BE1019425A5 - IMPROVEMENTS IN COMPOSITIONS AND RELATING TO COLON CLEANING COMPOSITIONS. - Google Patents

Abstract

The invention provides a dry composition for mixing with water, wherein the composition is optionally presented in two or more parts and comprises, per liter of solution to be prepared, the following compostants: (a) from 85 to 115g polyethylene glycol (PEG) having an average molecular weight of 2500 to 4500; (b) from 6 to 9 g of sodium sulfate; (c) 2 to 3 g of sodium chloride; (d) from 0.5 to 1.5 g of potassium chloride; (e) from 5 to 15 g of an organic acid component; and (f) orange flavoring. Also provided are solutions, kits, unit doses and methods that comprise or utilize the compositions.

Description

"Improvements in compositions and relating to 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 coionic evacuators.

Colon cleansing is important before many surgical or diagnostic procedures, including colonoscopy, barium enema examination, sigmoidoscopy, and colon surgery. Such procedures are often performed on an outpatient basis and it is therefore desirable that colon cleansing be done by the patient at home prior to arrival at the hospital or office where the procedure is to take place. It is therefore important that the patient's compliance be good without medical supervision so that a satisfactory cleaning of the colon is done before the procedure.

Intestinal lavage for which a large volume of an electrolyte solution containing sodium sulfate and polyethylene glycol (PEG) is ingested is one of the most common methods for colon cleansing. These osmotically active agents are not absorbable or are difficult to absorb and thus retain water in the intestine, resulting in copious diarrhea and colon cleansing. Although effective, these compositions have a very salty taste that has a negative effect on 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 agents to mask salinity and make the compositions more palatable. However, it has proved difficult to reduce or adequately mask the very unpleasant salty taste of these compositions while maintaining effective amounts of osmotic salts.

In addition, for effective cleaning, many of these compositions must be ingested in amounts between 2 and 4 liters. The unpleasant taste of these compositions combined with the large volumes that must be ingested is often the cause of nausea or vomiting, resulting in insufficient compliance of the patient and non-consumption of the total volume of solution.

A number of improved colon cleansing compositions are described in WO 2004/037292. The compositions described therein are effective despite being taken in less volume than other colon cleansing solutions. Typically, only 2 liters of solution should be taken by the patient. A colon cleansing composition according to WO 2004/037292 which comprises PEG, sodium sulfate, an ascorbate component and a lemon flavoring is marketed under the trademark MOVIPREP® (registered trademark of Velinor AG, a member of the group). Norgine). In the MOVIPREP product, PEG 3350, sodium sulfate, sodium chloride, potassium chloride, sweetener and lemon flavoring are supplied in a bag A and the ascorbate component (comprising ascorbic acid and sodium ascorbate) is supplied in a B bag.

Despite the success of MOVIPREP flavored with lemon, there is still room for improving taste, further reducing one of the main obstacles to patient compliance. Improving the taste of organic acid-containing colon cleansers or their salts, for example the ascorbate component in the MOVIPREP composition, presents a particular challenge in view of the taste effects to which the organic acids themselves contribute. It is difficult to mask the salinity of the colon cleansing compositions without rendering the compositions excessively sweet.

An important consideration for the viability of any medical product is the period of validity and stability of the product over time. It must be possible for medical products to be stored and / or distributed over extended periods of time, typically at least one year, more usually 2 or 3 years from the date of manufacture. There are several criteria to consider when evaluating the stability and validity of a product: it is important that the product remains sterile throughout its validity. It is also important that it remains effective throughout its validity, including that its taste does not deteriorate. In compositions which include flavoring agents, this includes the fact that the intensity of the flavoring agents should not significantly decrease during its period of validity. Finally, the physical appearance and the physical properties must not change significantly during the period of validity; this includes the fact that a powder must remain fluid and must not form aggregates over time. Nor should it discolor significantly. There is a risk that aggregates or lumps that appear in a stored powder may not be adequately dissolved when a patient prepares a solution with the powder. Incomplete dissolution may result in a solution whose constituents are present in incorrect amounts and such a solution may have altered efficacy and / or taste.

There have been known medical products containing orange flavoring which became lumpy or whose orange taste decreased below the desired level in a 6-month stability test and was therefore of short duration validity. This question of stability is a particular problem for products comprising ethylene glycol and electrolytes. For example, Laxido Orange is a constipation treatment marketed by Galen Limited (see http://www.qalen.co.uk) which contains 13.125 g of PEG, 350.7 mg of sodium chloride, 178.5 mg of sodium hydrogen carbonate, 46.6 mg of potassium chloride, potassium acesulfame and orange flavoring (containing glucose) and is supplied as a dry powder. To use it, the powder is mixed with 125 ml of water. The performance of Laxido Orange dry powder samples has been found to be poor in the 3 and 6 month stability tests. In the samples (in their pouch packaging as sold) stored at 25 ° C and 60% relative humidity, and in samples stored at 40 ° C and 75% relative humidity for 3 or 6 months, the powder that was originally white becomes off-white and forms small lumps. The person skilled in the art would thus be dissuaded from developing compositions of PEG and electrolytes flavored with orange.

Surprisingly, it has been found by the present inventors that when the flavoring in sachet A of the MOVIPREP composition is orange (instead of lemon), despite the fact that it comprises a mixture of PEG and electrolytes, the composition of the bag A passes all the tests of physical stability of 24 months, including for example the fact of remaining fluid and essentially free of lumps. It has also been found that solutions prepared with the contents of sachets A and B of the MOVIPREP product in which the flavoring agent in sachet A is orange (instead of lemon) are stable for a period of 24 hours in the stability tests in solution, including after storage for 12 months.

Current inventors have found that orange-flavored compositions have a better cost and acceptable stability in storage. Therefore, the present invention provides a dry composition to be mixed with water, comprising per liter of solution to be prepared, the following components: (a) 85 to 115 g of polyethylene glycol (PEG) having an average molecular weight of 2500 at 4500; (b) 6-9 g of sodium sulfate; (c) 2-3 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.

"Dry" means in this context that the composition does not contain added liquid, especially added water. For example, it is substantially free of water. Small amounts of water or other liquid may be present in some of the components even when supplied as "dry", for example a salt may be present as hydrate. Such amounts of water are not considered substantial. "Solution" includes in this context any mixture resulting from mixing the composition with water, whether completely dissolved or not. The composition is optionally presented in two or more parts. For example, it may be presented as a part A comprising components (a) to (d) and (f), and a part B comprising component (e). Component (f) may be optionally provided in a third part (part C) instead of being in part A or also in part A.

The orange flavoring agent in the compositions of the invention preferably comprises maltodextrin. Surprisingly, it has been found that solutions of compositions of the invention comprising aromatising agent containing maltodextrin as one of its components have a particularly acceptable taste, especially compositions containing maltodextrin in a quantity of 20%. at 90% by weight of the flavoring. Maltodextrin is present in the flavoring agent preferably in an amount of 20 to 80% by weight. For example, it is present in an amount of 35 to 80% by weight, for example 70 to 80% by weight of the flavoring. It has been found that a solution comprising a flavoring agent in which maltodextrin is present in an amount of less than 80% by weight of the flavoring agent is preferred over other solutions containing more maltodextrin. Maltodextrin is present in the flavoring agent preferably in an amount of less than 80% by weight of the flavoring agent.

The compositions of the invention preferably comprise orange flavoring in an amount of 0.1 to 0.9 g per liter of solution to be prepared, such as 0.3 to 0.8 g per liter, for example from 0.4 to 0.7 g per liter of solution to be prepared, for example from 0.5 to 0.7 g per liter of solution to be prepared, for example 0.6 g per liter. The compositions of the invention preferably comprise orange flavoring in an amount of greater than 0.5 g per liter, for example more than 0.55 g per liter of solution to be prepared. The amount of flavoring needed to provide the most acceptable taste depends to some extent on the levels of some of the other components present. If components (a) to (e) are present in amounts at the lower ends of their ranges, less flavoring is required. This applies to some extent to salts, but in particular to the organic acid component. It has been found that for a composition comprising from 8 to 12 g of organic acid component per liter of solution (for example 4.7 g of ascorbic acid and 5.9 g of sodium ascorbate), from 0.2 to 0.65 g of orange flavoring per liter of solution to be prepared (for example more than 0.5 g, for example 0.6 g) provides a particularly acceptable solution. In a composition comprising less organic acid component, a lesser amount of orange flavoring may be suitable. For example, if from 5 to 8 g of organic acid component per liter of solution were present, then 0.2 to 0.5 g of orange flavorant per liter of solution to be prepared may be adequate. If from 12 to 15 g of organic acid component per liter of solution were present, then 0.5 to 0.9 g of orange flavorant per liter of solution to be prepared might be needed.

In the case where the flavoring agent comprises maltodextrin in an amount of 20 to 90% by weight of the flavoring agent, from 0.3 to 0.8 g of orange flavoring per liter of solution gives 0, 0.6 to 0.72 g of maltodextrin per liter of solution and thus the maltodextrin represents from 0.042 to 0.73% of the dry composition by weight. In the case where the flavoring agent 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 from 0.14 to 0, 56 g of maltodextrin per liter of solution and thus the maltodextrin represents from 0.097 to 0.57% of the dry composition by weight. In the case where the flavoring comprises maltodextrin in an amount of 70 to 80% by weight of the flavoring agent, 0.4 to 0.7 g of orange flavoring per liter of solution provides 0, 28 to 0.56 g of maltodextrin per liter of solution and thus the maltodextrin is from 0.20 to 0.56% of the dry composition by weight. It has been found that a solution containing 0.442 g of maltodextrin per liter is preferable to solutions containing larger amounts of maltodextrin per liter. Accordingly, a preferred composition of the invention. comprises less than 0.56 g of maltodextrin per liter of solution, it contains, for example, from 0.28 to 0.56 g, for example from 0.35 to 0.5 g, for example from 0.41 to 0.47 g. g of maltodextrin per liter of solution to be prepared.

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

Maltodextrin in a flavoring for use in a composition of the invention may be from any suitable source. For example, it may be corn maltodextrin, potato maltodextrin or wheat maltodextrin. This is for example corn maltodextrin.

The orange flavoring may comprise a sugar, for example sucrose or dextrose (d-glucose), preferably dextrose. It may for example comprise 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 30 to 50%, for example 30 to 35% or 35 to 45%. For example, an orange flavoring may include the same amount of sucrose as maltodextrin.

In the case where the flavor comprises dextrose in an amount of 10 to 30% by weight of the flavoring, 0.3 to 0.8 g of orange flavoring per liter of solution provides 0.03 at 0.24 g of dextrose per liter of solution, and thus the dextrose represents from 0.021 to 0.24% of the dry composition by weight. In the case where the flavoring comprises dextrose in an amount of 15 to 25% by weight of the flavoring, 0.4 to 0.7 g of orange flavoring per liter of solution provides 0.06 at 0.175 g of dextrose per liter of solution, and thus the dextrose represents from 0.041 to 0.18% of the dry composition by weight. It has been found that a solution containing from 0.119 to 0.239 grams of dextrose per liter is preferable to solutions containing less dextrose per liter. Accordingly, a preferred composition of the invention comprises more than 0.10 g of dextrose per liter, for example from 0.10 g to 0.25 g of dextrose per liter of solution to be prepared. Since it is generally desirable to limit the amounts of sugar in intestinal preparations, a preferred composition of the invention comprises less than 0.20 g of dextrose per liter of solution to be prepared, for example from 0.100 g to 0.180 g, for example from 0.10 to 0.130 g of dextrose per liter of solution to be prepared.

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

The dextrose in a flavoring agent for use in a composition of the invention may be from any suitable source. For example, it can be derived from maize, rice, cassava, spathe or sago. This is for example corn dextrose. In a composition of the invention which comprises maltodextrin and dextrose, both may be from the same source.

In the case where the flavoring comprises sucrose in an amount of 35 to 45% by weight of the flavoring, 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 thus the sucrose represents from 0.097 to 0.32% of the dry composition by weight.

The orange flavoring may comprise chemically identical preparations to natural substances and / or natural flavoring preparations or components, eg orange oil, terpenes and terpenoids. Alternatively, the orange flavorant may be terpene-free or may include terpenes in such small amount that it is considered terpene-free in the flavor industry. In a preferred embodiment, the orange flavorant is substantially free of gum. Alternatively, it may comprise one or more gums, for example gum arabic, also known as gum acacia. The orange flavoring agent preferably comprises less than 2% by weight (based on the weight of the flavoring) of organic components other than flavoring preparations and components, for example less than 1%, for example less than 10 ppm. Certain flavoring components may cause aqueous solutions of compositions comprising them to become turbid. Some patients prefer to drink solutions that are clear.

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

Polyethylene glycol (PEG) used in compositions of the invention has an average molecular weight of 2500 to 4500. PEG can have an average molecular weight of 3000 to 4000. For example, the PEG can be PEG 3350 or PEG 4000 as defined in the national pharmacopoeias. Other examples of suitable PEG recognized in some national pharmacopoeias include Macrogols, for example Macrogol 4000. Optionally, PEG used in compositions of the invention may comprise two or more different PEG compounds.

Compositions of the invention comprise PEG in an amount of 85 to 115 g per liter of solution to be prepared, preferably in a range where the lower limit is 90, 95 or 100 g per liter and the upper limit is, independently, 110 or 105 g per liter; for example from 90 to 110 g per liter of solution to be prepared. For example, a composition of the invention may comprise 100 g of PEG per liter, for example 100 g of PEG 3350 per liter of solution to be prepared.

Compositions of the invention comprise sodium sulfate in an amount of 6 to 9 g per liter of solution to be prepared, preferably in a range in which the lower limit is 6.5, 7 or 7.5 g per liter and the upper limit is, independently, 8.5 or 8 g per liter; for example from 6.5 to 8.5 g per liter of solution to be prepared. For example, a composition of the invention may comprise 7.5 g of sodium sulfate per liter of solution to be prepared. The sodium sulfate in the compositions of the invention is preferably anhydrous.

Compositions of the invention comprise sodium chloride in an amount of 2 to 3 g per liter of solution to be prepared, preferably in a range in which the lower limit is 2.1, 2.2, 2.3. 4 or 2.5 g per liter and the upper limit is, independently, 2.9, 2.8, 2.7 or 2.6 g per liter; for example from 2.5 to 2.9 g per liter of solution to be prepared. For example, a composition of the invention may comprise 2,691 g of sodium chloride per liter of solution to be prepared.

Compositions of the invention comprise potassium chloride in an amount of 0.5 to 1.5 g per liter of solution to be prepared, preferably in a range in which 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; for example from 0.7 to 1.3 g per liter of solution to be prepared. For example, a composition of the invention may comprise 1.105 g or 1.015 g of potassium chloride per liter of solution to be prepared.

Compositions of the invention are preferably free of sodium bicarbonate.

Compositions of the invention comprise from 5 to 15 g of organic acid component per liter of solution to be prepared. 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.

The organic component is preferably present in an amount within a range where 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. liter; for example 7 to 12 g per liter of solution to be prepared, such as 9 to 11 g per liter of solution to be prepared. For example, a composition of the invention may comprise 10.6 g of an organic acid component per liter.

The organic acid is preferably ascorbic acid and / or citric acid, for example ascorbic acid.

Preferred salts of an organic acid are alkali metal or alkaline earth metal salts, for example a salt may be selected from one or more of sodium, potassium, magnesium and calcium.

For example, preferred salts of ascorbic acid include sodium ascorbate, potassium ascorbate, magnesium ascorbate, and calcium ascorbate. A particularly preferred ascorbic acid salt is sodium ascorbate. Preferred citric acid salts include sodium citrate, potassium citrate, magnesium citrate and calcium citrate. A particularly preferred citric acid salt is sodium citrate.

The organic acid component preferably comprises an organic acid and one or more salts of an organic acid. The salt or organic acid salts may be a salt (salts) of the same acid as the organic acid (organic acids) or it may be a salt or salts of a different organic acid (d). different organic acids). It is generally convenient for the organic salt to be a salt of the same acid as the organic acid. For example, a composition of 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 single one of a different organic acid, then a composition of the invention may include, for example, ascorbic acid and sodium citrate.

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

In one embodiment, a composition of the invention is substantially free of an added component comprising citric acid or a salt thereof. Some orange flavoring may intrinsically include a small amount of citric acid that is not considered substantial in this context.

Compositions of the invention may comprise one or more sweeteners. Sugar sweeteners are generally unsuitable for colon cleansing compositions because the provision of unabsorbed sugars in the colon provides a substrate for the bacteria. These sugars can be metabolized by bacteria to form explosive gases such as hydrogen and methane. The presence of explosive gases in the colon can be very dangerous when electrical equipment is to be used during colonoscopy or other procedures. Preferred sweeteners include aspartame, acesulfame potassium (acesulfame K), sacralose and saccharin and / or combinations thereof. For example, compositions of the invention may include aspartame and acesulfame potassium (acesulfame K) or both. For example, compositions of the invention may include sacralose and acesulfame potassium (acesulfame K) or both. Alternatively, compositions of the invention may be substantially free of added sweeteners, for example to reduce the number of different components in the compositions.

Aspartame may be present in an amount of 0.1 to 0.3 g per liter of solution to be prepared, more preferably in an amount within a range in which the lower limit is 0.12, 0.14, 0.16 or 0.18 g per liter and the upper limit is, independently, 0.24, 0.22 or 0.20 g per liter; for example, from 0.11 to 0.25. For example, a composition of the invention may comprise from 0.10 to 0.13 (for example 0.117) or from 0.16 to 0.19 (for example 0.175) or from 0.22 to 0.25 (for example 0.233) g of aspartame per liter. For example, a composition of the invention may comprise 0.175 g of aspartame per liter of solution to be prepared. In comparison with the lemon flavored compositions of the prior art, it is possible to use a smaller amount of aspartame than the 0.233 g per liter of the prior art, when the solution comprises an orange flavoring agent as in the present invention. For example, 0175 g of aspartame per liter of solution to be prepared 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 solution to be prepared, more preferably in an amount within a range in which the lower limit is 0.07 or 0.09. per liter and the upper limit is, independently, 0.12 or 0.11 g per liter. For example, a composition of the invention may comprise 0.059 or 0.117 g of acesulfame K per liter, for example 0.117 g of acesulfame K per liter of solution to be prepared.

Although sweeteners can be used to give the colon cleansing compositions a more acceptable taste, it is important that the compositions are not unacceptably sweet. As mentioned above, creating a composition that is acceptable enough for patients to drink about two liters is a challenge. It has been unexpectedly found that solutions of compositions of the present invention comprising 0.6 g of orange flavoring, 0.175 g of aspartame and 0.117 g of acesulfame K have a distinctly better taste than the prior art. These solutions are particularly acceptable for compositions that include maltodextrin (e.g., 0.28 to 0.56 g per liter) and dextrose (e.g., 0.10 to 0.25 g per liter).

In general, it is not necessary for the compositions of the invention to include preservatives. Nevertheless, low levels of antioxidants or preservatives can be used if necessary.

Commercial compositions of the type described and claimed in this document generally have manufacturing and regulatory tolerances of +/- 10%, or in some cases +/- 5%. The numerical values of this document should therefore preferably be treated with tolerances of +/- 10%, for example +/- 5%.

A preferred composition of the invention is a composition to be mixed with water, the composition being optionally presented in two or more parts and comprising, per liter of solution to be prepared, the following components: (a) 90 110 g of polyethylene glycol (PEG) having an average molecular weight of 3000 to 4000; (b) from 6.5 to 8.5 grams of sodium sulfate; (c) 2.5 to 2.9 g of sodium chloride; (d) from 0.7 to 1.3 g of potassium chloride; (e) from 5 to 15 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 1 : 9 to 9: 1; and (f) from 0.1 to 0.9g of orange flavorant.

Another preferred composition, optionally in two or more parts, to be mixed with water, comprises, per liter of solution to be prepared, the following components: (a) from 95 to 105 g of polyethylene glycol (PEG) 3350 or 4000; (b) 7 to 8 g of sodium sulfate; (c) from 2.6 to 2.8 g of sodium chloride; (d) from 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) from 0.1 to 0.9g of orange flavorant.

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

A particularly preferred composition, optionally in two or more parts, to be mixed with water comprises, per liter of solution to be prepared, 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 of potassium chloride; (e1) 4.7 g of ascorbic acid; (e2) 5.9 g of sodium ascorbate; (f) 0.6 g of orange flavoring.

(g1) 0.175 g of aspartame; and (g2) 0.117 g of acesulfame K.

A composition may, for example, be in powder, granules or any other suitable physical form. It may be, for example, a dry powder composition. "Dry" in this context means that the powder contains a sufficiently low level of moisture to be fluid. The organic acid component can be coated. Such a coating helps maintain the stability of the organic acid component. Otherwise, organic acids and organic acid salts may not be stable in the presence of even small amounts of moisture.

The compositions of the invention may be provided in bulk. The compositions may also be provided in unit dose form. A unit dose is generally an amount of composition suitable for preparing a defined volume of solution to be administered to the patient in a treatment. The volume may be any appropriate volume, for example, each unit dose may be suitable for preparing the total required volume of solution of the composition of the invention to be used for a single colon cleansing treatment. Alternatively, a unit dose may be suitable for preparing a defined volume, for example, one liter of solution of the composition of the invention, to be used in one of the steps of a two-stage cleaning regime or multiple steps.

The invention therefore provides a unit dose composition for mixing with water, the composition optionally being presented 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) from 6 to 9 g of sodium sulfate; (c) 2 to 3 g of sodium chloride; (d) from 0.5 to 1.5 g of potassium chloride; (e) from 5 to 15 g of an organic acid component; and (f) orange flavoring.

Unit dose compositions of the invention have the preferred characteristics described above with respect to compositions of the invention.

As mentioned above, it has been surprisingly found that dry powder compositions, examples of which are presented herein, remain fluid and lump-free in long-term stability tests. The invention thus further provides a dry powder composition comprising PEG and orange flavorant, which composition (i) is substantially free of glucose and (ii) is fluid and free of lumps after 3 months of use. storage at 25 ° C and 60% relative humidity. For example, it is fluid and free of lumps after 6, 12, 18 or 24 months of storage under these conditions. The dry powder composition may comprise, in addition to PEG and the orange flavorant, an alkali metal or alkaline earth metal sulfate. An alkali metal or alkaline earth metal sulphate may, for example, be selected from sodium sulphate, potassium sulphate and magnesium sulphate. Sodium sulfate is preferably present. For example, it may comprise more than one of sodium sulphate, potassium sulphate and magnesium sulphate, for example all three. The orange flavoring preferably comprises dextrose or sucrose. Preferred orange flavorants are as described hereinabove. The dry composition preferably comprises aspartame. More preferably, the dry powder composition remains fluid after 6 months of storage at 25 ° C and a relative humidity of 60%. The dry powder composition preferably remains fluid after 3 months of storage at 40 ° C. and at a relative humidity of 75%; for example, the dry powder composition remains fluid after 6 months of storage at 40 ° C and a relative humidity of 75%.

The dry powder composition may further comprise electrolytes selected from, for example, sodium chloride, potassium chloride and sodium bicarbonate. In one embodiment, the electrolytes may be sodium chloride, potassium chloride, and sodium bicarbonate. In another embodiment, the electrolytes may be sodium chloride, potassium chloride, and sodium sulfate. In another embodiment, the electrolytes may be sodium chloride, potassium chloride, sodium bicarbonate and sodium sulfate. The dry powder may further comprise one or more sweeteners selected from, for example, acesulfame K, sucralose, aspartame and saccharin.

The invention further provides a composition comprising an orange flavoring agent to be mixed with water for the preparation of an intestinal cleaning solution. The orange flavoring is preferably substantially free of glucose. The orange flavoring agent preferably comprises maltodextrin and / or dextrose and / or sucrose. Preferred orange flavorants are as described hereinabove. The composition preferably comprises aspartame. The composition preferably comprises acesulfame K. For example, the intestinal cleaning solution may be an intestinal cleaning solution containing PEG, which comprises an orange flavoring agent. Such intestinal cleaning solution may further comprise electrolytes selected from, for example, sodium chloride, potassium chloride, sodium bicarbonate and sodium sulfate. In a preferred embodiment, sodium sulfate is present. In one embodiment, the electrolytes may be sodium chloride, potassium chloride, and sodium sulfate. For example, sodium bicarbonate is not present. In an alternative embodiment, the electrolytes comprise sodium chloride, potassium chloride and sodium bicarbonate. In another embodiment, the electrolytes are sodium chloride, potassium chloride, sodium bicarbonate and sodium sulfate. The solution may further comprise one or more sweeteners selected from, for example, acesulfame K, sucralose, aspartame and saccharin. The solution may further comprise an organic acid component, for example an ascorbate component (e.g. a component comprising ascorbic acid and sodium ascorbate).

The invention further provides an intestinal cleaning solution comprising an orange flavoring. The orange flavoring is preferably substantially free of glucose. The orange flavoring agent preferably comprises maltodextrin and / or dextrose and / or sucrose. Preferred orange flavorants are as described hereinabove. The composition preferably comprises aspartame. Such a solution may have the characteristics described above with respect to a composition to be mixed with water. To be effective, an intestinal cleaning solution containing PEG is generally provided in a volume of more than 500 ml, for example 500 ml to 4000 ml. For example, a PEG-containing colon cleansing solution can be provided in two doses to form the treatment, each dose being, for example, 500 ml to 2000 ml, for example 1000 ml. A composition to be mixed with water to prepare a PEG-containing colon cleansing solution provides a quantity of components for preparing such volumes of solutions.

As described above, compositions of the invention are optionally in two or more parts. If the composition is in two or more parts, the organic acid component is preferably packaged separately from the other components of the composition. For example, a first portion of the composition may contain the components polyethylene glycol, sodium sulfate, sodium chloride, potassium chloride and orange flavoring, and a second portion may contain the organic acid component of the composition. In another embodiment, the sodium sulfate may be packaged separately from the other components. Such an embodiment may include two or more, for example three or more than three different parts. For example, a first portion of the composition may comprise the components polyethylene glycol, sodium chloride, potassium chloride and orange flavoring, 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 include additional components or may just include the components mentioned. In some embodiments, the flavoring component may be provided in a separate portion of the one or more other parts. In preferred embodiments however, the flavor component is packaged with the polyethylene glycol and / or sodium sulfate containing portion.

When the composition is supplied in bulk, for example, two or more parts may be measured or dispensed by metered rate devices or other suitable containers. When the composition is provided as a unit dose, two or more portions may be provided in sachets or other suitable containers. The contents of the different sachets or other suitable containers may be combined at the point of use to form a complete composition of the invention.

It is convenient for the patient that a composition of the invention is provided to him in the form of a kit, for example a box, comprising the composition of the invention and instructions for its use. These instructions may, for example, instruct on the use as described below in this document. The kit preferably comprises the composition in unit dose form as described above. The kit may provide the components of a composition of the invention in any number of parts, for example two parts, three parts or four parts. A kit may comprise, for example, a first portion of the composition provided in a first container containing polyethylene glycol, sodium sulfate, sodium chloride, potassium chloride, and orange flavorant, and a second part of the composition provided in a second container containing the organic acid component, the contents of these containers serving together to prepare a solution of a composition of the invention. For example, a container may be a sachet.

In an alternative embodiment of a kit, the sodium sulfate may be packaged separately from the other components. Such an embodiment may comprise two or more, for example three or more different parts and, therefore, a kit may comprise a part of the composition provided in a first container in which the polyethylene glycol, chloride components are located. sodium, potassium chloride and orange flavoring, a second part of the composition provided in a container containing the sodium sulfate, and a third part of the composition supplied in a container containing the acid component organic composition. For example, a container may be a sachet.

In another embodiment of a kit, the flavor component may be provided in a container separate from one or more other parts.

As discussed in more detail below, it may be desirable for a treatment to understand the patient's intake of two (or more) doses of compositions of the invention at different stages of a treatment. In situations in which each unit dose of the composition is intended to be used during one of the steps of a two-step or multi-step cleaning treatment, two or more of the first and second containers (e.g. sachets) may be provided in the kit, with each first and second container (eg sachets) serving together to prepare a solution of a composition of the invention, for example one liter of solution.

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

A preferred kit according to the invention comprises: (a) a first container in which there is a first composition, said first composition comprising, per liter of solution to be prepared: (a) from 90 to 110 g of polyethylene glycol (PEG) having an average molecular weight of 2500 to 4500; (ii) from 6.5 to 8.5 grams of sodium sulfate; (iii) from 0.7 to 1.3 g of sodium chloride; (iv) from 0.5 to 1.5 g of potassium chloride; and (v) 0.1 to 0.9 g of orange flavorant; and (b) a second container in which there is a second composition comprising from 5 to 15 g of a mixture of organic acid and one or more salts of an organic acid in a weight ratio of the organic acid to said one or more salts of an organic acid of 1: 9 to 9: 1 per liter of solution to be prepared.

Another preferred kit according to the present invention comprises: (a) a first container in which there is a first composition, said first composition comprising, per liter of solution to be prepared: (i) from 95 to 105 g of polyethylene glycol (PEG) 3350 or 4000; (ii) 7 to 8 g of sodium sulfate; (iii) from 2.5 to 2.8 g of sodium chloride; (iv) from 0.8 to 1.2 g of potassium chloride; and (v) from 0.4 to 0.7 g orange flavorant; and (b) a second container in which there is a second composition comprising from 8 to 12 g of an organic acid mixture and one or more salts of an organic acid in a weight ratio of the organic acid to one or more several salts of an organic acid of 4: 6 to 6: 4 per liter of solution to be prepared.

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

A particularly preferred kit according to the invention comprises: (a) a first container in which there is a first composition, said first composition comprising, per liter of solution to be prepared: (i) 100 g of PEG 3350; (ii) 7.5 g sodium sulphate; (iii) 2.691 g of 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 in which there is a second composition, said second composition comprising 4.7 g of ascorbic acid and 5.9 g of sodium ascorbate per liter of solution to be prepared.

Preferred containers include sachets, bottles, bins, cans or canisters. For example, the composition may be provided in a container (for example a can) of a certain volume (for example 1 liter) so that the required amount of water can be easily added to the powder in a measured manner. Sachets are also particularly preferred. It is preferred that one of the first and second compositions of one or both kits be in dry powder form.

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

Solutions according to the invention can be provided in any desired volume, for example from 0.2 to 2.5 liters, for example from 0.5 to 2 liters, for example 0.5 or 1 liter of solution in one or more containers. Solutions of the invention have the beneficial properties described above with reference to the compositions. Solutions of the invention have the preferred characteristics described above in connection with the compositions of the invention.

A preferred solution of the invention comprises: (a) from 90 to 110 g / l of polyethylene glycol (PEG) having an average molecular weight of 3000 to 4000; (b) from 6.5 to 8.5 g / l of sodium sulfate; (c) from 2.5 to 2.9 g / l of sodium chloride; (d) from 0.7 to 1.3 g / l of potassium chloride; (e) from 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 from 1: 9 to 9: 1; and (f) from 0.4 to 0.7 g / l of orange flavorant.

Another preferred solution of the invention comprises: (a) from 95 to 105 g / l of polyethylene glycol (PEG) 3350 or 4000; (b) 7 to 8 g / l of sodium sulfate; (c) from 2.6 to 2.8 g / l of sodium chloride; (d) from 0.8 to 1.2 g / l of potassium chloride; (e) from 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 from 4: 6 to 6: 4; and (f) from 0.4 to 0.7 g / l of orange flavorant.

A particularly preferred solution of the invention 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 of potassium chloride; (e1) 4.7 g / l of ascorbic acid; (e2) 5.9 g / l of sodium ascorbate; (f) 0.6 g / l orange flavorant; (g1) 0.175 g / l of aspartame; and (g2) 0.117 g / l acesulfame K.

In the solutions of the invention described above, the amounts of the individual components mentioned do not include solutes which may be present in the water used to prepare the solutions, for example in hard water areas, it may there are significant amounts of Ca2 + and Mg2 + carbonates, bicarbonates or sulphates present in the mains water.

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

A preferred solution of the invention comprises: (a) from 90 to 110 grams of polyethylene glycol (PEG) having an average molecular weight of 3000 to 4000; (b) from 46 to 60 mmol / l of sulfate ions; and (c) from 135 to 170 mmol / l of sodium present as sodium ions; (c1) from 52 to 67 mmol / l of chloride ions; (d) from 9.4 to 17 mmol / l of potassium present as potassium ions; (f) from 0.4 to 0.7 g / l of orange flavorant; and further comprises: (e) from 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 an organic acid of 1: 9 to 9: 1.

Another preferred solution of the invention comprises: (a) from 95 to 105 g / l of polyethylene glycol (PEG) 3350 or 4000; (b) from 49 to 56 mmol / l of sulfate ions; and (c) from 142 to 160 mmol / l of sodium present as sodium ions; (c1) from 55 to 64 mmol / l of chloride ions; (d) from 11 to 16 mmol / l of potassium present as potassium ions; (f) from 0.4 to 0.7 g / l of orange flavorant; and further comprises: (e) from 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 an organic acid of from 4: 6 to 6: 4.

A particularly preferred solution of the invention comprises: (a) 100 g / l polyethylene glycol (PEG) 3350; (b) 52.8 mmol / l of sulfate ions; and (c) 152 mmol / l of sodium present as sodium salts; (c1) 59.7 mmol / l of chloride ions; (d) 13.6 mmol / l of potassium present as potassium salts; (f) 0.6 g of orange flavoring; (g 1) 0.175 g / l of aspartame; and further comprises: (e) 56.5 mmol / l of ascorbate species, which ascorbate species comprise ascorbic acid, one or more ascorbic acid salts, or a mixture of ascorbic acid and one or more ascorbic acid salts; and (g2) 0.58 mmol / l of acesulfame species, which acesulfame species comprise acesulfame (6-methyl-1,2,3-oxathiazine-4 (3 / - /) - one 2 2-dioxide), one or more acesulfame salts, or a mixture of acesulfame and one or more acesulfame salts.

Another particularly preferred solution of the invention comprises: (a) 100 g / l polyethylene glycol (PEG) 3350; (b) 52.8 mmol / l of sulfate ions; (c) 181 mmol / l of sodium present as sodium salts; (c1) 59.7 mmol / l of chloride ions; (d) 14.2 mmol / l of potassium present as potassium salts; (f) 0.6 g of orange flavoring; (g1) 0.175 g / l of aspartame; (e) 56.5 mmol / l of ascorbate species, which ascorbate species comprise a mixture of ascorbic acid and ascorbate ions; and (g2) 0.58 mmol / l acesulfame (6-methyl-1,2,3-oxathiazine-4 (3H) -alone 2,2-dioxide) ions.

The invention further provides a composition for mixing with water for the preparation of a solution of the invention.

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

Preferably, such a composition has the preferred characteristics described above. Such a composition may comprise the various components in weight ratios based on absolute amounts, or amounts per liter, mentioned above. For example, such a composition comprises the following components in the following weight ratios: (a) 100 of polyethylene glycol (PEG) having an average molecular weight of 2,500 to 4,500 to (b) 7,500 of sodium sulfate at (c) 2,691 of sodium chloride at (d) 1.015 potassium chloride at (e1) 4.7 ascorbic acid at (e2) 5.9 sodium ascorbate at (f) 0.6 orange flavoring L The orange flavoring agent preferably comprises maltodextrin, for example at a level of 70-80% of the flavoring agent by weight, for example providing maltodextrin at a weight ratio to other components of 0.442. The orange flavoring agent preferably comprises dextrose, for example at a level of 15-25% of the flavoring agent by weight, for example providing dextrose at a weight ratio to other components of 0.119. The composition preferably further comprises a sweetener, for example the following sweeteners at the following weight ratios: (g1) 0.175 of aspartame, and (g2) 0.117 of acesulfame K.

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

The compositions and solutions of the invention may be used to clean the colon prior to performing a diagnostic, therapeutic or surgical procedure on the colon, rectum or anus or elsewhere in the abdomen. The diagnostic or surgical procedure may be, for example, an examination with barium enema, sigmoidoscopy or colon surgery.

The composition, solution, kit or unit dose of the invention may be provided for use as a medicament, for example for use in colon cleansing.

Accordingly, the present invention also provides a method of cleaning the colon of a subject in which the subject ingests an oral colon cleansing solution comprising: (a) from 85 to 115 g / l of polyethylene glycol (PEG) having a average molecular weight of 2500 to 4500; (b) from 6 to 9 g / l of sodium sulfate; (c) 2 to 3 g / l of sodium chloride; (d) from 0.5 to 1.5 g / l of potassium chloride; (e) from 5 to 15 g / l of an organic acid component; and (f) orange flavoring.

A solution for use in a method of the invention also has the characteristics described above with respect to the compositions and / or solutions of the invention.

The exact amount of solution to be administered in a method of the invention will depend on the subject being treated and the particular situation of the subject. For example, the subject may be an adult person. An appropriate volume of cleaning solution for an adult person can be 1.5 to 4 liters, while a proportionately smaller volume of cleaning solution is appropriate in the treatment of small children and a larger volume of cleaning solution is appropriate for patients with prolonged co-ion transit time. Typically, 2 liters of cleaning solution are administered to an adult person. For example, 1 to 2 liters of the colon cleanser are ingested by the subject. In one embodiment, the subject ingests in addition a quantity of clear liquid, for example a liter.

The total volume of solution is preferably administered over a period of 1 to 4 hours. This period of 1 to 4 hours can be a continuous period or a discontinuous period. In a discontinuous regimen, a portion of the solution, typically approximately half, may be administered the evening prior to the diagnostic, therapeutic or surgical procedure to be performed, the remainder of the solution being administered on the same day. day of the proceedings and before that.

Discontinuous administration may also involve the administration of a portion of the cleaning solution, followed by the administration of a clear liquid.

In a preferred regime of taking a cleaning solution of the invention, a 2 liter treatment is taken by the subject. The treatment can be taken as a divided treatment with 1 liter of cleaning solution taken in the evening before an examination or clinical procedure and 1 liter taken early in the morning of the day of the examination or procedure. Alternatively, 2 liters of the cleaning solution can be taken in the evening before the examination or procedure. Subjects are told not to take solid food from the moment they take the cleaning solution until after the examination or procedure.

Subjects can be told to prepare a first liter of cleaning solution by dissolving the dry powder supplied (eg provided in two sachets with the organic acid component in a sachet and the remaining components in a separate sachet) in water. and then take the solution over a period of one to two hours, for example by drinking a glass every 10 - 15 minutes. They may be told to then prepare the second liter of cleaning solution and drink it. It may be advisable for subjects to drink an extra liter of clear liquid to prevent them from feeling very thirsty and dehydrated. Water, clear soup, fruit juice (no pulp), non-alcoholic drinks, tea or coffee (no milk) are all appropriate.

Another possible variation of the above-mentioned regimen is a diet in which the total dose of colon cleansing treatment in adults is 2 liters (approximately 64 fluid ounces) of cleaning solution (with an additional 1 liter of clear liquids) taken Orally before colonoscopy or another examination or procedure in one of the following ways: 1) Split-rate regimen: In the evening before colonoscopy or another examination or procedure, the first liter (approximately 32 fluid ounces) Cleaning solution is taken in one hour (one glass of 250 ml / 8 fluid ounces every 15 minutes) and then 0.5 liter (approximately 16 fluid ounces) of clear liquid is drunk. Then, on the morning of the colonoscopy or another examination or other procedure, the second liter (approximately 32 fluid ounces) of cleaning solution is taken in one hour and then 0.5 liter (approximately 16 fluid ounces) clear fluid is drunk at least one hour before the start of colonoscopy.

2) Full-Day Diet (Full-Day) Only: At approximately 18:00 in the evening prior to colonoscopy or another examination or procedure, a first liter of cleansing solution is taken within one hour (one 250 ml glass / 8 fluid ounces every 15 minutes) and then, about 1.5 hours later, a second liter of cleaning solution (approximately 32 fluid ounces) is taken in one hour. In addition, 1 liter (approximately 32 fluid ounces) of additional clear fluid is taken during the evening before colonoscopy or another examination or other procedure.

Examples

The following nonlimiting examples illustrate the invention.

Flavorings tested included orange flavoring 1, orange flavoring 2 and orange flavoring 3. MOVIPREP® (available from Norgine Limited, New Road, Hengoed, Mid Glamorgan, CF82 8SJ , UK), a currently marketed colon cleansing preparation comprising a lemon flavoring (Ungerer lemon V3938-1N1), was used as a comparison.

Orange flavoring agent 1 comprises 72 - 76% by weight of corn maltodextrin and 19 - 21% by weight of corn dextrose, flavoring substances chemically identical to natural substances, natural flavor preparations and flavoring substances natural. It is substantially free of sucrose.

Orange flavoring agent 2 comprises 35-50% by weight of corn maltodextrin and 30-35% by weight of sucrose. It also includes flavoring preparations, starch and gum. It is substantially free of dextrose.

The orange flavoring agent 3 comprises 90 - 95% by weight of maltodextrin, terpene-free orange oil and gum. It is substantially free of dextrose and substantially free of sucrose.

(% by weight based on the weight of the flavoring.)

In each of Examples 1 to 4, ascorbic acid and sodium ascorbate were provided in a sachet (sachet B) as shown in Table 1b, and the other components were supplied in a separate sachet (sachet A) as shown in Table 1a. Each sachet A used in Examples 1, 2 and 4 also included the flavoring and sweetener in the respective amounts shown in Tables 2, 3 and 5 respectively. In each case, sachets A and B were mixed together and with water to give one liter (to make a "sample").

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

Table 1b: Composition per liter of sample - Bag B

Example 1 Comparison of the palatability of the various flavored colon cleansing preparations

Samples of five differently flavored colon cleansing preparations were given to 12 healthy volunteers in a Western country, and they were asked to rate each palatability on a scale of 1 (low) to 10 (high).

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

Table 2: Scores of palatability

As seen in Table 2, solutions comprising orange flavorant 1 or orange flavorant 2 have been preferred to the prior art lemon flavored solution. The orange flavoring agent 3 was not inferior to the prior art solution. Preferred solutions 1-1, 1-2 and 1-3 contained orange flavorant 1 and orange flavorant 2 which included maltodextrin at the levels indicated above. The solution comprising orange flavorant 1 has been especially preferred. The flavoring in this solution contains dextrose. Solutions 1-1, 1-2 were clear; solution 1-4 was somewhat opaque and solution 1-3 was cloudy.

Example 2: Comparison of palatability of different orange flavored colon cleansing solutions

Samples of 4 differently flavored colon cleansing solutions were given to a group of volunteers in a Western country, and they were asked to rate the palatability of each of the solutions on a scale of 1 (low) to 10 ( high). The results of the palatability tests are shown in Table 3. The number of subjects to whom each solution has been given is shown in the table.

Table 3: Scores of palatability

As seen in Table 3, orange-flavored solutions in which the flavoring agent comprises maltodextrin at a level such as in orange flavoring agent 1 and orange flavoring agent 2 have been preferred. . The solution comprising orange flavorant 1 was especially preferred, particularly when this flavoring was present at a level of 0.6 g per liter of solution. The flavoring agent in this solution also includes dextrose.

Example 3 Comparison of Palatability of Differentially Flavored Colon Cleansing Solutions

An additional study was conducted in which samples of 4 differently flavored colon cleansing solutions (including orange flavoring agent 1, orange flavoring agent 2, orange flavoring agent 3 or lemon of the prior art) were given to 15 healthy volunteers in a western country, and they were asked to evaluate the palatability of each of the chilled solutions on a scale of 1 (low) to 10 (high). Perceptions of taste may vary from one culture to another, but it is more efficient to manufacture and register the same pharmaceutical product for several countries. As a result, the taste test results in Example 1 and Example 2 and the additional study were combined to give the average palatability as shown in Table 4.

Table 4: Average palatability scores

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

Example 4 Comparison of Palatability of Different Levels of Sweetener and Orange Flavoring Agent

Samples of 8 different colon cleansing solutions each comprising a different amount of sweetener (either aspartame or sucralose) and flavoring (orange flavoring 1) were given to 4 healthy volunteers, and they were asked to assess the palatability of each of the solutions from 1 (low) to 10 (high). In addition to the flavoring and sweetener listed in Table 5, the samples also included 0.117 g of acesulfame K. The responses are summarized in Table 5. For three of the samples, only three of the volunteers provided an assessment. as for the level of flavoring.

Table 5: Scores of palatability

* results were obtained for only 3 subjects for these data points.

As shown in Table 5, orange flavorant 1 at a concentration of 0.6 g per liter with aspartame at a concentration of 0.175 g per liter was considered the most palatable combination. It is the combination in Example 4-2 that is the same as in Example 2-2.

Example 5: Comparison of palatability of orange flavored colon cleaning preparations

Samples of 6 different orange-flavored colon cleansing solutions were given to 7 healthy volunteers, and they were asked to rate the palatability of each on a scale of 1 (low) to 10 (high). One of the solutions (5-3) included orange flavorant 1 as used above in Examples 1-4, and the other five solutions included different variations of this flavoring. The composition of bag A contained the components of Table 1a with 0.175 g per liter of aspartame and 0.117 g per liter of acesulfame K, and orange flavorant. The composition of bag B was as shown in Table 1b. The 6 different orange flavoring agents each contained the same amounts of flavoring substances chemically identical to natural substances, natural flavor preparations and natural flavoring substances and were substantially free of sucrose. But each included different proportions of corn maltodextrin and maize dextrose, as shown in Table 6a, with the amounts being presented as percentages in Table 6b. Example 5-3 is identical to Examples 2-2 and 4-2. The results of the palatability tests are shown in Table 6a.

Table 6a: Scores of palatability

Table 6b: Quantities of components as percentages by weight

~ ~ I - 1 - - - - · 1 - - _ - I_ · _I _: ........-: - 1

As seen in Table 6a by comparison of taste scores for Examples 5-1 to 5-4 (which all include the same amount of maltodextrin), examples containing 0.119 g or 0.239 g of dextrose were preferred to the samples. containing less dextrose. A comparison of taste scores for Examples 5-3, 5-5 and 5-6 (which all include the same amount of dextrose) shows that Example 5-3 comprising 0.442 g of maltodextrin was preferred to Examples 5-6. 5 and 5-6 comprising larger amounts of maltodextrin.

It is seen that samples comprising orange flavorant containing 0.119 g or 0.239 g of dextrose per liter are preferred to samples containing less dextrose, and samples comprising orange flavorant containing 0.442 g of Maltodextrin per liter is preferred over samples containing larger amounts of maltodextrin.

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

Samples containing the components of Table 1a with 0.600 g orange flavorant 1 or 0.600 g orange flavorant 3 were subjected to the long-term stability test.

Table 7: Composition of dry powders for stability tests:

The compositions of Example 6-1 thus included the same components in the same amounts as Examples 2-2, 4-2 and 5-3. The compositions of Example 6-2 comprised the same components in the same amounts as Example 2-4. The components listed in Table 7 were packaged in bags (of the same type used for the commercial product sold as MOVIPREP®) and sealed. Three different manufactured batches of the composition of Example 6-1 were tested. Two different manufactured batches of the composition of Example 6-2 were tested. The pouches were placed under different conditions: a) 25 ° C / 60% relative humidity for 24 months for Example 6-1 and for 12 months for Example 6-2.

b) 40 ° C / 75% relative humidity for 6 months for Example 6-1 and 6-2.

The batches of Example 6-1 under conditions a) were evaluated after 1, 3, 6, 9, 12, 18 and 24 months. The batches of Example 6-2 under conditions a) were evaluated after 1, 3, 6, 9 and 12 months. The batches of both examples under conditions b) were evaluated after 1, 3 and 6 months.

The evaluation was conducted according to the following criteria:

Description of visual appearance Opalescence Color of solution PEG3350 content

Potassium content Sodium content

Chloride content Sulphate content

Moisture content pH

Reconstitution time Formaldehyde content

Taste Odor

All of the examples were within acceptable tolerances for each criterion in both types of conditions (25 ° C / 60% RH and 40 ° C / 75% RH). In particular, all the examples were fluid with no visible lumps at each of the time points and in both types of conditions.

Comparative Example 6b: Comparison with the Long-term Stability of a Composition of the Prior Art

Laxido Orange is a constipation treatment marketed by y Galen Limited (see http://www.qalen.co.uk) which comprises 13.125 g of PEG 3350, 350.7 mg of sodium chloride, 178.5 mg of sodium hydrogen carbonate, 46.6 mg of potassium chloride, potassium acesulfame and orange flavoring, and is supplied in the form of a dry powder.

Samples of Laxido Orange Dry powder were subjected to 6-month stability tests as described in Example 6a. Samples were within acceptable tolerances for most criteria in both types of conditions (25 ° C / 60% RH and 40 ° C / 75% RH). However, the samples showed small lumps visible both after 3 months and after 6 months in both types of conditions.

As a result, Laxido Orange samples deteriorated during the 3-month or 6-month test period. As seen above in Example 6a, the orange flavored compositions of the invention did not form lumps during the 3 or 6 month stability tests.

Claims (32)

A dry composition to be mixed with water, wherein the composition is optionally presented in two or more parts and comprises, per liter of solution to be prepared, the following components: (a) 85 to 115 g of polyethylene glycol (PEG) having an average molecular weight of 2500 to 4500; (b) 6-9 g of sodium sulfate; (c) 2-3 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 composition as claimed in claim 1, wherein the orange flavorant comprises maltodextrin in an amount of 30 to 80% by weight of the flavoring. A composition as claimed in claim 2, wherein the orange flavorant comprises maltodextrin in an amount of 70 to 80% by weight of the flavoring. A composition as claimed in claim 2 or 3, wherein the maltodextrin is maize maltodextrin. 5. A composition as claimed in any one of claims 1 to 4, wherein the orange flavorant comprises dextrose in an amount of 15 to 25% by weight of the flavoring. A composition as claimed in any one of claims 1 to 5, wherein the orange flavorant is substantially free of gum. A composition as claimed in any one of claims 1 to 6, wherein the orange flavoring comprises less than 2% by weight of organic components other than flavoring preparations and components. A composition as claimed in any one of claims 1 to 7, wherein the orange flavorant is present in an amount of 0.1 to 0.9 g per liter of solution to be prepared. A composition as claimed in any one of claims 1 to 8, wherein the composition comprises a sweetener, for example one of aspartame and acesulfame potassium (acesulfame K) or both. The composition as claimed in claim 9, wherein the aspartame is present in an amount of 0.175 g per liter of solution to be prepared. 11. A composition as claimed in claim 9 or claim 10, wherein the acesulfame potassium is present in an amount of 0.117 g per liter of solution to be prepared. A composition as claimed in any one of claims 1 to 11 comprising ascorbic acid and sodium ascorbate. A composition as claimed in any one of claims 1 to 12, wherein the composition is substantially free of sodium bicarbonate. A composition as claimed in any one of claims 1 to 13 comprising, per liter of solution to be prepared, 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 of potassium chloride; (e1) 4.7 g of ascorbic acid; (e2) 5.9 g of sodium ascorbate; (f) 0.6 g of orange flavoring. (g1) 0.175 g of aspartame; and (g2) 0.117 g of acesulfame K. 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) from 6 to 9 g / l of sodium sulfate; (c) 2 to 3 g / l of sodium chloride; (d) from 0.5 to 1.5 g / l of potassium chloride; (e) from 5 to 15 g / l of an organic acid component; and (f) orange flavoring. A kit that provides the components of a composition as claimed in any one of claims 1 to 14 in two or more parts. A kit as claimed in claim 16 comprising: (a) a first container in which there is a first composition, said first composition comprising, per liter of solution to be prepared: (a) 85 to 115 g of polyethylene glycol (PEG ) having an average molecular weight of 2500 to 4500; (ii) from 6 to 9 g of sodium sulfate; (iii) 2 to 3 g of sodium chloride; (iv) from 0.5 to 1.5 g of potassium chloride; and (v) orange flavoring; and (b) a second container in which there is a second composition comprising from 5 to 15 g of an organic acid component per liter of solution to be prepared. 18. A kit as claimed in claim 17 comprising two sachets having the components: SACHET 1 PEG 3350: 100,000 g Sodium sulphate: 7,500 g Sodium chloride: 2,691 g Potassium chloride: 1,015 g Aspartame: 0,175 g Acesulfame K: 0,117 g Orange flavoring: 0.6 g SACHET 2 Ascorbic acid: 4,700 g Sodium ascorbate: 5,900 g 19. A unit dose composition to be mixed with water, wherein the composition is optionally presented in two or more parts and comprises the following components: (a) 85 to 115 g of polyethylene glycol (PEG) having average molecular weight of 2500 to 4500; (b) from 6 to 9 g of sodium sulfate; (c) 2 to 3 g of sodium chloride; (d) from 0.5 to 1.5 g of potassium chloride; (e) from 5 to 15 g of an organic acid component; and (f) orange flavoring. A solution as claimed in claim 14, a kit as claimed in claim 16, 17 or 18, or unit dose as claimed in claim 19, which solution, which kit or unit dose has one or more of the characteristics. composition according to one or more of claims 2 to 14. 21. An oral cleaning solution comprising: (a) 85 to 115 g / l polyethylene glycol (PEG) having an average molecular weight of 2500 to 4500; (b) from 6 to 9 g / l of sodium sulfate; (c) 2 to 3 g / l of sodium chloride; (d) from 0.5 to 1.5 g / l of potassium chloride; (e) from 5 to 15 g / l of an organic acid component; and (f) orange flavoring for use in a colon cleansing method of a subject, wherein the subject ingests the solution. 22. The oral cleaning solution as claimed in claim 21, wherein from 1 to 2 liters of the colon cleansing solution is ingested by the subject. An oral cleaning solution as claimed in claim 22, wherein the colon cleansing solution is taken as a divided treatment with one liter of cleaning solution being taken in the evening before an examination or clinical procedure and 1 liter being taken early in the morning of the day of an examination or procedure. An oral cleaning solution as claimed in claim 21 or 22, wherein the colon cleansing solution is taken prior to an examination or procedure. 25. An oral cleaning solution as claimed in any one of claims 21 to 24, wherein the subject ingests in addition an additional liter of clear liquid. An oral cleaning solution as claimed in claim 21, wherein in the evening prior to a colonoscopy or other examination or other procedure, a first liter of cleaning solution is ingested in approximately one hour and then 0.5 liter of Clear fluid is ingested, and in the morning of colonoscopy or another examination or other procedure, a second liter of cleaning solution is ingested in approximately one hour, followed by 0.5 liter of clear fluid. An oral cleaning solution as claimed in claim 21, wherein in the evening prior to a colonoscopy or other examination or other procedure, a first liter of cleaning solution is ingested in approximately one hour and then, approximately 1.5 hour later, a second liter of cleaning solution is ingested in approximately one hour, an additional liter of additional clear liquid being ingested during the evening. 28. Dry powder composition comprising PEG and orange flavoring, which composition (i) is substantially free of glucose and (ii) is fluid and free of lumps after 3 months of storage at 25 ° C and 60% relative humidity. 29. A composition comprising orange flavoring agent to be mixed with water for the preparation of an intestinal cleaning solution. 30. Intestinal cleaning solution comprising an orange flavoring. 31. A composition as claimed in claim 28 or claim 29 or intestinal cleansing solution as claimed in claim 30, wherein the orange flavoring has one or more characteristics according to any one or more of Claims 2 to 8. 32. A composition as claimed in any one of claims 1 to 14, 28, 29 and 31, or solution as claimed in claim 15, 20 or 30 for use as an agent for cleaning the gastrointestinal tract. .