U.S. patent application number 16/823523 was filed with the patent office on 2020-08-27 for electrolyte purgative.
The applicant listed for this patent is Salix Pharmaceuticals, Inc.. Invention is credited to Thomas Julius Borody, Sanjay Ramrakha, John Saxon, Antony Wettstein.
Application Number | 20200268790 16/823523 |
Document ID | / |
Family ID | 1000004816313 |
Filed Date | 2020-08-27 |
United States Patent
Application |
20200268790 |
Kind Code |
A1 |
Borody; Thomas Julius ; et
al. |
August 27, 2020 |
ELECTROLYTE PURGATIVE
Abstract
The invention relates to compositions for use in purgatives, to
purgatives comprising such compositions, and to methods for
inducing purgation of the colon. The composition may comprise at
least one water-soluble sodium salt; at least one water-soluble
minimally degradable sugar in an amount, by weight, of from about 1
to about 3 times the weight of sodium ions in said composition; at
least one water-soluble potassium salt in an amount, by weight, of
from about 0.05 to about 1 time the weight of said sodium salt in
said composition; and at least one water-soluble magnesium salt,
wherein the weight of magnesium ions in said composition is from
0.1 to about 10 times the weight of sodium ions in said
composition.
Inventors: |
Borody; Thomas Julius;
(Sydney, AU) ; Ramrakha; Sanjay; (Sydney, AU)
; Saxon; John; (Sydney, AU) ; Wettstein;
Antony; (Sydney, AU) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Salix Pharmaceuticals, Inc. |
Bridgewater |
N |
US |
|
|
Family ID: |
1000004816313 |
Appl. No.: |
16/823523 |
Filed: |
March 19, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13111736 |
May 19, 2011 |
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16823523 |
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10506728 |
Jun 27, 2005 |
7993682 |
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13111736 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 33/00 20130101;
A61K 33/14 20130101; A61K 31/7004 20130101; A61K 31/194 20130101;
A61K 33/06 20130101 |
International
Class: |
A61K 33/06 20060101
A61K033/06; A61K 31/194 20060101 A61K031/194; A61K 33/14 20060101
A61K033/14; A61K 31/7004 20060101 A61K031/7004; A61K 33/00 20060101
A61K033/00 |
Claims
1. A composition for use in a purgative, the composition
comprising: (i) at least one water-soluble sodium salt; (ii) at
least one water-soluble minimally degradable sugar in an amount, by
weight, of from about 1 to about 3 times the weight of sodium ions
in said composition; (iii) at least one water-soluble potassium
salt in an amount, by weight, of from about 0.05 to about 1 times
the weight of said sodium salt in said composition; and (iv) at
least one water-soluble magnesium salt, wherein the weight of
magnesium ions in said composition is from about 0.1 to about 10
times the weight of sodium ions in said composition.
2. The composition of claim 1, wherein the minimally degradable
sugar is selected from the group consisting of xylose, xylotriose,
xylooligosaccharides, fructooligosaccharides, fructosans,
galactooligosaccharides, other oligosaccharides, and mixtures
thereof.
3. The compositions of claim 1, wherein the water-soluble sodium
salt is selected from the group consisting of sodium chloride,
sodium gluconate, sodium citrate, sodium aspartate and mixtures
thereof.
4. The composition of claim 1, wherein the water-soluble potassium
salt is selected from the group consisting of potassium chloride
and potassium tartrate.
5. The composition of claim 1, wherein the water-soluble magnesium
salt is selected from the group consisting of magnesium sulfate,
magnesium citrate and magnesium phosphate.
6. The composition of claim 1 further comprising at least one
additive selected from the group consisting of a flavouring
ingredient, a detergent stool-softening agent, citrate, lactate,
acetate, trace elements and nutritional elements.
7. The composition of claim 1 in the form of a soup or soup-like
composition, tablet, gel cap, capsule or sachet.
8. A purgative, comprising a hypertonic aqueous solution of the
composition of claim 1.
9. The purgative of claim 8 in the form of a unit dose having a
volume of from about 0.2 to 0.5 L and wherein the sodium salt or
salts are present in an amount from about 1 to about 10 g per unit
dose, the minimally degradable sugar or sugars in an amount of from
about 2 to about 20 g, the potassium salt or salts in an amount of
from about 0.5 to about 5 g and the magnesium salt or salts in an
amount of from about 1 to about 10 g per unit dose of the
purgative.
10. A method of inducing purgation of the colon of a patient in
need thereof, comprising administering to said patient a
composition of claim 1 in an amount effective to induce purgation
of the patient's colon.
11. A method of inducing purgation of the colon of a patient in
need thereof, comprising administering to the patient a composition
of a purgative of claim 8 in an amount effective to induce
purgation of the patient's colon.
12. A method for treatment or prevention of one or more of a member
selected from the group consisting of lavage-associated
hyponatremia, hypoosmolality, nausea, malaise, vomiting, headache
and convulsions, comprising administering to a patient in need of
such treatment a composition of claim 1 whereby lavage-associated
hyponatremia, hypoosmolality, nausea, malaise, vomiting, headache
or convulsions is treated or prevented.
13. A method for treatment or prevention of one or more of a member
selected from the group consisting of lavage-associated
hyponatremia, hypoosmolality, nausea, malaise, vomiting, headache
and convulsions, comprising administering to a patient in need of
such treatment a purgative of claim 8, whereby lavage-associated
hyponatremia, hypoosmolality, nausea, malaise, vomiting, headache
or convulsions is treated or prevented.
14. A method for the treatment or prevention of acute
gastrointestinal infections, comprising administering to a patient
in need of such treatment a composition of claim 1, whereby acute
gastrointestinal infection is treated or prevented.
15. A method for the treatment or prevention of acute
gastrointestinal infections, comprising administering to a patient
in need of such treatment a purgative of claim 8, whereby acute
gastrointestinal infection is treated or prevented.
16. A method for the treatment or prevention of constipation, acute
constipation, chronic constipation or constipation predominant
irritable bowel syndrome, comprising administering to a patient in
need of such treatment a composition of claim 1, whereby
constipation, acute constipation, chronic constipation or
constipation predominant irritable bowel syndrome is treated or
prevented.
17. A method for the treatment or prevention of constipation, acute
constipation, chronic constipation or constipation predominant
irritable bowel syndrome, comprising administering to a patient in
need of such treatment a purgative of claim 8, whereby
constipation, acute constipation, chronic constipation or
constipation predominant irritable bowel syndrome is treated or
prevented.
18. A method for pre-colonoscopic or pre-surgical lavage,
comprising administering to a patient a composition of claim 1.
19. A composition for use in a purgative, the composition
comprising: (i) at least one water-soluble sodium salt; (ii) at
least one water-soluble degradable sugar in an amount, by weight,
of from about 1 to about 3 times the weight of sodium ions in said
composition; (iii) at least one water-soluble potassium salt in an
amount, by weight, of from about 0.05 to about 1 times the weight
of said sodium salt in said composition; and (iv) at least one
water-soluble magnesium salt, wherein the weight of magnesium ions
in said composition is from about 0.1 to about 10 times the weight
of sodium ions in said composition.
20. A composition of claim 19 wherein the degradable sugar is
selected from the group consisting of glucose, L-glucose, sucrose,
fructose, galactose, lactose, mannitol and lactulose.
21. A purgative, comprising a hypertonic aqueous solution of the
composition of claim 19.
22. A method of inducing purgation of the colon of a patient in
need thereof, comprising administering to said patient in the
absence of diathermy a composition of claim 19 in an amount
effective to induce purgation of the patient's colon.
23. A method of inducing purgation of the colon of a patient in
need thereof, comprising administering to the patient in the
absence of diathermy a purgative of claim 21 in an amount effective
to induce purgation of the patient's colon.
24. A method for the treatment or prevention of one or more of a
member selected from the group consisting of lavage-associated
hyponatremia, hypoosmolality, nausea, malaise, vomiting, headache
and convulsions, comprising administering to a patient in need of
such treatment in the absence of diathermy a composition of claim
19, whereby lavage-associated hyponatremia, hypoosmolality, nausea,
malaise, vomiting, headache or convulsions are treated or
prevented.
25. A method for the treatment or prevention in the absence of
diathermy of one or more of a member selected from the group
consisting of lavage-associated hyponatremia, hypoosmolality,
nausea, malaise, vomiting, headache and convulsions, comprising
administering to a patient in need of such treatment in the absence
of diathermy a composition of a purgative of claim 21, whereby
lavage-associated hyponatremia, hypoosmolality, nausea, malaise,
vomiting, headache or convulsions are treated or prevented.
26. A method for the treatment or prevention of acute
gastrointestinal infections, comprising administering to a patient
in need of such treatment in the absence of diathermy a composition
of claim 19, whereby acute gastrointestinal infection is treated or
prevented.
27. A method for the treatment of prevention of acute
gastrointestinal infections, comprising administering to a patient
in need of such treatment in the absence of diathermy a purgative
of claim 21, whereby acute gastrointestinal infection is treated or
prevented.
28. A method for the treatment or prevention of constipation, acute
constipation, chronic constipation or constipation predominant
irritable bowel syndrome, comprising administering to a patient in
need of such treatment in the absence of diathermy a composition of
claim 19, whereby constipation, acute constipation, chronic
constipation or constipation predominant irritable bowel syndrome
is treated or prevented.
29. A method for the treatment or prevention of constipation, acute
constipation, chronic constipation or constipation predominant
irritable bowel syndrome, comprising administering to a patient in
need of such treatment in the absence of diathermy a purgative of
claim 21, whereby constipation, acute constipation, chronic
constipation or constipation predominant irritable bowel syndrome
is treated or prevented.
30. A method for pre-colonoscopic or pre-surgical lavage,
comprising administering to a patient in the absence of diathermy a
composition of claim 19.
31. The method of claim 30, wherein the method is selected from
among a simple purgative, an electrolyte replacement lavage, a
barium enema preparation, a CT "virtual colonoscopy", a
radiological application, an electrolyte replacement lavage, an
electrolyte replacement lavage for acute gastrointestinal
infection, a treatment for acute or chronic constipation and
related symptoms or a treatment for constipation predominant
irritable bowel syndrome, a regular laxative, or a treatment or
prevention of lavage-associate hyponatremia, hypoosmolality,
nausea, malaise, vomiting, headache or convulsions.
32. A method for pre-colonoscopic or pre-surgical lavage,
comprising administering to a patient in the absence of diathermy a
purgative of claim 21.
33. The method of claim 32, wherein the method is selected from
among a simple purgative, an electrolyte replacement lavage, a
barium enema preparation, a CT "virtual colonoscopy", a
radiological application, an electrolyte replacement lavage, an
electrolyte replacement lavage for acute gastrointestinal
infection, a treatment for acute or chronic constipation and
related symptoms or a treatment for constipation predominant
irritable bowel syndrome, a regular laxative, or a treatment or
prevention of lavage-associate hyponatremia, hypoosmolality,
nausea, malaise, vomiting, headache or convulsions.
34. A method for pre-colonoscopic or pre-surgical lavage,
comprising administering to a patient a purgative of claim 8.
35. The method of claim 34, wherein the method is selected from
among a simple purgative, an electrolyte replacement lavage, a
barium enema preparation, a CT "virtual colonoscopy", a
radiological application, an electrolyte replacement lavage, an
electrolyte replacement lavage for acute gastrointestinal
infection, a treatment for acute or chronic constipation and
related symptoms or a treatment for constipation predominant
irritable bowel syndrome, a regular laxative, or a treatment or
prevention of lavage-associate hyponatremia, hypoosmolality,
nausea, malaise, vomiting, headache or convulsions.
36. The method of claim 18, wherein the method is selected from
among a simple purgative, an electrolyte replacement lavage, a
barium enema preparation, a CT "virtual colonoscopy", a
radiological application, an electrolyte replacement lavage, an
electrolyte replacement lavage for acute gastrointestinal
infection, a treatment for acute or chronic constipation and
related symptoms or a treatment for constipation predominant
irritable bowel syndrome, a regular laxative, or a treatment or
prevention of lavage-associate hyponatremia, hypoosmolality,
nausea, malaise, vomiting, headache or convulsions.
Description
RELATED APPLICATIONS
[0001] This application is continuation of U.S. patent application
Ser. No. 10/506,728, filed Jun. 27, 2005 (now pending), which is a
national phase application claiming benefit of priority under 35
U.S.C. .sctn. 371 to Patent Convention Treaty (PCT) International
Application Serial No. PCT/AU2003/00257, filed Mar. 4, 2003, which
claims benefit of priority to Australian Provisional Patent
Application Serial No. PS 0887, filed on Mar. 4, 2002. The contents
of these applications are expressly incorporated herein by
reference in their entirely for all purposes.
FIELD OF THE INVENTION
[0002] The invention relates to compositions for use in purgatives,
to purgatives comprising such compositions, and to methods for
inducing purgation of the colon.
BACKGROUND ART
[0003] Colonic orthostatic lavage is an iatrogenic phenomenon
related to the administration of a purgative and therefore is
predictable in its action and side effects. It is important to make
the distinction between the use of iatrogenic purgation solutions
and fluid/electrolyte replacement solutions used for treatment of
vomiting and diarrhea associated with gastroenteritis. The use of
mainly hypotonic or isotonic solutions such as glucose-based
`Bangladesh` solution and rice-based solutions has been successful
in patients with gastroenteritis and dehydration, a highly
unpredictable disease. The physiological principle of coupled
sodium and glucose transport in a 1:1 molar ratio in the intestine
has been shown to be safe and effective.
[0004] Purgatives developed to date for orthostatic lavage to clean
the bowel of faecal matter prior to colonoscopy have taken the form
of either an isotonic, large volume lavage (e.g. Braintree's
Golytely) or more hypertonic lavage products such as Fleet's sodium
phosphate or sodium picosulfate (Picolax) products. The former
generally cause little homeostatic disturbance of intra-vascular
sodium and other electrolytes or fluid shifts because of their
isotonic nature, which minimizes electrolyte absorption/secretion
by the presence of high molecular weight polyethylene glycol (PEG
mw 3350). However, these preparations have recently been reported
to be associated with hyponatremia (Cohen D. C. et al., Lancet
357(9252): 282-283 (2001)). Products with sodium phosphate and
sodium picosulfate are felt to be better tolerated (Fincher R. K.,
et al., Am. J. Gastroenterol. 94(8): 2122-7 (1999)). However, these
products have also been associated with a significant hypo-osmolar
state and electrolyte imbalance, particularly hyponatremia. This,
to a large extent, is contributed to by a loss of electrolytes
through the resultant diarrhea caused by the lavage with
concomitant replacement of this loss by water (without
electrolytes) leading to hyponatremia and water intoxication
associated with a hypo-osmolar state.
[0005] The symptoms of headache, lethargy and nausea reported by
patients undergoing orthostatic lavage are felt to be due to an
osmotic shift with resultant dilutional hyponatremia that is
induced by the various bowel preparation products such as "Fleet",
Picolax etc. This effect appears to be more pronounced in adult
females, perhaps as a result of relatively less total body water
when compared to adult males and children (Fraser et al., Am. J.
Physiol. 256: R880-5 (1989)).
[0006] The clinical features of hyponatremia (hypoosmolality) are
highly variable and their severity correlates poorly with the level
of serum sodium. Classically, the clinical features of severe
hyponatremia are confusion, seizures and obtundation.
[0007] A decrease in plasma osmolality causes brain swelling
(cerebral edema) as water moves along osmotic gradients. In
response, the brain loses solute from the intra- and extra-cellular
fluid spaces, which returns brain water content back towards
normal. Once the brain has equilibrated (i.e. volume-adapted)
through solute losses, neurological features will be less prominent
or resolve.
[0008] The rate of fall of serum osmolality is generally better
correlated with morbidity and mortality than the actual magnitude
of the decrease (Arieff, A. I. et al., Medicine (Baltimore) 55:
121-9 (1976)), and is somewhat arbitrarily defined as
hypoosmolality developing over 24 to 48 hours. Mortality up to 50%
has been reported in patients with acute hyponatremia (Arieff, A.
I. et al., loc.cit.). Cerebral edema develops when hypoosmolality
exceeds the ability of the brain to regulate its volume by solute
losses. In experimental models, acute hyponatremia results in the
loss of sodium and chloride from the brain within 30 minutes,
whilst potassium loss is more delayed. All electrolyte losses are
maximal by 3 hours after initiation of hyponatremia (Melton, J. E.
et al., Am. J. Physiol. 252: F661-9 (1987)).
[0009] Hence in some situations the effects of the various bowel
purgative formulations currently available can lead to the
unpleasant side effects of headache, malaise and dizziness and
hypotension. Additionally, life threatening presentations of
hypo-osmolar grand mal epileptic seizures, asphyxia and death have
been reported.
[0010] Due to the accepted benefits of screening colonoscopic
surveillance programs for the detection of colonic polyps and bowel
cancer, the utilization of colonic lavage is increasing rapidly.
Indeed it is feasible that a large number of the population over
the age of 50 years is likely to undergo colonoscopic examination.
As a result, a considerable number of patients could potentially
develop lavage-related hyponatremia and hypo-osmolar water
intoxication with subsequent `dilution` of other electrolytes
leading to significant morbidity and potentially mortality.
[0011] Poor palatability leading to reduced patient compliance has
been an important issue in the failure of some of the currently
available products; either the volume is too large or the taste too
objectionable for certain patients to comply with taking the
prescribed bowel preparation. This leads to inadequate orthostatic
lavage causing poor visibility at colonoscopy.
[0012] There is therefore a need for a purgative composition that
reduces mortality and/or patient morbidity and/or which makes the
procedure of purgation of the colon much more pleasant for the
patient so as to facilitate patient compliance.
SUMMARY OF THE INVENTION
[0013] The present invention therefore provides novel
electrolyte-enhanced purgatives which may be administered in
relatively small liquid volumes, suitably in the form of a
palatable soup mixture, but which may also be formulated in various
other forms such as capsules, powders or compressed tablets. Thus,
the compositions and purgatives of the present invention cause a
purgative effect while ameliorating or overcoming the disadvantages
associated with the administration of prior art purgatives, namely
(a) symptoms associated with osmotic shifts and electrolyte
imbalance; (b) hyponatremia; and (c) poor patient compliance owing
to unpalatibility and/or the need to consume large volumes of
liquid.
[0014] In a first embodiment, the invention provides a composition
for use in a purgative, the composition comprising:
[0015] (i) at least one water-soluble sodium salt;
[0016] (ii) at least one water-soluble minimally degradable sugar
in an amount, by weight, of from about 1 to about 3 times the
weight of sodium ions in said composition;
[0017] (iii) at least one water-soluble potassium salt in an
amount, by weight, of from about 0.05 to about 1 times the weight
of said sodium salt in said composition; and
[0018] (iv) at least one water-soluble magnesium salt, wherein the
weight of magnesium ions in said composition is from about 0.1 to
about 10 times the weight of sodium ions in said composition.
[0019] In a second embodiment, the invention provides a purgative,
comprising a hypertonic aqueous solution of the composition of the
first embodiment.
[0020] In a third embodiment, the invention provides a method of
inducing purgation of the colon of a patient in need thereof,
comprising administering to said patient a composition of the first
embodiment or a purgative of the second embodiment in an amount
effective to induce purgation of the patient's colon.
[0021] In a fourth embodiment, the invention provides the use of a
composition of the first embodiment for the manufacture of a
purgative for inducing purgation of the colon.
[0022] In a fifth embodiment, the invention provides a method for
the treatment or prevention of one or more of a member selected
from the group consisting of lavage-associated hyponatremia,
hypoosmolality, nausea, malaise, vomiting, headache and
convulsions, comprising administering to a patient in need of such
treatment a composition of the first embodiment or a purgative of
the second embodiment.
[0023] In a sixth embodiment, the invention provides use of a
composition of the first embodiment for the manufacture of a
medicament for the treatment or prevention of one or more of a
member selected from the group consisting of lavage-associated
hyponatremia, hypoosmolality, nausea, malaise, vomiting, headache
and convulsions.
[0024] In a seventh embodiment, the invention provides a method for
the treatment or prevention of acute gastrointestinal infections,
comprising administering to a patient in need of such treatment a
composition of the first embodiment or a purgative of the second
embodiment.
[0025] In an eighth embodiment, the invention provides use of a
composition of the first embodiment for the manufacture of a
medicament for the treatment or prevention of acute
gastrointestinal infections.
[0026] In a ninth embodiment, the invention provides a method for
the treatment or prevention of constipation, acute constipation,
chronic constipation or constipation predominant irritable bowel
syndrome, comprising administering to a patient in need of such
treatment a composition of the first embodiment or a purgative of
the second embodiment.
[0027] In a tenth embodiment, the invention provides use of a
composition of the first embodiment for the manufacture of a
medicament for the treatment or prevention of constipation, acute
constipation, chronic constipation or constipation predominant
irritable bowel syndrome.
[0028] In an eleventh embodiment, the invention provides the
composition of the first embodiment or the purgative of the second
embodiment when used in pre-colonoscopic or pre-surgical lavage, as
a simple purgative, as electrolyte replacement lavage, as a barium
enema preparation, in CT "virtual colonoscopy", in radiological
applications, as electrolyte replacement lavage solutions, as
electrolyte replacement lavage solutions for acute gastrointestinal
infections, for symptomatic treatment in patients suffering from
acute or chronic constipation or related symptoms or constipation
predominant irritable bowel syndrome, as a regular laxative, or for
the treatment or prevention of lavage-associated hyponatremia,
hypoosmolality, nausea, malaise, vomiting, headache or
convulsions.
[0029] In a twelfth embodiment, the invention provides a
composition for use in a purgative, the composition comprising:
[0030] (i) at least one water-soluble sodium salt;
[0031] (ii) at least one water-soluble degradable sugar in an
amount, by weight, of from about 1 to about 3 times the weight of
sodium ions in said composition;
[0032] (iii) at least one water-soluble potassium salt in an
amount, by weight, of from about 0.05 to about 1 times the weight
of said sodium salt in said composition; and
[0033] (iv) at least one water-soluble magnesium salt, wherein the
weight of magnesium ions in said composition is from about 0.1 to
about 10 times the weight of sodium ions in said composition.
[0034] In a thirteenth embodiment, the invention provides a
purgative, comprising a hypertonic aqueous solution of the
composition of the twelfth embodiment.
[0035] In a fourteenth embodiment, the invention provides a method
of inducing purgation of the colon of a patient in need thereof,
comprising administering to said patient in the absence of
diathermy a composition of the twelfth embodiment or a purgative of
the thirteenth embodiment in an amount effective to induce
purgation of the patient's colon.
[0036] In a fifteenth embodiment, the invention provides the use of
a composition of the twelfth embodiment for the manufacture of a
purgative for inducing purgation of the colon in the absence of
diathermy.
[0037] In a sixteenth embodiment, the invention provides a method
for the treatment or prevention of one or more of a member selected
from the group consisting of lavage-associated hyponatremia,
hypoosmolality, nausea, malaise, vomiting, headache and
convulsions, comprising administering to a patient in need of such
treatment in the absence of diathermy a composition of the twelfth
embodiment or a purgative of the thirteenth embodiment.
[0038] In a seventeenth embodiment, the invention provides use of a
composition of the twelfth embodiment for the manufacture of a
medicament for the treatment or prevention in the absence of
diathermy of one or more of a member selected from the group
consisting of lavage-associated hyponatremia, hypoosmolality,
nausea, malaise, vomiting, headache and convulsions.
[0039] In an eighteenth embodiment, the invention provides a method
for the treatment or prevention of acute gastrointestinal
infections, comprising administering to a patient in need of such
treatment in the absence of diathermy a composition of the twelfth
embodiment or a purgative of the thirteenth embodiment.
[0040] In a nineteenth embodiment, the invention provides use of a
composition of the twelfth embodiment for the manufacture of a
medicament for the treatment or prevention of acute
gastrointestinal infections in the absence of diathermy.
[0041] In a twentieth embodiment, the invention provides a method
for the treatment or prevention of constipation, acute
constipation, chronic constipation or constipation predominant
irritable bowel syndrome, comprising administering to a patient in
need of such treatment in the absence of diathermy a composition of
the twelfth embodiment or a purgative of the thirteenth
embodiment.
[0042] In a twenty-first embodiment, the invention provides use of
a composition of the twelfth embodiment for the manufacture of a
medicament for the treatment or prevention of constipation, acute
constipation, chronic constipation or constipation predominant
irritable bowel syndrome in the absence of diathermy.
[0043] In a twenty-second embodiment, the invention provides the
composition of the twelfth embodiment or the purgative of the
thirteenth embodiment when used in the absence of diathermy in
pre-colonoscopic or pre-surgical lavage, as a simple purgative, as
electrolyte replacement lavage, as a barium enema preparation, in
CT "virtual colonoscopy", in radiological applications, as
electrolyte replacement lavage solutions, as electrolyte
replacement lavage solutions for acute gastrointestinal infections,
for symptomatic treatment in patients suffering from acute or
chronic constipation or related symptoms or constipation
predominant irritable bowel syndrome, as a regular laxative, or for
the treatment or prevention of lavage-associated hyponatremia,
hypoosmolality, nausea, malaise, vomiting, headache or
convulsions.
[0044] As used herein, unless the context clearly indicates
otherwise, the words "comprise", "comprises", "comprising" or other
variations thereof shall be understood as meaning that the stated
integer or integers is/are included and does not exclude other
integers from being present even though those other integers are
not explicitly stated.
[0045] The combined effects of the water-soluble sodium, potassium
and magnesium salts and the minimally degradable sugar(s) in the
compositions and purgatives of the invention cause a purgative
effect which is surprisingly greater than the effect that would
have been expected from the known effects of the same amounts of
the individual components of the compositions. That is, the amounts
of the salts required for simply performing their known purgative
function would be significantly greater if they were used singly.
Furthermore, the other benefits of the compositions and purgatives
of the present invention are not provided by compositions of only a
single component. Additionally, the increased tonicity of the
present purgatives compared to existing products enables a
reduction in the amount of each constituent while maintaining the
desired purgative effect. Thus, the components of the purgatives of
the invention cooperate to provide a purgative which is palatable
and which causes purgation without the side effects seen with prior
art compositions, in a way that could not have been predicted prior
to the present invention.
[0046] The invention provides formulations, which safely achieve
orthostatic bowel lavage without associated hypo-osmolar
hyponatremia. Furthermore, the inventors have found that these
formulations can achieve rapid resolution and symptom reversal
together with electrolyte replacement in certain infective
conditions of the gastrointestinal tract. The compositions of the
invention may also be used for patients with either acute or
chronic constipation, since their purgative effect, secondary to
combined hypertonic effect, is not associated with melanosis seen
particularly in patients taking senna-containing faecal softening
agents.
[0047] The additional function of the compositions is to combine
sugar and sodium in amounts that assist in transluminal absorption
of sodium and water. Individually, oral rehydration solutions
(compositions) utilize this principle. However the compositions of
the present invention have the unique and surprising feature of
causing a purgative effect while performing the function of
assisting in transluminal absorption of sodium and water.
[0048] Without wishing to be bound by theory, the present inventors
believe that the administration of a hyperosmolar sodium load
together with other electrolytes and sugar(s) and optionally trace
elements at a time when the maximum effect of the iatrogenic
purgative occurs reduces the gradient of change in serum
osmolarity. The present inventors propose that preventing the
osmolar and sodium shifts causes a reduction in the undesirable
side effects seen with administration of prior art purgatives, as
noted above.
[0049] The details of one or more embodiments of the invention are
set forth in the accompanying drawings and the description below.
Other features, objects, and advantages of the invention will be
apparent from the description and drawings, and from the
claims.
[0050] All publications, patents, patent applications cited herein
are hereby expressly incorporated by reference for all
purposes.
DETAILED DESCRIPTION OF THE INVENTION
[0051] As used herein, the expression "minimally degradable sugar"
is to be understood to mean a carbohydrate moiety that is
substantially resistant to endogenous digestion in the
gastrointestinal tract.
[0052] Typically, in the compositions of the invention, the
minimally degradable sugar is xylose or xylotriose. However, other
sugars including oligosaccharides such as other
xylooligosaccharidcs, fructooligosaccharidcs, fructosans,
galactooligosaccharidcs and the like may be used.
[0053] Glucose and other complex sugars used in standard oral
rehydration therapy lead to intestinal decomposition with the
formation of gases such as methane and hydrogen which have been
associated with explosion caused by diathermy (Altomare D. F. et
al., Dis Colon Rectum 36: 291-2 (1993)). The use of minimally
degradable sugars in the compositions of the present invention
prevents this from occurring and reduces the incidence of abdominal
cramps. In situations however where diathermy is not to be used,
the minimally degradable sugar can be replaced in the compositions
of the invention with a degradable sugar such as glucose,
L-glucose, sucrose, fructose, galactose or lactose.
[0054] The use of xylose (or other minimally degradable sugars)
allows for transport of sodium into the alimentary cellular
structure. The combination of xylose and sodium salts thus allows
for replacement of electrolytes from the induced faecorrhoea, in
particular sodium, potassium and chloride, and reduces the
dilutional hyponatremia associated with other products such as
Picoprep, Fleet and recently reported with polyethylene glycol.
[0055] Typically, in the compositions of the invention, the
water-soluble sodium salt is selected from the group consisting of
sodium chloride, sodium gluconate, sodium citrate and sodium
aspartate.
[0056] In one form of the compositions and purgatives of the
invention, they include at least one sodium salt other than sodium
chloride, more preferably sodium gluconate, sodium citrate or
sodium aspartate, which reduce the salty taste.
[0057] Typically, in the compositions of the invention, the
water-soluble potassium salt is selected from the group consisting
of potassium chloride and potassium tartrate. Usually, the ratio of
potassium salt(s) to sodium salt(s) in the compositions of the
invention is from about 1:1 to about 1:8, more usually from about
1:1.5 to about 1:6, still more usually from about 1:2 to about 1:5,
even more usually about 1:3, on a weight basis.
[0058] Typically, in the compositions of the invention, the
water-soluble magnesium salt is selected from the group consisting
of magnesium sulfate, magnesium citrate and magnesium phosphate.
Usually, the ratio of the weight of magnesium ions to the weight of
sodium ions in the compositions of the invention is from about 1:5
to about 5:1, more usually from about 1:3 to about 3:1, still more
usually from about 1:2 to about 2:1, even more usually about
1:1.
[0059] In the purgative of the second embodiment, the sodium salt
or salts is/arc typically present in an amount ranging from about
1-10 g, more typically about 5 g per unit dose of the purgative,
which will usually be a volume of from about 0.2 to 0.5 L.
[0060] In one form, the composition of the invention comprises
sodium chloride, potassium chloride, magnesium sulfate, and xylose
or other minimally degradable sugars.
[0061] The composition of the invention may be used for
colonoscopic lavage, as a simple purgative or in electrolyte
replacement therapy. The composition may be used with one or more
known purgatives and in that case will complement the purgative
effect of the other purgative(s) and thus reduce the amount
required of these purgative agents. For example a composition of
the present invention may be administered with a half dose of
Fleet, or a reduced number of Picoprep capsules.
[0062] The composition may further comprise one or more further
additives selected from citrate, lactate, acetate, trace elements
such as calcium and zinc, nutritional elements such as Vitamin B
complex, thiamine, Vitamin A, Vitamin C, Vitamin E, folic acid, and
biotin. These additives may be included in the compositions of the
invention in amounts which are based on the patient's daily dietary
requirements.
[0063] The ratio of minimally degradable sugar(s) to sodium ions in
the compositions and purgatives of the invention is from about 3:1
to 1:1 on a weight basis, and will more typically be about 2:1 to
1.4:1. The minimally degradable sugar or sugars is/are typically
present in an amount ranging from about 2 to 20 g, more typically
about 10 g per unit dose.
[0064] In the purgative of the second embodiment, the potassium
salt or salts is/are typically present in an amount ranging from
about 0.5 to 5 g per unit dose, more typically about 1 to 5 g per
unit dose, still more typically about 1.5 to 3 g per unit dose.
[0065] In the purgative of the second embodiment, the magnesium
salt or salts is/arc typically present in an amount ranging from
about 1 to about 10 g per unit dose, more typically about 3 to 5 g
per unit dose.
[0066] Typically, in a purgative of the second embodiment, sodium
is present at a concentration of from about 200-700 mosm. More
typically, the purgative includes sodium at about three times the
isotonic concentration (that is, about 270 mosm).
[0067] In the methods of the third embodiment, the composition of
the invention is typically administered in an amount sufficient to
provide to the patient the following quantities of the
components:
[0068] (i) sodium in an amount of from about 0.01 to about 1.5 g
per kg body weight, more usually about 0.05 to about 1 g per kg,
still more usually about 0.08 g per kg, in which case the
administered dose of sodium will approximate 5 g for an individual
weighing 60-70 kg;
[0069] (ii) the minimally degradable sugar or sugars in an amount
of from about 0.02 to about 3 g per kg of body weight, more usually
from about 0.1 to about 0.2 g per kg, still more usually about 0.15
g per kg in which case the administered dose of minimally
degradable sugar will approximate 10 g for an individual weighing
60-70 kg;
[0070] (iii) potassium in an amount of from about 0.005 to about
0.1 g per kg body weight, more usually from about 0.01 to about
0.05 g per kg, still more usually about 0.03 g per kg in which case
the administered dose approximates 2 g for an individual weighing
60-70 kg;
[0071] (iv) magnesium in an amount of from about 0.01 to about 1.5
g per kg body weight, more usually about 0.05 to about 1 g per kg,
still more usually about 0.08 g per kg in which case the
administered dose approximates 5 g for an individual weighing 60-70
kg.
[0072] In a typical procedure, following the oral ingestion of the
purgative of the invention, cool water in a volume greater than
three times the volume of the purgative hypertonic solution is
ingested.
[0073] The composition of the invention may further comprise a
detergent stool-softening agent such as sodium picosulfate.
Typically this will be present in an amount of from 5-25 mg;
however more typically about 10-15 mg will be used, per unit dose
of the composition.
[0074] The purgative of the second embodiment may suitably be
prepared by dissolving a required amount of a composition of the
first embodiment in a suitable quantity (typically from about 200
mL to 500 mL) of cold, warm or hot water.
[0075] In other forms the composition of the invention may be
compressed into tablets, gel caps or capsules. In this form it is
useful for pre-colonoscopic orthostatic lavage of the bowel, as
preparation for barium enema, in CT "virtual colonoscopy" and for
other radiological applications. It is also useful in pre-surgical
lavage e.g. for removal of the bowel for cancer, diverticulitis
etc. When formulated as tablets, the tablets may suitably comprise
a core of the sodium, potassium and magnesium salts, surrounded by
a coating of the minimally degradable sugar(s).
[0076] The composition or purgative of the invention may further
comprise at least one flavoring ingredient, such as chicken, beef,
vegetarian, Thai, seafood, spice or curry. Suitably, the purgative
of the second embodiment is formulated as a soup or soup-like
composition.
[0077] The psychological advantage of an easily tolerated fluid
with versatility of flavors is that it may be substituted for a
meal for patients who are on a restricted low residue clear fluids
regime. Using various flavors such as chicken, beef, vegetable,
kosher, gluten free, Thai, Japanese (teriyaki), Indian (curry) etc
in a soup mix which includes a composition of the first embodiment
allows for individual preference. If the purgative of the invention
is administered as a clear soup, the purgative is typically made up
using hot water rather than cool fluids. Improved tolerance and
compliance is thereby achieved, in part by reducing the volume of
the preparation to 350 ml and in part by providing a hypertonic
"tasty" meal, as opposed to 3 liters of an unpalatable isotonic
solution such as polyethylene glycol.
[0078] The purgative of the invention is an electrolyte replacement
product, which may accompany and augment the action of other
purgative agents such as products containing sodium picosulfate and
sodium phosphate (e.g. Fleet and Picolax/Picoprep). The purgative
of the invention, when administered in an effective amount to a
patient, contributes to lavage but leads to fewer complications
such as hyponatremia, and hypoosmolar dilutional state, and to
fewer symptoms such as dizziness, nausea, headache and hypotension,
than known purgative agents.
[0079] Although the ratio of individual salts in the compositions
of the invention may vary within the ranges stated above, it is the
combination of these salts added to a defined volume of water which
forms a hypertonic salt solution. The tonicity of fluid is the key
to the electrolyte replacement and purgative effect of the
purgatives of the invention.
[0080] As part of the preparation involves an intact thirst
mechanism which is provided by the hypertonic load, patients for
whom administration of compositions of the invention is to be used
with caution include the very young, the infirmed and demented,
those unable to self administer water or other fluids, and those
patients in which a large sodium load is undesirable (that is,
patients with LVEF <25%), renal failure patients, those with
advanced cardiac or renal disease and those with pituitary
adenoma/hypofunction.
[0081] The invention described herein provides an electrolyte
replacement lavage solution, which can have several roles. It can
be administered with hyper-osmolar solutions such as products
containing sodium picosulfate and sodium phosphate (e.g. Fleet and
Picolax/Picoprep). It can also be used as an electrolyte
replacement lavage solution for acute gastrointestinal infections
including salmonella, shigella, campylobacter or viral
gastroenteritis. This is applicable in particular to viral
gastritis or bacterial gastroenteritis so as to give patient's a
clearance of contents of the flora as well as replace electrolytes
that are being lost during the gastroenteritis. It can also provide
symptomatic improvement in those patients suffering from acute or
chronic constipation and related symptoms and for those with
constipation predominant irritable bowel syndrome (IBS). In
addition, the product can be used alone as an effective orthostatic
lavage for the following applications: prior to colonoscopy, CT
scanning "virtual colonoscopy", barium enema examination, or
intestinal surgery, or as a regular laxative. This is due to the
product allowing simultaneous lavage of the bowel and replacement
of essential electrolytes with fewer complications such as
hyponatremia, hypo-osmolar dilutional state, and fewer symptoms
such as dizziness, nausea and headache. The product can be used as
a treatment of constipation as a regular laxative since it does not
cause electrolyte losses.
[0082] The effective hypertonicity of the purgatives of the
invention will cause purgation when administered to a patient
undergoing a procedure for which purgation is required. These
patients adhere to bowel preparation protocols which commonly
instruct a low residue diet and clear fluids for 1 to 2 days prior
to the procedure for which they are being prepared. In
administering the purgatives of this invention a smaller volume
(approximately 200-500 ml) of hyperosmolar electrolyte enhanced
fluid is required as opposed to larger volumes (3-4 litres) of
isotonic balanced salt solution (Glycoprep). The patients continue
to consume clear fluids to maintain hydration. This is more
palatable and acceptable to the patient. The volume of the
purgatives of the present invention is much less (typically about
one tenth) of the volume of solutions of prior art purgatives which
are administered to a patient. Other fluid taken is part of a
normal diet, and hence is better tolerated and more palatable, with
better patient compliance.
[0083] The compositions and purgatives of the invention are
particularly useful for constipation and bloating, and as soup-like
preparations the purgatives of the invention are acceptable to
patients as a daily food product. As a flavored medication they
have particular use as simultaneous orthostatic lavage and
electrolyte replacement products in patients suffering with acute
gastroenteritis. When combined with added fluids they can be used
in patients with diarrhea without dehydration. This includes
traveler's diarrhea and similar acute bacterial gut infections. The
compositions and purgatives of the invention are also gluten free
and therefore acceptable to those with celiac disease.
[0084] The contained xylose and/or other minimally degradable
sugar(s) (being relatively inert as opposed to glucose) in
compositions of the invention is particularly important in
orthostatic lavage for colonoscopy as it will help to avoid
fermentation and volatile explosive gas production (e.g. methane
and hydrogen). The importance of this is that the potential of an
explosion during diathermy polypectomy is reduced.
[0085] One aim of the present invention is to replace lost sodium
as well as water resulting from bowel preparation in intact
epithelial cells devoid of toxin-induced block such as with cholera
toxin Na--K ATPase pump. The use of hypertonic solutions gives an
opportunity to restore the osmotic equilibrium, which is altered by
the induced water intoxication following replacement of fluid
without electrolytes in patients undergoing some of the established
bowel preparation protocols.
[0086] In a typical method of inducing purgation of the colon in a
patient, a composition of the invention is provided in the form of
a sachet which includes flavoring. The contents (typically weighing
about 25 g) when mixed with water, preferably heated, in a quantity
of 200-500 mls (1-10 ml/kg) will form a palatable soup, which may
be cool or heated to form a hypertonic preparation with an
osmolarity >350 mosm/1.
[0087] After consuming the above purgative dose, the patient will
be instructed to ingest cool water at least 3 times the volume, or
in an adult greater than 750-1000 mls of cool water.
[0088] The invention will be further described with reference to
the following examples; however, it is to be understood that the
invention is not limited to such examples.
EXAMPLES
Formulation Examples
[0089] The following formulations illustrate the compositions of
the invention. When dissolved in about 350 ml of water, they have
osmolarity in the range 500-800 mosm/1. Suitably, the formulations
may be mixed with about half a sachet (about 3.2 g) of commercial
powdered soup mix.
[0090] Formulation 1 [0091] Xylose 10 g [0092] Sodium chloride 5 g
[0093] Potassium chloride 1.5 g [0094] Magnesium sulfate 5 g [0095]
Bisacodyl 10 mg
[0096] Formulation 2 [0097] Xylose 10 [0098] Sodium chloride 5
[0099] Potassium chloride 1.5 g [0100] Magnesium sulfate 5 g
[0101] Formulation 3 [0102] Xylose 10 g [0103] Sodium chloride 5
[0104] Potassium chloride 1.5 g [0105] Magnesium sulfate 5 [0106]
Sodium picosulfate 10 mg
[0107] Formulation 4 [0108] Sodium chloride 10 [0109] Xylose 14
[0110] Potassium chloride 3 [0111] Magnesium sulfate 3 g
[0112] Formulation 5 [0113] Xylose 10 g [0114] Sodium citrate 3
[0115] Sodium chloride 2 g [0116] Potassium chloride 2 g [0117]
Magnesium sulfate 5 g [0118] Sodium picosulfate 15 mg
[0119] Formulation 6 [0120] Xylose 8 g [0121] Sodium chloride 3 g
[0122] Sodium citrate 2 g [0123] Potassium chloride 2 [0124]
Magnesium sulfate 10 g [0125] Sodium picosulfate 15 mg
Examples of Administration of Compositions of the Invention
Administration Example 1
[0126] At time zero 3 Bisacodyl 5 mg tabs and 350 ml of soup
containing Formulation 1 and 3.2 g of a commercial powdered soup
mix were taken by a normal male subject (75 kg) in two doses spaced
1/2-1 hour apart. Alternatively, the Formulation 1 may be added to
the Bisacodyl preparation in the form of a capsule.
[0127] At the time of taking the preparation, side effects
experienced were irritability and indigestion. Two large cups of
water were drunk freely by the patient before and after
administration of the formulation. At 1.5 hour commenced watery
diarrhea with minimal gas, which continued about every 10 minutes
for 1 hour (i.e. 6 occasions) with decreasing amounts of faecal
matter. At 3-4 hours no adverse affects were observed.
Administration Example 2
[0128] 350 ml of soup containing Formulation 2 and 3.2 g of a
commercial powdered soup mix were taken by a normal male subject
(75 kg) over 15 minutes followed by 1 liter of cold water. At 11/2
hours watery evacuation commenced with no flatulence and continued
at intervals of 10 minutes for 45 minutes then ceased. No cramps
and no headaches are associated with the treatment.
Administration Example 3
[0129] Formulations 5 and 6, which include sodium citrate and have
improved palatability, were administered as 350 ml of warm soup
containing 3.2 g of a commercial powdered soup mix, with similar
results as above. That is, 5 loose watery motions occurred over
1-11/2 hours duration after administration.
Administration Example 4
[0130] Combination with Picosulfate in Patient Undergoing
Colonoscopy
[0131] Formulation 3 above was used in a 40-year-old woman with
previously good health. Two sachets, each containing formulation 3
and 3.2 g of commercial powdered soup mix (one chicken flavored and
one beef flavored) were given six hours apart and cleaned the bowel
to enable colonoscopic evaluation without any complaints from the
patient of side effects of headache or lightheadedness.
Administration Example 5
[0132] Combination with Picoprep Capsules
[0133] A 72 year old male with a history of right hemicolectomy for
carcinoma of colon and constipation was given a single sachet
containing formulation 5 and 3.2 g of commercial powdered soup mix
in 350 ml water at 3 pin. This was followed by nine watery motions,
which commenced fifteen minutes after drinking the soup. The
instruction was to drink one liter of water following the soup. The
patient then took five one gram capsules of "Picoprep" at 6 pm,
again accompanied with one liter of water and had six further loose
motions. Overnight he had three loose motions. A colonoscopy was
successfully performed the next day at 11 am. There were no
reported side effects.
Administration Example 6
[0134] Treatment of Gastroenteritis
[0135] A child of 8 years with symptoms of crampy abdominal pain
was given a third of the amount of formulation 2 with onset of
loose motions within 1-2 hours and resolution of symptoms and no
untoward effect.
Administration Example 7
[0136] Treatment of Constipation
[0137] A 48 year lady with long standing constipation was given a
single preparation of formulation 3 as a soup containing 3.2 g of
commercial powdered soup mix and developed a result after one to
one and a half hours of taking the formulation. There were four
episodes in the space of ninety minutes when she had to evacuate
her bowel and apart from complaining of the "saltiness" of the
preparation it was well tolerated.
Administration Example 8
[0138] A 67 year old lady with a family history of colonic
carcinoma and single polyp removed three years prior was returning
for her surveillance colonoscopy. At the previous colonoscopy she
had used picosulfate--two sachets which resulted in profound
hyponatremia associated with nausea and vomiting, malaise and
severe headache. She required intravenous fluids prior to
colonoscopy. On return for surveillance colonoscopy three years
later the patient was afraid to take the picosulfate because she
was concerned about developing the same complications. As a result
she was given the two sachets of picosulfate but this time also
with two sachets of Formulation 3 mixed in beef flavored soup.
These were given six hours apart. The bowel was cleansed to the
caecum with excellent mucosal views. This time the patient did not
develop any nausea, vomiting, headaches, light headedness or
malaise. Her serum electrolytes were normal when tested.
INDUSTRIAL APPLICABILITY
[0139] The compositions of this invention are useful for
colonoscopic lavage, as simple purgatives or in electrolyte
replacement therapy, as preparations for barium enema, in CT
"virtual colonoscopy" and for other radiological applications, as
electrolyte replacement lavage solutions for acute gastrointestinal
infections, for symptomatic improvement in those patients suffering
from either acute or chronic constipation and related symptoms, or
as a regular laxative.
[0140] A number of embodiments of the invention have been
described. Nevertheless, it will be understood that various
modifications may be made without departing from the spirit and
scope of the invention. Accordingly, other embodiments are within
the scope of the following claims.
* * * * *