Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
1998-10-29
2001-03-13
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S400000
Reexamination Certificate
active
06200605
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to a composition useful as an antiflatulent dietary supplement.
DESCRIPTION OF THE RELATED ART
Flatulence is a normal human excretory function socially stigmatized in the United States. Flatulence is the result of the production of gases in the large intestine by anaerobic microbes, primarily bacteria, that are nourished by the contents of the intestinal lumen. Other than the bacteria themselves, which can number as great as one trillion per gram of colonic lumenal contents, the contents of the lumen of the large intestine include, aside from water and ions and other minor components, foodstuffs not digested during prior transit through the proximal portions of the alimentary canal: the mouth, esophagus, stomach and small intestine. It is these otherwise undigested lumenal contents which the microbes themselves may digest. End-products of the metabolism of these contents by the anaerobic microbes include various gases, including H
2
, CH
4
, etc. and short-chain fatty acids (SCFAs) such as acetic, propionic, and butyric acids. One of the primary loci of absorption of SCFAs out of the lumen and into colonic epithelia is the proximal portion of the colon, i.e. the cecum and ascending (right) colon. Gases are excreted through the lungs or via the external anal sphincter (EAS). Digestive processes in the colon are reviewed in: Cummings J H, Macfarlane G T (1991) The control and consequences of bacterial fermentation in the human colon.
Journal of Applied Bacteriology
70, 443-459; Nordgaard I, Mortensen P B (1995) Digestive processes in the human colon.
Nutrition
11, 37-45; Gibson G R, Roberfroid M B (1995) Dietary modulation of the human colonic microbiota: introducing the concept of prebiotics.
Journal of Nutrition
125, 1401-1412.
Previous inventions to relieve flatulence have in general been medications based upon compounds such as simethicone that lower the surface tension of gas bubbles evolved in the bowel lumen, hence lessening individual bubble volume and easing passage. Some such compositions are described in U.S. Pat. Nos. 4,127,650, 5,599,577, and 5,612,054. Useful as such inventions may be, they do not address the root cause of flatulence, i.e. the production of gas by the resident microbes. The use of a microbial galactosidase to prevent flatulence is known in the art but is limited in its potential effectiveness to flatulence caused by the fermentation of galactose-containing oligosaccharides. Moreover, such enzymatic preventatives are limited in their effectiveness by the ability of the enzyme to withstand the rigors of the environment of the stomach and the small intestine and by the uncertain probability that enzyme and substrate will productively collide.
None of the aforementioned inventions acts directly on the microbes that are directly responsible for gas production.
Synthesis and activity of sequential metabolic enzyme systems such as those that engage in anaerobic (fermentative) metabolism is in general regulated by certain end-products of the action of such metabolic pathways. If enzyme synthesis itself is regulated, the process is called repression; if enzyme activity alone, then feedback inhibition.
In the case of colon lumen microbes, the regulatory milieu is complicated by the fact that gases are excreted through the lungs or via the EAS while SCFAs are absorbed primarily in the proximal segments of the large intestine. Thus the microbes often continue to produce gas as long as a suitable food source is available, since end-products of metabolism do not always accumulate but instead can be released into the external environment or absorbed into the body.
BRIEF SUMMARY OF THE INVENTION
So to address a long-felt need for an effective antiflatulent, the inventor envisioned a supplement to the normal human diet which would comprise a food preservative, for example a food preservative generally recognized as safe that is also a metabolic end-product of microbial fermentation. (Preservatives generally recognized as safe are enumerated, and conditions of their approved use are listed, in 21 CFR 582, which is incorporated by reference.) Among such compounds are traditional food preservatives such as vinegar, consisting primarily of acetate and a fraction of SCFAs, in use for thousands of years to prevent food spoilage.
However, the ingestion of vinegar as such has not been shown to confer relief of flatulence.
Another preservative occurring as a metabolite in nature is benzoate. Ingestion of meaningful quantities of benzoate was found by the present inventor to induce severe and acute diuresis which was concluded to be potentially harmful. No antiflatulent property was noted.
From the observation of benzoate-induced diuresis, and from benzoate's lack of noticeable antiflatulent activity when ingested alone, it was inferred that a large proportion of benzoate must have been absorbed before it could arrive at the colon.
Hence a dietary supplement formulation was envisioned and developed that would include an end product of microbial fermentative metabolism safe for human consumption but not capable of being absorbed to a large degree before arriving at the lumen of the distal portions of the colon.
A composition consisting of citrus pectin and calcium propionate was developed and tested. The composition possessed considerable antiflatulent activity.
The utilization of a dietary supplement composition consisting of substances generally recognized as safe in order to diminish flatulence had not been known in the art. Such a composition proved useful to address a long-felt need for an effective antiflatulent. Related art did not in any way contemplate the use of, for instance, SCFAs as antiflatulents.
The invention is to be distinguished from drugs known in related art such as antibiotics which may kill microbes selectively or indiscriminately or which inhibit the synthesis of certain classes of macromolecules by microbes resident in the intestinal lumen. The current invention does not relate to such drugs since it has to do with the presentation of relatively non-toxic presumptive products of their own metabolism to anaerobic microbes resident in the colonic lumen.
The invention is also to be distinguished from so-called colonic delivery systems, such as those described in U.S. Pat. No. 5,525,634, that present drugs to the intestinal epithelial cells for absorption into the body. The current invention does not relate to such devices since it has to do with the presentation of relatively non-toxic presumptive products of their own metabolism to anaerobic microbes resident in the colonic lumen, not for absorption into the body.
The art teaches away from antiflatulent use of SCFAs. For example, while SCFAs were noted as being present in normal human feces, SCFAs administered in solution were shown to be rapidly absorbed from the colon. McNeil, N I et al. (1978) Short chain fatty acid absorption by the human large intestine. Gut 19, 819-822. The use of SCFAs, preservatives or microbistats (i.e., compositions used not to kill but rather to slow or control the growth of microbes) to manipulate flatulence has therefore not been contemplated in the art.
It should be noted that flatulence is a common adverse event associated with a variety of important classes of medications, including proton pump inhibitors (Langtry H D & Wilde M I,
Drugs
56, 447), HIV protease inhibitors (Moyle G J et al.,
J Clin Pharmacol
38, 736), nonsteroidal anti-inflammatory drugs (Bocanegra T S et al.,
J Rheumatol
25, 1602), and alpha-glucosidase inhibitors (Chan J C et al.,
Diabetes Care
21, 1058). From these reports, all published in 1998, one can justifiably infer that there is a need for an antiflatulent which the known art has not addressed.
DETAILED DESCRIPTION OF THE INVENTION
The usefulness of the antiflatulent dietary supplement was demonstrated in an exemplary 50 year-old individual who regularly consumes a high fiber diet consisting of whole grain breads and baked goods, bran cereals, and fresh fruits, especially apples, and
Page Thurman K.
Ware Todd D.
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