MX2013002737A - Combinations with probiotics for restoring alterations in intestinal function. - Google Patents

Abstract

The invention relates to an oral pharmaceutical composition comprising a probiotic, specifically Lactobacillus acidophilus, combined with an active principle selected from among trimebutine, propinox, lansoprazole, cinitapride, ranitidine and famotidine. The invention also relates to the use thereof for the production of a drug intended for the treatment of functional intestinal disorders, such as irritable bowel syndrome As a first embodiment, the present invention refers to an oral pharmaceutical composition for restoring alterations in intestinal function, which comprises a therapeutically effective amount of an active principle for treating different functional intestinal disorders and a therapeutically effective amount of a probiotic along with pharmaceutically acceptable excipients and optionally a therapeutically effective amount of at least a nutraceutical. An additional embodiment of the present invention refers to the process for preparing an oral pharmaceutical composition that comprises granulating, mixing and compressing a therapeutically effective amount of the active principle for treating functional intestinal disorders and a therapeutically effective amount of a probiotic along with pharmaceutically acceptable excipients. In an additional embodiment, the invention describes the use of a therapeutically effective amount of an active principle for treating different functional intestinal disorders along with a therapeutically effective amount of a probiotic, for the manufacture of a drug for restoring alterations in intestinal functions.

Description

COMBINATIONS WITH PROBIOTICS TO RESTORE ALTERATIONS OF THE INTESTINAL FUNCTION Field of the Invention The present invention relates to an association of Probiotics (PBTs) with different active ingredients (trimebutine, cinitapride, propinox, lansoprazole, esomeprazole, dexlansoprazole, ranitidine, famotidine and cimetidine) in single doses, or with other fixed associations (propinox + lysine clonixinate ) to restore alterations of intestinal function. Accordingly, the present composition is ideal in the treatment of various gastrointestinal functional disorders and Irritable Bowel Syndrome (SIL) or Irritable Colon (Cl). All these drugs act by modulating the motor or secretory functions of the digestive tract.

The PBTs are live microorganisms, which in sufficient quantities, confer benefit to the health of the host (WHO), through different mechanisms of protection and defense at the gastrointestinal level and regulation of the motility of the digestive tract.

The intestinal tract is an extremely complex ecosystem and represents one of the largest organs in contact with the external environment. One of the functions of the intestinal bacteria residing in the intestine is to collaborate in the digestion and absorption of different nutrients. Another important function is to stimulate the maturation of the immune system and provide protection against the different commensals, potentially pathogens. When the delicate intestinal ecological balance is altered by exogenous or endogenous factors (psychological, physiopathological, etc.), they are predisposed to infectious and immuno-inflammatory processes. The role played by the exogenous aggregate of PBTs is very important to reestablish that delicate balance that exists throughout the digestive tract and its physiological functions.

In Functional Digestive Disorders (TDF) and Irritable Colon Syndrome (SCI), as defined in the criteria of ROMA III, there is no organic pathology that can justify the presence of the different signs and symptoms. The signs and symptoms that are included within these two entities predominate the alterations of the intestinal transit, changes in the evacuatory rhythm (diarrhea, constipation), pain, epigastric burning, early satiety, post-prandial fullness, dysphagia, etc. There is a group of drugs to treat these TDF and SCI; The addition of probiotics to these drugs confers a superior response to the gastrointestinal tract (Gl), improving the barrier functions, inhibiting the growth of pathogens and modulating the inflammatory response, reducing visceral hypersensitivity and stabilizing the bacterial flora (J. Clin. Gastroenterol, 2012; 46: S52-S55).

Probiotics regulate intestinal bacteria by increasing the number of beneficial anaerobic bacteria and decreasing the population of potentially pathogenic microorganisms. The PBTs act on the intestinal ecosystem stimulating the immune mechanisms of the mucosa and stimulating non-immune mechanisms through antagonism and competition with potential pathogens. It is thought that these phenomena mediate most of the beneficial effects, including reducing the incidence and severity of diarrhea, one of the most widely recognized uses of probiotics.

The administration of probiotics generates different protective and defensive mechanisms at the intestinal level in three levels, namely: • Modulation of the intestinal environment: - Compete with pathogens for intestinal light nutrients and prevent their adherence to the intestinal epithelium.

- Improve the intestinal barrier function.

- Modulate peristalsis and mucus secretion.

- They favor the development of a beneficial flora.

· Secretion of active Molecules: - Bacteriocins and other peptides that interfere in the metabolism of bacteria, parasites, fungi and pathogenic viruses.

- Free fatty acids, lactic acid that is not absorbed and acts in the intestinal lumen, etc.

• Modulation of immunity: - Increase in the production of IgA and IgM by the host.

- They favor the functions of intestinal dendritic cells in cellular immunity. This action is well recognized in Acidophilus Lactobacilli.

- Modulation of cytokine release (IL10, IL12, Tumor Necrosis Factor alpha, etc.).

Strains such as Lactobacillus and Bifidobacterium are useful in reducing the severity and duration of infectious diarrhea. In addition, the PBTs exert their antiparasitic effect by modifying the parasite cycle in the intestine, decreasing the amount and viability of the eggs and infesting forms and interfering with their metabolism [Travers MA et al, J. Parasitol. Res. Volume 2011, doi: 10.1155 / 2011/610769].

Detailed description of the invention The present invention relates to an oral pharmaceutical composition, which is used to restore alterations of intestinal function, comprising a therapeutically effective amount of an active ingredient for the treatment of various gastrointestinal functional disorders and a therapeutically effective amount of a probiotic together to pharmaceutically acceptable excipients and optionally, a therapeutically effective amount of at least one nutraceutical.

Said active ingredient is selected from trimebutine, cinitapride, propinox, lansoprazole, esomeprazole, dexlansoprazole, ranitidine, famotidine, cimetidine or propinox combined with lysine clonixinate.

The probiotic employed comprises at least one bacterial strain selected from the group of the following species: Bifidobacteria sp, Lactobacillus sp, Bacillus sp, Lactococci, Streptococci sp, Enterococci and Yeasts, this probiotic specifically comprising a bacterial strain selected from: Bifidobacterium breve or brevis, Bifidobacterium lactis, Bifidobacterium longum, Bifidobacterium animalis, Lactobacillus acidophilus, Lactobacillus Reuteri, Lactobacillus bulgaricus, Lactobacillus casei, Lactobacillus plantarum, Lactobacillus paracasei, Lactobacillus rhamnosus, Lactobacillus salivarius, Lactobacillus fermentum, Lactobacillus johnsonii, Lactobacillus helveticus, Lactobacillus delbrueckii, Bacillus subtilis, Bacillus clausii, Streptococcus thermophilus, Streptococcus faecium, Streptococcus faecalis, tecalis Enterococci, Bacillus coagulans, Propionibacterium freudenreichii and Sacaromyces Boulardi. This probiotic is in a range of 1 x 103 CFU to 1 x 1014 CFU per dosage unit. On the other hand, the nutraceutical used is selected from a prebiotic, a vitamin or a mineral.

A further object of the present invention relates to the process for preparing an oral pharmaceutical composition comprising granulating, mixing and compressing a therapeutically effective amount of the active ingredient for the treatment of the various gastrointestinal functional disorders and a therapeutically effective amount of a Probiotic together with pharmaceutically acceptable excipients.

Finally, the present invention describes the use of a therapeutically effective amount of an active ingredient for the treatment of the various gastrointestinal functional disorders in combination with a therapeutically effective amount of a probiotic, for the manufacture of a medicament for restoring altered intestinal functions.

The composition described in the present invention is presented with different administration forms, said forms preferably being capsules, tablets, powders, sachets or microgranules for oral administration.

As can be seen in the embodiments, the presence of probiotics in the therapeutic formulation produces a positive influence at the level of restoring the balance of the intestinal flora thus improving the clinical / histopathological parameters observed.

The addition of probiotics to trimebutine confers a superior response to the Gl apparatus improving barrier functions, inhibiting the growth of pathogens and modulating the inflammatory response, reducing visceral hypersensitivity and stabilizing the bacterial flora comparing with the cases where the treatment was performed with trimebutine as monodroga.

In the example N ° 2 the observed results suggest that the intestinal microflora would play an important role in the visceral perception to the pain provoked by the abdominal distension.

This study was able to determine the effect of probiotics on intestinal flora and this on autonomic functions and visceral perception in experimental animals.

These dafos provide some kind of support in the evidence of the effect of probiotics in visceral pain and provide new mechanisms of action of probiotics in the treatment of different functional pathologies where visceral distension and abdominal pain predominate as symptomatic symptoms.

In example No. 3, the results clearly show, both clinically and histopathologically, that the addition of probiotics to the induction test of gastritis caused by indomethacin exerts a mild gastroprotective effect on the gastric mucosa, but when combined with a The usual pharmacological treatment, as in the case of the use of proton pump inhibitors such as lansoprazole, has a remarkable synergic effect, observing a significant decrease, both in the clinical symptoms and in the appearance of ulcers and gastritis histology, these being of milder degrees than observed in the rest of the active treatment groups.

This gastroprotective effect that can be added by probiotics would be given by the increase in the production of prostaglandins I and E (inhibited by the addition of indomethacin) by probiotics, which would act as a defense mechanism with protective effect of the gastric mucosa.

Exemplary embodiments Example No. 1 Live Test It was proposed to carry out in vivo tests on animals to evaluate the efficacy and therapeutic response of the association of different drugs for the treatment of TDF and SCI associated with probiotics.

Introduction Stress situations can influence dysfunctions that involve functional alterations at the intestinal level. TMBT, a drug used as a modulator of intestinal motility, and PBTs, microorganisms with the characteristics of conferring a microbial balance at this same level, play an important role in the restoration of altered intestinal functions. Experimental studies have documented intestinal pathophysiological alterations in responses to acute and chronic stress. Particularly, stress induced changes in rats that included increased gastrointestinal secretions, altered colonic motility, increased epithelial permeability, alterations or mitochondrial epithelial damage, alteration in the epithelium / bacteria interaction and increased inflammatory infiltrate. Although the mechanism of stress in causing such alterations is unknown, it is believed that there would be significant epithelial dysfunction.

Given the alteration of the mucosal barrier that occurs before different stress stimuli, it was decided to evaluate the clinical / histopathological improvement of the association of TMBT + PBTs to reduce or prevent the epithelial changes caused by stress. For this purpose, we developed an animal model of psychopathological stress mice based on the Water Avoidance Stress Model (WA) in mice. This model has the peculiarity that, to the exposed animals, it produces a drastic change of the intestinal epithelial barrier function, altering the host immunity and produces important inflammatory effects at the level of the jejunum, ileum and colon.

Here we investigated the presence of different intestinal signs / symptoms that occur under simulated stress situations in mice, before an active treatment of the association of TMBT alone and of TMBT with PBTs. and the histological changes observed in the 3 groups (control and active treatments).

For a first experience it was decided to combine the active ingredient Trimebutine (TMBT) with PBTs (Lactobacillus) to be administered orally in laboratory animals (mice).

The objective of this experiment is to evaluate the behavior of the association of TMBT + PBTs in an animal model of induced stress, similar to the symptoms related to the SCI, in order to evaluate the response to treatment of visceral hypersensitivity caused by stress. . The signs to be evaluated were the following: a) Signs of pain b) Diarrhea *: time to the beginning (days) of the first episode and frequency (number of average bowel movements on days 7, 15 and 20) c) Abdominal distension d) Histological changes of the intestinal mucosa * "Diarrhea" is defined (according to WHO) and deposition, three or more times a day (or more frequently) of loose (semi-liquid) or liquid stools.

Materials and methods Animals For this experiment, 30 mice of the Sprague-Dawley strain were used, which were selected, conditioned and divided into 3 groups of 10 animals each: 1) Control; 2) treated with TMBT for 20 days and 3) treated with TMBT + PBTs. for 20 days.

The last day of the experience (day 21), the animals were sacrificed by means of cervical dislocation. In turn, each group was divided into 2 subgroups (A and B) of 5 animals each to work in 2 series per group of trials (Table 1).

TABLE 1: Number of Mice Divided by Treatment Groups Stress Protocol The mice were conditioned, weighed, fed ad libitum and kept in a non-stress environment, separated into watertight compartments by treatment groups with a light-dark cycle of 12-12 hours for 4 days before the study procedures.

To facilitate the processes of experimentation, subgroup A and then subgroup B of animals are studied first.

The procedures are described as follows: The animals were placed on a 3 x 6 cm platform in the center of a 56 x 50 cm container containing 5 cm of water: The animals were subjected to this water aversion stimulus for a period of 1 hour per day for 15 days (Stress due to Water Avoidance).

- Once the stress experience was over, they were returned to their original cages, where they were kept in a basal state, as described above, where the different signs and symptoms of visceral hypersensitivity (signs of pain, abdominal distension) were evaluated. , diarrhea.) The stress stimulation procedure was performed for 15 days, leaving the last 5 days to all the study groups, in a basal state of no stress until completing the 20 days of experimentation.

The animals selected for the active treatment groups were treated with TMBT + PBTs from the first day of the experiment until the last (day 20). The control group never received any treatment during the whole experiment.

- Once the experiment was concluded, the next day (day 21) all the animals were sacrificed for the histopathological evaluation of the intestine.

- The animals were evaluated clinically in the different symptoms (signs of pain, diarrhea, abdominal distension) on day 7, 15 and 20.

- - In summary, the schedule of activities was as follows: Day 1 to 15: Subjection to Stress for Avoidance of Water for one hour a day. Start of treatment for active groups.

Days 7, 15 and 20: Evaluation of the different signs / symptoms: Signs of Pain; Diarrhea (number of bowel movements; Time to start the first episode of diarrhea); Abdominal distension.

Days 1 to 20: Treatments with TMBT and TMBT + PBTs for the active Groups and without treatment for the Control Group.

Day 21: Sacrifice of the animals and histopathological evaluation of the intestine.

Study Drugs The doses and compositions used were the following: - TMBT: 1, 5 mg, 2 times per day. Total dose: 3 mg per day orally.

- PBTs: 107 CFU, twice a day orally.

The active ingredients were given by oral route dissolved in 10 mL of drinking water, 2 times per day next to the main meals of the day (lunch and dinner), for 10 consecutive days.

Results of the experience The results obtained during the experimentation were divided based on the signs / symptoms that were evaluated during it, namely: 1) Signs of Pain: during the experiment an evaluation of the animals was made during the 24 h. It was decided to record the different signs of pain on days 7, 15, and 20. The points to be evaluated were the following: behavioral changes, alteration in feeding and behavior, aggressiveness, self-mutilation or damage, signs of protection, etc.

The findings observed were those described in table 2.

Table 2: Percentage of animals with Signs of Pain In Table 2 it can be seen that on day 15, 95% of the Control Group animals showed some sign of pain; in the Group treated with TMBT 60% of the animals and in the Group of the association with PBTs, half of them. On day 20, after 5 days of rest, a significant decrease in pain symptoms was noted in the group of animals treated with the TMBT + PBTs association (15%), where still 40% of the animals of the group treated with TMBT had some sign of pain. 2) Diarrhea: To evaluate the diarrhea 2 parameters were taken, namely: a) Time to start: at this point it was decided to arbitrarily take the appearance of diarrhea in the first 2 animals of each group and record the day of appearance. b) Number of average depositions on days 7, 15 and 20.

The data obtained are detailed in tables 3 and 4.

Table 3: Time until the onset of diarrhea.

In Table 3 it can be observed that, in the group treated with the association, there was a delay in the appearance of diarrhea in the first 2 animals. This could be explained by the presence of PBTs in the formulation that gives the intestine a balance in the microbial flora and thus delay the first diarrheal symptoms.

Table 4: Average number of stools.

In Table 4 it can be seen that the control group presented an average of 6.4 stools per day 15. On that same day, the group treated with the association presented almost half the number of stools, 3,4. On day 20 a total normalization was observed in the average number of stools in the Group treated with TMBT + PBTs, 1 deposition. This could be due to the fact that the intake of PBTs during 20 days has stabilized both the intestinal transit and the balance of the bacterial microflora. 3) Abdominal Distension: A very characteristic sign of these stress procedures is that of the appearance of abdominal distension, the same as occurs in Irritable Bowel Syndrome in humans.

Table 5 describes the findings with respect to what was observed with abdominal distension in the 3 treatment groups.

Table 5. Percentage of animals that showed abdominal distension.

As can be seen in Table 5, the presence of PBTs in the formulation with TMBT caused the presence of abdominal distension to be significantly reduced. On day 20, 70% of the animals presented abdominal distension, while the group treated with the association was 30%. This could be because the PBTs of the formulation and after 20 days of treatment, would lead to a balanced balance of the intestinal flora, thus decreasing the visceral sensitivity. 4) Histological changes of the intestinal mucosa: in order to make a clinical-histopathological correlation that could explain the different clinical signs / symptoms and see the different inflammatory responses of the intestinal mucosa to the different treatments in a situation of induced stress, it was decided to evaluate the intestinal mucosa of all the animals that participated in the experience. The two parameters to be evaluated were A) vellocytic morphological changes and B) presence of inflammatory cells in the lamina propria. In order to evaluate these histological changes, histological samples were taken from a 5 cm portion of the intestine of each animal. This was carried out on the 21st day of the study (sacrifice of the animal). The histological samples were fixed in a 10% formaldehyde solution, processed and fixed in a paraffin plug, and then stained with hematoxylin and eosin in order to be seen under an optical microscope by an observer "blind" to the experimentation, which did not He knows in which group the animals were.

Table 6 shows the findings in the histological changes of the intestinal mucosa, by treatment group (including control).

Table 6: Histological changes of the intestinal mucosa.

What the histological changes in the colonic mucosa show is the presence of a scarce amount of inflammatory cells in the lamina propria (1 cell per 50X field) in the mice treated with the association with PBTs. Another finding is the presence of a small amount of polymorphonuclear cells in the control group, suggesting acute inflammatory changes in the intestinal mucosa. All these mild inflammatory findings in the animals treated with the TMBT + PBTs association suggest that PBTs would play a predominant role in intestinal immune control.

Conclusions Based on the clinical findings obtained during the experimentation, it was observed that the animal groups responded better to the treatment of the association of TMBT + PBTs than to the group treated with TMBT alone. This was reflected in all the parameters evaluated: signs of pain, diarrhea and abdominal distension.

The presence of PBTs in the therapeutic formulation has a positive influence on the level of restoration of the intestinal flora balance, thus improving the clinical / histopathological parameters observed.

The addition of PBTs to the TMBT, would confer a superior response to the Gl apparatus improving the barrier functions, inhibit the growth of pathogens and modulate the inflammatory response, reduce visceral hypersensitivity and stabilize the bacterial flora that in the cases where the treatment was performed with the TMBT as monodroga.

Example No. 2 Introduction In cases of intestinal spasm, the most characteristic symptom is pain. Spasm is defined as involuntary, exaggerated and persistent contraction of the smooth muscle, both in the digestive system and in other organs and systems. Another cause of frequent spasm is intestinal distention, which would also cause contraction of the smooth muscle with the consequent appearance of pain.

The antispasmodic drugs act at the level of the muscarinic receptors of the smooth visceral musculature causing relaxation of the same, with the consequent decrease in pain. An example of drugs that act at this level is Propinox (PPNX). In addition, PPNX is associated with non-steroidal anti-inflammatory drugs (NSAIDs) as an analgesic effect in the treatment to mitigate the pain caused by the spasm of the intestinal smooth muscle. An example of this association is PPNX with Clonixinate of Usina (CLL).

In the case of PBTs it was observed that they could induce some type of analgesic effect in the intestine through the expression of intestinal receptors of u-opioids and cannabinoids.

Taking into account the mechanisms of action, both antispasmodic drugs and NSAIDs, and the analgesic effect described above PBTs, we proceeded to evaluate the analgesic effects of the active ingredients associated with PBTs, to see if there was a synergistic effect when adding the PBTs to the formulations.

The objective of this experiment is to evaluate the behavior of the association of PPNX + PBTs and the association of PPNX + CLL + PBTs in the signs of pain that cause spasms of the colonic musculature.

In order to determine the analgesic effect of the associations of active principles with PBTs versus the stimulation of the visceral pain provoked, it was decided to carry out a validated technique of "Colorectal Distension" (DC) in mice. This test consists of the placement of a 5 cm long latex balloon, connected to a sphygmomanometer, which is introduced into the descending and rectum colon of the animals. The DC is induced by blowing air through said walloon for 60 seconds, which after that time is removed so that the animal remains in a basal state. The pressures used to start the nociceptive responses by DC are 40 mmHg. This increase in pressure in the intestinal lumen is sufficient for the triggering of contractions of the abdominal muscles. In this test, the 80 mmHg of intraluminal pressure was not exceeded to avoid tissue damage. The different postures defined as behaviors related to pain were the following (from lowest to highest intensity of pain): a) Lick the abdomen b) Stretching the abdomen c) Press the abdomen against the floor d) Abdominal retraction e) Other pain symptoms not categorized (for example: self-mutilation, self-inflicted bodily harm, aggression).

All of these pain symptoms were recorded in the first 5 hours after the DC test with the balloon.

Pain signs were evaluated under the following conditions: Inject the balloon to 30 mmHg for 60 seconds, deflate the balloon and observe and record the behavior of the animal (pain signs) at baseline for 10 minutes. Then, this same procedure was continued by insufflating the balloon to 40, 50 and 70 mmHg.

This test of abdominal distension was carried out on day 1 of the experiment and on day 15.

Materials and methods.

In order to carry out the experimentation of the different associations of PBTs + PPNX and PBTs + PPNX + CLL, it was decided to divide it into 2 treatment tests, namely: 1) Example 2 A: Propinox + PBTs and 2) Example 2 B: Propinox + Lysine Clonixinate + PBTs. 1) Example 2 A: Propinox + PBTs.

Animals: Twenty adult mice of the Sprague-Dawley breed obtained from a bioterium were used, with a weight that ranged between 348 and 483 grams that were kept in individual cages with basal conditions of humidity and ambient temperature, with a circadian light-dark cycle of 12 hours each, with permanent availability of water and food ad libitum. This is called "basal state" The 20 animals were divided, in equal parts, into 4 treatment groups of 5 animals each, namely: a) Control Group. b) Group treated with PPNX. c) Group treated with PBTs. d) Group treated with PPNX + PBTs Study drugs: The doses and compositions used were the following: PPNX: 0.15 mg, twice a day, orally, with the main meals (lunch and dinner) dissolved in 2 mL of water. Total daily dose: 0.30 mg.

- PBTs: 107 CFU, twice a day orally with the main meals (lunch and dinner) dissolved in water.

- PPNX + PBTs: 0.15 mg of PPNX + 107 CFU of PBTs twice a day dissolved in 2 mL of water, orally, with the main meals (lunch and dinner).

The duration of the treatments was 15 consecutive days at a rate of 2 times per day orally.

Study protocol (activity chronogram): - Day -3 (Adequacy): 3 days before proceeding with the treatment and with the resulting Colorectal Distension procedure, the animals were maintained and adequate under basic feeding and hydration conditions in a non-stress environment, as described above. .

Day 1 (Colorectal Distension - Start of treatment): We proceeded with the DC test in all animals before the corresponding treatment was established. Records of all pain signs were taken and classified as mild, moderate and severe, as observed. This DC procedure was repeated in each experimental animal with different pressures (30, 40, 50 and 70 mmHg) with intervals of 10 minutes between each insufflation. After the same, the animals were left at baseline. At 10 minutes after the conclusion of the fourth and last colonic insufflation, treatment was started orally according to the group (Control, PPNX, PBTs and PPNX + PBTs).

- Day 2 - 14 (Treatment): in this period all the animals were kept in basal state under the treatment assigned to each group.

Day 15 (End of treatment - Coiorrectal Distension): this day the treatments were finalized and the second DC experience was carried out on all the animals in the same conditions described for Day 1.

Results of the Experience.

To assess the results obtained, the different symptoms observed were taken into account, from lower to higher intensity of pain, namely: a) Lick the abdomen b) Stretching the abdomen c) Press the abdomen against the floor d) Abdominal retraction e) Other pain symptoms not categorized (for example: self-mutilation, self-inflicted bodily harm, aggression).

To facilitate the interpretation and analysis of them, it was decided to divide the signs of pain into mild, moderate and severe, where: Mild Signs: Lick and stretch the abdomen Moderate Signs: Tighten the abdomen against the floor Severe signs: Abdominal retraction and other signs not categorized.

Table 7 describes the signs of pain found in the 4 treatment groups after the first test of Corectal Distension with 30, 50 and 70 mmHg of intestinal intraluminal pressure, on day 1.

Table 7. Pain signs in the first DC test in the 4 treatment groups.

In Table 7, a uniform behavior can be observed in the pain signs evaluated in the DC caused by different pressures, where the animals received no treatment. Already, at 40 mmHg of pressure, the distension begins to cause some slight signs of pain in some animals, but at 70 mmHg 100% of the animals experienced severe signs of pain (most had abdominal retraction, and only 2 animals showed signs of aggressiveness, one in the control group and the other in the group treated with PPNX) Table 8 shows the results obtained in the second DC test after 15 days of treatment in the different groups.

Table 8. Pain signs in the second DC test (day 15) in the 4 treatment groups.

Table 8 shows how the addition of PBTs to PPNX increases the pain threshold, mainly at the highest pressures (50 and 70 mmHg), where at 50 mmHg even 20% of the animals show no signs of pain , and 60% do so mildly, in relation to those treated only with PPNX, where all the animals already show signs of pain, 40% present them in a mild form and 60% in a moderate form. It can also be observed that the group treated with PBTs alone, shows a slight improvement in pain symptoms based on the control group (this is also observed in the pressure measurements of 50 and 70 mmHg). 2) Example 2 B: Propinox + Clonixinate of Usina + PBTs. (PPNX + CLL + PBTs) Animals: To carry out this experiment, 20 animals with the same characteristics and maintenance conditions were used as the animals used in Example 2B (with the association of PPNX + PBTs).

The 20 animals were divided, in equal parts, into 4 treatment groups of 5 animals each, namely: a) Control Group. b) Group treated with PPNX + CLL. c) Group treated with PBTs. d) Group treated with PPNX + PBTs + CLL Study drugs: The doses and compositions used were the following: - PPNX + CLL: 0.15 mg of PPNX + 0.7 mg of CLL, 2 times a day, orally, with the main meals (lunch and dinner) dissolved in 2 mL of water. Total daily dose: 0.30 mg.

- PBTs: 107 CFU, twice a day orally with the main meals (lunch and dinner) dissolved in water.

- PPNX + PBTs: 0.15 mg of PPNX + 107 CFU of PBTs twice a day dissolved in 2 mL of water, orally, with the main meals (lunch and dinner).

- PPNX + CLL + PBTs: 0.15 mg of PPNX + 0.7 mg of CLL + 107 CFU of PBTs twice a day dissolved in 2 mL of water, orally, with the main meals (lunch and dinner).

The duration of the treatments was 15 consecutive days at a rate of 2 times per day orally.

Study protocol (activity schedule): The schedule of activities was the same as the one carried out in the experimentation carried out in Test A, with the addition of CLL to 2nd. and 4th. treatment group.

Results of the Experience.

To evaluate the results, the same pain parameters were used as those used in Test A.

Table 9 shows the results obtained.

Table 9. Pain signs in the first DC test (day 1) in the 4 treatment groups.

In Table 9, it can be seen that pain signs were increasing as intracolonic pressures were increased. This test was performed on day 1, prior to the establishment of the corresponding treatments for each group.

Table 10 shows the results obtained after the 15-day treatment in the second DC test.

Table 10. Pain signs in the second DC test (day 15) in the 4 treatment groups.

Table 10 shows a greater analgesic effect than the addition of an AI E to the formulation, where only at 50 mmHg most of the animals (60%) show slight signs of pain, compared to 40% treated only with PPNX. A significant difference was also observed with the addition of PBTs to the formulation of PPNX + CLL, where at the maximum pressure exerted, severe signs of pain do not appear, and only 40% of the animals showed moderate signs, with slight signs of pain predominating. pain.

Conclusions The DC procedure has the ability to cause contractions and spasms in the intestinal smooth muscle. These spasms and contractions trigger nociceptive responses to the animal, which behave in ways other than pain. The drugs used in this experience are used to decrease spasms and NSAIDs to calm the pain caused by them. The addition of PBTs to the formulations would have a synergistic effect of analgesia before these pain stimuli to the colorectal distension, in addition to the immunomodulatory capacity that it has at this level.

These observed results suggest that the intestinal microflora would play an important role in the visceral perception of pain caused by abdominal distension. This study was able to determine the effect of PBTs on intestinal flora and this on autonomic functions and visceral perception in experimental animals.

These data provide some kind of support in the evidence of the effect of PBTs on visceral pain and provide new mechanisms of action of PBTs in the treatment of different functional pathologies where visceral distension and abdominal pain predominate as symptomatic symptoms.

Example N ° 3 Introduction Both gastric juice and intestinal microflora play a very important role as defense factors against microorganisms. Some imbalance in any of these two factors, predispose to different infections. Gastric juice, the main non-immune defense mechanism, is composed of hydrochloric acid and pepsin, which have a very important bactericidal power when the stomach pH is less than 3.0. At higher pHs, which are defined as a state of hypochlorhydria, it is more feasible to observe bacterial overgrowth and infections.

The formulations of drugs inhibiting acid secretion (inhibitors of the proton pump or blockers of the H2 receptors of the gastric secretory cells), during prolonged treatments, cause a state of hypochlorhydria, increasing the pH of the medium, which would alter significant local microflora, contributing to the increase or greater susceptibility to the appearance of infections. The effect of the PBTs at the level of the gastric mucosa would exert a protective effect 1) displacing the pathogenic resident bacteria; 2) stimulating the normal production of mucin by the intestinal epithelial cells; 3) preventing adhesion of pathogenic strains to epithelial cells; 4) modulating immune responses and 5) preventing, among other things, the appearance of ulcers related to H. pylori.

Classically, it has been considered that peptic ulcer is the result of an imbalance between aggressors and defenders of the gastroduodenal mucosa, imbalance that allows the harmful action or injury caused by acid and pepsin on the mucosa.

One way to classify gastritis is "erosive" and "non-erosive", depending on the severity of the mucosal lesion. Another way to classify them is based on the histopathological findings, in "acute" and "chronic". Acute gastritis is characterized by the presence of polymorphonuclear leukocytes in the mucosa; and the chronicles imply a certain degree of atrophy and / or metaplasia with mononuclear type inflammatory infiltrate. One of the most frequent causes of non-erosive gastritis is H. pylori infection. The infection by this gram-negative spiral microorganism leads to the inflammation of the gastric mucosa, which alters the secretory physiology, making the mucosa more susceptible to lesions by acid. Severe H. pylori infections can lead to the onset or development of Peptic ulcer disease (gastric / duodenal ulcer). The most commonly used standard therapeutic schemes are antisecretory drugs, both inhibitors of gastric H2 receptors (Ranitidine, Cimetidine, Famotidine) and proton pump inhibitors (Lansoprazole, Esomeprazole, Omeprazole, Dexlansoprazole, etc.), and antibiotics for the eradication of H. pylori (Amoxicillin, Clarithromycin, Metronidazole, etc).

Taking into account the above, we decided to evaluate the effectiveness of antisecretory drugs at the gastric level (such as inhibitors of H2 histamine receptors such as proton pump inhibitors) and the protective and immunomodulatory effect of PBTs in animals of experimentation in a model of "Gastric Ulcers / Erosive Gastritis Induced by Indomethacin". For this, it was decided to use the fixed association of lansoprazole + PBTs compared to lansoprazole and PBTs separately to evaluate the following points: 1) Emergence of erosive gastritis / ulcer. * 2) Histological changes of the gastric mucosa. 3) Time until the appearance of clinical signs of pain or other findings.

"The absence or presence of mild gastritis is considered a protective effect, the presence of gastritis of moderate or severe degree or the presence of ulcerations, is considered a non-protective effect (the degree of gastritis was classified according to the Sydney System) Materials and methods- Animals Mice of the Sprague Dawley species of both sexes were used, with a body weight between 250 and 300 g, which were adapted under laboratory conditions (temperature of 25 +/- 3 ° C, relative humidity of 60 +/- 5%, light / dark cycles of 12 hours, food intake and water ad libitum) for 7 days.

The sample consisted of 36 mice, distributed by simple randomization in four groups of nine mice each (3 experimental groups and one control), namely: - Group 1: Control (without active treatment).

- Group 2: Treaty with PBTs.

- Group 3: Treaty with Lansoprazole (LSPZL).

- Group 4: Treaty with the fixed association of LSPZL + PBTs.

Protocol of Erosive Gastric Ulcers / Gastritis Induced by Indomethacin An important cause of gastric mucosal damage is the consumption of NSAIDs. Approximately 25% of chronic users of these drugs have erosive gastritis of different degrees; from 10 to 30% develop peptic ulcer at some point under chronic treatment with NSAIDs, risking other complications such as gastrointestinal bleeding.

As is known, non-steroidal anti-inflammatories exert their action at the level of cyclooxygenases, inhibiting this pathway and giving rise to inhibition in the production of prostaglandins and the consequent alteration of the gastric mucosa.

The induction test for erosive gastritis by indomethacin is based on the fact that this NSAID causes gastric mucosal damage due to alteration in the production of prostaglandins. It consists in the administration in experimental animals, orally, an ulcerogenic dose of 1.32 mg / mL following the following administration protocol: once a day for 5 days; 2 days of rest; 5 days of administration and 3 days of rest.

Study Drugs The drugs, dose and frequency of administration were as follows: - PBTs: 107 CFU, 2 times a day, orally, for 15 days, at noon and at night, dissolved in 1.5 mL of drinking water.

LSPZL: 0.06 mg, twice a day, orally, for 15 days, at noon and at night, dissolved in 1.5 ml_ of drinking water.

- LSPZL + PBTs: 0.06 mg + 107 CFU, 2 times per day, orally, for 15 days, at noon and at night, dissolved in 1.5 mL of drinking water.

Macroscopic quantification of gastric lesions Lesions of the gastric mucosa were quantified macroscopically by two independent "blind" observers, and the results were expressed as the total sum of the length of the lesions (in millimeters).

Histology of the samples Once the macroscopic description of the stomach was made, samples of the lesions were taken, fixed in a solution of formaldehyde (10%), dehydrated in ethanol, embedded in paraffin and cut with a microtome in cross sections of 4 mm. , which were stained with hematoxylin and eosin. 10 images per animal were examined with an optical microscope.

Activities Schedule The four groups of animals were kept at baseline for 5 days before the start of the experiment.

- Day 1 to 5: Start of active treatments to active groups. Start of the indomethacin test and for 5 consecutive days. Clinical control of animals at 5th. day of treatment.

- Day 6 to 7: Rest period to indomethacin test for two days. Active treatment continues. Clinical control of animals.

- Day 8 to 12: Re-start of the indomethacin test for 5 days. Continuation with active treatments. Clinical control of animals at 10o. day of treatment.

- Day 13 to 15: Indomethacin test rest period and completion of active treatments. Clinical control of animals at 15th. day of treatment.

- Day 16: Sacrifice of the animals by decortication, autopsy, extraction of the stomach for its macroscopic and microscopic analysis.

Result of the Study The variables analyzed during the study were the following: 1) Clinical signs of pain or other findings * 1 2) Histological changes of the gastric mucosa evaluating the appearance of erosive gastritis / ulcer. * 2 * 1 The clinical signs to be evaluated were the following: behavioral changes, alteration in the feeding and behaviors, aggressiveness, self-mutilation or damage, signs of protection, vomiting, diarrhea, digestive hemorrhage, etc. * 2 The absence or presence of mild grade gastritis is considered a protective effect. The presence of gastritis of moderate or severe degree or the presence of ulcerations is considered a non-protective effect (the degree of gastritis was classified according to the Sydney System). 1) Clinical signs of pain or other findings: During the course of the experience it was decided to record the clinical signs in the rats on days 5, 10 and 15. The incidence of the same is described in Table 11 as percentages.

Table 11. Percentage of animals with signs of positive clinicians.

As can be seen in Table 11, 100% of the animals in the control group presented some clinical manifestation at day 15 of the experience, in contrast to 33% in the group treated with the association, achieving an improvement over the group treated with LSPZL, achieving a synergistic effect on clinical symptoms. Only two animals presented digestive bleeding in the control group. Another finding is that, in the group treated with the association of LSPZL + PBTs, signs of pain were mild, such as changes in behavior or changes in diet, and where in the control group, more aggressive behaviors were observed , presence of vomiting and signs of dehydration (decreased mobility, lethargy, etc.) and even a case of self-mutilation in one of the animals. 2) Histological changes of the gastric mucosa: In order to carry out a clinical-pathological correlation, it was decided to carry out a macroscopic and microscopic analysis of the stomach mucosa of all animals, and to be able to observe the effects of the assigned treatments.

Table 12 describes the findings made in the macroscopy of the stomachs of rats.

Table 12. Macroscopic lesions of the gastric mucosa.

Table 12 summarizes the extent of the various lesions found in the gastric mucosa at ocular inspection. A marked and significant decrease in the total ulcerated surface can be observed in the group of rats treated with the LSPZL + PBTs association. In percentage terms (detailed in parentheses), 100% was for the 65 mm found in the control group, observing a marked decrease of almost 9% in the group treated with the association.

Table 13. Microscopic findings of the gastric mucosa.

Table 13 describes the mild histological lesions in the group treated with the association of LSPZL + PBTs and more severe and even with some signs of mucosal ulceration in the case of the control group.

Conclusions Our results clearly show, both clinically and histopathologically, that the addition of PBTs to the induction test of gastritis caused by indomethacin exerts a mild gastroprotective effect on the gastric mucosa, but when combined with a usual pharmacological treatment, such as In the case of the use of proton pump inhibitors (LSPZL), they have a remarkable synergic effect, observing a significant decrease, both in the clinical symptoms and in the appearance of ulcers and histology of gastritis, these being of milder degrees than observed in the rest of the active treatment groups.

This gastroprotective effect that the aggregation of PBTs can exert would be given by the increase in the production of prostaglandins I and E (inhibited by the addition of indomethacin) by the PBTs, which would act as a defense mechanism with a protective effect of the gastric mucosa.

Example N ° 4 The process for preparing a capsule formulation containing: Per capsule % mg Trimebutine 200.00 50.00 Probiotic Lactobacillus acidophilus © 5.00 1.25 Galacto-oligosaccharides 50.00 12.50 Polyvinylpyrrolidone K 30 30.00 7.50 Pregelatinized starch 50.00 12.50 Microcrystalline cellulose 27.00 6.75 Croscarmellose sodium 25.00 6.25 Colloidal silicon dioxide 3.00 0.75 Magnesium stearate 10.00 2.50 Purified water © 1 10 © Equivalent to 1.00 x 10 CFU / tablet © EvaDora during the process PROCESSING METHOD The fractionation and handling of Probiotics should be carried out at no more than 20% relative humidity and 25 ° C temperature. 1. Dissolve Polyvinylpyrrolidone K30 in purified water. 2. Sieve through a 1 mm mesh and transfer to the mixer: Trimebutine, 50% of the Croscarmellose sodium and 70% of the pregelatinized starch. 3. Mix 2 minutes and add the solution obtained in point 1. Knead until obtaining the granulation point. 4. Calibrate the wet granulate by a 3 mm mesh. 5. Dry the calibrated granulate to obtain no more than 1% moisture taken at 80 ° C in thermobalance to constant weight. 6. Calibrate the dried granulate by a 0.6 mm mesh. 7. Mix the Probiotics with the remaining pregelatinized Starch and with the Galacto-oligosaccharides for 5 minutes. 8. Pre-add 1 cm sieve, silicon dioxide, remaining croscarmellose, microcrystalline cellulose and the mixture obtained in point 7 to the calibrated granulate of point 6. Mix 15 minutes. 9. Add the previously sieved Magnesium Stearate by 0.6 mm mesh to the mixture obtained in point 8. Mix 5 minutes. 10. Encapsulate to 400 mg ± 5% of net content Example N ° 5 The process for preparing a formulation of capsules containing Per capsule % mg Cinitapride acid tartrate 1.37 0.60 Probiotic Lactobacillus acidophilus® 5.00 2.17 Fructo-oligasaccharides 50.00 21 .74 Pregelatinized starch 61.00 26.52 Microcrystalline cellulose 99.13 43.10 Sodium glycolate starch 1 1.00 4.78 Colloidal silicon dioxide 1.00 0.43 Magnesium stearate 1.50 0.65 © Equivalent to 1.00 x 10 CFU / tablet PROCESSING METHOD The fractionation and handling of Probiotics should be carried out at no more than 20% relative humidity and 25 ° C temperature.

Sieve through a 1 mm mesh and transfer to the mixer, colloidal silicon dioxide, sodium starch glycolate and microcrystalline cellulose. Mix for 5 minutes Pre-mix manually for 3 minutes, previously sieved by 0.6 mm mesh: Pregelatinized starch, Cinitapride acid tartrate.

Add to the premix of point 2, Probiotic Lactobacillus acidophilus® and Fructooligasaccharides.

Add the premix obtained in point 3 to the mixture in point 1. Mix for 10 minutes.

Add the magnesium stearate previously sieved by 0.6 mm mesh to the mixture from step 4. Mix 3 minutes.

Encapsulate to 230 mg ± 5% of net content Example N ° 6 The process for preparing a capsule formulation is described Per capsule % mg Propinox hydrochloride 20.00 10.00 Probiotic Lactobacillus acidophilus © 5.00 2.50 Fructooligasaccharides 50.00 25.00 Sodium glycolate starch 10.00 5.00 Pregelatinized starch 40.00 20.00 Microcrystalline cellulose 72.00 36.00 Colloidal silicon dioxide 1.50 0.75 Magnesium stearate 1.50 0.65 © Equivalent to 1.00 x 109 CFU / tablet PROCESSING METHOD The fractionation and handling of Probiotics should be carried out at no more than 20% relative humidity and 25 ° C temperature. 1. Sieve through a 1 mm mesh and transfer to the mixer, colloidal silicon dioxide, sodium starch glycolate, propinox hydrochloride and microcrystalline cellulose. Mix for 5 minutes 2. Pre-mix for 3 minutes, previously sieved by 0.6 mm mesh: Pregelatinized starch, Probiotic Lactobacillus acidophilus® and Fructooligasaccharides.

Add to the mixture of point 1. Mix for 15 minutes. 3. Add the magnesium stearate previously sieved by 0.6 mm mesh to the mixture from step 2. Mix 3 minutes. 4. Encapsulate at 200 mg ± 5% theoretical weight Example N ° 7 The process for preparing a capsule formulation, containing microgranules of Lansoprazole, probiotics and prebiotics, is described.

Per capsule mg Lansoprazole 30.00 8.82 Probiotic Lactobacillus acidophilus © 5.00 1.47 Galacto-oligosaccharides 50.00 14.71 Granular sugar 78.00 22.94 Corn starch 41.00 12.06 Hydroxypropylcellulose 31.00 9.12 Magnesium carbonate 13.60 4.00 Titanium dioxide 2.10 0.62 Colloidal silicon dioxide 0.30 0.09 Pregelatinized starch 52.50 15.44 Microcrystalline cellulose 30.00 8.82 Talcum 1.50 0.44 Magnesium stearate 5.00 1.47 Purified water 562 Isopropyl Alcohol 100 © Equivalent to 1.00 x 109 CFU / tablet PROCESSING METHOD The fractionation and handling of Probiotics should be carried out at no more than 20% relative humidity and 25 ° C temperature. 1- Dissolve 40% of the sugar in 40% of the purified water. Add the isopropyl alcohol and stir until homogeneous. 2- Place 60% of the remaining sugar in a suitably sized pan, moisten it with the solution obtained in point 1, interspersed with Sprinkle corn starch until microgranules of the desired size are obtained. The microgranules obtained are dried to obtain no more than 1% humidity as measured in thermobalance at 80 ° C.

Humidify 50% of the Hydroxypropylcellulose in 30% of the remaining water, using a reactor of adequate capacity, slowly incorporate and with stirring 50% of the magnesium carbonate. Keep the agitation until dispersing it in a homogeneous way. Then and under continued agitation, incorporate Lansoprazole.

In another reactor of adequate capacity, wet the remaining fraction of the Hydroxypropylcellulose in the remaining purified water. Then, slowly and with agitation, add the rest of the magnesium carbonate. Keep the agitation until dispersing it in a homogeneous way. Then add the titanium dioxide and keep stirring until completely dispersed.

Place the sugar microgranules obtained in step 2 in a fluid bed of adequate capacity, apply the dispersion of active principle obtained in step. Dry until no more than 1% moisture taken at 80 ° C in thermobalance.

In a mixer of suitable capacity place pregelatinized starch, talc, and silicon dioxide and microcrystalline cellulose previously sieved by 0.6 mm mesh. Add probiotics and prebiotics. Mix for 15 minutes.

Add magnesium stearate previously sieved through a 0.6 mm mesh, mix for 5 minutes.

Encapsulate using proper equipment as indicated below: Lanzosprazole microgranules obtained in step 5: 195.7 mg Mixture of Probiotics + Prebiotics obtained in step 7: 144.3 mg Example N ° 8 The process for preparing a capsule formulation is described Per capsule % mg Ranitidine hydrochloride 167.40 52.31 Probiotic Lactobacillus acidophilus © 5.00 1.56 Fructooligasaccharides 50.00 15.63 Croscarmellose sodium 8.00 2.50 Pregelatinized starch 31.00 9.69 Microcrystalline cellulose 55.60 17.38 Colloidal silicon dioxide 2.00 0.63 Magnesium stearate 1.00. 0.31 © Equivalent to 1.00 x 109 CFU / tablet PROCESSING METHOD The fractionation and handling of Probiotics should be carried out at no more than 20% relative humidity and 25 ° C temperature. 1. Sieve through a 1 mm mesh and transfer to the mixer, colloidal silicon dioxide, Croscarmellose sodium, Ranitidine hydrochloride and microcrystalline cellulose. Mix for 5 minutes 2. Pre-mix for 3 minutes, previously sieved by 0.6 mm mesh: Pregelatinized starch, Probiotic Lactobacillus acidophilus® and Fructooligasaccharides. 3. Add the premix from point 2 to the mixture from point 1. Mix for 15 minutes. 4. Add the magnesium stearate previously sieved by 0.6 mm mesh to the mixture from step 3. Mix 3 minutes. 5. Encapsulate at 320 mg ± 5% theoretical weight Example N ° 9 The process for preparing a capsule formulation is described Per capsule % mg Famotidine 10.00 5.75 Probiotic Lactobacillus acidophilus © 5.00 2.87 Fructooligasaccharides 50.00 28.74 Sodium glycolate starch 10.00 5.75 Pregelatinized starch 35.00 20.11 Microcrystalline cellulose 62.00 35.63 Colloidal silicon dioxide 1.00 0.57 Magnesium stearate 1.00 0.57 F Equivalent to 1.00 x 109 CFU / tablet PROCESSING METHOD The fractionation and handling of Probiotics should be carried out at no more than 20% relative humidity and 25 ° C temperature.

Sieve through a 1 mm mesh and transfer to the mixer, colloidal silicon dioxide, sodium starch glycolate, famotidine and microcrystalline cellulose. Mix for 5 minutes Premix for 3 minutes, previously sieved by 0.6 mm mesh: Pregelatinized starch, Probiotic Lactobacillus acidophilus © and Fructooligasacáridos. Add to the mixture of point 1. Mix for 15 minutes.

Add the magnesium stearate previously sieved by 0.6 mm mesh to the mixture from step 3. Mix 3 minutes.

Encapsulate at 174 mg ± 5% theoretical weight Example No. 10 The process for preparing a capsule formulation is described c Per capsule J% mg Lysine Clonisinate 125.00 36.76 Propinox hydrochloride 20.00 5.88 Probiotic Lactobacillus acidophilus © 5.00 1.47 Galacto-oligosaccharides 50.00 14.71 0 Sodium glycolate starch 15.00 4.41 Pregelatinized starch 40.00 1 .76 Microcrystalline cellulose 81.50 23.97 Colloidal silicon dioxide 2.00 0.59 Magnesium stearate 1.50 0.44 5 © Equivalent to 1.00 x 109 CFU / tablet PROCESSING METHOD The fractionation and handling of Probiotics should be carried out at no more than 20% relative humidity and 25 ° C temperature.

Sieve through a 1 mm mesh and transfer to the mixer, colloidal silicon dioxide, sodium starch glycolate, propinox hydrochloride, lysine clonisinate, and microcrystalline cellulose. Mix for 5 minutes Premix for 3 minutes, previously sieved by 0.6 mm mesh: Pregelatinized starch, Probiotic Lactobacillus acidophilus © and Fructooligasacáridos.

Add to the mixture of point 1. Mix for 15 minutes.

Add the magnesium stearate previously sieved by 0.6 mm mesh to the mixture from step 4. Mix 3 minutes.

Encapsulate at 340 mg ± 5% theoretical weight.

Claims (10)

1 . An oral pharmaceutical combination, useful for restoring alterations of bowel function, comprising a therapeutically effective amount of an active ingredient for the treatment of various gastrointestinal functional disorders and a therapeutically effective amount of a probiotic together with pharmaceutically acceptable excipients, and optionally, a therapeutically effective amount of at least one nutraceutical.

2. An oral combination according to claim 1, wherein the active ingredient is selected from trimebutine, cinitapride, propinox, lansoprazole, esomeprazole, dexlansoprazole, ranitidine, famotidine, cimetidine or propinox combined with lysine clonixinate.

3. A pharmaceutical combination according to claim 1, wherein the probiotic comprises at least one bacterial strain selected from the group of the following species: Bifidobacteria sp, Lactobacillus sp, Bacillus sp, Lactococcus, Streptococcus sp, Enterococci and Yeast.

4. A "pharmaceutical combination" according to claim 3, wherein the Probiotic comprises at least one bacterial strain selected from: Bifidobacterium breve or brevis, Bifidobacterium lactis, Bifidobacterium longum, Bifidobacterium animalis, Lactobacillus acidophilus, Lactobacillus reuteri, Lactobacillus bulgaricus, Lactobacillus casei, Lactobacillus plantarum, Lactobacillus paracasei, Lactobacillus rhamnosus, Lactobacillus salivarius, Lactobacillus fermentum, Lactobacillus johnsonii, Lactobacillus helveticus, Lactobacillus delbrueckii, Bacillus Subtilis, Bacillus Clausii, Streptococcus thermophilus, Streptococcus faecium, Streptococcus faecalis, Enterococcus tecalis, Bacillus coagulans, Propionibacterium freudenreichii and Sacaromyces Boulardi.

5. A pharmaceutical combination according to claims 1 to 4, wherein the Probiotic is in a range of 1 x 103 CFU to 1 x 1014 CFU per dosage unit.

6. A pharmaceutical combination according to claims 1 to 5, wherein the nutraceutical is selected from a prebiotic, a vitamin or a mineral.

7. A pharmaceutical combination according to claim 1, whose dosage unit are preferably capsules, tablets, powders, sachets or microgranules for oral administration.

8. Process for preparing the combination of claim 1, comprising granulating, mixing and compressing a therapeutically effective amount of the active ingredient for the treatment of the various gastrointestinal functional disorders and a therapeutically effective amount of a Probiotic together with pharmaceutically acceptable excipients and optionally, a Therapeutically effective amount of at least one nutraceutical.

9. The use of the oral pharmaceutical combination of claim 1, for the manufacture of a medicament for restoring altered intestinal functions.

10. The use of a therapeutically effective amount of an active ingredient that is useful in the treatment of the various gastrointestinal functional disorders in combination with a therapeutically effective amount of a Probiotic and optionally, a therapeutically effective amount of at least one nutraceutical, for the manufacture of a medication to restore altered intestinal functions.