WO2012120027A1

WO2012120027A1 - Enema compositions

Info

Publication number: WO2012120027A1
Application number: PCT/EP2012/053872
Authority: WO
Inventors: Peter Stein
Original assignee: Norgine Bv
Priority date: 2011-03-08
Filing date: 2012-03-07
Publication date: 2012-09-13
Also published as: GB201103942D0

Abstract

The invention provides an aqueous liquid enema composition having a measured osmolality within the range of 350 to 2000 mOsmol/kg comprising (or consisting essentially of) polyethylene glycol. Associated applicators and methods of cleansing are also provided.

Description

ENEMA COMPOSITIONS

The present invention concerns liquid enema compositions for use, in particular, in cleansing the colon of a mammalian subject. More particularly, the present invention concerns polyethylene glycol (PEG) based enema compositions for cleansing the colon of a mammalian subject for use, in particular, in the treatment of various diseases or disorders of the gastrointestinal tract and/or in enabling subsequent inspection of the distal colon in various diagnostic, surgical and medical procedures. Other aspects and objects of the invention are described below.

Colon cleansing (sometimes referred to as colon clearing) is an important procedure prior to a number of diagnostic or surgical procedures where inspection of the colon is required. Examples of such procedures include whole colonic imaging by barium enema, colonoscopy or computed tomography (CT) in order to inspect the colon for signs indicating the development of a disease or disorder such as colon and/or colorectal cancer. Since two-thirds of colorectal cancers and adenomas are located in the rectum and sigmoid colon, sigmoidoscopy, particularly flexible sigmoidoscopy, has more recently been proposed as an initial or primary screen for these types of cancers since it is less invasive and can be carried out by specialist nurses and general practitioners. However, these procedures still require that the portion of the colon to be inspected is cleared of faecal matter before the procedure is carried out. Enema products currently sold on the market include those sold under the names Fleet Enema, Fleet Enema Extra^® and Fleet Bisacodyl Enema (C.B Fleet, Lynchburg, VA, USA). Fleet Enema contains Monobasic Sodium Phosphate Monohydrate, (19 g) and Dibasic Sodium Phosphate Heptahydrate, (7 g) per 118 ml dose. Fleet Bisacodyl

Enema contains lOmg of Bisacodyl per 30ml dose. A further example is Normacol^® (Norgine BV).

Bae S et al (2004); J.Pediatric Gastroenterology and Nutrition; Vol.39 (June), s231- 232 discloses the use of a PEG enema with electrolytes in the treatment of chronic functional constipation in children. No further information is provided as to the composition of the enema in particular how much PEG was used in the composition, the nature and amount of electrolytes used or its osmolality. Helman L. et al (2007); Acta Cirurgica Brasileira; Vol. 22(5); p 372 - 378 discloses a PEG-electrolyte based enema in a rabbit based model of appendicostomy.

Approximately 47g of PEG 4000, together with other electrolytes, was made up in one litre of distilled water. Following this, 300ml of the resulting solution (that is approximately 14g of PEG) was administered to each animal.

Bleiberg H. et al (2006); Annals of Oncology 17: 1328-1332 disclose a procedure whereby human subjects underwent, as a primary screen for colorectal cancer (CRC), flexible sigmoidoscopy followed by colonoscopy in the case of a positive finding from the sigmoidoscopy screen. Bowel preparation for the sigmoidoscopy primary screen consisted of three Fleet enemas. In contrast, bowel preparation for the colonoscopy procedure consisted of a PEG enema and a Fleet enema. No further details are provided as to the composition of the PEG enema used. It is an object of the present invention to provide a liquid enema composition that has an effective cleansing action at the distal colon, does not induce clinically significant changes in serum electrolytes and is not associated with adverse changes to the mucosa of the bowel. In a first aspect there is provided an aqueous liquid enema composition having a measured osmolality within the range of 350 to 2000 mOsmol/kg comprising (or consisting essentially of) polyethylene glycol.

In a further aspect of the invention there is provided an aqueous liquid enema composition comprising (or consisting essentially of) PEG at a concentration of 150 to 700g/l.

In other embodiments of the invention, there is provided an aqueous liquid enema composition comprising (or consisting essentially of) PEG of volume Vi having a measured osmolality ("Osm 1") of greater than 350mOsm/Kg wherein the volume V₂ of water required to be combined with Vi in order to reduce the measured osmolality of the composition to 350mOsm/Kg or less (e.g. 300 to 350 mOsm/Kg) is such that V₂ = y x Vi wherein y is between 2 and 15 inclusively. The polyethylene glycol (PEG) used in compositions of the invention has an average molecular weight (e.g. weight average molecular weight) of 2500Da to 8000Da. The PEG may have an average molecular weight of 3000 to 6000Da, for example, 3000 to 4500. In preferred embodiments, the PEG has an average molecular weight of 3350 or 4000 as defined in national pharmacopoeias. In certain national pharmacopaeias, suitable PEGs are referred to as Macrogols, for example, Macrogol 3350 or Macrogol 4000. Optionally, the PEG used in compositions of the invention may comprise two or more different PEG compounds.

Compositions of the invention comprise, or consist essentially of, PEG at a concentration of 150 to 700g/l PEG. Preferably the PEG is within a range wherein the lower limit is 150, 160, 170, 180, 190, 200, 250, 300, 350, 400, 450, 500, 550, 580 or 600g/L and the upper limit is, independently, 250, 300, 350, 400, 450, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700g/L. Particularly preferred ranges of PEG are 200g/l to 250g/l (such as 230g/l or thereabout), 350 to 400g/l (such as 384g/l or thereabout), 400 to 520g/l (e.g. 450g/l to 500g/l such as 461g/l or thereabout of PEG).

Compositions of the invention may optionally further comprise other components such as electrolytes, ascorbic acid and/or salts thereof (such as sodium ascorbate) and/or preservatives.

Compositions of the present invention may comprise one or more electrolytes selected from sodium chloride, potassium chloride and/or sodium bicarbonate.

Compositions of the invention may comprise sodium chloride in an amount of 0.8 to 20g per litre (for example 0.8 to 1. lg per litre), preferably within a range wherein the lower limit is 0.8, 1.0, 1.1, 1.2 or 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0 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. Compositions of the invention may comprise potassium chloride in an amount of 0.1 to 3.0 g per litre, preferably within a range wherein the lower limit is 0.12, 0.14, 0.16, 0.17 or 0.18 g per litre and the upper limit is, independently, 0.5, 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 1.9g per litre. Compositions of the invention may comprise sodium bicarbonate (also known as sodium hydrogen carbonate) in an amount of 0.30 to 1 lg per litre, preferably within a range wherein the lower limit is 0.3, 0.40, 0.50, 0.60, 0.65, 0.70, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0g per litre and the upper limit is, independently, 1.0, 1.1, 1.2, 2.0, 3.0, 4.0, 5.0, 6.0, 7.5, 8.5, 9.0, lOg per litre. Compositions of the invention may comprise ascorbic acid and/or a salt thereof.

Ascorbic acid and/or a salt thereof maybe present in a quantity of 0.4g per litre or greater. For example, ascorbic acid and/or a salt thereof maybe present within a range in which the lower limit is 0.4g or 0.5g per litre and the upper limit is, independently, 15g or lOg per litre. In certain embodiments, compositions of the present invention are substantially free of electrolytes such as described supra, and/or ascorbic acid and/or salts thereof and/or preservatives. By "substantially free" we mean that if present, it is below the lowest limit indicated supra for the particular component. In one embodiment, compositions of the present invention are substantially free of electrolytes as described supra and ascorbic acid and salts thereof and preservatives.

Accordingly therefore, in one embodiment, an aqueous liquid enema composition of the present invention comprises or consists essentially of the following components:

PEG within a range wherein the lower limit is 150, 160, 170, 180, 190, 200, 250, 300, 350, 400, 450, 500, 550, 580 or 600g/L and the upper limit is, independently,

250, 300, 350, 400, 450, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700g/L. Particularly preferred ranges of PEG are 200g/l to 250g/l (such as 230g/l or thereabout), 350 to 400g/l (such as 384g/l or thereabout) and 400 to 520g/l (e.g. 450g/l to 500g/l such as 461g/l or thereabout of PEG) wherein the composition is substantially free of sodium chloride, potassium chloride, sodium bicarbonate and ascorbic acid and salts thereof.

In certain aspects of the present invention, there is provided an aqueous liquid enema composition comprising or consisting essentially of PEG wherein the composition has a measured osmolality within the range of 350 to 2000 mOsm/Kg. Osmolality according to the invention is measured by the freezing point depression method using an osmometer. In certain embodiments of this aspect of the invention, the measured osmolality is within a range in which the lower limit is 350, 360, 370, 380, 390, 400, 410, 420, 430, 440 or 450 mOsm/Kg and the upper limit is, independently, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1200, 1400, 1600, 1800, 2000 mOsm/Kg.

Since polyethylene glycol can be resistant to freezing, it maybe necessary, particularly for high osmolality compositions of the invention, to dilute the composition with water prior to measurement. Accordingly, the osmolality of compositions of the invention maybe measured in relation to the volume of water required to be combined with a composition of the invention to bring the measured osmolality within a certain range. Since faecal water is considered to have a measured osmolality of around 350mOsm/Kg, a range of 300 to

350mOsm/Kg serves as a useful range in which to use. The volume of water required to bring the measured osmolality within this range also provides an indication of the volume of water that maybe drawn into the distal colon from the surrounding vasculature by compositions of the invention during use.

Accordingly, in other embodiments of this aspect of the present invention, there is provided an aqueous liquid enema composition comprising PEG of volume Vi having a measured osmolality of greater than 350mOsm/Kg ("Osm 1") wherein the volume V₂ of water required to be combined with Vi in order to bring the measured osmolality of the composition to 350mOsm/Kg or less (e.g. 300 to 350 mOsm/Kg) is such that V₂ = y x Vi wherein y is within the range of 2 and 15 inclusively. Osm 1 maybe greater than 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900 or 2000 mOsm/Kg. Osm 1 maybe within a range in which the lower limit is 350, 400, 450, 500, 550, 600, 650 or 700 mOsm/Kg and the upper limit is, independently, 800, 850, 900, 950, 1000, 1 100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900 or 2000 mOsm/Kg. Volume Vi maybe any convenient volume with which to measure. For example volume Vi maybe a unit measurement of the composition of the invention as described infra. Volume Vi maybe 50ml, 100ml,

150ml, 200ml, 250ml, 300ml, 350ml, 400ml, 450ml, 500ml or greater. Suitably, volume Vi is 50ml to 150ml, e.g. 100ml. The volume V₂ required to be combined with Vi to bring the measured osmolality of compositions of the invention to within the stated number or range (for example 350mOsm/Kg or less e.g. 300 to 350 mOsm/Kg) is such that V₂ = y x Vi wherein y is within the range of 2 to 15 inclusively. The factor y need not be an integer. In certain embodiments, y is between 2.0 to 3.0 inclusively e.g. 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9 and 3.0. In other embodiments, y is between 3.0 and 4.0 inclusively, e.g. 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0. In other embodiments, y is between 4.0 and 5.0 inclusively, e.g. 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0. In other embodiments, y is between 5.0 and 6.0 inclusively, e.g. 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0. In other embodiments, y is between 6.0 and 7.0 inclusively, e.g. 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0. In other embodiments, y is between 7.0 and 8.0, e.g. 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0. In other embodiments, y is between 8.0 and 9.0 inclusively e.g. 8.0, 8.1, 8.2, 8.3, 8.4, 8.5,

8.6, 8.7, 8.8, 8.9, 9.0. In other embodiments, y is between 9.0 and 10.0

inclusively, e.g. 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0. In other embodiments, y is within a range in which the lower limit is 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8 or 10.9, and the upper limit is, independently, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0.

In certain embodiments, compositions of the invention are aqueous solutions. Compositions of the invention maybe colloids, emulsions or suspensions.

Compositions of the invention are compatible with the distal colon mucosa therefore have a suitable pH such as neutral pH.

Compositions of the invention maybe heated to a suitable temperature for use. Generally a suitable temperature is one in which the composition causes no heat related damage or discomfort (hot or cold) during or following rectal

administration. Generally compositions of the invention maybe heated to room temperature or body temperature prior to administration. Suitably compositions of the invention are devoid of visible crystalline matter.

Preferably compositions of the invention are devoid of crystalline matter visible to the naked eye.

Compositions of the present invention are typically provided as a unit

measurement. A single unit measurement is an aqueous liquid enema composition of the invention of 80 to 200ml volume, preferably 100 to 150ml, e.g. 115 to 140ml such as 130ml.

Thus the present invention provides an aqueous liquid enema composition having a volume of 80 to 200ml; preferably 100 to 150ml e.g. 1 15ml to 140ml such as

130ml comprises or consists essentially of;

PEG of average molecular weight of 3000 to 4500 within a range of 150, 160, 170, 180, 190, 200, 250, 300, 350, 400, 450, 500, 550, 580 or 600g/L and the upper limit is, independently, 250, 300, 350, 400, 450, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690,

700g/L. Particularly preferred ranges of PEG are 200g/l to 250g/l (such as 230g/l or thereabout), 350 to 400g/l (such as 384g/l or thereabout) and 400 to 520g/l (e.g. 450g/l to 500g/l such as 461g/l or thereabout of PEG). The present invention also provides an aqueous liquid enema composition with a volume of 80 to 200ml; preferably 100 to 150ml e.g. 115ml to 140ml such as 130ml or thereabout comprising or consisting essentially of;

30g, 40g, 50g, 51g, 52g, 53g, 54g, 55g, 56g, 57g, 58g, 59g, 60g, 61g, 62g, 63g, 64g, or 65g of PEG of average molecular weight of 3000 to 4500.

In accordance with another aspect of the invention there is provided a composition as described herein for use in the treatment of constipation, particularly distal constipation. In accordance with one embodiment of the invention there is provided a method of promoting a bowel movement in a mammalian subject, particularly a human subject, which method comprises rectally administering to the subject, an effective amount of the composition of the invention as described herein.

In another embodiment of the invention, there is provided a method of cleansing at least the distal colon in a subject, particularly a human subject, which method comprises rectally administering to the subject, an effective amount of the composition of the invention as described herein.

The term "distal colon" as used in this specification, refers to that region of the colorectal system encompassed by the rectum, sigmoid colon, descending colon and splenic flexure of the mammalian subject. Compositions of the present invention maybe used in the treatment of

gastrointestinal disorders such as acute constipation (particularly distal

constipation) and/or chronic functional constipation and/or faecal impaction in mammals, particularly human. Of these, compositions of the invention are particularly suited for the treatment of distal constipation. Compositions of the invention maybe used in any circumstance where cleansing the distal colon of faecal matter is desired or needed, e.g. in patients prior to bowel surgery and other medical or diagnostic procedures, for example, in investigating the etiology of gastrointestinal pain or discomfort. Accordingly therefore, a method of treating a gastrointestinal disorder such as acute constipation (particularly distal

constipation) and/or chronic functional constipation and/or faecal impaction is provided which method comprises rectally administering to a mammalian subject (such as a human) an effective amount of a composition of the invention.

In another embodiment of the invention there is provided a method of cleansing at least the distal colon of a mammalian subject such as a human prior to a subsequent medical or diagnostic procedure which method comprises rectally administering to the subject an effective amount of a composition of the invention. The composition of the invention are typically administered prior to the subsequent procedure with sufficient time to promote at least one bowel movement and evacuation of faecal matter before commencement of the subsequent procedure.

In a particular embodiment, compositions of the invention may also be used to cleanse the distal colon prior to inspection in e.g. a sigmoidoscopy procedure, particularly flexible sigmoidoscopy, colonoscopy and radiographic examination, e.g. barium enema.

In one embodiment of the invention, compositions of the invention are used to cleanse the distal colon prior to flexible sigmoidoscopic inspection of the colon of a human subject for evidence of, for example, colorectal cancer (CRC) and/or pathological changes associated therewith, e.g. abnormal number of polyps or other pathological changes. This embodiment may further comprise an additional colonoscopy procedure if evidence of CRC or other disease or disorder is found, or otherwise indicated following inspection. This embodiment may also be used in conjunction with the faecal occult blood test (FOBT) as part of the diagnostic work-up of the attending physician in relation to suspected CRC or other diseases or disorders of the gastrointestinal tract.

Compositions of the present invention maybe administered either by the subject himself (self-administration) or by the attending physician, healthcare professional or care-provider.

In some embodiments, compositions of the invention maybe used in conjunction with orally administered laxatives. Such orally administered laxatives include bulk laxatives and/or osmotic laxatives such as PEG based laxatives (e.g.

MOVICOL^®, Norgine Ltd), particularly hypertonic PEG based laxatives such as MOVIPREP^® (Norgine Ltd).

In other embodiments, compositions of the invention are provided in a container such as a sachet, bottle, stickpack, can or pouch. Such containers may comprise or consist of a unit measurement of a composition of the invention necessary for cleansing at least the distal colon. Such containers maybe accompanied by instructions for use. In other embodiments, the composition of the invention is provided as a package containing a plurality of containers each comprising or consisting of a unit measurement of compositions of the invention, optionally accompanied with instructions for use. In other embodiments, compositions of the present invention are provided, particularly for self-administration, as part of a preloaded applicator for rectal administration comprising an effective amount of the composition of the invention. In certain embodiments for example, the applicator may comprise a squeezable container, such as a bottle or tube, within which an effective amount of a composition of the invention is disposed. The squeezable container may be composed of low density polyethylene (LDPE). The applicator preferably comprises a one-way valve which serves to regulate fluid communication of a composition of the invention between the container and a coupled nozzle. The nozzle is generally shaped and configured for comfortable insertion into the rectum of the subject. The nozzle may also be lubricated to assist insertion. The nozzle may further comprise a removable cap or sheath to protect the nozzle when not in use. When the container is squeezed, compositions of the invention are expelled from the nozzle into the distal colon. Examples of applicators include those devices disclosed in US2008/0215011 or otherwise commercially available e.g. the applicator device used in conjunction with Norgalax^® (Norgine Ltd).

Such preloaded devices maybe accompanied with instructions for use.

In other embodiments, compositions of the invention are provided as a kit of parts comprising the composition (which may be in dry form for subsequent combination with water) together with an unloaded applicator such as described supra, optionally accompanied with instructions for use.

In other embodiments there is provided the composition as described supra in dry form together with instructions to combine the dry form composition with water for use as an aqueous liquid enema. Exemplification

The following trial formulations are made:

Table 1

* except formulation 3 which was a volume of 130ml.

In order to identify potential formulations for a PEG based enema, osmolality investigations were performed. Since there is no osmotic barrier between the colon and the extracellular space, faecal water has an osmolality of approximately

350mOsm/Kg. Therefore, the volume of additional deionised water required to obtain an approximate osmolality of 350mOsm/Kg was determined as this would give an indication of the effectiveness of the test formulation as an enema. The trial formulations of Table 1 were initially made up to 100ml volume with deionised water. The osmolality of the resulting solutions were measured using an os in triplicate and the average value obtained. Where the determined osmolality was not measurable or was greater than 350mOsm/Kg ± 7mOsm/Kg, the solution was further diluted until an osmolality less than 350mOsm/Kg ± 7mOsm/Kg was obtained, see Table 2. Table 2

Formula Initial Osmolality/ Osmolality/ Osmolality/ Osmolality tion Osmolality volume volume volume / volume

Did not 470mOsm 244mOsm

1

freeze /150ml /200ml

Did not Did not Did not 477mOsm 327mOsm freeze Freeze/ 150ml freeze /300ml /350ml

-> 1953mOsm/ 1213mOsm/2 707mOsm/43 373mOsm/8 338mOsm

J

130ml 30ml 0ml 30ml /930ml

Claims

An aqueous liquid enema composition having a measured osmolality within the range of 350 to 2000 mOsmol/kg comprising (or consisting essentially of) polyethylene glycol.

An aqueous liquid enema composition comprising (or consisting essentially of) PEG at a concentration of 150 to 700g/l.

An aqueous liquid enema according to any preceding claim wherein the PEG is within a range wherein the lower limit is 150, 160, 170, 180, 190,200, 250, 300, 350, 400, 450, 500, 550, 580, 600g/L and the upper limit is,

independently, 250, 300, 350, 400, 450, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700g/L. An aqueous liquid enema composition according to any preceding claim wherein the PEG is within a range of 200g/l to 250g/l (such as 230g/l or thereabout), 350 to 400g/l (such as 384g/l or thereabout) and 400 to 520g/l (e.g. 450g/l to 500g/l such as 461g/l or thereabout of PEG).

An aqueous liquid enema composition according to any preceding claim wherein the measured osmolality is within a range in which the lower limit is 350, 360, 370, 380, 390, 400, 410, 420, 430, 440 or 450 mOsm/Kg and the upper limit is, independently, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1200, 1400, 1600, 1800, 2000 mOsm/Kg.

An aqueous liquid enema composition comprising (or consisting essentially of) PEG of volume Vi having a measured osmolality ("Osm 1") of greater than 350mOsm/Kg wherein the volume V₂ of water required to be combined with Vi in order to bring the measured osmolality of the composition to 350mOsm/Kg or less (e.g. 300 to 350 mOsm/Kg) is such that V₂ = y x Vi wherein y is within the range of 2 and 15 inclusively.

An aqueous liquid enema composition of claim 6 wherein Osm 1 is greater than 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200,1300, 1400, 1500, 1600, 1700, 1800, 1900 or 2000 mOsm/Kg. An aqueous liquid enema composition of claims 6 or 7 wherein Osm 1 is within a range in which the lower limit is 350, 400, 450, 500, 550, 600, 650 or 700 mOsm/Kg and the upper limit is, independently, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700,1800,1900 or 2000 mOsm/Kg.

9. An aqueous liquid enema composition of any one of claims 6 to 8 wherein Volume Vi is 50ml, 100ml, 150ml, 200ml, 250ml, 300ml, 350ml, 400ml, 450ml, 500ml or greater.

10. An aqueous liquid enema composition of any one of claims 6 to 9 wherein y is between 2.0 to 3.0 inclusively e.g. 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9 and 3.0.

1 1. An aqueous liquid enema composition according to any one of claims 6 to 9 wherein y is between 3.0 and 4.0 inclusively, e.g. 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0.

12. An aqueous liquid enema composition according to any one of claims 6 to 9 wherein y is between 4.0 and 5.0 inclusively, e.g. 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0.

13. An aqueous liquid enema composition according to any one of claims 6 to 9 wherein y is between 5.0 and 6.0 inclusively, e.g. 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0.

14. An aqueous liquid enema composition according to any one of claims 6 to 9 wherein y is between 6.0 and 7.0 inclusively, e.g. 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0.

15. An aqueous liquid enema composition according to any of claims 6 to 9

wherein y is between 7.0 and 8.0, e.g. 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8,

7.9, 8.0 y is between 7.0 and 8.0, e.g. 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0.

16. An aqueous liquid enema composition according to any one of claims 6 to 9 wherein y is between 8.0 and 9.0 inclusively e.g. 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0.

17. An aqueous liquid enema composition according to any one of claims 6 to 9 wherein y is between 9.0 and 10.0 inclusively, e.g. 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0.

18. An aqueous liquid enema composition according to any one of claims 6 to 9 wherein y is between a range in which the lower limit is 10.1, 10.2, 10.3, 10.4,

10.5, 10.6, 10.7, 10.8 or 10.9 inclusively, and the upper limit is,

independently, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0.

19. An aqueous liquid enema composition according to any preceding claim

further comprising a preservative.

20. An aqueous liquid enema composition according to any preceding claim further comprising a surfactant.

21. An aqueous liquid enema composition according to any preceding claim

further comprising one or more additional component(s) selected from sodium chloride, potassium chloride, sodium bicarbonate, ascorbic acid and/or salts thereof.

22. An aqueous liquid enema composition according to any one of claims 1 to 20 substantially free of sodium chloride, potassium chloride, sodium bicarbonate, ascorbic acid and/or salts thereof.

23. An aqueous liquid enema composition according to any preceding claim

wherein the composition has a pH compatible with the distal colon mucosa.

24. An aqueous liquid enema composition of claim 23 wherein the pH is neutral.

25. An aqueous liquid enema composition of any preceding claim for use in the treatment of constipation, particularly distal constipation.

26. An aqueous liquid enema composition according to any one of claims 1 to 24 for use in cleansing the distal colon.

27. An aqueous liquid enema composition according to any preceding claim in unit measurement of 100 to 200ml (e.g. 100 to 150ml such as 130ml or thereabout).

28. A pre-loaded applicator comprising the liquid enema composition of any

preceding claim optionally together with instructions for use.

29. A pre-loaded applicator of claim 28 comprising a squeezable container within which the composition is disposed.

30. A pre-loaded applicator according to any one of claims 28 or 29 further

comprising a coupled nozzle in fluid communication with the container such that when the container is squeezed the composition is expelled from the applicator via the nozzle.

31. A pre-loaded applicator according to claim 29 to 31 comprising a one-way valve that serves to regulate fluid communication between the container and nozzle such that when the container is squeezed the composition is expelled from the applicator via the nozzle.

32. A method of cleansing the distal colon of a mammalian subject, particularly a human subject, which method comprises rectally administering to the subject an effective amount of the composition according to any one of claims 1 to 24.

33. A method according to claim 32 wherein the distal colon is cleansed prior to inspection in e.g. a sigmoidoscopy procedure, particularly flexible

sigmoidoscopy, colonoscopy and radiographic examination, e.g. barium enema.

34. A method according to claim 33 wherein the distal colon is cleansed prior to flexible sigmoidoscopic inspection of the colon of a human subject for evidence of, for example, colorectal cancer (CRC) and/or pathological changes associated therewith, e.g. abnormal number of polyps or other pathological changes.

35. A method of claim 34 further comprising the step of performing a

colonoscopy if evidence of CRC and/or pathological changes associated therewith are found or otherwise indicated.

36. A method of promoting a bowel movement in a mammalian subject,

particularly a human subject, which method comprises rectally administering to the subject, an effective amount of the composition according to any one of claims 1 to 24.