DK201200057U1 - Improvements in and regarding colon cleansing compositions - Google Patents

Abstract

The preparation provides a dry composition for admixing with water, the composition optionally appearing in two or more parts and comprising per unit weight. In the final solution the following components are: (a) 85 to 115 g of polyethylene glycol (PEG) having an average molecular weight of 2,500 to 4,500, (b) 6 to 9 g of sodium sulfate, (c) 2 to 3 g of sodium chloride, (d) 0.5 to 1.5 g of potassium chloride, (e) 5 to 15 g of organic component and (f) orange flavoring. Also provided are solutions, kits and unit doses using the compositions.

Description

1DK 2012 00057 U3

Title: Improvements in, among other things, regarding colon cleansing compositions

The present invention relates to colon cleansing compositions for cleaning the gastrointestinal tract. Colon cleansing compositions are also known as washing solutions, intestinal preparations or colon cleansers.

Colon cleansing is important before several surgical or diagnostic procedures include: colonoscopy, barium lavage examination, sigmoid copy, and colon surgery. Such procedures are often performed on an outgoing patient and it is therefore desirable that colon cleansing be performed by the patient at home prior to arrival at the hospital or surgical site where the procedure is to be performed. Therefore, it is important that patient compliance be good without medical monitoring for satisfactory colon cleansing prior to the procedure.

Intestinal washing, in which a large volume of electrolyte solution containing sodium sulfate and polyethylene glycol (PG) is consumed, is one of the most common methods of colon cleansing. These osmotically active agents are non-absorbent or simply weakly absorbent and thus retain water in the gut, resulting in massive diarrhea and colon cleansing. Although effective, such compositions have a very salty taste which adversely affects patient compliance. Various attempts have been made to improve the taste of colon cleansing compositions to improve patient compliance by reducing sodium and sulfate content or by adding flavoring to mask salt flavors and make the compositions more appetizing. However, it has proved difficult to reduce or mask the very unpleasant salty taste of such compositions while maintaining effective amounts of the osmotic salts.

In addition, for effective cleaning, many of these compositions must be consumed in quantities between 2 and 4 liters. The unpleasant taste of these compositions together with the large volumes of solutions for intake often contribute to nausea or vomiting, resulting in poor patient compliance and failure to consume the full volume of solution.

A number of improved colon cleansing compositions are described in WO 2004/037292. The compositions described there are effective, although consumed with less volume than other colon cleansing solutions. Typically, just 2 liters of the solution is needed by the patient. A colon cleansing composition according to WO 2004/037292 which includes PEG, sodium sulfate, an ascorbate component and lemon flavor is commercially available under the trade name MOVIPREP® (registered trademark of Velinor AG, part of the Norgine group of companies). In the MOVIPREP product, a small bag of PEG 3350, sodium sulfate, sodium chloride, potassium chloride, sweetener and lemon flavor in a small bag A is added, and the ascorbate component (comprising ascorbic acid and sodium scorbate) is provided in a small bag B.

Despite the success of the lemon-flavored MOVIPREP composition, there is always room for improvement in taste, which will further reduce one of the main problems of patient compliance. Improving the taste of colon cleansing compositions containing organic acids or salts thereof, e.g. Ascorbate in the component MOVIPREP composition presents a particular challenge in light of the flavor effects contributed by the organic acids themselves. It is difficult to mask the salty taste of colon cleansing compositions without making the compositions excessively sweet.

An important consideration for the value of any medical product is the storage time and the stability of the product over time. It should be possible for medical products to be stored and / or shipped over a long period of time, typically at least 1 year and more commonly 2 to 3 years from the time of manufacture. There are several criteria to consider when assessing a product's stability and shelf life: it is important that the product remains sterile throughout its shelf life. It is also important that it remains effective throughout its storage time, including that the flavor is not degraded in compositions which include flavoring, including the fact that the flavoring intensity should not be significantly reduced during storage time. Finally, the physical appearance and physical properties should not change significantly with the storage time; this implies that a powder must remain fluid and not aggregate with time. Nor should it be discolored to any appreciable degree. There is a risk that aggregates or lumps present in the powder during storage will not dissolve properly when a patient prepares a solution with the powder. Incomplete solution may result in a solution containing its individual constituents in incorrect amounts, and such solution may have poor efficacy and / or taste.

It is known for some medicinal products containing orange flavor that they become lumpy or that the orange flavor is reduced to below the desired value in a 6 month stability test so that only short-term storage time is achieved. This stability problem is especially a point for products comprising polyethylene glycol and electrolytes. Eg. Laxido Orange is a constipation treatment marketed by Galen Limited (see http: /www.galen.co.uk) containing 13,125 g of PEG 3350, 350.7 mg of sodium chloride, 178.5 sodium bicarbonate, 46.6 mg of potassium chloride, potassium acesulfame and orange flavor (containing glucose) and comes as a dry powder. For use, powdered water is added up to 125 ml. It has been found that samples of Laxido Orange as dry powder do not perform well in the 3 and 6 month stability tests. In samples (in their small bags as they are sold) stored at 25 ° C and 60% relative humidity, and in samples stored at 40 * 0 and 75% relative humidity for 3 or 6 months, the white powder is initially off-white and gets small lumps. Therefore, one skilled in the art will be discouraged from developing orange flavor compositions with PEG and electrolytes.

It is surprisingly found by the inventors that when the flavoring in bag A of the MO-VIPREP composition is orange (instead of lemon) despite the fact that this includes a mixture of PEG and electrolytes, the composition in bag A comprises all physical stability tests above 24 months, including e.g. that it remains free-flowing and essentially free of lumps. It has also been found that solutions made from the contents of bags A and B of the MOVIPREP product, in which the taste in bag A is orange (instead of lemon), are stable over a period of 24 hours in solution stability tests. including after storage for 12 months.

The inventors have found that orange flavoring compositions have improved taste and acceptable storage stability.

Accordingly, the present invention provides a dry composition for admixing with water comprising per liter of final solution the following components: (a) 85 to 115 g of polyethylene glycol (PEG) having an average molecular weight of 2500 to 4500, (b) 6 to 9 g of sodium sulfate, (c) 2 to 3 g of sodium chloride, (d) 0.5 to 1.5 g of potassium chloride, (e) 5 to 15 g of organic acid component, and (f) orange flavor.

"Dry" in this context means that the composition has no added liquid, especially no added water. For example, it is essentially without water. Small amounts of water or other liquid may be present in some of the components, although supplied as "dry"; a salt can e.g. be present as a hydrate. Such quantities of water are not considered significant. "Solution" in this context includes any mixture resulting from mixing the composition with water, whether completely dissolved or not. The composition may appear in two or more parts. Eg. it may appear as a part A comprising components (a) to (d) and (f), and a portion 5DK 2012 00057 U3 B comprising component (s). Component (f) may optionally be provided in a third (part C) instead of or as well as in part A.

Preferably, the flavor in the compositions of the invention comprises maltodextrin. Solutions of the compositions of the preparation comprising flavors, including maltodextrin as one of its components, were surprisingly found to have particularly acceptable flavors, especially solutions of the compositions comprising maltodextrin in an amount of 20 to 90% by weight of the flavor. Preferably, the maltodextrin is present in the flavor in an amount of 20 to 80% by weight. Eg. it is present in an amount of 35 to 80% by weight, for example 70 to 80% by weight of the flavor. It has been found that a solution comprising flavoring in which maltodextrin is present in an amount of less than 80% by weight of flavoring was preferred over solutions containing more maltodextrin. Preferably, the maltodextrin is present in the flavor in an amount of less than 80% by weight of the flavor.

Preferably, compositions according to the invention comprise orange flavoring in an amount of 0.1 to 0.9 g per liter of finished solution, such as 0.3 to 0.8 g per liter, for example 0.4 to 0.7 g per liter of solution for preparation, for example 0.5 to 0.7 g per liter of solution for preparation, for example 0.6 g per liter. Preferably, the compositions of the invention comprise orange flavoring in an amount of more than 0.5 g per liter, for example more than 0.55 g per liter of final solution. The amount of flavoring necessary to provide the most acceptable flavor depends to some extent on the levels of some of the other components present. If components (a) to (b) are present in quantities at the lower end of their ranges, less flavor is needed. This applies to some extent to the salts, but in particular to the organic acid component. It has been found that for a composition comprising 8 to 12 g of organic acid component per liter of solution (e.g. 4.7 g of ascorbic acid and 5.9 g of sodium ascorbate), 0.2 to 0.65 g of orange flavoring per liter of final solution is obtained. (e.g., more than 0.5 g, e.g. 0.6 g) a particularly acceptable solution. In a composition comprising less organic acid component, a lower amount of orange flavor may be appropriate. For example, 5 to 8 g of organic acid 6 6DK 2012 00057 U3 component per liter of solution was present, then 0.2 to 0.5 g of orange flavoring per liter of solution for preparation could be fit, if 12 to 15 g of organic acid component per liter of solution would be present 0.5 to 0.9 g of orange flavoring per liter of solution are needed.

In the case where the flavor comprises maltodextrin in an amount of 20 to 90% by weight of the flavor, 0.3 to 0.8 g of orange flavoring per liter of solution provides 0.06 to 0.72 g of maltodextrin per liter of solution and thus maltodextrin is 0.042 to 0.73% by weight of the dry composition. In cases where the flavor comprises maltodextrin in an amount of 35 to 80% by weight, 0.4 to 0.7 g of orange flavoring per liter of solution provides 0.14 to 0.56 g of maltodextrin per liter of solution, and thus maltodextrin is 0.097 to 0. 57% by weight of the dry composition. In the case where the flavoring comprises maltodextrin in an amount of 70 to 80% by weight of the flavoring, 0.4 to 0.7g of orange flavoring per liter of solution provides 0.28 to 0.56g of maltodextrin per liter of solution and thus the maltodextrin is 0, 20 to 0.56% by weight of the dry composition. It was found that a solution containing 0.442 g of maltodextrin per liter was preferred over solutions containing greater amount of maltodextrin per liter. Accordingly, a preferred composition of the invention comprises less than 0.56 g of maltodextrin per liter of solution, e.g. it contains 0.28 to 0.56 g, for example 0.35 to 0.5 g, for example 0.41 to 0.47 g of maltodextrin per liter of final solution.

A preferred composition according to the preparation comprises 0.04 to 0.8% maltodextrin by weight of the dry composition. More preferably, it comprises 0.1 to 0.6% maltodextrin by weight of the dry composition, for example 0.2 to 0.6%.

Maltodextrin in a flavor when used in a composition according to the preparation may be from any suitable source. It may be, for example, corn maltodextrin (also known as corn maltodextrin), potato maltodextrin or wheat maltodextrin. For example, it is corn maltodextrin.

7 7GB 2012 00057 U3

The orange flavor may include a sugar, e.g. sucrose or dextrose (d-glucose), preferably dextrose. It can for example. include dextrose in an amount of 10 to 30%, for example 15 to 25% by weight. An orange flavoring may comprise sucrose in an amount of from 30 to 50%, for example from 30 to 35% or from 35 to 45%. Eg. For example, an orange flavoring may comprise the same amount of sucrose and maltodextrin.

In cases where the flavoring comprises dextrose in an amount of 10 to 30% by weight of the flavoring, 0.3 to 0.8g of orange flavoring per liter of solution provides 0.03 to 0.24g of dextrose per liter of solution and thus the dextrose is 0.021 to 0.24% by weight of the dry composition. In cases where the flavor comprises dextrose in an amount of from 15 to 25% by weight, 0.4 to 0.7 g of orange flavoring per liter of solution provides 0.06 to 0.175 g of dextrose per liter of solution and thus the dextrose is 0.041 to 0.18 % by weight of the dry composition. It was found that a solution containing 0.119 g or 0.239 g dextrose per liter was preferred over solutions containing less dextrose per liter. Accordingly, a preferred composition of the preparation comprises more than 0.10 g of dextrose per liter, e.g. 0.1 and to 0.25 g of dextrose per liter of final solution. In view of the fact that it is generally desirable to limit the amount of sugars in intestinal preparations, a preferred composition of the preparation comprises less than 0.20 g of dextrose per liter of solution for preparation, e.g. 0.100 g to 0.180 g, for example 0.110 to 0.130 g dextrose per liter of final solution.

A preferred composition of the invention comprises 0.02 to 0.25% dextrose by weight of the dry composition. More preferably, it comprises 0.05 to 0.15% dextrose by weight of the dry composition e.g. 0.075 to 0.125%.

Dextrose in a flavoring for use in a composition according to the preparation may be from any suitable source. Eg. It can be derived from corn, rice, cassava, corn husks or sago. Eg. it is corn dextrose. In a composition according to the invention, which comprises maltodextrin and dextrose 8, both can be from the same source. In cases where the flavor comprises sucrose in an amount of 35 to 45% by weight of the flavor, 0.4 to 0.7 g of orange flavoring per liter of solution provides 0.14 to 0.315 g of sucrose per liter of solution and the sucrose thus amounts to 0.097 to 0 , 32% by weight of the dry composition.

The orange flavoring may include natural identical and / or natural flavoring preparations or components, e.g. orange oil, terpenes and terpenoids. Alternatively, the orange flavoring may be terpenless or may include terpenes at such a low level that it is assumed to be terpenless in the flavor industry. In a preferred embodiment, the orange flavor is essentially rubber-free. Alternatively, it may comprise one or more rubbers, e.g. gum arabic also known as acacia gum. The orange flavoring preferably comprises less than 2% by weight (relative to the weight of the flavoring) of organic components, in addition to the flavor preparations and components, e.g. less than 1%, for example less than 10 ppm. Some components of flavors may cause aqueous solutions or compositions comprising these to become unclear. Some patients prefer to drink clear solutions.

Suitable flavors are available from International Flavors and Fragrances Inc, (Duddery Hili, Haverhill, Suffolk, CB9 8LG, England), Ungerer & Company (Sealand Road, Chester, England CH1 4LP) or Firmenich (Firmenich UK Ltd., Hayes Road, Southall , Middlesex UB2 5NN).

Polyethylene glycol (PEG) used in the compositions of the invention has an average molecular weight of 2500 to 4500. PEG may have a molecular weight of 3000 to 4000. For example, PEG may be PEG 3350 or PEG 4000 as defined by national pharmacopoeia. Further examples of suitable PEGs are known in some national pharmacopoeias and include macrogols, e.g. Macrogol 4000. Optionally, PEG used in compositions of the invention may comprise two or more different PEG compounds.

9 9GB 2012 00057 U3

Compositions for the preparation comprise PEG in an amount of 85 to 115 g per liter of solution for preparation, preferably in an area where the lower limit is 90, 95 or 100 g per liter and the upper limit is independently 110 or 105 g per liter, e.g. 90 to 110 g per liter of solution for preparation. A composition according to the preparation may comprise 100 g of PEG per liter, for example 100 g of PEG 3350 per liter of finished solution.

The compositions of the invention comprise sodium sulfate in an amount of 6 to 9 g per liter of final solution, preferably in an area where the lower limit is 6.5, 7 or 7.5 g per liter and the upper limit independently is 8.5 or 8 g per liter, e.g. 6.5 to 8.5 g per liter of solution for preparation. For example, a composition according to the preparation may comprise 7.5 g of sodium sulfate per liter of final solution. The sodium sulfate in the compositions of the preparation is preferably anhydrous.

Compositions according to the preparation comprise sodium chloride in an amount of 2 to 3 g per liter of final solution, preferably in an area where the lower limit is 2.1, 2.2, 2.3, 2.4 or 2.5 g per liter. and the upper limit is independently here 2.9, 2.8, 2.7 or 2.6 g per liter, for example 2.5 to 2.9 g per liter final solution. For example, a composition according to the preparation may comprise 2,691 g of sodium chloride per liter final solution.

Compositions according to the preparation comprise potassium chloride in an amount of 0.5 to 1.5 g per liter of final solution, preferably in an area where the lower limit is 0.6, 0.7, 0.8, 0.9 or 1.0 g per liter, and the upper limit is independently 1.4, 1.3, 1.2 or 1.1 g per liter, e.g. 0.7 to 1.3 g per liter of final solution. A composition according to the invention may e.g. comprise 1,105 g or 1,015 g of potassium chloride per liter of final solution.

The composition of the preparation is preferably without sodium hydrogen carbonate.

10 10DK 2012 00057 U3

The composition of the preparation comprises 5 to 15 g of organic acid component per liter of final preparation. The organic acid component comprises an organic acid, one or more salts of an organic acid or a mixture of an organic acid and one or more salts of an organic acid.

Preferably, the organic acid component is present in an amount in the range in which the lower limit is 6, 7, 8, 9 or 10 g per liter and the upper limit is independently 14,13,12 or 11 g per liter. eg. 7 to 12 g per liter of final solution, such as 9 to 11 g per liter of final solution. A composition according to the invention may e.g. comprise 10.6 g of organic acid component per liter.

The organic acid is preferably ascorbic acid and / or citric acid, e.g. ascorbic acid.

Preferred salts of an organic acid are alkali metal and alkaline earth metal salts, e.g. a salt may be selected from one or more of sodium, potassium, magnesium and calcium. Preferred salts of ascorbic acid include, for example, sodium ascorbate, potassium ascorbate, magnesium ascorbate and calcium ascorbate. A particularly preferred salt of ascorbic acid is sodium ascorbate. Preferred citric acid salts include sodium citrate, potassium citrate, magnesium citrate and calcium citrate. A particularly preferred salt of citric acid is sodium citrate.

Preferably, the organic acid component comprises both an organic acid and one or more salts of an organic acid. The organic salt or organic salts may be the salt (s) of the same acid as the organic acid (s), or it may be a salt or salts of one or more different organic acids. It is generally convenient that the organic acid salt is a salt of the same acid as the organic acid. Eg. For example, a composition according to the invention may comprise ascorbic acid and sodium ascorbate. A composition may include citric acid and sodium citrate. Alternatively, if the organic acid salt is a salt of a different organic acid, then a composition according to the preparation may e.g. include ascorbic acid and sodium citrate.

11 11DK 2012 00057 U3

Preferably, the organic acid and one or more salts of an organic acid are present in a weight ratio in the range of 1: 9 to 9: 1. The organic acid and / or the salt or salts of an organic acid can in practice be provided as hydrates. If a hydrate is used, the weight and / or weight ratio herein referred to as the weight and / or weight ratio of organic acid or the one or more salts of an organic acid without hydration water is calculated. Preferably, the organic acid and the salt or salts of an organic acid are present in a weight ratio in the range of 2: 8 to 8: 2, more preferably 3: 7 to 7: 3 and most preferably 4: 6 to 6: 4. For example, a composition according to the preparation may contain the organic acid and the salt or salts of an organic acid in a weight ratio of 4.7 to 5.9, e.g. 4.7 g of ascorbic acid and 5.9 g of sodium ascorbate per liter of final solution.

In one embodiment, a composition according to the invention is substantially devoid of an added component comprising citric acid or a salt thereof. Some orange flavors may in themselves include a small amount of citric acid which is not considered essential in this context.

Compositions according to the invention may comprise one or more sweeteners. Sugar based sweeteners are generally not suitable for colon cleansing compositions because the application of unabsorbed sugars to the colon provides a substrate for bacteria. Such sugars can be metabolized by the bacteria to form explosive gases such as hydrogen and methane. The presence of exclusive gases in the colon can be very dangerous when electrical equipment is used during colonoscopy or other methods. Preferred sweeteners include aspartame, potassium sulfam (acesulfame K), sucralose and saccharin and / or combinations thereof. For example, compositions according to the preparation may comprise one or both of aspartame and potassium acesulfame (acesulfame K). For example, compositions according to the preparation may comprise one or both of sucralose and potassium acesulfame (acesulfame K). Alternatively, the compositions of the invention may be substantially free of added sweetening agents, for example to minimize the number of different components of the compositions.

12 12GB 2012 00057 U3

Aspartame may be present in an amount of 0.1 to 0.3 g per liter of final solution, more preferably in an amount in the range in which the lower limit is 0.12, 0.14, 0.16 or 0.18 g per liter, and the upper limit independently thereof is 0.24, 0.22 or 0.20 g per liter, for example 0.11 to 0.25. For example, a composition according to the invention may comprise 0.10 to 0.13 (eg 0.117) or 0.16 to 0.19 (eg 0.175) or 0.22 to 0.25 (eg 0.233 ) g aspartame per liter. For example, a composition according to the preparation may comprise 0.175 g of aspartame per liter of final solution. Compared to the prior art lemon flavoring compositions, it is possible to use a lower amount of aspartame than in the prior art, 0.233 g per liter, when the solution includes an orange flavoring as in the present invention. Eg. 0.175 g of aspartame per liter of final solution is particularly preferred in a composition of the invention.

Acesulfame K may be present in an amount of 0.05 to 0.13 g per liter of final solution, more preferably in an area in which the low limit is 0.07 or 0.09 g per liter and the upper limit is independent. of which 0.12 or 0.11 g per liter. For example, a composition according to the preparation may comprise 0.059 or 0.117 g of acesulfame K per liter, e.g. 0.117 g of acesulfame K per liter of final solution.

While sweeteners can be used to give colon cleansing compositions a more acceptable taste, it is important that compositions are not unacceptably sweet. As mentioned above, creating a composition that is sufficiently acceptable for patients to drink about 2 liters is particularly challenging. Surprisingly, it has been found that solutions of compositions according to the preparation comprising 0.6 g of orange flavor, 0.175 g of aspartame and 0.117 g of acesulfame K have a particularly better taste than the solution of the prior art. These solutions are particularly acceptable for compositions comprising maltodextrin (e.g. 0.28 to 0.56 g per liter) and dextrose (e.g. 0.10 to 0.25 g per liter).

13 13GB 2012 00057 U3 In general, it is not necessary for the compositions according to the invention to include preservatives. Nevertheless, low concentrations of antioxidants or preservatives can be used if desired.

Commercial compositions of the type described herein and in the claims generally have manufacturing and regulatory tolerances of +/- 10% or in some cases +/- 5%.

Accordingly, numerical values herein should preferably be treated with tolerances of +/- 10%, for example +/- 5%.

A preferred composition of the invention is a composition for admixture with water, the composition optionally presenting in two or more parts and comprising per liter of final solution the following components: (a) 90 to 110 g of polyethylene glycol (PEG) having an average molecular weight of 3000 to 4000, (b) 6.5 to 8.5 g of sodium sulfate, (c) 2.5 to 2.9 g of sodium chloride, (d) 0.7 to 1.3 g of potassium chloride, (e) 5 to 15 g of a mixing an organic acid and one or more salts of an organic acid in a weight ratio of the organic acid to one or more salts of an organic acid of 1: 9 to 9: 1, and (f) 0.1 to 0 , 9 g orange flavoring.

Another preferred composition optionally in two or more portions for admixing with water comprises, per liter of final solution, the following components: (a) 95 to 105 g of polyethylene glycol (PEG) 3350 or 4000, (b) 7 to 8 g of sodium sulfate, (c) 2.6 to 2.8 g of sodium chloride, (d) 0.8 to 1.2 g of potassium chloride, (e) 8 to 12 g of a mixture of an organic acid and one or more salts of an organic acid in a weight ratio of the organic acid to one or more salts of an organic acid of 4: 6 to 6: 4, and (f) 0.1 to 0.9 g of orange flavoring.

Compositions according to the invention may comprise one or more sweeteners, although they may be substantially free of added sweeteners. A preferred composition comprises: (g) sweeteners.

A particularly preferred composition optionally in two or more portions for admixing with water comprises, per liter of final solution, the following components: (a) 100 g polyethylene glycol (PEG) 3350, (b) 7.5 g sodium sulfate, (c) 2.691 g sodium chloride, (d) 1.015 g of potassium chloride, (e1) 4.7 g of ascorbic acid, (f2) 5.9 g of sodium ascorbate, (f) 0.6 g of orange dye, (g1) 0.175 g of aspartame, and (g2) 0.117 g of acesulfame K.

A composition can e.g. be in the form of powder, granular or any other suitable physical form. For example, it may be a dry powder composition. "Dry" in this context means that the powder contains a sufficiently low level of moisture so that it is free-flowing. The organic acid component may be coated. Such coating helps maintain the stability of the organic acid component. Organic acids and salts of organic acids may otherwise be unstable in the presence of even small amounts of moisture.

The compositions of the invention may be provided in bulk form. Compositions may also be provided in unit dosage form. A unit dose is usually an amount of composition suitable for the composition of a defined volume of solution for administration to the patient in one treatment. The volume may be any suitable volume; for example, each unit dose may be suitable for preparing the total volume of solution of the composition of the preparation required to use a single colon cleansing treatment. Alternatively, a unit dose may be suitable to produce a defined volume, e.g. a liter of solution of the composition according to the invention, for use in one of the steps of a two-stage or multi-stage purification procedure.

Thus, the preparation provides a unit dose composition for admixture with water, the composition optionally appearing in two or more parts and comprising the following components: (a) 85 to 115 g of polyethylene glycol (PEG) having an average molecular weight of 2500 to 4500; b) 6 to 9 g of sodium sulfate, (c) 2 to 3 g of sodium chloride, (d) 0.5 to 1.5 g of potassium chloride, (e) 5 to 15 g of organic acid component, and (f) orange flavoring.

Unit dose compositions according to the invention have the preferred characteristics described above for the purpose of the compositions according to the invention.

As mentioned above, it has surprisingly been found that dry powder compositions, as set forth herein in Examples, remain sound and without lumps in long-term stability tests. Thus, the preparation further provides a dry powder composition comprising PEG and orange flavor, which composition (i) is substantially glucose-free and (ii) free-flowing and lump-free after 3 months storage at 25 ° C and 60% relative humidity. Eg. is the free-flowing and lump-free after 6, 12, 18 or 24 months of storage in these conditions. The dry powder composition may comprise, in addition to PEG and orange flavoring, an alkaline earth metal or an alkaline earth metal sulfate. An alkali metal or alkaline earth metal sulphate can e.g. be selected from sodium sulfate, potassium sulfate and magnesium sulfate. Preferably, sodium sulfate is present. Eg. it may comprise more than one among sodium sulfate, potassium sulfate and magnesium sulfate, e.g. all three. Preferably, orange flavoring comprises dextrose or sucrose. Preferred orange flavors are described above. Preferably, the dry composition comprises aspartame. More preferably, the dry powder preparation remains free-flowing after 6 months of storage and 60% relative humidity. Preferably, the dry powder composition remains free-flowing after 3 months of storage at 40 ° C and 75% relative humidity, e.g. the dry powder composition remains stable after 6 months of storage at 40 ° C and 75% relative humidity.

The dry powder composition may further comprise electrolytes, e.g. selected from sodium chloride, potassium chloride and sodium bicarbonate. In one embodiment, the electrolytes may be sodium chloride, potassium chloride, and sodium bicarbonate. In a further embodiment, the electrolytes may be sodium chloride, potassium chloride and sodium sulfate. In yet another embodiment, the electrolytes may be sodium chloride, potassium chloride, sodium bicarbonate and sodium sulfate. The dry powder may further comprise one or more sweetening agents, e.g. selected from acesulfame K, sucralose, aspartame and saccharin.

The preparation further provides a composition comprising an orange flavoring agent for admixture with water to prepare an intestinal cleansing solution. Preferably, the orange flavor is essentially glucose-free. Preferably, the orange flavoring comprises maltodextrin and / or dextrose and / or sucrose. Preferred orange flavors are as described above. Preferably, the composition comprises aspartame. Preferably, the composition comprises acesulfame K. For example. For example, the intestinal cleansing solution may be a PEG-containing intestinal cleansing solution comprising an orange flavoring agent. Such a gut-cleaning solution may further comprise electrolytes, e.g. selected from sodium chloride, potassium chloride, sodium bicarbonate and sodium sulfate. In a preferred embodiment, sodium sulfate is present. In a preferred embodiment, the electrolytes are sodium chloride, potassium chloride and sodium sulfate. Eg. sodium bicarbonate is not present. In an alternative embodiment, the electrolytes include sodium chloride, potassium chloride and sodium bicarbonate. In a further embodiment, the electrolytes are sodium chloride, potassium chloride, sodium bicarbonate and sodium sulfate. The solution may further comprise one or more sweeteners, e.g. selected from acesulfame K, sucralose, aspartame and saccharin. The solution may further comprise an organic acid component e.g. an ascorbate component (e.g., a component comprising ascorbic acid and sodium ascorbate).

18 18DK 2012 00057 U3

The preparation further provides an intestinal cleansing solution comprising an orange flavoring agent. Preferably, the orange flavor is essentially glucose-free. Preferably, the orange flavoring comprises maltodextrin and / or dextrose and / or sucrose.

Preferred orange flavors are as described above. Preferably, the solution comprises aspartame. Such a solution may have the characteristics described immediately above for a composition for admixing with water. In order to be effective, a PEG-containing intestinal cleansing solution is usually provided in a volume greater than 500 ml, e.g. 500 ml to 4000 ml. Eg. For example, a PEG-containing colon cleansing solution may be provided in two doses to constitute a treatment wherein each dose e.g. is from 500 ml to 2000 ml, for example 1000 ml. A composition for admixing with water to prepare a PEG-containing intestinal cleansing solution provides a plurality of components for preparing such volumes of solution.

As stated above, the compositions according to the invention are optionally in two or more parts. If the composition is in two or more parts, the organic acid component is packaged separately from other components of the composition. For example, a first portion of the composition may contain polyethylene glycol, sodium sulfate, sodium chloride, potassium chloride, and orange flavoring components, and a second portion may contain the organic acid component of the composition. In a further embodiment, the sodium sulfate can be packaged separately from the other components. Such an embodiment may comprise two or more, e.g. three or more different parts. Eg. For example, the first portion of the composition may contain polyethylene glycol, sodium chloride, potassium chloride and orange flavoring components. A second portion may contain sodium sulfate and a third portion may contain the organic acid component of the composition. Each of the parts may comprise additional components or may comprise only the component specified. In some embodiments, the flavor component may be provided in a separate portion from the other portion (s). However, in preferred embodiments, the flavor component is packed with the portion containing polyethylene glycol and / or sodium sulfate.

19 19GB 2012 00057 U3 When, for example, the composition is provided in bulk form, two or more parts can be metered or dispensed from metered metering devices or other suitable containers. When the composition is provided in unit dosage form, two or more portions may be provided in small bags or other suitable containers. The contents of the separate small bags or other suitable containers are mixed together at the time of their use to form a complete composition according to the invention.

It is convenient for the patient that a composition according to the invention is provided in the form of a kit, e.g. a box comprising the composition of the manufacture and directions for its use. Such instructions may, for example, indicate use as described below. The kit preferably comprises the composition in a unit dose as described above. The kit may provide the components of a composition according to the invention in any number of parts, e.g. two parts, three parts or four parts. A kit may comprise e.g. a first portion of the composition provided in a first container containing polyethylene glycol, sodium sulfate, sodium chloride, potassium chloride and orange flavoring, and a second portion of the composition is provided in a second container containing the organic acid component where the contents of these containers are together for the preparation of or composition according to the invention. Eg. the container may be a small bag.

In an alternative embodiment of a kit, the sodium sulfate may be packaged separately from other components. Such an embodiment may comprise two or more, e.g. Thus, three or more different parts and a kit may comprise a first part of composition provided in a first container containing polyethylene glycol, sodium chloride, potassium chloride and orange flavoring components, a second part of the composition is provided in a container containing sodium sulfate, and a third part of the composition is provided in a container containing the organic acid component for production. Eg. a container can be a small bag.

In a further embodiment of a kit, the flavoring component can be provided in a separate container from one or more parts.

As discussed further in detail below, it may be desirable for a treatment to involve the patient taking two (or more) doses of the compositions of manufacture in separate steps in one treatment. In situations in which each unit dose composition is intended for use in one of the steps of a two-stage or multi-stage treatment, two or more of the first and second containers (e.g. bags) are provided in the kit, where each other containers (e.g. bags) together are intended to produce a solution of a composition according to the invention, e.g. one liter of solution.

Accordingly, the present invention provides a kit comprising: (a) a first container containing a first composition, the first composition comprising per liter of final solution: (i) 85 to 115 g of polyethylene glycol (PEG) at an average molecular weight of 2500 to 4500; (ii) 6 to 9 g of sodium sulfate, (iii) 2 to 3 g of sodium chloride, (iv) 0.5 to 1.5 g of potassium chloride, and (v) orange flavoring, and (b) another container containing a second composition comprising 5 to 15 g of an organic acid component per liter of final solution.

21 21DK 2012 00057 U3

A preferred kit according to the invention comprises: (a) a first container containing a first composition, the first composition comprising per liter of final solution: (i) 90 to 110 g of polyethyl glycol (PEG) having an average molecular weight of 2500 to 4500, (ii) 6 , 5 to 8.5 g of sodium sulfate; (iii) 0.7 to 1.3 g of sodium chloride, (iv) 0.5 to 1.5 g of potassium chloride, and (v) 0.1 to 0.9 g of orange flavoring, and (b) another container containing another composition comprising 5 to 15 g of a mixture of an organic acid and one or more salts of an organic acid in a weight ratio with the organic acid and one or more salts of an organic acid of 1: 9 to 9: 1 per liter of final solution.

Another preferred kit according to the invention comprises: (a) a first container containing a first composition, the first composition comprising per liter of final solution: (i) 95 to 105 g of polyethylene glycol (PEG) 3350 or 4000; (ii) 7 to 8 g of sodium sulfate, (iii) 2.5 to 2.8 g of sodium chloride, (iv) 0.8 to 1.2 g of potassium chloride, and (v) 0.4 to 0, 7 g of orange flavor, and (b) another container containing a second composition comprising 8 to 12 g of a mixture of an organic acid and one or more salts of an organic acid in a weight ratio of the organic acid to one or more salts. of an organic acid of 4: 6 to 6: 4 per liter of final solution.

When the composition according to the preparation comprises one or more sweeteners, the sweetener (s) may be contained in the first container together with polyethylene glycol, sodium sulfate, sodium chloride, potassium chloride and orange flavoring.

A particularly preferred kit according to the invention comprises: (a) a first container containing a first composition, the first composition comprising per liter of final solution: (i) 100 g PEG 3350, (ii) 7.5 g sodium sulfate, (iii) 2.691 g sodium chloride , (iv) 1.015 g of potassium chloride, (v) 0.6 g of orange flavoring, (vi) 0.175 g of aspartame, and

(vii) 0.117 g of acesulfame K

and (b) a second container containing a second composition comprising 4.7 g of ascorbic acid and 5.9 g of sodium ascorbate per liter of final solution.

Preferred containers include small bags, bottles, tubs, jugs or cans. Eg. For example, the composition may be provided in a container (e.g., a jar) of small volume (e.g., 1 liter) so that the required amount of water can be easily metered onto the powder. Bags are also particularly preferred. It is preferable for one or both the first and second compositions of a kit to be in dry powder form.

A composition according to the invention may be provided as a composition e.g. a dry composition for preparing a solution as set forth above or alternatively as a solution in water. The preparation provides a solution in water of compositions described above. The present invention further provides an aqueous solution comprising water and: (a) 85 to 115 g / l polyethylene glycol (PEG) having an average molecular weight of 2500 to 4500, (b) 6 to 9 g / l sodium sulfate, (c) 2 to 3 g / l sodium chloride, (d) 0.5 to 1.5 g / l potassium chloride, 24 (f) 5 to 15 g / l inorganic acid component, and (f) orange flavoring.

Solutions according to the preparation may be provided in any desired volume, e.g. from 0.2 to 2.5 liters, e.g. from 0.5 to 2 liters, e.g. 0.5 or 1 liter of solution in one or more containers. Solutions of the preparation have favorable properties described above with reference to the compositions. The solution according to the invention has the preferred characteristics described above for the purpose of the compositions according to the invention.

A preferred solution of the preparation comprises: (a) 90 to 110 g / L polyethylene glycol (PEG) having an average molecular weight of 3000 to 4000, (b) 6.5 to 8.5 g / L sodium sulfate, (c) 2.5 to 2.9 g / l sodium chloride, (d) 0.7 to 1.3 g / l potassium chloride, (e) 5 to 15 g / l of a mixture of an organic acid and one or more salts of an organic acid in a weight ratio of the organic acid to one or more salts of an organic acid of 1: 9 to 9: 1, and (f) 0.4 to 0.7 g / l of orange flavor.

Another preferred solution of the preparation comprises: (a) 95 to 105 g / L of polyethylene glycol (PEG) 3350 or 4000; (b) 7 to 8 g / l sodium sulfate, (c) 2.6 to 2.8 g / l sodium chloride, (d) 0.8 to 1.2 g / l potassium chloride, (e) 8 to 12 g / l of a mixture of an organic acid and one or more salts of an organic acid in a weight ratio of the organic acid to one or more salts of an organic acid of 4: 6 to 6: 4, and ( f) 0.4 to 0.7 g / l orange flavoring.

A particularly preferred solution of the preparation comprises: (a) 100 g / l polyethylene glycol (PEG) 3350, (b) 7.5 g / l sodium sulfate, (c) 2.691 g / l sodium chloride, (d) 1.015 g / l potassium chloride, (e1) 4.7 g / l ascorbic acid, (e2) 5.9 g / l sodium ascorbate, (f) 0.6 g / l orange flavor, (g1) 0.175 g / l aspartame, and (g2) 0.117 g / l acesulfam K.

In the solutions of the preparation described above, the amounts of the individual components listed do not include any solutes which may be present in the water used to prepare the solutions; in hard water areas, e.g. be significant amounts of CA 2+ and Mg 2+ carbonates, hydrogen carbonates or sulfates present in tap water.

The present invention also provides an aqueous solution comprising (a) 85 to 115 g / l polyethylene glycol (PEG) having an average molecular weight of 2500 to 4500, (b) 42 to 63 mmol / l sulfate ions, and (c) 118 to 177 mmol / l sodium present as sodium ions, (c1) 41 to 71 mmol / l chloride ions, (d) 6.7 to 20 mmol / l potassium present as potassium ions, (f) orange flavoring, and further comprises (e) 5 to 15 g / l of an organic acid, one or more salts of an organic acid or a mixture of organic acid and one or more salts of an organic acid.

A preferred solution of the preparation comprises: (a) 90 to 110 g / l polyethylene glycol (PEG) having an average molecular weight of 3000 to 4000, (b) 46 to 60 mmol / l sulfate ions, and 27 (GB) 00057 U3 (c) 135 to 170 mmol / l sodium present as sodium ions, (c1) 52 to 67 mmol / l chloride ions, (d) 9.4 to 17 mmol / l potassium present as potassium ions, (f) 0.4 to 0.7 g / l of orange flavor, and further comprises (e) 5 to 15 g / l of a mixture of an organic acid and one or more salts of an organic acid and a weight ratio of the organic acid to one or more salts of an organic acid at 1: 9 to 9: 1.

Another preferred solution of the preparation comprises: (a) 95 to 105 g / l polyethylene glycol (PEG) 3350 or 4000, (b) 49 to 56 mmol / l sulfate ions, and (c) 142 to 160 mmol / l sodium present as sodium ions, (c1) 55 to 64 mmol / l chloride ions, (d) 11 to 16 mmol / l potassium present as potassium ions, (f) 0.4 to 0.7 g / l orange flavor, and further comprises: (e) 8 to 12 g / l of a mixture of an organic acid and one or more salts of an organic acid in a weight ratio of the organic acid to one or more salts of an organic acid of 4: 6 to 6: 4.

28 28DK 2012 00057 U3

A particularly preferred solution of the preparation comprises: (a) 100 g / l polyethylene glycol (PEG) 3350, (b) 52.8 mmol / l sulfate ions, and (c) 152 mmol sodium present as sodium salts, (c1) 59.7 (d) 13.6 mmol / l potassium present as potassium salts, (f) 0.6 g / l orange flavor, (g1) 0.175 g / l aspartame, and further comprises: (e) 56.6 (m 2) 0.58 mmol / l acesulfame species, which acesulfame species comprise acesulfam (6 to 6 mmol / l) of ascorbate species, comprising ascorbic acid, one or more salts of ascorbic acid or a mixture of ascorbic acid, and methyl-1,2,3-axathiazine-4 (3H) -one-2,2-dioxide), one or more salts of acesulfame or a mixture of acesulfame, and one or more salts of acesulfame.

Another particularly preferred solution of the preparation comprises: (a) 100 g / l polyethylene glycol (PEG) 3350, (b) 52.8 mmol / l sulfate ions, (c) 181 mmol / l sodium present as sodium salts , (c1) 59.7 mmol / l chloride ions, (d) 14.2 mmol / l potassium present as potassium salts, (f) 0.6 g / l orange flavor, (g1) 0.175 g / l aspartame, (e) 56.5 mmol / l of ascorbate species, which ascorbate species comprise a mixture of ascorbic acid and ascorbate, and (g (2-dioxide) - ions.

The preparation further provides a composition for admixing with water to prepare a solution according to the preparation.

The present invention further provides a composition for admixing with water comprising the components polyethylene glycol (PEG) having an average molecular weight of 2500 to 4500, sodium sulfate, sodium chloride, potassium chloride and an organic acid component in weight ratios: (a) 85 to 115 polyethylene glycol (PEG) average molecular weight of 2500 to 4500 to (b) 6 to 9 sodium sulfate to (c) 2 to 3 sodium chloride to (d) 0.5 to 1.5 potassium chloride to 30DK 2012 00057 U3 (e) 5 to 15 of an organic acid component , and (f) orange flavoring.

Preferably, such a composition has the preferred characteristics described above. Such a composition may comprise the various components in a weight ratio based on absolute quantities or quantities per liter listed above. Eg. such composition comprises the following components in the following weight ratios: (a) 100 polyethylene glycol (PEG) having an average molecular weight of 2500 to 4500 to (b) 7,500 sodium sulfate to (c) 2,691 sodium chloride to (d) 1,015 potassium chloride to (e1) 4 , 7 ascorbic acid to (e2) 5.9 sodium ascorbate to (f) 0.6 orange flavor.

Preferably, the orange flavoring comprises maltodextrin, e.g. at a level of 70-80% of the flavor by weight, and provides e.g. maltodextrin in a weight ratio to the other components of 0.442. Preferably, the orange flavoring comprises dextrose e.g. at a level of 15 to 25% of the flavor by weight, e.g. dextrose is obtained in a weight ratio to the other components of 0.119. Preferably, the composition further comprises a sweetening agent, e.g. the following in the following weight ratio: 31 31 GB 2012 00057 U3 (g1) 0.175 aspartame, and (g2) 0.117 acesulfame K.

Such a composition may be provided in two or more parts with, for example, components (e1) and (e2) wrapped separately from the other components.

The compositions and solutions of the preparation may be used to purify the colon prior to performing a diagnostic, therapeutic or surgical procedure on the colon, rectum or anus or elsewhere in the stomach. The diagnostic or surgical procedure may e.g. be colonoscopy, barium lavage examination, sigmoidoscopy or colon surgery.

The composition, solution, kit or unit dose of the preparation may be provided for use as a medicament, e.g. for use in purifying the colon.

Accordingly, the present invention also discloses the use of a colon cleansing solution comprising: (a) 85 to 115 g / L polyethylene glycol (PEG) having an average molecular weight of 2500 to 4500, (b) 6 to 9 g / L sodium sulfate, (c) 2 to 3 g / l sodium chloride, (d) 0.5 to 1.5 g / l potassium chloride, (e) 5 to 15 g / l of an organic acid component, and (f) orange flavoring 32 32GB 2012 00057 U3 for the preparation of a composition for purifying a patient's colon, wherein the patient is taking said colon cleansing solution orally.

A solution for use in a method of the preparation has the preferred characteristics described above for the compositions and / or solutions of the preparation.

The exact amount of solution for administration in a method of production will depend on the patient being treated and the particular situation of the patient. Eg. the patient may be an adult. An appropriate volume of cleaning solution for an adult may be from 1.5 to 4 liters, while a proportionally smaller volume of cleaning solution is appropriate for the treatment of young children and a higher volume of cleaning solution is appropriate in patients with prolonged colonic transit times. Typically, 2 liters of cleaning solution is administered to an adult human. Eg. 1 to 2 liters of the colon cleansing solution is consumed by the patient. In one embodiment, the patient consumes an additional amount of clear fluid, e.g. 1 liter.

Preferably, the total volume of the solution is administered over 1 to 4 hours. The 1 to 4 hours may be in a continuous or discontinuous period. In a course of administration using a discontinuous period, a portion of the solution, typically about half, will be administered the evening before the diagnostic, therapeutic or surgical procedure is to take place, with the remaining portion of the solution being administered on or before the procedure.

Discontinuous administration may also mean administration of a first portion of the cleaning solution followed by administration of a clear liquid.

In a preferred cure for taking a cleansing solution according to the preparation, a 2 liter treatment is taken by the patient. The treatment can be taken as part of treatment with 1 liter of cleaning solution taken the evening before a clinical examination or procedure, and 1 liter taken early in the morning on the day of the examination or procedure. Alternatively, 2 liters of cleaning solution can be taken in the evening before the examination or procedure. Patients are asked not to consume solid food from when they start taking the cleansing solution until after the examination or procedure.

Patients may be asked to prepare a first liter of cleaning solution by dissolving the dry powder provided (for example, provided in two bags with the organic acid component in one bag and the remaining components in a separate bag) in water, and then ingesting the solution. over 1 to 2 hours e.g. by drinking a glass every 10-15 minutes. They may then be asked to prepare and drink the second liter of cleaning solution. Patients may be advised to drink an additional liter of clear fluid to prevent them from feeling very thirsty and dehydrated. Water, clear soup, fruit juice (without pulp), liquid drinks, tea or coffee (without milk) are all suitable.

One possible variant of the above protocol is a protocol in which the entire treatment dose for colon cleansing for adult patients is 2 liters (about 64 fluid ounces) of cleansing solution (with 1 additional liter of clear fluid) taken orally prior to colonoscopy or other examination or procedure in a of the following pathways: 1) Shared dose regimen: The evening before colonoscopy or any other examination or procedure, the first liter (about 32 fluid ounces) of cleansing solution is taken over one hour (one glass of 250 ml / 8 fluid ounces every 15 minutes). and then 0.5 liters (about 16 fluid ounces) of clear liquid. Then, in the morning for the colonoscopy or other examination or procedure, the second liter (about 32 fluid ounces) of cleansing solution is taken over an hour and then 0.5 liters (about 16 fluid ounces) of clear fluid at least one hour prior to the start of the colonoscopy.

2.) Cure in the evening alone (full dose): Around 7 p.m. At about 18:00 in the evening before the colonoscopy or another examination or procedure, a first liter of cleaning solution is taken over an hour (a glass of 250 ml / 8 fluid ounces every 15 minutes) and then about 1.5 hours later another liter of cleaning solution (about 32 fluid ounces) is taken over an hour. In addition, 1 liter (approximately 32 fluid ounces) is consumed in the evening before the colonoscopy or other examination or procedure.

examples

The following non-limiting examples illustrate the creation.

The flavors tested included Orange Flavor 1, Orange Flavor 2 and Orange Flavor 3. MOVIPREP® (available from Norgine Limited, New Road, Hengoed, Mid Glamorgan, CF82 8SJ, England), a co-lemon cleansing product comprising a lemon flavor (Hunger Lemon V3938-1N1) was used for comparison.

Orange Flavor 1 includes 72-76 wt% corn maltodextrin and 19-21 wt% dextrose, nature-identical flavors, natural flavors and natural flavors. It is essentially without sucrose.

Orange Flavor 2 comprises 35-50 wt% corn maltodextrin and 30-35 wt% sucrose. It also includes flavoring, starch and rubber. It is essentially without dextrose.

Orange Flavor 3 comprises 90-95 wt% maltodextrin, terpenic orange oil and rubber. It is essentially without dextrose and essentially without sucrose.

(weight% is relative to the weight of the flavorings).

In each of Examples 1 to 4, ascorbic acid and sodium ascorbate were provided in a bag (bag B) as shown in Table 1 b, and the other components were provided in a separate bag (bag A) as shown in Table 1a. Each bag A used in Examples 1, 2 and 4 also included the flavoring and sweetening agent in the respective amounts set forth in Tables 2, 3 and 5. In each case, bags A and B were mixed together and added water to a liter (to produce a "sample").

35 35GB 2012 00057 U3

Table 1a: Composition per liter of sample - bag A

Component Amount (g) PEG 3350 100,000 Sodium Sulfate 7,500 Sodium Chloride 2,691 Potassium Chloride 1,015 Flavoring / Sweetening See Table 2-5

5 Table 1 b: Composition per liter of sample - bag B

Ascorbic acid 4.700 Sodium umascorbate 5.900

Example 1: Comparison of appetite of different flavored co-cleanse preparations 10 12 healthy volunteers in a western country were given samples of 5 different flavored co-cleanse preparations and asked to evaluate their appetite separately on a scale of 1 (low) to 10 (high).

The results of the appetite tests on cooled solutions are shown in Table 2.

Table 2: Appetite score

Example No. Flavor Flavor Flavor (g) Aspartame (g) Acesulfame K (g) Flavor Score (Average) 1-1 Orange Flavor 1 0.4 0.175 0.117 6.17 1-2 Orange Flavor 2 0.5 0.175 0.117 6.08 1 -3 Orange Flavor 3 0.6 0.175 0.117 5.92 1-4 Orange Flavor 4 0.4 0.175 0.117 4.92 36 DK 2012 00057 U3

Compare. 1-5 MOVIPREP Ungerer Lemon V3938-1N1) 0.34 0.233 0.117 4.92

As seen in Table 2, the solutions comprising Orange Flavor 1 or Orange Flavor 2 were preferred for the prior art citrus flavored solution. Orange Flavor 3 was not inferior to the prior art resolution. The preferred solutions 1-1, 1-2 and 1-3 contained Orange Flavor 1 and Orange Flavor 2 which comprise maltodextrin at the levels listed above. The solution comprising Orange Flavor 1 was particularly preferred. The flavor in the solution included dextrose. Solutions 1 -1,1-2 were clear, solution 1 -4 was slightly opaque and solution 1 -3 was cloudy.

10

Example 2: Comparison of appetite of various orange-flavored colon cleansing solutions

A group of healthy volunteers in an eastern country were given samples of 4 different to -15 flavored colon solutions and asked to evaluate the appetite of each of the solutions on a scale of 1 (low) to 10 (high). The results of the appetite tests are shown in Table 3. The number of patients receiving each solution is shown in the table.

20 Table 3: Appetite score

Example No. Flavor n Flavor (g) Aspartame (g) Potassium acesulfame (g) Score (average) 2-1 Orange Flavor 1 10 0.225 0.117 0.059 6.6 2-2 Orange Flavor 1 7 0.6 0.175 0.117 6, 86 2-3 Orange Flavor 2 9 0.6 0.175 0.117 5.8 2-4 Orange Flavor 3 5 0.6 0.175 0.117 4.8

As can be seen in Table 3, the orange flavored solutions in which the flavoring included maltodextrin at a level similar to that of Orange Flavor 1 and Orange Fla- 37 37 GB 2012 00057 U3 vour 2 were preferred. The solution comprising Orange Flavor 1 was particularly preferred, especially when the flavoring was present at a level of 0.6 g per liter of solution. The flavoring in this solution also included dextrose.

Example 3: Comparison of appetite of different tasting colon cleansing solutions

A further study was conducted in which 15 healthy volunteers in a western country were given samples of 4 different tasting colon cleansing solutions 10 (comprising Orange Flavor 1, Orange Flavor 2, Orange Flavor 3 or prior art lemon) and asked to evaluate the appetite of each of the the cooled solutions on a scale of 1 (low) to 10 (high). Flavors may vary between cultures, but it is more efficient to manufacture and register the same pharmaceutical product in several countries. Accordingly, the results of the experiments 15 in Example 1 and Example 2 and the additional study were pooled to give the average appetite as shown in Table 4.

Table 4: Average appetite score

Flavor Total n Flavor (g) Aspartame (g) Potassium acesulfame (g) Score (average) Orange Flavor 124 0.6, 0.5 or 0.4 0.175 or 0.117 0.117 or 0.059 5.62 MOVIPREP (Hunger Lemon V3938 -1N1) 27 0.34 0.233 0.117 4.63 20

As seen in Table 4, the orange flavoring solutions were preferred over the prior art lemon flavoring solution.

Example 4: Comparison of appetite of different levels of sea salt and Orange Flavor 38 38GB 2012 00057 U3 4 healthy volunteers were given samples of 8 different colon cleansing solutions, each containing a different amount of sweetener (either aspartame or sucralose) and flavoring (Orange Flavor 1) and asked to evaluate the appetite of each of the solutions on a scale of 1 (low) to 10 (high). In addition to the flavor and sweetener listed in Table 5, the samples also included 0.117 g of acesul fam K. The responses are summarized in Table 5. For three of the samples, only three of the volunteers provided a taste level evaluation.

10

Table 5: Appetite score

Ex. No. Amount of flavoring 1 (g) and sweetener (g) Average score Sweetener level Experienced flavor level Too high OK Too low OK too low 4-1 Orange Flavor 1 0.6 Aspartame 0.233 7.50 2 2 - - 3 1 4 -2 Orange Flavor 1 0.6 Aspartame 0.175 8.25 - 4 - - 4 4-3 Orange Flavor 1 0.5 Aspartame 0.233 7.00 1 2 1 - 2 2 4-4 Orange Flavor 1 0.5 Aspartame 0.175 7 , 00 - 4 - - 2 2 4-5 Orange Flavor 1 0.6 Sucralose 0.233 6.25 - 3 1 - 1 * 2 * 4-6 Orange Flavor 1 0.6 Sucralose 0.175 5.75 - 2 2 - - 3 * 4-7 Orange Flavor 1 0.5 Sucralose 0.233 7.25 - 3 1 - 3 * - 4-8 Orange Flavor 1 0.5 Sucralose 0.175 5.5 - 2 2 - 1 3 results were obtained for 3 people only these data points.

15 39 39GB 2012 00057 U3

As seen in Table 5, Orange Flavor 1 at a concentration of 0.6 g per liter with aspartame at a concentration of 0.175 g per liter was found to be the most appetizing combination. It is the combination of Example 4-2 which is the same as Example 2-2.

5

Example 5: Comparison of appetite of orange flavored colon cleansing preparations 7 healthy volunteers were given samples of 6 different orange flavored colon cleansing solutions and asked to evaluate the appetite of each on a scale of 1 (low) to 10 (high). One of the solutions (5-3) included Orange Flavor 1 as used in Examples 1 to 4, and the other 5 solutions included various variations of this flavoring. The Bag A composition contained the components of Table 1a together with 0.175 g per liter of aspartame and 0.117 g per liter of acesul-fam fam K, and orange flavoring. The bag B composition was shown in Table 1b. The 6 different orange flavors each contained the same amounts of natural flavors, natural flavors and natural flavors, and were essentially free of sucrose. However, each included different proportions of corn maltodextrin and corn dextrose as shown in Table 6a, with the 20 amounts shown as% in Table 6b. Example 5-3 is identical to Examples 2-2 and 4-2. The results of the appetite tests are shown in Table 6a.

Table 6a: Appetite score

Eks.nr. Weight of maltodextrin (g) Weight of dextrose (g) Weight of other flavor components (g) Taste score (average) 5-1 0.442 0.000 0.039 4.3 5-2 0.442 0.060 0.039 4.1 5-3 0.442 0.119 0.039 4.7 5-4 0.442 0.239 0.039 5.4 5-5 0.663 0.119 0.039 4.3 5-6 0.884 0.119 0.039 4.6 25 Table 6b: Quantities of components as percentages by weight 40 40DK 2012 00057 U3

Ex. No. Maltodextrin Dextrose Weight (g) weight% flavoring weight% dry composition weight (g) weight% flavoring weight% dry composition 5-1 0.442 91.89% 0.36% 0.000 0% 0% 5-2 0.442 81.70 % 0.36% 0.060 11.09% 0.05% 5-3 0.442 73.67% 0.36% 0.119 19.83% 0.10% 5-4 0.442 61.39% 0.36% 0.239 33, 19% 0.19% 5-5 0.663 80.76% 0.54% 0.119 14.50% 0.10% 5-6 0.884 84.84% 0.72% 0.119 11.42% 0.10%

As seen in Table 6a when comparing the taste score for example 5-1 to 5-4 (all of which comprise the same amount of maltodextrin), examples containing 0.119 g or 0.239 g dextrose were preferred for the samples containing minor dextrose. A comparison of the taste scores for example 5-3, 5-5 and 5-6 (all of which comprise the same amount of dextrose) shows that Examples 5-4 comprising 0.442 g of maltodextrin were preferred for Examples 5-5 and 5-6 comprising greater amounts of maltodextrin.

10

It is seen that samples comprising orange flavor containing 0.119 g or 0.239 g dextrose per liter are preferred for samples containing less dextrose and samples containing orange flavor containing 0.442 g maltodextrin per liter are preferred for samples containing larger amounts of maltodextrin.

15

Example 6a: Long-term stability of a composition according to the invention.

Samples containing the components of Table 1a with 0.600 g Orange Flavor 20 1 or 0.600 g Orange Flavor 3 were tested for long-term stability.

Table 7: Composition of dry powders for long-term testing: 41 DK 2012 00057 U3

Component Example 6-1 Amount (g) Example 6-2 Amount (g) PEG 3350 100,000 100,000 Sodium sulphate (anhydrous) 7,500 7,500 Sodium chloride 2,691 2,691 Potassium chloride 1,015 1,015 Aspartame 0.175 0.175 Potassium acesulfame 0.117 0.117 Orange Flavor 1 0.600 - Orange Flavor

Thus, the compositions of Example 6-1 comprise the same components in the same amounts as in Examples 2-2, 4-2 and 5-3. The compositions of Examples 6-2 comprised the same components in the same amounts as Examples 2-4. The components shown in Table 7 were packed in bags (of the same type used for the marketed product sold under the name MOVIPREP®) and sealed. Three different batches of the composition of Example 6-1 were tested. Two different batches of the composition of Example 6-2 were tested. The bags were placed under various conditions: 10 (a) 25 ° C / 60% RH for 24 months for example 6-1 and 12 months for example 6-2 (b) 40 ° C / 75% RH for 6 months for Examples 6-1 and 6-2.

15

The batches of Example 6-1 under conditions (a) were assessed at 1, 3, 6, 9, 12, 18 and 24 months. The batches in Example 6-2 under conditions (a) were evaluated at 1.3, 6, 9 and 12 months. The batches of both examples under conditions (b) were assessed at 1, 3 and 6 months. The ratings were based on the following 20 criteria:

Opalization PEG3350 content

Description of visual appearance Color of solution 42 GB 2012 00057 U3

potassium

Chlorine

moisture content

recovery time

Taste

sodium

sulphate

pH

formaldehyde Content

Smell

All samples were within acceptable tolerances for each criterion under both sets of conditions (25 ° C / 60% RH and 40 ° C / 75% RH). In particular, all samples were free-flowing with no visible lumps at any time under the conditions of both sets.

Comparative Example 6b: Comparison with the long-term stability of a prior art composition.

Laxido Orange is a constipation treatment marketed by Galen Limited (see http://www.galen.co.uk) which includes 13,125 g of PEG 3350, 350.7 mg of sodium chloride, 178.5 mg of sodium bicarbonate, 46.6 mg of potassium chloride , potassium acesulfame and orange flavoring, and comes as a dry powder.

Samples of Laxido Orange dry powder were subjected to a 6 month stability test as described in Example 6a. The samples were within the acceptable tolerances for most of the criteria under both sets of conditions (25 ° C / 60% RH and 40 ° C / 75% RH). However, the samples had small visible lumps both at the time of 3 months and 6 months for both sets of conditions.

Thus, samples of Laxido Orange were degraded during the trial period of 3 to 6 months. As seen above in Example 6a, the orange flavoring compositions of the manufacture do not form lumps in the stability tests at 3 or 6 months.

Claims (30)

43 43GB 2012 00057 U3 1. Dry composition for admixture with water, the composition optionally appearing in two or more parts and comprising per liter of final solution the following components: (a) 85 to 115 g of polyethylene glycol (PEG) having an average molecular weight of 2500 to 4500, (b) 6 to 9 g of sodium sulfate, (c) 2 to 3 g of sodium chloride, (d) 0.5 to 1.5 g of potassium chloride, (e) 5 to 15 g of an organic acid component, and (f) orange flavoring. The composition of claim 1, wherein the orange flavoring comprises maltodextrin in an amount of 30 to 80% by weight of the flavoring. The composition of claim 1, wherein the orange flavoring comprises maltodextrin in an amount of 70 to 80% by weight of the flavoring. The composition of claim 2 or 3, wherein the maltodextrin is corn maltodextrin. A composition according to any one of claims 1 to 4, wherein the orange flavoring comprises dextrose in an amount of 15 to 25% by weight of the flavoring. A composition according to any one of claims 1 to 5, wherein the orange flavoring substance is substantially rubber-free. 44 44GB 2012 00057 U3 A composition according to any one of claims 1 to 6, wherein the orange flavoring comprises less than 2% by weight of organic components, other than the flavorings and components. A composition according to any one of claims 1 to 7, wherein the orange flavoring agent is present in an amount of 0.1 to 0.9 g per liter of final solution. A composition according to any one of claims 1 to 8, wherein the composition comprises a sweetening agent, e.g. one or both of aspartame and potassium acesul fam (acesulfame K). The composition of claim 9, wherein aspartame is present in an amount of 0.175 g per liter of final solution. The composition of claim 9 or claim 10, wherein potassium acesulfame is present in an amount of 0.117 g per liter of final solution. A composition according to any one of claims 1 to 11 comprising ascorbic acid and sodium ascorbate. A composition according to any one of claims 1 to 12 comprising per liter of final solution, the following components: (a) 100 g of polyethylene glycol (PEG) 3350, (b) 7.5 g of sodium sulfate, (c) 2,691 g of sodium chloride, (d) 1,015 (g) Potassium Chloride, (e1) 4.7 g Ascorbic Acid, 45g 2012 00057 U3 (e2) 5.9 g Sodium Ascorbate, (f) 0.6 g Orange Flavor, (g1) 0.175 g Aspartame, and (g2) 0.117 g Acesulfame K . Aqueous solution comprising water and (a) 85 to 115 g / L polyethylene glycol (PEG) having an average molecular weight of 2500 to 4500, (b) 6 to 9 g / L sodium sulfate, (c) 2 to 3 g / L sodium chloride , (d) 0.5 to 1.5 g / L potassium chloride, (e) 5 to 15 g / L of an organic acid component, and (f) orange flavoring. A kit providing the components of a composition according to any one of claims 1 to 13 in two or more parts. The kit of claim 15 comprising: (a) a first container containing a first composition, said first composition comprising per liter of final solution: (i) 85 to 115 g of polyethylene glycol (PEG) having an average molecular weight of 2500 to 4500; (Ii) 6 to 9 g of sodium sulfate, (iii) 2 to 3 g of sodium chloride, (iv) 0.5 to 1.5 g of potassium chloride, and (v) orange flavoring and (b) a second container containing a different composition comprising 5 to 15 g of an organic acid component per liter of final solution. The kit of claim 16 comprising two bags comprising the components: POSE 1 PEG 3350: 100,000 g Sodium sulfate 7,500 g Sodium chloride 2,691 g Potassium chloride 1,015 g Aspartame 0.175 g Acesulfam K 0.117 g Orange flavoring 0.6 g POSE 2 Ascorbic acid 4,700 g Sodium ascorbate 5,900 18. A unit dose composition for admixture with water, wherein the composition may appear in two or more parts and comprises the following components: 47 to 47 (a) 85 to 115 g of polyethylene glycol (PEG) having an average molecular weight of 2500 to 4500, (b) 6 to 9 g of sodium sulfate, (c) 2 to 3 g of sodium chloride, (d) 0.5 to 1.5 g of potassium chloride, (e) 5 to 15 g of an organic acid component, and (f) orange flavoring. A solution according to claim 14, a kit according to claim 15, 16 or 17 or a unit dose according to claim 18, wherein the solution, kit or unit dose has one or more characteristics of a composition as claimed in any one or more of claims 2 to 13. Use of a colon cleansing solution comprising: (a) 85 to 115 g of polyethylene glycol (PEG) having an average molecular weight of 2500 to 4500, (b) 6 to 9 g of sodium sulfate, (c) 2 to 3 g of sodium chloride, (d) 0 , 5 to 1.5 g of potassium chloride, (e) 5 to 15 g of an organic acid component, and (f) orange flavoring 48 to prepare a composition for purifying a patient's colon where the patient is taking said colon cleansing solution orally. Use according to claim 20, in which 1 to 2 liters of the colon cleansing solution is consumed by the patient. Use according to claim 21, in which the colon cleansing solution is taken as a divided treatment with 1 liter of cleaning solution taken as the evening before a clinical examination or procedure, and 1 liter is taken early in the morning on the day of the examination or procedure. Use according to claim 20 or 21, wherein the colon cleansing solution is taken in the evening before an examination or procedure. Use according to any one of claims 20 to 23, wherein the patient further consumes one liter of clear liquid. Use according to claim 20, wherein the evening before a colonoscopy or other examination or procedure a first liter of cleaning solution is consumed in the course of approx. One liter and then 0.5 liters of clear liquid are consumed, and in the morning for the colonoscopy or another examination or procedure another liter of cleaning solution is consumed within approx. 1 hour followed by 0.5 liters of clear liquid. Use according to claim 20, wherein the first liter of cleaning solution is consumed in the evening before a colonoscopy or other examination or procedure. 1 hour and then approx. 1.5 hours later another liter of cleaning solution is consumed over ca. an hour with an additional liter of clear liquid consumed during the evening. A dry powder composition comprising PEG and orange flavoring, which composition (i) is substantially glucose free and (ii) free-flowing and lump-free after 3 months storage at 25 ° C and 60% relative humidity. DK 2012 00057 U3 49 A composition comprising an orange flavoring agent for admixture with water to prepare a gut cleaning solution. 29. Intestinal cleansing solution comprising an orange flavoring agent. A composition according to claim 27 or claim 28 or a gut cleaning solution according to claim 29, wherein the orange flavoring agent has one or more features disclosed in any one or more of claims 2 to 8.