Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2002-01-02
2004-02-03
Barts, Samuel (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S059000, C536S123100, C536S112000, C536S117000, C536S118000, C536S120000, C536S098000
Reexamination Certificate
active
06686341
ABSTRACT:
The present invention relates to nutritional compositions which contain certain classes of non-digestible polysaccharides. These compositions reduce the uptake of high molecular weight substances, allergens and microorganisms through the intestinal wall. In particular the present invention relates to reduction of the free transport of such substances through the tight junctions (TJs) of the intestines, without the transport of low molecular weight substances, such as nutrients, via the intestinal epithelium being impeded. The compositions can be used to prevent the increased permeability of the intestinal wall, due to various causes, and the penetration, resulting therefrom, of toxins, antigens and pathogenic microorganisms present in the lumen.
The structure and fraction of tight junctions is described, inter alia, in Ann. Rev.
Physiol. 60, 121-160 (1998) and in Ballard T. S. et al., Annu.Rev.Nutr., 1995, 15:35-55. Tight junctions do not form a rigid barrier but play an important role in diffusion through the intestinal epithelium from lumen to bloodstream and vice versa.
The permeability of the tight junctions is highly regulated and can be disturbed by disease and certain toxins in the lumen. Regulation takes place from the nervous system, the hormonal system and the immune system. When tight junctions are opened substances having a high molecular weight, allergens and even microorganisms will pass through the tight junctions. The translocation of substances having a high molecular weight can, under certain conditions, give rise to sensitisation of the immune system and result in allergic reactions on a subsequent exposure. Translocation of pathogenic microorganisms makes a substantial call on the immune system and, inter alia in periods of reduced resistance, can make persons and animals ill. The same applies, for example, in the case of bacterial toxins which have been able to pass through the epithelial layer and have been able to reach the bloodstream.
The invention now relates to nutritional compositions which contain slightly negatively charged non-digestible polysaccharides having a molecular weight of 8 kD to 40,000 kD, characterised in that the rise in the viscosity of the composition caused by the polysaccharides is less than 20 mPa·s.
In particular the invention relates to the use of these compositions to reduce the uptake of high molecular weight substances, allergens and microorganisms through the intestinal wall.
More particularly the invention relates to the use of the abovementioned compositions to reduce transport of high molecular weight substances, allergens and microorganisms through the tight junctions in the intestines.
Some of the polysaccharides described above have already been described previously. U.S. Pat. No. 2,813,797 and U.S. Pat. No. 2,834,684 describe the use of carboxymethyldextran as a thickener, by which means the nutrient acquires certain desirable functional characteristics. This viscosity-raising effect is, as will be described below, undesirable in the case of the present invention.
Furthermore, in WO 97/41899 the thickening action of oxidised dextrans is used to make a wound dressing through which the active components are released in a controlled and slow manner to the tissue located under the dressing.
EP 0 772 446 describes the use of a combination of chitosan and dextran sulphate to prevent damaged tissue undesirably adhering to surrounding tissue. EP 0 759 760 discloses the stimulating action of the combination of chitosan and dextran sulphate on the healing of skin wounds.
In EP 0 754 460 it is described that sulphated acid mucopolysaccharides and dextran sulphate can be used for the treatment of diseases associated with inflammation, such as rheumatoid arthritis, ischaemia of the heart or brain, atopic dermatitis, infiltration following organ transplant.
In EP 0 737 072 it is described that sulphated polysaccharides such as dextran sulphate can prevent binding of bacteria to the wall of the respiratory system. WO 96/30027 discloses that sulphated polysaccharides such as carragheenan and dextran sulphate can be used to combat Rotavirus infections. EP 0 719 783 describes the use of non-digestible highly phosphorylated polysaccharides in nutrients to increase calcium absorption.
None of these documents describes the beneficial effect of slightly negatively charged polysaccharides as defined in claim
1
of this Application. More particularly, it is not described that these polysaccharides have an effect on the tight junctions in the intestines and in the event of disturbance of the permeability of the tight junctions are able to reduce the transport of high molecular weight substances, allergens and microorganisms through the tight junctions into the intestines.
In addition to the significant reduction in the transport of harmful substances and microorganisms, a significant advantage of the present invention is that the normal transport of useful substances (nutrients) such as glucose, amino acids, dipeptides or trace elements is substantially maintained.
According to the invention, non-digestible polysaccharides are understood to be polysaccharides which are not or are barely digested or converted by the human digestive enzymes under the conditions prevailing in the body. It must be pointed out that some of the non-digestible polysaccharides can be fermented by the microorganisms present in the intestines (colon, caecum and part of the ileum). Without wishing to be tied to any theory, it is, however, expected that the effect of the polysaccharides on the paracellular transport does not take place via the fermentation products.
The extent to which the polysaccharides are digested can be determined using the method as described in Minekus, M., Ph.D Thesis, University of Utrecht, 1998, Development and validation of a dynamic model of the gastrointestinal tract, Section 2. The polysaccharides according to the invention are less than 50% and preferably less than 30% digestible.
Preferably, the polysaccharides according to the invention contain groups which are negatively charged at pH 5.5-8, such as carboxyl, sulphate or phosphate, in a quantity of 1 negatively charged group per 3 to 10,000 saccharide units, preferably 1 negatively charged group per 10 to 10,000 saccharide units. Polysaccharides in which the negatively charged groups are carboxyl groups are most preferred.
These polysaccharides can be obtained via a synthesis route or by making use of naturally occurring polysaccharides.
Examples of modified polysaccharides are dextrans into which a negative group has been introduced, for example carboxydextran or carboxymethyldextran. Following or during hydrolysis of a high molecular weight dextran, one or more carboxyl groups can be introduced into the molecule by derivatisation. Derivatisation can, for example, take place by using the Kiliani-Fischer reaction or by carboxymethylation with, for example, chloroacetic acid or by oxidation of, for example, the reducing end of the molecule. Neutral naturally occurring polysaccharides can also be provided with one or more acid groups in this way. Examples of suitable naturally occurring polysaccharides are gluco-mannans; (galacto)mannans, such as guar gum, tara gum, carob gum and locust bean gum; curdlan; agar agar; arabans; (arabino)galactans, tamarind gum, pullulan and (arabino)xylans. Preferably the shortened forms or the hydrolysis products of these polysaccharides are used. Mixtures of modified polysaccharides can also be used.
Naturally occurring polysaccharides such as gum arabic, some carragheen preparations, chia gum, psyllium, gum tragacanth, ghatti gum, okra gum, some hemicellulose preparations, welan gum, rhamsan gum, gellan gum and certain pectins with a high degree of esterification are suitable as such, but much more preferentially in the hydrolysed form or shortened form obtained in some other way.
When polysaccharides contain too many negatively charged groups, such as, for example, alginates, some carragheen preparations, gellan gum, xanthan gum, karaya gum and many
Bijlsma Pieter Brandt
Groot Jacques Alphons
Kiliaan Amanda Johanna
Timmermans Johannes Wilhelmus
Van Der Meulen Jan
Barts Samuel
Henry Michael C.
N.V. Nutricia
Young & Thompson
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