COMPOSITIONS COMPRISING A MINERAL SALT FOR ORAL USE

Abstract

Disclosed is a composition for oral use in the form of a granulate or micro-granule comprising a mineral salt combined with soluble fibre, said granulate or micro-granule being coated with sodium alginate and shellac.

Claims

1. Composition in the form of a granulate or micro-granule comprising a mineral salt selected from iron, zinc and copper salt and soluble fibers selected from soluble fructans having a degree of polymerization ranging between 3 and 10, said granulate or micro-granule being coated with shellac and sodium alginate.

2. Composition according to claim 1 wherein the mineral salt is an iron salt.

3. Composition according to claim 13 wherein the divalent iron salt is iron fumarate.

4. (canceled)

5. Composition according to claim 1, wherein said soluble fructan is selected from inulin and/or fructooligosaccharides.

6. Composition according to claim 5, wherein the weight percentage of fructans to the total composition ranges from 20% to 70%.

7. Composition according to claim 1, wherein the weight percentage of sodium alginate to the total composition ranges from 1% to 10%, the weight percentage of shellac to the total composition ranges from 1% to 10%, and the weight ratio of sodium alginate to shellac ranges between 1:4 and 4:1.

8. Composition according to claim 1, wherein the weight percentage of mineral salt to the total composition ranges from 25% to 75%.

9. A kit comprising: a. a liquid phase, acceptable in the food industry, in a bottle, and b. a powder phase in the measuring cap of said bottle, said cap containing a composition according to claim 1.

10. A food diet supplement, medical food or medical device comprising the compositions according to claim 1.

11. The food diet supplement, medical food or medical device according to claim 10 in the form of swallowable tablets, chewable tablets, capsules, effervescent pharmaceutical forms, granules to be reconstituted in water or to be dissolved in the mouth, softgels, syrups, solutions, suspensions or oral drops.

12. The composition according to claim 1, wherein said soluble fructans have a degree of polymerization between 3 and 5.

13. The composition according to claim 1, wherein the mineral salt is a divalent iron salt.

Description

DESCRIPTION OF THE INVENTION

[0024] The purpose of the present invention is to provide a solution that improves the organoleptic aspects and tolerability of mineral salts after oral administration, at the same time guaranteeing sufficient bioavailability, which is necessary to ensure that iron supplementation is effective for the user. The invention suggests the use of simple, convenient processes that do not alter the chemical nature of the ingredients and additives with health-giving properties. Surprisingly, the bioavailability of iron in the resulting granulate has proved similar to that of iron deriving from iron sulphate, the preferred form for pharmacological treatment due to its greater bioavailability.

[0025] The composition according to the invention comprises, in addition to said mineral salt, a soluble fibre with health-giving properties, preferably a soluble fructan.

[0026] Inulin is an example of a long-chain fructan with a degree of polymerisation of about 10, while fructooligosaccharides (FOS) are short-chain fructans generally having a degree of polymerisation ranging between 3 and 5. Fructooligosaccharides are generally used in products such as diet supplements due to their well-known health-giving properties. They are prebiotic fibres resistant to digestion in the gastrointestinal tract which arrive unmodified in the colon, where they are fermented by a limited number of bacteria, mainly bifidobacteria, promoting their growth and, by means of competition mechanisms, inhibiting the growth of pathogenic bacteria. It has been reported that prebiotic substances mitigate the adverse gastrointestinal effects of iron in children [Paganini, 2017]. They are usually available in diet supplements, and their dose ranges between 1 and 10 g/day.

[0027] The composition according to the invention comprises sodium alginate and shellac as well as mineral salt and soluble fructan.

[0028] Sodium alginate, extracted from seaweed cell walls, has the appearance of a gum. In the food industry it is classed as an additive and used as an emulsifying agent and thickener, but can be considered as a soluble fibre. Alginates are also used for their mucoprotective properties.

[0029] Shellac is a natural resin consisting of terpenes, obtained from the secretions of the insect Kerria lacca. The substance is soluble in basic aqueous solutions. As it is edible, shellac is widely used in the food industry as a polishing agent for pills and candies. It is classified as a food additive for said purpose, and is also used as a fruit coating to prevent deterioration after picking.

[0030] The weight percentage of soluble fructan in the composition according to the invention ranges between 20% and 70%, preferably between 35 and 55%, and most preferably between 40% and 45%.

[0031] The composition preferably comprises a soluble fructan selected from inulin and/or fructooligosaccharides. The fructan is advantageously in powder form, with a degree of polymerisation ranging between 3 and 10, more preferably between 3 and 5.

[0032] Sodium alginate is present in a weight percentage ranging between 1% and 10%, preferably between 1% and 5%, and more preferably between 1% and 2.5%.

[0033] Sodium alginate is present in an amount ranging between 1% and 10%, preferably between 1% and 5%, and more preferably between 1% and 2.5%.

[0034] Shellac is present in an amount ranging between 1% and 10%, preferably between 2% and 5%, and more preferably between 2% and 2.5%.

[0035] The sodium alginate to shellac ratio preferably ranges between 1:4 and 4:1.

[0036] According to a preferred aspect of the invention the mineral salt is iron, in order to make it tolerable for oral administration, in particular but not exclusively for sensitive individuals such as children, pregnant and lactating women, and individuals suffering from gastrointestinal disorders.

[0037] In an even more preferred aspect, the iron takes the form of divalent (ferrous) iron Fe.sup.2+.

[0038] The composition according to the invention comprises divalent iron salt Fe.sup.3+ in a percentage ranging between 25% and 75%, preferably between 40% and 60%, and most preferably between 50% and 55% by weight.

[0039] The divalent (ferrous) iron salt Fe.sup.2+ is preferably iron fumarate.

[0040] The composition according to the invention preferably comprises, or alternatively consists of, a divalent (ferrous) iron salt Fe.sup.2+, a soluble fructan, sodium alginate and shellac in the amounts stated above.

[0041] Most preferably, the composition according to the invention comprises, or alternatively consists of, iron fumarate, fructooligosaccharides, sodium alginate and shellac in the amounts stated above.

[0042] Advantageously, the compositions according to the invention take the form of a granule or micro-granule, made with fluid-bed granulation technology.

[0043] Said granulate or micro-granule can be suitably mixed with other substances and/or additives acceptable in the food and/or pharmaceutical industries, to advantageously provide an end product for oral use which takes the form of swallowable tablets, capsules, effervescent pharmaceutical forms, granulate designed to be reconstituted in water or dissolved directly in the mouth, softgels, syrups, solutions, suspensions or oral drops, packages in blister packs, pill boxes, bottles, sachets or stick packs, the various ingredients being selected in the appropriate physical form on the basis of the know-how of the skilled person.

[0044] A preferred aspect of the invention involves the production of chewable tablets containing said granulate. As illustrated above, patient compliance is a crucial aspect of iron deficiency treatment; in this respect, chewable tablets represent a more advantageous form than the widely available tablets and capsules, especially for children, individuals with swallowing difficulties, complicated in some cases by disorders (e.g. globus pharyngis), or individuals suffering from presbyphagia.

[0045] According to a further aspect thereof, the invention also provides a kit comprising: [0046] a liquid phase acceptable in the food industry in a bottle, and [0047] a powder phase in the measuring cap of said bottle, said cap containing all or part of a composition comprising a mineral salt, at least one soluble fructan, sodium alginate and shellac, and said bottle containing the remainder of said composition.

[0048] In a preferred embodiment, the kit according to the invention comprises a bottle including a measured amount of a liquid phase acceptable from the dietary standpoint and a measuring cap including a pre-set amount of the composition according to the invention.

[0049] The end product can be, for example, a food, a diet supplement, a special medical food, a medical device or a medicament.

[0050] It has been found that the compositions according to the invention possess organoleptic and iron tolerability characteristics, unexpectedly exhibiting bioavailability values similar to those of iron sulphate. In fact, as iron fumarate is notoriously far less water-soluble than iron sulphate (https://en.wikipedia.org/wiki/Iron(II)_fumarate; https://en.wikipedia.org/wiki/Iron(II)_sulfate) and has generically lower iron release than iron sulphate [Bannerman et al., 1996], it has surprisingly been observed that the majority of the iron released by the composition according to the invention is bioavailable in a similar percentage to iron sulphate.

[0051] The invention therefore improves the organoleptic characteristics of mineral salts, promoting their bioavailability.

EXAMPLES

Example I. Preparation of Granulate

[0052] A mixture of powders containing iron fumarate and FOS is prepared by accurately weighing the powders. The mixture is prepared in the rack of a fluid-bed granulator, and heated until an optimum temperature of 40-45° C. is reached. The mixture of powders is then introduced into the apparatus and kept in suspension by means of a continuous airstream; the granulation process subsequently takes place with water. At the end of said operation the resulting granules must be completely dried before the coating stage takes place. For this purpose, a solution obtained by dissolving precise amounts of sodium alginate and shellac in water is prepared separately; the solution is introduced into the spray nozzle of the apparatus and sprayed onto the moving powder mixture. The continuous airstream and regular spraying of the solution promote homogeneous distribution of the ingredients. Hot air subsequently causes the water to evaporate, and a granulate with the qualitative and quantitative composition shown in Table I is obtained at the end of the drying and cooling process

TABLE-US-00001 TABLE I Ingredient Composition Iron fumarate 50% Fructooligosaccharides (FOS) 45% Shellac Acquagold 2.5%  Sodium alginate 2.5% 

[0053] It was found that the compositions according to the invention possess excellent organoleptic and iron tolerability characteristics.

Example II. Evaluation of Organoleptic Characteristics of the Granulate According to the Invention

[0054] A portion of the granulate described in Example I and a portion of commercially available iron fumarate, both equivalent to 14 mg of elemental iron (100% of Nutrient Reference Value—EU Reg. 1169/2011) were weighed separately using known procedures. The amounts are reported in Table II.

TABLE-US-00002 TABLE II Sample A Sample B Amount (mg), Amount (mg), equivalent to 14 mg equivalent to 14 mg Ingredient of elemental iron Ingredient of elemental iron Granulate 96.6 mg Iron fumarate 45.1 mg according to the invention

[0055] The following trial protocol was used to evaluate the organoleptic characteristics of the two samples compared.

[0056] General Criteria

[0057] Each of the compositions listed in Table II above was tested on a group of 4 subjects. The inclusion criteria for admission to the test were solely ethical: the subjects had to be over the age of majority, healthy, and not suffering from any taste and/or iron metabolism alterations correlated with disorders and/or illnesses.

[0058] Trial Procedure

[0059] Each subject independently tasted first one and then the other sample of the example, maintaining a suitable time interval (at least 2 hours) between one tasting and the next, and rinsing their mouth, so that the evaluation of each administration was not influenced by the previous one.

[0060] Evaluation Criteria

[0061] On each tasting, the following parameters were evaluated: metallic odour and flavour, gastrointestinal tolerability, aftertaste, and staining of teeth, tongue and/or palate. Each parameter was evaluated on a scale ranging from 0 (unsatisfactory) to 5 (highly satisfactory).

TABLE-US-00003 Iron odour z1: unsatisfactory 2 3 4 5: highly satisfactory Gastrointestinal tolerability 1 : intolerable 2 3 4 5: highly tolerable Staining (e.g. teeth, tongue and/or palate) 1 : evident stains 2 3 4 5: no stains Metallic flavour 1 : intolerable 2 3 4 5: imperceptible Aftertaste 1: persistent aftertaste 2 3 4 5: no aftertaste

[0062] Results

[0063] The results are set out in Table III.

TABLE-US-00004 TABLE III Sample A Sample B Participant 1 Participant 1 Iron odour: 5 Iron odour: 5 Metallic flavour: 3 Metallic flavour: 1 Gastrointestinal tolerability: 5 Gastrointestinal tolerability: 3 Aftertaste: 4 Aftertaste: 1 Staining: 2 Staining: 2 Participant 2 Participant 2 Iron odour: 5 Iron odour: 4 Metallic flavour: 5 Metallic flavour: 3 Gastrointestinal tolerability: 5 Gastrointestinal tolerability: 5 Aftertaste: 5 Aftertaste: 5 Staining: 5 Staining: 4 Participant 3 Participant 3 Iron odour: 5 Iron odour: 5 Metallic flavour: 5 Metallic flavour: 3 Gastrointestinal tolerability: 5 Gastrointestinal tolerability: 5 Aftertaste: 4 Aftertaste: 2 Staining: 5 Staining: 5 Participant 4 Participant 4 Iron odour: 5 Iron odour: 5 Metallic flavour: 4 Metallic flavour: 2 Gastrointestinal tolerability: 5 Gastrointestinal tolerability: 5 Aftertaste: 4 Aftertaste: 4 Staining: 5 Staining: 5

[0064] Examination of the data collected demonstrates that the composition according to the invention generally exhibited improved organoleptic characteristics compared with iron fumarate. In particular, a definite improvement as regards the perception of a metallic flavour was observed. 50% of participants reported an improvement in the metallic aftertaste.

[0065] Surprisingly, it was found that the compositions containing iron fumarate exhibit similar bioavailability to that of iron sulphate.

Example III. Release and Bioavailability Study

[0066] The release profile and bioavailability of the composition according to the invention were analysed and measured by comparison with iron sulphate (the preferred form for pharmacological treatment) using an in vitro system, under conditions simulating the gastrointestinal environment.

[0067] The tests were conducted according to methods published in the international scientific literature and internally validated.

[0068] For the measurement of the comparative release profile, amounts of the two test samples were first weighed, both equivalent to 30 mg of elemental iron. The samples were initially placed in contact with a solution of HCl (0.1N) and incubated at a temperature of 37±0.5° C. A solution of Na.sub.2HPO.sub.4 was then added to the samples to buffer the pH to a value of 6.8. Said conditions were maintained throughout the remainder of the experiment. To evaluate the release profile of the iron, the two samples were centrifuged at 10,000 rpm at pre-set time intervals such as 1, 2, 4, 6 and 24 h. At the end of centrifugation the samples were taken up and analysed to evaluate the iron release profiles. The iron determination analyses were conducted with the ICP-OES THERMO FISHER ICAP 6300. Table IV shows the results of the release test.

TABLE-US-00005 TABLE IV IRON RELEASED TIME (h) Ferrous sulphate Granulate according to the invention 1 84.16 ± 1.07 73.99 ± 0.87 2 85.22 ± 0.98 77.96 ± 1.10 4 100.03 ± 0.20  79.87 ± 0.94 6 — 80.46 ± 1.57 24 — 80.53 ± 1.44

[0069] The in vitro bioavailability study was conducted by the dialysis membrane method. Said method, by its nature, is based on the physicochemical characteristics of the environments wherein the desired substance passes from one compartment to the other, and takes no account of any active mechanisms or biological interaction. The method involves three successive simulated digestion stages: buccal digestion in the presence of amylase, gastric digestion in the presence of pepsin, and finally, intestinal digestion in the presence of pancreatin.

[0070] Buccal Digestion

[0071] In order to simulate buccal digestion, suitable amounts of the test samples were placed in contact with 10 mg of amylase and 1.5 mL of PBS at pH 6.9 (10-3 M). The resulting mixtures were inserted into dialysis membranes (Spectrum Laboratories Inc., USA, MWCO: 12-14,000 Daltons), tightly closed at each end and immersed in vials containing PBS at pH 6.9. The samples were then incubated at a temperature of 37±0.5° C. for 5 minutes.

[0072] Gastric Digestion

[0073] After incubation, HCl (0.85N), pepsin and a solution of NaN.sub.3 (0.04% w/w) were added to the open membranes. The membranes were closed, placed in vials containing HCl (0.85N), and incubated at 37±0.5° C. for 2 h.

[0074] Intestinal Digestion

[0075] After said 2 h period, a solution of NaHCO.sub.3 (0.8 M) and pancreatin was added. The closed membranes were placed in vials containing PBS at pH 7.0, and incubated at a temperature of 37±0.5° C. for a further 4 h.

[0076] To evaluate the in vitro bioavailability of the iron, the solution contained in the vials was taken up after each digestion step, and the samples were analysed with an ICP-OES THERMO FISHER ICAP 6300.

[0077] Bioavailability is defined as the percentage of iron recovered in the bioaccessible fraction after in vitro digestion, in relation to the original undigested sample, and calculated with the equation: (bioaccessible fraction/total content)×100%. Table V shows the results of the bioavailability test.

TABLE-US-00006 TABLE V BIOACCESSIBLE FRACTIONS Granulate according DIGESTION Ferrous sulphate to the invention Buccal 8.61 ± 0.73 0.06 ± 0.03 Gastric 65.81 ± 1.39  71.36 ± 1.12  Intestinal 7.16 ± 0.41 7.64 ± 1.11 Bioavailability (%) 81.6% ± 2.53.sup.  79.1% ± 2.26.sup. 

[0078] The results demonstrated that, despite the different release profile, the cumulative bioavailability values of the three digestion stages (buccal, gastric and intestinal) were similar for the two samples tested. This demonstrates that the granulate according to the invention does not modify the release profile and bioavailability of iron compared with ferrous sulphate.

Example IV. Chewable Tablets

[0079] The active ingredients and excipients, in powder form, are precisely weighed and mixed in a mechanical mixer in the composition reported in Table VI. The resulting uniform mixture flows by gravity from a hopper to be introduced into the tablet press cavity.

TABLE-US-00007 TABLE VI Ingredient Composition Granulate according to the invention 206.40000 mg Vitamin C 147.70000 mg Copper gluconate 11.20000 mg Folic acid 0.55236 mg Sorbitol 1,294.14764 mg Sucralose 1.00000 mg Silicon dioxide 1.00000 mg Orange flavouring 30.00000 mg Magnesium stearate 28.00000 mg Maltodextrins 280.00000 mg [0080] Tablet weight: 2.00000 g [0081] Tablet format: round, diameter 18 [0082] Colour: white with brick red dots

Example V. Orodispersible Stick Packs

[0083] Active ingredients and excipients commonly used in the food industry, in powder form, are precisely weighed and mixed in a mechanical mixer in the composition reported in Table VII. The resulting uniform pre-measured mixture flows by gravity from a hopper to be introduced into the stick pack wrapping.

TABLE-US-00008 TABLE VII Ingredient Composition Granulate according to the invention 206.40000 mg Vitamin C 100.00000 mg Vitamin B12 2.10000 mg Folic acid 0.43400 mg Xylitol q.s. Sucralose q.s. Orange flavouring q.s. Silicon dioxide q.s. Maltodextrins q.s. [0084] Tablet weight: 1.50000 g [0085] Colour: white with brick red dots

Example VI. Assessment of the Organoleptic Characteristics of the Stick Packs Containing the Granulate According to the Invention

[0086] The following trial protocol was used to evaluate the organoleptic characteristics of the granulate according to the invention, inserted in a sample of orodispersible product as described in Example V.

[0087] General Criteria

[0088] The product described in Example V was tested on a group of 7 subjects. The inclusion criteria for admission to the test were solely ethical; the subjects had to be over the age of majority, healthy, and not affected by taste and/or iron metabolism alterations correlated with disorders and/or illnesses.

[0089] Trial Procedure

[0090] Each person independently tasted the product of Example V, after a suitable time had elapsed since the last intake of food or drinks, in order to evaluate each parameter sequentially, leaving a suitable interval (at least 2 hours) to elapse so that some parameters, such as gastric tolerability and aftertaste, could be evaluated.

[0091] Evaluation Criteria

[0092] On each tasting, the following parameters were evaluated: metallic odour and flavour, gastrointestinal tolerability, aftertaste, and staining of teeth, tongue and/or palate. Each parameter was evaluated on a scale ranging from 0 (unsatisfactory) to 5 (highly satisfactory).

TABLE-US-00009 Iron odour 1: unsatisfactory 2 3 4 5: highly satisfactory Gastrointestinal tolerability 1 : intolerable 2 3 4 5: highly tolerable Staining (e.g. teeth, tongue and/or palate) 1: evident stains 2 3 4 5: no stains Metallic flavour 1 : intolerable 2 3 4 5: imperceptible Aftertaste 1: persistent aftertaste 2 3 4 5: no aftertaste

[0093] Results

[0094] The results are set out in Table VIII.

TABLE-US-00010 TABLE VIII Participant 1 Iron odour: 5 Metallic flavour: 5 Gastrointestinal tolerability: 4 Aftertaste: 4 Staining: 5 Participant 2 Iron odour: 5 Metallic flavour: 4 Gastrointestinal tolerability: 4 Aftertaste: 4 Staining: 5 Participant 3 Iron odour: 4 Metallic flavour: 5 Gastrointestinal tolerability: 5 Aftertaste: 4 Staining: 5 Participant 4 Iron odour: 5 Metallic flavour: 5 Gastrointestinal tolerability: 4 Aftertaste: 4 Staining: 5 Participant 5 Iron odour: 5 Metallic flavour: 5 Gastrointestinal tolerability: 5 Aftertaste: 4 Staining: 5 Participant 6 Iron odour: 5 Metallic flavour: 3 Gastrointestinal tolerability: 5 Aftertaste: 4 Staining: 5 Participant 7 Iron odour: 5 Metallic flavour: 4 Gastrointestinal tolerability: 5 Aftertaste: 5 Staining: 5

[0095] The data collected demonstrate that the composition according to the invention was advantageously inserted in a formulation of the product, confirming the optimum organoleptic characteristics of the granulate according to the invention, already found in Example II; in particular, excellent tolerability was found in terms of metallic odour, flavour and aftertaste.

BIBLIOGRAPHY

[0096] Bannerman Judy, Campbell Norman R. C., Hasinoff Brian B., Venkataram Suresh. The dissolution of iron from various commercial preparations. Pharmaceutica Acta Helvetiae 1996 July; Vol. 71, Issue 2, Pages 129-133. [0097] EFSA Journal 2015; 13(10):4254. Scientific Opinion on Dietary Reference Values for iron. EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). European Food Safety Authority (EFSA), Parma, Italy. [0098] Fuqua Brie K, D Vulpe Christopher, J Anderson Gregory. Intestinal iron absorption. J Trace Elem Med Biol. 2012 June; 26(2-3):115-9. [0099] Hurrell Richard, Egli Ines. Iron bioavailability and dietary reference values. Am J Clin Nutr. 2010 May; 91(5):1461S-1467S. [0100] Nguyen Patricia, Nava-Ocampo Alejandro, Levy Amalia, O'Connor Deborah L, Einarson Tom R, Taddio Anna, Koren Gideon. Effect of iron content on the tolerability of prenatal multivitamins in pregnancy. BMC Pregnancy Child birth. 2008 May 15; 8:17. [0101] Paganini Daniela, Zimmermann Michael B. The effect of iron fortification and supplementation on the gut microbiome and diarrhea in infants and children: a review. AM J Clin Nutr. 2017 December; 106(Suppl 6):1688S-1693S.