Nutritional products comprising human milk oligosaccharides and methods for manufacture thereof
A method for the manufacture an infant formula or an infant nutritional product comprising mixture of human milk oligosaccharides is disclosed. The method involves the catalytic hydrogenolysis of compounds of the general formula 1 and 2 with particular oligosaccharide profiles.
1. A method for manufacturing an infant nutritional product or infant formula comprising a mixture of human milk oligosaccharides (HMOs), the method comprising: subjecting a mixture of at least two compounds selected from the group consisting of compounds of general formula 1 and compounds of general formula 2 to catalytic hydrogenolysis to remove,
wherein R is a group removable by the catalytic hydrogenolysis,
R 1 is independently a fucosyl or an H,
R 2 is an N-acetyl-lactosaminyl group or a lacto-N-biosyl group,
R 3 is an H or an N-acetyl-lactosaminyl group
R 4 is independently a sialyl or an H,
and salts thereof,
at least one of R 1 or R 4 is not H in general formula 2, and
a quantity of the mixture of the at least two compounds selected from the group consisting of compounds of general formula 1 and compounds of general formula 2 are selected such that the mixture of human milk oligosaccharides (HMOs) has an oligosaccharide profile that is substantially similar to a milk selected from the group consisting of colostrum breast milk, transitional breast milk and mature breast milk.
2. The method of claim 1 , wherein the catalytic hydrogenolysis is carried out in at least one protic solvent in the presence of a hydrogenolysis catalyst.
3. The method of claim 1 , wherein the at least two compounds are selected from the group consisting of R-glycosides of 2′-fucosyllactose, 3-fucosyllactose, 2′,3-difucosyllactose, 3′-sialyllactose, 6′-sialyllactose, 3′-sialyl-3-fucosyllactose, lacto-N-tetraose, lacto-N-neotetraose, LNFP-I, LNFP-II, LNFP-III, LNFP-V, LST-a, LST-b, LST-c, FLST-a, FLST-b, FLST-c, LNDFH-I, LNDFH-II, LNDFH-III, DS-LNT, FDS-LNT I and FDS-LNT II.
4. The method of claim 1 , wherein the infant nutritional product or infant formula is in a form selected from the group consisting of a liquid, a powder or a solid.
5. The method of claim 1 , comprising adding a component selected from the group consisting of pharmaceutically or nutritionally acceptable carriers, lactose, proteins, and fat to the mixture of human milk oligosaccharides.
6. The method of claim 1 , further comprising adding prebiotics to the mixture of human milk oligosaccharides.
7. The method of claim 1 , wherein the N-acetyl lactosaminyl group comprises a glycosyl residue comprising one or more N-acetyl-lactosaminyl and/or one or more lacto-N-biosyl groups, and at least one N-acetyl-lactosaminyl or lacto-N-biosyl group can be substituted with a sialyl and/or fucosyl residue; and
R 3 is N-acetyl-lactosaminyl group substituted with a glycosyl residue comprising one or more N-acetyl-lactosaminyl and/or one or more lacto-N-biosyl groups, and at least one N-acetyl-lactosaminyl or lacto-N-biosyl group is substituted with a sialyl and/or fucosyl residue.
8. A method for manufacturing an infant nutritional product or infant formula comprising a mixture of human milk oligosaccharides (HMOs), the method comprising: subjecting a mixture of at least two compounds selected from the group consisting of compounds of general formula 1 and general formula 2 to catalytic hydrogenolysis to remove R,
wherein R is a group removable by the catalytic hydrogenolysis,
R 1 is independently a fucosyl or an H,
R 2 is an N-acetyl-lactosaminyl group or a lacto-N-biosyl group,
R 3 is an H or an N-acetyl-lactosaminyl group,
R 4 is independently a sialyl or an H,
and salts thereof,
at least one of R 1 or R 4 is not H in general formula 2,
wherein the compounds of general formula 1 are selected from the group consisting of compounds of general formula 1a and compounds of general formula 1b,
R 2a is an N-acetyl-lactosaminyl group substituted with a glycosyl residue comprising one N-acetyl-lactosaminyl and/or one lacto-N-biosyl group; at least one N-acetyl-lactosaminyl or lacto-N-biosyl group is substituted with a sialyl and/or fucosyl residue,
R 3a is an H or an N-acetyl-lactosaminyl group substituted with a lacto-N-biosyl group; at least one N-acetyl-lactosaminyl or lacto-N-biosyl group is substituted with a sialyl and/or fucosyl residue,
R 2b is a lacto-N-biosyl group substituted with sialyl and/or fucosyl residue, and
R 3b is an H or an N-acetyl-lactosaminyl group substituted with one or two N-acetyl-lactosaminyl and/or one lacto-N-biosyl group; at least one N-acetyl-lactosaminyl or lacto-N-biosyl group is substituted with sialyl and/or fucosyl residue, and
a quantity of the mixture of the at least two compounds selected from the group consisting of compounds of general formula 1 and compounds of general formula 2 are selected such that the mixture of human milk oligosaccharides (HMOs) has an oligosaccharide profile that is substantially similar to a milk selected from the group consisting of colostrum breast milk, transitional breast milk and mature breast milk.
9. The method of claim 8 , wherein
the N-acetyl-lactosaminyl group in the glycosyl residue of R 2a in general formula 1a is attached to the another N-acetyl-lactosaminyl group with 1-3 interglycosidic linkage,
the lacto-N-biosyl group in the glycosyl residue of R 2a in general formula 1a is attached to the N-acetyl-lactosaminyl group with 1-3 interglycosidic linkage,
the lacto-N-biosyl group in the glycosyl residue of R 3a in general formula 1a is attached to the N-acetyl-lactosaminyl group with 1-3 interglycosidic linkage,
the N-acetyl-lactosaminyl group in the glycosyl residue of R 3b in general formula 1b is attached to the another N-acetyl-lactosaminyl group with 1-3 or 1-6 interglycosidic linkage, and/or
the lacto-N-biosyl group in the glycosyl residue of R 3b in general formula 1b is attached to the N-acetyl-lactosaminyl group with 1-3 interglycosidic linkage.
10. The method of claim 8 , wherein general formula 1a represents the R-glycosides of lacto-N-neotetraose, para-lacto-N-hexaose, para-lacto-N-neohexaose, lacto-N-neohexaose, para-lacto-N-octaose and lacto-N-neooctaose substituted with one or more sialyl and/or fucosyl residue, and general formula 1b represents the R-glycosides of lacto-N-tetraose, lacto-N-hexaose, lacto-N-octaose, iso-lacto-N-octaose, lacto-N-decaose and lacto-N-neodecaose substituted with one or more sialyl and/or fucosyl residue.
11. A method for manufacturing an infant nutritional product or infant formula comprising a mixture of human milk oligosaccharides (HMOs), the method comprising: subjecting a mixture of at least two compounds selected from the group consisting of compounds of general formula 1 and general formula 2 to catalytic hydrogenolysis to remove R,
wherein R is a group removable by the catalytic hydrogenolysis,
R 1 is independently a fucosyl or an H,
R 2 is an N-acetyl-lactosaminyl group or a lacto-N-biosyl group,
R 3 is an H or an N-acetyl-lactosaminyl group,
R 4 is independently a sialyl or an H,
and salts thereof,
at least one of R 1 or R 4 is not H in general formula 2,
the fucosyl residue attached to the N-acetyl-lactosaminyl and/or the lacto-N-biosyl group includes a linkage selected from the group consisting of
the galactose of the lacto-N-biosyl group with 1-2 interglycosidic linkage,
the N-acetyl-glucosamine of the lacto-N-biosyl group with 1-4 interglycosidic linkage, and
the N-acetyl-glucosamine of the N-acetyl-lactosaminyl group with 1-3 interglycosidic linkage; and
the sialyl residue attached to the N-acetyl-lactosaminyl and/or the lacto-N-biosyl group includes a linkage selected from the group consisting of
the galactose of the lacto-N-biosyl group with 2-3 interglycosidic linkage,
the N-acetyl-glucosamine of the lacto-N-biosyl group with 2-6 interglycosidic linkage, and
the galactose of the N-acetyl-lactosaminyl group with 2-6 interglycosidic linkage, and
a quantity of the mixture of the at least two compounds selected from the group consisting of compounds of general formula 1 and compounds of general formula 2 are selected such that the mixture of human milk oligosaccharides (HMOs) has an oligosaccharide profile that is substantially similar to a milk selected from the group consisting of colostrum breast milk, transitional breast milk and mature breast milk.
12. A method for manufacturing an infant nutritional product or infant formula comprising a mixture of human milk oligosaccharides (HMOs), the method comprising: subjecting a mixture of at least two compounds selected from the group consisting of compounds of general formula 1 and compounds of general formula 2 to catalytic hydrogenolysis to remove R,
wherein the R-glycoside is a β-anomer,
R 1 is independently a fucosyl or an H,
R 2 is an N-acetyl-lactosaminyl group or a lacto-N-biosyl group,
R 3 is an H or an N-acetyl-lactosaminyl group,
R 4 is independently a sialyl or an H,
and salts thereof,
at least one of R 1 or R 4 is not H in general formula 2, and
a quantity of the mixture of the at least two compounds selected from the group consisting of compounds of general formula 1 and compounds of general formula 2 are selected such that the mixture of human milk oligosaccharides (HMOs) has an oligosaccharide profile that is substantially similar to a milk selected from the group consisting of colostrum breast milk, transitional breast milk and mature breast milk.
13. The method of claim 12 , wherein the N-acetyl lactosaminyl group comprises a glycosyl residue comprising one or more N-acetyl-lactosaminyl and/or one or more lacto-N-biosyl groups, and at least one N-acetyl-lactosaminyl or lacto-N-biosyl group is substituted with a sialyl and/or fucosyl residue; and
R 3 is N-acetyl-lactosaminyl group substituted with a glycosyl residue comprising one or more N-acetyl-lactosaminyl and/or one or more lacto-N-biosyl groups, and at least one N-acetyl-lactosaminyl or lacto-N-biosyl group is substituted with one or more sialyl and/or fucosyl residue.
14. A method for manufacturing an infant nutritional product or infant formula comprising a mixture of human milk oligosaccharides (HMOs), the method comprising: subjecting a mixture of at least two compounds selected from the group consisting of compounds of general formula 1 and compounds of general formula 2 to catalytic hydrogenolysis to remove R,
wherein R is a benzyl,
R 1 is independently a fucosyl or an H,
R 2 is an N-acetyl-lactosaminyl group or a lacto-N-biosyl group,
R 3 is an H or an N-acetyl-lactosaminyl group,
R 4 is independently a sialyl or an H,
and salts thereof,
at least one of R 1 or R 4 is not H in general formula 2, and
a quantity of the mixture of the at least two compounds selected from the group consisting of compounds of general formula 1 and compounds of general formula 2 are selected such that the mixture of human milk oligosaccharides (HMOs) has an oligosaccharide profile that is substantially similar to a milk selected from the group consisting of colostrum breast milk, transitional breast milk and mature breast milk.
15. The method of claim 14 , wherein the N-acetyl lactosaminyl group comprises a glycosyl residue comprising one or more N-acetyl-lactosaminyl and/or one or more lacto-N-biosyl groups, and at least one N-acetyl-lactosaminyl or lacto-N-biosyl group can be substituted with a sialyl and/or fucosyl residue; and
R 3 is N-acetyl-lactosaminyl group substituted with a glycosyl residue comprising one or more N-acetyl-lactosaminyl and/or one or more lacto-N-biosyl groups, and at least one N-acetyl-lactosaminyl or lacto-N-biosyl group can be substituted with one or more sialyl and/or fucosyl residue.
16. A method for manufacturing an infant nutritional product or infant formula comprising a mixture of human milk oligosaccharides (HMOs), the method comprising: subjecting a mixture of at least two compounds selected from the group consisting of compounds of general formula 1 and general formula 2 to catalytic hydrogenolysis to remove R,
wherein R is a group removable by the catalytic hydrogenolysis,
R 1 is independently a fucosyl or an H,
R 2 is an N-acetyl-lactosaminyl group or a lacto-N-biosyl group,
R 3 is an H or an N-acetyl-lactosaminyl group,
R 4 is independently a sialyl or an H,
and salts thereof,
at least one of R 1 or R 4 is not H in general formula 2, and
a quantity of the mixture of the at least two compounds selected from the group consisting of compounds of general formula 1 and compounds of general formula 2 are selected such that the mixture of human milk oligosaccharides (HMOs) has an oligosaccharide profile that is substantially similar to a milk selected from the group consisting of colostrum breast milk, transitional breast milk and mature breast milk,
wherein the catalytic hydrogenation leads to human milk oligosaccharides (HMOs) according to general formula 3 and general formula 4
wherein R 1 is independently a fucosyl or an H,
R 2 is an N-acetyl-lactosaminyl group or a lacto-N-biosyl group,
R 3 is an H or an N-acetyl-lactosaminyl group,
R 4 is independently a sialyl or an H,
and salts thereof, and
at least one of R 1 or R 4 is not H in general formula 4.
17. The method of claim 16 , wherein the HMOs are selected from the group consisting of: 2′-fucosyllactose, 3-fucosyllactose, 2′,3-difucosyllactose, 3′-sialyllactose, 6′-sialyllactose, 3′-sialyl-3-fucosyllactose, lacto-N-tetraose, lacto-N-neotetraose, LNFP-I, LNFP-II, LNFP-III, LNFP-V, LST-a, LST-b, LST-c, FLST-a, FLST-b, FLST-c, LNDFH-I, LNDFH-II, LNDFH-III, DS-LNT, FDS-LNT I and FDS-LNT II.
18. The method of claim 16 , wherein the infant nutritional product or infant formula is in a form selected from the group consisting of a liquid, a powder and a solid.
19. The method of claim 16 , comprising adding a component selected from the group consisting of pharmaceutically or nutritionally acceptable carriers, lactose, proteins, and fat to the mixture of human milk oligosaccharides.
20. The method of claim 16 , further comprising adding prebiotics to the mixture of human milk oligosaccharides.
21. The method of claim 16 , wherein the HMOs according to general formula 3 are characterized by general formula 3a and general formula 3b
wherein
R 2a is an N-acetyl-lactosaminyl group substituted with a glycosyl residue comprising one N-acetyl-lactosaminyl and/or one lacto-N-biosyl group; at least one N-acetyl-lactosaminyl or lacto-N-biosyl group is substituted with a sialyl and/or fucosyl residue,
R 3a is an H or an N-acetyl-lactosaminyl group substituted with a lacto-N-biosyl group; at least one N-acetyl-lactosaminyl or lacto-N-biosyl group is substituted with a sialyl and/or fucosyl residue, and
R 2b is lacto-N-biosyl group substituted with a sialyl and/or fucosyl residue.
22. The method of claim 21 , wherein
the N-acetyl-lactosaminyl group in the glycosyl residue of R 2a in general formula 3a is attached to the another N-acetyl-lactosaminyl group with 1-3 interglycosidic linkage,
the lacto-N-biosyl group in the glycosyl residue of R 2a in general formula 3a is attached to the N-acetyl-lactosaminyl group with 1-3 interglycosidic linkage,
the lacto-N-biosyl group in the glycosyl residue of R 3a in general formula 3a is attached to the N-acetyl-lactosaminyl group with 1-3 interglycosidic linkage,
the N-acetyl-lactosaminyl group in the glycosyl residue of R 3b in general formula 3b is attached to the another N-acetyl-lactosaminyl group with 1-3 or 1-6 interglycosidic linkage, and and/or
the lacto-N-biosyl group in the glycosyl residue of R 3b in general formula 3b is attached to the N-acetyl-lactosaminyl group with 1-3 interglycosidic linkage.
23. The method of claim 21 , wherein general formula 3a represents lacto-N-neotetraose, para-lacto-N-hexaose, para-lacto-N-neohexaose, lacto-N-neohexaose, para-lacto-N-octaose and lacto-N-neooctaose optionally substituted with one or more sialyl and/or fucosyl residue, and general formula 3b represents lacto-N-tetraose, lacto-N-hexaose, lacto-N-octaose, iso-lacto-N-octaose, lacto-N-decaose and lacto-N-neodecaose optionally substituted with one or more sialyl and/or fucosyl residue.
24. The method of claim 21 , wherein
the fucosyl residue attached to the N-acetyl-lactosaminyl and/or the lacto-N-biosyl group includes a linkage selected from the group consisting of
the galactose of the lacto-N-biosyl group with 1-2 interglycosidic linkage,
the N-acetyl-glucosamine of the lacto-N-biosyl group with 1-4 interglycosidic linkage and
the N-acetyl-glucosamine of the N-acetyl-lactosaminyl group with 1-3 interglycosidic linkage,
the sialyl residue attached to the N-acetyl-lactosaminyl and/or the lacto-N-biosyl group includes a linkage selected from the group consisting of
the galactose of the lacto-N-biosyl group with 2-3 interglycosidic linkage,
the N-acetyl-glucosamine of the lacto-N-biosyl group with 2-6 interglycosidic linkage, and
the galactose of the N-acetyl-lactosaminyl group with 2-6 interglycosidic linkage.