U.S. patent application number 16/028819 was filed with the patent office on 2018-11-01 for compositions.
The applicant listed for this patent is NORGINE BV. Invention is credited to Mark Christodoulou, Lucy Clayton, Alasdair Cockett, Ian Davidson, Lynn Farrag, Marc Halphen, Leighton Jones, Vanik Petrossian, Peter Stein, David Tisi, Alex Ungar, Jeffrey Worthington.
Application Number | 20180311361 16/028819 |
Document ID | / |
Family ID | 49165735 |
Filed Date | 2018-11-01 |
United States Patent
Application |
20180311361 |
Kind Code |
A1 |
Clayton; Lucy ; et
al. |
November 1, 2018 |
Compositions
Abstract
The invention provides a colon cleansing solution comprising: a)
300 to 800 mmol per litre ascorbate anion provided by a mixture of:
(i) ascorbic acid and (ii) one or more salts of ascorbic acid the
components (i) and (ii) being present in a molar ratio of from
1:4.5 to 1:7.0; and b) 10 to 200 g per litre polyethylene glycol.
The invention also provides methods and kits associated with, or
making use of the solutions, and compositions for the preparation
of the solutions.
Inventors: |
Clayton; Lucy; (Uxbridge,
GB) ; Cockett; Alasdair; (Uxbridge, GB) ;
Christodoulou; Mark; (Uxbridge, GB) ; Davidson;
Ian; (Uxbridge, GB) ; Farrag; Lynn; (Uxbridge,
GB) ; Halphen; Marc; (London, GB) ; Jones;
Leighton; (Uxbridge, GB) ; Petrossian; Vanik;
(Woburn, MA) ; Stein; Peter; (Amsterdam Zuid-Oost,
NL) ; Tisi; David; (Woburn, MA) ; Ungar;
Alex; (Wigton, GB) ; Worthington; Jeffrey;
(Woburn, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
NORGINE BV |
Amsterdam Zuid-Oost |
|
NL |
|
|
Family ID: |
49165735 |
Appl. No.: |
16/028819 |
Filed: |
July 6, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15454132 |
Mar 9, 2017 |
10016504 |
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16028819 |
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15141054 |
Apr 28, 2016 |
9707297 |
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15454132 |
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|
14657495 |
Mar 13, 2015 |
9326969 |
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15141054 |
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14223127 |
Mar 24, 2014 |
8999313 |
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14657495 |
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PCT/EP2013/068738 |
Sep 10, 2013 |
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14223127 |
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61699488 |
Sep 11, 2012 |
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61787366 |
Mar 15, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/047 20130101;
A61P 31/00 20180101; A61P 1/10 20180101; A61K 9/08 20130101; A61K
9/0095 20130101; A61K 9/0053 20130101; A61K 47/26 20130101; A61K
31/765 20130101; A61K 33/14 20130101; A61K 31/375 20130101; A61K
47/10 20130101; A61K 47/02 20130101; A61K 47/12 20130101; A61P 1/00
20180101; A61K 33/04 20130101; Y10S 514/892 20130101; A61K 31/77
20130101; A61K 31/375 20130101; A61K 2300/00 20130101; A61K 31/765
20130101; A61K 2300/00 20130101; A61K 31/77 20130101; A61K 2300/00
20130101 |
International
Class: |
A61K 47/26 20060101
A61K047/26; A61K 33/04 20060101 A61K033/04; A61K 47/02 20060101
A61K047/02; A61K 31/77 20060101 A61K031/77; A61K 31/375 20060101
A61K031/375; A61K 47/10 20060101 A61K047/10; A61K 9/08 20060101
A61K009/08; A61K 47/12 20060101 A61K047/12; A61K 9/00 20060101
A61K009/00; A61K 31/047 20060101 A61K031/047; A61K 33/14 20060101
A61K033/14; A61K 47/18 20060101 A61K047/18; A61K 31/765 20060101
A61K031/765 |
Claims
1. A composition optionally presented in two or more parts for the
preparation of a first colon cleansing solution, comprising: (i)
87.5 to 110 g PEG having an average molecular weight of 2500 to
4500 Da; (ii) 7.5 to 10 g of one or more alkali metal sulphates,
alkaline earth metal sulphates or a mixture thereof; (iii) 1.5 to
2.5 g sodium chloride and 0.75 to 1.25 g potassium chloride; (iv)
optionally one or more flavouring agents; and (v) optionally one or
more sweeteners.
2. A composition as claimed in claim 1, comprising (i) 100 g PEG
having an average molecular weight of 3000 to 4000 Da; (ii) 9.0 g
sodium sulphate; (iii) 2.0 g sodium chloride and 1.0 g potassium
chloride; (iv) optionally one or more flavouring agents; and (v)
optionally one or more sweeteners
3. A composition as claimed in claim 2 wherein the sweetener is
selected from aspartame, acesulfame potassium (acesulfame K),
sucralose and saccharine, and/or combinations thereof.
4. A composition as claimed in claim 3 wherein the sweetener is
sucralose.
5. A composition comprising: a) 150 to 400 mmol ascorbate anion
provided by a mixture of: (i) ascorbic acid, and (ii) one or more
salts of ascorbic acid, the components (i) and (ii) being present
in a molar ratio of from 1:4.5 to 1:7.0; b) 5 to 100 g PEG having
an average molecular weight of 3000 to 4000 Da; c) sodium chloride
and potassium chloride; d) optionally sodium sulphate; e)
optionally one or more flavouring agents; f) optionally one or more
sweeteners.
6. A composition as claimed in claim 5 comprising: a) (i) 6.0 to 10
g ascorbic acid, and (ii) 40 to 60 g sodium ascorbate, the
components (i) and (ii) being present in a weight ratio of from
1:5.063 to 1:7.875; b) 30 to 50 g PEG having an average molecular
weight of 3000 to 4000 Da; c) 1.5 to 4 g sodium chloride and 0.5 to
3.5 g potassium chloride; d) one or more flavouring agents; and e)
one or more sweeteners.
7. A composition as claimed in claim 6 comprising a) (i) 7.54 g
ascorbic acid, and (ii) 48.11 g sodium ascorbate, b) 40 g PEG
having an average molecular weight of 3000 to 4000 Da; c) 3.20 g
sodium chloride and 1.20 g potassium chloride; d) one or more
flavouring agents; and e) one or more sweeteners.
8. A composition as claimed in claim 7 wherein the ascorbate and
PEG components are packaged separately from each other.
9. A composition as claimed in claim 7 wherein the sweetener is
0.5-1.25 g aspartame.
10. A kit comprising a first colon cleansing composition comprising
a composition as claimed in claim 1 and a second colon cleansing
composition comprising a) (i) 6.0 to 10 g ascorbic acid, and (ii)
40 to 60 g sodium ascorbate, the components (i) and (ii) being
present in a weight ratio of from 1:5.063 to 1:7.875; b) 30 to 50 g
PEG having an average molecular weight of 3000 to 4000 Da; c) 1.5
to 4 g sodium chloride and 0.5 to 3.5 g potassium chloride; d) one
or more flavouring agents; and e) one or more sweeteners. wherein
optionally the ascorbate component (a) is packaged separately to
the PEG component (b).
11. A kit comprising a first colon cleansing composition as claimed
in claim 2 and a second colon cleansing composition comprising a)
(i) 7.54 g ascorbic acid, and (ii) 48.11 g sodium ascorbate, b) 40
g PEG having an average molecular weight of 3000 to 4000 Da; c)
3.20 g sodium chloride and 1.20 g potassium chloride; d) one or
more flavouring agents; and e) one or more sweeteners. wherein
optionally the second colon cleansing composition comprises one
package comprising the ascorbate component and one package
comprising the PEG, sodium chloride and potassium chloride
components.
12. A kit comprising a first colon cleansing composition comprising
a composition as claimed in claim 2 and a second colon cleansing
composition containing: a) (i) 7.54 g ascorbic acid, and (ii) 48.11
g sodium ascorbate, b) 40 g PEG having an average molecular weight
of 3000 to 4000 Da; c) 3.20 g sodium chloride and 1.20 g potassium
chloride; d) one or more flavouring agents; and e) one or more
sweeteners; whereby component a) is packaged in a first compartment
and components b), c) e) and f) are packaged in a second
compartment.
13. A solution consisting essentially of: a) (i) 14 to 16 g per
litre ascorbic acid, and (ii) 92 to 100 g per litre sodium
ascorbate, b) 75 to 85 per litre PEG having an average molecular
weight of 3000 to 4000 Da; c) 6.0 to 6.8 g per litre sodium
chloride and 2.0 to 2.8 g per litre potassium chloride; d) one or
more flavouring agents; and e) one or more sweeteners, for use in
cleansing the colon of a mammal.
14. A solution as claimed in claim 13 consisting essentially of: a)
(i) 15.08 g per litre ascorbic acid, and (ii) 96.22 g per litre
sodium ascorbate, b) 80 g per litre PEG having an average molecular
weight of 3000 to 4000 Da; c) 6.4 g per litre sodium chloride and
2.4 g per litre potassium chloride; d) one or more flavouring
agents; and e) one or more sweeteners, for use in cleansing the
colon of a mammal.
15. A method of cleansing the colon comprising a first colon
cleansing agent and a second colon cleansing agent, said method
comprising: a subject taking an effective amount of a first colon
cleansing agent; and a subject taking an effective amount of a
second colon cleansing agent, the first colon cleansing solution in
a volume of 500 ml comprising: (i) 70 to 250 g per litre PEG having
an average molecular weight of 2500 to 4500 Da; (ii) 2.0 to 20 g
per litre of one or more alkali metal sulphates, alkaline earth
metal sulphates or a mixture thereof; (iii) 3.0-5.0 g per litre
sodium chloride and 1.5-2.5 g per litre potassium chloride; (iv)
optionally one or more flavouring agents; and (v) optionally one or
more sweeteners; the second colon cleansing agent being a solution
in 500 ml water of: a) (i) 6.0 to 10 g ascorbic acid, and (ii) 40
to 60 g sodium ascorbate, the components (i) and (ii) being present
in a weight ratio of from 1:5063 to 1:7.875; b) 30 to 50 g PEG
having an average molecular weight of 3000 to 4000 Da; c) 1.5 to 4
g sodium chloride and 0.5 to 3.5 g potassium chloride; d) one or
more flavouring agents; and e) one or more sweetener.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 15/454,132, filed Mar. 9, 2017, in issue, which application is
a continuation of U.S. application Ser. No. 15/141,054, filed Apr.
28, 2016, and issued as U.S. Pat. No. 9,707,297 on Jul. 18, 2017,
which application is a continuation of U.S. application Ser. No.
14/657,495, filed Mar. 13, 2015, and issued as U.S. Pat. No.
9,326,969 on May 3, 2016, which application is a continuation of
U.S. application Ser. No. 14/223,127, filed Mar. 24, 2014, and
issued as U.S. Pat. No. 8,999,313 on Apr. 7, 2015, which
application is a continuation of international (PCT) application
no. PCT/EP2013/068738, filed Sep. 10, 2013, and designating the US,
which claims priority to U.S. provisional patent application Nos.
61/699,488, filed Sep. 11, 2012, and 61/787,366, filed Mar. 15,
2013.
FIELD OF THE INVENTION
[0002] The present invention relates to a method of cleansing the
colon using colon cleansing solutions, and compositions and kits
associated therewith. Colon cleansing compositions are also known
as lavage solutions, bowel cleansers, purgatives or colonic
evacuants.
1. BACKGROUND
[0003] Colon or bowel cleansing is important before numerous
surgical or diagnostic procedures, including colonoscopy, barium
enema examination, sigmoidoscopy and colon surgery. Such procedures
are often carried out on an outpatient basis and thus it is
desirable that the colon cleansing be carried out by the patient at
home, prior to arrival at the hospital or surgery where the
procedure is to take place. It is therefore important that patient
compliance is good without medical supervision if satisfactory
colon cleansing is to be achieved prior to the procedure.
[0004] Intestinal lavage, in which a large volume of an aqueous
electrolyte solution containing sodium sulphate and polyethylene
glycol is ingested, is one of the most common methods for colon
cleansing.
[0005] These osmotically active agents are non-absorbable or only
poorly absorbable and thus retain water in the bowel, resulting in
copious diarrhoea and cleansing of the colon.
[0006] For effective cleansing, many of these compositions must be
ingested in quantities of between 2 to 4 litres. The unpleasant
taste of these compositions combined with the large volumes
required to be ingested often contributes to nausea or vomiting,
resulting in poor patient compliance and failure to consume the
full volume of solution. Poor patient compliance can lead to
inadequate preparation of the colon which can, in turn, lead to
cancellation or repetition of the colonoscopy becoming necessary
or, worse, non-detection of lesions or polyps indicative of cancer
risk.
[0007] A number of improved colon cleansing compositions are
described in WO 2004/037292. A colon cleansing composition
according to WO 2004/037292 that comprises polyethylene glycol
3350, sodium sulphate, an ascorbate component, electrolytes,
sweetener and flavouring is commercialised as a powder for oral
solution under the tradename MOVIPREP.RTM. (registered trademark of
Velinor AG, a member of the Norgine group of companies). The
MOVIPREP solution is effective despite being taken in a
substantially lower volume than other colon cleansing solutions.
Typically, only 2 litres of the solution need to be taken by an
adult patient (along with additional clear fluid), a significant
benefit when compared to taking 4 litres of previous solutions.
[0008] A recent advance in colon cleansing agents is provided by
the product marketed as SUPREP by Braintree Laboratories, Inc.
SUPRPEP contains 17.5 g sodium sulphate, 3.13 g potassium sulphate
and 1.6 g magnesium sulphate and it is taken in a volume of 16 US
fluid ounces (473 ml). A treatment comprises two doses of that
solution.
[0009] Various regimens for the timing of ingestion of colon
cleansing solutions are mentioned in the literature and in patient
information leaflets that accompany colon cleansing products. For
example, the MOVIPREP solution mentioned above may be taken
(optionally with additional clear liquids also being taken) in the
evening before the examination or procedure, or the MOVIPREP
solution may be taken in a "split-dose" regimen, with approximately
half of the cleansing solution being taken the evening before the
examination or procedure ("first dose"), and the remainder being
taken the following morning ("second dose"). Similarly, the SUPREP
product mentioned above is recommended to be taken as first dose in
the evening before the examination procedure, accompanied by an
additional quart of water (946 ml), followed by a second dose in
the morning of the procedure.
[0010] An alternative to the lavage solutions described above is
provided by low volume hypertonic salt solutions. Examples include
Fleet's phosphosoda product and sodium picosulphate solutions.
These are very concentrated salt solutions and patients need ingest
only a small volume of them (around 100 ml). However, these
products have been associated with a hypo-osmolar state and
electrolyte imbalance in subjects, particularly hyponatremia. They
are particularly counter-indicated in subjects with kidney
problems.
[0011] Despite the advances that have been made, all lavage-type
colon cleansing products on the market continue to require a
subject to ingest a large volume of solution (2 litres in the case
of the MOVIPREP solution). Many subjects find the ingestion of a
large volume unpleasant or difficult and poor patient compliance
thus remains a problem. There remains a need for alternative colon
cleansing solutions that are effective when ingested in small
volumes, but do not cause electrolyte imbalances in subjects. There
also remains a need for colon cleansing solutions that are more
pleasant to subjects to ingest, whilst retaining good cleansing
effectiveness.
2. SUMMARY OF THE INVENTION
[0012] The invention provides, in a first aspect, a colon cleansing
solution comprising:
a) 300 to 800 mmol per litre ascorbate anion provided by a mixture
of: [0013] (i) ascorbic acid and [0014] (ii) one or more salts of
ascorbic acid [0015] the components (i) and (ii) being present in a
molar ratio of from 1:4.5 to 1:7.0; and b) 10 to 200 g per litre
polyethylene glycol.
[0016] The solution of the invention has a surprisingly palatable
taste. The particular ratio of ascorbic acid to salt of ascorbic
acid enables the salty taste of ascorbate salt to be balanced by
sourness from acid to a palatable extent, whilst at the same time
not reducing the osmotic effect of the ascorbate component or
making the solution too sour. The solution is highly effective as a
colon cleansing solution when ingested in a lower volume than many
prior art solutions, and it has a good tolerability profile.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] FIG. 1 is a graph showing the results of the taste testing
of the solutions set forth in Table 1 herein.
[0018] FIG. 2 is a graph showing the results of the taste testing
of the solutions set forth in Table 2 herein.
[0019] FIG. 3 is a graph showing the results of the taste testing
of the solutions set forth in Table 3 herein.
[0020] FIG. 4 is a graph showing the results of the taste testing
of the solutions set forth in Table 4 herein.
3. DETAILED DESCRIPTION
a) Contents of Solutions
[0021] The solutions of the invention are aqueous solutions. The
mixture of ascorbic acid and one or more salts of ascorbic acid
will, for convenience, be referred to herein as the "ascorbate
component". Suitable salts of ascorbic acid include alkali metal
salts and alkaline earth metal salts. For example, a salt may be
selected from sodium, potassium, magnesium and calcium salts. For
example, preferred salts of ascorbic acid include sodium ascorbate,
potassium ascorbate, magnesium ascorbate and calcium ascorbate. The
molar ratio between (i) the ascorbic acid and (ii) the one or more
salts of ascorbic acid is the molar ratio of the ascorbate
moieties; for example, magnesium ascorbate comprises two moles of
ascorbate per mole of salt; for the ratio purposes, it is the
number of moles of ascorbate that is counted. Particularly
preferred salts of ascorbic acid are magnesium ascorbate and sodium
ascorbate, for example sodium ascorbate. In one embodiment, the
solution comprises ascorbic acid and sodium ascorbate (and
preferably no further ascorbate).
[0022] Preferably, the molar ratio of the components (i) and (ii)
is from 1:4.75 to 1:6.75; more preferably from 1:5.0 to 1:6.0; for
example from 1:5.40 to 1:5.80; for example 15:85.
[0023] The solution of the invention preferably comprises ascorbate
anion in a concentration of: 300-700 mmol per litre, for example
350-650 mmol per litre, for example 450-600 mmol per litre.
[0024] A solution of the invention may comprise 50 to 140 g/litre
of ascorbate component. For example, a solution of the invention
comprises 60 to 140 g/litre, for example 80 to 130 g/litre, for
example 80 to 120 g/litre, for example 100 to 120 g/litre of
ascorbate component.
[0025] Ascorbic acid has a molecular weight of 176 g/mol. Sodium
ascorbate has a molecular weight of 198 g/mol. Accordingly, a
mixture of ascorbic acid and sodium ascorbate in a molar ratio of
from 1:4.5 to 1:7.0 has ascorbic acid and sodium ascorbate present
in a weight ratio of 1:5.063 to 1:7.875.
[0026] For example, the weight ratio can be 1:5.344 to 1:7.594;
more preferably from 1:5.625 to 1:6.75; for example from 1:6.075 to
1:6.525, for example 1:6.38. For example, a solution of the
invention may comprise from 6 to 25 g/litre of ascorbic acid and 50
to 120 g/litre of sodium ascorbate, for example 12 to 20 g/litre of
ascorbic acid and 80 to 120 g/litre of sodium ascorbate (with the
ratio between them being as mentioned above). For example, a
solution of the invention may comprise from 14 to 16 g g/litre of
ascorbic acid and 92 to 100 g/litre of sodium ascorbate.
[0027] Potassium ascorbate has a molecular weight of 214 g/mol.
Accordingly, a mixture of ascorbic acid and potassium ascorbate in
a molar ratio of from 1:4.5 to 1:7.0 has ascorbic acid and
potassium ascorbate present in a weight ratio of 1:5.471 to
1:8.511. For example, the weight ratio can be 1:5.776 to 1:8.208;
more preferably from 1:6.080 to 1:7.295; for example from 1:6.565
to 1:7.052, for example 1:6.896. For example, a solution of the
invention may comprise from 6 to 25 g/litre of ascorbic acid and 50
to 125 g/litre of potassium ascorbate, for example 6 to 12 g/litre
of ascorbic acid and 80 to 120 g/litre of potassium ascorbate.
[0028] Magnesium ascorbate has a molecular weight of 374.5 g/mol
and each mole of magnesium ascorbate provides two moles of
ascorbate. Accordingly, a mixture of ascorbic acid and magnesium
ascorbate in a molar ratio of from 1:4.5 to 1:7.0 (of ascorbate
anion) has ascorbic acid and magnesium ascorbate present in a
weight ratio of 1:4.794 to 1:7.457. For example, the weight ratio
can be 1:5.061 to 1:7.191; more preferably from 1:5.326 to 1:6.397
for example from 1:5.753 to 1:6.179, for example 1:6.042. For
example, a solution of the invention may comprise from 6 to 25
g/litre of ascorbic acid and 45 to 120 g/litre of magnesium
ascorbate, for example 6 to 12 g/litre of ascorbic acid and 75 to
115 g/litre of magnesium ascorbate.
[0029] Depending on the pH of the solution, some ascorbate anion
may be protonated and thus exist as free ascorbic acid in solution.
At the pH of solutions that would typically be administered, only a
very minor proportion of ascorbate is protonated. In calculations
of concentrations of "ascorbate anion" herein, the concentration of
"ascorbate anion" is taken as the total concentration of all
ascorbate anion present, including the proportion that is
protonated.
[0030] The cleansing solution comprises polyethylene glycol. The
polyethylene glycol (PEG) may, for example, have an average
molecular weight of 2000 to 8000, for example 2500 to 4500 Da, for
example 2680 to 4020 Da, for example 3000 to 4000 Da. For example,
the PEG may be PEG 3350 or PEG 4000 as defined in national
pharmacopeias. PEG8000 may also be used. Further examples of
suitable PEGs recognized in some national pharmacopeias include
Macrogols, for example Macrogol 3350 or Macrogol 4000.
[0031] The cleansing solution comprises 10 to 200 g per litre of
PEG. Preferably, the solution comprises 20 to 160 g per litre of
PEG, more preferably 40 to 120 g per litre, for example 60 to 100 g
per litre, for example 75 to 85 g per litre, for example 80 g per
litre.
[0032] The cleansing solution may additionally comprise one or more
of:
c) one or more electrolytes; d) one or more alkali metal or
alkaline earth metal sulphates; e) one or more flavouring agents;
f) one or more sweeteners.
[0033] The cleansing solution may comprise one or more
electrolytes. Electrolytes include salts of sodium, potassium,
calcium and magnesium, particularly sodium and potassium; and salts
of chloride, iodide, bicarbonate and carbonate, particularly
chloride. Preferred electrolytes are sodium chloride and potassium
chloride. In an embodiment, the solution is essentially free from
sodium bicarbonate, for example essentially free from any
bicarbonate.
[0034] For example, the solution may comprise sodium chloride at a
concentration of 1 to 10 g per litre. For example, sodium chloride
may be present at a concentration of 3 to 8 g per litre, for
example 4 to 7 g per litre; for example 6.0 to 6.8 g per litre; for
example 5.6 g per litre or 6.4 g per litre.
[0035] For example, the solution may comprise potassium chloride at
a concentration of 1 to 10 g per litre. For example, potassium
chloride may be present at a concentration of 1 to 7 g per litre,
for example 1.5 to 5 g per litre, for example 1.5 to 3 g per litre,
for example 2.0 to 2.8 g per litre; for example 2.4 g per litre or
2.6 g per litre.
[0036] In an embodiment, the solution comprises sodium chloride and
potassium chloride. They can be present in the amounts mentioned
immediately above. For example, sodium chloride may be present at a
concentration of 4 to 7 g per litre and potassium chloride may be
present at a concentration of 1.5 to 3 g per litre.
[0037] The cleansing solution may comprise one or more alkali metal
sulphates, alkaline earth metal sulphates or a mixture thereof
(herein referred to as a "sulphate component"). An alkali metal or
alkaline earth metal sulphate may, for example, be selected from
sodium sulphate, potassium sulphate and magnesium sulphate. The
solution may comprise more than one of sodium sulphate, potassium
sulphate and magnesium sulphate, for example all three. Preferably,
the sulphate component is or includes sodium sulphate.
[0038] For example, the solution may comprise a sulphate component
at a concentration of 2 to 20 g per litre, for example 5 to 15 g
per litre, for example 8 to 15 g per litre, for example 10 to 14 g
per litre, for example 12 g per litre. The one or more sulphate
salts may be provided in any pharmaceutically acceptable form: they
may each be anhydrous, or be in a hydrated form. The weights
mentioned herein refer to the weight of the sulphate salt excluding
any water of hydration.
[0039] In an alternative preferred embodiment, the solution does
not comprise a sulphate component; that is to say that the solution
is essentially free from alkali metal sulphates and alkaline earth
metal sulphates; in particular essentially free from sodium
sulphate, potassium sulphate and magnesium sulphate.
[0040] Herein, the term "essentially free from" a component means
that the named component is present at a level that is below the
level that has any functional effect in the solution of the
invention in its use; for example, the named component may be at a
level that is below the level at which it has a measurable clinical
effect. For example, it may mean that the component is present at a
level of less than 0.1 g per litre; for example less than 0.03 g
per litre; for example less than 0.01 g per litre, for example less
than 0.003 g per litre, for example less than 0.001 g per
litre.
[0041] In the solutions of the invention described herein, the
quantities of the individual components recited do not include any
solutes that may be present in the water used to prepare the
solutions, for example, in hard water areas there may be
significant amounts of Ca.sup.2+ and Mg.sup.2+ carbonates,
bicarbonates or sulphates present in tap water.
[0042] The cleansing solution preferably includes a flavouring
agent. A flavouring for use in compositions of the invention should
preferably mask saltiness, be relatively sweet but not excessively
so, and be stable in the composition. A flavouring makes the
solutions more palatable and thus aids patient compliance.
Preferred flavourings include lemon e.g. Ungerer Lemon (available
from Ungerer Limited, Sealand Road, Chester, England CH1 4LP),
strawberry e.g. Ungerer Strawberry, grapefruit e.g. Ungerer
Grapefruit flavouring powder, blackcurrant e.g. Ungerer
Blackcurrant, pineapple e.g. IFF (International Flavours and
Fragrances) Pineapple flavouring powder, orange eg Firmenich
Orange, vanilla/lemon and lime e.g. IFF Vanilla and Givaudin Roure
Lemon and Lime Flav-o-lok, fruit punch eg Ungerer fruit punch,
citrus punch, mango, and berry. Those and further suitable
flavourings are available from International Flavours and
Fragrances Inc. (Duddery Hill, Haverhill, Suffolk, CB9 8LG,
England), Ungerer & Company (Sealand Road, Chester, England CH1
4LP) or Firmenich (Firmenich UK Ltd., Hayes Road, Southall,
Middlesex UB2 5NN). More preferred flavourings are lemon, kiwi,
strawberry, grapefruit, orange, fruit punch and mango. Citrus
flavour, orange grapefruit flavour and orange flavour are
particularly preferred.
[0043] The amount of flavouring required depends on the nature and
strength of the flavouring in question. Typically, it is 0.05 to
4.5 g per litre, for example 0.05 to 2.0 g per litre, for example
0.2 to 1.8 g per litre, for example 1.0 to 1.8 g per litre, for
example 3.0 to 4.5 g per litre, for example 0.3 g per litre or 1.2
g per litre, for example 3.2 or 4.2 g per litre.
[0044] The cleansing solution preferably includes a sweetener.
Sugar-based sweeteners are generally not suited for colon cleansing
compositions because the delivery of unabsorbed sugars to the colon
provides a substrate for bacteria. Such sugars may be metabolised
by the bacteria to form explosive gases such as hydrogen and
methane. The presence of explosive gases in the colon can be highly
dangerous when electrical apparatus is to be used during
colonoscopy or other procedures. Preferred sweeteners include
aspartame, acesulfame potassium (acesulfame K), sucralose and
saccharine, and/or combinations thereof. For example, compositions
of the invention may comprise one or both of aspartame and
acesulfame potassium (acesulfame K). For example, compositions of
the invention may comprise one or both of sucralose and acesulfame
potassium (acesulfame K). In a preferred embodiment, the solution
comprises aspartame or sucralose, for example aspartame.
[0045] Alternatively, compositions of the invention can be
essentially free from added sweeteners, for example to minimize the
number of different components in the compositions.
[0046] A souring agent (for example citric acid) may be present as
a taste enhancer. A souring agent is a component that imparts a
sourness to a composition. Other souring agents include malic acid,
acetic acid, tartaric acid, gluconodeltalactone, phosphoric acid,
succinic acid, phytic acid, lactic acid or salts thereof. The
souring agent (for example citric acid) may be provided in an
encapsulated form. The encapsulation provides a coating that
isolates the souring agent from other components and from air and
moisture prior to its use. Several encapsulated forms of citric
acid, or other souring agents, are commercially available. For
example, the encapsulation may be with a water-soluble coating.
[0047] The amount of sweetener required depends on the nature and
strength of the sweetener being considered. Typically, it is 0.10
to 4 g per litre. For example, the sweetener may be aspartame at
0.5 to 4 g per litre, for example 2.5 to 4.0 g per litre, for
example 3.0 g per litre, for example 3.86 g per litre.
[0048] Those quantities of aspartame are particularly suitable when
used with orange flavouring, for example orange flavouring at 0.2
to 1.8 g per litre, for example 1.0 to 1.8 g per litre, for example
0.3 g per litre, 0.875 g per litre or 1.2 g per litre. For example,
the sweetener may be aspartame at 1.0 to 2.5 g per litre, for
example 1.5 to 2.0 g per litre, for example 1.75 g per litre.
[0049] The invention thus provides a colon cleansing solution
comprising:
a) 300 to 800 mmol per litre ascorbate anion provided by a mixture
of [0050] (i) ascorbic acid and [0051] (ii) one or more salts of
ascorbic acid [0052] the components (i) and (ii) being present in a
molar ratio of from 1:4.5 to 1:7.0; b) 10 to 200 g per litre PEG.
c) one or more electrolytes; d) optionally one or more alkali metal
or alkaline earth metal sulphates; e) optionally one or more
flavouring agents; and f) optionally one or more sweeteners.
[0053] It will be apparent to the reader of this specification,
that the term "comprising" and grammatical variations thereof, in
relation to embodiments of the invention described, may be
substituted in all cases (unless the context dictates otherwise)
with the term "consisting essentially of" or "consisting of". In
the case of a solution that "consists of" or "consists essentially
of" the stated components, the balance is in each case made up of
water.
[0054] In particular, the invention provides a colon cleansing
solution comprising:
a) 300 to 800 mmol per litre ascorbate anion provided by a mixture
of [0055] (i) ascorbic acid and [0056] (ii) one or more salts of
ascorbic acid the components (i) and (ii) being present in a molar
ratio of from 1:4.5 to 1:7.0; b) 10 to 200 g per litre PEG having
an average molecular weight of 3000 to 4000 Da; c) sodium chloride
and potassium chloride; d) optionally sodium sulphate; e)
optionally one or more flavouring agents; and f) optionally one or
more sweeteners.
[0057] Each of c) and d) may be present in the concentrations
described above. Each of e) and f) may be as described above and/or
be in the concentrations described above.
[0058] In particular, the invention provides a colon cleansing
solution comprising:
a) 300 to 800 mmol per litre ascorbate anion provided by a mixture
of [0059] (i) ascorbic acid and [0060] (ii) one or more salts of
ascorbic acid the components (i) and (ii) being present in a molar
ratio of from 1:4.5 to 1:7.0; b) 10 to 200 g per litre PEG having
an average molecular weight of 3000 to 4000 Da; c) sodium chloride
and potassium chloride; e) one or more flavouring agents; and f)
one or more sweeteners.
[0061] In one embodiment, one or more components of c), d) (when
present), e) and f) are present in the solution. In an alternative
presentation, some or all of components c), d) (when present), e)
and f) may be provided separately from the solution, for example in
a tablet or capsule. For example, components c) and d) may be
provided in tablet form. In an embodiment, the solution may
comprise a) the ascorbate component and b) PEG, and optional
flavouring and sweetener (e) and f)), and a tablet or capsule may
comprise c) the one or more electrolytes (optionally with d), the
one or more alkali metal or alkaline earth metal sulphates), again
with optional flavouring and sweetener (e) and f). The flavouring
and sweeteners need not be the same in the tablet or capsule as in
the solution.
[0062] In one embodiment, the invention provides a colon cleansing
solution comprising:
a) [0063] (i) 12 to 20 g per litre ascorbic acid and [0064] (ii) 80
to 120 g per litre sodium ascorbate [0065] the components (i) and
(ii) being present in a weight ratio of from 1:5063 to 1:7.875; b)
60 to 100 g per litre PEG having an average molecular weight of
3000 to 4000 Da; c) 3 to 8 g per litre sodium chloride and 1 to 7 g
per litre potassium chloride; e) one or more flavouring agents; and
f) one or more sweeteners.
[0066] In an embodiment, the solution consists essentially of those
components; that is to say that it does not contain any further
components in significant quantities. The solution may, for
example, not contain any sulphate.
[0067] For example, the invention provides a colon cleansing
solution consisting essentially of:
a) [0068] (i) 14 to 16 g per litre ascorbic acid and [0069] (ii) 92
to 100 g per litre sodium ascorbate b) 75 to 85 per litre PEG
having an average molecular weight of 3000 to 4000 Da; c) 6.0 to
6.8 g per litre sodium chloride and 2.0 to 2.8 g per litre
potassium chloride; e) one or more flavouring agents; and f) one or
more sweeteners.
[0070] For example, the invention provides a colon cleansing
solution consisting essentially of:
a) [0071] (i) 15.08 g per litre ascorbic acid and [0072] (ii) 96.22
g per litre sodium ascorbate b) 80 g per litre PEG having an
average molecular weight of 3000 to 4000 Da; c) 6.4 g per litre
sodium chloride and 2.4 g per litre potassium chloride; e) one or
more flavouring agents; and f) one or more sweeteners.
[0073] For example, the flavouring and sweetener may be 1.20 g per
litre orange flavour and 3.86 g per litre aspartame. For example,
the flavouring and sweetener may be 3.20 g per litre citrus flavour
and 1.75 g per litre aspartame. For example, the flavouring and
sweetener may be 4.20 g per litre orange grapefruit flavour and
1.75 g per litre aspartame.
[0074] Preferably, the colon cleansing solution is hyper-osmotic.
That is to say that it has a higher osmotic strength than blood in
the human body. It may, for example have a measured osmolality in
the range 500 to 2000 mOsmol/kg. For example, the osmolality may be
in the range 700 to 1800 mOsmol/kg.
[0075] For example, the solutes in 500 ml of the solution may have
a measured V(350) value of from 1000 to 2000 ml, for example from
1300 to 2000 ml, for example from 1400 to 1900 ml, and be in a
volume of 400 to 600 ml, for example 500 ml. The V(350) value is
the volume of water that is required to provide a solution with an
osmolality of 350 mOsmol/kg, the total volume being the final
volume after a volume water has been added to a solution having an
initial volume.
[0076] Osmolality can be measured in various ways. In general,
either freezing point depression or vapour-pressure alteration is
used. For example, an Advanced Instruments, Inc Model 3250
osmometer (a freezing point depression device) can be used. Vapour
pressure measurement can also be used, for example using an ELITech
Group Vapro 5600 device. Osmolality values cited herein are
preferably taken to be values measured using a freezing point
depression osmometer, for example using an Advanced Instruments,
Inc Model 3250 osmometer following standard operating
procedure.
[0077] The invention provides a colon cleansing solution
comprising:
a) 300 to 800 mmol per litre ascorbate anion provided by a mixture
of [0078] (i) ascorbic acid and [0079] (ii) one or more salts of
ascorbic acid [0080] the components (i) and (ii) being present in a
molar ratio of from 1:4.5 to 1:7.0; and b) 10 to 200 g per litre
PEG having an average molecular weight of 3000 to 4000 Da; and 500
ml of the solution having a V(350) osmolality value of from 1300 to
2300 ml.
[0081] For example, 500 ml of the solution may have a V(350)
osmolality value of from 1500 to 2100 ml, for example from 1700 to
2000 ml, for example from 1800 to 1900 ml.
b) Additional Optional Contents of Solutions
[0082] Unless it is stated otherwise, the solutions of the
invention may include one or more additional optional
components:
(i) Antioxidants
[0083] In general it is not necessary for the solutions to include
preservatives or anti-oxidants. Nevertheless, low levels of
anti-oxidants or preservatives may be used if required.
(ii) Laxatives
[0084] In general, the solutions described herein are effective
without the need for any additional active ingredients.
Nevertheless, a further active ingredient may be included if
required. For example, a laxative may be present, for example a
stimulant laxative. For example, bisacodyl, castor oil, senna or
bisoxatin may be used. An example of a colon cleansing solution
containing bisoxatin is known from WO2013001315.
(iii) Contrast Media
[0085] For certain uses, one or more contrast media can be included
in a solution of the invention. Examples of contrast media include
barium or iodine products, diatrizoate (marketed, for example, as
HYPAQUE 50), metrizoate (marketed, for example, as ISOPAQUE 370),
ioxalgate (marketed, for example, as HEXABRIX), iopamidol
(marketed, for example, as ISOVUE 370), iohexol (marketed, for
example, as OMNIPAQUE 350), ioxilan (marketed, for example, as
OXILAN 350), iopramide (marketed, for example, as ULTRAVIST 370),
iodixanol (marketed, for example, as VISIPAQUE 320) and/or a
diatrizoic acid or its anionic form diatrizoate (also known as
amidotrizoic acid, or 3,5-diacetamido-2,4,6-triiodobenzoic acid;
marketed, for example, as HYPAQUE). Alternatively, the solution of
the invention may be used in conjunction with (e.g.,
simultaneously, before or after) administration of a contrast agent
or contrast media.
(iv) Dyes and Stains.
[0086] For certain uses (eg fluorescence endoscopy), one or more
dyes or stains that are markers of particular mucosal pathology can
be included in a solution of the invention. Stains may be
selective. For example, hexaminolevulinate may be used, for example
as its HCl salt (marketed as CYSVIEW). Other markers of colonic or
rectal mucosal pathology can be used. For example methylene blue,
which can stain the normal mucosa yet polyps do not stain and
become more clearly visible.
[0087] Further dyes and stains that may be mentioned include:
Curcumin, Riboflavin, Riboflavin-5'-phosphate, Tartrazine,
Quinoline Yellow, Sunset Yellow, FCF Orange, Yellow S, Cochineal,
Carminic acid, Carmines, Azorubine, Carmoisine, Ponceau 4R,
Cochineal Red A, Allura Red AC, Patent Blu EV, Indigotine, Indigo
carmine, Brilliant Blue FCF, Chlorophylls and chlorophyllins,
Copper complexes of chlorophylls and chlorophyllins, Green S, Plain
caramel, Brilliant Black BN, Black PN, Vegetable carbon, Brown HT,
Carotenes, Lutein, Beetroot Red, betanin, Anthocyanins, Calcium
carbonate, Titanium dioxide, Iron oxides and hydroxides, Amaranth,
Brown F, Erythrosine, Lithol Rubine B and/or Red 2G. Further dyes
and stains that may be mentioned include: acid fuchsine, Alba red,
Alizarin cyanine green F, Alizurol purple S5, Allura Red AC,
Alphazurine FGBrilliant lake red R, Dibromofluorescein,
Diiodofluorescein, Eosine, Erythrosine yellowish Na, Fast green
FCF, Flaming red, Fluorescein, Helindone pink CN, Indanthrene blue,
Lake bordeaux B, Lithol rubin B Ca, Naphthol yellow 5, Orange II,
Phloxine B, Ponceau 5X, Pyranine concentrated, Quinizarinegreen 5S,
Tetrabromo-fluorescein, Tetrachlorotetrabromo fluorescein, Toney
red, Uranine, Alcian Blue, Anazolene Sodium, Brilliant Green,
Cantaxanthin, Carthamin, Citrus Red 2, Evan's Blue, Fast Green FCF,
lndocyanine Green, Methyl Blue, Methylene Blue,
N-(p-Methoxyphenyl)-p-phenylenediamine, Ponceau 3R, Ponceau SX,
Pyranine, Rhodamine B, Saunders Red, Sudan Black B, Sulphan Blue,
Tolonium Chloride, and/or Vital Red or equivalents or any
combination thereof.
[0088] Alternatively, the solution of the invention may be used in
conjunction with (e.g., simultaneously, before or after)
administration of a dye or stain. A dye or a stain may be provided
in slow or delayed release form, for example delayed release
methylene blue (for example MMX format of colonic-released
methylene blue) may be mentioned.
(v) Surfactants
[0089] A surfactant may be included in a solution of the invention.
A surfactant may assist in avoiding the persistence of bubbles in
the colon. Such bubbles can interfere with the visualisation of
features of the colon during colonoscopy. Surfactants that may be
mentioned include simethicone (or any mixture of
polydimethylsiloxane and silica gel), dimethicone. Bowel cleansing
solutions containing simethicone are described in WO2009052256.
(vi) Lubricants
[0090] A lubricant may be included in a solution of the invention.
The inclusion of a lubricant can help with a colonoscope insertion
and facilitation within the performance of the colonoscopy.
Suitable lubricants include glycerol or silicone.
(vii) Biofilm-Disrupting Compounds
[0091] A biofilm disrupting compound may be included in a solution
of the invention. A compound that disrupts biofilms may assist in
separating an adherent polysaccharide DNA-containing layer, the
so-called "biofilm" from the colonic mucosa. Removal of that layer
may assist in achieving a cleaner and/or more easily visualized or
stained mucosa.
[0092] Biofilm-disrupting components or agents that may be
mentioned include enzymes such as deoxyribonuclease (DNase),
N-acetylcysteine, alginate lyase, glycoside hydrolase dispersin B;
Quorum-sensing inhibitors e.g., ribonucleic acid III inhibiting
peptide, Salvadora persica extracts, Competence-stimulating
peptide, Patulin and penicillic acid;
peptides--cathelicidin-derived peptides, small lytic peptide, PTP-7
(a small lytic peptide, see e.g., haridia (2011) J. Microbiol.
49(4):663-8, Epub 2011 Sep. 2), Nitric oxide, neo-emulsions; ozone,
lytic bacteriophages, lactoferrin, xylitol hydrogel, synthetic iron
chelators, cranberry components, curcumin, silver nanoparticles,
Acetyl-11-keto-P-boswellic acid (AKBA), barley coffee components,
probiotics, sinefungin, S-adenosylmethionine,
S-adenosyl-homocysteine, Delisea furanones, N-sulfonyl homoserine
lactones and/or macrolide antibiotics or any combination
thereof.
[0093] Alternatively, the solution of the invention may be used in
conjunction with (e.g., simultaneously, before or after)
administration of a biofilm-disrupting compound. A
biofilm-disrupting compound may be administered towards the end of
ingestion of the solution of the invention, or shortly after
completion of ingestion of the solution of the invention, so as to
disrupt the biofilm most just before the colonoscopy.
(viii) Organic Acids
[0094] Some of the osmotic load of the solution of the invention
may be provided by an organic acid or salts of an organic acid
other than ascorbic acid. For example, citric acid and/or salts
thereof may replace some or all of the ascorbate in solutions of
the invention. Throughout this description, ascorbic acid may be
replaced with citric acid. A salt of ascorbate may be replaced with
the salt of citrate. Sodium citrate, potassium citrate and
magnesium citrate are particularly preferred.
c) Uses of Solutions of the Invention
[0095] The solutions of the invention find use in cleansing the
colon or bowel. They are also useful in the treatment of fecal
impaction or constipation.
[0096] When carrying out a bowel cleansing treatment, a subject
typically takes a single dose or a split dose of cleansing
solution. In a split-dose treatment, typically two doses are taken
separated by a time interval, for example an overnight interval.
Alternatively, in a split-dose treatment two doses may be taken on
the same day, for example during the day before a therapeutic or
surgical procedure, or during the day of a therapeutic or surgical
procedure. Each dose in a split dose treatment is smaller than the
dose in the single dose treatment. In a split dose treatment, the
two doses may each have the same composition, or they may be
different.
[0097] For a single dose treatment, the solution of the invention
may be ingested in a volume of 700 to 1500 ml. For example, the
subject may ingest from 750 ml to 1300 ml of the solution, for
example 800 to 1200 ml, for example 900 to 1100 ml, for example
1000 ml. For example 33 or 34 US fluid ounces may be ingested. In
an embodiment, the subject may ingest some additional clear fluid.
The additional clear fluid may be ingested after ingesting the
solution. Alternatively, the additional clear fluid may be
co-administered with the intake of the solution of the invention.
By "co-administered" is meant the coordinated ingestion of a
solution of the invention with clear fluid; that is to say that the
subject ingests some of the solution of the invention but not
necessarily the whole dose, then some clear fluid and then more
solution of the invention.
[0098] For a split dose treatment, the solution of the invention
may be taken as one or both of the doses, each dose having a volume
of 200 to 1000 ml. For example, the subject may ingest (as one of
the doses) 300 ml to 1000 ml of the solution, for example 300 ml to
900 ml, for example 300 ml to 800 ml, for example 400 ml to 700 ml,
for example 400 to 600 ml, for example 450 to 550 ml, for example
500 ml. For example 16 or 17 US fluid ounces may be ingested.
[0099] The combined volume of the first and second doses is
preferably less than 2 litres. Preferably, it is 1750 ml or less,
for example 1500 ml or less, for example 1250 ml or less. For most
adult subjects, a combined volume of more than 500 ml is used, for
example more than 750 ml. For example, a combined volume of from
500 ml to 1750 ml is used, for example from 750 ml to 1500 ml, for
example from 1000 ml to 1500 ml, for example 1000 ml or 1250 ml.
For example the first dose may have a volume of 500 ml (for example
a volume of 16 or 17 US fluid ounces) or 750 ml (for example a
volume of 25 or 26 US fluid ounces) and the second dose may have a
volume of 500 ml (for example a volume of 16 or 17 US fluid
ounces).
[0100] In an embodiment, the subject may ingest some additional
clear fluid with each or either dose of colon cleansing solution.
The additional clear fluid may be taken after ingesting a dose of
the solution.
[0101] Alternatively, the additional clear fluid may be
co-administered with the intake of a dose of the solution of the
invention; that is to say that the subject ingests some of the
solution of the invention but not necessarily the whole dose, then
some clear fluid and then more solution of the invention.
[0102] In the method, there is typically a time interval between
ingesting the first dose and ingesting the second dose. Generally,
the time interval is at least 4 hours, for example 6 hours or more,
for example 8 hours or more. Typically, the time interval is less
than 15 hours. The time interval between starting to take the first
dose and starting to take the second dose may be, for example, the
time between an evening and the following morning, for example 12
to 16 hours, for example 14 hours. For example, the subject may
sleep (for example overnight) between taking the first and second
doses.
[0103] Alternatively, the time interval between ingesting the first
dose and ingesting the second dose can be at least 10 minutes, for
example from 10 minutes to 4 hours, for example from 30 minutes to
4 hours, for example from 30 minutes to two hours. For example, the
subject may ingest the first and second colon doses the evening
before a surgical or diagnostic procedure. The time interval
between ingesting the first solution and ingesting the second
solution can be determined by the time it takes for the subject to
experience a bowel movement. For example the subject takes the
second dose when the first bowel movement has occurred after
completing ingestion of the first solution. Alternatively, the
subject ingests the second dose when the first bowel movement has
occurred even if ingestion of the first dose is not complete.
[0104] During the ingestion of the first or second dose, or during
the time interval between the ingestion of the first dose and the
second dose, the subject may additionally take a stimulant laxative
(also known as a prokinetic agent). A stimulant laxative can assist
in bringing about good cleansing. Examples of stimulant laxatives
include contact laxatives, for example bisacodyl, castor oil, senna
or bisoxatin. Examples of stimulant laxatives also include
additional osmotic agents for example magnesium salts, for example
magnesium citrate. If a stimulant laxative is included in the
regimen, the length of the time interval can be shortened. For
example, it may be 10 minutes to 15 hours, for example 1 to 15
hours, for example 1 to 12 hours, for example 2 to 10 hours.
[0105] During the time interval between the administration of the
first dose and the second dose, it is very likely that the subject
will experience a bowel movement. Advantageously, the subject waits
until the bowel movement has occurred before taking the second
dose.
[0106] In a split dose treatment, the solution of the invention may
be taken for one or for both of the doses. Preferably, the solution
of the invention is taken as the second solution. For example, the
subject may ingest 300 ml to 1000 ml of the solution of the
invention as the second solution, for example 300 ml to 900 ml, for
example 300 ml to 800 ml, for example 400 ml to 700 ml, for example
400 to 600 ml, for example 450 to 550 ml, for example 500 ml. For
example 16 or 17 US fluid ounces may be ingested.
[0107] The first solution may be a solution of different
constitution from the second solution. Thus, in a preferred
embodiment of a split dose bowel cleansing treatment, a subject
takes a dose of an initial cleansing solution, optionally followed
by some additional clear fluid. After an interval, the subject then
takes a dose of the solution of the invention, optionally followed
by some additional clear fluid.
[0108] The volume of clear fluid that a subject ingests after the
first or second dose may be in a range with a lower limit of 100
ml, 200 ml, 300 ml, 400 ml or 500 ml. Preferably, the lower limit
is 300 ml, 400 ml or 500 ml. The volume may be in a range with an
upper limit of 1200 ml, 1100 ml, 1000 ml, 900 ml or 800 ml. For
example the volume may be in the range 100 ml to 1200 ml, for
example 200 ml to 1100 ml, for example 300 ml to 1000 ml, for
example 500 ml to 900 ml, for example 1000 ml, for example 875 ml,
for example 500 ml to 800 ml. For example the volume may be in the
range 300 ml to 900 ml, for example 400 ml to 800 ml, for example
500 ml to 800 ml. The additional clear fluid may be ingested in a
volume of at least 500 ml. For example it may be at least 16 or 17
US fluid ounces. The instructions provided to the subject may
suggest that the additional clear fluid is ingested over a period
of approximately one hour, for example in 150 to 200 ml fractions
every 15 to 20 minutes. The additional clear fluid may be taken
after taking a dose of the solution. Alternatively, the additional
clear fluid may be co-administered with the intake of a dose of the
solution of the invention; for example, the subject may ingest
clear fluid between fractions of the solution of the invention; for
example the subject may ingest a cup of the solution of the
invention, followed by a cup of clear fluid, followed by further
cups of the solution of the invention.
[0109] A clear fluid for taking as the additional clear fluid, or
for use as the clear fluid when making up a solution, may be any
fluid that allows inspection of colonic output. The clear fluid
should also not impede inspection of the colon during the
colonoscopy. Typically the clear fluid is a water-based beverage,
including, for example, water, lemonade, cola drinks, cordial
drinks, clear fruit juices and even clear alcohol-containing
beverages, for example beer. It is desirable that the clear fluid
does not contain substantial amounts of or essentially any dietary
fibre, as such fibre interferes with the cleansing of the colon
according to the present invention. Accordingly, fruit juices, for
example orange juice and kiwi juice, and fruit "squashes" should be
strained before use. Clear fruit cordials, for example lime cordial
or tea (for example green tea), are generally suitable. In view of
the desirability of avoiding drinks containing glucose, so as to
reduce the risk of explosive concentrations of hydrogen or methane
building up in the gut, "diet" drinks containing no or low sugar
are especially suitable, for example liquid drinks for diabetics,
diet Coke.RTM., diet lemonade, dietary carbonated drinks or dietary
cordials. The most preferred clear fluid is water.
[0110] The method of the invention may be used to cleanse the colon
prior to carrying out a diagnostic, therapeutic or surgical
procedure on the colon, rectum or anus or elsewhere in the abdomen
in a subject. The subject is most preferably a human. The
diagnostic or surgical procedure may, for example, be colonoscopy
(such as cap-assisted colonoscopy and/or narrow-band colonoscopy),
barium enema examination, sigmoidoscopy (for example flexible
sigmoidoscopy) or colon surgery. The method of the invention may be
a method of cleansing the colon prior to a surgical or diagnostic
procedure comprising administering the first solution and then
after a time interval administering the second solution prior to
said procedure.
[0111] The solutions, compositions and kits described herein also
find use in the treatment of constipation and fecal impaction. They
also find use in the treatment of severe bacterial infections of
the bowel. The invention thus provides solutions, compositions and
kits as described herein for use in the treatment of constipation
or fecal impaction, or in the treatment of severe bacterial
infections of the bowel. The invention also provides methods of
treating constipation or fecal impaction, or in the treating severe
bacterial infections of the bowel comprising administration of
solutions as described herein.
[0112] As mentioned above, the solutions of the invention find use
in cleansing the colon. The invention provides, in a further
aspect, a solution in water of:
a) 300 to 800 mmol per litre ascorbate anion provided by a mixture
of [0113] (i) ascorbic acid and [0114] (ii) one or more salts of
ascorbic acid the components (i) and (ii) being present in a molar
ratio of from 1:4.5 to 1:7.0; and b) optionally 10 to 200 g per
litre polyethylene glycol, for use in cleansing the colon of a
mammal.
[0115] The solution for use in cleansing the colon of a mammal
preferably comprises ascorbate anion in a concentration of: 300-700
mmol per litre, for example 350-650 mmol per litre, for example
450-600 mmol per litre. As set out above, the ascorbate anion is
provided by a mixture of ascorbic acid and one or more salts of
ascorbic acid. Preferred forms of the ascorbate component are as
set out above in section 3a).
[0116] In a preferred embodiment, PEG is present. Preferred forms
of the PEG and preferred amounts thereof are as set out above in
section 3a).
[0117] The solution for use in cleansing the colon of a mammal may
additionally comprise one or more of:
c) one or more electrolytes; d) one or more alkali metal or
alkaline earth metal sulphates; e) one or more flavouring agents;
f) one or more sweeteners.
[0118] For example, the solution for use in cleansing the colon of
a mammal additionally comprises elements c), e) and f) from that
list.
[0119] Preferred electrolytes and preferred amounts thereof are as
set out above in section 3a).
[0120] Preferred alkali metal or alkaline earth metal sulphates and
preferred amounts thereof are as set out above in section 3a).
[0121] Preferred flavouring agents and preferred amounts thereof
are as set out above in section 3a).
[0122] Preferred sweeteners and preferred amounts thereof are as
set out above in section 3a).
[0123] For example, the solution in water comprises:
a) 150 to 400 mmol ascorbate anion, provided by a mixture of [0124]
(i) ascorbic acid and [0125] (ii) one or more salts of ascorbic
acid the components (i) and (ii) being present in a molar ratio of
from 1:4.5 to 1:7.0; and b) optionally 5 to 100 g PEG.
[0126] In particular, the invention provides a solution
comprising:
a) 150 to 400 mmol ascorbate anion, provided by a mixture of [0127]
(i) ascorbic acid and [0128] (ii) one or more salts of ascorbic
acid the components (i) and (ii) being present in a molar ratio of
from 1:4.5 to 1:7.0; b) 5 to 100 g PEG having an average molecular
weight of 3000 to 4000 Da; c) sodium chloride and potassium
chloride; d) optionally sodium sulphate; e) optionally one or more
flavouring agents; and f) optionally one or more sweeteners for use
in cleansing the colon of a mammal.
[0129] Each of c) and d) may be as described above and/or be
present in the amounts described above in section 3a). Each of e)
and f) may be as described above and/or be in the amounts described
above section 3a).
[0130] In particular, the invention provides a solution consisting
essentially of:
a) [0131] (i) 14 to 16 g per litre ascorbic acid and [0132] (ii) 92
to 100 g per litre sodium ascorbate b) 75 to 85 per litre PEG
having an average molecular weight of 3000 to 4000 Da; c) 6.0 to
6.8 g per litre sodium chloride and 2.0 to 2.8 g per litre
potassium chloride; e) one or more flavouring agents; and f) one or
more sweeteners, for use in cleansing the colon of a mammal.
[0133] Each of c) and d) may be as described above and/or be
present in the amounts described above in section 3a). Each of e)
and f) may be as described above and/or be in the amounts described
above section 3a).
[0134] For example, the invention provides a solution consisting
essentially of:
a) [0135] (i) 15.08 g per litre ascorbic acid and [0136] (ii) 96.22
g per litre sodium ascorbate b) 80 g per litre PEG having an
average molecular weight of 3000 to 4000 Da; c) 6.4 g per litre
sodium chloride and 2.4 g per litre potassium chloride; e) one or
more flavouring agents; and f) one or more sweeteners, for use in
cleansing the colon of a mammal.
[0137] For example, the flavouring and sweetener may be 1.20 g per
litre orange flavour and 3.86 g per litre aspartame. For example,
the flavouring and sweetener may be 3.20 g per litre citrus flavour
and 1.75 g per litre aspartame. For example, the flavouring and
sweetener may be 4.20 g per litre orange grapefruit flavour and
1.75 g per litre aspartame.
[0138] As mentioned above, a bowel cleansing treatment typically
involves a subject taking a single dose or a split dose of
cleansing solution. The volume of solution that a subject takes in
a single dose treatment is described hereinabove. The subject may
take some additional clear fluid after taking the solution as
described hereinabove. The volume of solution that a subject takes
in a split dose treatment is described hereinabove. The subject may
take some additional clear fluid after each or either dose the
solution as described hereinabove.
d) Compositions for Preparing Doses of Solutions
[0139] The invention further provides a composition (for example a
dry composition, for example a powder) for the preparation of a
solution of the invention. A composition can be in a quantity for
the preparation of a dose of the solution, for example a 500 ml
dose (for example a 16 or 17 US fluid ounce dose). The invention
provides a composition for admixture with water, wherein the
composition is optionally presented in two or more parts and
comprises:
a) 150 to 400 mmol ascorbate anion provided by a mixture of: [0140]
(i) ascorbic acid and [0141] (ii) one or more salts of ascorbic
acid the components (i) and (ii) being present in a molar ratio of
from 1:4.5 to 1:7.0; and b) 5 to 100 g polyethylene glycol.
[0142] For example, the components may be in dry powder, granular
or other dry form. They may alternatively be in the form of
concentrates or slurries. Components may be in the same or
different physical forms. For example, the composition is a dry
composition, for example a dry powder composition. For example, one
or both of components a) and b) are dry powders. In a dry powder,
it is possible for one or more components to be a salt hydrate.
[0143] As set out above in section 3a), the ascorbate anion is
provided by a mixture of ascorbic acid and one or more salts of
ascorbic acid. Preferred forms of the ascorbate component are as
set out above in relation to solutions of the invention.
[0144] The composition of the invention preferably comprises
ascorbate anion in an amount of 150 to 350 mmol, for example
175-325 mmol, for example 225-300 mmol.
[0145] Ascorbic acid has a molecular weight of 176 g/mol and sodium
ascorbate has a molecular weight of 198 g/mol. Accordingly, the 150
to 400 mmol ascorbate anion can be provided by 3.3 to 12.8 g
ascorbic acid and 24.3 to 69 g sodium ascorbate, for example 5.0 to
10 g ascorbic acid and 40 to 60 g sodium ascorbate; for example 6.0
to 10 g ascorbic acid and 40 to 60 g sodium ascorbate; for example
7.0 to 8.0 g ascorbic acid and 44 to 52 g sodium ascorbate; for
example 7.0 to 8.0 g ascorbic acid and 46 to 50 g sodium
ascorbate.
[0146] Potassium ascorbate has a molecular weight of 214 g/mol.
Accordingly, the 150 to 400 mmol ascorbate anion can be provided by
3.3 to 12.8 g ascorbic acid and 26 to 75 g potassium ascorbate, for
example 5.0 to 10 g ascorbic acid and 45 to 65 g potassium
ascorbate; for example 7.0 to 8.0 g ascorbic acid and 47 to 56 g
sodium ascorbate.
[0147] Magnesium ascorbate has a molecular weight of 374.5 g/mol
and each mole of magnesium ascorbate provides two moles of
ascorbate. Accordingly, the 150 to 400 mmol ascorbate anion can be
provided by 3.3 to 12.8 g ascorbic acid and 23 to 65 g magnesium
ascorbate, for example 5.0 to 10 g ascorbic acid and 38 to 57 g
magnesium ascorbate; for example 7.0 to 8.0 g ascorbic acid and 42
to 49 g magnesium ascorbate.
[0148] In solid form, ascorbic acid is typically made up of
protonated free ascorbic acid. In calculations of concentrations of
"ascorbate anion" herein, the number of moles of "ascorbate anion"
is taken as the total concentration of all ascorbate anion present,
including the proportion that is protonated.
[0149] The weight of the ascorbate component may be 20 to 85 g, for
example 25 to 75 g, for example 20 to 60 g, for example 50 to 60
g.
[0150] In an embodiment, the ascorbate component comprises (or
consists essentially of) sodium ascorbate and ascorbic acid. For
example, they may be present in a total amount and in a weight
ratio as mentioned immediately above.
[0151] Preferred forms of the PEG are as set out above in section
3a), in relation to solutions of the invention. The composition
comprises 5 to 100 g of PEG. Preferably, the composition comprises
10 to 80 g of PEG, more preferably 20 to 60 g, for example 30 to 50
g, for example 37.5 to 42.5 g, for example 40 g of PEG.
[0152] The composition may additionally comprise one or more
of:
c) one or more electrolytes; d) one or more alkali metal or
alkaline earth metal sulphates; e) one or more flavouring agents;
and f) one or more sweeteners.
[0153] Preferred electrolytes are as set out above in section 3a),
in relation to solutions of the invention. For example, the
composition may comprise sodium chloride in an amount of 0.5 to 5
g, for example 1.5 to 4 g, for example 2.0 to 3.5 g, for example
2.8 g or 3.2 g. For example, the composition may comprise potassium
chloride in an amount of 0.5 to 5 g, for example 0.5 to 3.5 g, for
example 0.75 to 2.5 g, for example 0.75 to 1.5 g, for example 1.0
to 1.4 g, for example 1.2 g or 1.3 g. In an embodiment, the
composition is essentially free from sodium bicarbonate, for
example essentially free from any bicarbonate.
[0154] Preferred alkali metal or alkaline earth metal sulphates are
as set out above in section 3a), in relation to solutions of the
invention. For example, the composition may comprise a sulphate
component in an amount of 1 to 10 g, for example 2.5 to 7.5 g, for
example 4 to 7.5 g, for example 5 to 7 g, for example 6 g. The one
or more sulphate salts may be provided in any pharmaceutically
acceptable form: they may each be anhydrous, or be in a hydrated
form. The weights mentioned herein refer to the weight of the
sulphate salt excluding any water of hydration. A hydrate form may
be present in the dry powder composition, and that composition is
still considered "dry" herein. In an alternative preferred
embodiment, the composition does not comprise a sulphate component;
that is to say that the composition is essentially free from alkali
metal sulphates and alkaline earth metal sulphates; in particular
essentially free from sodium sulphate, potassium sulphate and
magnesium sulphate.
[0155] Preferred flavouring agents are as set out above in section
3a), in relation to solutions of the invention. For example the
amount of flavouring agent may be 0.025 to 2.25 g, for example
0.025 to 1.0 g, for example 0.1 to 0.9 g, for example 0.5 to 0.9 g,
for example 1.5 to 2.25 g, for example 0.15 g or 0.6 g, for example
1.6 or 2.1 g.
[0156] Preferred sweeteners are as set out above in section 3a), in
relation to solutions of the invention. The amount of sweetener
required depends on the nature and strength of the sweetener being
considered. For example the amount of sweetener may be 0.05 to 2 g,
for example 0.25 to 2 g, for example 1.25 to 2 g, for example 1.5
g, for example 1.93 g. Those quantities of aspartame are
particularly suitable when used with orange flavouring, for example
orange flavouring at 0.1 to 0.9 g, for example 0.5 to 0.9 g, for
example 0.15 g, 0.4375 g or 0.6 g. For example, the sweetener may
be aspartame at 0.5 to 1.25 g, for example 0.75 to 1.0 g, for
example 0.875 g.
[0157] In particular, the invention provides a composition
comprising:
a) 150 to 400 mmol ascorbate anion provided by a mixture of: [0158]
(i) ascorbic acid and [0159] (ii) one or more salts of ascorbic
acid the components (i) and (ii) being present in a molar ratio of
from 1:4.5 to 1:7.0; b) 5 to 100 g PEG having an average molecular
weight of 3000 to 4000 Da. c) sodium chloride and potassium
chloride; d) optionally sodium sulphate; e) optionally one or more
flavouring agents; f) optionally one or more sweeteners.
[0160] Each of c) and d) may be present in the amounts described
above. Each of e) and f) may be as described above and/or be in the
amounts described above.
[0161] In one embodiment, the invention provides a composition
comprising:
a) [0162] (i) 6.0 to 10 g ascorbic acid and [0163] (ii) 40 to 60 g
sodium ascorbate [0164] the components (i) and (ii) being present
in a weight ratio of from 1:5063 to 1:7.875; b) 30 to 50 g PEG
having an average molecular weight of 3000 to 4000 Da; c) 1.5 to 4
g sodium chloride and 0.5 to 3.5 g potassium chloride; e) one or
more flavouring agents; and f) one or more sweeteners.
[0165] In one embodiment, the invention provides a composition
comprising:
a) [0166] (i) 7.43 g ascorbic acid and [0167] (ii) 48.11 g sodium
ascorbate b) 40 g PEG having an average molecular weight of 3000 to
4000 Da; c) 3.20 g sodium chloride and 1.20 g potassium chloride;
e) one or more flavouring agents; and f) one or more
sweeteners.
[0168] For example, the flavouring and sweetener may be 0.60 g
orange flavour and 1.93 g aspartame. For example, the flavouring
and sweetener may be 1.60 g citrus flavour and 0.875 g aspartame.
For example, the flavouring and sweetener may be 2.10 g orange
grapefruit flavour and 0.875 g aspartame.
[0169] In an embodiment, the composition consists essentially of
those components; that is to say that it does not contain any
further components in significant quantities. The composition may,
for example, not contain any sulphate.
[0170] One or more of components a) to f) may be presented in solid
form, or in semi-solid form (for example in gel form).
[0171] In one embodiment, the one or more components of c), d)
(when present), e) and f) are present in the composition for making
up a solution. In an alternative presentation, some or all of
components c), d) (when present), e) and f) may be provided
separately from the composition for making up the solution, for
example in a tablet or capsule. In an embodiment, there may be
provided the ascorbate component and PEG, and optional flavouring
and sweetener, in a form for admixture with water, and a tablet or
capsule comprising the one or more electrolytes and/or the one or
more alkali metal or alkaline earth metal sulphates, again with
optional flavouring and sweetener. The flavouring and sweeteners
need not be the same in the tablet or capsule as in the composition
for admixture with water.
[0172] In some embodiments, it is desirable to package the
ascorbate and the PEG components separately from each other.
[0173] In an embodiment, the composition can be provided to the
subject with a plurality of flavouring agents (each optionally with
one or more sweeteners), each separately packaged. The subject can
then select a preferred flavouring (or flavouring and sweetener
combination) according to his or her taste. The subject also has
the choice of not using any flavouring or sweetener at all.
[0174] It will be apparent to the reader that all compounds and
compositions described herein are of a nature and quality suitable
for mammalian (especially human) consumption. For example, they are
of pharmaceutical grade. The pharmaceutically acceptable
compositions described herein may be provided in packaged form with
instructions for use.
e) Compositions for Preparing Solutions
[0175] In a further aspect, the invention provides a composition
comprising the following components in the following weight
ratios:
a) ascorbate anion 0.82 to 4.0 parts provided by a mixture of:
[0176] (i) ascorbic acid and [0177] (ii) one or more salts of
ascorbic acid the components (i) and (ii) being present in a molar
ratio of from 1:4.5 to 1:7.0; and b) polyethylene glycol 1.0
part.
[0178] As mentioned above, for example, the components may be in
dry powder, granular or other dry form. They may alternatively be
in the form of concentrates or slurries. Components may be in the
same or different physical forms. For example, the composition is a
dry composition, for example a dry powder composition. For example,
one or both of components a) and b) are dry powders.
[0179] As set out above, the ascorbate anion is provided by a
mixture of ascorbic acid and one or more salts of ascorbic acid.
Preferred forms of the ascorbate component are as set out above in
section 3a) in relation to solutions of the invention.
[0180] Preferred forms of the PEG are as set out above in section
3a) in relation to solutions of the invention. The composition of
the invention preferably comprises ascorbate anion in a weight
ratio to PEG of 0.82 to 3.0:1. More preferably, the weight ratio is
0.9 to 2.0:1, for example 1.0 to 1.5:1, for example 1.2 to 1.3:1.
As set out above, the ascorbate anion is provided by ascorbic acid
and a salt of ascorbic acid in a ratio of 1:4.5 to 1:7.0. The molar
ratio of the ascorbic acid and the one or more salts of ascorbic
acid is from 1:4.75 to 1:6.75; more preferably from 1:5.0 to 1:6.0;
for example from 1:5.40 to 1:5.80; for example 15:85. The salt of
ascorbic acid can be sodium ascorbate. A mixture of ascorbic acid
and sodium ascorbate in a molar ratio of from 1:4.5 to 1:7.0 has
ascorbic acid and sodium ascorbate present in a weight ratio of
1:5.063 to 1:7.875. A more preferred ratio is 1:5.344 to 1:7.594;
more preferably from 1:5.625 to 1:6.75; for example from 1:6.075 to
1:6.525, for example 1:6.38.
[0181] In a composition in which the weight ratio of ascorbate
anion to PEG is 0.82 to 3.0:1, and in which the ascorbate anion is
provided by ascorbic acid and a sodium ascorbate in a molar ratio
of 1:4.5 to 1:7.0, the weight ratio of ascorbic acid:sodium
ascorbate:PEG is 0.1031 to 0.5486:0.7591-2.970:1. For example, the
weight ratio can be 0.12 to 0.30:0.9 to 1.9:1; more preferably 0.15
to 0.25:1.0 to 1.5:1; for example 0.185 to 0.190:1.15 to 1.25:1;
for example 0.1885:1.203:1.
[0182] The composition may additionally comprise one or more
of:
c) one or more electrolytes; d) one or more alkali metal or
alkaline earth metal sulphates; e) one or more flavouring agents;
f) one or more sweeteners.
[0183] Preferred electrolytes are as set out above in section 3a)
in relation to solutions of the invention. For example, the
composition may comprise sodium chloride in a weight ratio to PEG
of 0.005 to 0.5:1, for example 0.01 to 0.3:1, for example 0.03 to
0.2:1, for example 0.04 to 0.15:1, for example 0.05 to 0.1:1, for
example 0.06 to 0.09:1. For example, the composition may comprise
potassium chloride in a weight ratio to PEG of 0.005 to 0.30:1, for
example 0.01 to 0.20:1, for example 0.01 to 0.10:1, for example
0.02 to 0.04:1.
[0184] For example, the invention provides a composition comprising
the following components in the following weight ratios:
a) ascorbate anion: 0.82 to 4.0 parts; b) polyethylene glycol: 1.0
part; c1) sodium chloride: 0.005 to 1.0 parts; and c2) potassium
chloride: 0.005 to 1.0 parts; the ascorbate anion being provided by
[0185] (i) ascorbic acid and [0186] (ii) one or more salts of
ascorbic acid the components (i) and (ii) being present in a molar
ratio of from 1:4.5 to 1:7.0.
[0187] The composition is preferably essentially free from sodium
bicarbonate. For example, it is essentially free from any
bicarbonate.
[0188] Preferred alkali metal or alkaline earth metal sulphates are
as set out above in section 3a) in relation to solutions of the
invention. For example, the composition may comprise a sulphate
component (for example sodium sulphate) in a weight ratio to PEG of
0.01 to 0.50:1, For example, the composition may comprise a
sulphate component (for example sodium sulphate) in a weight ratio
to PEG of 0.02 to 0.25:1, for example 0.03 to 0.22:1, for example
0.05 to 0.20:1, for example 0.10 to 0.20:1.
[0189] In an embodiment, the composition does not comprise a
sulphate component; that is to say that the composition is
essentially free from alkali metal sulphates and alkaline earth
metal sulphates; in particular essentially free from sodium
sulphate, potassium sulphate and magnesium sulphate.
[0190] Preferred flavouring agents are as set out above in section
3a) in relation to solutions of the invention. For example the
composition may comprise a flavouring agent in a weight ratio to
PEG of 0.0005 to 0.050:1, for example 0.001 to 0.025:1, for example
0.0025 to 0.020:1.
[0191] Preferred sweeteners are as set out above in section 3a) in
relation to solutions of the invention. For example the composition
may comprise a sweetener in a weight ratio to PEG of 0.0005 to
0.1:1, for example 0.001 to 0.075:1, for example 0.002 to
0.050:1.
[0192] In particular, the invention provides a composition
comprising the following components in the following weight
ratios:
a) ascorbate anion: 0.82 to 4.0 parts b) PEG having an average
molecular weight of 3000 to 4000 Da: 1.0 part. c) sodium chloride
and potassium chloride; d) optionally sodium sulphate; e)
optionally one or more flavouring agents; and f) optionally one or
more sweeteners; the ascorbate anion being provided by [0193] (i)
ascorbic acid and [0194] (ii) one or more salts of ascorbic acid
the components (i) and (ii) being present in a molar ratio of from
1:4.5 to 1:7.0.
[0195] Each of c) and d) may be present in the weight ratios to PEG
described above. Each of e) and f) may be as described above and/or
be in the weight ratios to PEG described above.
[0196] In one embodiment, the invention provides a composition
comprising the following components in the following weight
ratios:
a) [0197] (i) ascorbic acid: 0.12 to 0.30 parts; and [0198] (ii)
sodium ascorbate: 0.9 to 1.9 parts [0199] the components (i) and
(ii) being present in a weight ratio of from 1:5063 to 1:7.875; b)
PEG having an average molecular weight of 3000 to 4000 Da: 1 part
c) sodium chloride 0.05 to 0.10 parts and litre potassium chloride
0.02 to 0.04 parts; e) one or more flavouring agents: 0.001 to
0.075 parts; and f) one or more sweeteners: 0.002 to 0.050
parts.
[0200] For example, the composition may comprise the following
components in the following weight ratios:
a) [0201] (i) ascorbic acid: 0.189 parts; and [0202] (ii) sodium
ascorbate: 1.20 parts b) PEG having an average molecular weight of
3000 to 4000 Da: 1 part c) sodium chloride 0.08 parts and litre
potassium chloride 0.03 parts; e) one or more flavouring agents:
0.001 to 0.075 parts; and f) one or more sweeteners: 0.002 to 0.050
parts.
[0203] For example, the flavouring and sweetener may be 0.015 parts
orange flavour and 0.048 parts aspartame. For example, the
flavouring and sweetener may be 0.040 parts citrus flavour and
0.022 parts aspartame. For example, the flavouring and sweetener
may be 0.053 parts orange grapefruit flavour and 0.022 parts
aspartame.
[0204] In an embodiment, the composition consists essentially of
those components; that is to say that it does not contain any
further components in significant quantities. The composition may,
for example, not contain any sulphate.
[0205] Preferred compositions of the invention are dry
compositions, for example dry powder compositions.
[0206] In a further aspect, the invention provides a composition
comprising the following components in the following weight ratios:
[0207] (i) ascorbic acid: 1 part and [0208] (ii) one or more salts
of ascorbic acid: 5.063 to 7.875 parts
[0209] The salt of ascorbic acid can be sodium ascorbate. A mixture
of ascorbic acid and sodium ascorbate in a molar ratio of from
1:4.5 to 1:7.0 has ascorbic acid and sodium ascorbate present in a
weight ratio of 1:5.063 to 1:7.875. A more preferred ratio is
1:5.344 to 1:7.594; more preferably from 1:5.625 to 1:6.75; for
example from 1:6.075 to 1:6.525, for example 1:6.38.
f) Methods of Preparing Solutions and Compositions
[0210] The invention further provides a method of preparing a
solution of the invention comprising combining the components of
the solution with water. The method comprises the step of combining
the components with water and admixing. Some or all of the
components may be in physical association with each other before
the water is added. In some embodiments, the components of the
composition are provided in more than one part; that is to say that
they are packaged separately. All of the components may be combined
with each other before combining with water. For example, if
flavouring agent and sweetener are packaged separately from other
components, they may be combined with the other components before
combining with water. One or some of the components may be combined
with water and admixed in a first step and then some or all of the
remaining components may be added in a second step. For example,
the components may be in dry form, for example in powder form.
[0211] As set out above in section 3d), the invention provides a
composition (for example a dry composition, for example a powder)
for the preparation of a solution of the invention. The invention
further provides a method of preparing a composition of the
invention comprising combining the components of the composition.
For example, the method may be a method of preparing a composition
of the invention in powder form. As set out in section 3d) above,
the components for the preparation of a solution of the invention
may be presented in two or more parts. The invention thus further
provides a method of preparing a composition of the invention
comprising combining some, but not all of the components of the
composition. The invention thus provides a method comprising
blending a mixture of: [0212] (i) ascorbic acid: 1 part and [0213]
(ii) one or more salts of ascorbic acid: 5.063 to 7.875 parts
[0214] The salt of ascorbic acid can be sodium ascorbate. A mixture
of ascorbic acid and sodium ascorbate in a molar ratio of from
1:4.5 to 1:7.0 has ascorbic acid and sodium ascorbate present in a
weight ratio of 1:5.063 to 1:7.875. A more preferred ratio is
1:5.344 to 1:7.594; more preferably from 1:5.625 to 1:6.75; for
example from 1:6.075 to 1:6.525, for example 1:6.38.
[0215] The method may comprise blending a mixture of: [0216] (i)
ascorbic acid and [0217] (ii) one or more salts of ascorbic acid
the components (i) and (ii) being present in a molar ratio of from
1:4.5 to 1:7.0.
[0218] Preferred salts of ascorbic acid are as set out above in
section 3a). Preferred ratios of components (i) and (ii) are as set
out above in section 3a).
[0219] The method may further comprise blending a mixture of:
a) ascorbate anion: 0.82 to 4.0 parts; b) polyethylene glycol: 1.0
part; c1) sodium chloride: 0.005 to 1.0 parts; and c2) potassium
chloride: 0.005 to 1.0 parts; the ascorbate anion being provided by
[0220] (i) ascorbic acid and [0221] (ii) one or more salts of
ascorbic acid the components (i) and (ii) being present in a molar
ratio of from 1:4.5 to 1:7.0.
[0222] The components may be weighed out and added together before
blending, or the components may be added into a blend mixture in
any desired order.
[0223] Blending of the compositions in bulk may, for example, be
carried out on a 100 Kg, 500 Kg or 1000 Kg scale. After blending,
the composition is divided into smaller portions for packaging into
dosage amounts. The invention thus provides a method comprising the
step of dividing bulk composition as set out in section 3e) above
into smaller portions. The invention also provides a method
comprising the step of filling containers with individual dosage
amounts of bulk composition as set out in section 3e). The
invention thus provides a method comprising the step of filling a
container with a composition as set out in section 3d). The
composition as set out in section 3d) may be presented in two or
more parts. The method may thus comprise the step of filling a
container with some but not all of the components of a composition
as set out in section 3d).
4. ALTERNATIVE SOLUTIONS
[0224] The invention also provides a colon cleansing solution does
not contain any ascorbic acid. The invention thus provides, in a
second aspect, a colon cleansing solution comprising:
a) 360 to 440 mmol per litre ascorbate anion provided by one or
more salts of ascorbic acid b) 10 to 200 g per litre polyethylene
glycol; the solution being essentially free from ascorbic acid.
[0225] The solution of the invention has advantageous properties.
The solution of the invention has a surprisingly palatable taste
and it is highly effective as a colon cleansing solution with a
good tolerability profile.
5. DETAILED DESCRIPTION
a) Contents of Solutions
[0226] The solutions of the invention are aqueous solutions.
Suitable salts of ascorbic acid include alkali metal salts and
alkaline earth metal salts. For example a salt may be selected from
sodium, potassium, magnesium and calcium salts. For example,
preferred salts of ascorbic acid include sodium ascorbate,
potassium ascorbate, magnesium ascorbate and calcium ascorbate.
Particularly preferred salts of ascorbic acid are magnesium
ascorbate and sodium ascorbate, for example sodium ascorbate. In
one embodiment, the solution comprises sodium ascorbate and no
further ascorbate.
[0227] The solution of the invention preferably comprises ascorbate
anion in a concentration of: 370-430 mmol per litre, for example
380-420 mmol per litre, for example 400-410 mmol per litre.
[0228] A solution of the invention may comprise 72 to 88 g/litre of
ascorbate salt. For example, a solution of the invention comprises
75 to 85 g/litre, for example 78 to 82 g/litre, for example 80
g/litre.
[0229] Sodium ascorbate has a molecular weight of 198 g/mol.
Accordingly, a solution of the invention may comprise sodium
ascorbate at 71.3-87.1 g per litre, for example 73.3-85.1 g per
litre for example 75.2-83.2 g per litre, for example 79.2-80.2 g
per litre.
[0230] Potassium ascorbate has a molecular weight of 214 g/mol.
Accordingly, a solution of the invention may comprise potassium
ascorbate at 77.0-94.2 g per litre, 79.2-92.0 g per litre, for
example 81.3-89.9 g per litre, for example 85.6-86.7 g per
litre.
[0231] Magnesium ascorbate has a molecular weight of 374.5 g/mol
and each mole of magnesium ascorbate provides two moles of
ascorbate. Accordingly, a solution of the invention may comprise
magnesium ascorbate at 67.4-82.4 g per litre, for example 69.3-80.5
g per litre, for example 71.2-78.6 g per litre, for example
74.9-75.8 g per litre.
[0232] Depending on the pH of the solution, some ascorbate anion
may be protonated and thus exist as free ascorbic acid in solution.
At the pH of solutions that would typically be administered, only a
minor proportion of ascorbate is protonated. In calculations of
concentrations of "ascorbate anion" herein, the concentration of
"ascorbate anion" is taken as the total concentration of all
ascorbate anion present, including the proportion that is
protonated.
[0233] The cleansing solution comprises polyethylene glycol. The
polyethylene glycol (PEG) may be as described above in section 3a).
The cleansing solution comprises 10 to 200 g per litre of PEG.
Preferably, the solution comprises 20 to 160 g per litre of PEG,
more preferably 40 to 120 g per litre, for example 60 to 100 g per
litre, for example 75 to 85 g per litre, for example 80 g per
litre.
[0234] The cleansing solution may additionally comprise one or more
of:
c) one or more electrolytes; d) one or more alkali metal or
alkaline earth metal sulphates; e) one or more flavouring agents;
f) one or more sweeteners.
[0235] The cleansing solution may comprise one or more
electrolytes. Electrolytes include salts of sodium, potassium,
calcium and magnesium, particularly sodium and potassium; and salts
of chloride, iodide, bicarbonate and carbonate, particularly
chloride. Preferred electrolytes are sodium chloride and potassium
chloride. In an embodiment, the solution is essentially free from
sodium bicarbonate, for example essentially free from any
bicarbonate.
[0236] For example, the solution may comprise sodium chloride at a
concentration of 1 to 10 g per litre. For example, sodium chloride
may be present at a concentration of 3 to 8 g per litre, for
example 4 to 7 g per litre; for example 4.5 to 5.5 g per litre; for
example 5.0 g per litre or 5.6 g per litre.
[0237] For example, the solution may comprise potassium chloride at
a concentration of 1 to 10 g per litre. For example, potassium
chloride may be present at a concentration of 1 to 7 g per litre,
for example 1.5 to 5 g per litre, for example 1.5 to 3 g per litre,
for example 1.7 to 2.8 g per litre; for example 1.8 g per litre or
2.6 g per litre.
[0238] In an embodiment, the solution comprises sodium chloride and
potassium chloride. They can be present in the amounts mentioned
immediately above. For example, sodium chloride may be present at a
concentration of 4 to 7 g per litre and potassium chloride may be
present at a concentration of 1.5 to 3 g per litre.
[0239] The cleansing solution may comprise one or more alkali metal
sulphates, alkaline earth metal sulphates or a mixture thereof
(herein referred to as a "sulphate component"). The sulphate
component and the quantity thereof may be as described above in
section 3a).
[0240] In an alternative preferred embodiment, the solution does
not comprise a sulphate component; that is to say that the solution
is essentially free from alkali metal sulphates and alkaline earth
metal sulphates; in particular essentially free from sodium
sulphate, potassium sulphate and magnesium sulphate.
[0241] In the solutions of the invention described herein, the
quantities of the individual components recited do not include any
solutes that may be present in the water used to prepare the
solutions, for example, in hard water areas there may be
significant amounts of Ca.sup.2+ and Mg.sup.2+ carbonates,
bicarbonates or sulphates present in tap water.
[0242] The cleansing solution preferably includes a flavouring
agent. The flavouring may be as described above in section 3a).
Lemon/lime flavour and orange flavour are particularly
preferred.
[0243] The amount of flavouring required depends on the nature and
strength of the flavouring in question. Typically, it is 0.05 to
4.5 g per litre, for example 0.05 to 2.0 g per litre, for example
0.5 to 1.8 g per litre, for example 2.5 to 4.5 g per litre, for
example 0.6 g per litre or 1.6 g per litre, for example 3.2 or 4.3
g per litre.
[0244] The cleansing solution preferably includes a sweetener. The
sweetener may be as described above in section 3a).
[0245] Alternatively, compositions of the invention can be
essentially free from added sweeteners, for example to minimize the
number of different components in the compositions.
[0246] A souring agent (for example citric acid) may be present as
a taste enhancer. A souring agent is a component that imparts a
sourness to a composition. Other souring agents include malic acid,
acetic acid, tartaric acid, gluconodeltalactone, phosphoric acid,
succinic acid, phytic acid, lactic acid or salts thereof. The
souring agent (for example citric acid) may be provided in an
encapsulated form. The encapsulation provides a coating that
isolates the souring agent from other components and from air and
moisture prior to its use. Several encapsulated forms of citric
acid, or other souring agents, are commercially available. For
example, the encapsulation may be with a water-soluble coating.
[0247] The amount of sweetener required depends on the nature and
strength of the sweetener being considered. Typically, it is 0.10
to 4 g per litre. For example, the sweetener may be aspartame at
0.5 to 4 g per litre, for example 2.5 to 4.0 g per litre, for
example 2.0 g per litre, for example 2.2 g per litre or 3.25 g per
litre. Those quantities of aspartame are particularly suitable when
used with orange flavouring, for example orange flavouring at 0.2
to 1.8 g per litre, for example 0.5 to 1.8 g per litre, for example
0.6 g per litre or 1.6 g per litre or 3.25 g per litre.
[0248] The invention thus provides a colon cleansing solution
comprising:
a) 360 to 440 mmol per litre ascorbate anion provided by one or
more salts of ascorbic acid; b) 10 to 200 g per litre PEG; c) one
or more electrolytes; d) optionally one or more alkali metal or
alkaline earth metal sulphates; e) optionally one or more
flavouring agents; and f) optionally one or more sweeteners; the
solution being essentially free from ascorbic acid.
[0249] In particular, the invention provides a colon cleansing
solution comprising:
a) 360 to 440 mmol per litre ascorbate anion provided by one or
more salts of ascorbic acid; b) 10 to 200 g per litre PEG having an
average molecular weight of 3000 to 4000 Da; c) sodium chloride and
potassium chloride; d) optionally sodium sulphate; e) optionally
one or more flavouring agents; and f) optionally one or more
sweeteners; the solution being essentially free from ascorbic
acid.
[0250] Each of c) and d) may be present in the concentrations
described above. Each of e) and f) may be as described above and/or
be in the concentrations described above.
[0251] In particular, the invention provides a colon cleansing
solution comprising:
a) 360 to 440 mmol per litre ascorbate anion provided by one or
more salts of ascorbic acid; b) 10 to 200 g per litre PEG having an
average molecular weight of 3000 to 4000 Da; c) sodium chloride and
potassium chloride; e) one or more flavouring agents; and f) one or
more sweeteners; the solution being essentially free from ascorbic
acid.
[0252] In one embodiment, the one or more components of c), d)
(when present), e) and f) are present in the solution. In an
alternative presentation, some or all of components c), d) (when
present), e) and f) may be provided separately from the solution,
for example in a tablet or capsule. In an embodiment, the solution
may comprise a) the ascorbate component and b) PEG, and optional
flavouring and sweetener (e) and f)), and a tablet or capsule may
comprise c) the one or more electrolytes and/or d) the one or more
alkali metal or alkaline earth metal sulphates, again with optional
flavouring and sweetener (e) and f)). The flavouring and sweeteners
need not be the same in the tablet or capsule as in the
solution.
[0253] In one embodiment, the invention provides a colon cleansing
solution comprising:
a) 71.3 to 87.1 g per litre sodium ascorbate b) 60 to 100 g per
litre PEG having an average molecular weight of 3000 to 4000 Da; c)
3 to 8 g per litre sodium chloride and 1 to 7 g per litre potassium
chloride; e) one or more flavouring agents; and f) one or more
sweeteners.
[0254] In an embodiment, the solution consists essentially of those
components; that is to say that it does not contain any further
components in significant quantities. The solution may, for
example, not contain any sulphate.
[0255] In particular, the invention provides a solution consisting
essentially of:
a) 75 to 85 g per litre sodium ascorbate b) 75 to 85 per litre PEG
having an average molecular weight of 3000 to 4000 Da; c) 4.5 to
5.5 g per litre sodium chloride and 1.5 to 2.3 g per litre
potassium chloride; e) one or more flavouring agents; and f) one or
more sweeteners.
[0256] For example, the invention provides a colon cleansing
solution consisting essentially of:
a) 80 g per litre sodium ascorbate b) 80 g per litre PEG having an
average molecular weight of 3000 to 4000 Da; c) 5.0 g per litre
sodium chloride and 1.80 g per litre potassium chloride; e) one or
more flavouring agents; and f) one or more sweeteners.
[0257] For example, the flavouring and sweetener may be 1.60 g per
litre orange flavour and 2.20 g per litre aspartame. For example,
the flavouring and sweetener may be 3.20 g per litre lemon/lime
flavour and 3.25 g per litre aspartame. For example, the flavouring
and sweetener may be 4.30 g per litre orange grapefruit flavour and
3.25 g per litre aspartame.
[0258] Preferably, the colon cleansing solution is hyper-osmotic.
That is to say that it has a higher osmotic strength than blood in
the human body. It may, for example have a measured osmolality in
the range 500 to 2000 mOsmol/kg. For example, the osmolality may be
in the range 700 to 1800 mOsmol/kg. For example, the solutes in 500
ml of the solution may have a measured V(350) value of from 1000 to
2000 ml, for example from 1300 to 1700 ml, for example from 1400 to
1600 ml, and be in a volume of 400 to 600 ml, for example 500
ml.
[0259] The invention provides a colon cleansing solution
comprising:
a) 360 to 440 mmol per litre ascorbate anion provided by one or
more salts of ascorbic acid b) 10 to 200 g per litre polyethylene
glycol; the solution being essentially free from ascorbic acid, and
500 ml of the solution having a V(350) osmolality value of from
1000 to 2000 ml.
[0260] For example, 500 ml of the solution may have a V(350)
osmolality value of from 1200 to 1800 ml, for example from 1400 to
1600 ml.
b) Additional Optional Contents of Solutions
[0261] The solutions of the invention may include additional
optional components as set out above in section 3b).
c) Uses of Solutions of the Invention
[0262] Uses of solutions of the invention are as set out above in
section 3c). The invention thus provides, in a further aspect a
solution in water of:
a) 360 to 440 mmol per litre ascorbate anion provided by one or
more salts of ascorbic acid; and b) optionally 10 to 200 g per
litre polyethylene glycol, the solution being essentially free from
ascorbic acid, for use in cleansing the colon of a mammal.
[0263] The solution for use in cleansing the colon of a mammal
preferably comprises ascorbate anion in a concentration of: 370-430
mmol per litre, for example 380-420 mmol per litre, for example
400-410 mmol per litre. As set out above, the ascorbate anion is
provided by one or more salts of ascorbic acid. Preferred forms of
the ascorbate component are as set out above in section 5a).
[0264] In a preferred embodiment, PEG is present. Preferred forms
of the PEG and preferred amounts thereof are as set out above in
section 5a).
[0265] The solution for use in cleansing the colon of a mammal may
additionally comprise one or more of:
c) one or more electrolytes; d) one or more alkali metal or
alkaline earth metal sulphates; e) one or more flavouring agents;
f) one or more sweeteners.
[0266] For example, the solution for use in cleansing the colon of
a mammal additionally comprises elements c), e) and f) from that
list.
[0267] Preferred electrolytes and preferred amounts thereof are as
set out above in section 5a).
[0268] Preferred alkali metal or alkaline earth metal sulphates and
preferred amounts thereof are as set out above in section 5a).
[0269] Preferred flavouring agents and preferred amounts thereof
are as set out above in section 5a).
[0270] Preferred sweeteners and preferred amounts thereof are as
set out above in section 5a).
[0271] For example, the solution in water comprises:
a) 180 to 220 mmol ascorbate anion provided by one or more salts of
ascorbic acid; and b) optionally 5 to 100 g PEG. the solution being
essentially free from ascorbic acid.
[0272] In particular, the invention provides a solution
comprising:
a) 180 to 220 mmol ascorbate anion provided by one or more salts of
ascorbic acid; b) 5 to 100 g PEG having an average molecular weight
of 3000 to 4000 Da; c) sodium chloride and potassium chloride; d)
optionally sodium sulphate; e) optionally one or more flavouring
agents; and f) optionally one or more sweeteners, the solution
being essentially free from ascorbic acid for use in cleansing the
colon of a mammal.
[0273] Each of c) and d) may be as described above and/or be
present in the amounts described above in relation to solutions of
the invention. Each of e) and f) may be as described above and/or
be in the amounts described above in section 5a).
[0274] In particular, the invention provides a solution consisting
essentially of:
a) 75 to 85 g per litre sodium ascorbate b) 75 to 85 per litre PEG
having an average molecular weight of 3000 to 4000 Da; c) 4.5 to
5.5 g per litre sodium chloride and 1.5 to 2.3 g per litre
potassium chloride; e) one or more flavouring agents; and f) one or
more sweeteners, for use in cleansing the colon of a mammal.
[0275] For example, the invention provides a solution consisting
essentially of:
a) 80 g per litre sodium ascorbate b) 80 g per litre PEG having an
average molecular weight of 3000 to 4000 Da; c) 5.0 g per litre
sodium chloride and 1.80 g per litre potassium chloride; e) one or
more flavouring agents; and f) one or more sweeteners. for use in
cleansing the colon of a mammal.
[0276] For example, the flavouring and sweetener may be 1.60 g per
litre orange flavour and 2.20 g per litre aspartame. For example,
the flavouring and sweetener may be 3.20 g per litre lemon/lime
flavour and 3.25 g per litre aspartame. For example, the flavouring
and sweetener may be 4.30 g per litre orange grapefruit flavour and
3.25 g per litre aspartame.
[0277] As mentioned above, a bowel cleansing treatment typically
involves a subject taking a single dose or a split dose of
cleansing solution. The volume of solution that a subject takes in
a single dose treatment is described hereinabove in section 3c).
The subject may take some additional clear fluid after taking the
solution as described hereinabove.
[0278] The volume of solution that a subject takes in a split dose
treatment is described hereinabove in section 3c). The subject may
take some additional clear fluid after each or either dose the
solution as described hereinabove.
d) Compositions for Preparing Doses of Solutions
[0279] The invention further provides a composition (for example a
dry composition, for example a powder) for the preparation of a
solution of the invention. A composition can be provided in a
quantity for the preparation of a dose of the solution, for example
a 500 ml dose. The invention provides a composition for admixture
with water, wherein the composition is optionally presented in two
or more parts and comprises:
a) 180 to 220 mmol ascorbate anion provided by one or more salts of
ascorbic acid; and b) 5 to 100 g polyethylene glycol; the solution
being essentially free from ascorbic acid.
[0280] For example, the components may be in dry powder, granular
or other dry form. They may alternatively be in the form of
concentrates or slurries. Components may be in the same or
different physical forms. For example, the composition is a dry
composition, for example a dry powder composition. For example, one
or both of components a) and b) are dry powders.
[0281] As set out above in section 5a), the ascorbate anion may be
provided by one or more salts of ascorbic acid. Preferred forms of
the ascorbate component are as set out above in relation to
solutions of the invention.
[0282] The composition of the invention preferably comprises
ascorbate anion in an amount of: 185 to 215 mmol, for example 190
to 210 mmol, for example 200-205 mmol.
[0283] Sodium ascorbate has a molecular weight of 198 g/mol.
Accordingly, the 180 to 220 mmol ascorbate anion can be provided by
35.6 to 43.6 g sodium ascorbate. For example, the sodium ascorbate
may be present at a level of 36.6 to 42.6 g, for example 37.6 to
41.6 g, for example 39.6 to 40.6 g.
[0284] Potassium ascorbate has a molecular weight of 214 g/mol.
Accordingly, the 180 to 220 mmol ascorbate anion can be provided by
38.5 to 47.1 g potassium ascorbate. For example, the potassium
ascorbate may be present at a level of 39.6 to 46.0 g, for example
40.7 to 44.9 g, for example 42.8 to 43.9 g.
[0285] Magnesium ascorbate has a molecular weight of 374.5 g/mol
and each mole of magnesium ascorbate provides two moles of
ascorbate. Accordingly, the 180 to 220 mmol ascorbate anion can be
provided by 33.7 to 41.2 g magnesium ascorbate. For example, the
magnesium ascorbate may be present at a level of 34.6 to 40.3 g,
for example 35.6 to 39.3 g, for example 37.5 to 38.4 g.
[0286] The weight of the ascorbate salt component may be 33 to 47
g, for example 35 to 45 g, for example 37 to 43 g.
[0287] In an embodiment, the ascorbate component consists
essentially of sodium ascorbate alone. For example, it may be
present in an amount as mentioned immediately above.
[0288] Preferred forms of the PEG are as set out in section 5a)
above in relation to solutions of the invention. The composition
comprises 5 to 100 g of PEG. Preferably, the composition comprises
10 to 80 g of PEG, more preferably 20 to 60 g, for example 30 to 50
g, for example 37.5 to 42.5 g, for example 40 g of PEG.
[0289] The composition may additionally comprise one or more
of:
c) one or more electrolytes; d) one or more alkali metal or
alkaline earth metal sulphates; e) one or more flavouring agents;
and f) one or more sweeteners.
[0290] Preferred electrolytes are as set out above in section 5a)
in relation to solutions of the invention. For example, the
composition may comprise sodium chloride in an amount of 0.5 to 5
g, for example 1.5 to 4 g, for example 2.0 to 3.5 g, for example
2.5 or 2.8 g. For example, the composition may comprise potassium
chloride in an amount of 0.5 to 5 g, for example 0.5 to 3.5 g, for
example 0.75 to 2.5 g, for example 0.75 to 1.5 g, for example 0.85
to 1.4 g, for example 0.9 or 1.3 g. In an embodiment, the
composition is essentially free from sodium bicarbonate, for
example essentially free from any bicarbonate.
[0291] Preferred alkali metal or alkaline earth metal sulphates are
as set out above in relation to solutions of the invention. For
example, the composition may comprise a sulphate component in an
amount of 1 to 10 g, for example 2.5 to 7.5 g, for example 4 to 7.5
g, for example 5 to 7 g, for example 6 g. The one or more sulphate
salts may be provided in any pharmaceutically acceptable form: they
may each be anhydrous, or be in a hydrated form. The weights
mentioned herein refer to the weight of the sulphate salt excluding
any water of hydration. A hydrate form may be present in the dry
powder composition, and that composition is still considered "dry"
herein. In an alternative preferred embodiment, the composition
does not comprise a sulphate component; that is to say that the
solution is essentially free from alkali metal sulphates and
alkaline earth metal sulphates; in particular essentially free from
sodium sulphate, potassium sulphate and magnesium sulphate.
[0292] Preferred flavouring agents are as set out above in section
5a) in relation to solutions of the invention. For example the
amount of flavouring agent may be 0.025 to 2.25 g, for example
0.025 to 1.0 g, for example 0.25 to 0.9 g, for example 1.25 to 2.25
g, for example 0.3 g or 0.8 g, for example 1.6 or 2.15 g.
[0293] Preferred sweeteners are as set out above in relation to
solutions of the invention. For example the amount of sweetener may
be 0.05 to 2 g. For example, the sweetener may be aspartame at 0.25
to 2 g, for example at 1.25 to 2.0 g, for example 1.0, 1.1 g or
1.625 g. Those quantities of aspartame are particularly suitable
when used with orange flavouring, for example orange flavouring at
0.1 to 0.9 g, for example 0.25 to 0.9 g, for example 0.3, 0.8 g or
1.625 g.
[0294] In particular, the invention provides a composition
comprising:
a) 180 to 220 mmol ascorbate anion provided by one or more salts of
ascorbic acid; b) 5 to 100 g PEG having an average molecular weight
of 3000 to 4000 Da. c) sodium chloride and potassium chloride; d)
optionally sodium sulphate; e) optionally one or more flavouring
agents; f) optionally one or more sweeteners; the solution being
essentially free from ascorbic acid.
[0295] Each of c) and d) may be present in the amounts described
above. Each of e) and f) may be as described above and/or be in the
amounts described above.
[0296] In one embodiment, the invention provides composition
comprising:
a) 35.65 to 43.55 g sodium ascorbate b) 30 to 50 g PEG having an
average molecular weight of 3000 to 4000 Da; c) 1.5 to 4 g sodium
chloride and 0.5 to 3.5 g potassium chloride; e) one or more
flavouring agents; and f) one or more sweeteners.
[0297] In one embodiment, the invention provides a composition
comprising:
a) 40 g sodium ascorbate b) 40 g PEG having an average molecular
weight of 3000 to 4000 Da; c) 2.50 g sodium chloride and 0.90 g
potassium chloride; e) one or more flavouring agents; and f) one or
more sweeteners.
[0298] For example, the flavouring and sweetener may be 0.80 g
orange flavour and 1.10 g aspartame. For example, the flavouring
and sweetener may be 1.60 g lemon/lime flavour and 1.625 g
aspartame. For example, the flavouring and sweetener may be 2.15 g
orange grapefruit flavour and 1.625 g aspartame.
[0299] In an embodiment, the composition consists essentially of
those components; that is to say that it does not contain any
further components in significant quantities. The composition may,
for example, not contain any sulphate.
[0300] One or more components a) to f) may be presented in solid
form, or in semi-solid form (for example in gel form).
[0301] In one embodiment, the one or more components of c), d) e)
and f) are present in the composition for making up a solution. In
an alternative presentation, some or all of components c), d) e)
and f) may be provided separately from the composition for making
up the solution, for example in a tablet or capsule. In an
embodiment, there may be provided the ascorbate component and PEG,
and optional flavouring and sweetener, in a form for admixture with
water, and a tablet or capsule comprising the one or more
electrolytes and/or the one or more alkali metal or alkaline earth
metal sulphates, again with optional flavouring and sweetener. The
flavouring and sweeteners need not be the same in the tablet or
capsule as in the composition for admixture with water.
[0302] In some embodiments, it is desirable to package the
ascorbate and the PEG components separately from each other.
[0303] In an embodiment, the composition can be provided to the
subject with a plurality of flavouring agents (each optionally with
one or more sweeteners), each separately packaged. The subject can
then select a preferred flavouring (or flavouring and sweetener
combination) according to his or her taste. The subject also has
the choice of not using any flavouring or sweetener at all.
[0304] It will be apparent to the reader that all compounds and
compositions described herein are of a nature and quality suitable
for mammalian (especially human) consumption. For example, they are
of pharmaceutical grade. The pharmaceutically acceptable
compositions described herein may be provided in packaged form with
instructions for use.
e) Compositions for Preparing Solutions
[0305] In a further aspect, the invention provides a composition
comprising the following components in the following weight
ratios:
a) ascorbate anion 0.78 to 1.2 parts; and b) polyethylene glycol
1.0 part; the ascorbate anion being provided by one or more salts
of ascorbic acid; the composition being essentially free from
ascorbic acid.
[0306] As mentioned above, for example, the components may be in
dry powder, granular or other dry form. They may alternatively be
in the form of concentrates or slurries. Components may be in the
same or different physical forms. For example, the composition is a
dry composition, for example a dry powder composition. For example,
one or both of components a) and b) are dry powders.
[0307] As set out above, the ascorbate anion is provided by one or
more salts of ascorbic acid. Preferred forms of the ascorbate
component are as set out above in section 5a) in relation to
solutions of the invention. Preferred salts are sodium, potassium
and magnesium ascorbate, especially sodium ascorbate.
[0308] Preferred forms of the PEG are as set out above in section
5a) in relation to solutions of the invention. The composition of
the invention preferably comprises ascorbate anion in a weight
ratio to PEG of 0.80 to 1.0:1. More preferably, the weight ratio is
0.85 to 0.95:1, for example 0.86 to 0.90:1, for example 0.88:1.
[0309] The preferred ascorbate salt is sodium ascorbate. The
composition of the invention preferably comprises sodium ascorbate
and PEG in a weight ratio of 0.90 to 1.125:1. More preferably, the
weight ratio is 0.956 to 1.069:1, for example 0.968 to 1.013:1, for
example 0.99:1, for example 1:1.
[0310] The composition may additionally comprise one or more
of:
c) one or more electrolytes; d) one or more alkali metal or
alkaline earth metal sulphates; e) one or more flavouring agents;
f) one or more sweeteners.
[0311] Preferred electrolytes are as set out above in section 5a)
in relation to solutions of the invention. For example, the
composition may comprise sodium chloride in a weight ratio to PEG
of 0.005 to 0.5:1, for example 0.01 to 0.3:1, for example 0.02 to
0.2:1, for example 0.03 to 0.15:1, for example 0.04 to 0.1:1, for
example 0.05 to 0.08:1. For example, the composition may comprise
potassium chloride in a weight ratio to PEG of 0.005 to 0.30:1, for
example 0.01 to 0.20:1, for example 0.01 to 0.10:1, for example
0.02 to 0.04:1.
[0312] For example, the invention provides a composition comprising
the following components in the following weight ratios:
a) ascorbate anion: 0.78 to 1.2 parts; b) polyethylene glycol: 1.0
part; c1) sodium chloride: 0.005 to 1.0 parts; and c2) potassium
chloride: 0.005 to 1.0 parts; the ascorbate anion being provided by
one or more salts of ascorbic acid; the composition being
essentially free from ascorbic acid.
[0313] The composition is preferably essentially free from sodium
bicarbonate. For example, it is essentially free from any
bicarbonate.
[0314] Preferred alkali metal or alkaline earth metal sulphates are
as set out above in section 5a) in relation to solutions of the
invention. For example, the composition may comprise a sulphate
component (for example sodium sulphate) in a weight ratio to PEG of
0.01 to 0.50:1, For example, the composition may comprise a
sulphate component (for example sodium sulphate) in a weight ratio
to PEG of 0.02 to 0.25:1, for example 0.03 to 0.22:1, for example
0.05 to 0.20:1, for example 0.10 to 0.20:1.
[0315] In an alternative preferred embodiment, the composition does
not comprise a sulphate component; that is to say that the
composition is essentially free from alkali metal sulphates and
alkaline earth metal sulphates; in particular essentially free from
sodium sulphate, potassium sulphate and magnesium sulphate.
[0316] Preferred flavouring agents are as set out above in section
5a) in relation to solutions of the invention. For example the
composition may comprise a flavouring agent in a weight ratio to
PEG of 0.0005 to 0.05:1, for example 0.001 to 0.050:1, for example
0.003 to 0.030:1.
[0317] Preferred sweeteners are as set out above in section 5a) in
relation to solutions of the invention. For example the composition
may comprise a sweetener in a weight ratio to PEG of 0.0005 to
0.025:1, for example 0.001 to 0.050:1, for example 0.01 to
0.035:1.
[0318] In particular, the invention provides a composition
comprising the following components in the following weight
ratios:
a) ascorbate anion: 0.78 to 1.2 parts b) PEG having an average
molecular weight of 3000 to 4000 Da: 1.0 part. c) sodium chloride
and potassium chloride; d) optionally sodium sulphate; e)
optionally one or more flavouring agents; and f) optionally one or
more sweeteners. the ascorbate anion being provided by one or more
salts of ascorbic acid; the composition being essentially free from
ascorbic acid.
[0319] Each of c) and d) may be present in the weight ratios to PEG
described above. Each of e) and f) may be as described above and/or
be in the weight ratios to PEG described above.
[0320] In one embodiment, the invention provides a composition
comprising the following components in the following weight
ratios:
a) sodium ascorbate: 0.90 to 1.125 parts b) PEG having an average
molecular weight of 3000 to 4000 Da: 1 part c) sodium chloride 0.04
to 0.10 parts and litre potassium chloride 0.02 to 0.04 parts; e)
one or more flavouring agents: 0.001 to 0.075 parts; and f) one or
more sweeteners: 0.002 to 0.050 parts.
[0321] For example, the composition may comprise the following
components in the following weight ratios:
a) sodium ascorbate: 1.0 parts b) PEG having an average molecular
weight of 3000 to 4000 Da: 1 part c) sodium chloride 0.0625 parts
and litre potassium chloride 0.0225 parts; e) one or more
flavouring agents: 0.001 to 0.075 parts; and f) one or more
sweeteners: 0.002 to 0.050 parts.
[0322] For example, the flavouring and sweetener may be 0.020 parts
orange flavour and 0.0275 parts aspartame. For example, the
flavouring and sweetener may be 0.040 parts lemon/lime flavour and
0.041 parts aspartame. For example, the flavouring and sweetener
may be 0.054 parts orange flavour and 0.041 parts aspartame.
[0323] In an embodiment, the composition consists essentially of
those components; that is to say that it does not contain any
further components in significant quantities. The composition may,
for example, not contain any sulphate.
[0324] Preferred compositions of the invention are dry
compositions, for example dry powder compositions.
f) Methods of Preparing Solutions and Compositions
[0325] The invention further provides a method of preparing a
solution of the invention comprising combining the components of
the solution with water. The method comprises the step of combining
the components with water and admixing. Some or all of the
components may be in physical association with each other before
the water is added. In some embodiments, the components of the
composition are provided in more than one part; that is to say that
they are packaged separately. All of the components may be combined
with each other before combining with water. For example, if
flavouring agent and sweetener are packaged separately from other
components, they may be combined with the other components before
combining with water. One or some of the components may be combined
with water and admixed in a first step and then or all of the
remaining components may be added in a second step. For example,
the components may be in dry form, for example in powder form.
[0326] As set out above in section 5d), the invention provides a
composition (for example a dry composition, for example a powder)
for the preparation of a solution of the invention. The invention
further provides a method of preparing a composition of the
invention comprising combining the components of the composition.
For example, the method may be a method of preparing a composition
of the invention in powder form. The method may comprise blending a
mixture of:
a) ascorbate anion 0.78 to 1.2 parts; and b) polyethylene glycol
1.0 part; the ascorbate anion being provided by one or more salts
of ascorbic acid; the composition being essentially free from
ascorbic acid
[0327] Preferred ascorbate salts are as set out above in section
5a). Preferred ratios of components a) and b) as set out above in
section 5a). Preferably the ascorbate anion is in a weight ratio to
PEG of 0.80 to 1.0:1. More preferably, the weight ratio is 0.85 to
0.95:1, for example 0.86 to 0.90:1, for example 0.88:1.
[0328] The preferred ascorbate salt is sodium ascorbate. Preferably
the sodium ascorbate and PEG are in a weight ratio of 0.90 to
1.125:1. More preferably, the weight ratio is 0.956 to 1.069:1, for
example 0.968 to 1.013:1, for example 0.99:1, for example 1:1.
[0329] The method may further comprise blending a mixture of:
a) ascorbate anion: 0.78 to 1.2 parts; b) polyethylene glycol: 1.0
part; c1) sodium chloride: 0.005 to 1.0 parts; and c2) potassium
chloride: 0.005 to 1.0 parts; the ascorbate anion being provided by
one or more salts of ascorbic acid; the composition being
essentially free from ascorbic acid.
[0330] Preferred ratio amounts of sodium chloride to PEG and
potassium chloride to PEG are as set out above in section 5e).
[0331] The components may be weighed out and added together before
blending, or the components may be added into a blend mixture in
any desired order.
[0332] Blending of the compositions in bulk may, for example, be
carried out on a tonne scale. After blending, the composition is
divided into smaller portions for packaging into dosage amounts.
The invention thus provides a method comprising the step of
dividing bulk composition as set out in section 5e) above into
smaller portions. The invention also provides a method comprising
the step of filling containers with individual dosage amounts of
bulk composition as set out in section 5e). The invention thus
provides a method comprising the step of filling a container with a
composition as set out in section 5d). The composition as set out
in section 5d) may be presented in two or more parts. The method
may thus comprise the step of filling a container with some but not
all of the components of a composition as set out in section
5d).
6. METHODS OF CLEANSING AND SOLUTIONS FOR USE IN THEM
a) Split-Dose Colon Cleansing Treatments
[0333] The solutions and compositions of the first and second
aspects of the invention set out in sections 2 to 5 above find
particular use in split dose colon cleansing treatments in which
the subject takes two different agents (for example two different
solutions): a first colon cleansing agent (for example solution),
followed by a second colon cleansing agent (for example solution).
Herein, the "second colon cleansing agent" means the agent that is
taken chronologically second, after the "first colon cleansing
agent". Preferably, the solution of the first or second aspect of
the invention is the second colon cleansing agent. Alternatively,
it may be the first agent. The invention thus provides, in a third
aspect a method of cleansing the colon of a mammal comprising:
[0334] the subject taking an effective amount of a first colon
cleansing agent; and then [0335] the subject taking an effective
amount of a second colon cleansing agent, the second colon
cleansing agent being a solution of the first or second aspect of
the invention described above. Preferably, the first colon
cleansing agent is of different composition from the second colon
cleansing agent. The first colon cleansing agent may be a colon
cleansing solution. Alternatively, it may be a colon cleansing
agent in solid form, for example in the form of a tablet, for
example a PEG-containing tablet, or a bisacodyl-containing tablet.
The first colon cleansing agent may, for example, contain a
laxative, for example a stimulant laxative. For example, bisacodyl,
castor oil, senna or bisoxatin may be used.
[0336] The invention also provides a method of cleansing the colon
of a mammal comprising: [0337] the subject taking an effective
amount of a first colon cleansing agent; and then [0338] the
subject taking an effective amount of a second colon cleansing
agent, the second colon cleansing agent being a solution comprising
a) 300 to 800 mmol per litre ascorbate anion provided by a mixture
of: [0339] (i) ascorbic acid and [0340] (ii) one or more salts of
ascorbic acid the components (i) and (ii) being present in a molar
ratio of from 1:4.5 to 1:7.0; and b) optionally 10 to 200 g per
litre polyethylene glycol.
[0341] The invention also provides a method of cleansing the colon
of a mammal comprising: [0342] the subject taking an effective
amount of a first colon cleansing agent; and then [0343] the
subject taking an effective amount of a second colon cleansing
agent, the second colon cleansing agent being a solution comprising
a) 360 to 440 mmol per litre ascorbate anion provided by one or
more salts of ascorbic acid; and b) optionally 10 to 200 g per
litre polyethylene glycol; the solution being essentially free from
ascorbic acid.
[0344] The method of the invention may be used to cleanse the colon
prior to carrying out a diagnostic, therapeutic or surgical
procedure on the colon, rectum or anus or elsewhere in the abdomen.
The diagnostic or surgical procedure may, for example, be
colonoscopy, barium enema examination, sigmoidoscopy or colon
surgery. The method of the invention is generally finished less
than 8 hours before carrying out the diagnostic, therapeutic or
surgical procedure on the colon, rectum or anus or elsewhere in the
abdomen. Preferably, it is finished less than 4 hours before.
[0345] The invention further provides a method of conducting a
diagnostic or surgical procedure, for example, a colonoscopy,
barium enema examination, sigmoidoscopy or colon surgery,
comprising the steps of:
a) cleansing the colon by a method of the invention, and then b)
carrying out the diagnostic or surgical procedure.
[0346] The invention further provides a first colon cleansing
agent, and a second colon cleansing agent, for use in a method of
cleansing the colon comprising: [0347] the subject taking an
effective amount of a first colon cleansing agent; [0348] the
subject taking an effective amount of a second colon cleansing
agent, the second colon cleansing agent being a solution of the
first or second aspect of the invention described above.
[0349] The invention further provides a first colon cleansing
agent, and a second colon cleansing agent, for use in a method of
cleansing the colon comprising: [0350] the subject taking an
effective amount of a first colon cleansing agent; [0351] the
subject taking an effective amount of a second colon cleansing
agent, the second colon cleansing agent being a solution in water
of: a) 300 to 800 mmol per litre ascorbate anion provided by a
mixture of [0352] (i) ascorbic acid and [0353] (ii) one or more
salts of ascorbic acid the components (i) and (ii) being present in
a molar ratio of from 1:4.5 to 1:7.0; and b) optionally 10 to 200 g
per litre polyethylene glycol.
[0354] In an embodiment, the first agent is different from the
second.
[0355] The invention further provides a first colon cleansing
agent, and a second colon cleansing agent, for use in a method of
cleansing the colon comprising: [0356] the subject taking an
effective amount of a first colon cleansing agent; [0357] the
subject taking an effective amount of a second colon cleansing
agent, the second colon cleansing agent being a solution in water
of: a) 360 to 440 mmol per litre ascorbate anion provided by one or
more salts of ascorbic acid; and b) optionally 10 to 200 g per
litre polyethylene glycol. the solution being essentially free from
ascorbic acid.
[0358] In an embodiment, the first agent is different from the
second. Further details of possible first colon cleansing agents
are provided below in section 6b)
[0359] The second colon cleansing agent is preferably as described
hereinabove in sections 2 to 5 in relation to solutions and uses of
the first and second aspects of the invention. It is preferably
used in a volume as described hereinabove in relation to solutions
and uses of the invention as described hereinabove in sections 2 to
5.
[0360] The first and second colon cleansing agents may be provided
in a kit. Further details of such kits are provided in section 8)
below.
b) The "First" Colon Cleansing Agent
[0361] The first cleansing agent may be a solution, referred to as
the first colon cleansing solution. The first colon cleansing
solution may, for example, be a bowel content suspending agent. The
first colon cleansing solution may comprise polyethylene glycol
and/or an alkali metal sulphate, an alkaline earth metal sulphate
or a mixture thereof. The first colon cleansing solution may be
hyper-osmotic.
[0362] Preferably, the first colon cleansing solution comprises
polyethylene glycol (PEG). The polyethylene glycol (PEG) may have
an average molecular weight of 2000 to 8000, for example 2500 to
4500 Da, for example 2680 to 4020 Da, for example 3000 to 4000 Da.
For example, the PEG may be PEG 3350 or PEG 4000 as defined in
national pharmacopeias. PEG8000 may also be used. Further examples
of suitable PEGs recognized in some national pharmacopeias include
Macrogols, for example Macrogol 3350 or Macrogol 4000.
[0363] Preferably, the first colon cleansing solution comprises 70
to 250 g per litre of PEG. Preferably, the solution comprises 130
to 250 g per litre PEG, for example 90 to 200 g per litre of PEG,
more preferably 100 to 200 g per litre, for example 120 to 150 g
per litre, for example 133.3 g per litre; for example 150 to 250 g
per litre, for example 175 to 225 g per litre, for example 200 g
per litre.
[0364] Preferably, the first colon cleansing solution comprises one
or more alkali metal sulphates, alkaline earth metal sulphates or a
mixture thereof (herein referred to as a "sulphate component"). An
alkali metal or alkaline earth metal sulphate may, for example, be
selected from sodium sulphate, potassium sulphate and magnesium
sulphate. The solution may comprise more than one of sodium
sulphate, potassium sulphate and magnesium sulphate, for example
all three. Preferably, the sulphate component is or includes sodium
sulphate.
[0365] Preferably, the first colon cleansing solution comprises a
sulphate component (for example sodium sulphate) at a concentration
of 2 to 20 g per litre, for example 2 to 15 g per litre, for
example 5 to 15 g per litre, for example 8 to 12 g per litre, for
example 8 or 12 g per litre; for example 10 to 20 g per litre, for
example 15 to 20 g per litre, for example 17 to 19 g per litre, for
example 18 g per litre. For example, the first colon cleansing
solution comprises 8.0 to 20 g per litre of one or more alkali
metal sulphates, alkaline earth metal sulphates or a mixture
thereof.
[0366] Accordingly, the first colon cleansing solution may
comprise:
(i) 70 to 250 g per litre PEG having an average molecular weight of
2500 to 4500 Da. (ii) 2.0 to 20 g per litre of one or more alkali
metal sulphates, alkaline earth metal sulphates or a mixture
thereof (iii) optionally one or more electrolytes; (iv) optionally
one or more flavouring agents; and (v) optionally one or more
sweeteners.
[0367] The first colon cleansing solution may comprise one or more
electrolytes. Electrolytes include salts of sodium, potassium,
calcium and magnesium, particularly sodium and potassium; and salts
of chloride, iodide, bicarbonate and carbonate, particularly
chloride. Preferred electrolytes are sodium chloride and potassium
chloride. In an embodiment, sodium bicarbonate is not included.
[0368] For example, the first colon cleansing solution may comprise
sodium chloride at a concentration of 0.5 to 5.0 g per litre. For
example, sodium chloride may be present at a concentration of 1.0
to 4.0 g per litre, for example 1.0 to 3.0 g per litre, for example
1.5 to 3.0 g per litre, for example 2.0 to 3.0 g per litre; for
example 3.0 to 5.0 g per litre, for example 3.5 to 4.5 g per litre,
for example 4.0 g per litre.
[0369] For example, the first colon cleansing solution may comprise
potassium chloride at a concentration of 1 to 10 g per litre. For
example, potassium chloride may be present at a concentration of
0.05 to 5.0 g per litre, for example 0.1 to 3.0 g per litre, for
example 0.2 to 2.0 g per litre, for example 0.5 to 1.5 g per litre,
for example 0.5 to 1.1 g per litre; for example 1.5 to 2.5 g per
litre, for example 1.8 to 2.2 g per litre, for example 2.0 g per
litre.
[0370] In an embodiment, the first colon cleansing solution
comprises sodium chloride and potassium chloride. They can be
present in the amounts mentioned immediately above. For example,
sodium chloride may be present at a concentration of 1.0 to 3.0 g
per litre and potassium chloride may be present at a concentration
of 2.5 to 3.0 g per litre; for example, sodium chloride may be
present at a concentration of 3.0 to 5.0 g per litre and potassium
chloride may be present at a concentration of 0.5 to 1.1 g per
litre.
[0371] In an embodiment, the first colon cleansing solution
comprises sodium chloride and potassium chloride. They can be
present in the amounts mentioned immediately above. For example,
sodium chloride may be present at a concentration of 1.5 to 3.0 g
per litre and potassium chloride may be present at a concentration
of 0.2 to 2.0 g per litre; for example, sodium chloride may be
present at a concentration of 3.0 to 5.0 g per litre and potassium
chloride may be present at a concentration of 1.5 to 2.5 g per
litre.
[0372] For example, the first colon cleansing solution
comprises:
(i) 90 to 200 g per litre PEG having an average molecular weight of
2500 to 4500 Da. (ii) 2.0 to 15 g per litre of one or more alkali
metal sulphates, alkaline earth metal sulphates or a mixture
thereof (iii) 0.5 to 5.0 g per litre sodium chloride, and 0.05 to
5.0 g per litre potassium chloride; (iv) optionally one or more
flavouring agents; and (v) optionally one or more sweeteners.
[0373] In an embodiment, the first colon cleansing solution may be
a solution as commercialised under the tradename MOVIPREP.RTM..
[0374] The first colon cleansing solution preferably includes a
flavouring agent. The first colon cleansing solution preferably
includes a sweetener. Flavouring agents and sweeteners may be as
described hereinabove.
[0375] For example, a flavouring for use in the first colon
cleansing solution should preferably mask saltiness, be relatively
sweet but not excessively so, and be stable in the composition. A
flavouring makes the solutions more palatable and thus aids patient
compliance. Preferred flavourings include lemon e.g. Ungerer Lemon
(available from Ungerer Limited, Sealand Road, Chester, England CH1
4LP) strawberry e.g. Ungerer Strawberry, grapefruit e.g. Ungerer
Grapefruit flavouring powder, blackcurrant e.g. Ungerer
Blackcurrant, pineapple e.g. IFF (International Flavours and
Fragrances) Pineapple flavouring powder, orange eg Firmenich
Orange, and vanilla/lemon and lime e.g. IFF Vanilla and Givaudin
Roure Lemon and Lime Flav-o-lok, fruit punch eg Ungerer fruit
punch, citrus punch, mango, and berry. Those and further suitable
flavourings are available from International Flavours and
Fragrances Inc. (Duddery Hill, Haverhill, Suffolk, CB9 8LG,
England), Ungerer & Company (Sealand Road, Chester, England CH1
4LP) or Firmenich (Firmenich UK Ltd., Hayes Road, Southall,
Middlesex UB2 5NN). More preferred flavourings are lemon, kiwi,
strawberry grapefruit, fruit punch and mango. Fruit punch and mango
are especially preferred flavours.
[0376] A particularly preferred flavouring is fruit punch flavour,
for example at a level of 0.4 to 3.5 g per litre, for example 0.4
to 1.2 g per litre, for example 0.938, 1.0 or 3.18 g per litre.
[0377] The first cleansing solution preferably includes a
sweetener. Preferred sweeteners include aspartame, acesulfame
potassium (acesulfame K), sucralose and saccharine, and/or
combinations thereof. For example, the solution may comprise one or
both of aspartame and acesulfame potassium (acesulfame K). For
example, it may comprise one or both of sucralose and acesulfame
potassium (acesulfame K). In a preferred embodiment, the solution
comprises aspartame or sucralose, for example sucralose. Preferred
sweeteners include aspartame, acesulfame potassium (acesulfame K),
sucralose and saccharine, and/or combinations thereof. For example,
compositions of the invention may comprise one or both of aspartame
and acesulfame potassium (acesulfame K). For example, compositions
of the invention may comprise one or both of sucralose and
acesulfame potassium (acesulfame K). In a preferred embodiment, the
solution comprises aspartame or sucralose, for example
aspartame.
[0378] Alternatively, compositions of the invention can be
essentially free from added sweeteners, for example to minimize the
number of different components in the compositions.
[0379] A souring agent (for example citric acid) may be present as
a taste enhancer. A souring agent is a component that imparts a
sourness to a composition. Other souring agents include malic acid,
acetic acid, tartaric acid, gluconodeltalactone, phosphoric acid,
succinic acid, phytic acid, lactic acid or salts thereof. It may be
present at a level of from 0.1 to 3.0 g per litre, for example 0.3
to 2.0 g per litre, for example 0.5 to 2.0 g per litre, for example
0.75 g, 1.0 g, 1.06 g, 1.25 g or 1.5 g per litre. The souring agent
(for example citric acid) may be provided in an encapsulated form.
The encapsulation provides a coating that isolates the souring
agent from other components and from air and moisture prior to its
use. Several encapsulated forms of citric acid, or other souring
agents, are commercially available. For example, the encapsulation
may be with a water-soluble coating.
[0380] The amount of sweetener required depends on the nature and
strength of the sweetener being considered. Typically, it is 0.10
to 4 g per litre. For example, the sweetener may be sucralose at
0.1 to 3.0 g per litre, for example 0.3 to 2.0 g per litre, for
example 0.5 to 2.0 g per litre, for example 0.5 to 1.3 g per litre
for example 0.63 g, 0.80 g, 1.0 g or 1.58 g per litre.
[0381] The first cleansing solution may include one or more further
optional components. Such components may be as set out above in
section 3b).
[0382] In an embodiment, the first colon cleansing solution has a
volume of from 400 to 600 ml (for example 500 ml), and contains the
quantities of solutes described in the section immediately above.
For example the volume may be 16 or 17 US fluid ounces. For
example, the invention provides colon cleansing solution
comprising:
(i) 175 to 220 g per litre PEG having an average molecular weight
of 2500 to 4500 Da. (ii) 15 to 20 g per litre of one or more alkali
metal sulphates, alkaline earth metal sulphates or a mixture
thereof (iii) 3.0 to 5.0 g per litre sodium chloride, and 1.5 to
2.5 g per litre potassium chloride; (iv) optionally one or more
flavouring agents; and (v) optionally one or more sweeteners.
[0383] Such a solution has a smaller volume than cleansing
solutions that are generally used.
[0384] In an embodiment, the first colon cleansing solution is
provided in a volume of from 300 ml up to 1200 ml. For example, the
first solution may have a volume in a range with a lower limit of
300 ml, 400 ml, 500 ml, 600 ml or 700 ml. Preferably, the lower
limit is 500 ml, 600 ml or 700 ml. The volume may be in a range
with an upper limit of 1200 ml, 1100 ml, 1000 ml, 900 ml or 800 ml.
For example the volume may be in the range 400 ml to 1100 ml, for
example 500 ml to 1000 ml, for example 600 ml to 900 ml, for
example 700 ml to 800 ml. For example, the first colon cleansing
solution is provided in a volume of 750 ml. For example the volume
may be in the range 400 ml to 600 ml. For example, the first colon
cleansing solution is provided in a volume of 500 ml. For example
it may be in a volume of 16 or 17 US fluid ounces. The most
appropriate volume will depend on the exact components of the
solution and the amounts in which they are present. In general, for
a solution of higher osmotic strength, a smaller volume will be
required.
[0385] The first cleansing solution may, for example, have a
measured osmolality in the range 200 to 2000 mOsmol/kg, 200 to 1500
mOsmol/kg. In a preferred embodiment, it is hyper-osmotic. It may,
for example have a measured osmolality in the range 320 to 1500
mOsmol. For example, the measured osmolality of the first cleansing
solution is in the range 330 to 1200 mOsmol/kg, for example 340 to
1000 mOsmol/kg, for example 350 to 800 mOsmol/kg, for example 350
to 700 mOsmol/kg. For example, the solutes in the solution may have
a V(350) value of from 800 to 1600 ml, for example from 1000 to
1400 ml, for example from 1150 to 1250 ml, and be in a volume of
400 to 600 ml, for example 500 ml.
[0386] The invention further provides a composition optionally
presented in two or more parts for the preparation of a first colon
cleansing solution. For example the composition may comprise:
(i) 87.5 to 110 g PEG having an average molecular weight of 2500 to
4500 Da. (ii) 7.5 to 10 g of one or more alkali metal sulphates,
alkaline earth metal sulphates or a mixture thereof (iii) 1.5 to
2.5 g sodium chloride and 0.75 to 1.25 g potassium chloride; (iv)
optionally one or more flavouring agents; and (v) optionally one or
more sweeteners.
[0387] For example the composition may comprise:
(i) 100 g PEG having an average molecular weight of 3000 to 4000
Da. (ii) 9.0 g sodium sulphate (iii) 2.0 g sodium chloride and 1.0
g potassium chloride; (iv) optionally one or more flavouring
agents; and (v) optionally one or more sweeteners.
[0388] For example, the flavouring and sweetener may be 0.469 g
fruit punch flavouring, 0.476 g sucralose and 0.792 g citric acid.
For example, the flavouring and sweetener may be 0.500 g fruit
punch flavouring, 0.40 g sucralose and 0.75 g citric acid. For
example, the flavouring and sweetener may be 1.43 g mango
flavouring, 0.79 g sucralose and 1.74 g citric acid. For example,
the flavouring and sweetener may be 1.59 g fruit punch flavouring,
0.79 g sucralose and 1.74 g citric acid. Citric acid may optionally
be packaged separately from the other components.
[0389] Particular first solutions S1 and S2, and particular second
solutions T1 and T2 are described in the examples section below. In
a preferred aspect of the present invention, there is provided a
method of cleansing the colon of a subject comprising (or
consisting essentially of):
administering to the subject a cleansing solution of S2 as set
forth herein; administering to the subject a cleansing solution of
T1 as set forth herein.
[0390] In preferred embodiments of this aspect of the invention,
the cleansing solution of S2 is administered to the subject before
the cleansing solution of T1 is administered. It is particularly
preferred that S2 is administered to the subject and then,
following a time interval (such as disclosed herein), T1 is
administered to the subject. In further preferred embodiments of
this aspect of the invention, additional fluid (such as clear
fluid) is administered to the subject in conjunction with S2 and/or
T1. For example, additional clear fluid (such as 500 ml or
thereabout, or 1000 ml or thereabout) is administered to the
subject following administration of S2 and/or T1. Alternatively,
additional clear fluid is administered to the subject during
administration of S2 and/or T1. In typical embodiments, the
cleansing solution of S2 and/or T1 is self-administered.
7. USE OF SWEETENER IN COLON CLEANSING SOLUTION
[0391] It has been found by the current inventors that a
sulphate-containing colon cleansing solution that contains a
souring agent (for example citric acid) and sucralose is
particularly palatable.
[0392] The invention further provides, according to a fourth
aspect, a colon cleansing solution comprising:
(i) 70 to 250 g per litre PEG having an average molecular weight of
2500 to 4500 Da; (ii) 2.0 to 20 g per litre of one or more alkali
metal sulphates, alkaline earth metal sulphates or a mixture
thereof; (iii 1) optionally 1.0 to 5.0 g per litre sodium chloride;
(iii 2) optionally 0.5 to 1.5 (for example 0.5 to 1.1) g per litre
potassium chloride; (iv) optionally one or more flavouring agents;
(v) sucralose; and (vi) one or more souring agents.
[0393] Further, the invention provides a method for improving the
palatability of a sulphate-containing colon cleansing solution
comprising including in the solution 0.1 to 3.0 g per litre
sucralose and 0.1 to 4.0 g per litre of souring agent, for example
0.1 to 3.0 g per litre of souring agent, for example citric acid.
The invention provides a method for diminishing the poor taste of a
sulphate-containing colon cleansing solution comprising including
in the solution 0.1 to 3.0 g per litre sucralose and 0.1 to 4.0 g
of souring agent, for example 0.1 to 3.0 g per litre of souring
agent, for example citric acid.
[0394] It is postulated that the improved palatability is
associated with a reduced perceived saltiness of the solutions. The
invention thus provides a method for reducing the perceived
saltiness of a sulphate-containing colon cleansing solution
comprising including in the solution 0.1 to 3.0 g per litre
sucralose and 0.1 to 4.0 g per litre of souring agent, for example
0.1 to 3.0 g per litre of souring agent, for example citric acid.
"Reduction" here is taken to mean as compared with an equivalent
solution without the sucralose and souring agent.
[0395] A souring agent may be selected from citric acid, malic
acid, acetic acid, tartaric acid, gluconodeltalactone, phosphoric
acid, succinic acid, phytic acid, lactic acid or salts thereof. For
example, the souring agent may be citric acid. It may be present at
a level of from 0.1 to 4.0 g per litre, for example 0.1 to 3.0 g
per litre, for example 0.3 to 2.0 g per litre, for example 0.5 to
2.0 g per litre, for example 0.75 g, 1.0 g, 1.06 g, 1.25 g or 1.5 g
per litre. For example, it may be at a level of 3.0 to 4.0 g per
litre, for example 3.48 g per litre. Citric acid, or another
souring agent, may be provided in an encapsulated form. The
encapsulation provides a coating that isolates the souring agent
from other components and from air and moisture prior to its use.
Several encapsulated forms of citric acid, or other souring agents,
are commercially available. For example, the encapsulation may be
with a water-soluble coating.
[0396] The sucralose may, for example be present at a level of 0.1
to 3.0 g per litre, for example 0.3 to 2.0 g per litre, for example
0.5 to 2.0 g per litre, for example 0.5 to 1.3 g per litre for
example 0.63 g, 0.80 g, or 1.0 g per litre. For example, it may be
at a level of 1.58 g per litre.
[0397] When sucralose and citric acid are used, a particularly
preferred flavouring is fruit punch flavour, for example at a level
of 0.4 to 1.2 g per litre, for example 0.625 g per litre or 1.0 g
per litre.
[0398] There is also provided a composition for the preparation of
such a solution, for example by admixture with water. Preferred
amounts of each of components (i) to (iv) in the solutions and
compositions of the fourth aspect of the invention are as set out
for the first colon cleansing solutions and first colon cleansing
compositions hereinabove in section 6b).
[0399] A colon cleansing solution according to the fourth aspect of
the invention may contain PEG, sulphate, sodium chloride, potassium
chloride and flavouring in amounts and types as described
hereinabove in relation to the first colon cleansing solution in
section 6b).
[0400] A colon cleansing solution according to the fourth aspect of
the invention may be used together with a solution of the first or
second aspect of the invention as set out in sections 2 to 5.
Alternatively, it may be used in combination with a different other
colon cleansing solution, or used in a suitable volume on its own.
If used on its own, it may be used in a single dose or in a split
dose administration. The invention provides a method of cleansing
the colon of a subject comprising administering a solution of the
fourth aspect of the invention. The solution may be administered on
its own or in combination with a further, different, solution.
8. KITS
a) Kits Providing a Composition for the Preparation of a Solution
of the Invention
[0401] As set out above in section 2d), the invention provides a
composition for admixture with water (for example a dry
composition, for example a powder), wherein the composition is
optionally presented in two or more parts and comprises the
components of a solution of the invention. If the components are
provided in two or more parts, they may be provided in a kit. The
invention thus provides a kit comprising:
a) 150 to 400 mmol ascorbate anion provided by a mixture of: [0402]
(i) ascorbic acid and [0403] (ii) one or more salts of ascorbic
acid the components (i) and (ii) being present in a molar ratio of
from 1:4.5 to 1:7.0; and b) 5 to 100 g polyethylene glycol.
[0404] The kit may further comprise additional components as set
out in sections 3a), 3b) and 3d) above, and in the amounts set out
there. For example, the kit may contain:
a) 150 to 400 mmol ascorbate anion provided by a mixture of: [0405]
(i) ascorbic acid and [0406] (ii) one or more salts of ascorbic
acid the components (i) and (ii) being present in a molar ratio of
from 1:4.5 to 1:7.0; b) 5 to 100 g PEG having an average molecular
weight of 3000 to 4000 Da. c) sodium chloride and potassium
chloride; d) optionally sodium sulphate; e) optionally one or more
flavouring agents; f) optionally one or more sweeteners.
[0407] Each of c) and d) may be present in the amounts described in
section 3a) and 3d) above. Each of e) and f) may be as described
above and/or be in the amounts described in section 3a) and 3d)
above.
[0408] In one embodiment, the kit contains:
a) [0409] (i) 6.0 to 10 g ascorbic acid and [0410] (ii) 40 to 60 g
sodium ascorbate [0411] the components (i) and (ii) being present
in a weight ratio of from 1:5063 to 1:7.875; b) 30 to 50 g PEG
having an average molecular weight of 3000 to 4000 Da; c) 1.5 to 4
g sodium chloride and 0.5 to 3.5 g potassium chloride; e) one or
more flavouring agents; and f) one or more sweeteners.
[0412] In an embodiment of a kit of the invention, the ascorbate
component a) is packaged separately from the PEG component b). The
remaining elements may be packaged together with the PEG
component.
[0413] In an embodiment of a kit of the invention, the flavouring
component e) or the sweetener component f) may be provided
separately from other components. The kit may provide several
alternative flavourings, allowing the subject to decide themselves
which flavouring from a range of flavourings to use.
[0414] For example, the kit may contain:
a) [0415] (i) 7.54 g ascorbic acid and [0416] (ii) 48.11 g sodium
ascorbate b) 40 g PEG having an average molecular weight of 3000 to
4000 Da; c) 3.20 g sodium chloride and 1.20 g potassium chloride;
e) one or more flavouring agents; and f) one or more sweeteners;
whereby component a) is packaged in a first compartment and
components b), c) e) and f) are packaged in a second
compartment.
[0417] One or more of the components may be in a dry powder form
(for example the ascorbate component or the PEG component may be in
dry powder form), whilst some of the remaining components (for
example the sodium chloride or the potassium chloride) are in the
form of a tablet or in a semi-solid (for example gel) form. In such
an embodiment, the subject may be instructed to dissolve the powder
components in water and drink it, and instructed to take the tablet
or semi-solid form without dissolution. If a semi-solid form (for
example gel) is present, the subject may be instructed to add it to
water before ingesting it, or the subject may be instructed to take
it as provided.
[0418] As set out above in section 5d), the invention provides a
composition for admixture with water (for example a dry
composition, for example a powder), wherein the composition is
optionally presented in two or more parts and comprises the
components of a solution of the invention. If the components are
provided in two or more parts, they may be provided in a kit. The
invention thus provides a kit comprising:
a) 180 to 220 mmol ascorbate anion provided by one or more salts of
ascorbic acid; and b) 5 to 100 g polyethylene glycol; the kit being
essentially free from ascorbic acid.
[0419] The kit may further comprise additional components as set
out in sections 5a), 5b) and 5d) above, and in the amounts set out
there. For example, the kit may contain:
a) 180 to 220 mmol ascorbate anion provided by one or more salts of
ascorbic acid; b) 5 to 100 g PEG having an average molecular weight
of 3000 to 4000 Da. c) sodium chloride and potassium chloride; d)
optionally sodium sulphate; e) optionally one or more flavouring
agents; f) optionally one or more sweeteners; the kit being
essentially free from ascorbic acid.
[0420] Each of c) and d) may be present in the amounts described in
section 5a) and 5d) above. Each of e) and f) may be as described
above and/or be in the amounts described in section 5a) and 5d)
above.
[0421] In one embodiment, the kit contains:
a) 35.65 to 43.55 g sodium ascorbate b) 30 to 50 g PEG having an
average molecular weight of 3000 to 4000 Da; c) 1.5 to 4 g sodium
chloride and 0.5 to 3.5 g potassium chloride; e) one or more
flavouring agents; and f) one or more sweeteners; the kit being
essentially free from ascorbic acid.
[0422] In an embodiment of a kit of the invention, the ascorbate
component a) is packaged separately from the PEG component b). The
remaining components may be packaged together with the PEG
component.
[0423] In an embodiment of a kit of the invention, the flavouring
component e) or the sweetener component f) may be provided
separately from other components. The kit may provide several
alternative flavourings, allowing the subject to decide themselves
which flavouring from a range of flavourings to use.
[0424] For example, the kit may contain:
a) 40 g sodium ascorbate b) 40 g PEG having an average molecular
weight of 3000 to 4000 Da; c) 2.50 g sodium chloride and 0.90 g
potassium chloride; e) one or more flavouring agents; and f) one or
more sweeteners; whereby component a) is packaged in a first
compartment and components b), c) e) and f) are packaged in a
second compartment.
[0425] In a further embodiment, one or more of the components may
be in a dry powder form (for example the ascorbate component or the
PEG component may be in dry powder form), whilst some of the
remaining components (for example the sodium chloride or the
potassium chloride) are in the form of a tablet or in a semi-solid
(for example gel) form. In such an embodiment, the subject may be
instructed to dissolve the powder components in water and drink it,
and instructed to take the tablet or semi-solid form without
dissolution. If a semi-solid form (for example gel) is present, the
subject may be instructed to add it to water before ingesting it,
or the subject may be instructed to take it as provided.
[0426] It is convenient for the patient for a kit of the invention
to be provided in the form of, for example, a box. In a kit of the
invention the first and/or second parts may each contained in one
or more containers. Examples of suitable containers include tubs,
bags and sachets. A preferred container is a sachet.
[0427] In one embodiment, the composition of the invention can be
provided in a multi-chambered container, for example of the type
disclosed in WO2012/105524. A multi-chambered container may have a
partition wall and two separate powders can be stored separated
from each other. In addition, in a container of the type disclosed
in WO2012/105524, a powdered medicine, which has been stored in a
separated state, can be simply and readily mixed at the time of use
to provide an aqueous solution.
[0428] For example, a multi-chambered container comprises a
substantially flat pouch formed from a flexible film, a partition
wall configured as a detachable seal detachably welding opposing
inner surfaces of the pouch, and a pour port for infusion and
discharge of a liquid, that is attached to the periphery of the
pouch so as to open into one of the plurality of partitioned
chambers. For example, the partition wall comprises a horizontal
section which extends along a gusseted bottom section of the pouch
and a perpendicular section which is curved from the horizontal
section to a pouch upper section. The partition wall may, for
example, be frangible. For example, a first partitioned chamber
having a large capacity is formed on one side of the partition wall
close to the bottom section of the pouch, a second partitioned
chamber having a small capacity is formed on the other side of the
partition wall, and the pour port opens into the first partitioned
chamber.
b) Kits Providing Treatments According to the Invention
[0429] As set out above in section 6), the invention provides
various split-dose treatments for colon cleansing in which the
subject takes two different agents. The invention thus provides a
kit comprising: [0430] a first colon cleansing agent, and [0431] a
second colon cleansing agent, the second colon cleansing agent
being a solution of the first or second aspect of the invention
described above.
[0432] The invention provides a kit comprising: [0433] a first
colon cleansing agent, and [0434] a second colon cleansing agent,
the second colon agent solution being a solution in water of: a)
300 to 800 mmol per litre ascorbate anion provided by a mixture of
[0435] (i) ascorbic acid and [0436] (ii) one or more salts of
ascorbic acid the components (i) and (ii) being present in a molar
ratio of from 1:4.5 to 1:7.0; and b) optionally 10 to 200 g per
litre polyethylene glycol.
[0437] The invention also provides a kit comprising: [0438] a first
colon cleansing agent, and [0439] a second colon cleansing agent,
the second colon cleansing agent being a solution in water of: a)
360 to 440 mmol per litre ascorbate anion provided by one or more
salts of ascorbic acid; and b) optionally 10 to 200 g per litre
polyethylene glycol; the solution being essentially free from
ascorbic acid.
[0440] In an embodiment, the first agent is different from the
second.
[0441] A kit of the invention may provide compositions for the
preparation of the colon cleansing solutions. The invention thus
further provides a kit comprising:
A) a first component, being a composition, optionally presented in
two or more parts for the preparation of a first colon cleansing
solution as described above by admixture with water; and B) a
second component, being a composition, optionally presented in two
or more parts for the preparation of a second colon cleansing
solution by admixture with water, the second colon cleansing
solution being a solution as described hereinabove in relation to
solutions and uses of the first or second aspects of the invention
as set out in sections 2 to 5.
[0442] Preferably, the first solution is of different composition
from the second.
[0443] Accordingly, a kit of the invention may comprise:
A) a first component, being a composition optionally presented in
two or more parts for the preparation of a first colon cleansing
solution comprising: (i) 52.5 to 187.5 g PEG having an average
molecular weight of 2500 to 4500 Da. (ii) 1.5 to 15 g of one or
more alkali metal sulphates, alkaline earth metal sulphates or a
mixture thereof (iii) optionally one or more electrolytes; (iv)
optionally one or more flavouring agents; and (v) optionally one or
more sweeteners, and B) a second component, being a composition
optionally presented in two or more parts for the preparation of a
second colon cleansing solution, comprising a) 150 to 400 mmol
ascorbate anion provided by a mixture of: [0444] (i) ascorbic acid
and [0445] (ii) one or more salts of ascorbic acid the components
(i) and (ii) being present in a molar ratio of from 1:4.5 to 1:7.0;
and b) optionally 5 to 100 g polyethylene glycol, the first
solution being different from the second.
[0446] A kit of the invention may comprise:
A) a first component, being a composition optionally presented in
two or more parts for the preparation of a first colon cleansing
solution comprising: (i) 52.5 to 187.5 g PEG having an average
molecular weight of 2500 to 4500 Da. (ii) 1.5 to 15 g of one or
more alkali metal sulphates, alkaline earth metal sulphates or a
mixture thereof (iii) optionally one or more electrolytes; (iv)
optionally one or more flavouring agents; and (v) optionally one or
more sweeteners, and B) a second component, being a composition
optionally presented in two or more parts for the preparation of a
second colon cleansing solution, comprising a) 360 to 440 mmol
ascorbate anion provided one or more salts of ascorbic acid; and b)
optionally 5 to 100 g polyethylene glycol, the solution being
essentially free from ascorbic acid; the first solution being
different from the second.
[0447] The first component may be a composition for the preparation
of a solution as set out in section 6b) above. The first component
preferably comprises 97.5 to 187.5 g of PEG, for example 67.5 to
150 g of PEG, more preferably 75 to 150 g, for example 90 to 112.5
g, for example 100 g PEG.
[0448] Preferably, the first component comprises a sulphate
component (for example sodium sulphate) in an amount of 1.5 to
11.25 g, for example 3.75 to 11.25 g, for example 6 to 9 g, for
example 6 or 9 g. For example, the first component comprises 6.0 to
15 g of one or more alkali metal sulphates, alkaline earth metal
sulphates or a mixture thereof. For example it comprises 9 g of
sodium sulphate.
[0449] Preferably, the first component comprises sodium chloride in
an amount of 0.375 to 3.75 g. For example, sodium chloride may be
present in an amount of 0.75 to 3.0 g, for example 0.75 to 2.25 g,
for example 1.125 to 2.25 g, for example 1.5 to 2.25 g, for example
2.0 g.
[0450] For example, the first component comprises potassium
chloride in an amount of 0.75 to 7.5 g. For example, potassium
chloride may be present in an amount of 0.0375 to 3.75 g, for
example 0.075 to 2.25 g, for example 0.15 to 1.5 g, for example
0.375 to 1.125 g, for example 0.375 to 0.825 g, for example 1.0
g.
[0451] In an embodiment, the first component comprises sodium
chloride and potassium chloride. They can be present in the amounts
mentioned immediately above. For example, sodium chloride may be
present in an amount of 1.125 to 2.25 g and potassium chloride may
be present in an amount of 0.15 to 1.5 g; for example 2.0 g sodium
chloride and 1.0 g potassium chloride.
[0452] The second component of the kit of compositions of the
invention is preferably a composition for the preparation of a
solution of the first or second aspect of the invention as
described hereinabove in sections 3 or 5.
[0453] Accordingly, the kit may comprise:
A) a first component, being a composition optionally presented in
two or more parts for the preparation of a first colon cleansing
solution comprising: (i) 87.5 to 110 g PEG having an average
molecular weight of 2500 to 4500 Da. (ii) 7.5 to 10 g of one or
more alkali metal sulphates, alkaline earth metal sulphates or a
mixture thereof (iii) 1.5 to 2.5 g sodium chloride and 0.75 to 1.25
g potassium chloride; (iv) optionally one or more flavouring
agents; and (v) optionally one or more sweeteners, and B) a second
component, being a composition optionally presented in two or more
parts for the preparation of a second colon cleansing solution,
comprising a) [0454] (i) 6.0 to 10 g ascorbic acid and [0455] (ii)
40 to 60 g sodium ascorbate [0456] the components (i) and (ii)
being present in a weight ratio of from 1:5063 to 1:7.875; b) 30 to
50 g PEG having an average molecular weight of 3000 to 4000 Da; c)
1.5 to 4 g sodium chloride and 0.5 to 3.5 g potassium chloride; e)
one or more flavouring agents; and f) one or more sweeteners.
[0457] In an embodiment of a kit of the invention, in component B)
the ascorbate component a) is packaged separately from the PEG
component b). The remaining elements of component B) may be
packaged together with the PEG component.
[0458] For example, a kit may comprise:
A) a first component, being a composition optionally presented in
two or more parts for the preparation of a first colon cleansing
solution comprising: (i) 100 g PEG having an average molecular
weight of 3000 to 4000 Da. (ii) 9.0 g sodium sulphate (iii) 2.0 g
sodium chloride and 1.0 g potassium chloride; (iv) optionally one
or more flavouring agents; and (v) optionally one or more
sweeteners, and B) a second component for the preparation of a
second colon cleansing solution, comprising a) [0459] (i) 7.54 g
ascorbic acid and [0460] (ii) 48.11 g sodium ascorbate b) 40 g PEG
having an average molecular weight of 3000 to 4000 Da; c) 3.20 g
sodium chloride and 1.20 g potassium chloride; e) one or more
flavouring agents; and f) one or more sweeteners; whereby component
a) is packaged in a first compartment and components b), c) e) and
f) are packaged in a second compartment.
[0461] For example, the flavouring and sweetener in the first
component may be 0.469 g fruit punch flavouring, 0.476 g sucralose
and 0.792 g citric acid. For example, the flavouring and sweetener
may be 0.500 g fruit punch flavouring, 0.40 g sucralose and 0.75 g
citric acid. For example, the flavouring and sweetener may be 1.43
g mango flavouring, 0.79 g sucralose and 1.74 g citric acid. For
example, the flavouring and sweetener may be 1.59 g fruit punch
flavouring, 0.79 g sucralose and 1.74 g citric acid. Citric acid
may optionally be packaged separately from the other
components.
[0462] For example, the flavouring and sweetener in the second
component may be 0.60 g orange flavour and 1.93 g aspartame. For
example, the flavouring and sweetener may be 1.60 g citrus flavour
and 0.875 g aspartame. For example, the flavouring and sweetener
may be 2.10 g orange grapefruit flavour and 0.875 g aspartame.
[0463] Alternatively, the kit may comprise:
A) a first component, being a composition optionally presented in
two or more parts for the preparation of a first colon cleansing
solution comprising: (i) 87.5 to 110 g PEG having an average
molecular weight of 2500 to 4500 Da. (ii) 7.5 to 10 g of one or
more alkali metal sulphates, alkaline earth metal sulphates or a
mixture thereof (iii) 1.5 to 2.5 g sodium chloride and 0.75 to 1.25
g potassium chloride; (iv) optionally one or more flavouring
agents; and (v) optionally one or more sweeteners, and B) a second
component, being a composition optionally presented in two or more
parts for the preparation of a second colon cleansing solution,
comprising a) 35.65 to 43.55 g sodium ascorbate b) 30 to 50 g PEG
having an average molecular weight of 3000 to 4000 Da; c) 1.5 to 4
g sodium chloride and 0.5 to 3.5 g potassium chloride; e) one or
more flavouring agents; and f) one or more sweeteners.
[0464] In an embodiment of a kit of the invention, in component B)
the ascorbate component a) is packaged separately from the PEG
component b). The remaining elements of component B) may be
packaged together with the PEG component.
[0465] For example, a kit may comprise:
A) a first component, being a composition optionally presented in
two or more parts for the preparation of a first colon cleansing
solution comprising: (i) 100 g PEG having an average molecular
weight of 3000 to 4000 Da. (ii) 9.0 g sodium sulphate (iii) 2.0 g
sodium chloride and 1.0 g potassium chloride; (iv) optionally one
or more flavouring agents; and (v) optionally one or more
sweeteners, and B) a second component for the preparation of a
second colon cleansing solution, comprising a) 40 g sodium
ascorbate b) 40 g PEG having an average molecular weight of 3000 to
4000 Da; c) 2.50 g sodium chloride and 0.90 g potassium chloride;
e) one or more flavouring agents; and f) one or more sweeteners;
whereby component a) is packaged in a first compartment and
components b), c) e) and f) are packaged in a second
compartment.
[0466] For example, the flavouring and sweetener in the first
component may be 0.469 g fruit punch flavouring, 0.476 g sucralose
and 0.792 g citric acid. For example, the flavouring and sweetener
may be 0.500 g fruit punch flavouring, 0.40 g sucralose and 0.75 g
citric acid. For example, the flavouring and sweetener may be 1.43
g mango flavouring, 0.79 g sucralose and 1.74 g citric acid. For
example, the flavouring and sweetener may be 1.59 g fruit punch
flavouring, 0.79 g sucralose and 1.74 g citric acid. Citric acid
may optionally be packaged separately from the other
components.
[0467] For example, the flavouring and sweetener in the second
component may be 0.80 g orange flavour and 1.10 g aspartame. For
example, the flavouring and sweetener may be 1.60 g lemon/lime
flavour and 1.625 g aspartame. For example, the flavouring and
sweetener may be 2.15 g orange grapefruit flavour and 1.625 g
aspartame.
[0468] Preferably, the kit further comprises instructions for use.
In an embodiment, a kit of the invention has instructions that
instruct the user of the volume to which each component is to be
made up with water. For example, the specified volume of water for
each solution is less than one litre. For example, the specified
volume for the first component may be 300 ml to 1200 ml, for
example 600 ml to 900 ml, for example 750 ml; for example it may be
a volume of 25 or 26 US fluid ounces, for example 400 to 600 ml,
for example 500 ml. For example it may be a volume of 16 or 17 US
fluid ounces. For example, the specified volume for the second
component may be from 250 ml to 1000 ml, for example 400 ml to 700
ml, for example 500 ml. For example it may be a volume of 16 or 17
US fluid ounces. Further volumes that may be specified in the
instructions are the volumes set out hereinabove in relation to the
methods of the invention.
[0469] In general, the instructions specify that the first and
second solutions are to be ingested in succession with a time
interval between them. In an embodiment, the instructions specify
that the first cleansing solution is ingested first followed, after
a time interval (for example the time between an evening and the
following morning) by ingestion of the second cleansing solution.
The time interval is preferably as described above in relation to
the methods of the invention. The instructions may specify that the
components in the kit be made up into solutions and then taken in
accordance with the description set out above in section 6 for the
first solution and sections 3c) and 5c) for the second
solution.
[0470] For example, components A) and B) may be in dry powder,
granular or other dry form. They may alternatively be in the form
of concentrates or slurries. Components A) and B) may be in the
same or different physical forms. Components within A) and B) may
be in the same or different physical forms. For example, one or
both of components A) and B) are dry powders. A portion of either
or each of components A) and B) may be in the form of one or more
solid tablets or capsules.
[0471] It is convenient for the patient for a kit of the invention
to be provided in the form of, for example, a box. In a kit of the
invention the first and/or second components may each contained in
one or more containers. In particular, the second component may be
contained in more than one container. For example, if the second
component comprises both ascorbic acid and PEG then the ascorbic
acid and PEG may be contained in separate containers. The other
constituents of the second component (for example one or more of
sodium chloride, potassium chloride and sodium sulphate) may be in
either of the separate containers. For example, they may be in the
container containing the PEG.
[0472] If a flavouring component is present in the first or second
solution, then in a kit of the invention, the flavouring component
for the relevant solution may be provided in a separate container
from the other constituents of that solution.
[0473] Examples of suitable containers include tubs, bags and
sachets. A preferred container is a sachet.
[0474] In one embodiment, the composition of the invention can be
provided in a multi-chambered container, for example of the type
disclosed in WO2012/105524, as described above in section 8a).
[0475] In one embodiment, a kit comprises:
A) a first sachet comprising a first composition for the
preparation of the first cleansing solution; B1) a second sachet;
B2) a third sachet; wherein the second and third sachets together
provide a composition for the preparation of the second cleansing
solution.
[0476] For example, in a kit of the invention as mentioned
immediately above:
A) the first sachet comprises polyethylene glycol and/or sodium
sulphate; B1) the second sachet comprises one or more components
selected from polyethylene glycol, one or more alkali metal
sulphates, alkaline earth metal sulphates or a mixture thereof and
electrolytes; and B2) the third sachet comprises one or more salts
of ascorbic acid and, if appropriate, ascorbic acid; the contents
of sachets (B1) and (B2) together providing the components for the
second cleansing solution.
[0477] For example, in a further embodiment of a kit of the
invention, rather than being provided within a first sachet (A)
with the PEG, some or all of the sulphate(s), electrolytes,
flavouring agents and sweeteners are provided in the form of a
tablet or capsule. In a further embodiment of a kit of the
invention, rather than being provided within a second or third
sachet (B1 or B2) with the PEG, ascorbic acid or ascorbate
component, some or all of the sulphate(s), electrolytes, flavouring
agents and sweeteners are provided in the form of a tablet or
capsule.
[0478] A kit may contain one treatment, for example a cleansing
treatment, or several treatments. A treatment generally comprises
one dose of the first cleansing solution (or components for
preparing the first cleansing solution) and one dose of the second
cleansing solution (or components for preparing the first cleansing
solution). In a kit of the invention, preferably the first
component comprises one dose of the first cleansing solution, and
the second component comprises one dose of the second cleansing
solution.
[0479] A kit of the invention may be for use in a method of
cleansing the colon comprising: [0480] the subject taking an
effective amount of a first colon cleansing solution as described
herein; and then [0481] the subject taking an effective amount of a
second colon cleansing solution as described herein.
9. ALTERNATIVE COLON CLEANSING REGIMENS
a) General
[0482] The solutions and compositions of the first and second
aspects of the invention described above in sections 2 to 5 find
further use in split dose colon cleansing treatments in which the
subject takes two different solutions (a first colon cleansing
solution, followed by a second colon cleansing solution) in which
the solution of the first or second aspect of the invention is the
first colon cleansing solution. In a fifth aspect, the invention
thus provides a method of cleansing the colon of a mammal
comprising: [0483] the subject taking an effective amount of a
first colon cleansing solution; and then [0484] the subject taking
an effective amount of a second colon cleansing solution, the first
colon cleansing solution being a solution of the first or second
aspect of the invention described above in sections 2 to 5.
[0485] The invention also provides a method of cleansing the colon
of a mammal comprising: [0486] the subject taking an effective
amount of a first colon cleansing solution; and then [0487] the
subject taking an effective amount of a second colon cleansing
solution, the first colon cleansing solution being a solution
comprising a) 300 to 800 mmol per litre ascorbate anion provided by
a mixture of: [0488] (i) ascorbic acid and [0489] (ii) one or more
salts of ascorbic acid the components (i) and (ii) being present in
a molar ratio of from 1:4.5 to 1:7.0; and b) optionally 10 to 200 g
per litre polyethylene glycol.
[0490] The invention also provides a method of cleansing the colon
of a mammal comprising: [0491] the subject taking an effective
amount of a first colon cleansing solution; and then [0492] the
subject taking an effective amount of a second colon cleansing
solution, the first colon cleansing solution being a solution
comprising a) 360 to 440 mmol per litre ascorbate anion provided by
one or more salts of ascorbic acid; and b) optionally 10 to 200 g
per litre polyethylene glycol; the solution being essentially free
from ascorbic acid.
[0493] The solutions and methods of the fifth aspect of the
invention may have the features described above in relation to the
solutions and methods of the third aspect of the invention as set
out in section 6 above.
b) Alternative:
[0494] The invention also provides a method of cleansing the colon
of a subject comprising: [0495] administering to the subject an
effective amount of a first cleansing solution; and then after a
time interval [0496] administering to the subject an effective
amount of a second cleansing solution, wherein the first cleansing
solution is hyper-osmotic and contains ascorbic acid, one or more
salts of ascorbic acid, or a mixture thereof (for example ascorbic
acid and sodium ascorbate, for example sodium ascorbate); and
wherein the second cleansing solution is either substantially free
from ascorbic acid and salts thereof, or contains ascorbic acid,
one or more salts of ascorbic acid, or a mixture thereof, in an
amount providing a lower concentration of ascorbate anion than is
present in the first cleansing solution. The first cleansing
solution may comprise PEG and electrolytes (for example sodium
chloride and potassium chloride). The second solution may comprise
PEG; it may comprise an alkali metal or alkaline earth metal
sulphate (for example sodium sulphate); it may comprise
electrolytes (for example sodium chloride and potassium chloride).
There are also provided kits comprising a first and a second
solution according to the invention, and kits comprising
compositions for preparing the first and second solutions.
[0497] The first cleansing solution contains a higher concentration
of ascorbate anion than is present in the second cleansing
solution. For example, the first cleansing solution contains twice
the concentration of the ascorbate anion than the second cleansing
solution or more. For example, the first solution contains three
times or more, four times or more, or five times or more the
concentration of the ascorbate anion than the second cleansing
solution. For example, the first cleansing solution contains a
concentration of the ascorbate anion that is at least 50 mmol per
litre greater than that of the second cleansing solution. That is
to say that the first solution contains a concentration of
ascorbate anion that is at least 50 mmol per litre greater than
that of the second solution. For example, the first solution
contains a concentration of the ascorbate anion that is greater by
at least 100 mmol per litre, for example at least 200 mmol per
litre, at least 300 mmol per litre.
[0498] For example, the second cleansing solution may be
substantially free from an ascorbate component.
[0499] For example, the first cleansing solution may comprise:
[0500] 56.6 g sodium ascorbate, or [0501] 33.9 g sodium ascorbate
and 20.1 g ascorbic acid, or [0502] 33.9 g sodium ascorbate, or
[0503] 33.9 g sodium ascorbate and 21.4 g magnesium ascorbate.
[0504] The first cleansing solution may further comprise
polyethylene glycol. The polyethylene glycol (PEG) may, for
example, have an average molecular weight of 2500 to 4500 Da, for
example 3000 to 4000 Da. For example, the PEG may be PEG 3350 or
PEG 4000 as defined in national pharmacopeias. Further examples of
suitable PEGs recognized in some national pharmacopeias include
Macrogols, for example Macrogol 4000.
[0505] For example, the first cleansing solution may comprise 20 g
or 40 g PEG 3350. For example, the first cleansing solution may
have a volume of 500 ml. For example it may have a volume of 16 or
17 US fluid ounces.
[0506] The second cleansing solution may comprise polyethylene
glycol and/or an alkali metal sulphate, an alkaline earth metal
sulphate, or a mixture thereof.
[0507] The polyethylene glycol (PEG) in the second cleansing
solution may be as described immediately above for the first
cleansing solution. The PEG in the second cleansing solution can be
a different PEG from the PEG in the second cleansing solution. For
example, one PEG may be PEG3350 and the other PEG may be PEG4000.
For example, the second cleansing solution may comprise 100 g PEG
3350. For example, the second cleansing solution may have a volume
of 750 ml. For example it may have a volume of 25 or 26 US fluid
ounces.
[0508] The second cleansing solution preferably comprises an alkali
metal sulphate, an alkaline earth metal sulphate or a mixture
thereof. An alkali metal or alkaline earth metal sulphate may, for
example, be selected from sodium sulphate, potassium sulphate and
magnesium sulphate. The solution may comprise more than one of
sodium sulphate, potassium sulphate and magnesium sulphate, for
example all three. Preferably, the alkali metal sulphate, an
alkaline earth metal sulphate or the mixture thereof is or includes
sodium sulphate. Preferably, an alkali metal sulphate or alkaline
earth metal sulphate (for example sodium sulphate) is
anhydrous.
[0509] For example, the second cleansing solution may have a volume
of 750 ml and comprise 3 g, 6 g or 9 g of sodium sulphate.
[0510] The first and/or second cleansing solution(s) may further
comprise one or more of:
a) one or more electrolytes; b) one or more flavouring agents; c)
one or more sweeteners.
[0511] Electrolytes include salts of sodium, potassium, calcium and
magnesium, particularly sodium and potassium; and salts of
chloride, iodide, bicarbonate and carbonate, particularly chloride.
Preferred electrolytes are sodium chloride and potassium chloride.
In an embodiment, the first and/or second solution is substantially
free from sodium bicarbonate.
[0512] For example, the second cleansing solution may have a volume
of 750 ml and comprise 1.4 g sodium chloride and 0.3 g potassium
chloride; or 1.6 g sodium chloride and 0.7 g potassium chloride; or
2.0 g sodium chloride and 1.0 g potassium chloride.
[0513] For example, the first cleansing solution may have a volume
of 500 ml and comprise 3.5 g sodium chloride and 2.2 g potassium
chloride; or 2.7 g sodium chloride and 1.3 g potassium chloride; or
2.8 g sodium chloride and 1.3 g potassium chloride; or 2.8 g sodium
chloride and 2.0 g potassium chloride; or 3.1 g sodium chloride and
1.3 g potassium chloride. For example the first cleansing solution
is substantially free from sodium bicarbonate.
[0514] The first and/or second cleansing solution(s) preferably
include a flavouring agent. Flavouring for use in compositions of
the invention should preferably mask saltiness, be relatively sweet
but not excessively so, and be stable in the composition.
Flavouring makes the solutions more palatable and thus aids patient
compliance. Preferred flavourings include lemon e.g. Ungerer Lemon
(available from Ungerer Limited, Sealand Road, Chester, England CH1
4LP) strawberry e.g. Ungerer Strawberry, grapefruit e.g. Ungerer
Grapefruit flavouring powder, blackcurrant e.g. Ungerer
Blackcurrant, pineapple e.g. IFF (International Flavours and
Fragrances) Pineapple flavouring powder, orange eg Firmenich
Orange, vanilla/lemon and lime e.g. IFF Vanilla and Givaudin Roure
Lemon and Lime Flav-o-lok, fruit punch eg Ungerer fruit punch,
citrus punch, mango, and berry. Those and further suitable
flavourings are available from International Flavours and
Fragrances Inc. (Duddery Hill, Haverhill, Suffolk, CB9 8LG,
England), Ungerer & Company (Sealand Road, Chester, England CH1
4LP) or Firmenich (Firmenich UK Ltd., Hayes Road, Southall,
Middlesex UB2 5NN). More preferred flavourings are lemon, kiwi,
strawberry, grapefruit, orange, fruit punch and mango.
[0515] Fruit punch and mango are especially preferred flavourings
for the first solution. The most preferred flavourings for the
second solution are lemon flavour and orange flavour.
[0516] The first and/or second cleansing solution(s) preferably
include a sweetener. Sugar-based sweeteners are generally not
suited for colon cleansing compositions because the delivery of
unabsorbed sugars to the colon provides a substrate for bacteria.
Such sugars may be metabolised by the bacteria to form explosive
gases such as hydrogen and methane. The presence of explosive gases
in the colon can be highly dangerous when electrical apparatus is
to be used during colonoscopy or other procedures. Preferred
sweeteners include aspartame, acesulfame potassium (acesulfame K),
sucralose and saccharine, and/or combinations thereof. For example,
compositions of the invention may comprise one or both of aspartame
and acesulfame potassium (acesulfame K). For example, compositions
of the invention may comprise one or both of sucralose and
acesulfame potassium (acesulfame K). Alternatively, compositions of
the invention can be substantially free from added sweeteners, for
example to minimize the number of different components in the
compositions. Citric acid may also be present as a taste
enhancer.
EXAMPLES
General Description of Sample Evaluation Protocol
[0517] The same sample evaluation protocol was used for the taste
tests of all of the solutions described below that were taste
tested. The protocol was as follows: [0518] 1. The solution was
sipped from 1 oz cups, swished in the mouth, and expectorated.
[0519] 2. Initial flavour was immediately evaluated (t=0). [0520]
3. The aftertaste was evaluated at periodic time intervals: 1, 3
and 5 minutes. [0521] 4. Upon completing the evaluation, the
panelists cleansed their palates using spring water and unsalted
crackers.
[0522] The Panelists were asked to provide a score of their
perception of the intensity of the saltiness of the solutions,
using the scale:
Intensity Scale: 0=None
[0523] 1=Slight [0524] 2=Moderate [0525] 3=Strong
[0526] In general the panel consisted of from 2 to 8 tasters. The
average saltiness intensity score was plotted against time.
Example 1: Sodium Ascorbate/Ascorbic Acid Solutions
[0527] In an initial set of solutions containing PEG3350 (40 g),
sodium chloride (2.8 g), potassium chloride (1.3 g) and sodium
ascorbate (56.6 g), it was found that the sweeteners sucralose and
aspartame were most effective in reducing the perceived saltiness
of the solution. Acesulfame-K and sodium saccharin were less
effective.
[0528] The solutions in Tables 1 and 2 were prepared and taste
tested. The results of the taste testing are shown in FIGS. 1 and
2.
TABLE-US-00001 TABLE 1 Aspartame-containing solutions Water Sodium
Ascorbic Molar to Vol/ Sol'n PEG3350/g NaCl/g KCl/g Aspartame/g
Ascorbate/g Acid/g ratio ml F1 40 2.8 1.3 0 56.60 0 100:0 500 F2 40
2.8 1.3 2.0 56.60 0 100:0 500 F3 40 2.8 1.3 2.0 39.62 15.10 70:30
500 F4 40 2.8 1.3 2.0 45.28 10.06 80:20 500 F5 40 2.8 1.3 2.0 48.11
7.55 85:15 500 F6 40 2.8 1.3 2.0 50.94 5.03 90:10 500
TABLE-US-00002 TABLE 2 Sucralose-containing solutions Water Sodium
Ascorbic Molar to Vol/ Sol'n PEG3350/g NaCl/g KCl/g Sucralose/g
Ascorbate/g Acid/g ratio ml G1 40 2.8 1.3 0 56.60 0 100:0 500 G2 40
2.8 1.3 1.5 56.60 0 100:0 500 G3 40 2.8 1.3 1.5 39.62 15.10 70:30
500 G4 40 2.8 1.3 1.5 45.28 10.06 80:20 500 G5 40 2.8 1.3 1.5 48.11
7.55 85:15 500 G6 40 2.8 1.3 1.5 50.94 5.03 90:10 500
[0529] In FIGS. 1 and 2, it is seen that the saltiness intensity is
reduced most in the solution containing sodium ascorbate and
ascorbic acid in the ratio 85:15, ie solutions F5 and G5.
Example 2: Sodium Ascorbate Solutions and Taste Testing
[0530] The solutions in Table 3 were prepared and taste tested. The
results of the taste testing are shown in FIG. 3.
TABLE-US-00003 TABLE 3 Sodium ascorbate solutions PEG3350/ NaCl/
KCl/ Sodium Water to Sol'n g g g Aspartame/g Ascorbate/g Vol/ml H1
40 2.8 1.3 0 56.6 500 H2 40 2.8 1.3 0 40 500 H3 40 2.8 1.3 1.00 40
500 H4 40 2.8 1.3 1.25 40 500 H5 40 2.8 1.3 1.50 40 500
[0531] In FIG. 3, it is seen that the saltiness intensity is
reduced by decreasing the amount of sodium ascorbate in the
solution (compare H1 vs H2). It is further seen that the saltiness
is reduced most by 1.25 g/500 ml of aspartame.
Example 3: PEG-Electrolyte Solutions and Taste Testing
[0532] In an initial set of solutions containing PEG3350 (100 g),
sodium sulphate (9.0 g), sodium chloride (1.4 g), potassium
chloride (0.3 g), it was found that the sweeteners sucralose
(0.1%), aspartame (0.4%) or a mixture of the two (sucralose
0.07%/aspartame 0.12%) were most effective in reducing the
perceived saltiness of the solution. Acesulfame-K, sodium saccharin
and other mixtures were less effective.
[0533] The solutions in Table 4 were prepared and taste tested. The
results of the taste testing are shown in FIG. 4.
TABLE-US-00004 TABLE 4 PEG-electrolyte solutions Citric Water to
Sol'n PEG3350/g Na.sub.2SO.sub.4/g NaCl/g KCl/g Sucralose/g Acid/g
Vol/ml I1 100.0 9.0 1.4 0.3 0 0 500 I2 100.0 9.0 1.4 0.3 0.50 0 500
I3 100.0 9.0 1.4 0.3 0.50 0.375 500 I4 100.0 9.0 1.4 0.3 0.50 0.50
500 I5 100.0 9.0 1.4 0.3 0.50 0.625 500
[0534] The results of the taste testing are shown in FIG. 4. It is
seen that the solutions containing citric acid were perceived as
less salty than the solutions without citric acid.
Example 4: Bowel Cleansing Solutions
[0535] The following bowel cleansing solutions of the invention
were prepared. For solution S1, the components shown in Table 5
were combined in dry powder form and sealed in respective sachets A
and B as indicated in the table. The solution was then prepared by
dissolving the contents in water to the volume stated in the
penultimate column. Solution S2 was prepared in an analogous
manner.
TABLE-US-00005 TABLE 5 Sachet A Fruit Sachet B Water
Na.sub.2SO.sub.4 Punch Citric to Vol/ V(350)/ Sol'n PEG3350/g
(anhyd)/g NaCl/g KCl/g Sucralose/g Flavouring/g Acid/g ml ml S1
100.00 9.00 2.00 1.00 0.476 0.469 0.792 750 1180 S2 100.00 9.00
2.00 1.00 0.40 0.500 0.75 500 1210
[0536] For solution T1, the components shown in Table 6 were
combined in dry powder form and sealed in respective sachets C and
D as indicated in the table. The solution was then prepared by
mixing the contents of the two sachets together and then dissolving
them in water to the volume stated in the penultimate column.
Solution T2 was prepared in an analogous manner.
TABLE-US-00006 TABLE 6 Sachet C Sachet D Water Orange Sodium
Ascorbic to Vol/ V (350)/ Sol'n PEG3350/g NaCl/g KCl/g Aspartame/g
Flavour/g Ascorbate/g Acid/g ml ml T1 40.00 3.20 1.20 1.93 0.60
48.11 7.54 500 1850 T2 40.00 2.50 0.90 1.10 0.80 40.00 0 500
1500
Example 4a --V(350) Osmolality Measurements
[0537] In order to assess the osmotic strength of the solutions, it
was determined how much water was required to provide a solution
with measured osmolality of 350 mOsmol/kg from the amounts of the
components in Tables 5 and 6.
[0538] To each solution prepared by dissolving the components in
Tables 5 and 6 above in 500 ml of deionised water was added further
deionised water until it reached an osmolality of 350 mOsmol/kg.
The total volumes (including the initial 500 ml) required to reach
an osmolality of 350 mOsmol/kg are recorded in Tables 5 and 6 in
the final columns Osmolalities were measured using an Advanced
Instruments, Inc Model 3250 osmometer. The osmometer was operated
following standard instructions: after the device passes a
calibration check, the "Low Range" osmolality range (0 to 2000
mOsmol/kg) is selected, and a sample tube containing 250 .mu.l of
sample solution is placed in the freezing chamber. The "start"
button is then pressed. When the measurement is completed, the
device displays the measurement result and that is recorded.
Example 4b--Bowel Cleansing
[0539] In a bowel cleansing study, subjects are given solutions S1
or S2 in an evening followed by T1 or T2 the following morning. In
a variant, subjects are given solution T1 or T2 in an evening
followed by S1 or S2 the following morning.
[0540] Each subject receives the solution regimen in the split dose
intake: [0541] Evening dose: Day 1; start intake between 17:00 and
18:00 for an intake period of up to 2 hours after fasting from
14:00 hours. [0542] Morning dose: Day 2; start intake between 07:00
and 08:00 for an intake period of 2 hours.
[0543] Following each dose additional clear liquid will be consumed
to make the total dose and additional clear fluid ingested equal to
at least 3 L in the case of Arms 1 to 6, 8 and 9, and at least 2 L
in the case of Arm 7.
[0544] Each dose of cleansing solution is reconstituted with water
from the appropriate pair of sachets containing powder for oral
solution. The cleansing solution can be cooled in the fridge based
on subject preference. Evening cleansing solution dose is drunk
within 2 hours after the start of the intake on the evening of Day
1. At least the indicated additional clear fluid is also consumed,
preferably within 1 hour after the end of intake of cleansing
solution in the evening.
[0545] In the morning of Day 2, the second dose is drunk within 2
hours after the start of intake. At least the indicated additional
clear fluid is also consumed, preferably within 1 hour after the
end of intake of cleansing solution in the morning. The total
duration of each intake of cleansing solution and clear fluid
intake should normally not exceed 3 hours. Each subject is
instructed to drink the assigned cleansing solutions as 100 mL
fractions every 10 minutes. The mandatory additional clear liquid
intake (water) after the cleansing solution intake can be taken by
the subject as prefers, usually within 1 hour after completion of
each cleansing solution intake. The start time and finish time of
intake is recorded. The volume of any cleansing solution or
additional clear fluid left in the respective containers is
measured. In arms 6 to 9 the volume of fluid consumed ad libitum is
monitored and recorded.
TABLE-US-00007 TABLE 7 Arm Arm 1 Arm 2 Arm 3 Arm 4 Arm 5 Evening S1
T1 S2 MOVIPREP T1 (750 ml) (500 ml) (500 ml) (1000 ml) (500 ml) 875
ml 875 ml 1000 ml 500 ml 1000 ml additional additional additional
additional additional clear fluid clear fluid clear fluid clear
fluid clear fluid Morning T1 S1 T1 MOVIPREP S2 (500 ml) (750 ml)
(500 ml) (1000 ml) (500 ml) 875 ml 875 ml 1000 ml 500 ml 1000 ml
additional additional additional additional additional clear fluid
clear fluid clear fluid clear fluid clear fluid
TABLE-US-00008 TABLE 8 Arm Arm 6 Arm 7 Arm 8 Arm 9 Evening S2 S2 S2
MOVIPREP (500 ml) (500 ml) (500 ml) (1000 ml) Additional Additional
Additional additional clear fluid: clear fluid: clear fluid: clear
fluid: minimum minimum minimum minimum 1000 ml or 500 ml, or 1000
ml or 500 ml or more ad lib. more ad lib more ad lib more ad lib
Morning T1 T1 T2 MOVIPREP (500 ml) (500 ml) (500 ml) (1000 ml)
Additional Additional Additional additional clear fluid: clear
fluid: clear fluid: clear fluid: minimum minimum minimum minimum
1000 ml or 500 ml, or 1000 ml or 500 ml or more ad lib more ad lib
more ad lib more ad lib
[0546] Stool output is measured from the start of the intake on the
evening of Day 1 and over the following 24 hours. "Stool" is the
term used to refer to all bowel effluent. Mostly, it is liquid. The
following are also assessed [0547] Tolerability (vomiting rate).
[0548] Time and volume of cleansing solution to reach a clear
effluent.
[0549] In certain subjects, the following are also assessed: [0550]
Colon cleansing success. [0551] The segmental cleansing scores for
each of the five colon segments. [0552] Pharmacokinetic evaluation
of key active ingredients: Ascorbate components and their
metabolite (oxalic acid) in blood, urine and feces and PEG3350 and
electrolytes in feces at defined time points, to demonstrate
biological activities. Electrolytes in blood and urine are
quantified using standard clinical chemistry methods.
[0553] The study described above was carried out in two parts:
Parts A and B.
Part A:
[0554] In the part A, 120 subjects (70 male, 50 female) were
allocated to the four study Arms, Arms 1 to 4. They were given the
solutions as set out in Table 7. At the time of filing, the full
statistical analysis of the results is not complete. The interim
results based on a preliminary analysis of the data and available
at the time of filing are shown in Table 9.
TABLE-US-00009 TABLE 9 Arm Arm 1 Arm 2 Arm 3 Arm 4 Number of
subjects 30 30/29* 30 30/29* Mean Stool Weight (g) 2951 g 3219 g
3399 g 2491 g Stool Weight 90% 2680 g- 2963 g- 3221 g- 2213 g-
confidence interval (g) 3222 g 3475 g 3578 g 2769 g Protocol total
IMP 1250 ml 1250 ml 1000 ml 2000 ml volume Protocol total
additional 1750 ml 1750 ml 2000 ml 1000 ml clear fluid volume
Vomiting rate 1 (3.33%) 3 (10%) 1 (3.33%) 1 (3.33%)
[0555] Overall, the compliance level was good. However, in each of
Arms 2 and 4, 30 subjects began the study, but one subject left the
study after consuming the first solution, and before any stool
sample could be collected (thus 29 subjects are indicated (*)). The
stool weight data are based on the set of 30 subjects for Arms 1
and 3, and on the set of 29 subjects for Arms 2 and 4. Both of
those subjects who left the study had the symptom of vomiting. They
are included in the vomiting rate results.
[0556] It is seen that in each of Arms 1, 2 and 3 the subjects
achieved a higher mean stool output weight than in Arm 4, which
represents a prior art colon cleansing solution. This was achieved
with the subjects in each of Arms 1, 2 and 3 consuming a lower
total volume of bowel cleansing solution (investigational medicinal
product "IMP") than in Arm 4. The vomiting rate for Arm 2 was
higher than for the other arms. The vomiting rate for each of the
solutions was within expected limits for a bowel cleansing
solution.
Part B:
[0557] In part B, 120 subjects (54 male, 66 female) were allocated
to the four study Arms, Arms 6 to 9. They were given the solutions
as set out in Table 8. Mean stool output was highest in Arm 7 and
slightly lower in Arm 6. Arm 8 gave a lower mean stool output, but
all of Arms 6, 7 and 8 gave a higher mean stool output than Arm 9,
which represents a prior art colon cleansing solution. Mean stool
output exceeded 2400 g in all arms. Mean stool output in Arms 6 and
7 exceeded 3000 g.
[0558] The subjects in part B underwent colonoscopy and the quality
of cleansing was graded by the colonoscopist, who was not aware of
which cleansing treatment had been administered. Grading used the
Harefield Cleansing Scale. For details of the Harefield Cleansing
Scale, see Halphen et al., Gastrointestinal Endoscopy, 2013, 78,
121-131. The Harefield Cleansing Scale grades colon cleansing as
Grade A, B, C or D, A being the best. Grades A and B are considered
a successful cleansing; Grades C and D are considered an
unsuccessful cleansing. At the time of filing, the full statistical
analysis of the results is not complete. The interim results based
on a preliminary analysis of the data and available at the time of
filing are shown in Table 10.
TABLE-US-00010 TABLE 10 Arm Arm 6 Arm 7 Arm 8 Arm 9 Number of
subjects 30 30 30 30 Protocol total IMP 1000 ml 1000 ml 1000 ml
2000 ml volume Protocol minimum total 2000 ml 1000 ml 2000 ml 1000
ml additional clear fluid volume Grade A 22 28 20 6 Grade B 8 2 7
21 Grade C 0 0 3 2 Grade D 0 0 0 1
[0559] It is seen in Table 10 that there was a higher proportion of
Grade A cleansing in each of Arms 6, 7 and 8 than in Arm 9. This
was achieved with the subjects in each of Arms 6, 7 and 8 consuming
a lower total volume of bowel cleansing solution (investigational
medicinal product "IMP") than in Arm 9.
Example 5: Bowel Cleansing Solutions
[0560] The following bowel cleansing solutions of the invention are
prepared. For solution S3, the components shown in Table 11 are
combined in dry powder form and sealed in respective sachets A and
B as indicated in the table. The solution is then prepared by
dissolving the contents in water to the volume stated in the far
right-hand column. Solution S4 is prepared in an analogous
manner
TABLE-US-00011 TABLE 11 Sachet A Fruit Sachet B Water
Na.sub.2SO.sub.4 Mango Punch Citric to Vol/ Sol'n PEG3350/g
(anhyd)/g NaCl/g KCl/g Sucralose/g Flavouring/g Flavouring/g
Acid#/g ml S3 100.00 9.00 2.00 1.00 0.79 1.43 -- 1.74 500 S4 100.00
9.00 2.00 1.00 0.79 -- 1.59 1.74 500 # citric acid encapsulated
with water soluble coating
[0561] For solution T3, the components shown in Table 12 are
combined in dry powder form and sealed in respective sachets C and
D as indicated in the table. The solution is then prepared by
mixing the contents of the two sachets together and then dissolving
them in water to the volume stated in the far right-hand column.
Solutions T4, T5 and T6 are prepared in an analogous manner.
TABLE-US-00012 TABLE 12 Sachet C Orange Sachet D Water Citrus
Gr'fruit Sodium Ascorbic to Vol/ Sol'n PEG3350/g NaCl/g KCl/g
Aspartame/g Flavour/g flavour Ascorbate/g Acid/g ml T3 40.00 3.20
1.20 0.875 1.6 -- 48.11 7.54 500 T4 40.00 3.20 1.20 0.875 -- 2.1
48.11 7.54 500
TABLE-US-00013 TABLE 13 Sachet C Lemon/ Sachet D Water Lime Orange
Sodium Ascorbic to Vol/ Sol'n PEG3350/g NaCl/g KCl/g Aspartame/g
Flavour/g flavour Ascorbate/g Acid/g ml T5 40.00 2.50 0.90 1.625
1.6 -- 40.00 -- 500 T6 40.00 2.50 0.90 1.625 -- 2.15 40.00 --
500
* * * * *