U.S. patent application number 15/303753 was filed with the patent office on 2017-02-02 for composition based on xyloglucan and proteins for the treatment of intestinal disorders.
This patent application is currently assigned to NOVINTETHICAL PHARMA SA. The applicant listed for this patent is NOVINTETHICAL PHARMA SA. Invention is credited to Miguel Angel Alonso Cohen, Marco Di Fulvio, Michele Giuseppe Di Schiena.
Application Number | 20170027980 15/303753 |
Document ID | / |
Family ID | 50897780 |
Filed Date | 2017-02-02 |
United States Patent
Application |
20170027980 |
Kind Code |
A1 |
Cohen; Miguel Angel Alonso ;
et al. |
February 2, 2017 |
COMPOSITION BASED ON XYLOGLUCAN AND PROTEINS FOR THE TREATMENT OF
INTESTINAL DISORDERS
Abstract
Disclosed are compositions comprising synergic combinations of
xyloglucans and plant or animal proteins, which are useful in the
treatment of intestinal disorders.
Inventors: |
Cohen; Miguel Angel Alonso;
(Barcelona, ES) ; Di Schiena; Michele Giuseppe;
(Robecco Sul Naviglio (MI), IT) ; Di Fulvio; Marco;
(Pambio Noranco, Lugano, CH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
NOVINTETHICAL PHARMA SA |
Pambio Noranco, Lugano |
|
CH |
|
|
Assignee: |
NOVINTETHICAL PHARMA SA
Lugano
CH
|
Family ID: |
50897780 |
Appl. No.: |
15/303753 |
Filed: |
April 15, 2015 |
PCT Filed: |
April 15, 2015 |
PCT NO: |
PCT/EP2015/058162 |
371 Date: |
October 13, 2016 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 45/06 20130101;
A61K 47/42 20130101; A61K 47/36 20130101; A61K 31/80 20130101; A61K
36/28 20130101; A61K 36/48 20130101; A61P 1/00 20180101; A61P 13/00
20180101; A61K 35/02 20130101; A61K 31/716 20130101; A61K 38/01
20130101; A61K 31/732 20130101; A61K 31/733 20130101; A61K 9/0078
20130101; A61K 31/00 20130101; A61K 31/704 20130101; A61K 38/01
20130101; A61K 47/36 20130101; A61K 31/716 20130101; A61K 2300/00
20130101; A61K 31/733 20130101; A61K 2300/00 20130101; A61K 31/704
20130101; A61K 2300/00 20130101; A61K 31/80 20130101; A61K 2300/00
20130101; A61K 31/732 20130101; A61K 2300/00 20130101; A61K 36/28
20130101; A61K 2300/00 20130101; A61K 36/48 20130101; A61K 2300/00
20130101 |
International
Class: |
A61K 31/716 20060101
A61K031/716; A61K 45/06 20060101 A61K045/06; A61K 47/42 20060101
A61K047/42 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 15, 2014 |
IT |
MI2014A000705 |
Claims
1. Combinations of xyloglucans or extracts containing them and of
gelatin for use in the prevention and treatment of diarrhoea,
Crohn's disease, ulcerative colitis and irritable bowel syndrome
(IBS), diverticulosis, the early stages of diverticulitis, coeliac
disease, lactose intolerance, traveller's diarrhoea, cystitis and
cystopyelitis.
2-3. (canceled)
4. Combinations according to claim 1 wherein the weight ratio
between xyloglucan and gelatine is between 1:0.5 and 1:30.
5. Combinations according to claim 1 further comprising excipients
and/or other active ingredients.
6. Combinations according to claim 5 wherein the other active
ingredients are selected from antibiotics, antimotility agents,
steroidal or non-steroidal anti-inflammatories, compounds for the
treatment of gastrointestinal bloating, mesalazine, sucralfate,
natural or synthetic polysaccharides, hyaluronic acid, guar gum,
xanthan gum, cellulose and hemicellulose, hydroxypropyl cellulose,
carrageenans, carbomers, ferulic acid; polyphenols, probiotics and
electrolytes.
Description
[0001] The invention relates to synergic combinations of
xyloglucans and plant or animal proteins and compositions for the
treatment of intestinal disorders, especially diarrhoeal forms of
various origins.
PRIOR ART
[0002] Diarrhoea is a symptom of many gastrointestinal disorders
and is often incapacitating and dangerous, especially in children
and the elderly. Acute diarrhoea is mainly caused by intestinal
infections, but can also be due to the use of medicaments or
radiotherapy and to other pathological conditions (diverticulitis,
heavy-metal poisoning, intestinal ischaemia, allergies and
intolerances).
[0003] Acute diarrhoea with an infectious cause is a serious
problem in developing countries; it is believed to cause the death
of at least 4 million children under 5 years old every year.
[0004] Chronic diarrhoea is generally due to irritable bowel
syndrome, coeliac disease or inflammatory bowel diseases (Crohn's
disease, ulcerative rectocolitis).
[0005] In view of their different aetiologies, various treatment
options are available, based on the administration of
antibiotics/antibacterials, spasmolytics/anticholinergics,
probiotics, or opioid receptor agonists. However, some of said
treatments must be administered with great caution, because they do
not act on the causal pathological process.
[0006] To prevent said adverse effects, complexes of tannins
complexed with animal proteins and gelatins, in particular with
gelatin of bovine origin, albumin, casein or ovalbumin, have been
proposed for some time.
[0007] For example, the use of said complexes in the treatment of
the various forms of diarrhoea is disclosed in EP 1764105, EP
2526939, EP 2361623 and U.S. 20090062191. Gelatin tannate has been
available on the market for some time as a medical device for the
treatment of acute diarrhoea.
[0008] Xyloglucans are molecules consisting of a linear backbone of
.beta.-1,4-glucans with short side branches. The latter bond due to
the xylose bonded to oxygen in the 6 position of the sugar. Said
side chains can also contain other sugars such as arabinose and
fucose.
[0009] Xyloglucans belong to the hemicellulose family, which
combines with cellulose in the cell wall of the higher plants. A
particularly rich source of xyloglucan is the seeds of tamarind
(Tamarindus indica), a tropical tree originating from East
Africa.
[0010] Xyloglucan-rich tamarind seed extracts are known and have
been used in the medical field mainly as viscosity-controlling
agents in ophthalmic compositions (U.S. 6,056,950), as mucoadhesive
agents (WO 2006131262), as artificial tears (WO 2009/044423), as
anti-infective agents (WO 2011147767) and as anti-inflammatory
agents (WO 2011147768).
DESCRIPTION OF THE INVENTION
[0011] It has now surprisingly been found that combinations of
xyloglucans with plant or animal proteins compatible with oral
administration to humans are particularly effective in the
treatment and prevention of diarrhoea and other infectious and/or
inflammatory intestinal disorders. Xyloglucans exert a film-forming
effect in the intestinal mucosa which reduces the permeability of
the tight junctions of the intestinal mucosa, and therefore
prevents the entry of the pathogens responsible for acute
intestinal infections. The film-forming effect is not affected by
variations in pH.
[0012] The invention therefore relates to pharmaceutical
compositions comprising, as active ingredients, xyloglucans or
extracts containing them, combined with at least one plant or
animal protein selected from gelatine, albumin, ovalbumin, casein,
pea protein and soya protein and suitable excipients, and
optionally with other active ingredients useful for the prevention
and treatment of gastrointestinal and urogenital disorders.
[0013] Xyloglucans extracted from Tamarindus indica are available
on the market, for example from Indena (Italy) (Xilogel.RTM.) and
DSP Gokyo Food & Chemical (Japan) (Glyloid.RTM.). The average
molecular weight is between 400,000 and 650,000 daltons.
[0014] Preferred proteins include gelatin and pea protein. Gelatin
is particularly preferred.
[0015] The weight ratio of xyloglucan to protein ranges between
1:0.5 and 1:30. The combination of xyloglucan and protein forming
the subject of the invention constitutes the active ingredient of
oral pharmaceutical formulations.
[0016] Examples of suitable forms of administration include
capsules, tablets, solutions, suspensions, granules, gels and the
like.
[0017] Other active ingredients with which xyloglucans and protein
can be combined include antibiotics, antimotility agents, steroidal
and non-steroidal anti-inflammatories, compounds for the treatment
of gastrointestinal bloating (simethicone and the like),
mesalazine, sucralfate, natural and synthetic polysaccharides such
as pectins, chitosan (animal or vegetable), hyaluronic acid, guar
gum, xanthan gum, cellulose and hemicellulose and derivatives such
as hydroxypropylcellulose, carrageenans, carbomers, and
crosslinking/polymerising compounds such as ferulic acid;
polyphenols, such as gall polyphenols, polyphenols from grape pips,
probiotics such as Lactobacilli, Bifidobacteria, yeasts and the
like.
[0018] In the compositions according to the invention, xyloglucans
can be present in a wide concentration range which depends on the
type of composition and the therapeutic indication for which they
are intended.
[0019] The xyloglucan is administered orally at doses ranging
between 0.5 mg/dose and 200 mg/dose, preferably between 10 mg/dose
and 100 mg/dose.
[0020] The protein, in particular gelatin, is administered orally
at doses ranging between 10 mg/dose and 3000 mg/dose, preferably
between 50 mg/dose and 500 mg/dose.
[0021] The compositions according to the invention are useful for
the treatment and prevention of gastrointestinal disorders and
other disorders that originate in the gastrointestinal system and
are transferred to other systems, such as the urogenital system. It
is known that the Gram-negative bacteria present in the intestine,
in particular Escherichia coli, can proliferate in said organ and
migrate to the urinary tract, where they cause 90% of urogenital
infections such as cystitis, cystopyelitis and the like.
[0022] In particular, the compositions according to the invention
are useful to prevent the proliferation of pathogens in the
gastrointestinal system and transfer them to other systems of the
human body through the tight intestinal junctions, to protect the
intestinal mucosa against chemical or physical agents which can
reduce the functionality and natural regeneration of the intestinal
epithelium, and to reduce the paracellular flow of pathogens
through the intestinal walls.
[0023] The compositions according to the invention have also proved
useful for the prevention and treatment of damage to the intestinal
mucosa and the consequent inflammatory symptoms, such as
diverticulosis and the early stages of diverticulitis; for the
treatment of symptoms resulting from food allergies (e.g.
intolerance of lactose, gluten, etc.); for the prevention and
treatment of digestive disorders (gas production, bloating, stomach
rumble and flatulence); and for the prevention and treatment of
damage to the intestinal mucosa deriving from local inflammatory
phenomena of transient or chronic origin, in particular for the
treatment of Crohn's disease, ulcerative colitis and irritable
bowel syndrome (IBS).
[0024] The compositions according to the invention can be
advantageously used to treat diarrhoea in combination with oral
rehydration electrolytes, such as mucomimetics, and to inhibit the
adherence of bacteria to the mucosa and subsequent proliferation
involving dysbiosis, optionally combined with probiotics or
tyndallised bacteria. The compositions according to the invention
are useful for the prevention and treatment of travellers'
diarrhoea.
[0025] The compositions according to the invention effectively
protect the mucosa and reduce the adherence to it of some
pathogens, such as gas-producing bacteria.
[0026] The examples below illustrate the invention in greater
detail.
EXAMPLE 1
[0027] Composition for the prevention and treatment of diarrhoea;
single-dose sachet
TABLE-US-00001 Xyloglucan 0.100 g Gelatin 0.050 g Inulin 1.650 g
Maltodextrin 1.195 g Stevioside (Stevia) 0.015 g Tuttifrutti
flavouring (Firmenich) 0.015 g E160 (a) colouring (betacarotene)
0.025 g
EXAMPLE 2
[0028] Composition for the prevention and treatment of diarrhoea;
hard capsule
TABLE-US-00002 Xyloglucan 0.1 g Gelatin 3.0 g Matricaria E.S. 0.026
g Pectin 0.050 g Dimethicone 0.020 g Kaolin 0.020 g Magnesium
stearate 0.080 g
EXAMPLE 3
[0029] Composition for the prevention and treatment of diarrhoea;
tablet
TABLE-US-00003 Xyloglucan 0.1 g Pea protein 0.5 g Lactose 0.063 g
Anhydrous colloidal silicon dioxide 0.002 g Microcrystalline
cellulose 0.030 g Magnesium stearate 0.003 g
[0030] EXAMPLE 4
Bioassays: Protection Against Intestinal Fluid Secretion Induced by
Cholera Toxin in Rats
[0031] Four groups of Wistar rats (200-220 g) were treated orally
with 12.5 mg/kg of xyloglucan, 125 mg/kg of gelatin and the
combination of said two ingredients of the combination, at the same
dose. Six hours after administration, the groups of animals were
treated with cholera toxin at the dose of 6 .mu.g/ml.
[0032] Two hours after the toxin treatment the water content of the
intestinal loop was measured.
[0033] The results obtained, shown in the Figure and in the
following Table, demonstrate that xyloglucan alone did not reduce
the fluid secretion. Equally, gelatin alone did not exhibit a
significant effect, whereas the effects of the combination proved
statistically significant.
TABLE-US-00004 12.5 mg 12.5 mg 125 mg 12.5 mg xyloglucan/kg/
xyloglucan/kg/ Saline + gelatine/kg/ xyloglucan/kg/ PO.sup.5 +
Gelatin PO.sup.5 + Gelatin Basal .sup.1 CT.sup.2 PO.sup.3 - 6 hours
PO.sup.7 -6 hours (125 mg/kg).sup.6 -6 hours (250 mg/kg).sup.6 - 12
hours Grams/loop 0.41 .+-. 0.11 1.04 .+-. 0.32 1.01 .+-. 0.39 1.26
.+-. 0.18 0.77 .+-. 0.15 0.75 .+-. 0.16 p NS.sup.4 NS.sup.4 NS
Significant Significant (p < 0.01) (p < 0.05)
EXAMPLE 5
Clinical Trial
[0034] A multicentre controlled parallel-group clinical trial was
conducted by administering to patients suffering from acute
diarrhoea the combination according to the invention (xyloglucan
400 mg/day and gelatin 200 mg/day), the probiotic S. boulardii (at
the dose of 7.times.10.sup.9 cells/dose), and diosmectite
(Smecta.RTM., 3.times.3 g sachets/day). The speed of onset of
clinical efficacy was evaluated in the three groups (reduction in
duration of acute diarrhoea and the correlated symptoms). The
symptoms examined were nausea, vomiting, flatulence, abdominal pain
and stool emissions. The symptoms declined in all three groups. The
combination according to the invention led to more rapid action,
inhibiting the diarrhoea within 24 hours of the start of the
treatment. Abdominal pain was monitored throughout the treatment.
The patients did not present vomiting after 48 and 72 hours. The
combination according to the invention gave rise to a more rapid
reduction in stool emissions rated as grades 6 and 7 on the Bristol
scale, with a 60% reduction as against 34% and 39% respectively for
diosmectite and S. boulardii. After 48 hours this type of emission
had almost entirely disappeared in all three groups. The
combination according to the invention therefore proved to be the
fastest-acting in preventing stool emissions.
* * * * *