Formula with galactomannan gum and non digestible oligosaccharides

Abstract

The present invention relates to anti-regurgitation formula with locust bean gum and non-digestible oligosaccharides for improved effect on functional gastro-intestinal disorders in infants and young children.

Claims

1.-17. (canceled)

18. A method for treating and/or reducing the risk of at least one functional gastro-intestinal disorder of the lower intestinal tract in infants or young children suffering from regurgitation by administering a nutritional composition comprising galactomannan gum as thickener and non-digestible oligosaccharides to said infants or young children.

19. A method for one or more of a. increasing stool frequency, b. increasing gastro-intestinal transit time, c. improving stool consistency by decreasing the number of watery stools and hard stools, d. decreasing crying time, e. decreasing abdominal pain, f. decreasing fussiness, g. decreasing abdominal distention, h. decreasing abdominal bloating, i. decreasing medication relating to functional gastro-intestinal tract disorders in infants or young children suffering from regurgitation by administering a nutritional composition comprising galactomannan gum as thickener and non-digestible oligosaccharides to said infants or young children.

20.-21. (canceled)

22. The method according to claim 18, wherein the functional gastro-intestinal disorder is selected from a. constipation, b. flatulence, c. diarrhea, d. cramps and/or colics.

23. The method according to claim 18, which additionally is for treating regurgitation.

24. The method according to claim 18, wherein the non digestible oligosaccharides are selected from the group consisting of fructo-oligosaccharides, non-digestible dextrins, galacto-oligosaccharides, xylo-oligosaccharides, arabino-oligosaccharides, arabinogalacto-oligosaccharides, gluco-oligosaccharides, glucomanno-oligosaccharides, galactomanno-oligosaccharides, mannan-oligosaccharides, chito-oligosaccharides, uronic acid oligosaccharides, sialyloligosaccharides and fuco-oligosaccharides, and mixtures thereof.

25. The method according to claim 18, wherein the non digestible oligosaccharides are selected from the group consisting of fructo-oligosaccharides and galacto-oligosaccharides.

26. The method according to claim 18, wherein the nutritional composition comprises 0.25 to 0.75 g non-digestible oligosaccharides per 100 ml.

27. The method according to claim 18, wherein the galactomannan gum as thickener is locust bean gum.

28. The method according to claim 18, wherein the nutritional composition comprises 0.1-0.6 g galactomannan gum as thickener per 100 ml.

29. The method according to claim 18, wherein the nutritional composition comprises at least 30 wt % intact casein based on total protein.

30. The method according to claim 18, wherein at least part of the nutritional composition is fermented by lactic acid producing bacteria and wherein the nutritional composition comprises 0.25 wt % to 0.8 wt % L-lactic acid based on dry weight of the composition.

31. The method according to claim 18, wherein the nutritional composition is an infant formula, a follow on formula or a young child formula.

32. The method according to claim 18, wherein the nutritional composition comprises 3′-galactosyllactose.

33. The method according to claim 18, which is for treating and/or reducing the risk of flatulence.

34. The method according to claim 19, which is for improving stool consistency by decreasing the number of watery stools and hard stools.

35. The method according to claim 18, wherein the infant or young child is suffering from more severe gastrointestinal distress.

36. The method according to claim 35, wherein the infant or young child suffering from more severe gastrointestinal distress, is an infant or young child having an IGSQ-score of 35 or more.

Description

EXAMPLES

Example 1: Formula with Locust Bean Gum with or without Non-Digestible Oligosaccharides: Effects on Gastro-Intestinal Symptoms

[0062] A clinical trial was performed with healthy, term infants with an age less than 3.5 months that had a history of regurgitation.

[0063] As a control diet an infant formula with 0.4 g locust bean gum per 100 ml was used. As a test diet an infant formula similar to the control diet, but additionally comprising 0.8 g/100 ml non-digestible oligosaccharides (scGOS/IcFOS w/w 9:1) was used.

[0064] Both formulas had casein/whey protein in a 8/2 w/w ratio, more than 80 wt % lactose based on total digestible carbohydrates, and LC-PUFA (DHA 0.02% based on total fatty acids and ARA 0.35 wt % based on total fatty acids).

[0065] Formula was given for 8 weeks, with visits on t=0, t=2, t=4 and t=8 weeks (and a call at t=1 week).

[0066] 25 infants were enrolled in the test group (ITT), and 19 infants completed the study (PP), 20% drop-out. 23 infants were enrolled in the control group (ITT), and 15 completed the study (PP), 35% drop-out.

Results

[0067] The group that consumed the formula with locust bean gum and GOS/IcFOS showed less gastrointestinal symptoms after 8 weeks compared to the control group. The largest effect in the test group compared to the control group were mainly observed for reduced abdominal distension. This effect was statistically significantly different.

[0068] At week 4 and 8 the stool consistency in the test group was more soft formed than the control group, but the percentage of both watery stools and hard stools was less in the test group than in the control group. This is surprising, as NDO like GOS/FOS are known to reduce the consistency of stools. The test product showed a trend towards less watery and less hard/dry, but more soften stools (the latter statistically significant).

[0069] These results are indicative for an improved effect of NDO in the presence of a gallactomannan thickener on constipation, flatulence, or gasiness, diarrhea and cramps and/or colics, and also on stool frequency, gastro-intestinal transit time, stool consistency, crying time, abdominal pain, fussiness, abdominal distention, abdominal bloating, use of medication relating to functional gastro-intestinal tract disorders.

Example 2: Reduced FGIDs in Infants Consuming Partly Fermented Formula with Locust Bean Gum as Thickener and Non-Digestible Oligosaccharides Versus Partly Fermented Formula with Locust Bean Gum but without Non-Digestible Oligosaccharides

[0070] In a clinical trial the effect of two anti-regurgitation infant formulas on FGIDs was compared. Formula 1, the control diet, was an infant formula comprising 15 wt % of the fermented formula Lactofidus™ (present on the market in France as Lactofidia from Gallia) based on dry weight (delivering about 0.17 wt % L-lactic acid) and 2.7 wt % locust bean gum based on dry weight. After reconstitution with water to a ready to drink formula, the formula comprises 0.4 g LBG per 100 ml. This formula is the same formula as the formula of example 2 of WO 2010/120172. The weight ratio casein to whey protein is 6 to 4. The amount of lactose was about 60 wt % based on total digestible carbohydrates. Formula 1 is on the market in France as Gallia A. R.

[0071] Formula 2, the test diet, was an infant formula comprising 30% fermented formula Lactofidus™ (present on the market in France as Lactofidia from Gallia) based on dry weight (delivering about 0.33 wt % L-lactic acid) and 2.7 wt % LBG and 2.7 wt % scGOS/IcFOS is an 9:1 wt ratio (source GOS VivinalGOS®, source IcFOS Raftilin® HP) based on dry weight. After reconstitution with water to a ready to drink formula the formula comprises 0.4 g LBG per 100 ml and 0.4 g scGOS/IcFOS mix. The formula also contained 0.2 wt % docosahexaenoic acid based on total fatty acids and 0.2 wt % arachidonic acid based on total fatty acids. The amount of lactose was above 95 wt % based on total digestible carbohydrates. The weight ratio casein to whey protein is 6 to 4. The amount of 3′-galactosyllactose is about 15 mg per 100 ml.

[0072] 182 fully formula fed healthy term infants aged between 3-13 weeks at inclusion and diagnosed with uncomplicated regurgitation based on Rome IV criteria were included after independent ethical committee approval and registration of the study. The intervention duration was 4 weeks with optional 4 weeks extension.

[0073] At first baseline visit, t=0, baseline characteristics, anthropometrics and medical history was recorded. At visit 2, t=2 weeks, and visit 3, t=4 weeks, (serious) adverse events ((S)AE), concomittant medication and anthropometrics were recorded. On a daily base, during the first 4 weeks, stool characteristics, regurgitation severity and formula intake was registered by the parents. Gastro-intestinal symptoms (IGSQ score—Infant Gastrointestinal Symptom Questionnaire) were recorded on a weekly basis. This is a 13-item interviewer-administers questionnaire that allows parents to describe the frequency and intensity of their infants's GI signs and symptoms for the previous 7 days (Riley et al, 2015 Clinical Pediatrics 54:1167-1174). For the infants participating in the optional second part visit 4 was performed at 8 weeks, where anthropometrics, concomittant medication and (S)AE were recorded.

[0074] 92 infants were enrolled in the test group, and randomized and treated. 80 completed the end visit at 4 weeks. 58 infants enrolled the optional additional phase and 55 infants completed this phase. 90 infants were enrolled in the control group, were randomized and 89 were treated. 69 infants completed the end visit at 4 weeks. 54 infants enrolled the optional additional phase and 44 infants completed this phase.

[0075] All-in-all less infants of the control group completed the trial and this was mainly due to non-serious adverse events, diarrhea being the most prevalent. However, the number of drop outs was not higher than for similar clinical trials with healthy infants.

[0076] The primary outcome parameter is the IGSQ sum-score at 4 weeks after product use in the per protocol group. An increased sum score indicates increase gastro-intestinal symptoms.

Results

[0077] Baseline characteristics of the infants in both groups were very similar. All growth characterisitics (weight-for-age, length-for-age, weight-for-length and head circumference) were similar in both groups, and adequate growth was observed in line with the WHO z-scores for growth.

[0078] In the per protocol (PP) group the overall mean and median score of IGSQ was around 35 at the start of the intervention for both groups. Scores above 30 are considered a clinically relevant gastrointestinal tract burden. An improvement, i.e. decrease in score, to a value below 30 was observed after 1 week intervention in both groups, with a further decrease in week 2, 3 and 4. The mean and median IGSQ score was lower in the test group at t=2, 3 and 4 weeks when compared to the control. Also the decrease in mean and median IGSQ score compared to the base line was higher in the test group than in the control group.

[0079] At t=4 weeks the difference on median IGSQ score between test and control was −1.412 (s.e. 0.985), so less gastrointestinal symptoms were observed in the test group. Breaking down on individual items, the effects in the test group were observed on less difficulties of passing bowel movements, less crying time, less days that the baby was fuzzy, and less days that gas seem to make the baby uncomfortable or fussy.

[0080] The number of (serious) adverse effects ((S)AE) was higher in the control group (AE 29/92, 31.3% vs 33/89, 37.1%. SAE 3/92, 3.3% vs 7/89, 7/9%). Again, the number of (S)AE as such in the control group is not more that normally can be expected in a clinical trial like this and the type of (S)AEs were in line with what can be expected in this population. The adverse events in the control group versus test group mainly related to gastrointestinal disorders, 12.0 vs 23.6% (p=0.05). Looking at specific gastrointestinal disorders a decrease in flatulence 0 vs 5.6% (p=0.027) in the test group was the most prominent, but also occurrence of abdominal discomfort, constipation, diarrhea, dyspepsia, GERD, hard faeces, colics, vomiting, and regurgitation were reportedly lower in the test group than in the control group.

[0081] Medication related to alimentary tract and metabolism was less in the test group than in the control group (15.2% vs 20.2%). This concerned mainly drugs for acid-related disorders and drugs for functional GI-disorders (as classified by ATC therapeutic subgroup 2nd level, WHO Drug 2017/Q3).

[0082] Stool characteristics were very comparable between both groups with low incidences of watery stools or hard stools. However, in the test group the stool frequency was slightly higher than in the control group. Stool consistency was a bit lower in the test group than in the control group in the first two weeks of the study. Overall, stool frequency was however in physiological ranges and lower compared to the values observed for breastfed infants. The distribution over the different stool consistency scores was comparable between the groups, with a bit more softer stools in week 2 and 3 of the intervention group. Days were there was at least one watery stool, and days with at least 3 watery stools was a higher in the control group

[0083] These results are indicative for an improved effect of NDO in the presence of a gallactomannan thickener on constipation, flatulence, or gasiness, diarrhea and cramps and/or colics, and also on stool frequency, gastro-intestinal transit time, stool consistency, crying time, abdominal pain, fussiness, abdominal distention, abdominal bloating, use of medication relating to functional gastro-intestinal tract disorders.

Example 3

[0084] A post hoc analysis on subpopulation level was performed on the results of the clinical trial described above in example 2. A subgroup of infants was selected with a baseline IGSQ sum score ≥35 (the overall median). From Riley et al. 2015 Clin Pediatr 54:1167 it can be concluded that scoring higher than 30-35 on the IGSQ corresponds to more concerning gastro intestinal symptom burden or more severe gastrointestinal distress, evidenced by a higher frequency and severity of stooling, spitting/up/vomiting/crying/fussiness and flatulence.

[0085] A statistically significant higher improvement of the IGSQ scores was observed in the test group versus control group (Per-Protocol population, n=82; p=0.008), using Mixed Model Repeated Measurement (MRMM) whereas this improvement was not statistically significant between study groups in the subgroup of infants with a baseline IGSQ sum score <35 (MMRM, p=0.320), see FIG. 1.

[0086] The improvement on the IGSQ score of the test group was mainly due to lower gastrointestinal tract disorders, in particular related to the IGSQ cluster stooling, a composite score, based on the individual item scores of frequency of passing hard stools during the past week (0 times in the week; 1 time in the week; 2-3 times in the week; 4-6 times in the week; 7 or more times in the week) and frequency of having difficulties with passing hard stools during the past week.

[0087] Also the cluster crying in the subpopulation of infants with baseline IGSQ sum score ≥35 seems to show a more favourable pattern over time for the test group with respect to the one of the control group.

[0088] Since especially these children with increased gastrointestinal distress are more likely to be prescribed medication, these findings are relevant for daily practice since in many cases of functional GI disorders, medications are prescribed rather than providing nutritional support.

Statistical Analyses

[0089] The primary analysis was based on the Per-Protocol (PP) population, as defined prior to database lock. Equivalence between study groups was examined by analyzing whether the 2-sided 90% Confidence Interval (CI) of the difference in the mean IGSQ sum score at Week 4 laid within the predefined equivalence margins (α of 0.05). Data were analyzed using a linear Mixed Model Repeated Measurement (MMRM) approach on the post-baseline IGSQ sum scores with treatment, time (categorical) and interaction between treatment and time as fixed effects, baseline IGSQ sum score as adjustment covariate and center as random effect. Sensitivity analyses included the analysis of the All-Subjects-Randomised population, assessing the Missing At Random assumption and adjustment for potential covariates. An interaction test was performed to analyze the impact of the baseline IGSQ sum score on the intervention effect (predefined cut-off p-value <0.1 used to keep interaction in the model), followed by post-hoc subgroup analyses using a similar MMRM model as described above. Results were compared between groups using a Mann-Whitney Test. A Cochran-Mantel-Haenszel test was used to compare groups for the distribution over the different stool consistency categories and the incidence of diarrhea was compared based on a logistic regression model. All statistical analyses were performed using SAS Life Science Analytics Framework version 4.7.3 (SAS Institute Inc, Cary, N.C., USA).

Example 4

[0090] Packed powdered infant formula intended for infants 6 to 12 month of age.

[0091] After reconstitution to a ready to drink formula (13.64 g powder per 100 ml) the composition comprised per 100 ml:

[0092] 66 kcal

[0093] 3.4 g fat (3.3 g vegetable fat; fish oil and microbial oil as source of DHA and ARA),

[0094] 1.3 g protein (0.5 g whey protein; 0.8 g casein)

[0095] 7.3 g digestible carbohydrates (7 g lactose)

[0096] 0.375 g scGOS (of which 0.24 g has a DP 3 or higher, and 15 mg is 3′-GL) and 0.04 g IcFOS.

[0097] 0.4 g locust bean gum

[0098] 30% of the compostion is fermented formula (Lactofidia from Gallia) delivering about 0.45 g L-lactic acid.

[0099] The viscosity is above 10 mPa.Math.s when measured at 10 s.sup.−1 at 37° C.

[0100] On the package is indicated that the formula is an anti-regurgitation formula for treatment of regurgitation. The package further comprises at least one of the following indications: for use in prevention or treatment of mild functional gastro-intestinal disorders of the lower intestinal tract. Preferably it comprises an indication for treatment or prevention of diarrhea and/or watery stools or for use in reducing flatulence.