WO2025191623A1

WO2025191623A1 - Oral compositions for the treatment of irritable bowel syndrome

Info

Publication number: WO2025191623A1
Application number: PCT/IT2025/050054
Authority: WO
Inventors: Michele DI STEFANO
Original assignee: Bioticare&research Srl
Current assignee: Bioticare&research Srl
Priority date: 2024-03-14
Filing date: 2025-03-13
Publication date: 2025-09-18
Anticipated expiration: 2026-09-14

Abstract

The present invention concerns oral combinations for the treatment of irritable bowel syndrome (IBS) and similar inflammatory bowel diseases. The combinations are based on three active ingredients: butyric acid or a pharmaceutically acceptable salt or ester thereof which can provide butyric acid in vivo, palmitoylethanolamide (PEA) and Chios mastic (CMC). Such products are able to exert an enhanced action in the treatment of irritable bowel syndrome (IBS) when administered in combination with each other. The weight ratio of butyric acid:PEA:Chios mastic in the composition is equal to (1 -3):(1 -3):(1 -3), and the daily dosage of each of the active ingredients is between 100 mg and 500 mg.

Description

ORAL COMPOSITIONS FOR THE TREATMENT OF IRRITABLE BOWEL SYNDROME

DESCRIPTION

Field of the invention

The present invention relates to oral compositions for the treatment of irritable bowel syndrome. More specifically, the invention concerns combinations of three active ingredients, butyric acid in salt or ester form, palmitoylethanolamide (PEA) and Chios mastic, which, when administered in combination, are able to exert an enhanced action in the treatment of irritable bowel syndrome (IBS) and related intestinal inflammatory diseases.

Background of the invention

Irritable Bowel Syndrome (IBS) is a symptomatic complex that includes abdominal pain and bowel irregularity, due to functional motor alterations of the colon.

The clinical classification and pathological definition of IBS, especially for research purposes, are based on the so-called "Rome Criteria" that have long been adopted by health authorities at an international level and reached their 4th edition in 2016 (Drossman, G.A., Functional Gastrointestinal Disorders: History, Pathophysiology, Clinical Features, and Rome IV, Gastroenterology 2016, 150:1262-1279). In clinical practice, the Rome criteria can be a guide, but they are not rigorously applied, so the term IBS refers to any symptom suggestive of intestinal disorders that is associated with changes in bowel habits, whether constipated (IBS-C), diarrhoeal (IBS-D) or mixed, i.e. with alternating constipation and diarrhoea (IBS-M).

According to the definition of the Rome criteria IV (2016), IBS is a variable combination of chronic or recurrent symptoms not explained by structural or biochemical abnormalities, related to disorders of the gut-brain axis (central and enteric nervous system). For the diagnosis, the criteria are as follows: abdominal pain recurring, on average, at least 1 day a week in the last three months, associated with two or more of the following criteria:

• related to defecation;

• associated with changes in the frequency of evacuations;

• associated with changes in the form/consistency of stool (classified according to a scale known as the “Bristol Scale”).

Immune activation also plays an important role in irritable bowel syndrome. The immune system located in the submucosa of the alimentary canal is the main immune system of the human body, and the activation of this impressive system, and the associated intestinal inflammation, appear to play a major role in the pathogenesis of IBS. This consideration is supported by various observations, such as the following:

1 ) up to 1/3 of patients with infectious gastroenteritis develop persistent digestive symptoms;

2) some subgroups of patients have increased numbers of immune cells in the intestinal mucosa;

3) inflammatory mediators can alter both intestinal motor activity and visceral sensitivity;

4) patients with chronic inflammatory bowel disease in remission or with microscopic colitis frequently present with IBS symptoms.

A fundamental role is played by mast cells and the mediators they release during the phases of inflammatory activation. In fact, a significant subgroup of patients with IBS has a greater number of mast cells in close anatomical correlation with the innervation of the colonic and ileal mucosa and submucosa. These mast cells, once activated, are able to release a wide range of mediators, including histamine, serotonin, prostaglandins, proteases, which can determine an increase in the excitability of both intrinsic enteric neurons and extrinsic afferent neurons, with consequent anomalies of gastrointestinal motor functions and visceral hypersensitivity. Of particular interest is the finding of the strong correlation detected between the number of mast cells activated in prox- imity to the nerve fibres present at the level of the colonic mucosa and the severity and frequency of abdominal pain in patients with IBS. This data is further evidence of the important role that mast cells play in the genesis of the symptoms complained of by patients with IBS.

An altered permeability of the intestinal barrier may contribute to the physiopathology of irritable bowel syndrome, playing a key role in the relationship between the host and the external environment. The intestinal barrier is, with its 200 m², the largest surface of the human body in contact with the outside and is made up of a mucous layer and the simple cylindrical palisade of enter- ocytes, joined together by intercellular junctional complexes, represented by the tight junctions (or zonulae occludentes), which play a central role in the regulation of paracellular permeability.

The tight junctions are transmembrane protein complexes that interact with the zonula occludens proteins which, in turn, bind to the actin of the cytoskeleton. The contraction of actin filaments determines the opening of the junctions with consequent increase in permeability to fluids, electrolytes and molecules deriving from the diet, or of bacterial origin. Under normal conditions, the intestinal barrier allows only relatively small quantities of antigenic molecules to cross the mucosa and interact with the immune system. Otherwise, an altered barrier function allows the passage of a greater quantity of antigens, capable of activating a real immune process that, by damaging the mucosa, further alters permeability. This can trigger a chronicization of intestinal inflammation.

Both in vitro and in vivo studies confirm that IBS patients have altered intestinal mucosal permeability, likely due to molecular alterations in junctional complexes, particularly “zonula occludens-V. This alteration is probably not only genetic, but also acquired, since intestinal infections, drugs, food allergies and even psychophysical stress can cause an increase in intestinal mucosal permeability. It has been found that the increase in intestinal permeability observed in IBS patients in the presence of food allergies is in turn related to the perceived severity of abdominal pain.

The choice of the drug therapy for IBS is based on the severity and type of symptoms presented by the patient. The therapy will be directed to the subtype of IBS considering the predominant symptom: pain, diarrhoea, constipation and presence or absence of abdominal swelling and distension.

For abdominal pain, antispasmodic drugs (or spasmolytics) have been widely used. These are divided into musculotropic agents, which act on the smooth muscles inducing their relaxation, and anticholinergic agents, which act by blocking the effects of a neurotransmitter, acetylcholine, at the neurovegeta- tive level. Their use is aimed at reducing the muscle tone of the abdominal wall or reducing the intestinal contractile response to intraluminal or extrinsic stimuli. Of these drugs, however, those that act with an anticholinergic mechanism (such as cimetropium bromide) would be less indicated, because they can worsen constipation and have unwanted systemic effects. Muscle-tropic antispasmodics, such as mebeverine, have proven to be more effective in improving abdominal pain, because they lack anticholinergic effects.

Antidepressants are also usefully used in patients with chronic continuous pain. In particular, tricyclic antidepressants modulate the perception of pain, independently of their psychotropic effect. The therapeutic effect is achieved with doses lower than those used in the treatment of depression and independently of the presence of depression. A possible adverse effect of tricyclic antidepressants, due to their anticholinergic action, is the slowing of intestinal transit.

Psychotherapy has also been used with some success in the treatment of abdominal pain, but it is not an easy treatment to take advantage of.

In the case of suspected IBS with diarrheal and/or mixed bowel habits, which is the case considered in the research that led to the present invention, it is recommended to first assess the presence of lactose intolerance, either from the anamnesis or by means of a breath test after taking lactose. After this preliminary investigation, in mild cases of IBS, faecal thickeners (diosmectite 3-6 g/day, kaolin 4-8 g/day) and probiotics are used, which have an anti-fermenta- tive and anti-inflammatory action in the intestinal ecosystem.

Furthermore, therapy with non-absorbable antibiotics has been shown to be effective in improving distension, abdominal pain and stool consistency. Such drugs also have a specific indication in cases of bacterial hyperproliferation of the small intestine, demonstrable by the hydrogen breath test after taking glucose or lactulose.

It has also been shown that mesalazine, a nonsteroidal anti-inflammatory drug, at a dosage of 800 mg three times a day, can reduce the number of mast cells and the degree of inflammation in the colonic mucosa. Therefore, this therapy has been proposed for all those cases in which it is conceivable that immune activation and mucosal inflammation play an important role in causing the symptoms of IBS. Mesalazine appears to be particularly indicated for patients with low-grade inflammation, evidenced by histobiopsy of the ileo-colo-rectal mucosa.

In recent years, a new drug has made its way into scientific research oriented to the treatment of forms of irritable bowel syndrome associated with diarrheal stool, eluxadoline. Patients with IBS with diarrhoea may, in fact, benefit from taking this drug with opioid effects, as demonstrated by a recent study published in the New England Journal of Medicine (Lembo A.J. et al., N. Engl. J. Med. 2016; 374:242-253). The authors tested the drug's efficacy on over 2,400 patients with IBS with diarrhoea, randomizing them to take eluxadoline or a placebo. After 26 weeks of treatment, the improvement in abdominal pain and stool consistency was greater with eluxadoline than in cases treated with the placebo.

Among the non-pharmacological but nutraceutical or food supplement treatments for IBS, butyrate-based supplementation, palmitoylethanolamide (PEA)-based supplementation and Chios mastic-based supplementation have attracted considerable interest.

Among the short-chain fatty acids produced by intestinal bacteria, butyric acid (or butanoic acid according to the IUPAC nomenclature, with the formula CH3CH2CH2COOH), is known to perform several beneficial functions in the gastrointestinal tract. The butyric anion, butyrate, is easily absorbed by enteric cells and used as a primary source of energy. In addition, butyric acid is an important regulator of colonocyte proliferation and apoptosis, intestinal tract motility and the composition of the relative microbiota, as well as being involved in immunoregulation processes and anti-inflammatory activity. (Hamer H.M. et aL, J. Aliment. Pharmacol. Ther. 2007, 27:104-1 19; Zaleski A. et aL, Prz. Gastroenterol. 2013; 8 (6): 350-353).

In light of this, butyric acid supplementation has been found to be useful in maintaining a healthy intestine, ensuring good functionality and protecting it from inflammation. In particular, it has been confirmed that butyric acid (butyrate) contributes to:

• performing an anti-inflammatory action on the intestinal wall, suppressing the activity of some proteins that trigger inflammation, as well as through the control of the immune response by regulating the activity of T lymphocytes;

• improving intestinal motility by modulating the absorption of ions (potassium, sodium and chlorine) and the consistency of stool;

• maintaining the protective mucus layer of the intestine and restoring the balance of the microbiota;

• improving insulin sensitivity and energy balance, and therefore also weight control;

• reducing the symptoms of intestinal permeability syndrome.

Several studies have indicated the beneficial anti-inflammatory effect of butyrate in the treatment of IBD (Inflammatory Bowel Disease, chronic inflammatory intestinal diseases) and IBS, through oral food supplements (Lewandowski K. et aL, Gastroenterology Rev. 2022; 17 (1 ) 28-34).

Generally, the microbiota of patients with IBS-C showed characteristics more similar to that of healthy subjects, while the microbiota of subjects with IBS-D and that of subjects with IBS-M were more similar to each other, differing more from the microbiota of healthy subjects. It is important to note that the microbiota of patients with IBS was found to have less biodiversity than that of healthy subjects, in particular associated with a lack of specific butyrate-produc- ing strains. This feature was found mostly in patients with IBS-D and IBS-M, demonstrating in these patients a clear deficiency of butyrate at intestinal level. (Pozuelo M. et al., Nature Scientific Reports 2015, 5:12693).

In the cited study, it was demonstrated that butyrate is essential in maintaining the integrity of the intestinal barrier, as this metabolite provides approximately 75% of the energy necessary for the survival of the colonocyte. Furthermore, it was highlighted that a lack of butyrate at the colonic level can worsen the clinical picture of diarrhoea, because its absence seems to reduce the absorption of both sodium and water at the intestinal level. The results of the study highlight the importance of adopting a specific bacterial strategy for the various subgroups of IBS, and suggest that a supplementation based on butyrate producers can be of great advantage in particular in patients with IBS-D.

Palmitoylethanolamide (PEA) is a substance of natural origin discovered in the 1950s, which gained notoriety thanks to the pioneering work of Rita Levi Montalcini, who in 1993 revealed its complex mechanism of action, paving the way for new therapeutic applications.

Chemically, PEA is a long-chain molecule of carbon atoms that combines a fatty acid, palmitic acid (or hexadecanoic acid, 16:0), one of the most common saturated fatty acids in both animals and plants, with an ethanolamine group, and has the following formula:

PEA is produced naturally by the body, being an endogenous molecule, although its synthesis decreases with age. Its name comes from the fact that it was first identified in palm oil, but it is also found in foods such as milk and dairy products, egg yolk, soybeans, peanuts and many others, although in small quantities. Chemically, palmitoylethanolamide belongs to the acylethanolamide family, like the endocannabinoid anandamide, a neuromodulator that mimics the effects of cannabinoids. It is now recognized that PEA is synthesized by immune and nervous cells implicated in chronic pain and inflammation communication pathways to maintain cellular homeostasis when this is disturbed by external stressors that cause inflammation, neuronal damage and pain (Skaper S.D. and Facci L., Philos. Trans. R. Soc. Lon. B. Biol. Sci. 2012, 367:3312- 3325). In fact, endogenous PEA levels increase in response to external stressors. However, in chronic conditions such levels may be inadequate to ensure homeostasis, and for this reason the possibility of supplementing exogenous PEA has been considered, which has shown analgesic and anti-inflammatory effects.

In fact, PEA regulates the activation of mast cells, cells present in the connective tissue, especially in the pelvic-abdominal region, which are activated in case of inflammation, and is able to interact physiologically with the body's cannabinoid receptors.

Furthermore, numerous studies have shown that the administration of PEA in a condition of induced colitis significantly lowers the intestinal inflammation marker monitored to evaluate the disease, bringing it back to values similar to the control. Further literature has also shown that the role of promoting intestinal health that PEA is able to play is not limited to the anti-inflammatory and analgesic effect. Very interestingly, PEA has also been shown to be able to improve the situation of increased intestinal permeability due to induced colitis (Borrelli F. et al., Br. J. Pharmacol. 2015, 172:142-158).

With reference to the two food supplements butyrate and PEA, the published international patent application W02022/024057 (in the name of Unifarco S.p.A.) proposes the use of a combination of the two mentioned compounds for the treatment and prevention of inflammatory disorders and diseases of the intestinal tract, such as IBD and IBS. As described in the document, sodium butyrate and palmitoylethanolamide can be used together, the first in daily dosages between 400 and 3000 mg (preferably 900 mg) and the second in daily dosages between 200 and 1200 mg (preferably 300 mg), in oral dosage forms, both in two separate formulations and in a single formulation, with the condition that the butyrate:PEA weight ratio is between 2:1 and 6:1 . According to the document, this combination allows to reduce the healing time compared to the administration of the single active ingredients sodium butyrate and PEA.

Chios mastic, (CMG) produced by the plant Pistacia lentiscus var. chia, has been used for more than 2500 years in traditional Greek medicine for the treatment of numerous diseases, thanks to the anti-inflammatory and antioxidant properties of its components. In particular, Chios mastic has long been attributed the ability to mitigate the symptoms of gastritis and gastroesophageal reflux (Dimas K.S. et aL, In Vivo 2012, 26:777-786).

There is a large emerging body of evidence supporting the anti-inflammatory activity of Chios mastic in animal model studies. The anti-inflammatory action appears to be exerted through the inhibition of the production of pro- inflammatory substances. In particular, the administration of solid and liquid types of mastic appears to inhibit the secretion of prostaglandins along with the inducible expression of nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 by macrophages, both at the protein and mRNA levels, in experimental animal models. (Boutemine, I.M., et al., Inflammopharmacol. 2021 , 29:1225- 1239; Gharazi P. et al., Res. J. Pharmacogn. 2021 , 8:37-49). At the intestinal level, literature data obtained in animal models show that CMG reduces proin- flammatory cytokines such as IL-6 and TNF-a, and increases the levels of in- terleukin-a17A, which is considered a key protective factor in the development and recurrence of IBD.

In addition, data from human studies point in the same direction. In 2019, a team of Italian researchers identified the possible beneficial mechanisms of the plant in a preparation of human cells by using a model of gastric mucosa. The model was put in contact with an extract of increasing doses of Chios mastic, maintaining everything in an incubator at 37°C and finding that the levels of the main primary inflammatory cytokines, such as IL-1 a, IL-6 and TNF-a were significantly reduced. Furthermore, Chios mastic was also able to act on the biological permeability of the epithelial lining of the gastric mucosa, thus limiting its access to any chemical or bacterial agents. (Zorzan M, et aL, J. Functional Foods 2019, 54:92-7).

In a 2007 pilot clinical study (Kaliora A.C. et aL, World J. Gastroenterol. 2007, 13:748-753) involving 10 patients with mild to moderately active Crohn's disease recruited for treatment with Chios mastic for 4 weeks (2.2 g/day), the following results were obtained. A significant decrease in the disease activity index, assessed by the reduction of plasma interleukin-6 levels and CRP levels compared to baseline, was observed, while no significant side effects were reported. In the same patient cohort, a significant reduction in TNF-a secretion was subsequently reported following mastic treatment, suggesting an additional inhibitory mechanism of monocyte chemotaxis, and thus providing further support for the role of Chios mastic as a regulator of the immune system.

Based on the results of that pilot study, in 2019 Papada and colleagues (Papada E. et al., Phytother. Res. 2019, 33(2): 360-369) designed and performed a randomized controlled trial to further evaluate the impact of Chios mastic on patients with inflammatory bowel disease. A total of 60 patients were randomly assigned to receive Chios mastic (2.8 g/day) or placebo for 3 months, in addition to standard medications. Patients treated with Chios mastic had a significant decrease in faecal lysozyme compared to patients treated with placebo, which is indicative of lower disease activity. In addition, there was a significant improvement in the Inflammatory Bowel Disease Questionnaire scores, reflecting a beneficial effect on patients' quality of life, in the Chios mastic arm compared to baseline (Papada E. et al., Nutrients 2018, 10: 1779).

When the same protocol was applied (Papada E. et al., Phytomedicine 2019, 56: 40-47) to 68 patients with inactive IBD for 6 months, patients assigned to the Chios mastic group as an add-on to standard drug, unlike the controls, did not show any increase in interleukin-6 or the faecal biomarkers calprotectin and lactoferrin. The latter are neutrophil-derived proteins whose concentrations typically increase in patients with gastrointestinal mucosal inflammation. Furthermore, the study also highlighted that oral administration of Chios mastic can reduce the level of free amino acids in plasma, a surrogate of inflammation and cellular homeostasis, and may play a key role in the pathways that regulate intestinal health.

Based on these data it has been stated, with reference to IBD, that Chios mastic can be used as a supplement to reduce disease activity, improve nutritional status and maintain clinical remission in patients with this syndrome (Ot- tria R. et al., Int. J. Mol. Sei. 2023, 24: 12038).

In light of the above, the object of the present invention is to provide a pharmaceutical, nutraceutical or food supplement preparation that can be administered orally as a replacement for or in addition to current pharmacological therapies for IBS, and in general for intestinal inflammatory diseases such as IBD, which shows improved efficacy compared to prior art products, and at the same time allows for a reduction in the dosages to be administered to the patient.

Summary of the invention

As noted above, the available literature data on the three active ingredients, butyric acid, PEA and Chios mastic in the gastroenterological field refer to studies carried out mostly on the single molecule, with rare exceptions, such as that represented by the international patent application W02022/024057, already discussed.

In general, the daily dose of sodium butyrate used in clinical studies varies depending on the application, from 300 mg to 4000 mg. In particular, for intestinal well-being a daily dosage of at least 600 mg, up to 1500 mg, is recommended.

The daily dose of palmitoylethanolamide used in clinical studies to control pain varies from 300 mg to 1200 mg, 600 mg/day being the daily dose most commonly found in studies.

As already noted, document W02022/024057, which proposes a combination of these two agents for the treatment of inflammatory diseases of the intestinal tract, describes preferred daily dosages of 900 mg for butyrate and 300 mg for PEA.

On the other hand, with regard to Chios mastic, the daily dose of Chios mastic used in clinical studies for the treatment of IBD ranges from 2200 mg to 2800 mg.

It has now been found, according to the present invention, that the oral administration of Chios mastic in combination with PEA and butyrate results in a notable and well-documented synergistic effect, which is reflected in a surprising increase in efficacy of the three active ingredients when combined together. The synergistic effect observed between the three agents when they are administered together, which is not simply additive, allows to significantly reduce the doses of each active ingredient compared to the doses commonly used in products containing only one, or even two, of the individual active agents. Some of the experiments conducted in this regard are reported below.

According to the present invention, synergistic combinations of butyric acid (generally in the form a salt or ester thereof), palmitoylethanolamide (PEA) and Chios mastic (CMG) are proposed, wherein the daily dosage of each of said active ingredients is not more than 500 mg, for use in the treatment of irritable bowel syndrome (IBS) and, in general, of chronic intestinal diseases with an inflammatory basis. The latter may be colonopathies related to an altered trophism of the intestinal mucosa, Crohn's disease and chronic inflammatory intestinal diseases (IBD).

According to the invention, the weight ratio of butyric acid, PEA and Chios mastic is (1 -3):(1 -3):(1 -3), it being understood that the amount by weight of each of the ingredients in the formulation may be from 1 to 3 times the amount by weight of each of the others.

Brief description of the drawings

The specific features of the invention, as well as its advantages, will become more evident with reference to the following detailed description, as well as to the experimental work on patients with IBS reported below and summarized in Table 1 below. The experimental results are also reported in the relevant drawings, wherein:

Figure 1 shows in histogram form the comparison between the therapeutic efficacy of each of the individual butyrate agents, PEA and CMG and that of the combination of the three compounds according to the invention, taking into account the intensity of abdominal pain;

Figure 2 shows in histogram form the results of the same clinical trial, taking into account the frequency of abdominal pain episodes;

Figure 3 shows in histogram form the results of the same clinical trial, taking into account flatulence problems;

Figure 4 shows in histogram form the results of the same clinical trial, taking into account diarrhoea episodes;

Figure 5 shows in histogram form the results of the same clinical trial, taking into account the episodes of urgent stool pressure;

Figure 6 shows in histogram form the results of the same clinical trial, taking into account the episodes of nausea;

Figure 7 shows in histogram form the results of the same clinical trial, taking into account the episodes of vomiting; and

Figure 8 shows, again in histogram form, the results of the same clinical trial, taking into account the general score in the VAS scale for measuring pain (visual analogue scale).

Detail description of the invention

The present invention therefore specifically concerns oral pharmaceutical or nutraceutical compositions for use in the treatment of irritable bowel syndrome (IBS) and in general of chronic inflammatory bowel diseases (IBD) comprising, as active ingredients: butyric acid or a pharmaceutically acceptable salt or ester thereof which is a source of butyric acid in vivo, palmitoylethanolamide or PEA, and

Chios mastic, wherein the weight ratio butyric acid:PEA:Chios mastic is equal to (1 -3):(1 -3):(1 - 3) and the daily dosage of each of said active ingredients is between 100 mg and 500 mg.

According to some preferred embodiments of the invention, the three active ingredients mentioned are the only active ingredients of the composition, the remainder consisting of excipients.

As already noted, butyric acid in the composition exerts an anti-inflammatory action on the intestinal wall, suppressing the activity of some proteins that trigger inflammation. In addition, it controls the immune response, regulating the activity of T lymphocytes, and promotes intestinal motility, modulating the absorption of ions (potassium, sodium and chlorine) and the consistency of the stool. Finally, the action of butyric acid reduces intestinal permeability, with consequent reduction in the access of harmful non-self substances and microorganisms.

In turn, palmitoylethanolamide (PEA) limits the inflammatory state (reactivity of the immune system) and nociception, with consequent modulation of the inflammatory factors that contribute to the alteration of the barrier.

The action of these two active ingredients is added to that of Chios mastic, which determines a reduction in pro-inflammatory cytokines such as IL-6 and TNF-a and an increase in the levels of interleukin-a17A, which is considered a key protective factor in the development and recurrence of IBD.

Actually, what distinguishes the formulations of the present invention is the marked synergistic effect of the three agents when administered in combination with each other, which allows to obtain an unexpectedly improved therapeutic effect in terms of relief from abdominal pain, reduction of symptoms of diarrhoea and flatulence, and all the other typical inconveniences of irritable bowel syndrome.

In the formulation of the invention, the salt or ester that is a source of butyric acid in vivo is preferably sodium or calcium butyrate, but it is also possible to provide in the composition other sources of butyrate, such as for example methylbutyrate and ethylbutyrate.

According to some preferred embodiments, the compositions are particularly indicated for the treatment of IBS, and each dosage unit of the composition of the invention comprises the following quantities of active ingredients: sodium butyrate from 150 mg to 300 mg, PEA from 150 mg to 300 mg, and Chios mastic from 100 mg to 200 mg, the daily dosage being from 1 to 3 dosage units. For better bioavailability of the active ingredients, it is preferred to divide the daily dose into 3 dosage units, to be distributed throughout the day.

The compositions according to the invention can be used for the production of a pharmaceutical, nutraceutical or food supplement preparation, or of a food intended for special medical purposes. In particular, said dosage units can be tablets, hard or soft capsules, sachets, pellets, lozenges, chewing gum or cachets.

In addition to the active ingredients, oral dosage units may include the usual excipients known in the pharmaceutical art, such as bulking agents and diluents, anti-caking agents, binders, lubricants (including anti-adherents and glidants), adsorbents, antioxidants, sweeteners, and the like. Such excipients are chosen and dosed also in relation to the type of dosage form envisaged and the methods of administration.

In particular, dosage units may be gastro-resistant coated capsules or tablets, preferably coated with Eudragit® film, which allows colon-specific gas- troprotection.

According to some further preferred embodiments, the present invention relates to oral pharmaceutical or nutraceutical compositions for use in the treatment of IBS, wherein the dosage units are gastro-resistant tablets containing as active ingredients from 150 mg to 200 mg of sodium butyrate, from 150 to 200 mg of PEA and from 100 to 150 mg of Chios mastic, and the daily dosage is 3 tablets distributed throughout the day. In a further preferred manner, said gastro-resistant tablets contain 150 mg of sodium butyrate, 150 mg of PEA and 100 mg of Chios mastic, the remainder consisting of excipients.

EXAMPLES

Some specific embodiments of the formulations for the treatment of IBS according to the invention are described below by way of example but not of limitation, together with the results of the clinical trials carried out.

EXAMPLE 1

Preparation with PEA, sodium butyrate and Chios mastic in a 1 :1 :1 ratio

The formulation was as follows:

The procedure for preparing tablets from the above listed ingredients was as follows.

In a container of appropriate size, the colloidal anhydrous silica was weighed, and the powder was placed into a mill, activating it at a high speed until a fine powder without visible granules was obtained. Then the three active ingredients Chios mastic, PEA and sodium butyrate, were weighed and added to the mill with the anhydrous silica. Subsequently, the previously weighed dibasic calcium phosphate and microcrystalline cellulose were added to the mill and mixed for 10 minutes at a speed of 20 rpm. Finally, talc, magnesium stearate and hydrogenated castor oil were weighed and added to the mixture previously obtained and mixed for 1 minute at a speed of 20 rpm.

The homogeneously mixed powder obtained from the previous operations was placed into the hopper of a rotary tablet press, and after having checked and, if necessary, calibrated the machine again, production is carried out until the mixture is used up. During the production phase, samples were taken to verify the homogeneity of the product.

EXAMPLE 2

Preparation with PEA, sodium butyrate and Chios mastic in a 1 ,5:1 :1 ratio

The formulation was as follows:

The procedure for preparing the tablets from the above ingredients was the same as in Example 1 .

EXAMPLE 3 Preparation with PEA, sodium butyrate and Chios mastic in a 2:1 :1 ratio

The formulation was as follows:

EXAMPLE 4 Preparation with PEA, sodium butyrate and Chios mastic in a 3:1 :1 ratio

The formulation was as follows:

EXAMPLE 5

Preparation with PEA, sodium butyrate and Chios mastic in a 1 :1, 5:1 ratio

The formulation was as follows:

EXAMPLE 6

Preparation with PEA, sodium butyrate and Chios mastic in a 1 :2:1 ratio The formulation was as follows:

EXAMPLE 7 Preparation with PEA, sodium butyrate and Chios mastic in a 1 :3:1 ratio

The formulation was as follows:

EXAMPLE 8 Preparation with PEA, sodium butyrate and Chios mastic in a 1 :1 :1 ,5 ratio

The formulation was as follows:

The procedure for preparing the tablets from the above ingredients was the same as in Example 1 . EXAMPLE 9

Preparation with PEA, sodium butyrate and Chios mastic in a 1 :1 :2 ratio

The formulation was as follows:

EXAMPLE 10 Preparation with PEA, sodium butyrate and Chios mastic in a 1 :1 :3 ratio

The formulation was as follows:

Again, the procedure for preparing the tablets from the above ingredients was the same as in Example 1 .

Evaluation of the synergistic effect in IBS of the addition of Chios mastic in the formulation butyrate-PEA

Five groups of 20 young adult patients, both male and female, with diarrhoea-variant IBS, with a proven diagnosis and in therapeutic wash-out for at least 6 weeks were created as follows:

- Group 1 : sodium butyrate: administration of 1 g enteric-coated tablets containing 450 mg of sodium butyrate 3 times a day for 12 weeks;

- Group 2: PEA: administration of 1 g enteric-coated tablets containing 450 mg of PEA 3 times a day for 12 weeks;

- Group 3: CMG: administration of 1 g enteric-coated tablets containing 450 mg of CMG 3 times a day for 12 weeks;

- Group 4: PEA - butyrate: administration of 1 g enteric-coated tablets containing 225 mg of sodium butyrate and 225 mg of PEA (weight ratio butyr- ate:PEA 1 :1 ) 3 times a day for 12 weeks;

- Group 5: PEA - butyrate - CMG: administration of 1 g enteric-coated tablets containing 150 mg of sodium butyrate, 150 mg of PEA and 150 mg of CMG (weight ratio butyrate:PEA:CMG 1 :1 :1 ) 3 times a day for 12 weeks. Each group presented stable symptoms, with moderate-severe abdominal pain >4 on the VAS scale for measuring pain (visual analogue scale).; Scott, J., Huskisson, E.C. Graphic representation of pain, Pain 1976, 2(2):175- 184). The SF-36 scale was also used to evaluate the patients’ condition. (Short

5 Form Health Survey; ApoIone G., Mosconi P. The Italian SF-36 health survey: translation, validation and norming, J. Clin. Epidemiol. 1998, 51 : 1 1 , 1025- 1036).

The program for all five groups was as follows

• Baseline assessment with VAS and SF-36;

10 • Treatment for 12 weeks;

• Re-evaluation at 12 weeks with VAS and SF-36;

• Rescue therapy: antispasmodic, loperamide.

The results of the above tests are reported in the following table.

TABLE 1 The results shown in Table 1 are also shown individually in the form of a histogram for each symptom in the attached Figures 1-7, while Figure 8 shows the overall results of the VAS evaluations. These results demonstrate that the synergistic effect between the three components used for the formulation is clearly evident in the treatment of the pathology considered.

Compared to the baseline severity score of the individual symptoms, the components administered separately are already able to determine a reduction in the score. Furthermore, the positive effect of reducing the severity score of the symptoms is already evident by combining the first two components of the formulation according to the invention: the administration of butyric acid and PEA determines a reduction in the severity of the symptoms of a greater entity than what would be expected with the use of the individual active ingredients.

In fact, the combination of butyric acid and PEA, tested in the patients of group 4, would already seem to develop a synergy at intestinal level between the active ingredients, which in fact exert a complementary effect. This effect, however, is still considerably lower than that obtained with the combination of the three components according to the invention, with the addition of Chios mastic (patients in group 5).

The anti-inflammatory effect of butyric acid is based on the one hand on the blocking of the activity of some proteins with pro-inflammatory effects, but on the other also on the modulation of the immune response, in particular the response by T lymphocytes. This is coordinated with the anti-inflammatory effect of PEA which, by modulating inflammation, has a positive effect on the prevention of damage to the intestinal barrier and, therefore, of the consequent alteration of intestinal permeability. In fact, for both active ingredients a positive effect in the improvement of excessive intestinal permeability found in IBS had already been found.

As shown by the data presented in the table above, the combination with the third component, Chios mastic, which is active per se in reducing the activity of pro-inflammatory cytokines, adds a further effect that works in the same direction. This significantly influences the picture of reduction of the degree of activity of mucosal inflammation and the modulation of both the activity and the differentiation of T lymphocytes, still within the context of the mucosal immune response.

The combination of the three active ingredients shows, therefore, a sig- nificant and unpredictable synergy based on what is known about the three individual agents, and this synergy is able to determine an important therapeutic effect in patients with diarrhoea-variant irritable bowel syndrome, but probably also in patients with acute diarrhoea.

The present invention has been described with reference to some spe- cific embodiments thereof, but it is to be understood that variations or modifications may be made thereto by those skilled in the art without thereby departing from the scope of protection of the invention, as defined by the attached claims.

Claims

1. An oral pharmaceutical or nutraceutical composition for use in the treatment of irritable bowel syndrome (IBS), and in general of chronic intestinal inflammatory diseases (IBD), comprising, as active ingredients: butyric acid or a pharmaceutically acceptable salt or ester thereof which is a source of butyric acid in vivo, palmitoylethanolamide or PEA, and

2. The oral composition for use in the treatment of IBS and IBD according to claim 1 , wherein said active ingredients are the only active ingredients of the composition, the rest consisting of excipients.

3. The oral composition for use in the treatment of IBS and IBD according to claims 1 or 2, wherein said salt or ester which being a source of butyric acid in vivo is sodium or calcium butyrate.

4. The oral composition for use in the treatment of IBS according to claims 1 -3, wherein each dosage unit of the composition comprises the following active ingredients: from 150 mg to 300 mg of sodium butyrate, from 150 mg to 300 mg of PEA, and from 100 mg to 200 mg of Chios mastic and the daily dosage is from 1 to 3 dosage units, distributed throughout the day.

5. The oral composition for use in the treatment of IBS according to claim 4, wherein said daily dosage is 3 dosage units, distributed throughout the day.

6. The oral composition for use in the treatment of IBS according to any one of the preceding claims, wherein said dosage units are tablets, hard or soft capsules, sachets, pellets, lozenges, chewing gum or cachets.

7. The oral composition for use in the treatment of IBS according to claim 6, wherein said dosage units are gastro-resistant coated tablets.

8. The oral composition for use in the treatment of IBS according to any one of the preceding claims, wherein said dosage units are gastro-resistant tablets containing as active ingredients from 150 to 200 mg of sodium butyrate, from 150 to 200 mg of PEA and from 100 to 150 mg of Chios mastic, and the daily dosage is 3 tablets distributed throughout the day.

9. The oral composition for use in the treatment of IBS according to claim 8, wherein said gastro-resistant tablets contain 150 mg of sodium butyrate, 150 mg of PEA, and 100 mg of Chios mastic, the rest consisting of excipients.