Colonoscopy—preparation

Abstract

The invention provides a colon cleansing solution comprising: a) 300 to 2000 mmol per litre ascorbate anion provided by ascorbic acid, one or more salts of ascorbic acid, or a mixture thereof; and h) 10 to 200 g per litre polyethylene glycol. The invention also provides methods and kits associated with, or making use of the solutions. The invention also provides a method of cleansing the colon of a subject comprising: —administering to the subject an effect amount of a first cleansing solution; and then after a time interval—administering to the subject an effective amount of a second cleansing solution, wherein the two cleansing solutions are as described in the specification.

Claims

1. A colon cleansing composition, comprising: 52.5 to 187.5 g PEG having an average molecular weight of 2500 to 4500 Da; and 3.75 to 15 g of one or more alkali metal sulphates, alkaline earth metal sulphates or a mixture thereof; wherein the composition is configured for colon cleansing in an ingestion volume of 400 to 600 ml of water; and wherein the composition is free from ascorbate components.

2. The composition of claim 1, wherein the ingestion volume is about 500 ml of water.

3. The composition of claim 1, wherein the PEG is in the range of 75 to 150 g.

4. The composition of claim 1, wherein the PEG is in the range of 90 to 112.5 g.

5. The composition of claim 1, wherein the PEG is in the amount of 100 g.

6. The composition of claim 1, wherein the one or more alkali metal sulphates, alkaline earth metal sulphates or the mixture thereof is in the range of 6 to 15 g.

7. The composition of claim 1, wherein the one or more alkali metal sulphates, alkaline earth metal sulphates or the mixture thereof is in the amount of 9 g.

8. The composition of claim 1, further comprising: 0.75 to 2.25 g sodium chloride; and 0.075 to 2.25 g potassium chloride.

9. The composition of claim 1, further comprising a sweetener wherein the sweetener is sucralose.

10. The composition of claim 1, further comprising citric acid.

11. The composition of claim 1, further comprising: 1.5 to 2.25 g sodium chloride, 0.15 to 1.5 g potassium chloride, sucralose, and citric acid; wherein: the PEG is in the amount of 100 g and the average molecular weight is 3000 to 4000 Da; and the one or more alkali metal sulphates, alkaline earth metal sulphates or the mixture thereof is in the amount of 9 g sodium sulphate.

12. The composition of claim 1, wherein the polyethylene glycol is present at a level between 77.8% and 98.0% w/w; and the sulphate component is present at a level between 2.0% and 22.2% w/w.

13. A colon cleansing solution, comprising: 130 to 250 g per liter PEG having an average molecular weight of 2500 to 4500 Da; and 15 to 20 g per liter of one or more alkali metal sulphates, alkaline earth metal sulphates or a mixture thereof; and 400 to 600 ml water; wherein the solution is free from ascorbate components.

14. The solution of claim 13, further comprising: 1.0 to 4.0 g per liter sodium chloride; and 0.1 to 3.0 g per liter potassium chloride.

15. The solution of claim 13, further comprising a sweetener wherein the sweetener is sucralose.

16. The solution of claim 13, further comprising citric acid.

17. A method of cleansing a colon of a subject comprising administering the solution of claim 13.

18. A method of cleansing a colon of a subject comprising administering the solution of claim 13 in combination with a different colon cleansing solution.

19. A colon cleansing solution, consisting essentially of: 130 to 250 g per liter PEG having an average molecular weight of 2500 to 4500 Da; 15 to 20 g per liter of one or more alkali metal sulphates, alkaline earth metal sulphates or a mixture thereof; 400-600 ml water; optionally 0.5 to 5.0 g per liter sodium chloride; optionally 0.1 to 3.0 g per liter potassium chloride; optionally one or more flavoring agents; and optionally one or more sweeteners; wherein the solution is free from ascorbate components.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 is a graph showing the mean concentration of ascorbic acid (μg/ml) in plasma over time in subjects receiving the split dose treatment of MOVIPREP.

(2) FIG. 2 is a graph showing the mean concentration of ascorbic acid (μg/ml) in plasma over time in subjects receiving the single dose treatment of MOVIPREP.

EXPERIMENTAL

(3) Pharmacokinetic Evaluation and Mass Balance Study

(4) An investigation into the pharmacokinetics and mass balance of a solution in water of MOVIPREP powder for oral solution was carried out following oral administration using single dose or split dose intake in healthy male subjects.

(5) Subjects:

(6) The subjects were healthy male volunteers aged 18 to 45 years. The subjects' written informed consent was obtained. The subjects were willing, able and competent to complete the procedure and to comply with the study instructions. The subjects had to not meet any of the exclusion criteria. 24 subjects were randomly allocated into two groups: 12 into the single-dose group and 12 into the split-dose group.

(7) Study Medication:

(8) The study medication administered was a solution in water of MOVIPREP powder for oral solution. The total dose was 2 litres of the solution for each subject. The solution contains, per litre:

(9) PEG3350: 100 g

(10) Sodium Sulphate: 7.500 g

(11) Ascorbic Acid: 4.700 g

(12) Sodium Ascorbate: 5.900 g

(13) Sodium chloride: 2.691 g

(14) Potassium chloride: 1.015 g

(15) Lemon-flavour and Sweetener

(16) The 4.700 g ascorbic acid and 5.900 g sodium ascorbate together provide the equivalent of 9.944 g ascorbic acid. A 2 litre dose thus provides the equivalent of 19.89 g of ascorbic acid.

(17) Treatment Regimens:

(18) The single dose group took the solution as follows:

(19) 2 L of solution were consumed between 17:00 and 20:00 on Day −1. The first litre was consumed within the first hour, with at least 500 ml of additional clear fluid. The second litre was consumed within two hours, with at least 500 ml of additional clear fluid.

(20) The split dose group took the solution as follows:

(21) 1 L of solution was consumed between 18:00 and 19:30 on Day −1. The litre was consumed within the 90 minutes, with at least 500 ml of additional clear fluid. The second litre was consumed between 07:00 and 08:30 on Day 0 (the day on which a colonoscopy procedure would be carried out in a clinical situation). The litre was consumed within the 90 minutes, with at least 500 ml of additional clear fluid.

(22) Sample collection for monitoring of PK parameters in blood and recovery of components in faeces and urine:

(23) Urine and faeces were collected throughout the procedure. Cumulative content amounts of components under investigation in the urine were obtained from measured concentrations of the components and measured actual volume of urine. Similarly, the cumulative content amounts of components under investigation in the faeces were obtained from measured concentrations of the components and measured actual mass of faeces. The defined time points for analysis of urine and faeces were at Ohr, 2 hr, 4 hr, 8 hr, 12 hr, 12.97 hr, 18 hr, 24 hr, 25.93 hr, 36 hr, 48 hr, 60 hr, 72 hr and 120 hr after the start of intake of the first litre of study medication. Blood samples were collected from the subjects at particular time points through the procedure.

(24) Sample Evaluation:

(25) The cumulative amounts of ascorbic acid, PEG3350, chloride, sulphate, sodium and potassium in plasma, faeces and urine were evaluated. The PK profiles of ascorbic acid, PEG3350, chloride, sulphate, sodium and potassium in the plasma were evaluated. Plasma renin and aldosterone were checked at all PK time points.

(26) For higher accuracy, the analysis of the recovery of ascorbic acid was extended to include also its metabolites dehydro-ascorbic acid and oxalic acid in urine and faeces.

(27) Completion of Study:

(28) Of the 12 subjects in the single-dose group, 4 had to be excluded from the analysis due to protocol violations, so 8 subjects were evaluated,

(29) Of the 12 subjects in the split-dose group, 1 had to be excluded from the analysis due to protocol violations, so 11 subjects were evaluated.

(30) Results:

(31) General:

(32) The mean cumulative recovery of ascorbic acid (including metabolites dehydroascorbic acid and oxalic acid) and PEG3350 in faeces and urine was comparable for the subjects in both treatment groups. The data collected on the cumulative amount of chloride, sulphate, sodium and potassium were comparable between the subjects in both treatment groups insofar as there was a continuous elimination in urine plus faeces (i.e. no plateau was reached). Furthermore, the PK parameters (AUC.sub.0-∞, AUC.sub.last, C.sub.max, K.sub.et, V.sub.d and t.sub.1/2) determined for ascorbic acid, sulphate, chloride, sulphate, sodium and potassium were comparable for the subjects in the single dose and the split dose group; especially the values for AUC.sub.last (i.e. exposure) were nearly identical for both groups.

(33) Recovery and Mass Balance of Ascorbic Acid:

(34) The ascorbic acid was to a significant extent excreted in faeces. The cumulative recovery of ascorbic acid and its metabolites from 0 to 120 hours after the start of intake of the first litre of study medication is shown in Table 1 for the single-does group and in Table 2 for the split-dose group. In the final column of Tables 1 and 2, there is given the plasma concentration of ascorbate (not including its metabolites) at the stated time points. That information in Tables 1 and 2 is taken from the graphs shown in FIGS. 1 and 2 respectively.

(35) TABLE-US-00001 TABLE 1 Single Dose Group Time/hr Urine/g Faeces/g Total/g Plasma μg/ml 0 0.000 ± 0.000  0.000 ± 0.000  0.00 ± 0.000 11.5 2 0.125 ± 0.0964  4.718 ± 3.5639  4.84 ± 3.643 43.0 4 0.456 ± 0.1193 11.961 ± 1.4291 12.42 ± 1.418 52.5 8 1.278 ± 0.2492 13.577 ± 1.2776 14.86 ± 1.243 38.0 12 1.472 ± 0.3116 13.587 ± 1.2882 15.06 ± 1.248 23.0 12.97 1.472 ± 0.3116 13.587 ± 1.2882 15.06 ± 1.248 20.0 18 2.202 ± 0.4252 13.909 ± 1.2864 16.11 ± 1.253 17.2 24 2.740 ± 0.5025 13.947 ± 1.2870 16.69 ± 1.210 13.2 25.93 2.814 ± 0.5112 13.952 ± 1.2859 16.77 ± 1.218 13.2 36 3.162 ± 0.6042 13.952 ± 1.2860 17.11 ± 1.209 12.8 48 3.977 ± 0.7192 13.972 ± 1.2901 17.95 ± 1.369 12.3 60 4.605 ± 0.9177 13.982 ± 1.2964 18.59 ± 1.733 12.0 72 5.104 ± 1.1514 14.018 ± 1.3020 19.12 ± 1.920 12.3 120 6.501 ± 1.9053 14.041 ± 1.3203 20.54 ± 2.723 Not measured From 12.97 to 1.342 ± 0.4857  0.365 ± 0.4459 1.707 ± 0.780 N/A 25.93

(36) TABLE-US-00002 TABLE 2 Split Dose Group Time/hr Urine/g Faeces/g Total/g Blood μg/ml 0 0.000 ± 0.000  0.000 ± 0.000  0.00 ± 0.000 10.5 2 0.248 ± 0.3552  2.356 ± 2.0088  2.60 ± 2.213 36.5 4 0.586 ± 0.3951  3.810 ± 2.4661  4.40 ± 2.592 34.3 8 0.860 ± 0.5437  4.836 ± 2.4106  5.70 ± 2.607 25.0 12 0.860 ± 0.5437  4.836 ± 2.4106  5.70 ± 2.607 16.2 12.97 1.180 ± 0.6712  5.022 ± 2.4831  6.20 ± 2.772 15.0 18 2.220 ± 0.7555 10.239 ± 4.6259 12.46 ± 4.885 25.5 24 3.323 ± 1.3183  1.010 ± 4.5147 14.33 ± 4.993 16.0 25.93 3.482 ± 1.3946 11.047 ± 4.5342 14.53 ± 5.123 15.8 36 4.351 ± 2.3023 11.062 ± 4.5147 15.41 ± 5.556 13.0 48 5.432 ± 3.3304 11.104 ± 4.5497 16.54 ± 6.200 11.6 60 6.228 ± 3.9837 11.109 ± 4.5519 17.34 ± 6.685 11.4 72 7.069 ± 4.5654 11.141 ± 4.5649 18.21 ± 7.104 11.4 120 9.123 ± 5.4605 11.195 ± 4.6225 20.32 ± 7.930 Not measured From 12.97 to 2.302 ± 1.2932  6.025 ± 2.4704 8.327 ± 3.113 N/A 25.93

Discussion

(37) Of the 19.89 g ingested ascorbic acid equivalents contained in 2 litres of MOVIPREP solution 103.35% were found to be recovered in urine and faeces of the single-dose group subjects after 120 hours, and 103.05% were found to be recovered in urine and faeces of the subjects in the split-dose group after 120 hours. There was no statistically significant difference between the total recovered amount of ascorbic acid between the two groups.

(38) There was, however, a difference between the timing of the recovery and between the distribution of the ascorbic acid between urine and faeces. It is seen in Tables 1 and 2 that in the split dose group, the distribution of the total recovered 20.32 g ascorbic acid between urine and faeces is in the ratio 9.123 g:11.1.95 g, ie 44.9%:55.1% (or 1:1.23) whilst, in the single dose group, the distribution of the total recovered 20.54 g ascorbic acid between urine and faeces is in the ratio 6.501 g:14.041 g, ie 31.6% 68.4% (or 1:2.16).

(39) The final column of each of Tables 1 and 2 shows the plasma level of ascorbate/ascorbic acid at the stated time points. The measurement does not include metabolites of ascorbic acid, and it does not take account of ascorbate in other compartments in the body. Nevertheless, increases in plasma ascorbate are clearly seen in the hours following administration of the solution.

(40) In order to compare the recovery of ascorbic acid during the different phases of the protocol, two time intervals were defined: the first time interval was between time zero, ie. the start of the intake of the first litre of study medication and time “x”, where “x” represents the minimal starting time point of the intake of the second litre of study medication for split dose group (from time 0 to 12.97 hrs). The second time interval was from time “x” to time 2x (from 12.97 to 25.93 hrs).

(41) It is seen that, during the second time interval, 6.025 g of ascorbic acid are recovered from faeces of the split-dose group, compared with 5.022 g during the first time interval. The 6.025 g in the second time interval is closer to being half of the 13,587 g seen over the first time interval in the single-dose group. That is to say that the second dose of the split-dose treatment follows a similar time course to the (only) dose in the single-dose treatment.

(42) The differences in the recovered amounts of components between the first and the second time intervals are statistically significant for ascorbic acid (incl metabolites) in faeces (p=0.0078) and urine plus faeces (p=0.0078) for the single dose group subjects, and in urine (p=0.0020) and urine plus faeces (p=0.0322) of the split dose group subjects.

EXAMPLES

(43) 1. Bowel Cleansing Solutions

Example 1a—Contents of Solutions

(44) The following bowel cleansing solutions of the invention were prepared. For solution A1, the components shown in Table 3 were combined in dry powder form and sealed in a sachet. The solution was then prepared by dissolving the contents in water to the volume stated in the penultimate column. Solutions A2 and A3 were prepared in an analogous manner.

(45) TABLE-US-00003 TABLE 3 Water Na.sub.2SO.sub.4 to Sol'n PEG3350/g (anhyd)/g NaCl/g KCl/g Vol/ml V(350)/ml A1 100 3 1.4 0.3 750 725 A2 100 6 1.6 0.7 750 915 A3 100 9 2.0 1.0 750 1080

(46) For solution B1, the components shown in Table 4 were combined in dry powder form and sealed in respective sachets A and B as indicated in the table. The solution was then prepared by mixing the contents of the two sachets together and then dissolving them in water to the volume stated in the penultimate column. Solutions B2 to B5 were prepared in an analogous manner.

(47) TABLE-US-00004 TABLE 4 Sachet A Sachet B Na.sub.2SO.sub.4 Sodium Ascorbic Magnesium Water to Sol'n PEG3350/g (anhyd)/g NaCl/g KCl/g Ascorbate/g Acid/g Ascorbate/g Vol/ml V(350)/ml B1 40 — 3.5 2.2 56.6 — — 500 2000 B2 20 — 2.7 1.3 33.9 20.1 — 500 1570 B3 40 — 2.8 1.3 33.9 20.1 — 500 1600 B4 40 6 2.8 2.0 33.9 — — 500 1700 B5 40 — 3.1 1.3 33.9 — 21.4 500 1700

(48) The solutions additionally contained sweetener and flavouring sufficient to improve their palatability.

(49) In the case of the solutions in Table 4, those components were in sachet A. The solutions were not optimised for palatability.

Example 1b—V(350) Osmolality Measurements

(50) In order to assess the osmotic strength of the solutions, it was determined how much water was required to provide a solution with measured osmolality of 350 mOsmol/kg from the amounts of the components in Tables 3 and 4.

(51) To each solution prepared by dissolving the components in Tables 3 and 4 above in 500 ml of deionised was added further deionised water until it reached an osmolality of 350 mOsmol/kg. After a volume was found in a first experiment, a second experiment was carried out in which the volume of water found in the first experiment was added to the contents of a new sachet in one aliquot. It was then checked that the resulting solution had an osmolality of 350+/−7 mOsmol/kg. In every case, it did. The volumes are recorded in Tables 3 and 4 in the final columns. Osmolalities were measured using an Advanced Instruments, Inc Model 3250 osmometer. The osmometer was operated following standard instructions: after the device passes a calibration check, the “Low Range” osmolality range (0 to 2000 mOsmol/kg) is selected, and a sample tube containing 250 μl of sample solution is placed in the freezing chamber. The “start” button is then pressed. When the measurement is completed, the device displays the measurement result and that is recorded.

Example 2: Bowel Cleansing of Subjects

(52) An open, randomised, single centre phase I study to investigate the pharmacodynamic effects (stool weight) of the various modified gut cleansing solutions. The study had two sequential parts (Part 1 and Part 2). In both parts investigational medicinal product (IMP) was administered in the evening of Day 1 and the morning of Day 2. In Part 1 of the study, three different solutions A given in the evening were combined in turn with a fixed solution B given in the morning. In addition, one group of subjects received MOVIPREP®, as reference product.

(53) In Part 2 of the study, the selected solution A from Part 1 was given as the evening dose in combination with four different solutions B as the morning dose. Stool output was assessed.

(54) Number of Patients (Planned and Analysed):

(55) Planned: at least 160 evaluable cases in the entire study (20 evaluable subjects per treatment group)

(56) Analysed: 161 evaluable cases (part A: 81 subjects; part B: 80 subjects), Patients were subjected to inclusion and exclusion criteria.

(57) Dosage Regimen:

(58) Each subject received his/her solution regimen in the split dose intake: Evening dose: Day 1; start intake between 17:00 and 18:00 pm for an intake period of up to 2 hours after fasting from 14:00 pm. Morning dose: Day 2; start intake between 7:00 and 8:00 am for an intake period of up to 2 hours. 4 hours after complete intake of the morning dose, the first meal was provided, but not before completion of the planned safety laboratory blood drawing.

(59) After the end of the intake of each dose of the investigational solution, the subjects were instructed to take further clear liquid (water).

(60) Screened healthy subjects provided one stool collection after a complete bowel motion in the 7 days before the planned admission to the unit for baseline evaluation. After admission to the unit, all defecated faeces were collected after each bowel movement. Stool appearance and weight was determined for each collected stool fraction. Faecal samples were taken until at least 15:00 pm on Day 4 and an attempt was made to collect a final faecal sample prior to discharge from the phase 1 unit.

(61) Solutions: Part 1:

(62) TABLE-US-00005 TABLE 5a Na.sub.2SO.sub.4 Ascorbic Sodium Water to Sol'n PEG3350/g (anhyd)/g NaCl/g KCl/g acid ascorbate Vol/ml A2 100 6 1.6 0.7 — — 750 A3 100 9 2.0 1.0 — — 750 A4 75 5.6 2.0 0.8 — — 750 A-Mov 100 7.5 2.691 1.015 4.7 5.9 1000

(63) TABLE-US-00006 TABLE 5b Sachet A Sachet B Na.sub.2SO.sub.4 Sodium Ascorbic Magnesium Water to Sol'n PEG3350/g (anhyd)/g NaCl/g KCl/g Ascorbate/g Acid/g Ascorbate/g Vol/ml B3 40 — 2.8 1.3 33.9 20.1 — 500 B-Mov 100 7.5 2.691 1.015 5.9 4.7 1000

(64) The subjects were randomised into four groups (1:1:1:1), and given one of the three solutions A2, A3 and A4 in Table 5a as the evening dose, followed by solution B3 as the morning dose, or (for the fourth group) given MOVIPREP solution for both doses (ie A-Mov followed by B-Mov). Solutions A2 and A3 are solutions of the invention. Solution A4 is a reference solution. Solutions A-Mov and B-Mov are the commercially available MOVIPREP solution. Each of solutions A2 to A4 was taken in a dose of 750 ml; the MOVIPREP solution was taken in a dose of 1000 ml as indicated in the product instructions.

(65) In addition to the investigation formulations intake, the subjects were instructed to take further clear liquid (water). In the case of solutions A2 to A4, they were instructed to take 1750 mL of further clear liquid (875 ml, after the evening dose, and 875 mL after the morning dose). In the case of A-Mov, MOVIPREP®, they were instructed to take 1000 mL of further clear liquid (500 mL after the evening dose, and 500 mL after the morning dose).

(66) Solutions: Part 2:

(67) TABLE-US-00007 TABLE 6a Na.sub.2SO.sub.4 Ascorbic Sodium Water to Sol'n PEG3350/g (anhyd)/g NaCl/g KCl/g acid ascorbate Vol/ml A3 100 9 2.0 1.0 — — 750

(68) TABLE-US-00008 TABLE 6b Sachet A Sachet B Na.sub.2SO.sub.4 Sodium Ascorbic Magnesium Water to Sol'n PEG3350/g (anhyd)/g NaCl/g KCl/g NaHCO.sub.3/g Ascorbate/g Acid/g Ascorbate/g Vol/ml B1 40 — 3.5 2.2 56.6 — — 500 B4 40 6   2.8 2.0 33.9 — — 500 B5 40 — 3.1 1.3 33.9 — 21.4 500 B6 29 4.8 1.4 0.9 2.2 — 23.3 — 500

(69) The subjects were randomised into four groups (1:1:1:1), and given solution A3 in Table 6a as the evening dose, followed by one of: solutions B1, B4, B5 and B6 as the morning dose. Solutions B1, B4 and B5 are solutions of the invention. Solution B6 is a reference solution.

(70) In addition to the investigation formulations intake, the subjects were instructed to take further clear liquid (water). In each case, they were instructed to take 1750 mL of further clear liquid (875 mL after the evening dose, and 875 mL after the morning dose).

(71) Efficacy:

(72) The primary variable in the clinical study was the stool weight output generated by the investigational solutions (combined evening and morning dosing on Day 1 and Day 2) over 24 hours from the start of the intake of the evening solution. The reference value of the study was set to a stool weight of approximately 2500 g or greater; which it is desired to be reached in order to demonstrate positive pharmacodynamic effects indicating a potential as a colon cleansing agent.

(73) In addition to the primary trial variable mentioned above, stool output was separately measured and recorded for a) the time between when the subject starts to take the evening dose (17:00 to 18:00 on Day 1) and the time the subject starts to take the morning dose (7 am to Sam on Day 2); and b) the time the subject starts to take the morning dose (7 am to Sam on Day 2) and midnight on Day 2.

(74) Results:

(75) TABLE-US-00009 TABLE 7a Study Part 1: Stool Weight (g); full analysis set (FAS, N = 81) Treatment N 24 hr Median/g 24 hr Mean/g 24 hr STD/g A2 + B3 20 2981.3 3021.2 599.5 A3 + B3 21 3493.2 3386.1 602.74 A4 + B3 20 2796.80 2794 688.27 A-Mov + B-Mov 20 3145.95 2973.7 479.41

(76) In the table, the “24 hr Median” is the median stool output in the 24 hours from the time the subject starts to take the evening dose (ie 17:00 to 18:00 on Day 1 to the same time on Day 2); the “24 hr Mean” is the mean of the 24 hour data, and the STD is the standard deviation.

(77) TABLE-US-00010 TABLE 7b Study Part 1: Stool Weight (g); full analysis set (FAS, N = 81) pm stool am stool pm stool am stool Treatment N median/g median/g mean/g mean/g A2 + B3 20 925.8 2380.0 867.07 2196.9 A3 + B3 21 1178.5 2405.7 1184.34 2262.39 A4 + B3 20 826.7 2244.8 832.33 2005.25 A-Mov + B-Mov 20 1629.2 1536.4 1567.26 1453.83

(78) The “pm stool median” is the median stool output between the time the subject starts to take the evening dose (17:00 to 18:00 on Day 1) and the time the subject starts to take the morning dose (7 am to 8 am on Day 2). The “am stool median” is the median stool output between the time the subject starts to take the morning dose (7 am to 8 am on Day 2) and midnight on Day 2. The “pm stool mean” and “am stool mean” entries are the corresponding mean values.

(79) It is generally considered that a total stool output of approximately 2500 g is required in order to achieve acceptable bowel cleansing. A stool output of approximately 2500 g or greater than that is thus indicative that a solution has good potential for use as a bowel cleansing solution. Both A2+B3 and A3+B3 resulted in a median stool weight of significantly greater than 2500 g. The commercial MOVIPREP® solution also achieved a median stool output of in excess of 2500 g, as was to be expected. The stool output was highest for A3+B3. Solution B3 was therefore selected to be the morning solution for Part 2 of the study. The observed stool output was achieved for MOVIPREP with the ingestion of 2 litres of investigational solution. For the A2+B3 and A3+B3 solutions, the mean stool weights were achieved using a total investigational solution volume of 1250 ml.

(80) Solutions A2 and A3 were effective in contributing to an effective cleansing with any of the solutions with which they were used. It is seen from the “am stool median” and “pm stool median” figures that the stool output immediately after the ingestion of the A2 and A3 solutions was less copious than after the B solutions. The A2 and A3 solutions contributed to the effective bowel cleansing. Given that the subject will often wish to sleep between taking the first bowel cleansing solution and the second solution, it may be advantageous for the first cleansing solution to result in a slightly lower stool output than the second cleansing solution.

(81) TABLE-US-00011 TABLE 8a Study Part 2: Stool Weight (g); full analysis set (FAS, N = 80) Treatment N 24 hr Median/g 24 hr Mean/g 24 hr STD/g A3 + B1 20 3128.9 2898.2 856.6 A3 + B4 20 2546 2453.3 775.1 A3 + B5 20 2440.1 2501.2 1000.3 A3 + B6 20 2466.8 2485.6 496.1

(82) TABLE-US-00012 TABLE 8b Study Part 2: Stool Weight (g); full analysis set (FAS, N = 80) pm stool am stool pm stool am stool Treatment N median/g median/g mean/g mean/g A3 + B1 20 1170.0 2146.4 1087.59 1846.41 A3 + B4 20 1156.5 1467.2 1114.64 1370.69 A3 + B5 20 1091.1 1448.6 1039.42 1574.65 A3 + B6 20 1210.7 1436.2 1163.93 1402.64

(83) A3+B1 and A3+B4 resulted in a 24 hour median stool output weight of greater than 2500 g. For the combination A3+B5, the median stool output was just under 2500 g, but the mean stool output was over 2500 g. Thus, all of the solution combinations of the invention (A3+B1, A3+B4 and A3+B5) resulted in a 24 hour mean or median stool output weight of greater than 2500 g.

(84) Considering the data from tables 7a, 7b, 8a and 8b together, B1, B3, B4 and B5 solutions have been shown to be effective bowel cleansing solutions when used in combination with any other solution with which they were used. The particularly copious stool output seen in the “am stool mean” figures shows that the solutions are especially effective.

(85) In the case of A3+B1, the median stool weight was significantly greater than 2500 g. It is again noteworthy that the mean stool weights were achieved using a total investigational solution volume of only 1250 ml.

(86) Solution A3 in combination with reference solution B6 resulted in stool output that was not statistically significantly different from 2500 g.