U.S. patent application number 10/068750 was filed with the patent office on 2003-08-07 for probiotic/prebiotic composition and delivery method.
This patent application is currently assigned to Corpak MedSystems, Inc.. Invention is credited to Monte, Woodrow C..
Application Number | 20030147857 10/068750 |
Document ID | / |
Family ID | 27659095 |
Filed Date | 2003-08-07 |
United States Patent
Application |
20030147857 |
Kind Code |
A1 |
Monte, Woodrow C. |
August 7, 2003 |
Probiotic/prebiotic composition and delivery method
Abstract
A prebiotic, composition comprising a probiotic and prebiotic,
and method of delivering a probiotic, prebiotic or composition
directly into the intestinal tract of a mammal are disclosed. The
probiotic is any beneficial bacteria and the prebiotic is a
substance beneficial to a probiotic. Most preferably, the prebiotic
includes a mucopolysaccharide. The method preferably involves
delivering the probiotic, prebiotic or composition via a delivery
tube, such as an enteral feeding tube, directly to a position
downstream of the stomach, most preferably to the jejunum.
Inventors: |
Monte, Woodrow C.;
(Riverton, NZ) |
Correspondence
Address: |
Squire, Sanders & Dempsey L.L.P.
Intellectual Property Dept.
Two Renaissance Square
40 North Central Avenue, Suite 2700
Phoenix
AZ
85004-4498
US
|
Assignee: |
Corpak MedSystems, Inc.
|
Family ID: |
27659095 |
Appl. No.: |
10/068750 |
Filed: |
February 5, 2002 |
Current U.S.
Class: |
424/93.4 ;
514/54 |
Current CPC
Class: |
A61K 35/747 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 35/745 20130101;
A61K 35/747 20130101; A61K 35/745 20130101 |
Class at
Publication: |
424/93.4 ;
514/54 |
International
Class: |
A61K 045/00; A61K
031/715 |
Claims
What is claimed is:
1. A composition comprising a probiotic and a prebiotic.
2. The composition of claim 1 wherein the probiotic comprises one
or more bacteria from the group consisting of Bifidobacteria and
Lactobacillus.
3. The composition of claim 1 wherein the prebiotic comprises a
mucopolysaccharide.
4. The composition of claim 3 that further comprises pectin.
5. The composition of claim 3 wherein the prebiotic comprises one
or more of the group consisting of chitin, agar and carraganan.
6. The composition of claim 3 wherein the prebiotic comprises
chitin.
7. The composition of claim 3 wherein the probiotic comprises one
or more of the bacteria of the group consisting of Bifidobacteria
and Lactobacilli.
8. The composition of claim 3 wherein the probiotic comprises a
Lactobacilli.
9. The composition of claim 8 wherein the probiotic comprises one
or more of the group comprising L. acidophilus, L. casei, L.
fermentum, L. salivaroes, L. brevis, L. leichmannii, L. plantarum
and L. cellobiosius.
10. The composition of claim 3 wherein the probiotic comprises B.
adolescentis.
11. The composition of claim 3 wherein the probiotic comprises L.
acidophilus.
12. The composition of claim 3 that is formed as part of a
tablet.
13. The composition of claim 3 that is contained within a
capsule.
14. The composition of claim 3 that includes 10.sup.6 or more
probiotic.
15. The composition of claim 3 that includes 0.1-10% probiotic and
90-99.9% prebiotic.
16. The composition of claim 3 that further comprises an
oligosaccharide.
17. The composition of claim 15 that further comprises an
oligosaccharide.
18. A method of directly introducing into the gastrointestinal
tract of a human, downstream of the stomach, the composition of
claim 1.
19. A method of directly introducing into the gastrointestinal
tract of a human, downstream of the stomach, the composition of
claim 3.
20. The method of claim 18 wherein the composition of claim 1 is
introduced directly into the jejunum.
21. The method of claim 19 wherein the composition of claim 3 is
introduced directly into the jejunum.
22. The composition of claim 3 wherein the composition is
agglomerated into particles and then dried.
23. A method of introducing into the intestinal tract of a human,
downstream of the stomach, a beneficial substance, by utilizing a
delivery tube having a first end upstream of the stomach and a
second end in the gastrointestinal tract downstream of the stomach,
the method comprising: (a) introducing the beneficial substance
into the first end of the delivery tube; and (b) allowing the
beneficial substance to exit the second end of the delivery tube
where it enters the intestinal tract downstream of the stomach.
24. The method of claim 23 wherein the beneficial substance is a
prebiotic.
25. The method of claim 23 wherein the beneficial substance is a
probiotic.
26. The method of claim 23 wherein the beneficial substance is a
composition comprising a prebiotic and a probiotic.
27. The method of claim 23 wherein the second end of the delivery
tube is in the jejunum.
28. The method of claim 23 wherein the first end of the delivery
tube is outside of the nose.
29. The method of claim 24 wherein the prebiotic includes an AG
30. The method of claim 26 wherein the prebiotic includes an
AG.
31. The method of claim 24 wherein the prebiotic includes a
non-starch polysaccharide.
32. The method of claim 26 wherein the prebiotic includes a
non-starch polysaccharide.
33. The method of claim 24 wherein the prebiotic includes a
mucopolysaccharide.
34. The method of claim 26 wherein the prebiotic includes a
mucopolysaccharide.
35. The method of claim 24 wherein the prebiotic includes an
oligosaccharide.
36. The method of claim 26 wherein the prebiotic includes an
oligosaccharide.
37. The method of claim 36 wherein the prebiotic includes a
FOS.
38. The method of claim 37 wherein the prebiotic includes a
FOS.
39. The method of claim 25 wherein the probiotic includes a
Bifidobacteria.
40. The method of claim 26 wherein the probiotic includes a
Bifidobacteria.
41. The method of claim 40 wherein the probiotic includes B.
adolescentis.
42. The method of claim 41 wherein the probiotic includes B.
adolescentis.
43. The method of claim 25 wherein the probiotic includes
Bacteroides.
44. The method of claim 26 wherein the probiotic includes
Bacteroides.
45. The method of claim 25 wherein 10.sup.6 or greater probiotic
are introduced into the first end of the delivery to be.
46. The method of claim 26 wherein 10.sup.6 or greater probiotic
are introduced into the first end of the delivery to be.
47. The method of claim 24 wherein the prebiotic includes
inulin.
48. The method of claim 26 wherein the prebiotic includes
inulin.
49. The method of claim 23 wherein the delivery to be is an enteral
to be feeding device.
50. The method of claim 26 wherein the composition comprises
0.1-10% probiotic and 90-99.9% prebiotic.
51. The method of claim 26 wherein the composition comprises 1-10%
probiotic and 90-99% prebiotic.
52. The method of claim 26 wherein the composition comprises
0.1-99% probiotic and 1-99.9% prebiotic.
53. The method of claim 24 wherein the prebiotic comprises one or
more of the group consisting of chitin, agar and carraganan.
54. The method of claim 26 that comprises a mucopolysaccharide and
an oligopolysaccharide.
55. The method of claim 26 wherein the prebiotic comprises one or
more of the group consisting of chitin, agar and carraganan.
56. The method of claim 24 wherein the prebiotic has a particle
size of 25 microns or less.
57. The method of claim 26 wherein the prebiotic has a particle
size of 25 microns or less.
58. The method of claim 26 wherein the probiotic has a particle
size of 25 microns or less.
59. The method of claim 23 wherein an enteral food is also
introduced into the first end of the delivery tube and allowed to
exit the second end of the delivery tube.
Description
FIELD OF INVENTION
[0001] The present invention relates to a prebiotic, a composition
comprising a prebiotic and a probiotic, and a method of
administering either a prebiotic, a composition or a probiotic
directly into the intestinal tract of a mammal.
BACKGROUND OF THE INVENTION
[0002] For the purpose of this application, the following terms
have the following meanings: "Probiotic" means live bacteria (also
called microflora or microorganisms) that confer a beneficial
effect when an effective amount is introduced into the intestinal
tract of a mammal. "Prebiotic" means any substance that can be
consumed by a relevant probiotic, or that otherwise assists in
keeping the relevant probiotic alive or stimulates its growth, and
includes mucopolysaccharides, oligosaccharides, polysaccharides,
amino acids, vitamins, nutrient precursors and proteins.
"Compliment" or "complimentary" with respect to a prebiotic means
that the prebiotic is consumed by, or otherwise assists in keeping
alive or stimulates the growth of, a relevant probiotic.
"Beneficial substance" means a prebiotic, probiotic or composition
comprising probiotic and prebiotic. "Effective amount" means any
non-zero amount of a beneficial substance that is introduced into
the intestinal tract of a subject, wherein the beneficial substance
is not inherently present in food stuffs being introduced into the
subject's gastrointestinal tract. "Intestinal tract" or
"gastrointestinal tract" means the tract from the mouth to the anus
and includes the stomach and intestines (including the ileum,
duodenum, jejunum, caecum, crasum (large intestine), rectum, and
tenue (small intestine, which includes the tenue mesenteriale).
"Delivery tube" means any passageway or conduit inserted into or
otherwise placed in the body for introducing a beneficial substance
directly into a part of the intestinal tract, and includes enteral
feeding tubes. "Downstream" or "beneath" means any part of the
intestinal tract downstream of the organ referenced. "Upstream"
means any part of the body upstream of the organ referenced.
"Subject" means a mammal to which a beneficial substance is
administered.
[0003] Certain bacteria (included in the foregoing definition of
probiotic) have been shown to be beneficial to human
gastrointestinal health. The human gastrointestinal tract contains
an estimated 100.times.10.sup.9 viable bacteria, representing as
many as 100 or more different species. About Probiotics,
www.probiohealth.com. While few microorganisms are found in the
stomach because of its high acidity, their numbers increase
downstream of the stomach. Natasha Trener, Probiotics: The
Foundation of Your Health, Now and Forever (Excerpts),
www.natren.com. The greatest numbers and variety are found in the
large intestine. Id.
[0004] Probiotics assist in keeping harmful pathogenic species in
check. At least some probiotics attach to the intestinal wall and
produce a mildly acidic environment (in part due to the excretion
lactic acid) that curbs the growth of certain harmful,
disease-causing bacterial species. About Probiotics, supra.
Probiotics are also believed to assist in important nutrient
assimilation, producing many important enzymes and potentially
increasing the bioavailability of, and synthesizing, some vitamins
(particularly the Bs and K), fatty acids, lactase, and calcium. Why
You Need to Take The Friendly Probiotic Bacteria in Friendly
Colonizer, www.elexa.com.
[0005] Among other benefits conferred by probiotics are believed to
be: strengthening of the immune system, neutralization of toxins,
normalization of bowel movements, control of cholesterol,
countering of allergies and skin problems, and the prevention of
yeast and fungal infections. About Probiotics, supra; Probiotics:
The Foundation of Your Healths Now and Forever, supra; Why You Need
to Take the Friendly Probiotic Bacteria for Friendly Colonizer,
supra.
[0006] The major bacteria in the intestines can be roughly divided
into three groups: (a) lactic acid bacteria, including
Lactobacilli, Bifidobacteria, and streptococci; (b) anaerobic
bacteria; and (c) aerobic bacteria. At least Lactobacilli,
Streptococci, and Bifidobacteria confer beneficial effects to
mammals, particularly humans, and are included in the definition of
probiotic herein.
[0007] Lactobacilli (i.e., bacteria of the genus Lactobacillus,
abbreviated as "L.") have been used for several hundred years as
food presentations and for promoting human health. About
Probiotics, supra. Lactobacilli found in the human intestinal tract
include L. acidophilus, L. casei, L. fermentum, L. saliva roes, L.
brevis, L. leichmannii, L. plantarum, and L. cellobiosus.
[0008] L. acidophilus has been shown to be useful in treating
conditions such as antibiotic-induced imbalances in the
gastrointestinal microflora, hypercholesterolemia, vaginal
infections, E. coli infection, depressed immunity, cancerous
tumors, chronic granulomatous disease, and lactose indigestion. A.
G. Shauss, Method of Action, Clinical Application, and Toxicity
Data, 3 J. Advancement Med. 163 (1990). It has also been shown that
the activities of fecal bacterial enzymes thought to play a role in
conversion of procarcinogens to carcinogens, such as
betaglucuronidase, nitroreductase, and azoreductase, were reduced
2- to 4-fold in persons taking L. acidophilus supplements. B. R.
Goldin & L. S. Gorbach, "The Effect of Milk and Lactobacillus
Feeding on Human Intestinal Bacterial Enzyme Activity,"39 Amer. J.
Chin. Nutr. 756 (1984). These results suggest that dietary
supplementation with L. acidophilus may reduce the risk of
developing colon cancer.
[0009] Lactobacilli also produce organic acids that reduce
intestinal pH thereby inhibiting the growth of acid-sensitive
undesirable bacteria. Why You Need to Take the Friendly Probiotic
Bacteria for Friendly Colonizer, supra. Lactobacilli produce lactic
acid, hydrogen peroxide, and possibly acetic and benzoic acids. In
vitro studies have shown L. acidophilus to inhibit the growth of
pathogenic bacteria such as Campylobacter pylori, Staphylococcus
aureus, Pseudomonas aeruginosa, and Sarcina lutea. K. M. Shahani et
al., "Natural Antibiotic Activity of Lactobacillus Acidophilus and
Bulgaricus,"11 Cultured Dairy Products J. 14 (1976).
[0010] Bifidobacteria are also known to exert a beneficial
influence on human health. These bacteria exert antimicrobial
activity in the human intestine by producing short chain fatty
acids (SCFAs) such as acetic, propionic, and butyric acids, as well
as lactic and formic acids, as a result of carbohydrate metabolism.
The most plentiful SCFA produced by Bifidobacteria is acetic acid,
which is an antimicrobial to gastrointestinal pathogens such as
yeasts, molds, and certain other bacteria. Further, both
Lactobacilli and Bifidobacteria may produce other antimicrobial
substances, such as bacteriocins, that also inhibit the growth and
proliferation of certain harmful bacteria.
[0011] Additionally, SCFAs are believed to support normal
gastrointestinal function by increasing colonic blood flow,
stimulating pancreatic enzyme secretion, promoting sodium and water
absorption and intestinal mucosal growth. Bifidobacteria are also
believed to deconjugate bile salts to free bile acids, which are
more inhibitory to susceptible bacteria than are the conjugated
forms.
[0012] Therapeutic applications of Bifidobacteria are used to treat
diarrhea, constipation, and hepatic encephalopathy with
hyperammonemia. Additional benefits are believed to include the
production of B vitamins and breakdown of carcinogenic
N-nitrosamines.
[0013] Bifidobacteria constitute the predominant microorganisms in
the fecal microflora of week-old breast-fed infants, making up
85-99% of the bacterial population. Upon weaning or upon an event
such as an infection, vaccination, or a sudden change in diet, the
balance of microorganisms in the gastrointestinal tract of these
babies can be upset. The Bifidobacterial population in adults is
generally stable. However, changes in diet, administration of
antibiotics, exposure to gamma radiation or X-rays, disease,
pollutants, stress, or other disturbances can result in an
overgrowth of potentially pathogenic bacteria and/or a decrease in
beneficial bacteria (e., Lactobacilli and/or Bifidobacteria). About
Probiotics, supra. Bifidobacteria numbers can be significantly
reduced in elderly people for other reasons, for example, due to a
reduction of secreted gastric juices.
[0014] Without sufficient numbers of probiotics, intestinal ecology
may be thrown off balance, which can potentially result in health
problems. Probiotic supplements may be used to increase the number
of probiotics in the intestinal tract. About Probiotics, supra. As
mentioned in "Probiotics, Prebiotics & Synbiotics: Harnessing
Enormous Potential," Nutraceuticals World (September 2001), a trend
regarding probiotics is finding novel delivery systems,
particularly because acidity in the stomach is detrimental to many
probiotics and may destroy as much as 90-95% of such probiotics
during their passage through the stomach. To date, improving the
protection of probiotics from stomach acid has included using
enteric coated capsules and microencapsulation. Such types of
microencapsulation include technology known as Probiocap.TM. by
Institut Rosell.
[0015] Known prebiotics include dietary fibers, such as
polysaccharides and oligosaccharides, that have the ability to
increase the number of probiotic, which leads to the benefit(s)
conferred by the probiotic. For example, an increase of beneficial
Bifidobacteria is likely to change the intestinal pH to support an
increase of Bifidobacteria, and which decreases pathogenic
organisms. A prebiotic may also provide one or more of the
following benefits: (1) indirectly produce short chain fatty acids
(SCFAs) that in turn have a trophic (nourishing) effect on the
intestinal epithelium, supporting its integrity as a defense
barrier against invading organisms; (2) indirectly produce immune
stimulants, by the promotion of Bifidobacteria that excrete an end
product inhibitory to pathogenic bacteria; (3) promote a
host-mediated attack against tumor sites and promote certain
strains of Lactobacilli that have immune-modulating activity,
enhancing phagocyte activity in the blood; and (4) indirectly
provide any of the benefits of an increased number of probiotic
whose number increased due at least in part to the presence of the
prebiotic. A prebiotic may also affect the production of certain
bacteria enzymes, such as decreasing glucosidase that is associated
with the absorption of intestinal cholesterol, associated with the
formation of secondary bile acid that is considered a
co-carcinogen.
[0016] However, while known prebiotics break down to provide
carbohydrates for probiotics, some probiotics also require amino
acids for nourishment.
[0017] It would therefore be desirable to have a prebiotic that was
resistant to stomach acids and that provided carbohydrates and
amino acids to support probiotic growth. It would also be desirable
to introduce a probiotic into the intestinal tract in a manner that
alleviates the destruction caused by stomach acid and enables the
probiotic to quickly enter the intestines, where it can be of most
benefit.
SUMMARY OF THE INVENTION
[0018] One aspect of the invention is a novel prebiotic comprising
a mucopolysaccharide. Preferred mucopolysaccharides are chitin,
agar and carraganan. Mucopolysaccharides are resistant to stomach
acids; much of a mucopolysaccharide passes through the stomach to
the intestines where it is digested by one or more probiotics.
Mucopolysaccharides decompose into carbohydrates and amino acids,
thus providing high-quality nourishment for certain probiotics. The
most preferred prebiotic according to the invention comprises a
mucopolysaccharide and an oligopolysaccharide.
[0019] Another aspect of the invention is a composition comprising
a probiotic and prebiotic, wherein the prebiotic is selected to
compliment a relevant probiotic and preferably includes a
mucopolysaccharide. Mucopolysaccharides tend to agglomerate when
wet, forming a globule having a mucous-like or gelatinous coating
and a relatively dry interior. Probiotics in the interior of such a
globule are at least partially protected from stomach acids and, if
the composition passes through the stomach, a greater number of
probiotic survives and enters the intestines alive.
[0020] The invention also includes a novel method for delivering a
beneficial substance directly into the intestinal tract, preferably
downstream of the stomach, and most preferably into the jejunum.
The method preferably utilizes a delivery tube, such as an enteral
feeding tube, through which the beneficial substance is conveyed
directly into the intestines. In that manner the beneficial
substance is delivered directly to where it can provide beneficial
results (ultimately, an increase in the number of probiotic) and
avoid most of the stomach acids.
[0021] Any aspect of the present invention that requires the
introduction of a beneficial substance into the gastrointestinal
tract of a subject requires that an effective amount be
introduced.
BRIEF DESCRIPTION OF THE DRAWING
[0022] FIG. 1 shows a cross-sectional view of an abdomen including
a delivery tube that may be used to practice the invention.
DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT
[0023] The invention comprises one or more of the following: (a) a
novel prebiotic, namely a mucopolysaccharide, (b) a composition
comprising a prebiotic (preferably including a mucopoysaccharide)
and a probiotic, and/or (c) a method for delivering a beneficial
substance directly into the intestinal tract downstream of the
stomach, most preferably into the jejunum.
[0024] As used in this specification and the appended claims, the
singular forms "a," "an," and "the" include both the singular and
the plural unless the context clearly dictates otherwise. For
example, a composition containing "a probiotic" includes a
composition having one probiotic or two or more probiotics, and "a
prebiotic" includes a prebiotic or two or more prebiotics. Each of
the terms "includes," "include," "comprises" and "comprise" means
"includes at least." For example, "a prebiotic comprising FOS"
means the prebiotic includes at least FOS; it may also include
other prebiotics and/or other substances.
[0025] Probiotics that may be used to practice the invention are
bacteria that benefit mammalian (particularly human) health,
particularly gastrointestinal health. Preferably, the probiotic
includes one or more of a Lactobacilli and Bifidobacteria. Specific
probiotics that may be used include, but are not limited to, one or
more of L. acidophilus, L. reuteri, L. curvatus, L. bulgaricus, L.
grasseri, L. casei, L. fermentum, L. caveasicus, L. helveticus, L.
lactis, L. salivarius, L. rhamnosus, L. brevis, L. leichmanni, L.
plantarum, L. cellobiosus, L. buchneri, Bifidobacterium
(abbreviated as "B.") laterosporus, B. breve, B. subtilus, L.
sporogenes (also known as Bacillus coagulans), pediococcus
acidilactici, pediococcus pentosaceus, enterococcus faecium, B.
adolescentis, B. infantis, B. longum, B. thermophilum, B. animalis,
and B. bifidum. Steptococcus thermphilius may also be used, which
is believed to improve lactose digestion and make micronutrients
more available to the host. The Eight Active Cultures in Cascade
Fresh, www.cascadefresh.com. Other probiotics that may be used
include Lactococcus lactis cremoris, S. diacetylactis and S.
intermedius. Most preferably, the probiotic includes one or more of
L. acidophilus, B. adolescentis and B. bifidum.
[0026] Commercially available strains of L. acidophilus include
NCRM and Lactobacillus acidophilus DDS-1, manufactured by Nebraska
Cultures, Inc. and Lactobacillus rhamnosus GG, manufactured by
LGG--Research and Development, which is deposited in the American
Type Culture Collection, coded ATCC 53103. Another commercially
available strain of Lactobacilli is KE-99 LACTO by Probiohealth,
Inc. of Los Angeles, Calif.
[0027] In addition to the benefits already described herein, a
brief description of some benefits attributed to some of the
preferred probiotics follows: L. casei is highly prolific and
hardy. It produces lactic acid and digests a wide range of
carbohydrates. Because of its ability to eliminate protein wastes
from the intestine before they enter the bloodstream, it is
believed to benefit the immune system. L. plantarum produces lactic
acid and acts as a natural antibiotic (as acidophilin). L.
salivarius is effective in eliminating bowel toxemia, and it
produces B and K vitamins, enzymes, and lactic acid, and aids in
the production of lactase. L. bulgaricus produces lactic acid and
enhances the digestion of milk sugar. Streptococcus thermophilus
produces lactic acid and lactase.
[0028] There is no published standard for the amount of bacteria
that should be in a probiotic product or dosage, only estimated
figures ranging from 10.sup.6 to 10.sup.10 bacteria per day,
depending on the condition of the host. However, probiotics are
generally safe and well tolerated by humans even at high
dosages.
[0029] A prebiotic according to the invention is complimentary to
at least one probiotic (a) present in a composition according to
the invention, (b) administered separately to a subject to whom the
prebiotic is administered, and/or (c) already present in the
gastrointestinal tract of a subject to whom the prebiotic is
administered. Determining whether a prebiotic is complimentary to a
probiotic may be done in a number of ways known to those skilled in
the art. For example, the effect could be gauged by a plate count
of probiotic present in a subject's feces or the pH of a subject's
chyme, a lowering of which would likely indicate an increased
number of probiotic. Alternatively, a probiotic could be cultured
in vitro with a selected prebiotic and without the probiotic. Tests
could then be conducted to determine relative growth curves over
time.
[0030] The prebiotic may comprise one or more of the following (a)
an oligosaccharide, (b) a fructo-oligosaccharide ("FOS"), such as a
soy fructo-oligosaccharide, inulin or banana fiber, (c) a pectin or
pectic polysaccharide, (d) a mannan, such as guar gum, locust bean
gum, konjac, or xanthan gum, (e) a pentosan, beta-glucan, arabinan
and galactan, such as larch arabinogalactan, and (f) mixtures
thereof.
[0031] FOS are long-chain polysaccharides comprised primarily of
fructose monosaccharides bonded together by
1-.beta.-D-fructofuranosyl linkages. Upon ingestion,
fructo-oligosaccharides are only partially hydrolyzed as they pass
through the mouth, stomach, and small intestine. In the large
intestine, they became food for certain probiotics, such as L.
acidophilus and B. infantis and are metabolized into SCFAs, mainly
acetic, propionic, butyric, and lactic acids. As a consequence of
this fermentation, a considerable amount of bacterial mass is
produced. This results in increased numbers of probiotic, a lowered
intestinal pH, and is believed to inhibit pathogens. A pH decrease
will increase solubility of calcium and other minerals and may
enhance the absorption of calcium and magnesium. Illustrative
fructo-oligosaccharides include inulin, banana fiber, and soy
fructo-oligosaccharides, and are found in honey, beer, onion,
asparagus, Chinese chive, maple sugar, oats, and Jerusalem
artichoke.
[0032] Inulin is produced naturally in an estimated 36,000 or more
plants worldwide including onion, asparagus, artichoke, and many
cereals. Chicory root and Jerusalem artichoke each contain a
significant amount of inulin. In addition to encouraging the growth
of probiotics, some animal studies and some human clinicals suggest
that inulin oligosaccharides provide the benefit of enhancing
calcium and magnesium absorption in the small intestine.
[0033] The pectins and pectic polysaccharides (high and low
methoxyl pectins) may also be used as a prebiotic. Pectin is a
highly water soluble, noncellulosic polysaccharide fiber that
occurs naturally as a partial methyl ester of .alpha.-(1.fwdarw.4)
linked D-polygalacturonate sequences interrupted with
(1.fwdarw.2)-L-rhamnose residues. The term pectic polysaccharides
refers to galacturonans or, more commonly, rhamno-galacturonans
wherein (1-4)-.alpha.-D-galacturonan chains are interrupted at
intervals by insertion of (1-2)-.alpha.-L-rhamnose residues. Other
constituent sugars attached as side chains include D-galactose,
L-arabinose, D-xylose, and, less frequently, L-frucose and
D-glucuronic acid. Most of these sugars occur in short side chains,
although D-galactose and L-arabinose are found in multiple units.
Extremely complicated side chains containing neutral pectic
polymers such as galactans and arabinans, xyloglucans, and
galactomannans have been reported.
[0034] Pectin is usually extracted from the primary cell walls of
certain plants. Rich sources of pectin include lemon and orange
rinds, which contain about 30% by weight of pectin. Pectins are
used as gelling and thickening agents in food technology and as an
antidiarrheal in veterinary medicine.
[0035] Mannans (such as glucomannans and galactomannans), such as
guar gum, locust bean gum, konjac, and xanthan gum, are present in
some plant cell walls. The glucomannans are generally comprised of
(1-4)-.beta.-linked glucose and mannose units, while the
galactomannans are generally comprised of a (1-4)-.beta.-mannan
backbone substituted with single units of (1-6)-.alpha.-galactose.
Many endospermic legumes, such as guar and locust bean, contain
galactomannans in the endosperm during seed development.
Glucomannans have also been found as a minor component of cereal
grains.
[0036] Guar gum is produced from the ground endosperms of Cyamopsis
tetragonolobus, a legume cultivated in India as a livestock feed.
The water soluble fraction, which typically comprises about 85% of
guar gum is also known as guaran.
[0037] Arabingalactans ("AG") are non-starch polysaccharides used
as a dietary fiber, and which exist in many edible sources
including carrots, larch, radishes, black beans, pears, maize,
wheat, red wine, tomatoes and coconuts. AG resists digestion by the
enzymes in saliva and the small intestine and enters the large
bowel where it is fermented by at least some of the resident
probiotics. Studies have shown that the majority of probiotics that
ferment AG are Bifidobacterium. Fermentation of AG by various
species of these genera produce SCFAs that lower colon pH, favoring
the growth of these probiotics and acting as a natural
antimicrobial agent, as previously mentioned. This is believed to
lead to a lowering of ammonia in the colon, which is a distinct
benefit since excess ammonia is associated with an increase in
carcinogenic activity.
[0038] The production of SCFAs from the AG fermentation leads to
relatively high butyrate concentrations. In addition to butyrate's
trophic effects on mucosa, it is believed to be beneficial to the
colon epithelium. Further, a defect in butyrate metabolism has been
identified in ulcerative colitis patients. At least one comparison
of the fermentation of AG and other polysaccharides showed that AG
produced significantly more butyrate than either pectin or xylan.
Both animal and human studies have shown a reduction of pathogenic
bacteria in the colon when AG is consumed, and an increase in B.
longum.
[0039] Some specific commercial prebiotics that may be used to
practice the invention include (1) FOS such as BeFlora.TM.,
manufactured by Triarco Industries, Wayne, N.J.; (2) short chain
FOS, such as NutraFlora.RTM., distributed by GTC Nutrition, Golden
Colo.; (3) inulin, such as Raftiline.RTM. and Raftilose.RTM.,
manufactured by Orafiti of Malvern, Pa., Frutafit.RTM. by Imperial
Sensus of Sugarland, Tex., and Inuflora.TM., manufactured by Marlyn
Neutraceuticals of Phoenix, Ariz.; (4) resistant starch, such as
Hi-Maize.TM., manufactured by Imperial Sensus; (5) starches such as
Fibersol-2.TM., manufactured by Matsutani America, Decatur, Ill.,
and which is derived from natural corn starch, (6) larch
arabinogalactan AG derived from the Larch tree, and (7) Lacty.RTM.
derived from lactitol, which is a hydrogenated lactose manufactured
by Purac America, Lincolnshire, Ill. Polylactose could also be
used, if available.
[0040] A preferred prebiotic is a mucopolysaccharide. As previously
discussed, some benefits of mucopolysaccharides are:
[0041] (a) they are not readily digested by stomach acids;
[0042] (b) they tend to agglomerate when wet, forming globules with
a gelatinous exterior and relatively dry interior; probiotics in
the interior are at least partially protected from stomach acids;
and
[0043] (c) they decompose to provide both carbohydrates and amino
acids to probiotics.
[0044] Mucopolysaccharides are a class of polysaccharide molecules,
also known as glycosaminoglycans, composed of amino-sugars
chemically linked into repeating units that give a linear
unbranched polymeric compound. The amino-sugar constituents are
typically ordinary monosaccharides that contain a nitrogen atom
covalently bound to one of the ring carbons of the sugar portion.
The nitrogen is, in turn, either bonded to two atoms of hydrogen
(termed a primary amino-group) or to another carbon atom (hence, a
substituted amino-group). The mucopolysaccharides are similar
structurally to animal and plant polysaccharides such as glycogen
and starch. Chitin is a particularly plentiful mucopolysaccharide
and is found in the shells of lobsters, crayfish, crabs, insects,
and many other invertebrate organisms. The copepods, a group of
microscopic marine organisms of the class Crustacea, alone are
considered to synthesize about 10.sup.9 tons of chitin per
year.
[0045] Heparin, an anticoagulant used widely in the treatment of
blood clotting disorders, such as pulmonary embolus, is another
mucopolysaccharide, although it is not preferred for practicing the
invention. Another mucopolysaccharide is hyaluronic acid, a
molecule found universally in the connective tissues of animals and
in the fluids of their eyes and joints. Hyaluronic acid in
association with protein has been isolated from various organisms.
Some other mucopolysaccharides include agar, carraganan and other
mucopolysaccharides extracted from seaweed, which are available
through various companies such as FMC Marine Colloids.
[0046] A beneficial substance according to the invention may be
provided and/or used in any manner or form; if a delivery method is
specified, the beneficial substance is supplied in a form suitable
to the delivery method. Most preferably the beneficial substance is
first prepared as a dried and ground particulate, and then added to
a liquid before administration to a subject. If the beneficial
substance includes mucopolysaccharides or gums, it preferably
agglomerates when the water is added.
[0047] A composition according to the invention includes a
probiotic and a prebiotic. Preferably the prebiotic compliments the
probiotic in the composition, but the prebiotic may compliment
another probiotic, such as one present in the intestines but not in
the composition. Most preferably, a prebiotic used in a composition
includes a mucopolysaccharide. Any mucopolysaccharide, either plant
(such as agar) or animal (such as chitin) may be used. A beneficial
substance is preferably provided freeze dried and ground into a
fine powder. Probiotic may be provided already ground or may be
ground using any suitable method or system, such as a hammer mill.
Commercial sources for freeze-dried and/or ground probiotics are
available and known to those knowledgeable in the art of
probiotics. Prebiotic is preferably formed or ground into a fine
dry powder (using any suitable method or system, such as a hammer
mill) having a particle size equal to or less than 25 microns. The
probiotic and prebiotic may be ground together into a composition,
or the ground prebiotic and ground probiotic may be mixed using any
suitable method or system, such as a ribbon blender. If ground with
the prebiotic, the probiotic would have the same particle size as
the prebiotic. If administered via a delivery tube, as discussed in
more detail below, the particle size of the beneficial substance
should be small enough to enable the beneficial substance to be
suspended in a liquid and pass through the delivery tube.
[0048] In addition, a probiotic may be grown in any suitable
prebiotic, including a mucopolysaccharide or prebiotic including a
mucopolysaccharide. Such as a probiotic culture and prebiotic could
then be freeze dried and ground together to form a composition.
[0049] The preferred composition would consist of up to 20%
(0.1-99%) probiotic and up to 99.9% (1-99.9%) prebiotic. A
composition may be delivered in combination with any other
substance or compound, such as enteral food, as long as the other
substance or compound does not destroy the ability of the
beneficial substance to confer a beneficial effect. For example,
the composition may comprise prebiotics other than those
specifically described herein, such as bifidius factor (currently
available only from human milk), minerals, vitamins,
phytochemicals, enzymes, lactoperoxidase, thiocyanate salt,
lactoferrin, gluconic acid, phytochemical, amino acids and/or other
substances that may benefit the probiotic of choice or otherwise
benefit the subject.
[0050] A beneficial substance including mucopolysaccharide may be
ingested orally, either as a tablet, capsule or drink. Or, the
beneficial substance including a mucopolysaccharide or gum may be
placed in powder form into agglomerator where moisture is sprayed
onto it to form globules having a gelatinous coating. The particles
dry and can be administered in any of the methods described herein,
e.g., by stirring into water and consumed as a drink, being placed
into a capsule and swallowed, or through a delivery tube.
[0051] A beneficial substance according to the invention may also
be directly delivered in any manner directly into the
gastrointestinal tract, preferably downstream of the stomach
directly into the intestines, most preferably into the jejunum.
Some known techniques for placing a delivery tube into the
intestine, and that may be used to practice the invention, include:
(1) placement of a percutaneous endoscopic gastrostomy (PEG) tube
and passing a weighted or non-weighted feeding tube into the
duodenum or jejunum; (2) surgically placing a direct jejunostomy
tube; or, (3) placing a tube directly into the jejunum with a known
PEG-like procedure, whereby the jejunum is accessed by
stab-piercing the jejunum from outside the abdominal wall. Other
methods that may be used to practice the invention, and that are
currently used for enteral delivery of fluids, are disclosed in
U.S. Pat. Nos. 5,562,615; 4,487,604; 4,498,843; 4,518,327;
4,515,584; 4,636,144; 4,832,584; 4,884,013; 4,913,703 and
5,251,027, the respective disclosures of which are incorporated
herein by reference. A beneficial substance may also be delivered
by a surgically formed gastrostomy or by a percutaneous endoscopic
technique requiring no laparotomy as disclosed in, for example,
Gauderer & Ponsky, "A Simplified Technique For Constructing A
Tube Feeding Gastrostomy," Surgery, Gynecology & Obstetrics,
vol. 152, pp. 82-85 (June 1981), the disclosure of which is
incorporated herein by reference.
[0052] One preferred method for delivering a beneficial substance
directly into the intestinal tract is disclosed in U.S. Pat. No.
4,594,074, the disclosure of which is incorporated herein by
reference. This patent discloses an enteral tube feeding device.
Enteral feeding usually involves the use of a percutaneous access
catheter, such as a gastrostomy feeding tube, for introducing food
and/or medicine directly into the gastrointestinal tract. The
administered substance is usually a liquid conveyed directly into
the intestinal tract by a nasogastrointestinal tube, generally
referred to as an enteral feeding tube. U.S. Pat. No. 4,594,074
basically discloses an to enteral feeding tube utilizing a tube
insert or bolus disposed on a distal end of the tube. The bolus
contains at least one opening defining the tube outlet and has an
internal design that substantially approximates the fluid flow
characteristics of an open-ended tube yet does not easily become
occluded with mucous and feeding material.
[0053] Referring now to FIG. 1, a preferred delivery tube 10 is a
nasogastrointestinal feeding tube of the type described in U.S.
Pat. No. 4,594,074. Tube 10 has a first end 10A positioned outside
of the subject's nose and a second end 10B positioned downstream of
the stomach, inside the jejunum. Alternatively, a preferred
delivery tube according to the invention may have a first end at
any position outside of the intestines, such as outside of the
mouth, and a second end preferably positioned downstream of the
stomach, so that a beneficial substance introduced into the first
end exits the second end at a point downstream of the stomach.
[0054] Another preferred method for delivering a beneficial
substance directly into the intestinal tract is disclosed in U.S.
Pat. No. 4,795,430, the disclosure of which is incorporated herein
by reference. This patent discloses a device for intubating an
ostomy, as for example, a gastrostomy, formed by a percutaneous
endoscopic technique. The device employs a multi-lumen enteral
feeding tube, preferably having at least a fluid delivery lumen and
an inflation lumen. The tube includes a port near one end to
dispose the inflation lumen to ambient air and an outlet at the
other end to convey fluid from within the fluid lumen into the
patient. A retention member, preferably an inflatable cuff, is
joined near the other end of the tube. The device is utilized to
intubate a gastrostomy formed by a percutaneous endoscopic
technique.
[0055] A beneficial substance according to the invention is
introduced into a delivery tube, such as any of the described
enteral feeding tubes, preferably by first wetting the particulate
beneficial substance and then placing it in the tube's conduit,
where it is conveyed directly to the gastrointestinal tract,
preferably downstream of the stomach and most preferably to the
jejunum. This may be done by placing the particulate beneficial
substance into a syringe and adding water so that the beneficial
substance is dispersed (preferably homogeneously) throughout the
water. This dispersion can then be placed directly into the
conduit, to a line going to the conduit or to a reservoir of fluid
leading to the conduit, so it an be delivered directly into the
gastrointestinal track.
[0056] Additionally, it is possible to include a beneficial
substance according to the invention in the form of a tablet or
capsule. Any capsule or tablet suitable for at least partially
protecting the probiotic as it passes through the stomach, thus
allowing a greater amount of probiotic to enter the large intestine
than would enter without use of the capsule or tablet, may be used.
Such a tablet may have a generally homogenous composition or
include individual layers containing the various constituents of
the tablet (such as the probiotic and prebiotic).
[0057] Tablets according to the invention can be produced in any
suitable manner, and two particular methods are described herein.
First, the powder mixtures of carriers and auxiliaries (e.g.,
release agents) and active ingredients (probiotics, vitamins,
prebiotics, etc.) may be placed in a commercially available
tabletting machine in one or more layers. The probiotic should not
be exposed to any constituent that would destabilizing or destroy
it. Each ingredient should be well dried and preferably have a
water content of 0.1% or less. The powdered constituents are then
tabletted to form a tablet. The press pressure is preferably
between 50 and 120 Newtons.
[0058] Alternatively, individual layers of, for example, probiotic
and prebiotic, can be formed separately, with press pressures
preferably between 20 and 80 Newtons used for the individual
layers. The layers preformed in this way are then pressed at press
pressures of between 50 and 120 Newtons to create the finished
multilayer tablet. This pressing method has the advantage that the
layers which have a different compressibility on account of their
different composition can be exposed to individual press pressures,
which can be advantageous both with respect to the shelf life of
the multilayer tablet as a whole and with respect to the stability
of active ingredients in the individual layers. In addition, the
boundary layer between two layers in juxtaposition has a smaller
active surface due to the preforming, whereby the possibility of
the reaction or destabilization of sensitive active ingredients,
including the probiotic, is reduced.
[0059] Another method of encapsulating a beneficial substance
according to the invention is disclosed in U.S. Pat. No. 6,309,666,
the disclosure of which, except for the Abstract and Background
sections, are incorporated herein by reference.
[0060] Having described preferred embodiments of the invention,
alterations and modifications within its scope may occur to others.
The scope of the invention is not limited to the particular
examples, process steps, or materials disclosed as preferred
embodiments but is instead set forth in the appended claims and
legal equivalents thereof.
* * * * *
References