boswellia serrata (Boswellia serrata Roxb.) and has a minimum titer of 30%, preferably 65% ​​of boswellic acids. Aspect 5. An oral tablet according to aspect 3 or 4, wherein the black pepper is derived from the fruit of the pepper (Piper nigrum L.) plant and has a minimum potency of 80%, preferably 95% piperine. Aspect 6. An oral tablet according to any one of Aspects 1 to 5, wherein the turmeric is contained in an amount of 80 to 150 mg by weight, more preferably in an amount equal to 100 mg, relative to the total weight of the tablet, the boswellia is contained in an amount of 150 to 300 mg, more preferably in an amount of 200 mg, and the dried pomegranate extract is contained in an amount of 200 to 350 mg by weight, more preferably in an amount of 250 mg, relative to the total weight of the tablet. Aspect 7. The oral tablet according to aspects 3 to 6, comprising black pepper in an amount comprising 1 to 5 mg, more preferably 2 mg, by weight relative to the total weight of the tablet. Embodiment 8. An oral tablet according to any of embodiments 1 to 7, comprising a probiotic. Aspect 9. An oral tablet according to any one of aspects 1 to 8, comprising a postbiotic selected from indole, and a short chain fatty acid (SCFA) selected from propionic acid, butyric acid and formic acid. Aspect 10. An oral tablet according to any of aspects 1 to 9, comprising a gastro-resistant coating comprising or consisting of shellac. Aspect 11. An oral tablet according to any one of aspects 1 to 10 in the form of a dietary supplement. Aspect 12. An oral tablet according to any of aspects 1 to 11 for use as an adjunct in the treatment of colon disorders caused by suspected or confirmed altered inflammatory status and destabilization of the microbiota. Aspect 13. The oral tablet according to aspect 12, wherein said colon disorder caused by suspected or confirmed altered inflammatory status and destabilization of microbiota is selected from inflammatory bowel diseases selected from colitis selected from unclassifiable colitis, collagenous (storage) colitis, drug-induced colitis, and non-specific colitis, diverticular disease selected from symptomatic uncomplicated diverticulosis (SUDD), diverticulitis, segmental colitis (SCAD) complicated with diverticulosis, ulcerative proctocolitis (RCU), and Crohn's disease. Aspect 14. The oral tablet of any of aspects 12 or 13, wherein the tablet is administered twice daily.

[0031] In the following examples, the composition of tablet subjects of the invention, as well as laboratory and clinical tests, are reported below for purposes of illustration and not limitation. EXAMPLES

[0032] Example 1 The following specific examples of tablet subjects of the present invention are reported below.

[0033] [Table 2]

[0034] Example 2 - Comparative evaluation between uncoated Ibidi tablets and uncoated tablets according to the formulation reported in Example 1 We propose an approach to evaluate the performance of the tablet according to the invention and the IBIDI tablet in two tests used as references by the Pharmacopoeias.

[0035] The proposed evaluation will determine the resistance of the formulation according to the invention to the gastric environment (dissolution test) and the release time of one of its components, ellagic acid from pomegranate, in the intestinal environment. The dissolution time will be a parameter that allows to estimate the site of powder release based on the intestinal transit time.

[0036] Decomposition test The samples are tested in a disintegration assay using the equipment and operating conditions described in the Pharmacopoeia, with particular reference to the conditions and limitations provided for validating gastroresistant tablets (medium: 0.1 N HCl, no clear change for 2 hours; then disintegration within 60 minutes in phosphate buffer pH 6.8 at a temperature of 36-38 °C).

[0037] Dissolution Test The samples were tested in a dissolution assay using the apparatus and operating conditions described in the Pharmacopoeia: an instrument with a cylindrical vessel equipped with a hemispherical bottom and a blade or basket stirrer was used.

[0038] Elution medium: Start with an “acid cycle” (750 ml HCl 0.1M, 2 hours), followed by an additional “buffer cycle” (250 ml Na3PO4 0.2M, 45-60 minutes). Alternatively, the following may be used:

[0039] "Acid cycle" (1000ml HCl 0.1M, 2 hours). Remove the acid and start the "buffer cycle" (1000ml buffer pH 6.8, 45-60 minutes). The results carried out in the disintegration test are reported in Figure 1. The picture highlights the gastroresistant effect of the tablets according to the invention, since after 5 hours in the acid solution the tablets remain intact (retain their original shape), whereas the formulation without HPMR technology is already dissolved after the first 2 hours in the acid environment.

[0040] The results of the dissolution test are reported in Figure 2. The results of the dissolution test carried out only on the ellagic acid contained in two tablets (IBIDI tablet and tablet of Example 1) highlight that the release of the active ingredient from the tablet according to the invention is compatible with the slow release concept and therefore with colonic release, when compared with the much faster release profile of the ellagic acid contained in the known IBIDI tablet.

[0041] Example 3 - Efficacy evaluation in an ex vivo experimental model of IBD (inflammatory bowel disease) mice The samples were tested in an ex vivo experimental model in mice to quantitatively evaluate the effect of the presence of graded concentrations of the tablets of the invention in the culture medium and to determine specific markers of oxidative stress and inflammation resulting from morphological and structural changes of chronic inflammation of the colonic mucosa.

[0042] The parameters taken into account are: effect on nitric oxide synthase and the determination of thiobarbituric acid derivatives as stable markers of lipid peroxidation, effect on the activity of inflammatory cytokines such as prostaglandin E2 and serotonin.

[0043] The results of this study are reported in FIG. From these results, the tablet subject of the present invention is A significant reduction in nitrite levels, an indicator of nitrosative stress, can be determined due to increased production of nitric oxide by inducible nitric oxide synthase (iNOS) in the intestine; · It can reduce 5-HT levels in the colon of LPS-stimulated mice (inflammatory stimulus); Reduces tissue levels of serotonin and PGE2, which play key roles as proinflammatory cytokines in ulcerative colitis It is derived that:

[0044] Example 4 - Clinical Trials A clinical trial was designed to test the efficacy of the tablet of the present invention versus controls in optimizing recrudescence therapy for mild to moderately active ulcerative proctitis by monitoring quality of life (by sibdq) and inflammatory indicators including fecal calprotectin, clinical indicators (Mayo partial score) and perceived abdominal pain (VAS scale).

[0045] protocol 20 patients with active RCU (diagnosed by standard criteria) requiring therapy for relapse treatment were recruited: Ten patients received relapse therapy (deltacortene, budesonide MMX and / or rectal) - Group C (control) 10 patients received the tablet subject of the invention (the composition of which is reported in Example 1) in addition to relapse therapy (Deltacortene, Budesonide MMX and / or rectal) - Group A

[0046] Test period 6 months of treatment followed by 3 months of follow-up Pharmacology Patients treated with the tablet formulation of the present invention will take two tablets daily in addition to their normally prescribed therapy. Clinical trial evaluations (at T0, T1 and T2 time points) were: - Assessment of inflammation parameters, e.g. fecal calprotectin Assessment of Mayo partial disease activity score (MPS) Abdominal pain VAS scale assessment - Bristol Stool Chart assessment of stool consistency -Submission of the SIBDQ questionnaire to assess quality of life It is assumed that:

[0047] Selection Criteria : Age: 18-75 years - Clinically confirmed diagnosis of mild to moderately active RCU (MPS 2-7) requiring steroid therapy for relapse

[0048] Exclusion criteria Rectal only RCU (E1) -Patients who had previously undergone colectomy Patients who are being treated with immunosuppressants or biologics or who require anti-relapse medications Patients with MPS score <2 or >7

[0049] Implementation Sheet ·When recruiting T0 Clinical evaluation of disease status using Mayo partial score, Bristol scale, pain VAS scale, inflammation index record, and patient quality of life status (SIBDQ). T1 3 months Clinical evaluation of disease status using Mayo partial score, Bristol scale, pain VAS scale, inflammation index record, and patient quality of life status (SIBDQ). T2 6 months Clinical evaluation of disease status using Mayo partial score, Bristol scale, pain VAS scale, inflammation index record, and patient quality of life status (SIBDQ). The most important results at T1=3 months and T2=6 months are reported in Figures 4A, 4B, 4C, and 4D.

[0050] In Figure 4A, Group A, which is envisaged to receive two tablets according to the invention, has an improved inflammatory profile (reduction vs. T0 and T1) versus the control group, where an early increase in fecal calprotectin is observed.

[0051] As can be seen in Figure 4B, the quality of life of Group A also improved (improved) within the 3 and 6 month treatment periods, whereas Group C did not report any improvement in their quality of life. In Figure 4C it can be seen that within group A the general state of the disease, as observed clinically by the MPS test, has improved (score reduction) to the extent that it excludes the patients from the criteria for active RCU (MPS test 2-7), unlike the control group, where it can be seen that values ​​higher than 2 still indicate active RCU.

[0052] In Figure 4D, it can be seen that the perception of abdominal pain as clinically observed by the VAS test (VAS scale 0 to 10) improved (score reduction) in Group A, which differs from the control group in which the deterioration of symptoms was evident.

[0053] List of references

[0054] [Table 3-1]

[0055] [Table 3-2]

Claims

1. 1. A colonic release oral tablet comprising as active ingredients a dry extract of turmeric, pomegranate and boswellia, said release being ensured by the presence of a combination of sodium alginate and hydroxypropyl methylcellulose in a relational matrix in which the active ingredients are dispersed, said sodium alginate and said hydroxypropyl methylcellulose being present in said matrix in a weight ratio comprised between 1:25 and 1:

10.

2. 2. The oral tablet of claim 1 containing a dry extract of black pepper.

3. 3. The oral tablet according to any one of claims 1 to 2, wherein the dried turmeric extract is derived from the rhizome of turmeric (Curcuma longa L) and has a minimum potency of 90% curcumin and curcuminoids, the dried pomegranate extract is derived from the fruit of pomegranate (Punica granatum L.) and has a minimum potency of 20% ellagic acid, and the dried boswellia extract is derived from the gum resin of Boswellia serrata Roxb. and has a minimum potency of 30% boswellic acid.

4. 4. The oral tablet of claim 2 or 3, wherein the black pepper is derived from the fruit of the pepper (Piper nigrum L.) plant and has a minimum potency of 80% piperine.

5. 5. The oral tablet according to claim 1, wherein the turmeric is contained in an amount comprising 80 to 150 mg by weight relative to the total weight of the tablet, the boswellia is contained in an amount comprising 150 to 300 mg by weight, and the dried pomegranate extract is contained in an amount comprising 200 to 350 mg by weight relative to the total weight of the tablet.

6. An oral tablet according to claims 2 to 5, containing black pepper in an amount comprising 1 to 5 mg by weight relative to the total weight of the tablet.

7. The oral tablet according to any one of claims 1 to 6, comprising probiotics.

8. 8. The oral tablet according to any one of claims 1 to 7, comprising a postbiotic selected from indole and a short chain fatty acid (SCFA) selected from propionic acid, butyric acid and formic acid.

9. An oral tablet according to any one of claims 1 to 8, comprising a gastro-resistant coating comprising or consisting of shellac.

10. The oral tablet according to any one of claims 1 to 9 in the form of a dietary supplement.

11. The oral tablet according to any one of claims 1 to 10 for use as an adjunct in the treatment of colon disorders caused by suspected or confirmed altered inflammatory status and destabilization of the microflora.

12. 12. The oral tablet of claim 11, wherein the colon disorder caused by suspected or confirmed altered inflammatory status and destabilization of the microbiota is selected from inflammatory bowel diseases selected from colitis selected from unclassifiable colitis, collagen (storage) colitis, drug-induced colitis, and non-specific colitis, diverticular disease selected from symptomatic uncomplicated diverticulosis (SUDD), diverticulitis, segmental colitis with diverticulosis (SCAD), ulcerative proctocolitis (RCU), and Crohn's disease.

13. 13. The oral tablet of claim 11 or 12, wherein the tablet is administered twice daily.

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