U.S. patent application number 13/387791 was filed with the patent office on 2012-05-31 for solutions comprising polyethylene glycol and electrolytes.
Invention is credited to Frances Morrissey, Dawn Padfield, Chris Seldon.
Application Number | 20120135090 13/387791 |
Document ID | / |
Family ID | 41067102 |
Filed Date | 2012-05-31 |
United States Patent
Application |
20120135090 |
Kind Code |
A1 |
Seldon; Chris ; et
al. |
May 31, 2012 |
SOLUTIONS COMPRISING POLYETHYLENE GLYCOL AND ELECTROLYTES
Abstract
The invention provides a solution in water comprising the
following components at the following concentrations: (a)
N.times.(70 to 130) g/L polyethylene glycol (PEG) having an average
molecular weight of 2500 to 4500; (b) N.times.(1.6 to 4.0) g/L
sodium chloride; (c) N.times.(0.2 to 0.6) g/L potassium chloride;
(d) N.times.(0.6 to 2.2) g/L sodium bicarbonate; (e) N.times.an
amount of preservative; (f) optionally N.times.an amount of
flavouring; and (g) optionally N.times.an amount of sweetener where
N is in the range of 2 to 8. The solution is a concentrate for
dilution. In use it is diluted N-fold with water to provide a
solution for administration to a subject for the treatment of
constipation or faecal impaction. Also provided are solutions,
kits, unit doses and methods that comprise or use the
solutions.
Inventors: |
Seldon; Chris; (Rhondda,
GB) ; Padfield; Dawn; (Mid-Glamorgan, GB) ;
Morrissey; Frances; (Mid Glamorgan, GB) |
Family ID: |
41067102 |
Appl. No.: |
13/387791 |
Filed: |
July 30, 2010 |
PCT Filed: |
July 30, 2010 |
PCT NO: |
PCT/GB2010/001455 |
371 Date: |
January 30, 2012 |
Current U.S.
Class: |
424/679 |
Current CPC
Class: |
A61K 47/10 20130101;
A61K 47/14 20130101; A61K 31/77 20130101; A61P 1/10 20180101; A61K
9/0095 20130101; A61K 31/08 20130101; A61K 33/14 20130101 |
Class at
Publication: |
424/679 |
International
Class: |
A61K 33/14 20060101
A61K033/14; A61P 1/10 20060101 A61P001/10 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 30, 2009 |
GB |
0913295.2 |
Claims
1. A solution in water comprising the following components at the
following concentrations: (a) N.times.(70 to 130) g/L polyethylene
glycol (PEG) having an average molecular weight of 2500 to 4500;
(b) N.times.(1.6 to 4.0) g/L sodium chloride; (c) N.times.(0.2 to
0.6) g/L potassium chloride; (d) N.times.(0.6 to 2.2) g/L sodium
bicarbonate; (e) N.times.an amount of preservative; (f) optionally
N.times.an amount of flavouring; and (g) optionally N.times.an
amount of sweetener where N is in the range of 2 to 8.
2. A solution as claimed in claim 1, wherein the solution comprises
N.times.(0.3 to 1.4) g/L of preservative.
3. A solution as claimed in claim 1, wherein the preservative
comprises methyl paraben, ethyl paraben or benzyl alcohol, or a
mixture of two or more of them.
4. A solution as claimed in claim 1 comprising N.times.(0.02 to
0.2) g/L of sweetener, for example comprising one or both of
acesulfame K and sucralose, and/or the solution comprises
N.times.(0.2 to 2) g/L of flavouring, for example Orange Juice or
Tropical Fruit flavour.
5. A solution as claimed in claim 1 comprising the following
components at the following concentrations: (a) 350 to 600 g/L
polyethylene glycol (PEG) having an average molecular weight of
2500 to 4500; (b) 8.0 to 20 g/L sodium chloride; (c) 1.0 to 3.0 g/L
potassium chloride; (d) 3.0 to 11 g/L sodium bicarbonate; (e)
preservative; (f) optional flavouring; and (g) optional
sweetener.
6. A solution as claimed in claim 5, wherein the solution comprises
1.5 to 7.0 g/L of preservative.
7. A solution as claimed in claim 5, wherein the preservative
comprises methyl paraben, ethyl paraben or benzyl alcohol, or a
mixture of two or more of them.
8. A solution as claimed in claim 5 comprising 0.1 to 1.0 g/L of
sweetener, for example comprising one or both of acesulfame K and
sucralose, and/or the solution comprises 1.0 to 10 g/L of
flavouring, for example Orange Juice or Tropical Fruit flavour.
9. A solution as claimed in claim 1 comprising the following
components at the following concentrations: (a) 525 g/L
polyethylene glycol (PEG) having an average molecular weight of
2500 to 4500; (b) 14.028 g/L sodium chloride; (c) 1.864 g/L
potassium chloride; (d) 7.140 g/L sodium bicarbonate; (e)
preservative; (f) optional flavouring; and (g) optional
sweetener.
10. A solution as claimed in claim 9 comprising: (e) 2.5 or 3.5 g/L
preservative; (f) 3.2 g/L flavouring; and (g) 0.52 g/L
sweetener.
11. A solution as claimed in claim 1 that is substantially free
from any sulphate component.
12. A container containing a solution as claimed in claim 1, for
example containing 25 ml, 100 ml, 150 ml, 250 ml or 500 ml of
solution.
13. A container as claimed in claim 12 containing: (a)
x.times.262.50 g polyethylene glycol (PEG) 3350; (b) x.times.7.014
g sodium chloride; (c) x.times.0.932 g potassium chloride; (d)
x.times.3.570 g sodium bicarbonate; (e) x.times.an amount of
preservative; (f) optionally x.times.an amount of flavouring; (g)
optionally x.times.an amount of sweetener; and (h) water to
x.times.500 ml; Wherein x is 0.5 to 2, for example x is 0.5 or
1.
14. A kit comprising a container as claimed in claim 12 together
with instructions for use, for example instructing the user to
dilute a stated volume of the solution with a stated volume of
water.
15. A kit comprising a container as claimed in claim 12 together
with a measuring accessory for measuring out a defined volume of
the solution.
16. A method of preparing a concentrate solution as claimed in
claim 1 comprising combining the components (a) to (g) with
water.
17. A method of preparing a solution for the treatment of
constipation or faecal impaction, which method comprises combining
a solution as claimed in claim 1 with water.
18. A solution that has been prepared by combining a solution as
claimed in claim 1 with water.
19-20. (canceled)
21. A method of treating constipation or faecal impaction, which
method comprises administering orally to the subject a solution as
claimed in claim 18.
22. A solution as claimed in claim 5 that is substantially free
from any sulphate component.
Description
[0001] The present invention relates to solutions for the treatment
of constipation or faecal impaction. In particular it relates to
concentrates for use in the preparation of solutions comprising
polyethylene glycol (PEG) and electrolytes.
[0002] Constipation is a widespread condition which generally gives
rise to discomfort. The physical presence of faeces retained in the
colon and/or the rectum gives rise to a feeling of malaise and
headaches. In extreme cases of prolonged constipation, dyschezia
may result from the presence of scybala or faecaliths in the
rectum.
[0003] Numerous treatments of constipation have been developed,
including dietary manipulation (e.g. increasing the fibre content
of the diet and removing foods considered to be constipation
causing), laxatives and enemas. Laxatives are agents that promote
and assist defecation. Osmotic laxatives act to retain water in the
colonic lumen thereby counteracting the normal dehydrating action
of the colon. By suppressing the dehydration action of the colon,
the osmotic laxative produces a faecal stream which is softer,
bulkier and easier to expel.
[0004] A number of osmotic laxative treatments currently in use
comprise polyethylene glycol (PEG) and electrolytes. Various such
PEG/electrolyte products are on the market in many countries. An
example of such a product is MOVICOL (registered trademark of Edra
AG, exclusively licensed to the Norgine group of companies, and
marketed in the UK by Norgine Limited, Chaplin House, Widewater
Place, Moorhall Road, Harefield, Uxbridge, Middlesex UB9 6NS,
United Kingdom). MOVICOL is provided in a sachet containing 13.8 g
powder for making up into an oral solution. Each sachet contains:
13.1250 g Macrogol (polyethylene glycol (PEG)) 3350, 0.3507 g
sodium chloride, 0.1785 g sodium bicarbonate and 0.0466 g potassium
chloride. This is the standard dose of MOVICOL. It also contains
flavouring and sweetener. MOVICOL has been on the market since
1995. MOVICOL PLAIN is essentially the same as MOVICOL but it does
not contain flavouring or sweetener, so to adjust for the potassium
content of the sweetener, it contains slightly more potassium
chloride. Each sachet of MOVICOL PLAIN contains: 13.1250 g Macrogol
(polyethylene glycol (PEG)) 3350, 0.3508 g sodium chloride, 0.1786
g sodium bicarbonate and 0.0502 g potassium chloride. When MOVICOL
or MOVICOL PLAIN is made into a drink with water to a volume of 125
millilitres, each sachet gives the equivalent of: 65
millimoles/litre sodium, 53 millimoles/litre chloride, 17
millimoles/litre bicarbonate and 5.4 millimoles/litre
potassium.
[0005] One standard dose of MOVICOL is provided as a unit treatment
in powder form in one sachet. Patients are advised to combine the
powder contents of a sachet with water to make up a drink of 125
ml. It is found that dissolution can, in practice, take some time.
It is important with a solution of the MOVICOL type that the
patient does not to attempt to speed the dissolution by heating as
that will lead to decomposition of the bicarbonate component. The
time taken for the powder to dissolve causes inefficiency in the
care-home or hospital setting where solutions are prepared by
professional care-providers. In the self-administration domestic
setting, it can cause frustration in the patient and risks the
patient taking an incompletely dissolved preparation, which would
reduce the efficacy of the treatment. The sachets are made of a
laminate consisting of four layers: low density polyethylene,
aluminium, low density polyethylene and paper. Some patients have
difficulties manipulating and tearing open the sachets. The sachets
are not re-usable.
[0006] For the treatment of constipation, patients are advised to
take one sachet dissolved to 125 ml 1-3 times a day, according to
the severity of the constipation. Treatment with MOVICOL usually
lasts about 2 weeks. There are various situations in which MOVICOL
is recommended for longer treatments than 2 weeks, particularly in
patients who take drugs that cause constipation (eg opioids, such
as morphine) or have a disease that has associated constipation
(for example Parkinson's disease or multiple sclerosis (MS)).
Usually, for long term treatment in such chronic treatment
situations, the number of doses per day can be adjusted down to
either one or two.
[0007] For the treatment of faecal impaction, the recommended
treatment is 8 sachets a day (each dissolved to 125 ml), taken
within 6 hours. That number of doses may be needed for up to 3
days.
[0008] MOVICOL sachets can be provided in boxes of 2, 6, 8, 10, 20,
30, 50, 60 or 100 sachets. Not all pack size boxes are necessarily
marketed at any one time. Examples of marketed boxes are those
containing 6, 30 or 100 sachets in the box (ie 6, 30 or 100
standard doses). Those boxes have the following dimensions:
[0009] 6 pack:
[0010] Has dimensions 14.5 cm.times.3.7 cm.times.13.0 cm, giving a
volume of 697.45 cm.sup.3 per pack, ie 116.24 cm.sup.3 per standard
dose.
[0011] 30 pack:
[0012] Has dimensions 14.5 cm.times.9.0 cm.times.13.0 cm, giving a
volume of 1696.50 cm.sup.3 per pack, ie 56.55 cm.sup.3 per standard
dose.
[0013] 100 pack:
[0014] Has dimensions 29.0 cm.times.14.5 cm.times.12.5 cm, giving a
volume of 5256.25 cm.sup.3 per pack, ie 52.56 cm.sup.3 per standard
dose.
[0015] Each sachet measures roughly 12 cm by 7 cm and is flat,
bulging to around 1 cm thickness when full.
[0016] Since many patients take MOVICOL or similar
constipation-treatment solutions chronically (ie for extended
periods), it is common for it to be necessary to store these large
multi-pack boxes either in a patient's home or in a care-home or
hospital drug storage cupboard. In a patient's home or in a
care-home or hospital, medicinal products must be stored carefully
and safely, and medicinal product storage space is generally at a
premium. The large amount of space taken up by the necessary
multi-pack boxes can be costly and cause difficulties.
[0017] Concentrated solutions of some pharmaceuticals for dilution
are known, and a small number are on the market. Despite there
being scope for practical improvements in use for the powder
PEG/electrolye compositions on the market, no concentrated
solutions of PEG/electrolyes for dilution to PEG-containing
laxatives have been developed to commercialisation. Concentrated
solutions of PEG/sodium sulphate lavage solutions have been
proposed (see WO 2005/049049 and JP 1-11-132527), but no such
solutions have been commercialised. In WO2005/049049 it was
disclosed that "concentrated solutions of polyethylene glycol are
chemically stable and do not support microbial growth" and thus do
not need preservatives. In JP H1-132527, data are presented showing
that in solutions of 118 g/L PEG 4000, 11.4 g/L sodium sulphate,
1.48 g/L potassium sulphate, 2.93 g/L sodium chloride and 3.37 g/L
sodium bicarbonate, and solutions with 1.5, 2 and 2.5 times those
concentrations, "there was no propagation of the micro-organisms at
all". It was thus disclosed that "no sterilization or added
preservatives" were needed. However, and in contrast to those
publications, the current inventors have found that a concentrated
solution of PEG, sodium chloride, potassium chloride and sodium
bicarbonate (and no sodium sulphate), supports microbial growth to
an unacceptable extent.
[0018] It has been found by the present inventors that a
preservative is essential in solutions comprising N.times.(70 to
130) g/L PEG having an average molecular weight of 2500 to 4500,
(b) N.times.(1.6 to 4.0) g/L sodium chloride, (c) N.times.(0.2 to
0.6) g/L potassium chloride, and (d) N.times.(0.6 to 2.2) g/L
sodium bicarbonate (and no sodium sulphate), where N is in the
range 2 to 8, for example in solutions comprising 350 to 600 g/L
PEG having an average molecular weight of 2500 to 4500, 8.0 to 20
g/L sodium chloride, 1.0 to 3.0 g/L potassium chloride and 3.0 to
11 g/L sodium bicarbonate (and no sodium sulphate). Inclusion of a
suitable amount of a suitable preservative in such a solution
allows microbial growth to be limited or eliminated.
[0019] Accordingly, in order to overcome the above-mentioned
difficulties, there is provided a solution in water comprising the
following components at the following concentrations: [0020] (a)
N.times.(70 to 130) g/L PEG having an average molecular weight of
2500 to 4500; [0021] (b) N.times.(1.6 to 4.0) g/L sodium chloride;
[0022] (c) N.times.(0.2 to 0.6) g/L potassium chloride; [0023] (d)
N.times.(0.6 to 2.2) g/L sodium bicarbonate; [0024] (e) N.times.an
amount of preservative; [0025] (f) optionally N.times.an amount of
flavouring; and [0026] (g) optionally N.times.an amount of
sweetener [0027] where N is a number in the range of 2 to 8.
[0028] The solution is a concentrate for N-fold dilution with water
to provide a solution for ingestion comprising the following
components at the following concentrations: [0029] (a) 70 to 130
g/L PEG having an average molecular weight of 2500 to 4500; [0030]
(b) 1.6 to 4.0 g/L sodium chloride; [0031] (c) 0.2 to 0.6 g/L
potassium chloride; [0032] (d) 0.6 to 2.2 g/L sodium bicarbonate;
[0033] (e) an amount of preservative; [0034] (f) optionally an
amount of flavouring; and [0035] (g) optionally an amount of
sweetener.
[0036] The concentrate solution is preferably accompanied by
instructions instructing the user to dilute with water by N-fold. N
need not be an integer, but it is the same number for each
component. Dilution of a solution of volume V by N-fold requires
the addition of a volume (N-1).times.V of water. Preferably N is
from 3 to 7, for example from 4 to 6, for example 5.
[0037] Preferably, the amount of PEG is N.times.(70 to 120) g /L,
more preferably N.times.(80 to 120) g/L, more preferably
N.times.(95 to 115) g/L, for example N.times.105 g/L. Preferably,
the amount of sodium chloride N.times.(2.1 to 3.5) g/L, more
preferably N.times.(2.4 to 3.2) g/L, more preferably N.times.(2.6
to 3.0) g/L, for example approximately N.times.2.8 g, for example
N.times.2.8056 g/L. Preferably, the amount of potassium chloride is
N.times.(0.28 to 0.45) g/L, more preferably N.times.(0.32 to 0.42)
g/L, more preferably N.times.(0.35 to 0.40) g/L, for example
approximately N.times.0.37 g/L, for example N.times.0.3728 g/L.
Preferably, the amount of sodium bicarbonate is N.times.(1.1 to
1.7) g/L, more preferably N.times.(1.2 to 1.6) g/L, more preferably
N.times.(1.35 to 1.50) g/L, for example approximately N.times.1.4
g/L, for example N.times.1.428 g/L.
[0038] For example, the invention provides a concentrate solution
in water comprising the following components at the following
concentrations: [0039] (a) 350 to 600 g/L PEG having an average
molecular weight of 2500 to 4500; [0040] (b) 8.0 to 20 g/L sodium
chloride; [0041] (c) 1.0 to 3.0 g/L potassium chloride; [0042] (d)
3.0 to 11 g/L sodium bicarbonate; [0043] (e) preservative; [0044]
(f) optional flavouring; and [0045] (g) optional sweetener.
[0046] Solutions of the invention are preferably substantially free
from any sulphate component.
[0047] In particular, solutions of the invention are preferably
substantially free from sodium sulphate. In this context,
"substantially free from any sulphate component" is taken to mean
free from any added sulphate component. Negligible amounts of
sulphate salts may be present in other added components, or in the
water that is used in the solutions. Such amounts are not
substantial in this context.
[0048] In use, the solution of the invention is diluted with
additional water to provide a medicament for drinking by a patient.
The solution of the invention can thus be regarded as a
concentrate. In use, a solution of the invention is, for example,
diluted with approximately four times its volume of water to
generate an approximately five-fold diluted solution. For example,
a 25 ml unit of the concentrate solution may be diluted with from
75 to 125 ml of water to give a solution of from 100 ml to 150
ml.
[0049] A "solution" in the context of the present invention
includes any mixture resulting from admixture of or combination of
the components (a) to (g) with water, whether fully dissolved or
not. In a preferred embodiments, the components (a) to (g) are
fully dissolved.
[0050] Solutions of the invention have been found to be
particularly convenient for use in providing one or more of the
following advantages:
[0051] 1. They can be made up to the medicament solution for
drinking in less time than the dry powder compositions of the prior
art.
[0052] 2. They enable storage of the medicament in a smaller volume
than for sachets of dry powder of the prior art.
[0053] 3. They have a shelf life sufficiently long to be acceptable
in a pharmaceutical product.
[0054] These are expanded on below:
[0055] 1. It has been found that the solutions of the invention can
be diluted to the concentration required for ingestion more rapidly
than the dry powders of the prior art. The solution at the
concentration for ingestion is prepared essentially instantly once
the concentrate solution of the invention is mixed with the
diluting water. There is no delay for the dissolution of dry
powder. The rapid preparation of the solution for ingestion reduces
the time taken to prepare the medicament. That reduction in time
brings about improved efficiency in the care-home or hospital
setting where solutions are prepared by professional
care-providers. In the self-administration, domestic setting, it
reduces the risk of patient frustration and improves patient
compliance.
[0056] 2. A unit treatment may be provided in a unit container.
Suitable containers include bottles, pouches, vials or sealed cups.
Such containers suitably have the volume required to accommodate
the unit treatment. Preferably, they do not include air-pockets or
significant wasted space. In that way, storage space is minimized.
Provided the unit containers are appropriately shaped for efficient
packing (eg cylindrical, cuboid or hexagonal, though many other
shapes are possible), and provided wasted volume is minimised, a
unit treatment can be stored in a volume only little greater than
its own volume. Thus, when a solution of the invention comprises
525 g of PEG 3350 per litre and N is 5, then 25 ml of that is
required to provide the 13.125 g of PEG in a standard dose and, in
storage, that will occupy (with its container) only slightly more
than 25 cm.sup.3, for example 30 cm.sup.3. That represents a space
saving of around 20 cm.sup.3 compared with the over 50 cm.sup.3
storage space required per unit treatment (ie per standard dose)
mentioned above in relation to sachets of dry powder comprising the
same quantity of ingredients.
[0057] The solution of the invention may be provided in a container
having a volume that is for multiple unit treatments. The invention
thus further provides a container that contains sufficient solution
for any convenient number of unit treatments. For example, the
container might provide 1, 2, 4, 5, 8, 10, 12, 15, 20, 25, 30, 35,
40, 50, 60, 70, 75, 80 or 100 unit treatments. For example, if a
solution of the invention comprises 525 g of PEG 3350 per litre,
and 25 ml are required to provide the 13.125 g of PEG in a standard
dose, then a container may provide 25 ml, 50 ml, 100 ml, 125 ml,
150 ml, 200 ml, 250 ml, 300 ml, 375 ml, 500 ml, 625 ml, 750 ml, 875
ml or 1 l of solution. For example a container may contain one or
more unit treatments of solution, each unit treatment having a
volume of 20 to 50 ml, for example 25 ml, or each unit treatment
having a volume of 7.5 to 25 ml, for example 12.5 ml. For example,
a container (for example a bottle) of the invention provides 100
ml, 150 ml, 250 ml or 500 ml of solution of the invention.
[0058] Suitable containers include bottles, for example with a
re-closable closure. A re-closable closure may be child-proof. A
re-closable closure may be tamper-evident. Containers may for
example be made of plastic or glass, for example polyethylene
terephthalate (PET). They may be circular in cross-section, for
example they may be a right circular cylinder. They may be
transparent, translucent or opaque; containers may be coloured, for
example amber.
[0059] Considering again a 25 ml unit treatment that provides the
13.125 g of PEG in a standard dose, then 20 unit treatments are
provided in a container of 500 ml volume. The container can be
designed with a shape that takes up minimal unnecessary space and
thus the 20 unit treatments may be stored in a volume of only a
little over 500 cm.sup.3. That is to say that they occupy only
slightly over 25 cm.sup.3 each. That represents a space saving of
around 20 cm.sup.3 compared with the over 50 cm.sup.3 storage space
required per standard dose mentioned above in relation to sachets
of dry powder comprising the same quantity of ingredients.
[0060] In addition, a container containing multiple unit treatments
has further practical and environmental advantages in that it is
easier to use and generates less waste than multiple sachets. Such
a container can potentially be re-used or recycled, something that
is not possible with sachets.
[0061] 3. As mentioned above, in contrast to the published art, it
has been found by the present inventors that, in solutions
comprising N.times.(70 to 130) g/L PEG having an average molecular
weight of 2500 to 4500, (b) N.times.(1.6 to 4.0) g/L sodium
chloride, (c) N.times.(0.2 to 0.6) g/L potassium chloride, and (d)
N.times.(0.6 to 2.2) g/L sodium bicarbonate (and no sodium
sulphate), when N is in the range 2 to 8, for example 350 to 600
g/L PEG having an average molecular weight of 2500 to 4500, 8.0 to
20 g/L sodium chloride, 1.0 to 3.0 g/L potassium chloride and 3.0
to 11 g/L sodium bicarbonate (and no sodium sulphate), a
preservative is essential. Inclusion of a suitable amount of a
suitable preservative in such a solution allows microbial growth to
be limited or eliminated, and thus acceptable shelf or storage life
to be achieved.
[0062] Various national and regional pharmacopoeias set criteria
that oral preparations must fulfil regarding their propensity to
support micro-organism growth. For example, in order to meet the
criteria of the European Pharmacopoeia for an oral preparation, a
solution must satisfy the following: 3 log units drop in number of
viable micro-organisms for bacteria over 14 days (typically
assessed using Pseudomonas aeruginosa, Escherichia coli and
Staphylococcus aureus, the drop being required for each), and I log
unit drop for yeasts and moulds over 14 days (typically assessed
using Candida albicans and Aspergilus niger). Also, for bacteria
and yeasts/moulds, there must then be no increase from 14 days to
28 days. It has been found that, in a solution comprising
N.times.(70 to 130) g/L PEG having an average molecular weight of
2500 to 4500, (b) N.times.(1.6 to 4.0) g/L sodium chloride, (c)
N.times.(0.2 to 0.6) g/L potassium chloride, and (d) N.times.(0.6
to 2.2) g/L sodium bicarbonate (and no sodium sulphate), where N is
in the range 2 to 8, for example a solution comprising 350 to 600
g/L PEG having an average molecular weight of 2500 to 4500, 8.0 to
20 g/L sodium chloride, 1.0 to 3.0 g/L potassium chloride and 3.0
to 11 g/L sodium bicarbonate (and no sodium sulphate), yeast and
mould growth containment do not meet these criteria if no effective
preservative is included.
[0063] Various preservatives are known for use in liquid oral
preparations. Examples of such preservatives include sodium propyl
paraben, methyl paraben, ethyl paraben, propyl paraben, benzyl
alcohol and phenoxyethanol. Further preservatives that are known
for use in liquid oral preparations (including foods) include
benzoic acid, dehydroacetic acid, sorbic acid, Bronopol, propylene
glycol and glyceryl triacetate. Alcohols are used as preservatives
in some preparations.
[0064] The preservative component may comprise one, two or more
preservatives. The preservative may be (i) a separate component
from the other components of the solution and mixed therewith, (ii)
a constituent part of a flavouring component (f), sweetener
component (g) or other component of a solution of the invention, or
(iii) both (i) and (ii).
[0065] Particularly preferred preservatives are those that are
active and/or do not degrade over time at alkaline pH. Preferred
preservatives include sodium propyl paraben, methyl paraben, ethyl
paraben, propyl paraben, benzyl alcohol, phenoxyethanol, propylene
glycol, glyceryl triacetate and blends of two or more of those.
Methyl paraben, ethyl paraben, propyl paraben, benzyl alcohol and
phenoxyethanol and blends of two or more of those are particularly
preferred. Appropriate preservatives may be provided as salts, for
example sodium salts. In solutions of the invention, a preservative
is preferably not provided as a salt; if a preservative is provided
as a salt, then the electrolyte components (b) to (d) may need to
be adjusted so that the total concentration of each electrolyte
remains at the required level. For example, if a preservative is
used in the form of a sodium salt, it may be necessary to reduce
the amount of sodium chloride present.
[0066] It is important that the level of preservative in any oral
formulation does not exceed recommended safe levels for oral use.
For an oral preparation that will be given to a patient several
times per day, it is important that the cumulative level of
preservative is sufficiently low not to exceed recommended daily
intake levels. Preferred preservatives have ADI (acceptable daily
intake) levels that have been confirmed by suitable regulatory
bodies, for example the EFSA. Methyl paraben, ethyl paraben, benzyl
alcohol and blends of two or more of those are particularly
preferred.
[0067] For the solutions of the present invention, it has been
found that the preservative may be present at a level of from 0.5
to 10 g per litre of solution (ie 0.05 to 1 w/v %), for example 1.5
to 7.0 g per litre of solution (ie 0.15 to 0.7 w/v %). For example,
a preservative may be present at a level of from 1.0 to 5.0 g per
litre of solution (ie 0.1 to 0.5 w/v %), for example 2.0 to 4.0 g
per litre of solution (ie 0.2 to 0.4 w/v %). For example, a
preservative may be present at a level of from N.times.(0.1 to 2.0)
g per litre of solution, for example from N.times.(0.3 to 1.4) g
per litre of solution, for example from N.times.(0.2 to 1.0) g per
litre of solution, for example N.times.(0.4 to 0.8) g per litre of
solution.
[0068] Certain preservatives have limited solubility in water. The
effectiveness of a preservative can be improved by the inclusion of
a solubilising agent. Examples of solubilising agents include
benzyl alcohol, phenoxyethanol and propylene glycol. A solubilising
agent may be (i) a separate component from the other components of
the solution and mixed therewith, (ii) a constituent part of a
preservative component (e), a flavouring component (f), sweetener
component (g) or other component of a solution of the invention, or
(iii) both (i) and (ii). It is important that the level of a
solubilising agent in any oral formulation does not exceed
recommended safe levels.
[0069] In a preferred embodiment, a preservative comprises 20-30%
by weight (relative to the weight of the preservative) paraben
(which may be a single paraben or a mixture of parabens), and
70-80% by weight solubiliser. It is thus preferred that, in one
embodiment, a solution of the invention includes one or both of
methyl paraben and ethyl paraben, and benzyl alcohol. In an
embodiment, a solution of the invention includes one or both of
methyl paraben and ethyl paraben, and phenoxyethanol.
[0070] Therefore, suitable preservatives should fulfil multiple
criteria: they should be active and/or not degrade over time at
alkaline pH, and be sufficiently effective to fulfill national and
regional pharmacopoeial criteria regarding micro-organism growth
when used in an amount that is safe for human consumption.
[0071] It has been found that a blend of methyl paraben, ethyl
paraben and benzyl alcohol is particularly effective as a
preservative component in a solution of the invention (not
containing sodium sulphate), and that effective anti-microbial
preservation is achieved with a particularly low level of
preservative. Preferably, a solution of the invention includes all
three of methyl paraben, ethyl paraben and benzyl alcohol. For
example, they may be present in a weight ratio methyl paraben:
ethyl paraben: benzyl alcohol of 1 to 3:1:5 to 12, for example 1.5
to 2.5:1 7 to 9. For example, in the ratio 18:9:73. It has been
found that a blend of methyl paraben, ethyl paraben and benzyl
alcohol is particularly effective in preventing the growth of
Aspergilus niger. That mould can be particularly challenging in
solutions of high osmolality, for example concentrate solutions
such as those of the invention.
[0072] Preferably, a blend of methyl paraben, ethyl paraben and
benzyl alcohol is present at a level of from N.times.(0.3 to 1.4) g
per litre of solution, preferably from 1.5 to 7.0 g per litre of
solution (ie 0.15 to 0.70 w/v %), preferably from 2.0 to 7.0 g per
litre of solution (ie 0.20 to 0.70 w/v %), for example
(particularly when the solution comprises an Orange Juice flavour)
from 2.5 to 7.0 g per litre of solution (ie 0.25 to 0.7 w/v %), for
example 2.5 to 5.0 g per litre of solution (ie 0.25 to 0.5 w/v %).
A preferred solution comprises 2.5 g or 3.5 g of a blend of methyl
paraben, ethyl paraben and benzyl alcohol per litre, for example
2.5 g or 3.5 g per litre of a blend of methyl paraben (18%), ethyl
paraben (9%) and benzyl alcohol (73%), the weight % being based on
the weight of the preservative component.
[0073] Accordingly, a preferred concentrate solution of the
invention comprises: [0074] (a) N.times.(70 to 130) g/L PEG having
an average molecular weight of 2500 to 4500; [0075] (b)
N.times.(1.6 to 4.0) g/L sodium chloride; [0076] (c) N.times.(0.2
to 0.6) g/L potassium chloride; [0077] (d) N.times.(0.6 to 2.2) g/L
sodium bicarbonate; [0078] (e) N.times.(0.3 to 1.4) g/L of
preservative comprising methyl paraben, ethyl paraben or benzyl
alcohol, or a mixture of two or more of them; [0079] (f) optionally
N.times.an amount of flavouring; and [0080] (g) optionally
N.times.an amount of sweetener
[0081] where N is in the range of 2 to 8.
[0082] For example, a preferred concentrate solution of the
invention comprises the following components at the following
concentrations: [0083] (a) 350 to 600 g/L PEG having an average
molecular weight of 2500 to 4500; [0084] (b) 8.0 to 20 g/L sodium
chloride; [0085] (c) 1.0 to 3.0 g/L potassium chloride; [0086] (d)
3.0 to 11 g/L sodium bicarbonate; [0087] (e) 1.5 to 7.0 g/L of
preservative comprising methyl paraben, ethyl paraben or benzyl
alcohol, or a mixture of two or more of them; [0088] (f) optional
flavouring; and [0089] (g) optional sweetener.
[0090] It has also been found that blends of methyl paraben, ethyl
paraben and phenoxyethanol have good effectiveness as a
preservative in a solution of the invention (not containing sodium
sulphate). For example, a solution of the invention includes all
three of methyl paraben, ethyl paraben and phenoxyethanol. For
example, they may be present in a weight ratio methyl paraben:ethyl
paraben:phenoxyethanol of 1 to 3:1:5 to 12, for example 1.2 to
2.5:1:7 to 9. For example, in the ratio 18:9:73, or 15:10:75.
[0091] A blend of methyl paraben, ethyl paraben and phenoxyethanol
may be present at a level of from N.times.(1.0 to 2.0 g) per litre
of solution, preferably from 5.0 to 10 g per litre of solution (ie
0.5 to 1.0 w/v %), for example 5.0 to 8.0 g per litre of solution
(ie 0.5 to 0.8 w/v %). For example, a solution comprises 5.0 g of a
blend of methyl paraben, ethyl paraben and phenoxyethanol per
litre, for example 5.0 g per litre of a blend of methyl paraben
(18%), ethyl paraben (9%) and phenoxyethanol (73%), the weight %
being based on the weight of the preservative component.
[0092] In a further embodiment, a concentrate solution of the
invention comprises: [0093] (a) N.times.(70 to 130) g/L PEG having
an average molecular weight of 2500 to 4500; [0094] (b)
N.times.(1.6 to 4.0) g/L sodium chloride; [0095] (c) N.times.(0.2
to 0.6) g/L potassium chloride; [0096] (d) N.times.(0.6 to 2.2) g/L
sodium bicarbonate; [0097] (e) N.times.(2.0 to 2.0) g/L of
preservative comprising methyl paraben, ethyl paraben or
phenoxyethanol, or a mixture of two or more of them; [0098] (f)
optionally N.times.an amount of flavouring; and [0099] (g)
optionally N.times.an amount of sweetener
[0100] where N is in the range of 2 to 8.
[0101] For example, a concentrate solution in water comprising the
following components at the following concentrations: [0102] (a)
350 to 600 g/L PEG having an average molecular weight of 2500 to
4500; [0103] (b) 8.0 to 20 g/L sodium chloride; [0104] (c) 1.0 to
3.0 g/L potassium chloride; [0105] (d) 3.0 to 11 g/L sodium
bicarbonate; [0106] (e) 5.0 to 10.0 g/L of preservative comprising
methyl paraben, ethyl paraben or phenoxyethanol, or a mixture of
two or more of them; [0107] (f) optional flavouring; and [0108] (g)
optional sweetener.
[0109] The polyethylene glycol (PEG) used in solutions of the
invention has an average molecular weight (for example a weight
average molecular weight), of 2500 Da to 4500 Da. The PEG may have
an average molecular weight of 3000 to 4000. For example, the PEG
may be PEG 3350 or PEG 4000 as defined in national pharmacopoeias.
Further examples of suitable PEGs recognized in some national
pharmacopoeias include Macrogols, for example Macrogol 4000.
Optionally, the PEG used in compositions of the invention may
comprise two or more different PEG compounds.
[0110] Depending on the molecular weight of the PEG in a solution
of the invention, the upper limit of concentration of the PEG may
be limited by the water solubility of the PEG. For certain values
of N, it necessary for the (70 to 130)g factor in the N.times.(70
to 130)g/L amount to be nearer the lower end of the (70 to 130)g
range for reasons of solubility. Solutions of the invention
therefore preferably comprise PEG in an amount of 350 to 600 g per
litre, preferably within a range wherein the lower limit is 400,
450 or 500 g per litre and the upper limit is, independently, 600,
575 or 550 g per litre; for example 500 to 550 g per litre. For
example a solution of the invention may comprise 525 g of PEG per
litre, for example 525 g of PEG 3350 per litre.
[0111] Solutions of the invention preferably comprise sodium
chloride in an amount of 8.0 to 20 g per litre of solution to be
made, preferably within a range wherein the lower limit is 10, 11,
12 or 13 g per litre and the upper limit is, independently, 18, 17,
16 or 15 g per litre; for example 13 to 15 g per litre. For example
a solution of the invention may comprise approximately 14 g of
sodium chloride per litre, for example 14.028 g per litre.
[0112] Solutions of the invention preferably comprise potassium
chloride in an amount of 1.0 to 3.0 g per litre, preferably within
a range wherein the lower limit is 1.2, 1.4, 1.6, 1.7 or 1.8 g per
litre and the upper limit is, independently, 2.7, 2.5, 2.3, 2.1 or
2.0 g per litre; for example 1.6 to 2.1 g per litre, for example
1.8 to 1.9 g per litre. For example a solution of the invention may
comprise 1.864 g of potassium chloride per litre. An alternative
solution of the invention may comprise 1.268 g or 2.008 g of
potassium chloride per litre. In an embodiment, the potassium ion
content may be provided by a potassium salt other than potassium
chloride.
[0113] Solutions of the invention preferably comprise sodium
bicarbonate (also known as sodium hydrogen carbonate) in an amount
of 3.0 to 11 g per litre, preferably within a range wherein the
lower limit is 5.0, 6.0, 6.5 or 7.0 g per litre and the upper limit
is, independently, 10, 9.0, 8.0 or 7.5 g per litre; for example 6.5
to 8.0 g per litre. For example a solution of the invention may
comprise approximately 7.1 g per litre, for example 7.140 g per
litre.
[0114] In a solution of the invention, the weight ratio of the
components PEG, sodium chloride, potassium chloride and sodium
bicarbonate is preferably approximately 13.125(PEG): 0.3507 (NaCl):
0.0466 (KCl): 0.1785 (NaHCO.sub.3), ie approximately 282 (PEG): 7.5
(NaCl): 1 (KCl): 3.8 (NaHCO.sub.3). For example it may be within
the ranges 250 to 450 (PEG): 5 to 15 (NaCl): 1 (KCl): 3 to 7.5
(NaHCO.sub.3), for example 250 to 300 (PEG): 5 to 10 (NaCl): 1
(KCl): 3 to 5 (NaHCO.sub.3), for example within the ranges 275 to
285 (PEG): 7 to 8 (NaCl): 1 (KCl): 3.6 to 4.0 (NaHCO.sub.3).
[0115] In another embodiment of a solution of the invention, the
molar ratio of the individual ions in the components sodium
chloride, potassium chloride and sodium bicarbonate is preferably
approximately 65(Na.sup.+): 53 (CO: 5.0 (K.sup.+): 17
(HCO.sub.3.sup.-), ie approximately 13 (Na.sup.+): 10.6 (Cl.sup.-):
1 (K.sup.+): 3.4 (HCO.sub.3.sup.-). For example it may be within
the ranges 11 to 15 (Na.sup.+): 8 to 13 (Cl.sup.-): 1 (K.sup.+):
2.8 to 4.0 (HCO.sub.3.sup.-), for example within the ranges 12 to
14 (Na.sup.+): 9 to 11 (a): 1 (K.sup.+): 3.2 to 3.6
(HCO.sub.3.sup.-).
[0116] The invention provides a solution in water comprising the
following components at the following concentrations: [0117] (a)
N.times.(16 to 52) mmol/L PEG having an average molecular weight of
2500 to 4500; [0118] (b1) N.times.(34 to 94) mmol/L sodium present
as sodium ions; [0119] (b2) N.times.(2.7 to 8.0) mmol/L potassium
present as potassium ions; [0120] (c) N.times.(30 to 76) mmol/L
chloride ions; [0121] (d) N.times.(7 to 26) mmol/L bicarbonate
ions; [0122] (e) N.times.an amount of preservative; [0123] (f)
optionally N.times.an amount of flavouring; and [0124] (g)
optionally N.times.an amount of sweetener [0125] where N is in the
range of 2 to 8.
[0126] The solution is a concentrate for N-fold dilution with water
to provide a solution for ingestion comprising the following
components at the following concentrations: [0127] (a) 16 to 52
mmol/L PEG having an average molecular weight of 2500 to 4500;
[0128] (b1) 34 to 94 mmol/L sodium present as sodium ions; [0129]
(b2) 2.7 to 8.0 mmol/L potassium present as potassium ions; [0130]
(c) 30 to 76 mmol/L chloride ions; [0131] (d) 7 to 26 mmol/L
bicarbonate ions; [0132] (e) an amount of preservative; [0133] (f)
optionally an amount of flavouring; and [0134] (g) optionally an
amount of sweetener.
[0135] The concentrate solution is preferably accompanied by
instructions instructing the user to dilute with water by N-fold. N
need not be an integer, but it is the same number for each
component. Dilution of a solution of volume V by N-fold requires
the addition of a volume (N-1).times.V of water. Preferably N is
from 3 to 7, for example from 4 to 6, for example 5.
[0136] Preferably, the concentration of PEG is N.times.(28 to 36)
mmol/L, for example N.times.31.3mmol/L. Preferably, the
concentration of sodium ions is N.times.(49 to 80) mmol/L, more
preferably N.times.(60 to 70) mmol/L, for example N.times.65
mmol/L. Preferably, the concentration of potassium ions is
N.times.(3.8 to 6.0) mmol/L, more preferably N.times.(5.1 to 5.7)
mmol/L, for example N.times.5.4 mmol/L. Preferably, the
concentration of chloride ions is N.times.(40 to 66) mmol/L, more
preferably N.times.(47 to 59) mmol/L, for example N.times.53
mmol/L. Preferably, the concentration of bicarbonate ions is
N.times.(13 to 20) mmol/L, more preferably N.times.(15 to 19)
mmol/L, for example N.times.17 mmol/L.
[0137] For example, the invention provides a solution in water
comprising the following components at the following
concentrations: [0138] (a) 78 to 240 mmol/L PEG having an average
molecular weight of 2500 to 4500; [0139] (b1) 173 to 473 mmol/L
sodium present as sodium ions; [0140] (b2) 13 to 40 mmol/L
potassium present as potassium ions; [0141] (c) 150 to 382 mmol/L
chloride ions; [0142] (d) 36 to 131 mmol/L bicarbonate ions; [0143]
(e) preservative; [0144] (f) optional flavouring; and [0145] (g)
optional sweetener.
[0146] Solutions of the invention preferably comprise sodium
present as sodium ions in an amount of 173 to 473 mmol per litre,
preferably within a range wherein the lower limit is 231, 259, 282
or 305 mmol per litre and the upper limit is, independently, 427,
398, 369 or 345 mmol per litre; for example 305 to 345 mmol per
litre. For example, a solution of the invention may comprise
approximately 325 mmol sodium present as sodium ions per litre.
[0147] In one embodiment, solutions of the invention preferably
comprise potassium present as potassium ions in an amount of 14 to
43 mmol per litre, preferably within a range wherein the lower
limit is 17, 23 or 26 mmol per litre and the upper limit is,
independently, 39, 34 or 29 mmol per litre; for example from 26 to
29 mmol per litre. For example a solution of the invention may
comprise approximately 27 mmol potassium present as potassium ions
per litre.
[0148] In another embodiment, solutions of the invention preferably
comprise potassium present as potassium ions in an amount of 13 to
40 mmol per litre, preferably within a range wherein the lower
limit is 16, 19, 21, 23 or 24 mmol per litre and the upper limit
is, independently, 36, 34, 31, 28 or 27 mmol per litre; for example
21 to 28 mmol per litre, for example from 24 to 25 mmol per litre.
For example a solution of the invention may comprise approximately
25 mmol potassium present as potassium ions per litre.
[0149] Solutions of the invention preferably comprise chloride ions
in an amount of 150 to 382 mmol per litre, preferably within a
range wherein the lower limit is 187, 207, 226 or 245 mmol per
litre and the upper limit is, independently, 344, 325, 305 or 284
mmol per litre; for example from 246 to 281 mmol per litre. For
example a solution of the invention may comprise approximately 265
mmol chloride ions per litre.
[0150] Solutions of the invention preferably comprise bicarbonate
ions in an amount of 36 to 131 mmol per litre, preferably within a
range wherein the lower limit is 60, 71, 77 or 83 mmol per litre
and the upper limit is, independently, 119, 107, 95 or 89 mmol per
litre; for example 77 to 95 mmol per litre. For example a solution
of the invention may comprise approximately 85 mmol per litre.
[0151] Solutions of the invention optionally comprise one or more
flavourings. Flavourings assist in making the solutions in their
diluted form for ingestion more palatable to certain patients.
[0152] The exact level of flavouring required depends on the
intensity of flavour desired, and the nature and strength of the
flavour in question. Typically, a flavouring may be present at a
level of N.times.(0.2 to 2) g per litre, for example 1 to 10 g per
litre, for example from 1 to 5 g per litre, especially from 2 to 4
g per litre, for example 3.2 g per litre. Examples of flavours that
can be used include orange, lemon-lime, lemon, citrus, chocolate,
tropical fruit, aloe vera, tea, strawberry, grapefruit,
blackcurrant, pineapple and vanilla. Preferred flavours are orange
juice flavour and tropical fruit flavour. Citrus flavour may also
be used.
[0153] Those and further suitable flavourings are available from
various flavour manufacturers and suppliers, for example
International Flavours and Fragrances Inc. (Duddery Hill,
Haverhill, Suffolk, CB9 8LG, England), Ungerer & Company
(Sealand Road, Chester, England CH1 4LP), Firmenich (Firmenich UK
Ltd., Hayes Road, Southall, Middlesex UB2 5NN) or S. Black Ltd
(Foxholes Business Park, John Tate Road, Hertford, Herts, SG13 7YH,
United Kingdom).
[0154] Solutions of the invention may comprise one or more
sweeteners. Preferred sweeteners include aspartame, acesulfame
potassium (acesulfame K), sucralose and saccharine and combinations
thereof. For example, solutions of the invention may comprise one
or both of sucralose and acesulfame potassium (acesulfame K).
Typically, a sweetener may be present at a level of N.times.(0.02
to 0.2) g per litre, for example 0.1 to 1 g per litre
[0155] In an embodiment, acesulfame K is present in an amount of
N.times.(0.04 to 0.12)g per litre, preferably 0.20 to 0.60 g per
litre, preferably within in a range in which the lower limit is
0.20, 0.30 or 0.35 g per litre and the upper limit is,
independently, 0.60, 0.50 or 0.45 g per litre. For example, a
solution of the invention may comprise 0.40 g acesulfame K per
litre.
[0156] In one embodiment, solutions of the invention preferably
comprise acesulfame ions in an amount of 1.0 to 3.0 mmol per litre,
preferably within in a range in which the lower limit is 1.0, 1.5
or 1.7 mmol per litre and the upper limit is, independently, 3.0,
2.5 or 2.2 mmol per litre. For example, a solution of the invention
may comprise approximately 2.0 mmol acesulfame ions per litre.
[0157] In one embodiment, the invention provides a solution in
water comprising the following components at the following
concentrations: [0158] (a) N.times.(16 to 52) mmol/L PEG having an
average molecular weight of 2500 to 4500; [0159] (b1) N.times.(34
to 94) mmol/L sodium present as sodium ions; [0160] (c1)
N.times.(2.7 to 8.0) mmol/L potassium present as potassium ions;
[0161] (b2) N.times.(30 to 76) mmol/L chloride ions; [0162] (d)
N.times.(7 to 26) mmol/L bicarbonate ions; [0163] (e) N.times.an
amount of preservative; [0164] (f) optionally N.times.an amount of
flavouring; and [0165] (g1) N.times.(0.29 to 0.45) mmol/L
acesulfame ions; [0166] (g2) optionally N.times.an amount of
additional sweetener [0167] where N is in the range of 2 to 8.
[0168] The solution is a concentrate for N-fold dilution with water
to provide a solution for ingestion comprising the following
components at the following concentrations: [0169] (a) 16 to 52
mmol/L PEG having an average molecular weight of 2500 to 4500;
[0170] (b1) 34 to 94 mmol/L sodium present as sodium ions; [0171]
(c1) 2.7 to 8.0 mmol/L potassium present as potassium ions; [0172]
(b2) 30 to 76 mmol/L chloride ions; [0173] (d) 7 to 26 mmol/L
bicarbonate ions; [0174] (e) an amount of preservative; [0175] (f)
optionally an amount of flavouring; and [0176] (g1) 0.29 to 0.45
mmol/L acesulfame ions; [0177] (g2) optionally an amount of
additional sweetener
[0178] The concentrate solution is preferably accompanied by
instructions instructing the user to dilute with water by N-fold. N
need not be an integer, but it is the same number for each
component. Dilution of a solution of volume V by N-fold requires
the addition of a volume (N-1).times.V of water. Preferably N is
from 3 to 7, for example from 4 to 6, for example 5.
[0179] For example, in one embodiment the invention provides a
solution in water, comprising the following components at the
following concentrations: [0180] (a) 78 to 240 mmol/L PEG having an
average molecular weight of 2500 to 4500; [0181] (b1) 173 to 473
mmol/L sodium present as sodium ions; [0182] (c) 14 to 43 mmol/L
potassium present as potassium ions; [0183] (b2) 150 to 382 mmol/L
chloride ions; [0184] (d) 36 to 131 mmol/L bicarbonate ions; [0185]
(e) preservative; [0186] (f) optional flavouring; and [0187] (g1)
1.0 to 3.0 mmol/L acesulfame ions; [0188] (g2) optional additional
sweetener.
[0189] In one embodiment of a solution of the invention, the molar
ratio of the individual ions in the components sodium chloride,
potassium chloride, sodium bicarbonate and acesulfame K is
preferably approximately 65(Na.sup.+): 53 (Cl.sup.-): 5.4
(K.sup.+): 17 (HCO.sub.3.sup.-), ie approximately 12 (Na.sup.+): 10
(Cl.sup.-): 1 (K.sup.+): 3 (HCO.sub.3.sup.-), For example it may be
within the ranges 10 to 14 (Na.sup.+): 8 to 12 (Cl.sup.-): 1
(K.sup.+): 2.5 to 3.7 (HCO.sub.3.sup.-), for example within the
ranges 11 to 13 (Na.sup.+): 9 to 11 (Cl.sup.-): 1 (K.sup.+): 2.9 to
3.3 (HCO.sub.3.sup.-).
[0190] In an embodiment, sucralose is present in an amount of
N.times.(0.012 to 0.04) g per litre, preferably 0.06 to 0.20 g per
litre, preferably within in a range in which the lower limit is
0.06, 0.08 or 0.10 g per litre and the upper limit is,
independently, 0.20, 0.18, 0.16 or 0.14 g per litre. For example, a
solution of the invention may comprise 0.12 g sucralose per
litre.
[0191] In an embodiment, the solution comprises both sucralose and
acesulfame potassium (acesulfame K). Preferably, acesulfame K is
present in an amount of 0.20 to 0.60 g per litre and sucralose is
present in an amount of 0.06 to 0.20 g per litre. Preferably
acesulfame K is present in an amount within a range in which the
lower limit is 0.20, 0.30 or 0.35 g per litre and the upper limit
is, independently, 0.60, 0.50 or 0.45 g per litre, and sucralose is
present in an amount within a range in which the lower limit is
0.06, 0.08 or 0.10 g per litre and the upper limit is,
independently, 0.20, 0.18, 0.16 or 0.14 g per litre. For example, a
solution of the invention may comprise 0.40 g acesulfame K per
litre and 0.12 g sucralose per litre.
[0192] Solutions of the invention are preferably substantially free
from added citrate ions. Citrate ions are provided for example by
citric acid and sodium citrate. Some fruit flavourings may
intrinsically contain a small amount of citric acid. Those amounts
are not considered substantial in this context. Solutions of the
invention are preferably substantially free from added acid.
Hydrogen ions are provided for example by organic acids (for
example citric acid or ascorbic acid) or inorganic acids (for
example hydrochloric acid). Some fruit flavourings may
intrinsically contain small amounts of organic acids. Those amounts
are not considered substantial in this context. Solutions of the
invention preferably have a pH of 8.0 to 11.0, preferably 8.0 to
10.5, for example 8.4 to 9.0. Measurements of pH may, for example,
be carried out with a Hanna Instruments "pH ep" temperature
compensating pH meter.
[0193] The invention further provides a method of preparing a
concentrate solution of the invention comprising combining the
following components with water to the following concentrations:
[0194] (a) N.times.(70 to 130) g/L PEG having an average molecular
weight of 2500 to 4500; [0195] (b) N.times.(1.6 to 4.0) g/L sodium
chloride; [0196] (c) N.times.(0.2 to 0.6) g/L potassium chloride;
[0197] (d) N.times.(0.6 to 2.2) g/L sodium bicarbonate; [0198] (e)
N.times.an amount of preservative; [0199] (f) optionally N.times.an
amount of flavouring; and [0200] (g) optionally N.times.an amount
of sweetener [0201] where N is in the range of 2 to 8.
[0202] For example, the method comprises combining the following
components with water to the following concentrations: [0203] (a)
350 to 600 g/L PEG having an average molecular weight of 2500 to
4500; [0204] (b) 8.0 to 20 g/L sodium chloride; [0205] (c) 1.0 to
3.0 g/L potassium chloride; [0206] (d) 3.0 to 11 g/L sodium
bicarbonate; [0207] (e) preservative; [0208] (f) optional
flavouring; and [0209] (g) optional sweetener.
[0210] Depending on the identities of the preservative, optional
flavouring or optional sweetener and the amounts of the components,
it may be beneficial to warm the liquid mixture during the method
of preparing the concentrate. For example, it may be beneficial to
warm the water (or a portion of it) to dissolve the preservative
prior to combining the preservative with one or more other
component of the concentrate. It is found that to prepare one litre
of a concentrate solution comprising (a) 525 g/L PEG having an
average molecular weight of 2500 to 4500; (b) 14,028 g/L sodium
chloride; (c) 1.864 g/L potassium chloride; (d) 7.140 g/L sodium
bicarbonate; (e) 2.5 or 3.5 g/L preservative; (f) 3.2 g/L
flavouring; and (g) 0.52 g/L sweetener (for example it may comprise
0.40 g/L acesulfame K and 0.12 g/L sucralose), approximately 549 ml
of water are needed.
[0211] In certain settings, where a concentrate solution is to be
used soon after it has been prepared, a concentrate solution might
not require an added preservative component. Accordingly, there is
provided a solution in water comprising the following components at
the following concentrations: [0212] (a) N.times.(70 to 130) g/L
PEG having an average molecular weight of 2500 to 4500; [0213] (b)
N.times.(1.6 to 4.0) g/L sodium chloride; [0214] (c) N.times.(0.2
to 0.6) g/L potassium chloride; [0215] (d) N.times.(0.6 to 2.2) g/L
sodium bicarbonate; [0216] (f) optionally N.times.an amount of
flavouring; and [0217] (g) optionally N.times.an amount of
sweetener [0218] where N is in the range of 2 to 8.
[0219] The solution is a concentrate for N-fold dilution with water
to provide a solution for ingestion comprising the following
components at the following concentrations: [0220] (a) 70 to 130
g/L PEG having an average molecular weight of 2500 to 4500; [0221]
(b) 1.6 to 4.0 g/L sodium chloride; [0222] (c) 0.2 to 0.6 g/L
potassium chloride; [0223] (d) 0.6 to 2.2 g/L sodium bicarbonate;
[0224] (f) optionally an amount of flavouring; and [0225] (g)
optionally an amount of sweetener
[0226] The concentrate solution is preferably accompanied by
instructions instructing the user to dilute with water by N-fold. N
need not be an integer, but it is the same number for each
component. Dilution of a solution of volume V by N-fold requires
the addition of a volume (N-1).times.V of water. Preferably N is
from 3 to 7, for example from 4 to 6, for example 5.
[0227] For example, such a solution has the following components at
the following concentrations: [0228] (a) 350 to 600 g/L PEG having
an average molecular weight of 2500 to 4500; [0229] (b) 8.0 to 20
g/L sodium chloride; [0230] (c) 1.0 to 3.0 g/L potassium chloride;
[0231] (d) 3.0 to 11 g/L sodium bicarbonate; optional flavouring;
and [0232] (g) optional sweetener.
[0233] In all respects other than in relation to the added
preservative component, the solution has the preferred features
described elsewhere herein. Containers and kits comprising such
solutions, methods of preparing such solutions are also
provided.
[0234] A preferred embodiment of a solution of the invention is a
solution in water comprising the following components at the
following concentrations: [0235] (a) 525 g/L PEG having an average
molecular weight of 2500 to 4500; [0236] (b) 14.028 g/L sodium
chloride; [0237] (c) 1.864 g/L potassium chloride; [0238] (d) 7.140
g/L sodium bicarbonate; [0239] (e) preservative; [0240] (f)
optional flavouring; and [0241] (g) optional sweetener.
[0242] For example, the preservative may be present in a
concentration of 2.5 or 3.5 g/L. For example, the flavouring may be
present in a concentration of 3.2 g/L. For example, the sweetener
may be present in a concentration of 0.52 g/L (for example it may
comprise 0.40 g acesulfame K and 0.12 g sucralose). Such a solution
is typically diluted five-fold for use.
[0243] A preferred embodiment of a solution of the invention is a
solution in water comprising the following components at the
following concentrations: [0244] (a) 420 g/L PEG having an average
molecular weight of 2500 to 4500; [0245] (b) 11.2224 g/L sodium
chloride; [0246] (c) 1.4912 g/L potassium chloride; [0247] (d)
5.712 g/L sodium bicarbonate; [0248] (e) preservative; [0249] (f)
optional flavouring; and [0250] (g) optional sweetener.
[0251] For example, the preservative may be present in a
concentration of 2.0 or 2.8 g/L. For example, the flavouring may be
present in a concentration of 2.56 g/L. For example, the sweetener
may be present in a concentration of 0.416 g/L (for example it may
comprise 0.32 g acesulfame K and 0.096 g sucralose). Such a
solution is typically diluted four-fold for use.
[0252] As discussed above, in use, the solution of the invention is
combined with additional water to provide a medicament for drinking
by a patient. A solution of the invention is, for example, diluted
with approximately four times its volume of water to generate an
approximately five-fold diluted solution (for the case when N=5).
For example, a 25 ml unit of the solution may be diluted with from
75 to 125 ml of water to give a solution of from 100 ml to 150 ml.
Particularly in the domestic setting, very accurate dilution is not
generally possible or convenient. In patient instructions, the
dilution step might be referred to as diluting a 25 ml unit of
solution (which might be referred to as "5 teaspoons") with water
to make a 125 ml solution (which might be referred to as
"approximately half a glass of solution"). For example, a 25 ml
unit of solution is diluted in 100 ml of water to give 125 ml of
final solution for drinking.
[0253] A typical dose is 125 ml of diluted solution, and such a
dose preferably contains the active ingredients in the amounts
shown in the Table below (in addition to any preservative,
flavouring and sweetener). As the absence of the Acesulfame K
sweetener in a MOVICOL PLAIN solution makes it necessary to
increase the amount of potassium chloride, a separate set of
amounts is shown for a "plain" solution. In an alternative setting
(for example for paediatric use or in patients with mild
constipation), a typical dose is 62.5 ml of diluted solution and
such a dose preferably contains the alternative amounts of active
ingredients shown in the Table below:
TABLE-US-00001 Amount/g per 125 ml Amount/g per 62.5 ml With With
sweetener/ sweetener/ Component flavouring "plain" flavouring
"plain" PEG 3350 13.1250 13.1250 6.563 6.563 Sodium Chloride 0.3507
0.3508 0.1754 0.1754 Potassium Chloride 0.0466 0.0502 0.0233 0.0251
Sodium Bicarbonate 0.1785 0.1786 0.0893 0.0893
[0254] For the preparation of a 125 ml dose, an appropriate volume
of the concentrate solution of the invention is diluted with water
to make 125 ml.
[0255] Accordingly, the invention further provides a unit treatment
of a solution of the invention, the unit treatment having the
volume necessary to provide 11 to 15 g of PEG when diluted with
water to 125m1. An alternative unit treatment of a solution of the
invention has the volume necessary to provide 5.5 to 7.5 g of PEG
when diluted to 62.5 ml. For example, a unit treatment has the
volume necessary to provide the components in the amounts shown in
the table immediately above.
[0256] For example, a unit treatment may be from 10 to 50 ml of the
concentrate solution of the invention. For example, if a solution
of the invention comprises 525 g of PEG 3350 per litre, then 25 ml
are required to provide the amount of PEG shown in the table above.
A unit treatment is thus preferably from 20 to 40 ml, for example
25 to 30 ml, especially 25 ml. Accordingly, the invention further
provides a unit treatment of from 10 to 50 ml of the solution of
the invention. Preferably, a unit treatment is from 20 to 40 ml,
for example 25 to 30 ml, especially 25 ml. For use in an
alternative setting (for example for paediatric use or in patients
with mild constipation) mentioned above, all of the quantities in a
unit treatment are halved.
[0257] The invention provides a unit treatment comprising 7.8 to
62.5 ml of water comprising the following components at the
following concentrations: [0258] (a) N.times.(70 to 130) g/L PEG
having an average molecular weight of 2500 to 4500; [0259] (b)
N.times.(1.6 to 4.0) g/L sodium chloride; [0260] (c) N.times.(0.2
to 0.6) g/L potassium chloride; [0261] (d) N.times.(0.6 to 2.2) g/L
sodium bicarbonate; [0262] (e) N.times.an amount of preservative;
[0263] (f) optionally N.times.an amount of flavouring; and [0264]
(g) optionally N.times.an amount of sweetener
[0265] where N is in the range of 2 to 8.
[0266] For example, a unit treatment may comprise 10 to 50 ml of a
solution in water comprising the following components at the
following concentrations: [0267] (a) 350 to 600 g/L PEG having an
average molecular weight of 2500 to 4500; [0268] (b) 8.0 to 20 g/L
sodium chloride; [0269] (c) 1.0 to 3.0 g/L potassium chloride;
[0270] (d) 3.0 to 11 g/L sodium bicarbonate; [0271] (e)
preservative; [0272] (f) optional flavouring; and [0273] (g)
optional sweetener.
[0274] In preferred aspects, the solution in a unit treatment has
the features mentioned above in relation to the solutions of the
invention.
[0275] A unit treatment may comprise 7.8 to 62.5 ml, for example 10
to 50 ml of a solution in water comprising the following components
in the following weights: [0276] (a) 3.50 to 30 g PEG having an
average molecular weight of 2500 to 4500; [0277] (b) 0.08 to 1.0 g
sodium chloride; [0278] (c) 0.01 to 0.15 g potassium chloride;
[0279] (d) 0.03 to 0.55 g sodium bicarbonate; [0280] (e)
preservative; [0281] (f) optional flavouring; and [0282] (g)
optional sweetener.
[0283] A preferred unit treatment comprises 10 to 50 ml of a
solution in water comprising the following components in the
following weights: [0284] (a) 11 to 15 g PEG having an average
molecular weight of 2500 to 4500; [0285] (b) 0.3 to 0.4 g sodium
chloride; [0286] (c) 0.035 to 0.055 g potassium chloride; [0287]
(d) 0.15 to 0.25 g sodium bicarbonate; [0288] (e) preservative;
[0289] (f) optional flavouring; and [0290] (g) optional
sweetener.
[0291] A preferred unit treatment comprises 20 to 50 ml of a
solution in water comprising the following components in the
following weights: [0292] (a) 13.125 g PEG having an average
molecular weight of 3350; [0293] (b) 0.3507 g sodium chloride;
[0294] (c) 0.0466 g potassium chloride; [0295] (d) 0.1785 g sodium
bicarbonate; [0296] (e) preservative; [0297] (f) optional
flavouring; and [0298] (g) optional sweetener.
[0299] Such a unit treatment is, for example, for dilution with
water in a volume dependent on the concentration of the
ingredients. A 20 ml unit treatment would typically be combined
with 105 ml of water; a 25 ml unit treatment would typically be
combined with 100 ml of water; a 30 ml unit treatment would
typically be combined with 95 ml of water; a 40 ml unit treatment
would typically be combined with 85 ml of water and a 50 ml unit
treatment would typically be combined with 75 ml of water.
[0300] For use in an alternative setting (for example for
paediatric use or in patients with mild constipation) mentioned
above, all of the quantities in a unit treatment are halved. Thus,
an alternative preferred unit treatment comprises 10 to 25 ml of a
solution in water comprising the following components in the
following weights: [0301] (a) 6.563 g PEG having an average
molecular weight of 3350; [0302] (b) 0.01754 g sodium chloride;
[0303] (c) 0.0233 g potassium chloride; [0304] (d) 0.0893 g sodium
bicarbonate; [0305] (e) preservative; [0306] (f) optional
flavouring; and [0307] (g) optional sweetener.
[0308] Such a unit treatment is, for example, for dilution with
water in a volume dependent on the concentration of the
ingredients. A 10 ml unit treatment would typically be combined
with 52.5 ml of water; a 15 ml unit treatment would typically be
combined with 47.5 ml of water; a 20 ml unit treatment would
typically be combined with 42.5 ml of water; a 25 ml unit treatment
would typically be combined with 37.5 ml of water.
[0309] As mentioned above, the invention provides a container
containing a solution of the invention. Such a container may, for
example, contain: [0310] (a) N.times.(10 to 16) g PEG having an
average molecular weight of 2500 to 4500; [0311] (b) N.times.(0.26
to 0.44) g sodium chloride; [0312] (c) N.times.(0.035 to 0.056) g
potassium chloride; [0313] (d) N.times.(0.14 to 0.22) g sodium
bicarbonate; [0314] (e) N.times.an amount of preservative; [0315]
(f) optionally N.times.an amount of flavouring; and [0316] (g)
optionally N.times.an amount of sweetener [0317] (h) water to a
volume V [0318] wherein is N is 1 to 80, V is 20 ml to 1000 ml, and
V(in ml) is such that V/N.ltoreq.67.5.
[0319] For example, a container may contain: [0320] (a)
x.times.262.50 g polyethylene glycol (PEG) 3350; [0321] (b)
x.times.7.014 g sodium chloride; [0322] (c) x.times.0.932 g
potassium chloride; [0323] (d) x.times.3.570 g sodium bicarbonate;
[0324] (e) x.times.an amount of preservative; [0325] (f) optionally
x.times.an amount of flavouring; [0326] (g) optionally x.times.an
amount of sweetener; and [0327] (h) water to x.times.500 ml; [0328]
Where x is 0.5 to 2, for example x is 0.5 or 1.
[0329] Such a container may, for example, contain: [0330] (a)
262,50 g PEG 3350; [0331] (b) 7.014 g sodium chloride; [0332] (c)
0.932 g potassium chloride; [0333] (d) 3.570 g sodium bicarbonate;
[0334] (e) preservative; [0335] (f) optional flavouring; [0336] (g)
optional sweetener; and [0337] (h) water to 500 ml
[0338] An alternative container may contain: [0339] (a) 131.25 g
PEG 3350; [0340] (b) 3.507 g sodium chloride; [0341] (c) 0.466 g
potassium chloride; [0342] (d) 1.785 g sodium bicarbonate; [0343]
(e) preservative; [0344] (f) optional flavouring; [0345] (g)
optional sweetener; and [0346] (h) water to 250 ml
[0347] An alternative container may contain: [0348] (a) 78.75 g PEG
3350; [0349] (b) 2.1042 g sodium chloride; [0350] (c) 0.2796 g
potassium chloride; [0351] (d) 1.071 g sodium bicarbonate; [0352]
(e) preservative; [0353] (f) optional flavouring; [0354] (g)
optional sweetener; and [0355] (h) water to 150 ml
[0356] An alternative container may contain: [0357] (a) 52.5 g PEG
3350; [0358] (b) 1.4028 g sodium chloride; [0359] (c) 0.1864 g
potassium chloride; [0360] (d) 0.714 g sodium bicarbonate; [0361]
(e) preservative; [0362] (f) optional flavouring; [0363] (g)
optional sweetener; and [0364] (h) water to 100 ml
[0365] In such containers, preferred amounts and identities of
preservative, flavouring and sweetener are as described above in
relation to solutions of the invention, adjusted where necessary
for the amount of water in the containers.
[0366] The solutions of the present invention, optionally presented
in a container comprising multiple treatment units, are preferably
provided with instructions for use. The instructions may instruct
the user to dilute a stated volume of the solution of the invention
with a stated volume of water. For example, the instructions may
instruct the user to dilute the solution to a volume of 125 ml for
use. If the solution of the invention comprises 525 g of PEG 3350
per litre, then 25 ml are required to provide the amount of PEG
shown in the table above, and the instructions may instruct the
user to dilute 25 ml of the solution with 100 ml of water. 25 ml
equates to 5 conventional teaspoons. 100 ml equates to a
conventional "half glassful of water". For the level of accuracy
typically required for this form of medication, approximate units
of volume such as "teaspoons" and "glasses" are generally adequate,
and patient information may be appropriately phrased. For use in an
alternative setting (for example for paediatric use or in patients
with mild constipation) mentioned above, the instructions may
instruct the user to dilute 12.5 ml of the solution with 50 ml of
water. 12.5 ml equates to 2.5 conventional teaspoons. 50 ml equates
to a conventional "quarter glassful of water".
[0367] The invention further provides a kit comprising a container
containing a solution of the invention together with instructions
as set out above, for example instructing the user to dilute a
stated volume of the solution of the invention with a particular
volume of water. The invention further provides a kit comprising a
container containing a solution of the invention together with a
measuring accessory for measuring out a defined volume of the
solution. Examples of measuring accessories include measuring cups,
measuring spoons, measuring tubes, and syringes. If the solution of
the invention comprises 525 g of PEG 3350 per litre, then 25 ml are
required to provide the amount of PEG shown in the table above.
Thus, the measuring accessory preferably enables the measurement of
a 25 ml unit treatment out of the bottle.
[0368] The measuring accessory may be adapted to attach to the
container, for example it may be in the form of a cap that fits
over and grips onto the closure of the container in storage and can
be held separately from the container for measuring out a required
volume of solution. The measuring accessory may have a measurement
volume such that several measurement accessories-ful provide the
required unit treatment volume. For example, for the provision of a
25 ml unit treatment volume, a measuring accessory might provide
for measuring a volume of 25 ml, 12.5 ml (two needed), 8.333 ml
(three needed), 6.25 ml (4 needed) or 5 ml (5 needed). A suitable
measuring accessory may have the required volume as its total
capacity, or it may be provided with one or more gradation lines to
indicate the required volume. In one embodiment, the measuring
accessory is a cap that provides for the measurement of a 25 ml
unit volume. For use in an alternative setting (for example for
paediatric use or in patients with mild constipation) mentioned
above, the volumes mentioned here are all halved. For distribution
and sale, a container may be provided in an outer packaging, such
as a carton. Instructions may be provided on a medium, for example
paper, inside the outer packaging. Instructions may be printed onto
the outer packaging, or onto the container itself. A carton may
contain the container, a measuring accessory and instructions.
[0369] The invention provides a method of preparing a solution for
the treatment of constipation or faecal impaction, which method
comprises combining a volume (for example a treatment unit volume)
of a solution of the invention with water. The invention provides a
method of preparing a laxative solution comprising combining a
volume (for example a treatment unit volume) of a solution of the
invention with water. The invention further provides a laxative
solution or a faecal impaction treatment solution that has been
prepared by combining a solution of the invention with water.
[0370] After a solution of the invention has been diluted by
combining with water, the resultant laxative solution is suitable
for use in the treatment of constipation or faecal impaction.
Accordingly, the present invention also provides a method of
treating constipation or faecal impaction comprising administering
orally to a subject a laxative solution prepared by combining a
solution of the invention with water. The invention also provides a
solution prepared by combining a solution of the invention with
water for use as a medicament; for example the medicament can be
for use in the treatment of constipation or faecal impaction. A
solution for use in a method of the invention has the preferred
features described above in respect of the solutions of the
invention.
[0371] In a preferred regime a patient is instructed to take 25 ml
of a solution of the invention diluted in 100 ml water 1-3 times
daily in divided doses, according to the individual response or the
severity of the constipation. For the treatment of faecal
impaction, a patient is instructed to take 25 ml of a solution of
the invention diluted in 100 ml water 1-8 times daily, according to
the individual response or the severity of the faecal
impaction.
[0372] The invention further provides a solution in water, of the
following components at the following concentrations: [0373] (a) 70
to 130 g/L PEG having an average molecular weight of 2500 to 4500;
[0374] (b) 1.6 to 4.0 g/L sodium chloride; [0375] (c) 0.2 to 0.6
g/L potassium chloride; [0376] (d) 0.6 to 2.2 g/L sodium
bicarbonate; [0377] (e) optional preservative; [0378] (f) optional
flavouring; and [0379] (g1) sucralose [0380] (g2) optional
additional sweetener .
[0381] The solution has been found to have a particularly
acceptable taste. Sucralose may, for example, be present in an
amount of 0.012 to 0.04 g per litre, preferably within in a range
in which the lower limit is 0.012, 0.016 or 0.020 g per litre and
the upper limit is, independently, 0.004, 0.036, 0.032 or 0.028 g
per litre. For example, such a solution may comprise 0.024 g
sucralose per litre. The solution may comprise optional
preservative (e), optional flavouring (f) and optional additional
sweetener (g2) of the types described elsewhere herein. The
concentrations of the components (a) to (g2) in such a solution are
preferably the amounts arrived at after dilution of a concentrate
solution of the invention described above, for example the
concentration of a component may be one fifth of the concentration
described above for that component in relation to a concentrate
solution of the invention. The solution is suitable for use as a
medicament, for example for the treatment of constipation, or
faecal impaction, and a method of treatment of such conditions is
also provided. The stated components may be provided in a form for
combination with water to provide such a solution. For example, the
components may be provided as a concentrated solution in water, or
as a dry powder. A dry powder may be provided in a sachet, for
example containing a unit dose. For example a sachet may contain
13.1250 g Macrogol (Polyethylene glycol) 3350, 0.3507 g sodium
chloride, 0.1785 g sodium bicarbonate, 0.0466 or 0.0502 g potassium
chloride and sucralose.
[0382] The invention further provides a solution in water, of the
following components at the following concentrations: [0383] (a) 70
to 130 g/L PEG having an average molecular weight of 2500 to 4500;
[0384] (b) 1.6 to 4.0 g/L sodium chloride; [0385] (c) 0.2 to 0.6
g/L potassium chloride; [0386] (d) 0.6 to 2.2 g/L sodium
bicarbonate; [0387] (e) optional preservative; [0388] (f)
flavouring selected from orange juice and tropical fruit; and
[0389] (g) optional sweetener.
[0390] The solution has been found to have a particularly
acceptable taste. The flavouring selected from orange juice and
tropical fruit flavouring may be present at a level of from 0.2 to
2.0 g per litre, for example from 0.2 to 1 g per litre, especially
from 0.4 to 0.8 g per litre, for example 0.64 g per litre. The
solution may comprise optional preservative (e) and optional
sweetener (g) of the types described elsewhere herein. The
concentrations of the components (a) to (g) in such a solution are
preferably the amounts arrived at after dilution of a concentrate
solution of the invention described above, for example the
concentration of a component may be one fifth of the concentration
described above for that component in relation to a concentrate
solution of the invention. The solution is suitable for use as a
medicament, for example for the treatment of constipation, or
faecal impaction, and a method of treatment of such conditions is
also provided. The stated components may be provided in a form for
combination with water to provide such a solution. For example, the
components may be provided as a concentrated solution in water, or
as a dry powder. A dry powder may be provided in a sachet, for
example containing a unit dose. For example a sachet may contain
13.1250 g Macrogol (Polyethylene glycol) 3350, 0.3507 g sodium
chloride, 0.1785 g sodium bicarbonate, 0.0466 or 0.0502 g potassium
chloride and flavouring selected from orange juice and tropical
fruit.
EXAMPLES
[0391] The following non-limiting Examples illustrate the
invention. All of the solutions in the Examples comprise the
components of Table 1.
TABLE-US-00002 TABLE 1 Common components of the solutions of the
Examples Component Quantity/g PEG 3350 13.1250 Sodium Chloride
0.3507 Potassium Chloride 0.0466* Sodium Bicarbonate 0.1785
Acesulfame K 0.0100** Optional Preservative As indicated Optional
Flavour As indicated Optional Additional As indicated Sweetener
Water As indicated *different amount was used in Solution 1B;
**absent from Solution 1B
Examples 1, 2 and 3
Microbiological Testing of Solutions
[0392] In each of Examples 1, 2 and 3 that follow, the
microbiological testing was carried out as follows:
[0393] The microbiological condition of the samples was determined
following the European Pharmacopoeia (EP) 5.6 Section 2.6 12
"Microbiological Examination of Non-Sterile Products (Total Viable
Aerobic Count)". In each case in Examples 1, 2 and 3, no microbial
contaminants could be detected in the samples and they were
concluded to be in good visible and microbiological condition
containing less than 10 colony forming units per g (CFU/g). In
some, but not all instances, the pH of the sample was measured. pH
measurements can be carried out with a Hanna Instruments "pH ep"
temperature compensating pH meter. In some instances, the pH of a
sample was adjusted before the testing was commenced (as
indicated).
[0394] Microbial Challenge Test Protocol:
[0395] Five 20 g portions of each sample were transferred to
sterile glass bottles and inoculated separately with 0.2 ml culture
of the test species as detailed below. The test species used
include the following shown in Table 2, which are referred to in
the Table with the abbreviations used hereinafter.
TABLE-US-00003 TABLE 2 Species Abbreviation Pseudomonas aeruginosa
P Escherichia coli E Staphylococcus aureus S Candida albicans C
Aspergilus niger A
[0396] The inoculated sample portions were mixed using sterile
implements and stored at room temperature. The challenge test
protocol of the EP 1999 was then followed. In the results tables
below, the initial innoculum level (in CFU/g) is given in the first
column, and the numbers of CFU/g present after 14 and 28 days are
given on the subsequent columns. For Candida albicans and
Aspergilus niger, a "Factor" is given in the Tables. That factor is
the multiple by which the numbers of CFU/g had been reduced from
the initial innoculum level by 14 days. The EP Pass Criteria are as
shown in Table 3 as set out in table 5.1.3-0.3 Oral preparations in
the European Pharmacopoeia (EP) 6.0, Section 5.1.3 "Efficacy of
antimicrobial preservation".
TABLE-US-00004 TABLE 3 Log Drop from Baseline Value Test Species 14
days 28 days Bacteria 3 NI Yeasts/moulds 1 NI NI = no increase
Comparative Example 1
Microbiological Testing of Solutions Lacking Preservative
[0397] Solutions 1A and 1B were prepared, containing the components
in the amounts shown in Table 1 above (except that, for solution
1B, there was no Acesulfame K, and the quantity of potassium
chloride was 0.0502 g) together with the components in Table 4 per
32.5 ml. (1 litre of solution was prepared in each case, containing
a total weight of 424.95 g of solid in the case of 1A and 421.68 g
of solid in the case of 1B).
TABLE-US-00005 TABLE 4 Additional Solution 1A Solution 1B Component
(g/32.5 mL) (g/32.5 mL) Lemon-Lime Flavour 0.1000 -- Water to 32.5
ml to 32.5 ml Measured pH 8.8 8.8
[0398] The Lemon-Lime Flavour is the flavouring in the MOVICOL
powder marketed in the UK by Norgine Limited (Chaplin House,
Widewater Place, Moorhall Road, Harefield, Uxbridge, Middlesex UB9
6NS, United Kingdom). Solutions 1A and 1B are most readily prepared
by dissolution of the commercially available MOVICOL Lemon-Lime
flavour powder, and MOVICOL PLAIN (ie unflavoured) powder,
respectively. Such solutions may be prepared by dissolving 20
commercially available sachets in water to 650 ml.
TABLE-US-00006 Test Results Table 5: Test Species and Initial
Solution 1A Solution 1B Inoculum Level CFU per g after: CFU per g
after: (CFU/g) 14 days 28 days 14 days 28 days P: NCTC 12924 <10
<10 <10 <10 3.3 .times. 10.sup.7 E: NCTC 12923 <10
<10 <10 <10 1.1 .times. 10.sup.6 S: NCTC 10788 <10
<10 <10 <10 1.6 .times. 10.sup.6 C: NCPF 3179 6.1 .times.
10.sup.4 7.3 .times. 10.sup.3 3.8 .times. 10.sup.5 2.9 .times.
10.sup.5 1.0 .times. 10.sup.6 A: NCPF 2275 1.4 .times. 10.sup.5 4.0
.times. 10.sup.4 9.0 .times. 10.sup.3 8.0 .times. 10.sup.4 1.3
.times. 10.sup.4 C. Albicans Factor 14 d 16 2.6 A. Niger Factor 14
d 3.5 1.75
[0399] The 1B solution did not achieve the required log reduction
for yeast. The 1A solution did not achieve the required log
reduction for either yeast or mould. Accordingly, the solutions
without any preservative were found not to be suitable for use as
concentrates for the preparation of oral medicaments.
Example 2
Microbiological Testing of Solutions Including Preservative
[0400] Solutions 2A to 2Q were prepared. Each solution contained
the components shown in Table 1, together with the individual
components shown in Tables 6a and 6b.
[0401] Sodium propyl paraben (sodium propyl 4-hydroxbenzoate) is
available under the tradename Iscaguard PS. A blend of methyl
paraben (18%), ethyl paraben (9%) and benzyl alcohol (73%) is
available under the tradename Iscaguard MEB. Phenoxyethanol is
available under the tradename Iscaguard PE. Methyl paraben is
available under the tradename Iscaguard M. Ethyl paraben is
available under the tradename Iscaguard E. Propyl paraben is
available under the tradename Iscaguard P. A blend of methyl
paraben (18%), ethyl paraben (9%) and phenoxyethanol (73%) is
available under the tradename Iscaguard MEP. All of those Iscaguard
products are available from ISCA UK Ltd (Nine
[0402] Mile Point Industrial Estate, Crosskeys, Newport, NP 11 7HZ,
UK). A blend of methyl paraben (15%), ethyl paraben (10%) and
phenoxyethanol (75%) is available from S. Black Ltd (Foxholes
Business Park, John Tate Road, Hertford, Herts, SG13 7YH, United
Kingdom) under the tradename Paratexin BSB.
[0403] In Tables 6a and 6b, the flavour "TF" is Tropical Fruit and
the flavour "OJ" is Orange Juice. They are available from Firmenich
UK Ltd. (Hayes Road, Southall, Middlesex UB2 5NN). A summary of the
preservative efficacy test results (C. Albicans and A. Niger only)
is shown in Tables 6a and 6b. Details are shown in tables 7 to
11b.
TABLE-US-00007 TABLE 6a Component 2A 2B 2C 2D 2E 2F 2G 2H Flavour
None None 0.0375 gTF 0.0375 gTF 0.0375 gTF 0.0375 gTF 0.0375 gTF
0.0375 gTF Sucralose None None 0.0150 g 0.0150 g 0.0150 g 0.0150 g
0.0150 g 0.0150 g Sodium propyl para- 0.05% 0.1% ben (sodium propyl
[0.01625 g] [0.0325 g] 4-hydroxybenzoate) Blend of methyl para-
0.3% 0.5% 0.7% ben (18%), ethyl [0.075 g] [0.125 g] [0.175 g]
paraben (9%) and benzyl alcohol (73%) Phenoxyethanol 0.7% [0.175 g]
Methyl paraben 0.15% (as sodium salt) [0.0375 g] Ethyl paraben
0.10% (as sodium salt) [0.025 g] Blend of methyl para- 0.5% ben
(18%), ethyl [0.125 g] paraben (9%) and phenoxyethanol (73%) Water
to 32.5 ml to 32.5 ml to 25 ml to 25 ml to 25 ml to 25 ml to 25 ml
to 25 ml pH 8.8* 8.8* 8.8 8.8 8.7 7.0** 7.0** 8.7 C. Albicans 10 39
1800 1500 2200 33000 26000 >10.sup.5 Factor 14 d A. Niger 1.4
2.0 330 100 440 2.0 9.2 91 Factor 14 d EP Protocol Pass -- -- Pass
Pass Pass -- -- Pass Table No 7 7 8 8 8 9 9 10 *= adjusted to 8.8
with HCl. **= adjusted to 7.0 with citric acid Solutions 2A and 2B
were prepared in 11 batches, solutions 2C, 2D, 2E and2H were
prepared in batches of 500 ml, and solutions 2F and 2G were
prepared in batches of 200 ml.
TABLE-US-00008 TABLE 6b Com- ponent 2I 2J 2K 2L 2M 2N 2P 2Q Flavour
0.0375 gTF 0.0375 gTF 0.0800 gOJ 0.0800 gOJ 0.0800 gOJ 0.0800 gOJ
0.0800 gOJ 0.0800 gOJ Sucralose 0.0150 g 0.0150 g 0.003 g 0.003 g
0.003 g 0.003 g 0.003 g 0.003 g Methyl 0.18% 0.225% 0.0675% 0.0675%
paraben [0.045 g] [0.05625 g] [0.0169 g] [0.0169 g] Propyl 0.02%
0.025% paraben [0.005 g] [0.00625 g] Ethyl 0.0338% 0.0338% paraben
[0.0084 g] [0.0084 g] Benzyl 0.1825% 0.2163% alcohol [0.0456 g]
[0.05406 g] Propylene 3.75 g 3.75 g glycol Blend of 0.5% 0.8%
methyl [0.125 g] [0.200 g] paraben (15%), ethyl para- ben (10%) and
phe- noxyeth- anol (75%) Water to 25 ml to 25 ml to 25 ml to 25 ml
to 25 ml to 25 ml to 25 ml to 25 ml 8.3 8.5 C. Albi- >10.sup.5
>10.sup.5 >10.sup.5 >10.sup.5 >10.sup.5 >10.sup.5
>10.sup.5 >10.sup.5 cans Fac- tor 14 d A. Niger 14 25
>10.sup.5 >10.sup.5 3.0 3.8 2.6 5.3 Factor Regrowth 14 d at
28 days EP Pro- -- Pass Pass -- -- -- -- -- tocol Pass Table No 10
10 11a 11a 11a 11b 11b 11b Solutions 2I and 2J were prepared in
batches of 500 ml. Solutions 2K, 2L, 2M, 2N, 2P and 2Q were
prepared in batches of 250 ml.
TABLE-US-00009 Test Run II - Test Results Table 7: Test Species and
Initial Solution 2A Solution 2B Inoculum CFU per g after: CFU per g
after: Level (CFU/g) 14 days 28 days 14 days 28 days P: NCTC 12924
<10 <10 <10 <10 4.7 .times. 10.sup.6 E: NCTC 12923
<10 <10 <10 <10 2.7 .times. 10.sup.6 S: NCTC 10788
<10 <10 <10 <10 3.3 .times. 10.sup.6 C: NCPF 3179 1.4
.times. 10.sup.5 1.3 .times. 10.sup.5 3.6 .times. 10.sup.4 3.5
.times. 10.sup.4 1.4 .times. 10.sup.6 A: NCPF 2275 2.8 .times.
10.sup.5 3.0 .times. 10.sup.5 2.0 .times. 10.sup.5 2.0 .times.
10.sup.5 4.0 .times. 10.sup.5
TABLE-US-00010 Test Run III--Test Results Table 8: Test Species and
Solution 2C CFU Solution 2D CFU Solution 2E CFU Initial Inoculum
per g after: per g after: per g after: Level (CFU/g) 14 days 28
days 14 days 28 days 14 days 28 days P: NCTC 12924 <10 <10
<10 <10 <10 <10 3.8 .times. 10.sup.6 E: NCTC 12923
<10 <10 <10 <10 <10 <10 6.0 .times. 10.sup.6 S:
NCTC 10788 50 <10 1.1 .times. 10.sup.2 <10 <10 <10 4.2
.times. 10.sup.6 C: NCPF 3179 1.9 .times. 10.sup.2 <10 2.4
.times. 10.sup.2 <10 1.6 .times. 10.sup.2 <10 3.5 .times.
10.sup.5 A: NCPF 2275 1.2 .times. 10.sup.3 10 4.0 .times. 10.sup.3
30 9.0 .times. 10.sup.2 <10 4.0 .times. 10.sup.5
TABLE-US-00011 Test Run IV - Test Results Table 9: Test Species and
Initial Solution 2F Solution 2G Inoculum CFU per g after: CFU per g
after: Level (CFU/g) 14 days 28 days 14 days 28 days P: ATCC 9027
<10 <10 <10 <10 1.9 .times. 10.sup.6 S: ATCC 6538 2.5
.times. 10.sup.3 <10 6.8 .times. 10.sup.5 5.0 .times. 10.sup.2
1.5 .times. 10.sup.6 C: NCTC NCPF 3179 40 <10 50 <10 1.3
.times. 10.sup.6 A: ATCC 16404 1.8 .times. 10.sup.5 4.1 .times.
10.sup.4 3.8 .times. 10.sup.4 3.2 .times. 10.sup.2 3.5 .times.
10.sup.5
TABLE-US-00012 Test Run V--Test Results Table 10: Test Species and
Solution 2H CFU Solution 2I CFU Solution 2J CFU Initial Inoculum
per g after: per g after: per g after: Level (CFU/g) 14 days 28
days 14 days 28 days 14 days 28 days P: NCTC 12924 <10 <10
<10 <10 <10 <10 7.3 .times. 10.sup.7 E: NCTC 12923
<10 <10 <10 <10 <10 <10 4.3 .times. 10.sup.6 S:
NCTC 10788 <10 <10 1.3 .times. 10.sup.4 <10 3.9 .times.
10.sup.2 <10 4.3 .times. 10.sup.6 C: NCPF 3179 <10 <10 20
<10 <10 <10 6.6 .times. 10.sup.6 A: NCPF 2275 1.1 .times.
10.sup.3 <10 7.0 .times. 10.sup.3 4.1 .times. 10.sup.3 4.0
.times. 10.sup.3 2.2 .times. 10.sup.2 1.0 .times. 10.sup.5
TABLE-US-00013 Test Run VI--Test Results Tables 11a and 11b: Test
Species and Solution 2K CFU Solution 2L CFU Solution 2M CFU Initial
Inoculum per g after: per g after: per g after: Level (CFU/g) 14
days 28 days 14 days 28 days 14 days 28 days P: NCTC 12924 <10
<10 <10 <10 <10 <10 3.2 .times. 10.sup.6 E: NCTC
12923 <10 <10 <10 <10 <10 <10 4.0 .times.
10.sup.6 S: NCTC 10788 <10 <10 <10 <10 <10 <10
1.4 .times. 10.sup.6 C: NCPF 3179 <10 <10 <10 <10
<10 <10 3.2 .times. 10.sup.6 A: NCPF 2275 <10 <10
<10 40 3.3 .times. 10.sup.5 2.1 .times. 10.sup.4 1.0 .times.
10.sup.6 Test Species and Solution 2N CFU Solution 2P CFU Solution
2Q CFU Initial Inoculum per g after: per g after: per g after:
Level (CFU/g) 14 days 28 days 14 days 28 days 14 days 28 days P:
NCTC 12924 <10 <10 <10 <10 <10 <10 3.2 .times.
10.sup.6 E: NCTC 12923 <10 <10 <10 <10 <10 <10
4.0 .times. 10.sup.6 S: NCTC 10788 <10 <10 <10 <10
<10 <10 1.4 .times. 10.sup.6 C: NCPF 3179 <10 <10 20
<10 <10 <10 3.2 .times. 10.sup.6 A: NCPF 2275 2.6 .times.
10.sup.5 2.2 .times. 10.sup.4 3.8 .times. 10.sup.5 4.0 .times.
10.sup.4 1.9 .times. 10.sup.5 20 1.0 .times. 10.sup.6
[0404] It is seen from the results in tables 7 to 11 (summarized in
Table 6), that the majority of the preservatives achieved a
reduction in the number of viable micro-organisms in the assays. It
is seen that the combination of Blend of methyl paraben, ethyl
paraben and benzyl alcohol was especially effective against the
mould (A. niger).
[0405] The 2A, 2B, 2M, 2N, 2P and 2Q solutions did not achieve the
required log reduction for mould (A. niger) to pass the European
Pharmacopoeial criteria, though a reduction in the number of viable
micro-organisms was observed. The 2F solution did not achieve the
required log reduction for bacteria (S. aureus) or mould (A. niger)
at the 14 day time point. Likewise, the 2G solution did not achieve
the required log reduction for bacteria (S. aureus) or mould (A.
niger) at the 14 day time point. Solution 2I also failed to achieve
the required log reduction for the bacterium S. aureus. In solution
2L, re-growth of A. niger was observed.
[0406] Accordingly, although solutions 2A, 2B, 2F, 2G, 21, 2L, 2M,
2N, 2P and 2Q showed a reduction in the number of viable
micro-organisms for each organism, they were found not to be
sufficiently preserved for oral pharmaceutical use with the tested
level of preservative.
[0407] The 2C, 2D, 2E, 2H, 2J, and 2K solutions achieved the
required log reduction for bacteria, yeast and mould. Accordingly,
the solutions were found to be suitable for oral pharmaceutical
use.
Example 3
Microbiological Testing of Solutions Including Methyl Paraben,
Ethyl Paraben and Benzyl Alcohol Preservative Blend
[0408] Solutions 3A to 3D were prepared. Each solution contained
the components shown in Table 1, together with the individual
components shown in Table 12.
TABLE-US-00014 TABLE 12 Component 3A 3B 3C 3D Flavour 0.0800 g OJ
0.0800 g OJ 0.0800 g OJ 0.0800 g OJ Sucralose 0.0030 g 0.0030 g
0.0030 g 0.0030 g Blend of 0.1% 0.15% 0.2% 0.25% methyl paraben
[0.025 g] [0.0375 g] [0.050 g] [0.0625 g] (18%), ethyl paraben (9%)
and benzyl alcohol (73%) Water to 25 ml to 25 ml to 25 ml to 25 ml
C. Albicans 2000 4100 2200 2700 Factor 14 d A. Niger 8.5 5.7 8.5 11
Factor 14 d EP Protocol -- -- -- Pass Pass Table No 13a 13a 13b
13b
[0409] In Table 12, the flavour "OJ" is Orange Juice flavour,
available from Firmenich UK Ltd. (Hayes Road, Southall, Middlesex
UB2 5NN).
[0410] Solutions 3A to 3D were each prepared as 200 ml batches.
TABLE-US-00015 Test Run VII - Test Results Tables 13a and 13b: Test
Species and Solution 3A Solution 3B Initial Inoculum CFU per g
after: CFU per g after: Level (CFU/g) 14 days 28 days 14 days 28
days P: NCTC 12924 <10 <10 <10 <10 7.9 .times. 10.sup.6
E: NCTC 12923 <10 <10 <10 <10 9.2 .times. 10.sup.6 S:
NCTC 10788 1.4 .times. 10.sup.3 <10 1.6 .times. 10.sup.3 <10
1.1 .times. 10.sup.7 C: NCPF 3179 9.7 .times. 10.sup.2 <10 4.6
.times. 10.sup.2 <10 1.9 .times. 10.sup.6 A: NCPF 2275 4.0
.times. 10.sup.4 1.0 .times. 10.sup.4 6.0 .times. 10.sup.4 4.0
.times. 10.sup.4 3.4 .times. 10.sup.5 Test Species and Solution 3C
Solution 3D Initial Inoculum CFU per g after: CFU per g after:
Level (CFU/g) 14 days 28 days 14 days 28 days P: NCTC 12924 <10
<10 <10 <10 7.9 .times. 10.sup.6 E: NCTC 12923 <10
<10 <10 <10 9.2 .times. 10.sup.6 S: NCTC 10788 7.0 .times.
10.sup.2 <10 1.4 .times. 10.sup.3 10 1.1 .times. 10.sup.7 C:
NCPF 3179 8.5 .times. 10.sup.2 <10 7.0 .times. 10.sup.2 <10
1.9 .times. 10.sup.6 A: NCPF 2275 4.0 .times. 10.sup.4 1.1 .times.
10.sup.4 3.0 .times. 10.sup.4 4.0 .times. 10.sup.3 3.4 .times.
10.sup.5
[0411] Solutions 3E to 3G were prepared. Each solution contained
the components shown in Table 1, together with the individual
components shown in Table 14.
TABLE-US-00016 TABLE 14 3E (comparative Component Example) 3F 3G
Flavour 0.0800 g TF 0.0800 g TF 0.0800 g TF Sucralose 0.0030 g
0.0030 g 0.0030 g Blend of methyl paraben None 0.30% 0.35% (18%),
ethyl paraben (9%) [0.075 g] [0.0875 g] and benzyl alcohol (73%)
Water to 25 ml to 25 ml to 25 ml C. Albicans Factor 14 d 2500 1900
700 A. Niger Factor 14 d 7 25 29 EP Protocol Pass -- Pass Pass
Table No 15 15 15
[0412] In Table 14, the flavour "TF" is Tropical Fruit, available
from Firmenich UK Ltd. (Hayes Road, Southall, Middlesex UB2
5NN).
[0413] Solutions 3E to 3G were each prepared as 500 ml batches by
adding preservative to 500 ml of a stock solution of the other
components, the stock solution having been prepared in a volume of
21.
TABLE-US-00017 Test Run VIII--Test Results Table 15: Test Species
and Solution 3E CFU Solution 3F CFU Solution 3G CFU Initial
Inoculum per g after: per g after: per g after: Level (CFU/g) 14
days 28 days 14 days 28 days 14 days 28 days P: NCTC 12924 <10
<10 <10 <10 <10 <10 2.2 .times. 10.sup.6 E: NCTC
12923 <10 <10 <10 <10 <10 <10 2.0 .times.
10.sup.6 S: NCTC 10788 1.0 .times. 10.sup.2 <10 <10 <10
<10 <10 1.0 .times. 10.sup.6 C: NCPF 3179 1.1 .times.
10.sup.3 30 1.5 .times. 10.sup.3 30 4.0 .times. 10.sup.3 10 2.8
.times. 10.sup.6 A: NCPF 2275 5.0 .times. 10.sup.5 9.0 .times.
10.sup.4 1.4 .times. 10.sup.5 6.0 .times. 10.sup.4 1.2 .times.
10.sup.5 8.0 .times. 10.sup.4 3.5 .times. 10.sup.6
[0414] The 3A, 3B and 3C solutions did not achieve the required log
reduction for mould (A. niger) at the 0.1, 0.15 and 0.2% levels of
preservative. Solution 3D, with the 0.25% level of preservative,
achieved the required log reduction against all test species.
Accordingly, solution 3D was found to be suitable for
pharmaceutical use.
Example 4
Solutions of the Invention
[0415] Solutions 4A to 4B were prepared. The solutions contained
the components shown in Table 16.
TABLE-US-00018 TABLE 16 Composition of solutions Component 4A
Quantity/g 4B Quantity/g PEG 3350 262.500 262.500 Sodium Chloride
7.014 7.014 Potassium Chloride 0.932 0.932 Sodium Bicarbonate 3.570
3.570 Acesulfame K 0.200 0.200 Sucralose 0.060 0.060 Blend of
methyl paraben (18%), 1.250 1.750 ethyl paraben (9%) and benzyl
alcohol (73%) Orange Juice Flavour 1.600 None Tropical Fruit
Flavour None 1.600 Water To 500 ml To 500 ml
[0416] Solutions with the components of 4A and 4B shown in Table 16
achieved the required log reduction against all test species
(Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus,
Candida albicans, and Aspergilus niger) as required by the European
Pharmacopoeia as described above. Accordingly, solutions 4A and 4B
are found to be suitable for oral pharmaceutical use.
Example 5
Container Containing a Solution of the Invention
[0417] Bottle 5a: A 500 ml polyethylene terephthalate (PET) bottle
contains 500 ml of solution 4A described in Example 4 above. The
bottle is provided with a re-closable closure, and a cap that fits
over and grips onto the closure. The cap is suitable for measuring
a 25 ml unit treatment volume. The bottle is provided in a carton
with instructions for use. The instructions include the instruction
that 25 ml of the solution should be measured out and diluted with
100 ml water to make a 125 ml treatment dose.
[0418] In analogous bottles, Bottle 5b, contains 500 ml of solution
4B described in Example 4 above; Bottle 5c is a 250 ml polyethylene
terephthalate (PET) bottle containing 250 ml of solution 4A; and
Bottle 5d is a 250 ml polyethylene terephthalate (PET) bottle
containing 250 ml of solution 4B described in Example 4 above.
[0419] Bottles 5e, 5f, 5g and 5h are the same as bottles 5a, 5b, 5c
and 5d respectively, but with a cap that is suitable for measuring
a 12.5 ml unit treatment volume, and instructions that include
instruction that 12.5 ml of the solution should be measured out and
diluted with 50 ml water to make a 62.5 ml treatment dose.
* * * * *