Ready-to-use laxative liquid pharmaceutical composition and process for its preparation

Abstract

The present invention relates to a ready-to-administer liquid laxative pharmaceutical composition, preferably for use in bowel cleansing before surgery, colonoscopy or radiographic inspection of the colon, and a process for its preparation. Compared to similar known compositions, the laxative pharmaceutical composition of the invention having a pH closer to neutrality, exhibits superior physical and chemical stability.

Description

[0001] TITLE

[0002] “Ready-to-use laxative liquid pharmaceutical composition and process for its preparation”

[0003] DESCRIPTION

[0004] The present invention relates to a laxative liquid pharmaceutical composition ready for oral administration suitable for the pre-treatment of patients undergoing surgery, colonoscopy or radiographic inspection of the colon, and to a process for its preparation.

[0005] Compared to similar known ready-to-use compositions, the laxative pharmaceutical composition of the invention has a pH closer to neutrality and, surprisingly, it is characterized by a superior physical and chemical stability.

[0006] STATE OF THE ART

[0007] Powdered laxative compositions, such as Pharmabio's Picolight Powder® (KR), including citric acid, magnesium oxide and sodium picosulfate, are available on the market. These powders are mainly used as purgatives in the pre-treatment of patients undergoing surgery, colonoscopy or colon X-ray inspection and are taken orally, after dissolution in an appropriate amount of water at the time of intake.

[0008] Preparing the solution extemporaneously, however, can be difficult for some patients. Even some patients may mistakenly introduce the powder into the oral cavity and drink the water afterwards, risking burns due to the strong exothermic reaction.

[0009] On the other hand, it is not possible to prepare the solution in advance and store it until intake, as it is physically unstable: in fact, citric acid and magnesium oxide may react to form magnesium citrate that may precipitate at the bottom of the container. Consequently, by using a stored solution, the patient may not take the full dosage of the medicine and thus not have the desired purging effect.

[0010] To overcome the problems discussed above, ready-to-use (RTU) liquid compositions stabilized by the addition of carboxylic acids, particularly by malic acid, have been developed and marketed with the tradename, for instance, of Clenpiq®.

[0011] Document EP3120835B1 (herein EP’835), in the name Pharmabio, discloses and claims laxative liquid pharmaceutical compositions for the pre-treatment of patients in case of surgery, colonoscopy or radiographic inspection of the colon, said compositions comprising sodium picosulfate, magnesium oxide, citric acid, malic acid, in a weight ratio of 0.003 to 0.009, 1 to 3, 3.5 to 10.5, 0.01 to 13 respectively, and water, and having a pH of 4.1 to 5.4. According to the description (par. 0018), the composition is said to be stable in that pH range. In fact, for pH below 4.1 , in addition to poor palatability due to excessive sourness, there is an increase in the degradation of sodium picosulfate with the formation of byproducts, in particular of Impurity A, namely 4-[(pyridin-2-yl)(4-hydroxy- phenyhl)methyl]phenyl sulfate sodium salt of formula while for pH above 5.4, difficulty in dissolving magnesium oxide and consequent precipitation is observed. In this regard, the document (par. 0004) teaches that if the pH of the composition is kept low, precipitation tends to decrease, however sodium picosulfate becomes unstable (see par. 0005 of the corresponding US9827231 B2).

[0012] The compositions of EP’835 are prepared according to a process (therein sketched in Figure 1 and described at par. 0043 - 0046) whereby the powders of the ingredients are admixed together, also in different order, and water is added to the solid admixture only in the last step.

[0013] Document W02017031121A1 (Liang et al), herein WO’121 , describes liquid compositions comprising sodium picosulfate, magnesium citrate and at least a precipitation inhibitor wherein the precipitation inhibitor can be a carboxylic acid, an ammonium salt or a soluble anionic polymer. The composition can be in the form of an aqueous solution having a pH in the range from about 4.0 to 6.5, preferably from about 4.0 to about 5.5.

[0014] In the description, the compositions actually containing malic acid have a pH in the range from 4.7 to 5.1 (see the examples Ex. 5-8, Ex. 41-44, Ex. 47-48 and Ex. 166-167). These compositions are prepared by dissolving sodium picosulfate and magnesium citrate, premixed in a sachet of Prepopik®, in water followed by malic acid dissolution and, finally, by adjusting the pH with sodium hydroxide or hydrochloric acid.

[0015] Document WO2018009761 A1 (Ferring), herein WO’761 , relates to liquid pharmaceutical compositions containing picosulfate, magnesium citrate and an antioxidant (claim 1) that may further comprise a carboxylic acid (claim 16), such as inter alia, malic acid (claims 17 and 18). The composition preferably has a pH in the range from about 4.5 to about 5.2 (claim 26). In the description, the compositions actually containing malic acid, namely the compositions of the examples F, G, J, 6-10, 11-15, 16-23, have a pH in the range from 4.83 to 5.2. These compositions are prepared by dissolving malic acid, citric acid and magnesium oxide in water, by next adjusting the pH and, finally, by adding sodium picosulfate.

[0016] In view of the above, it appears that prior art consistently teaches that, when malic acid is used as stabilizer, the pH of the composition has to be set in a range from a minimum of about 4.1 to a maximum of about 5.4 in order to have an acceptable physical and chemical stability. However, the Applicant in its investigations has found that the physical stability of the compositions described in EP’835, WO’121 and WO’761 having a pH from 4.1 to 5.4, was not enough to ensure that the ingredients remain dissolved and the correct dosage is maintained for long periods of time. In fact, as shown in the present experimental part (see for instance Example 4C), during stability studies on EP’835, WO’121 and WO’761 compositions, precipitation and / or turbidity was observed at some stage while it would be desirable to further improve physical stability and composition shelf life while preserving chemical stability as well.

[0017] Palatability is an additional challenge for drug compliance, particularly felt in this specific area because patients generally have to ingest rather large amounts of the purgative solution. Accordingly, it would be further advantageous having in addition to an increased stability, an acceptable palatability even with a lower content of sweeteners, flavours and / or taste modulators, in line with the current trend in pharmaceuticals to reduce the intake of excipients, thus minimizing their potential toxicity and caloric contribution.

[0018] In light of the state of the art, there remains a need to provide a laxative liquid pharmaceutical composition that without adding further stabilizers is more stable than similar known compositions and, preferably, has a lower content of sweeteners, flavourings and / or taste modulators.

[0019] SUMMARY OF THE INVENTION

[0020] The Applicant wishing to prepare ready-to-use laxative compositions characterized by longer shelf life and possibly less sourness undertook some studies starting from the acidic liquid compositions containing malic acid described in EP’835 and raised the pH to values closer to neutrality. In doing so, physical instability problems with precipitate formation during storage were encountered.

[0021] The Applicant unexpectedly succeeded in solving the problem of precipitate formation in these higher pH compositions and even improved their physical stability, over a broad pH range, compared to the more acidic prior art compositions, without adding further stabilizers and without substantial changes other than the manufacturing process.

[0022] Accordingly, an object of the present invention is a liquid pharmaceutical composition comprising from 0.002 to 0.010 % wt of sodium picosulfate, from 1.0 to 3.0 % wt of magnesium oxide, from 3.5 to 10.5 % wt of citric acid, from 0.01 to 13.0 % wt of malic acid, optionally one or more pharmaceutically acceptable excipient(s) and water, wherein the composition has a pH higher than 5.4 and, preferably, lower than 7.6.

[0023] This composition is physically and chemically more stable and less sour than similar compositions having pH of 5.4 or lower.

[0024] A further object of the present invention is a liquid pharmaceutical composition comprising from 0.002 to 0.010 % wt of sodium picosulfate, from 1.0 to 3.0 % wt of magnesium oxide, from 3.5 to 10.5 % wt of citric acid, from 0.01 to 13.0 % wt of malic acid, optionally one or more pharmaceutically acceptable excipient(s) and water, wherein the pH of the liquid pharmaceutical composition is from 4.5 to 8.0, preferably higher than 5.0, more preferably higher than 5.4 and / or preferably lower than 7.6, and wherein the composition is obtainable according to a process comprising:

[0025] (i) providing at least an alkalinizing agent in amount from 1.0 to 8.0 % wt, preferably dissolved in water to provide a first aqueous solution having a pH from 12.0 to 14.0,

[0026] (ii) providing malic acid in amount from 0.01 to 13.0 % wt, contacting it with the at least an alkalinizing agent and with water, preferably contacting it with the first aqueous solution, and dissolving to provide a second aqueous solution,

[0027] (iii) adding citric acid to the previous second aqueous solution, in amount from 3.5 to 10.5 % wt, and dissolving it, to provide a third aqueous solution,

[0028] (iv) adding magnesium oxide to the previous third aqueous solution, in amount from 1.0 to 3.0 % wt, dissolving it to provide a fourth aqueous solution,

[0029] (v) optionally adding at least a preservative agent to the previous fourth aqueous solution, then at least an antioxidant and dissolving them to provide a fifth aqueous solution,

[0030] (vi) adding sodium picosulfate in amount from 0.002 to 0.010 % wt and optionally other pharmaceutically acceptable excipients to the previous fourth or fifth aqueous solution, and dissolving them to provide a sixth aqueous solution, and

[0031] (vii) optionally if needed, adjusting the pH of the previous sixth aqueous solution at a value from 4.5 to 8.0, preferably at a value higher than 5.0, more preferably higher than 5.4 and preferably lower than 7.6, in which water is added in one or more of the previous steps in a preferred total amount from 70 to 95 % wt, all the percentages by weight being referred to the weight of the composition, to provide the composition according to the invention.

[0032] A further object of the present invention is a process for preparing the liquid pharmaceutical composition of the invention as depicted above.

[0033] A further object of the present invention is the liquid pharmaceutical composition of the invention for use as a medicament.

[0034] A further object of the present invention is the liquid pharmaceutical composition of the invention for use as a purgative or colon cleansing composition, in particular for the pretreatment of patients undergoing surgery, colonoscopy or radiographic inspection of the colon.

[0035] The composition and the manufacturing process thereof according to the invention are better than similar previous compositions and processes as demonstrated in the present experimental part.

[0036] BRIEF DESCRIPTION OF THE FIGURES Figures 1 (1 A - 1 F) and 2 (2A - 2C) show the pictures of bottles of compositions prepared according to the invention compared to corresponding comparative compositions prepared following the process of EP’835 (in each picture, the composition of the invention is on the left while the corresponding comparative composition is on the right) after 18 and 24 months at 25°C and 60% RH of stability study (see Table 7 and Table 7A for details).

[0037] Figure 3 (3A - 3C) shows the bar charts illustrating precipitate formation during stability studies on invention (dotted bar) vs comparative (white bar) compositions.

[0038] Figures 4 (4A - 4C), 5 (5A - 5D) and 6 (6A) show the pictures of bottles of compositions according to the invention compared to corresponding comparative compositions (in each picture, composition of the invention is on the left vs corresponding comparative composition is on the right) when subjected to a stability study at 2-8°C (fridge) up to 24 months (see Tables 8 to 11 for details).

[0039] Figure 6B is a picture of a bottle showing the line drawn on the exterior of the wall, used as reference to measure the height of the precipitate formed during stability studies.

[0040] Figure 6C to 6G are pictures showing the jellification of the mixture that occurred during the preparation of the composition according to prior art processes of WO’121 or WO’761 (in Fig. 6D to 6G prior processes on the left compared to invention process on the right).

[0041] Figure 6H is a graph on stability studies reporting at which freezing -thawing cycle and the percentage of vials for which turbidity / precipitation appeared when vials of comparative compositions, prepared according to WO’121 process, and vials of inventive composition, prepared according to the inventive process, were subjected up to 15 freezing-thawing cycles.

[0042] Figure 6I are two pictures showing the turbidity of the compositions prepared according to WO’761 process (left) in comparison with the corresponding compositions prepared according to the inventive process (right) after 9 freezing-thawing cycles.

[0043] Figure 7 is a flow diagram illustrating a process for manufacturing a composition according to the present invention.

[0044] DETAILED DESCRIPTION OF THE INVENTION

[0045] Unless otherwise stated, the percentages of the ingredients in the composition and of reactants in the process for the manufacture thereof are percentages by weight referred to the weight of the composition of the invention.

[0046] In the present description, the term “absence of precipitation” means that no precipitate is present or that a very light precipitate is present that does not generate turbidity or opacity upon agitation.

[0047] The term “turbidity” means that a light precipitate is present that generates opacity of the composition upon agitation. According to an aspect, the present invention provides a liquid pharmaceutical composition comprising from 0.002 to 0.010 % wt of sodium picosulfate, from 1.0 to 3.0 % wt % wt of magnesium oxide, from 3.5 to 10.5 % wt % wt of citric acid, from 0.01 to 13.0 % wt of malic acid, optionally one or more pharmaceutically acceptable excipient(s) and water, the composition having a pH higher than 5.4.

[0048] Preferably the present invention provides a liquid pharmaceutical composition comprising from 0.002 to 0.010 % wt of sodium picosulfate, from 1.0 to 3.0 % wt % wt of magnesium oxide, from 3.5 to 10.5 % wt of citric acid, from 0.01 to 13.0 % wt of malic acid, optionally one or more pharmaceutically acceptable excipient(s) and water, the composition having a pH higher than 5.4 and comprising at to Impurity A, derived from sodium picosulfate, in amount lower than 0.2 % (HPLC analysis as described in the experimental part).

[0049] Preferably, the present invention provides a liquid pharmaceutical composition comprising from 0.003 to 0.009 % wt of sodium picosulfate, from 1.5 to 2.5 % wt of magnesium oxide, from 5.0 to 8.0 % wt of citric acid, from 3.0 to 8.0 % wt of malic acid, optionally one or more pharmaceutically acceptable excipient(s) and water, the composition having a pH higher than 5.4.

[0050] More preferably, the present invention provides a liquid pharmaceutical composition comprising from 0.004 to 0.008 % wt of sodium picosulfate, from 1.8 to 2.2 % wt of magnesium oxide, from 5.5 to 7.0 % wt of citric acid, from 4.0 to 6.0 % wt of malic acid, optionally one or more pharmaceutically acceptable excipient(s) and water, the composition having a pH higher than 5.4.

[0051] In one embodiment, the composition according to the invention comprises less than 5%, preferably less than 4%, more preferably less than 3% wt of malic acid. As demonstrated in the experimental section (see Table 7A), the present composition is more stable than previous compositions even in the presence of lower amounts of malic acid as stabilizer.

[0052] The above compositions preferably have a pH higher than 6.0, more preferably higher than 6.4 or than 6.5. The above composition preferably has a pH lower than 7.6, more preferably a pH lower than 7.0.

[0053] The above composition preferably has a pH higher than 5.0, than 5.4 and lower than 7.6, more preferably a pH from 6.0 to 7.0, even more preferably a pH from 6.4 to 6.6.

[0054] The above composition may have a pH higher than 6.5 and lower than 8.0, preferably higher than 6.5 and lower than 7.6.

[0055] The above composition is characterized by an improved stability as shown in the present experimental section.

[0056] An embodiment of the composition of the invention has a pH from 6.0 to 7.0 and comprises (% wt):

[0057] Malic acid 4.0 - 6.0 % Citric acid 5.5 - 7.0 %

[0058] Magnesium oxide 1.8 - 2.2 %

[0059] Sodium picosulfate 0.004 - 0.008 %

[0060] Optional excipients

[0061] Purified water up to 100%

[0062] An embodiment of the composition of the invention has a pH from 6.0 to 7.0 and comprises

[0063] (% wt):

[0064] Malic acid 4.0 - 6.0 %

[0065] Citric acid 5.5 - 7.0 %

[0066] Magnesium oxide 1.8 - 2.2 %

[0067] Parabens 0.05 - 0.15%

[0068] Antioxidant 0.2 -1.0%

[0069] Sodium picosulfate 0.004 - 0.008 %

[0070] Optional excipients Purified water up to 100%

[0071] A preferred embodiment of the composition of the invention has a pH of about 6.5 and comprises (% wt):

[0072] Malic acid 4.5 - 5.5 %

[0073] Citric acid 6.0 - 6.5 %

[0074] Magnesium oxide 1.9 - 2.1 %

[0075] Parabens 0.07 - 0.12 %

[0076] Sodium metabisulfite 0.4 - 0.6%

[0077] Sodium picosulfate 0.004 - 0.008 %

[0078] Optional excipients

[0079] Purified water up to 100%.

[0080] With a pH of about 6.5, a pH ranging from 6.4 to 6.6 is meant.

[0081] Preferably, the above embodiments of the composition of the invention are prepared according to the process of the invention.

[0082] According to a preferred aspect, the present invention provides a liquid pharmaceutical composition comprising from 0.002 to 0.010 % wt of sodium picosulfate, from 1.0 to 3.0 % wt of magnesium oxide, from 3.5 to 10.5 % wt of citric acid, from 0.01 to 13.0 % wt of malic acid, optionally one or more pharmaceutically acceptable excipient(s) and water, wherein the pH of the liquid pharmaceutical composition is from 4.5 to 8.0, preferably higher than 5.0, more preferably higher than 5.4 and lower than 7.6, and wherein the composition is obtainable according to a preferred process comprising: (i) providing at least an alkalinizing agent, preferably sodium hydroxide, in amount from 1 to 7%, preferably from 2.0 to 6.0 % wt, said alkalinizing agent being pre-dissolved in water to provide a first aqueous solution having a pH from 13.0 to 14.0,

[0083] (ii) providing malic acid in amount from 0.01 to 13.0 % wt, contacting it with the first aqueous solution and dissolving it to provide a second aqueous solution, with a pH preferably ranging from 12.0 to 13.0,

[0084] (iii) adding citric acid to the previous second aqueous solution, in amount from 3.5 to 10.5 % wt, and dissolving it, to provide a third aqueous solution, with a pH ranging from 3.5 to 4.5,

[0085] (iv) adding magnesium oxide to the previous third aqueous solution, in amount from 1.0 to 3.0 % wt, dissolving it to provide a fourth aqueous solution, with a pH preferably ranging from 7.5 to 9.0,

[0086] (v) optionally, adding at least a preservative agent to the previous fourth aqueous solution, then at least an antioxidant and dissolving them to provide a fifth aqueous solution,

[0087] (vi) adding sodium picosulfate in amount from 0.002 to 0.010 % wt and optionally other pharmaceutically acceptable excipients to the previous fourth or fifth aqueous solution, and dissolving them to provide a sixth aqueous solution, and

[0088] (vii) optionally adjusting the pH of the previous sixth aqueous solution, at a value preferably higher than 5.0, more preferably higher than 5.4 and lower than 7.6, in which water is added in one or more of the previous steps in a preferred total amount from 75 to 85 % wt, all the percentages by weight being referred to the weight of the composition, to provide the composition according to the invention.

[0089] Preferred features of the process of the invention are reported in the following section and are applicable mutatis mutandis to the preparation of all the previous described compositions.

[0090] The above compositions preferably have a final pH higher than 6.0, more preferably higher than 6.4 or 6.5. The above compositions preferably have a final pH from 5.5 to 7.5, more preferably from 6.0 to 7.0, even more preferably from 6.4 to 6.6.

[0091] In an embodiment, the above compositions preferably have a pH higher than 6.5 and lower than 8.0.

[0092] In the above compositions, obtainable according to the present process, preferably the amount of the ingredients are from 0.003 to 0.009 % wt of sodium picosulfate, from 1.5 to 2.5 % wt of magnesium oxide, from 5.0 to 8.0 % wt of citric acid, from 3.0 to 8.0 % wt of malic acid and from 70 to 90 % wt of water and the final pH is higher than 5.4, more preferably the amount of the ingredients are from 0.004 to 0.008 % wt of sodium picosulfate, from 1.8 to 2.2 % wt of magnesium oxide, from 5.5 to 7.0 % wt of citric acid, from 4.0 to 6.0 % wt of malic acid and from 75 to 85 % wt of water and the final pH is from 6.0 to 7.0.

[0093] The malic acid used in the present composition may include l-malic acid and d-malic acid, however preferably racemic malic acid is used.

[0094] The citric acid used in the present composition may include hydrated forms, however preferably anhydrous citric acid is used.

[0095] The magnesium oxide used in the present composition may include light and heavy magnesium oxide, however preferably light magnesium oxide is used.

[0096] The composition of the invention comprises water, in particular purified water suitable for pharmaceutical use. Water can be the only solvent or additional water-soluble or water- miscible solvents can also be present, for instance alcohols, including C2-C4 alcohols such as ethanol, or glycols such as propylene glycol or polyethylene glycol.

[0097] Preferably, in the composition of the invention water is present in amount higher than 60%, more preferably higher than 70% wt, even more preferably higher than 75% wt.

[0098] In the composition of the invention, water is preferably present in amount from 70 to 90 % wt, more preferably from 75 to 85 % wt.

[0099] Preferably, water is the only solvent of the composition of the invention.

[0100] The composition of the invention is a liquid composition, preferably is a solution, typically a transparent, colourless or slightly yellowish solution.

[0101] The composition of the invention is a liquid composition suitable for oral administration.

[0102] The composition of the invention may include at least one antioxidant, preferably an antioxidant chosen from water-soluble antioxidants such as for instance ascorbic acid, sodium ascorbate, sodium metabisulfite, potassium metabisulfite, sodium sulfite, sodium thiosulfate, sulfur dioxide erythorbic acid or propionic acid, more preferably comprises sodium metabisulfite.

[0103] The composition of the invention may include other pharmaceutically acceptable excipients such as, for instance, preservative agents, sweeteners and flavours, stabilizers and pH adjusters.

[0104] The composition of the invention may include at least one preservative agent, preferably a preservative agent chosen for instance among potassium or sodium sorbate, potassium or sodium benzoate, parabens (a class of 4-hydroxybenzoic acid esters used as biological preservative agents) and the like, more preferably comprises at least a paraben selected from methyl, ethyl, propyl, butyl esters, their salts and admixtures thereof.

[0105] Preferably, when the pH of the composition is higher than 5.4, especially from 6.0 to 7.0, parabens are used, in particular sodium methylparaben and / or sodium propylparaben.

[0106] The composition of the invention may include sweeteners, flavours and taste modulators to increase the medication compliance. Advantageously the composition of the present invention may contain less sweeteners and flavours compared to previous similar more acidic compositions.

[0107] Preferably, the composition of the present invention comprises a total amount of sweeteners, flavours and taste modulators lower than 0.3 % wt, more preferably lower than 0.2% wt.

[0108] The composition of the invention may include stabilizers, for instance chelating agents such as ethylenediaminetetraacetic acid (EDTA) and the like. However, advantageously the composition of the present invention shows high stability even in the absence of chelating agents.

[0109] The composition of the invention may include at least a pH adjuster, for instance an alkalinizing agent such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, ammonia, potassium citrate, triethanolamine and sodium citrate and the like, more preferably sodium hydroxide. Possibly, also an acidifying agent may be used such as for instance hydrochloric acid, phosphoric acid, sulfuric acid or preferably carboxylic acids such as malic acid, and the like.

[0110] The pH adjuster upon reaction with other acidic or basic ingredients of the composition may form salts that may be present as additional components of the composition, e.g., sodium chloride, sodium sulfate, potassium sulfate, potassium chloride and the like.

[0111] The liquid composition according to the invention can be prepared according to a process comprising:

[0112] (i) providing at least an alkalinizing agent in amount from 1.0 to 8.0 % wt, preferably dissolved in water to provide a first aqueous solution having a pH from 12.0 to 14.0,

[0113] (ii) providing malic acid in amount from 0.01 to 13.0 % wt, contacting it with the at least an alkalinizing agent and with water, preferably contacting it with the first aqueous solution, and dissolving it to provide a second aqueous solution,

[0114] (iii) adding citric acid to the previous second aqueous solution, in amount from 3.5 to 10.5 % wt, and dissolving it, to provide a third aqueous solution,

[0115] (iv) adding magnesium oxide to the previous third aqueous solution, in amount from 1.0 to 3.0 % wt, dissolving it to provide a fourth aqueous solution,

[0116] (v) optionally, adding at least a preservative agent to the previous fourth aqueous solution, then at least an antioxidant and dissolving them to provide a fifth aqueous solution,

[0117] (vi) adding sodium picosulfate in amount from 0.002 to 0.010 % wt and optionally other pharmaceutically acceptable excipients to the previous fourth or fifth aqueous solution, and dissolving them to provide a sixth aqueous solution, and

[0118] (vii) if needed, adjusting the pH of the previous sixth aqueous solution at a value from 4.5 to 8.0, preferably at a value higher than 5.0, more preferably higher than 5.4 and lower than 7.6, in which water is added in one or more of the previous steps in a preferred total amount from 70 to 95 % wt, all the percentages by weight being referred to the weight of the composition, to provide the composition according to the invention.

[0119] In step (i) of the process according to the invention, preferably the alkalinizing agent is predissolved in water to provide the first aqueous solution, which preferably has a pH from 13.0 to 14.0. As demonstrated in the Examples 5B and 5C, the addition of NaOH as a solid is less advantageous due to a slow dissolution and to the related possible carbonation problems.

[0120] The alkalinizing agent is preferably selected among sodium hydroxide, potassium hydroxide, sodium bicarbonate, ammonia, potassium citrate, triethanolamine and sodium citrate and the like, more preferably is sodium hydroxide. Preferably, the alkalinizing agent is in amount from 2.0 to 6.0 % wt, most preferably the alkalinizing agent is sodium hydroxide in amount from 2.0 to 6.0 % wt.

[0121] Preferably, an amount of water between 75 % and 95 %, more preferably between 80 % and 95% of the total amount of water is added in this step.

[0122] In step (ii) of the process according to the invention, malic acid is preferably added to the first aqueous solution, either as a solid or as a solution, such as an aqueous solution.

[0123] In alternative, less preferably, malic acid and the alkalinizing acid may be added to water in any other order and therein dissolved.

[0124] More preferably, malic acid is added as a solid to the first aqueous solution of the alkalinizing agent. Typically, complete dissolution may be achieved in less than 20 minutes, preferably in less than 10 minutes, preferably under stirring. Preferably, malic acid is added in amount from 3.0 to 8.0 % wt, more preferably from 4.0 to 6.0 % wt. Typically, after malic acid addition, a solution is obtained, with a pH ranging from about 12 to 13. The Applicant has understood that under these conditions, namely by providing substantially all the alkalinizing agent at the very beginning of the process and by next adding the malic acid, the formation of a gel, which occurred with prior art processes (see for instance in the experimental part Ex. 5D, Ex. 3.35 to Ex. 3.38 reproducing the teaching of WO’761 or Ex. 3.31 , Ex. 3.32 reproducing the teaching of WO’121) is avoided.

[0125] In step (iii) of the process according to the invention, citric acid is added to the second aqueous solution, either as a solid or as a solution, such as an aqueous solution. Preferably, citric acid is added as a solid. Preferably, citric acid is added when the second solution temperature is lower than 40°C, more preferably lower than 35°C. Advantageously the second solution can be cooled as known in the art. The Applicant believes that controlling the temperature of the solution upon addition of citric acid may prevent its degradation and reduce formation of by-products such as oxalic acid. Typically, complete dissolution may be achieved in less than 20 minutes, preferably in less than 10 minutes, preferably under stirring. Preferably, citric acid can be added in amount from 5.0 to 8.0 % wt, more preferably from 5.5 to 7.0 % wt. Typically, after the addition of citric acid, the pH of the solution drops to about 4. The Applicant believes that this low pH is advantageous to have a smooth solubilisation of magnesium oxide.

[0126] In step (iv) of the process according to the invention, magnesium oxide is added to the third aqueous solution, either as a solid or as a suspension, such as an aqueous suspension. Preferably, magnesium oxide is added as a solid. Preferably, magnesium oxide can be added in amount from 1 .5 to 2.5 % wt, more preferably from 1 .8 to 2.2 % wt. The Applicant has observed that upon the addition of magnesium oxide, the temperature of the solution increases up to about 55°C due to an exothermic reaction between citric acid and magnesium oxide. A cooling step is then preferably applied to lower the temperature. Furthermore, the final pH of the fourth solution upon magnesium oxide dissolution typically raises to a value between about 8.0 and 8.5.

[0127] In the optional step (v) of the process according to the invention, at least a preservative agent may be added to the previous fourth aqueous solution, either as a solid or as a solution, such as an aqueous solution, preferably as an aqueous solution. Preferably, the preservative agent is added when the fourth solution temperature is lower than 40°C, more preferably lower than 35°C. Advantageously the fourth solution can be cooled down as known in the art. Preferably the at least a preservative agent comprises one or more parabens, in total amount preferably from 0.05 to 0.20 % wt, more preferably from 0.07 to 0.15 % wt. When preservative agents are parabens, the dissolution is smooth thanks to the pH of the fourth solution (preferably pH from about 8 to about 9), which is close to the parabens’ pKa.

[0128] Preferably, after complete dissolution of the at least a preservative agent, at least an antioxidant is added. Preferably the at least an antioxidant is added in amount from 0.2 to 1.0 % wt, more preferably from 0.4 to 0.6 % wt. Preferably, the at least an antioxidant is sodium metabisulfite. When the antioxidant is sodium metabisulfite, the final pH of the fifth solution may be typically from about 6.3 to 6.5.

[0129] In step (vi) of the process according to the invention, sodium picosulfate is added to the fourth or fifth aqueous solution, either as a solid or as a solution, such as an aqueous solution. Preferably, sodium picosulfate is added as a solid. Preferably, sodium picosulfate is added when the fifth solution temperature is lower than 40°C, more preferably lower than 35°C even more preferably lower than 30°C. Preferably, sodium picosulfate can be added with in amount from 0.002 to 0.010 % wt, more preferably from 0.003 to 0.009 % wt, even more preferably from 0.004 to 0.008 % wt.

[0130] Optionally, pharmaceutically acceptable excipients can be added in one or more of the process steps. Advantageously excipients such as sweeteners, flavours and taste modulators, and in general possible thermosensitive excipients, are preferably added in step (vi) to prevent any possible thermal degradation that may occur if added in preceding more exothermic steps.

[0131] In step (vii) of the process according to the invention, the pH of the previous sixth aqueous solution can be adjusted, if needed, to a value from 4.5 to 8.0, preferably to a value higher than 5.0, more preferably higher than 5.4 and lower than 7.6, more preferably to a pH value from 6.0 to 7.0, more preferably to a pH from 6.4 to 6.6, by addition of at least a pH adjuster, such as an acidifying or an alkalinizing agent, as known to the skilled person. Optionally, also part of the water can be added herein.

[0132] Preferably, all the steps of the process of the invention are carried out under stirring. Preferably steps from iii) to vii) are carried out at a temperature lower than 40°C.

[0133] The amount of the ingredients used in the above process of the invention may be suitably adjusted as known to the skilled person to provide the composition of the invention with one or more of the preferences previously expressed.

[0134] In the preparation process of the invention, water may be added in one or more portions. In a preferred embodiment, more than 50 % wt, more than 60 % wt, more than 70% wt, more preferably more than 80 % wt, preferably about 90% wt of the total amount of water is added in step (i) and the remaining amount preferably in step (vii), up to the final volume.

[0135] Preferably, the process according to the invention includes at least one final filtration step that can be performed using techniques and equipment known to the skilled person.

[0136] The process of the invention is further characterized by one or more of the following features:

[0137] - the alkalinizing agent is selected among sodium hydroxide, potassium hydroxide, sodium bicarbonate, ammonia, potassium citrate, triethanolamine and sodium citrate, preferably is sodium hydroxide, and it is dissolved in water providing a first aqueous solution (i);

[0138] - malic acid, citric acid and magnesium oxide are added in solid form (ii, iii and vi);

[0139] - in steps (iii) to (vii) the temperature of the solutions is kept lower than 40°C, preferably lower than 35°C;

[0140] - in step (v) at least a paraben is added to the fourth aqueous solution followed, after dissolution, by addition of sodium metabisulfite as antioxidant;

[0141] - about 90 % wt of the total amount of water is added in step (i).

[0142] In a preferred embodiment, the present process comprises:

[0143] (i) providing a first aqueous solution having a pH from 13.0 to 14.0, comprising sodium hydroxide in amount from 2.0 to 6.0 % wt,

[0144] (ii) adding malic acid preferably in solid form, to the first aqueous solution, in amount from 4.0 to 6.0 % wt, and dissolving it to provide a second aqueous solution, (iii) adding citric acid preferably in solid form, to the previous second aqueous solution, at a temperature lower than 40°C, in amount from 5.5 to 7.0 % wt, and dissolving it, to provide a third aqueous solution,

[0145] (iv) adding magnesium oxide preferably in solid form, to the previous third aqueous solution, in amount from 1 .8 to 2.2 % wt, and dissolving it to provide a fourth aqueous solution,

[0146] (v) adding at least a paraben, preferably as an aqueous solution, in amount from 0.07 to 0.12 % wt, to the previous fourth aqueous solution, at a temperature lower than 40°C, then adding sodium metabisulfite in amount from 0.4 to 0.6 % wt, and dissolving them to provide a fifth aqueous solution,

[0147] (vi) adding sodium picosulfate preferably in solid form, in amount from 0.004 to 0.008 % wt and optionally other pharmaceutically acceptable excipients to the previous fourth or fifth aqueous solution, at a temperature lower than 40°C, and dissolving them to provide a sixth aqueous solution, and

[0148] (vii) if needed, adjusting the pH of the previous sixth aqueous solution at value from 6.0 to 7.0, in which water is added in total amount from 75 to 85 % wt, all the percentages by weight being referred to the weight of the composition, to provide a preferred liquid composition according to the invention.

[0149] Preferably, before any final filtration to remove possible insoluble products, pH and density of the aqueous liquid composition are checked using conventional methods.

[0150] According to the invention, the pH of the composition prepared according to the present process is preferably higher than 5.0, more preferably higher than 5.4 and preferably lower than 7.6, more preferably higher than 6.0, even more preferably higher than 6,4. If the pH deviates from the specification values, it is possible to intervene by adding an alkalinizing agent, preferably the same alkalinizing agent already used, or an acidifying acid, preferably malic acid, until the pH value is corrected.

[0151] In the present process, the order of the addition of the ingredients and their amount and, furthermore, temperatures and pH conditions, are important in order to provide the desired composition of the invention, having a low content of by-products and a good physical and chemical stability.

[0152] A significant advantage, especially at industrial level, of the present preparation process is the non-gelling of the mixture which, instead, occurs with other processes. The present process is thus less cumbersome and faster than the previous ones, as it does not require the laborious and time-consuming stirring necessary to remove the gel phase. As demonstrated in the present experimental part (see Example 5), a different manufacturing process, in particular a different order of addition of the ingredients, can result in turbidity, precipitation or jellification or, even if a clear solution is obtained, in instability in the long term. Other experimental data regarding the stability of identical compositions prepared according either to the present process or to the prior processes described in EP’835 (see Examples 1 to 4), WO’121 or WO’761 (Ex. 4C) further demonstrate that the physical form of the ingredients, the order of addition and the conditions of dissolution influence the stability of the final composition.

[0153] In the known process of EP’835, all the ingredients were pre-mixed in the solid state and, only in the last step, the powder mixture was dissolved in the solvent. The Applicant observed that the dissolution step is quite exothermic and potentially damaging for the ingredients, especially for the more thermos-sensitive compounds. Similarly, in the process of WO’121 most of the APIs are already mixed up in powder form from the beginning while malic acid addition and pH fine tuning are carried out at the end. On the contrary, in the process of WO’761 the ingredients are added stepwise as in the present process but with the important difference of the pH of the medium along the steps.

[0154] In the present process, an initial aqueous solution of the alkalinizing agent with malic acid is preferably prepared, followed by the addition and dissolution of citric acid and magnesium oxide, and then of the other ingredients. In this process, the pH conditions are optimal for in sequence dissolution of the ingredients without re-precipitation and the thermal degradation may be minimized due to temperature control.

[0155] Unexpectedly, the composition prepared according to the process of the invention shows superior stability after storage, in terms of precipitation and impurities, compared to the composition comprising the same ingredients but prepared according to previous processes, such as the process of EP’835 (see Example 3 and Example 4), the process of WO’121 or WO’761 (see Ex. 4C). Advantageously, the present process provides for compositions chemically more stable too with a lower content of picosulfate Impurity A compared to prior processes (see Ex. 1 , Ex. 4D).

[0156] A possible process for manufacturing the composition according to the present invention is illustrated in the flow diagram of Figure 7. As illustrated, the process for preparing the present composition may include initially weighing and adding in sequence, preferably under stirring, sodium hydroxide aqueous solution, malic acid, citric acid, magnesium oxide and water (steps i - iv), preferably cooling below 35°C, adding the preservative agents and the antioxidants, if present (step v), adding sodium picosulfate, optional sweeteners and flavours (step vi), preferably checking pH and density, possibly adjusting the pH and optionally adding the remaining water (step vii). Finally, the solution is preferably filtered and packaged.

[0157] Following preparation, the liquid composition of the invention can be packaged in a suitable container (e.g., bottles, vials etc), which can include one or two or more doses of the composition and can be sealed with a closure. Preferably, each bottle contains a single dose. Possibly one or more botles may be packaged together, providing the patient with the doses required for an entire treatment.

[0158] A single dose of the liquid composition of the invention may vary in volume and amount of the ingredients e.g. it may have a volume from 50 ml to 500 ml, preferably from 100 to 200 ml, more preferably from 140 ml to 180 ml. A preferred single dose volume is of about 150 - 160 ml.

[0159] The composition of the invention is physically and chemically stable for a long time, for instance for at least sixty days, at least about ninety days, at least about six months, preferably at least about a year, at least about 18 months, more preferably at least about two or three years, if stored for instance at 25°C and 60% of RH (see Ex. 4A) or even longer if stored at 2-8°C (Ex.4B).

[0160] The composition of the invention is more stable than previous compositions (Ex. 4C, Ex. 4D). The composition of the invention is physically and chemically more stable than the compositions described in EP’835, WO’121 or WO’671 as demonstrated in the present experimental part.

[0161] The term "stable" when used to refer to liquid compositions as described herein refers to lack of significant degradation of the active ingredients in the solution and / or the lack of visible precipitation over a given period. In general, stability can be evaluated or indicated by a number of methods, such as the amount of impurity and / or degradation products, the amount of visible precipitate and / or the amount of the active ingredients that is chemically unchanged over the storage period.

[0162] In particular, in the present composition, stored at 25°C, 60% RH the content change of the active ingredients (sodium picosulfate, citric acid and magnesium oxide) up to 36 months may be within ±5.0 % wt, preferably within ±3.0 % wt, more preferably within ± 1.0% wt, and the content of impurity A may be lower than 0.5% wt.

[0163] Preferably, the present composition at to (HPLC analysis just after manufacture) comprises Impurity A, derived from sodium picosulfate, in amount lower than 0.2 %.

[0164] In one embodiment, the composition of the invention when stored at 25°C / 60% RH for 24 months comprises Impurity A in amount lower than 1%, even lower than 0.5% or 0.4% or 0.2%.

[0165] The composition of the present invention shows a physical stability higher than the physical stability of prior art similar compositions. In particular, the compositions prepared according to the present process have unexpectedly proven to be more stable than compositions prepared according to EP’835, WO’121 or WO761 in a wide range of pH, from acidic to neutral to slightly basic, showing no formation of precipitate or a slight turbidity or a delayed precipitation or formation of less precipitate, in conclusion showing a superior stability and, accordingly, shelf-life. In particular, the present process confers superior stability to the same compositions known in the art having a pH lower than 5.4 as demonstrated for instance under Ex. 4C.

[0166] The stability at higher pH was unexpected and in contrast with the common teaching on these compositions provided by the state of the art. Advantageously the compositions of the present invention, in particular those having a pH higher than 5.0, more preferably higher than 5.4, preferably higher than 6, more preferably a pH around 6.5, are characterized by less sourness and may advantageously contain less sweeteners and / or flavours.

[0167] The present composition may thus increase the ease of storage and transport, the shelf life of the composition and even medication compliance.

[0168] The pharmaceutical liquid composition of the invention may be used to treat constipation or in a method for bowel, in particular colon, inspection or any diagnostic procedure or for cleansing prior to surgery, for instance prior to colonoscopy, endoscopy or colon X-ray inspection.

[0169] When used for clearance of the bowel, e.g., prior to X-ray examination, endoscopy or surgery, it can be useful to administer two doses of the liquid composition. For example, the following procedures may be used.

[0170] The composition can be given as a split dose administration where a first dose of the composition is taken the evening before the procedure, which can be followed by administration of clear liquid. Then, a second dose of the composition can be taken the morning of the procedure, which can be followed by administration of clear liquid.

[0171] The composition can also be given as a split dose administration where two doses of the composition are taken the day before the procedure. For example, one dose of the liquid composition can be taken in the afternoon, which can be followed by administration of clear liquid. Then, a second dose of the composition can be taken in the late evening, which can be followed by administration of clear liquid.

[0172] The composition can also be given as a split dose administration where two doses of the composition are taken the morning of the day the procedure when the procedure is planned in the afternoon or evening.

[0173] EXPERIMENTAL PART

[0174] In order to better illustrate the present invention, the following non-limiting examples are now provided. Unless otherwise stated, the percentages are percentages by weight (% wt).

[0175] Methods

[0176] Assay of citric acid

[0177] Citric acid was identified and quantitatively analysed by using an isocratic UPLC (ultra high- pressure chromatography) method. Under the analytical conditions set below, citric acid had a retention time of about 3.45 min. The equipment used in the analysis was as follows:

[0178] Waters UPLC system with PDA detector at 230 nm or equivalent.

[0179] UPLC column: Waters Acquity UPLC HSS T3 column 1.8 pm, 3.0 mm x 100 mm, chromatography column with C18 reverse phased bonded silica (1.8 pm particle size and 100 A pore size).

[0180] The mobile phase was a TFA (Trifluoroacetic acid) 0.05 % v / v solution with a pH around 2. For the UPLC analysis, instrument parameters were set as indicated in Table 1.

[0181] Table 1

[0182] Ail samples and standards were prepared at a concentration of 0.3 g / L. A standard solution of citric acid was prepared by accurately weighing 0.3 grams of citric acid reference standard, diluting it in 1000 mL of water and finally filtering it with a 0.22 pm PVDF filter.

[0183] Samples were prepared by transferring 0.2 g of bulk or drug product solution to a 50 mL volumetric flask and diluting to volume with water and finally filtering with a 0.22 pm PVDF filter.

[0184] Assay of Sodium Picosulfate and related impurities

[0185] The presence of picosulfate and of related impurities was detected by HPLC. For simplicity, in the analysis the response factor of the impurity was assumed to be equal to the response factor of picosulfate so that the ratio of the signal (e.g., peak area in HPLC) for the impurity to that of picosulfate measured the relative amounts of impurity and picosulfate.

[0186] Under the used analytical conditions, sodium picosulfate had a retention time of about 18 minutes, Impurity A of 27 minutes and Impurity B (4,4'-[(pyridin-2-yl)methylene]diphenol) of 31 minutes.

[0187] Sodium picosulfate was quantitatively identified and analysed using a reversed-phase HPLC (high pressure chromatography) method and a PDA detector.

[0188] The equipment used in the analysis was as follows:

[0189] Waters HPLC system with a photo diode array (PDA) detector at 225 nm.

[0190] HPLC column: Waters XBridge BEH RP18 4.6 mm x 250 mm chromatography column, which contains a C18 reverse phase (3.5 pm particle size and 130 A pore size).

[0191] HPLC pre-column: Waters XBridge BEH Shield RP18 VanGuard Cartridge 3.9 mm x 5 mm, which contains a C18 reverse phase, a 3.5 pm particle size and a 130 A pore size. For the first mobile phase (mobile phase A) an admixture of Acetonitrile : Isopropanol : THF (85:10:5) was used. For the second mobile phase (mobile phase B), HPLC-grade water was used. For the third mobile phase (mobile phase C), an admixture of Acetonitrile : Isopropanol (80:20) was used. For the fourth mobile phase (mobile phase D) 63 mM phosphoric acid buffer at pH 7.00 was used. M illi-Q® ultrapure water was used for dilution of all standards and samples.

[0192] For the HPLC analysis, instrument parameters were set as indicated in Table 2 and a mobile phase gradient was run for each injection as indicated in Table 3.

[0193] Table 2

[0194] Table 3

[0195] Mobile Phase Gradient for HPLC Analysis

[0196] Both samples and standard were diluted to a given concentration and finally filtered by

[0197] Nylon filters, prior HPLC analysis.

[0198] Assay of Magnesium Oxide

[0199] Magnesium Oxide was quantitatively analysed by volumetric titration with EDTA 0.1 M.

[0200] The equipment used was as follows: 10 mL glass burette; 50 mL, 100 mL and 1000 mL volumetric flasks; 500 mL Erlenmeyer flask; Pipettes and micropipettes.

[0201] Samples were prepared by transferring 10 g of bulk or drug product solution to a 100 mL volumetric flask, adding 5 mL of HCI 10% v / v and diluting to volume with water. Then pipetting 15 mL and diluting with 85 mL of water in an Erlenmeyer flask. Finally adding 10 mL ammonium buffer (pH around 10), 3 drops of Eriochrome Black indicator and titrating the solution with 0,1 M disodium EDTA to a clear blue colour.

[0202] Assay of Sodium methylparaben and Sodium propylparaben Sodium methylparaben and sodium propylparaben were identified and quantitatively analysed with an isocratic HPLC method. Under the used analytical conditions, sodium methylparaben had a retention time of about 3.6 min and sodium propylparaben of about 7 min. The equipment used in the analysis was as follows:

[0203] Waters HPLC system with a PDA detector or equivalent at 254 nm.

[0204] HPLC column: Lichrosphere RP-Select B 5pm 250x4 mm

[0205] The mobile phase was: methanol 60% - Acetic Acid 1 mM 40%.

[0206] For the HPLC analysis, instrument parameters were set as indicated in Table 4.

[0207] Table 4

[0208] All samples and standards were prepared at concentrations of 0.01 g / l sodium methylparaben and 0,001 g / l sodium propylparaben. Standard solutions of sodium methylparaben and sodium propylparaben were prepared by accurately weighing 0.1 grams of sodium methyiparaben and 0.01 grams of sodium propylparaben reference standards, which were solubilized in 100 mL of sample solution (60% / 40% v / v - acetic acid 1mM / methanol). Then, 1 mL of the resulting solution was transferred into a 100 mL volumetric flask and diluted up to 100 mL with the sample solution. The standard solution was finally filtered with a PTFE filter. Samples were prepared by transferring 1 gram of bulk or drug product solution to a 100 mL volumetric flask, diluting to volume with sample solution and, finally, filtering an aliquot on PTFE filter.

[0209] Assay of Sodium metabisulfite

[0210] Sodium metabisulfite was quantitatively analysed using volumetric titration with Iodine 0.1 M. The equipment used in the analysis was as follows:

[0211] 10 mL glass burette; 250 mL Erlenmeyer flask; pipettes and micropipettes.

[0212] A standard solution of Sodium metabisulfite was prepared by accurately weighing 0.023 grams of Sodium metabisulfite reference standard, diluting with 30 mL of water in an Erlenmeyer flask, then shaking with a magnetic stirrer for 1 minute. Samples were prepared by transferring 5 grams of bulk or drug product solution to a 250 mL Erlenmeyer flask, adding 30 mL of deionised water, shaking with magnetic stirrer for 1 minute, dissolving with 5 mL of HCI 10% and admixing for 1 minute. pH measurement pH was measured with pHmeter Sension pH31 . 40 mL of sample were introduced into a 50 mL beaker and then the pH was measured with the pHmeter.

[0213] Example 1

[0214] In this Example, a composition according to the invention (Ex. 1 - I NV) was prepared from the ingredients in the respective amounts reported in the following Table 5:

[0215] Table 5: composition Ex. 1 (INV)

[0216] * containing NaOH in amount of 5.65 g / dose; 3.21 % wt in which all the ingredients were of pharmaceutical acceptable grade and had the following characteristics: Malic acid: melting point: 128°C-132°C; assay: 99.0-101.0%; racemic; Citric acid: anhydrous, melting point: about 153°C, with decomposition; assay: 99.5 - 100.5%;

[0217] Magnesium oxide: light magnesium oxide, assay (on ignited basis, Eur. Ph.): 98.0-100.5%; Sodium methylparaben: melting point: 128°C-132°C; assay: 95.0-102.0%; Sodium propylparaben: melting point: 96°C-99°C; assay: 94.0-102.0%; Sodium metabisulfite: assay: 95.0-100.5%; Sodium picosulfate: total impurities < 0.5%; water content (Karl- Fischer): between 3.0 to 5.0%; assay 98.5 - 100.5%; sweetness modulator: natural flavour comprising steviol analogues, maltodextrins and gum; Grenadine flavour: clear reddish purple solution; alcohol (v / v %): 42.50-46.50%; Sucralose: assay (on dry basis) (%): 98.0- 102.0%; Specific Rotation: +84.0° - +87.5°. As can be seen from Table 5 above, the present composition, having a pH of 6.5, had a total amount of sweeteners, flavours and taste modulators of about 0.16 % wt (Sweetness modulator 0.05 % wt, Grenadine flavour 0.09 % wt and Sucralose 0.02 % wt), which is lower than the amount present in prior art more acidic composition (for instance embodiment 1 of EP’835, contains acesulfame potassium, sucralose and an orange fragrance ingredient in total amount of 0.32 % wt).

[0218] A batch of the composition of Table 5 was prepared according to the following process. Purified water (90 % of the total amount of water reported in Table 5) was introduced into a reactor, then the aqueous sodium hydroxide solution (50% wt) having a pH around 14 was added under stirring, followed by the solid malic acid. The admixture was stirred up to complete dissolution, reaching a pH between 12 and 13 and a temperature of about 42°C. The solution was cooled below 40°C and then solid citric acid was added under stirring. After dissolution of citric acid, the pH of the solution was about 4. Solid magnesium oxide was then added and the admixture stirred up to complete dissolution. The temperature of the solution raised up to about 55°C and the pH at 8.0 - 8.5. After cooling the solution below 35°C (water jacket), the preservative agents (parabens) previously dissolved in water (1 % wt of the total amount of water of the composition) were then introduced under vigorous stirring and then, upon dissolution, sodium metabisulfite was added under stirring, bringing the pH at around 6.3 - 6.5. Finally, sodium picosulfate, sweeteners and flavours were added and stirred up to dissolution. The pH of the resulting solution was checked and brought to about 6.5 with the aqueous NaOH solution (50% wt). The remaining amount of water was added at this stage to reach the final volume. The final composition, filtered on a polypropylene fibers filter, appeared as a clear and colourless solution. The process did not require nitrogen atmosphere.

[0219] The final composition was subjected to the following analyses at to with the reported results:

[0220] - Appearance by visual inspection: transparent, colourless solution;

[0221] - pH: 6.5;

[0222] - Picosulfate Assay: 100%

[0223] - Impurity A: 0.18%

[0224] - Citric acid Assay: 101%

[0225] - Magnesium oxide Assay: 100%

[0226] - Sodium methylparaben Assay: 97%

[0227] - Sodium propylparaben Assay: 103%

[0228] Impurity A the by-product derived from picosulfate named 4-[(pyridin-2-yl)(4-hydroxy- phenyhl)methyl]phenyl sodium sulfate), herein identified by HPLC, is mentioned in EP’835 (par. 0015 and 0041). Impurity B was not detectable.

[0229] Example 2 A comparative composition (Ex. 2 - COMP), comprising the same ingredients, in the same amounts and having the same pH of the composition of the invention of Ex. 1 was prepared according to the process described in the patent EP’835. in particular, this comparative composition was prepared by first mixing all solid ingredients in powder form until a homogeneous admixture was obtained, then adding the solvent to the powder admixture, mixing until completely dissolved and, finally, bringing the pH to 6.5 with aqueous NaOH. During the dissolution, the admixture reached the temperature of 51°C. The final composition appeared as a clear and colourless solution.

[0230] Example 3

[0231] In order to study the factors influencing the physical stability of the compositions, different compositions, according to the invention or comparative, having the same composition reported in Example 1 , were prepared by varying the final pH, the content of malic acid and the manufacturing process, as summarized in the following Tables 6, 6A and 6B:

[0232] Table 6

[0233] * at pH of 4.5 sodium benzoate was chosen as preservative agent instead of the parabens used in all the other compositions at higher pH due to scarce activity of parabens at pH 4.5;

[0234] ** g / dose of 160 ml.

[0235] The compositions of the Examples 3.2, 3.4, 3.6 and 3.8 corresponds to the compositions claimed by EP’835.

[0236] In order to evaluate the relevance of the preparation process on the composition stability further compositions were prepared as illustrated below.

[0237] The compositions of Ex. 3.31 and Ex. 3.32 were prepared in line with the process described in WO’121 (see therein Ex. 5 - 8). The manufacturing process described in WO’121 started from Prepopik ™ solid mixture (sodium picosulfate, magnesium oxide and anhydrous citric acid) which was dissolved in water, followed by addition of malic acid and finally by adjustment of the solution pH. In the present experiments of Ex. 3.31 and Ex. 3.32, solid sodium picosulfate, anhydrous citric acid, magnesium oxide, sodium metabisulfite, sodium methylparaben, sodium propylparaben, sweet modulator, grenadine flavour and sucralose were vigorously mixed in a bag. The mixture was then dissolved in water (80% of the total amount) and, once the solubilization was completed, solid malic acid was added to the solution and stirred up to dissolution. Solid NaOH was then used to adjust the pH of the solutions of Ex. 3.31 and Ex. 3.32 to 4.9 and 6.5, respectively. The remaining amount of water was finally added to the solutions. The compositions of Ex. 3.33 and Ex. 3.34 were prepared according to the inventive process of Example 1.

[0238] The detailed compositions of Ex. 3.31 to Ex. 3.34 are reported in the following Table 6A:

[0239] Table 6A

[0240] *Added as pellets **Added as a solution (50% w / w)

[0241] While manufacturing the compositions of Ex. 3.31 and Ex. 3.32, jellification occurred during the addition of NaOH to adjust the pH as shown in Figure 6C. This inconvenient did not happen for the inventive compositions of Ex. 3.33 and Ex. 3.34. In fact, according to the process of the present invention, most of the aq. NaOH was added at the beginning of the preparation, when no other component, except water, was present. On the contrary, in WO’121 process, the addition of NaOH was made when almost all the composition components were present thus resulting in a gel, which needed extra time to be solubilized by stirring.

[0242] Further comparative compositions (Ex. 3.35 to Ex. 3.42) were prepared according to WO’761 process or to the present inventive process, as depicted in Table 6B below. These compositions substantially corresponded to the compositions of Table 15, Formulation 11 of WO’761 but for the absence of Cranberry flavour, whose effect on the composition stability was negligible. In these compositions, in addition to the process, we also explored the effect of different amounts of malic acid, NaOH, water and, accordingly, of different pH. The slight variability in the amounts of components were due to different amounts of sodium hydroxide and water used to adjust the final pH. The qualitative-quantitative composition of Ex. 3.35 to Ex. 3.42, their preparation process and their final pH are reported in the summarizing Table 6B below:

[0243] Table 6B (%wt)

[0244] For the sake of clarity, the features of the composition of Ex. 3.35 to Ex. 3.42 more relevant for stability assessment are summarized in Table 6C below:

[0245] Table 6C

[0246] The process of the invention used for manufacturing the compositions of Ex. 3.39 to Ex. 3.42 included the following steps. Sodium hydroxide (solid pellets) was added to water (80% of the total amount) and dissolved under stirring. Malic acid was then added, followed by disodium EDTA and anhydrous citric acid, each addition occurring upon complete dissolution of the previous ingredient and only when the temperature dropped below 40°C. Magnesium oxide was then added to the solution, which was stirred up to dissolution and up to a temperature below 35°C. A solution of sodium benzoate in water was added to the mixture containing all the other components, followed by the addition of sodium disulfite. Sodium picosulfate, acesulfame K and sucralose were then added in this order. Once a homogeneous solution was obtained, the pH of the final composition was adjusted with sodium hydroxide (solid pellets) if necessary. Finally, the remaining amount of water was added. The preparation was done under normal atmosphere (no nitrogen).

[0247] The process of WO’761 Formulation 11 used for manufacturing the composition of Ex. 3.35 to Ex 3.38 included the following steps. Water, 75% of the total amount, was poured into a vessel, then disodium EDTA, sodium benzoate and malic acid were added and dissolved under magnetic stirring, followed by anhydrous citric acid and magnesium oxide. The mixture was stirred up to complete dissolution and for further 25 minutes. When the temperature of the mixture fell below 30°C, sucralose and acesulfame K were added under stirring. When completely dissolved, sodium hydroxide (solid pellets) was added and completely solubilized. When the temperature of the mixture dropped below 30°C, the pH was measured, the solution was filtered through PTFE filters (0.2 pm) thus providing a solution named Mixture 1. A second mixture, named Mixture 2, was prepared by adding sodium disulfite to another vessel containing the remaining amount of water (25% of the total amount) and by stirring up to dissolution. Mixture 2 was slowly added to Mixture 1 and stirred for 5 minutes thus providing Mixture 3. The pH of Mixture 3 was then adjusted with sodium hydroxide (solid pellets), if necessary. To complete the preparation of the composition, sodium picosulfate was added and the mixture stirred for 5 minutes thus providing the final composition. During manufacture, signs of instability were monitored. In manufacturing the compositions of Ex. 3.35 to Ex. 3.38, jellification occurred during the addition of NaOH to adjust the pH. This inconvenient did not occur or occurred minimally for the compositions of Ex. 3.39 to Ex. 3.42 prepared according to the inventive process. In fact, according to the process of the present invention, most of the NaOH was added at the very beginning of the preparation, when no other component, except water, was present. On the contrary, in the comparative process, the addition of NaOH was made in the middle of the preparation process (i.e., after the addition of disodium EDTA, sodium benzoate, malic acid, anhydrous citric acid and magnesium oxide) thus resulting in a gel, which needed extra time to be solubilized to provide the final composition. Figures from 6D to 6G show the pictures of the compositions prepared according to WO’761 (on the left) in comparison with the same compositions prepared according to the inventive process (on the right) of Ex. 3.35 vs Ex. 3.39 (Fig. 6D), Ex. 3.36 vs Ex. 3.40 (Fig. 6E), Ex. 3.37 vs Ex. 3.41 (Fig. 6F) and Ex. 3.38 vs Ex. 3.42 (Fig. 6G). From these pictures, formation of gel in higher amount was evident for the compositions prepared according to the WO'761 process. Example 4: Stability studies

[0248] Compositions of Ex. 1 (Table 5), Ex. 2 and Ex. 3, reported in Tables 6, 6A or 6B were packaged in 150 ml PET bottles and / or 10 ml glass vials and used to assess the stability of the composition according to the following A), B) or C) conditions:

[0249] Ex. 4A: stability at 25°C and 60 % RH (relative humidity) Ex. 4B: stability at 2-8°C (fridge)

[0250] Three bottles for each composition under each condition (A or B) were evaluated for precipitate formation at different times.

[0251] For the compositions stored at 25°C (A) or at 2-8°C (B), the physical stability was assessed by visual inspection (absence / presence of turbidity or absence / presence of precipitate), by measuring, when possible, the height of the precipitate in the bottle by using a calibre and, for some of them, by turbidimetric analysis. In order to measure the precipitate height with the calibre, a vertical line was drawn in a specific point of the bottle and used as a reference line, during the stability experiment, as illustrated in Figure 6B.

[0252] Ex. 4C: stability after freezing-thawing cycles: the compositions, packaged in 10 ml glass vials, were subjected to cycles of freezing-thawing as follows.

[0253] 10 mL of the composition test solution were placed in a 10 mL glass vial and subjected to freezing-thawing cycles in which the solution was frozen at -20 °C and, after at least 24 h, thawed at room temperature for 24 h. This sequence was repeated more times as detailed below (freezing - thawing cycles). At the end of each cycle, the vial was inspected for turbidity and / or precipitation at the bottom of the vial and the number of the cycles at which a precipitate was formed annotated.

[0254] Ex. 4A Results of physical stability studies at 25°C and 60 % RH (condition A)

[0255] The stability of the compositions was evaluated by visual inspection. The outcome of the visual inspection on some relevant compositions under comparison is commented in Table 7 and Table 7A below while the appearance of the same compositions in their bottles is shown in Figures 1 and 2 (invention left, comparative right):

[0256] Table 7: stability results at 25°C, 60% RH (18 months)

[0257] - 1 -

[0258] Table 7A: stability results at 25°C, 60% RH (24 months)

[0259] From the results reported in Table 7 and Table 7A above and from the pictures of Figures 1 - 2, it appeared that the compositions manufactured according to the process of the invention always resulted physically more stable - no or less precipitate or turbidity - than analogous compositions having the same malic acid content and pH but prepared differently, namely by first admixing ail the ingredients in solid form and finally dissolving the resulting admixture in water, as described in EP’835. The stability of the compositions was also evaluated by turbidimetric analysis (Turbidimeter Thermo-Orion COD.9977) on samples stored for 28 months at 25°C, 60% RH or at 2-8°C. Two samples of each composition were analyzed. Each sample was analyzed three times. Considering the high opacity of some samples and the measurement range of the instrument (i.e., reliable values are considered below 1000 NTU, Nephelometric Turbidimetry Units), a 1 :8 dilution was needed to measure the turbidity of such samples. The final turbidity value was calculated by multiplying the average of the three measures per sample by the dilution factor. The results are reported in Table 7B below:

[0260] Table 7B (turbidimetry values, 28 month) prepared according to the process of the invention compared with the compositions prepared with the process described in EP’835.

[0261] The composition of Example 1 according to the invention, stored at 25°C and 60% RH, proved to be stable for up to 36 months and within specifications, as summarized in Table 7C below:

[0262] Table 7C

[0263] Ex. 4B Results of physical stability studies at 2-8°C (fridge) at different pH (condition B) The stability of the compositions was evaluated by visual inspection and by measuring the height of the precipitate with a calibre at different pH and malic acid content. The outcome of the visual inspection is reported in Tables 8 to 11 below while the appearance of the same compositions in their bottles is shown in the Figures 4 to 6A.

[0264] Table 8: precipitate formation stability results at 2-8°C (0 to 24 months) pH 4.5

[0265] Keys: Malic acid amount is in g / dose (g / 160 m ); to means at the beginning of stability study while the other times refer to months (t2 - 124); “no” means that precipitation did not occur or did not generate turbidity or opacity of the solution upon agitation; “turb” means that turbidity was observed, namely that a precipitate that generates turbidity or opacity of the solution upon agitation was present but was not measurable; when a number is present it represents the height of precipitate measured with a calibre (mm) along the reference line (see Fig. 6B) at that time.

[0266] As can be seen from the data shown in Table 8 above, the compositions at pH 4.5, prepared according to the process of the invention, performed better, in terms of physical stability, than the corresponding compositions made according to EP’835, because either the solution remained clear (no turbidity, see Ex. 3.1 vs Ex. 3.2) or the precipitation was prevented (see Ex. 3.3 vs Ex. 3.4). When the amount of stabilizer was low (4.81 malic acid) the composition of the invention was anyway better than the comparative (less precipitate see Ex. 3.5 vs Ex. 3.6).

[0267] Pictures of the compositions of Ex. 3.3 (left, process of the invention) and Ex. 3.4 (right, process of EP’835) in their bottles - both containing 6.81 g of malic acid, having a pH of about 4.5 but different manufacturing process, after 9 and 18 months of storage at 2 - 8°C, are shown in Figures 4A and 4B respectively. From the picture of Figure 4A it clearly appears that after 9 months the turbidity of the composition of Ex. 3.4 prepared according to EP’835 process (right) is higher than that of the composition of Ex. 3.3 prepared according to the process of the invention (left). Further, at 18 months, a precipitate is clearly visible at the bottom of the bottle of the composition of Ex. 3.4 while it is not for the composition of Ex. 3.3 (see Figure 4B).

[0268] In conclusion, given the same composition, at pH of 4.5 the compositions prepared according to the present process proved to be physically more stable than those prepared according to prior art process.

[0269] Table 9: precipitate formation stability results at 2-8°C (0 to 24 months) pH 5.5

[0270] <eys: as above.

[0271] As can be seen from the data shown in Table 9 above, the compositions at pH 5.5 prepared according to the process of the invention of Ex. 3.9 and 3.13 performed better in terms of physical stability than the corresponding composition made according to EP’835 (Ex. 3.10 and 3.14), because either precipitation was prevented (see Ex. 3.9) or, when precipitation occurred, the amount of precipitate was lower (Ex. 3.13 vs Ex. 3.14). From the picture of Figure 4C it appears that after 24 months the turbidity of the composition of Ex. 3.10 prepared according to EP’835 process (right) was higher than that of the composition of Ex. 3.9 prepared according to the process of the invention (left).

[0272] A bar chart reporting the height of precipitate (mm) vs time for the compositions having pH 5.5 and a malic acid content of 4.81 g / dose of Ex. 3.13 (dotted bar - process of the invention) and Ex. 3.14 (white bar - EP’835 process) is reported in Figure 3A (Statistics: Two-Tailed t-test - a = 0.05. *P < 0.05).

[0273] In conclusion, given the same composition, at pH of 5.5 the compositions prepared according to the present process proved to be physically more stable than those prepared according to EP’835 process.

[0274] Table 10: precipitate formation stability results at 2-8°C (0 to 24 months) pH 6.5

[0275] Keys: as above.

[0276] As can be seen from the data shown in Table 10 above, the compositions at pH 6.5 prepared according to the process of the invention of Ex. 3.17 and Ex. 3.19 performed better, in terms of physical stability, than the corresponding compositions made according to EP’835 (Ex. 3.18 and Ex. 3.20), because either turbidity or precipitation were prevented (see Ex. 3.17 invention vs Ex. 3.18 comparative) or, when occurred, the amount of precipitate was lower (Ex. 3.19 vs Ex. 3.20). A bar chart reporting the height of precipitate (mm) vs time for the composition having pH 6.5 and a malic acid content of 4.81 g / dose of Ex. 3.19 (dotted bar- process of the invention) and Ex. 3.20 (white bar - EP’835 process) is reported in Figure 3B (Statistics: Two-Tailed t-test - a = 0.05).

[0277] Pictures of the compositions of Ex. 3.17 (left) and Ex. 3.18 (right) in their bottles - both containing 6.81 g of malic acid, having a pH of about 6.5 but different manufacturing process, kept at 2 - 8°C for 6, 9, 18 and 24 months are shown in Figures 5A to 5D respectively. From the pictures of Figures 5A and 5B it clearly appears that the turbidity of the composition of Ex. 3.18 prepared according to EP’835 process (right) was higher than that of the composition of Ex. 3.17 prepared according to the process of the invention (left), which remained clear. Furthermore, at 18 and 24 months (see Figure 5C and Figure 5D) a precipitate was visible and higher at the bottom of the bottle of the composition of Ex. 3.18 (right) while little precipitate was visible for the composition of Ex. 3.17 (left).

[0278] In conclusion, given the same composition, at pH of 6.5 the compositions prepared according to the present process proved to be physically more stable than those prepared according to EP’835 process.

[0279] Table 11 : precipitate formation stability results at 2-8°C (0 to 24 months) pH 7.5

[0280] Keys: as above.

[0281] From the data shown in Table 11 above, the composition at pH 7.5 containing 6.81 g of malic acid prepared according to the process of the invention (Ex. 3.25), seemed to perform similarly up to 18 months in terms of physical stability to the corresponding compositions made according to EP’835 (Ex. 3.26), because in both cases only turbidity appeared and precipitation was prevented. However, by visual inspection, the composition according to the invention seemed more stable due to a minor turbidity. In this respect, pictures of the compositions of Ex. 3.25 (invention) and Ex. 3.26 (comparative), having a pH of about 7.5 and containing 6.81 g of malic acid but made by a different manufacturing process, kept at 2 - 8°C for 18 months, are shown in Figure 6A (Ex. 3.25 left and Ex. 3.26 right). From Figure 6A it clearly appears that the turbidity of the composition of Ex. 3.26 prepared according to EP’835 process (right) was higher than that of the composition of Ex. 3.25 prepared according to the process of the invention (left). Furthermore, after 24 months a precipitate was present in the comparative composition only (Ex. 3.26) and not in the composition of the invention (Ex.3.25) (see Table 11 above). Furthermore, at 24 months, the inventive composition of Ex. 3.25 resulted better than the comparative of Ex. 3.26, as it only showed turbidity instead of precipitation.

[0282] Regarding the compositions having the lowest stabilizer content (malic acid, 2.81 g / dose Ex. 3.29 Inv vs Ex. 3.30 Comp) both showed precipitate formation after 2 months. However, the height of the precipitate was always lower for the composition of the invention compared with the comparative composition.

[0283] In conclusion, given the same composition, at pH of 7.5 the compositions prepared according to the present process proved to be physically more stable than those prepared according to EP’835 process.

[0284] Furthermore, the stability data in Tables 8 - 11 above also showed that, for the same preparation process and malic acid content, an increase in pH resulted in greater physical stability of the composition (i.e. turbidity or precipitation delayed in time or less abundant precipitation) contrary to the prior art teaching.

[0285] This unexpected increase in physical stability was evident by comparing the turbidity and precipitate formation of the following compositions:

[0286] - Ex. 3.13 (Tab. 9, pH 5.5) vs Ex. 3.19 (Tab. 10, pH 6.5) both prepared according to the process of the invention and both containing 4.81 g / dose of malic acid (see at t6 and t9 less precipitate at higher pH);

[0287] - Ex. 3.3 (Tab. 8, pH 4.5) vs Ex. 3.17 (Tab. 10, pH 6.5) both prepared according to the inventive process and both containing 6.81 g / dose of malic acid (see no turbidity up to t9 at higher pH).

[0288] Ex. 4C Results of physical stability studies under freezing-thawing cycles (condition C) The results of the stability studies under freezing-thawing cycles - are presented in the following Table 12:

[0289] Table 12: physical stability after 10 cycles

[0290] In Table 12, * g / dose of 160 ml; “no” means that no precipitate was formed upon 10 cycles of freezing-thawing. On the contrary, if a precipitate was formed, the number of the cycle at which the precipitation started was reported.

[0291] From the data reported above, it appears that in this test and for these specific compositions higher amount of malic acid, namely 6.81 and 8.81 g / dose, prevented precipitation also in the compositions prepared according to EP’835 process. However, the stabilizing effect of malic acid in high amount was not seen for the compositions prepared according to EP’835 process subjected to conventional stability test (storage at 25°C and 60 % RH- see Table 7 and Table 7A) where the compositions prepared according to the inventive process resulted more stable. For lower malic acid content, for instance for the tested compositions comprising 4.81 g / dose, an earlier precipitation occurred at almost all the tested pH when the composition was prepared according to prior art (EP’835). Similar results were obtained for the compositions comprising 2.81 g / dose of malic acid. This outcome evidenced a superior stability of the compositions prepared according to the process of the invention.

[0292] In conclusion, in the stability data provided above (stability at room temperature, at 2-8°C and under freezing-thawing conditions), no precipitation or a delay in the appearance of a precipitate or of turbidity was seen for the compositions prepared according to the process of invention compared with the compositions prepared as described in EP’835. Overall, when precipitation occurred, the volume of precipitate generated from the compositions of the invention was lower than that from the compositions of EP’835.

[0293] Hence, the compositions of the present invention prepared according to the present process proved to be physically more stable than the compositions of EP’835.

[0294] Further investigations were carried out to assess the possible influence of the process of WO’121 on the composition’s stability.

[0295] In particular, the compositions of Table 6A of Ex. 3.31 (pH 4.9) and Ex. 3.32 (pH 6.5), prepared according to the process of WO’121 , as well as the composition of Ex. 3.34 (pH 6.5) prepared according to the inventive process of Example 1 , all the compositions containing 5% wt of malic acid, were subjected to up to 15 cycles of freezing-thawing. Both physical and chemical stability were evaluated.

[0296] The results on the physical stability are summarized in the graph of Figure 6H. In this graph, the percentage of vials of each composition for which turbidity I precipitation and the freezing -thawing cycle at which it appeared are shown. It can be seen from the graph that precipitation occurred only for the compositions prepared according to WO’121 process, in particular in 20% of the vials of Ex. 3.31 and in 40% of the vials of Ex. 3.32, while no precipitation was observed for the vials of Ex. 3.34 (inventive process). In conclusion, the composition manufactured according to the inventive process (Ex. 3.34) resulted more stable than the compositions prepared in line with WO’121 process (Ex. 3.31 and Ex. 3.32).

[0297] These preliminary observations were predictive of a long-term superior physical stability of the composition prepared according to the invention with respect to the composition prepared according to WO’121. In fact, it appeared that the composition of Ex. 3.34 did not show any turbidity or precipitation up to 15 cycles of freeze-thawing and resulted to be the most stable.

[0298] Further investigations were carried out to assess the possible influence of the process of WO’761 on the composition’s stability.

[0299] Regarding the compositions of Ex. 3.37 and of Ex. 3.38, prepared according to WO’761 process, and of Ex. 3.41 and Ex. 3.42 prepared according to the inventive process, their physical stability was evaluated up to 10 (12 vials each) and up to 15 (6 vials each) freezingthawing cycles, by visual inspection.

[0300] The composition of Ex. 3.42 (inventive process) appeared to be physically more stable than the corresponding comparative of Ex. 3.38 (WO’761 process) in view of the later occurrence of turbidity as disclosed in Table 12A below:

[0301] Table 12A (12 vials)

[0302] Figure 3C showed a bar chart reporting the height of precipitate (mm) vs freezing-thawing cycles for the compositions having pH 4.9 and a malic acid content of 2.82% wt of Ex. 3.41 (dotted bar-process of the invention) and Ex. 3.37 (white bar- WO’761 process) (Statistics: unpaired t-test. *p<0.05; **p<0.01). These preliminary observations were predictive of a long-term superior physical stability of the composition of the invention with respect to the composition prepared according to WO’761.

[0303] The picture of Figure 6I showed a higher turbidity for the composition of Ex. 3.37 prepared according to WO’761 process (left) compared with the composition of Ex. 3.41 prepared according to the inventive process (right) after 9 freezing-thawing cycles. These compositions contained 2.82 % wt of malic acid and had a pH of 4.9.

[0304] In conclusion, the compositions prepared according to the present process proved to be physically more stable than the compositions prepared according to WO’121 or WO’761 . Ex. 4D Chemical stability

[0305] The composition according to the invention of Ex. 1 was analysed after 24, 30 and 36 months under storage at 25°C and 60% RH. At 24 months, these were the results:

[0306] - Appearance: transparent, colourless solution;

[0307] - pH: 6.45;

[0308] - Picosulfate Assay: 99.5%

[0309] - Citric acid Assay: 105%

[0310] - Magnesium oxide Assay: 102%

[0311] - Sodium methylparaben Assay: 93.5%

[0312] - Sodium propylparaben Assay: 95.0%

[0313] Impurity A was always well below the limit of 2% during the study, in particular at 30 months it was present in amount of about 0.20 % wt in line with the significant chemical stability of the composition of the invention. In this respect, the more acidic compositions of EP’835 resulted to have a higher content of impurity A (see Table 5 of EP’835, impurity A at 24 months from 0.25 to 1.98 % wt, depending on the pH, when malic acid was used as stabilizer).

[0314] The chemical stability of the comparative compositions of Ex. 3.31 and of Ex. 3.32, prepared according to WO’121 process, and of the composition of Ex. 3.33 and Ex. 3.34, prepared according to the inventive process, was evaluated by detecting Impurity A content after 15 freezing-thawing cycles, with the results shown in Table 12B below:

[0315] Table 12B

[0316] * below detection limit.

[0317] The amount of impurity A was expressed as percentage of the area of the main peak resulting from the HPLC analysis. It can be seen from the data of Table 12B that no impurity A was detected for the composition of Ex. 3.33 and Ex. 3.34 prepared according to the inventive process while a certain level of impurity A was measured for the compositions of Ex. 3.31 and Ex. 3.32 prepared according to WO’121 process. This outcome was a clear indication of the higher stability conferred by the inventive process to sodium picosulfate. The chemical stability of the compositions of Ex. 3.37 and of Ex. 3.38, prepared according to WO’761 process, and of Ex. 3.41 and Ex. 3.42 prepared according to the inventive process, was evaluated by detecting Impurity A after 15 freezing-thawing cycles, with the results shown in Table 12C below:

[0318] Table 12C

[0319] * below detection limit.

[0320] It can be seen from the data of Table 12C that no impurity A was detected for the compositions prepared according to the inventive process of Ex. 3.41 and Ex. 3.42 while a certain level of impurity A was measured for the compositions prepared according to WO’761 process of Ex. 3.37 and Ex. 3.38.

[0321] In conclusion, the composition of the present invention prepared according to the present process proved to be chemically more stable than the compositions prepared according to the process of WO’ 121 or WO’761.

[0322] Example 5: comparative study on the preparation process The process of the invention was compared with other similar processes, in which the order of the addition and / or the kind of some ingredients, were changed, as summarized in the following Tables 13 and 14.

[0323] In these tables, the ingredients are listed from top to bottom in the order of addition.

[0324] Table 13: investigation on sodium hydroxide (form and mode of addition)

[0325] Keys: Parabens sol.: solution of sodium methyl- and propyl-parabens; Modulator: sweetness modulator.

[0326] In these experiments, we investigated the effect of NaOH on the reaction course and composition stability by varying its physical form (solid or aq. solution) and mode of addition (beginning, middle or end of the process, in a single or in more portions). Furthermore, we preliminary investigated whether the order of addition of metabisulfite and parabens and their concentration had any effect on the preparation. The compositions comprised the same ingredients and amounts of Example 1 , as reported in Table 5, unless otherwise specified. The preparation of Ex. 5B comprised potassium sorbate while the others parabens. The preparation of Ex. 5C, Ex. 5D and Ex. 5E included 0.18% wt of sodium methylparaben and 0.01 % wt of sodium propylparaben. The preparation of Ex. 5F and Ex. 5A included 0.09% wt of sodium methylparaben and 0.01% wt of sodium propylparaben. In these experiments, a chelating agent (EDTA, in amount of 0.1 % wt) was used, however as demonstrated by the above studies on the composition of Example 1 , its presence was not essential for composition stability.

[0327] The experiments provided the following outcomes:

[0328] Ex. 5B: when NaOH was added as a solid to the aq. solution containing malic acid, citric acid and magnesium oxide, the process was longer, due to the time needed for the dissolution. Considering that NaOH can trap CO2, the longer the dissolution, the greater the probability of carbonation and the lower the efficiency of the process. The pH after incorporation of solid NaOH was too low (pH 3.54). The composition did not pass the test of efficacy of antimicrobial preservation (test of European Pharmacopeia: 04 / 2022:50103). Potassium sorbate had scarce preservative activity at pH 6.

[0329] Ex. 5C: as most of NaOH was added to water as a solid at the beginning, the process was longer than that of Ex. 5A due to the time needed for the dissolution of the NaOH. Considering that NaOH can trap CO2, the longer the dissolution, the greater the probability of carbonation and the lower the efficiency of the process. Upon addition of the parabens after metabisulfite turbidity appeared. A precipitate in form of needles was observed after 21 days at room temperature.

[0330] Ex. 5D: the sequence of addition of this process is similar to that described in WO761 ; upon the first addition of NaOH to the aq. solution containing malic acid, citric acid and magnesium oxide turbidity appeared and jollification occurred. The process of WO’761 was also fully reworked under Ex. 3.35 to Ex. 3.38.

[0331] Ex. 5E: even if the initial steps and the addition of parabens before metabisulfite are in line with the present preferred process, upon addition of parabens at a too high concentration (0.19%) formation of a precipitate occurred.

[0332] Ex. 5A (see process of Example 1 above) and 5F: the processes according to a preferred process of the invention, with an early addition of NaOH as aqueous solution, of parabens before metabisulfite and in concentrations lower than 0.19%, provided for clear and stable solutions. In conclusion, using NaOH as aqueous solution was preferred and, when present, parabens were preferably added in low amount and before metabisulfite.

[0333] Furthermore, several process variants were carried out to specifically investigate the best process conditions when parabens are present as preservative agents, as depicted in the following Table 14: Table 14: investigation on parabens (form and order of addition)

[0334] Keys:1up to paraben dissolution; SMP: sodium methylparaben; SPP: sodium propylparaben; MgO: magnesium oxide; picosulfate: sodium picosulfate; metabisulfite: sodium metabisulfite; for all the above compositions SMP was present at a cone, of 0.18% wt; and SPP of 0.02% wt; in Ex. 5H, Ex. 5I, Ex. 5J and Ex. 5M the parabens were added in a solid form; in Ex. 5K, Ex. 5L, Ex. 5N and Ex. 50, the parabens were added as aqueous solutions; unless otherwise specified, ingredients and amounts are as those reported for Example 1 (Table 5).

[0335] The experiments provided the following outcomes:

[0336] Ex. 5G: The dissolution of the parabens did not occur until the pH reached 8.8.

[0337] Ex. 5H: A recovery of parabens below 100% was observed, due to degradation at such a high pH (pH 14). An impurity - corresponding to parabens impurity A according to European Pharmacopoeia - was detected in a significant amount (70% of methylparaben was in the form of impurity, by HPLC). In conclusion, a too high pH favored decomposition.

[0338] Ex. 5I: The parabens were not solubilized and a sediment was formed. For these reasons, further addition of components was not studied.

[0339] Ex. 5J: The parabens were not solubilized and a sediment was formed.

[0340] Ex. 5K: After a few hours of storage of the composition at 2-8°C a precipitate was formed. Ex. 5L, Ex. 5M, Ex. 5N, Ex. 50: After a few days of storage of the composition at 2-8°C a precipitate was formed. The precipitation of parabens from some of the compositions was confirmed through a characterization study on the precipitates (by FTIR).

[0341] In order to assess the effect of parabens concentration on precipitation, a study was done on the composition of Ex. 5F by reducing the concentration of sodium methylparaben from 0.18% to 0.09% wt. No precipitation was observed after 1 month at 2-8°C and at 25°C, 65% RH.

[0342] A further study was done to understand if the addition of the parabens in a solid form or in a liquid form (i.e., previously dissolved in water) had an impact on the dissolution of these molecules and on the preparation of the final composition. In this regard, a composition having the composition of Ex. 5A but using solid parabens, was prepared (Ex. 5P) in a single dose scale. On this small scale, the parabens added in a solid form were hard to dissolve, making preferable the addition of an aqueous solution thereof. On the other hand, on industrial scale, the addition of parabens by using a mixer for solids (ALVAK), allowed their smooth addition and dissolution even in solid form without any problem on the final composition.

[0343] In conclusion, from the data reported above, it appeared that in case parabens were selected as preservative agents for the composition, the preferred conditions were:

[0344] - parabens had to be added to the aqueous solution of sodium hydroxide, malic acid and citric acid at a pH preferably from 8.0 to 8.5 in order to favor parabens dissolution, prevent re-precipitation and minimize byproducts formation;

[0345] - accordingly, metabisulfite had to be preferably added after parabens as otherwise it would have decreased the pH below 8.0, making dissolution of parabens difficult;

[0346] - preferably, the concentration of parabens had to be lower than 0.18% wt, more preferably lower than 0.10% wt, even more preferably of about 0.09% wt to minimize precipitation;

[0347] - in lab / pilot scale parabens were preferably added as aqueous solutions while they could be easily dissolved also as solids on industrial scale;

[0348] - parabens concentration was not critical for the appearance of degradation impurity;

[0349] - the order of addition of the ingredients was important for successful preparation of the composition, especially regarding the addition of NaOH and - if present - of parabens. Example 6: palatability study

[0350] With the aim to evaluate the palatability of the compositions, two compositions having different pH, comprising the same ingredients but free of preservative agents, sweeteners and flavourings, as depicted in the following Table 15, were prepared as described in Example 1 .

[0351] Table 15

[0352] The compositions were tasted by a panel of three persons who judged the composition of Ex. 6A as sour while that of Ex. 6B as not sour but a little salty.

[0353] The compositions of the invention, which are more stable than previous similar compositions also at higher pH around neutrality, can thus advantageously have an acceptable palatability even with lower amounts of sweeteners and flavourings.

Claims

CLAIMS1) A liquid pharmaceutical composition comprising from 0.002 to 0.010 % wt of sodium picosulfate, from 1.0 to 3.0 % wt of magnesium oxide, from 3.5 to 10.5 % wt of citric acid, from 0.01 to 13.0 % wt of malic acid, optionally one or more pharmaceutically acceptable excipient(s) and water, wherein the composition has a pH higher than 5.4 and, preferably, lower than 7.6.2) A liquid pharmaceutical composition comprising from 0.002 to 0.010 % wt of sodium picosulfate, from 1.0 to 3.0 % wt of magnesium oxide, from 3.5 to 10.5 % wt of citric acid, from 0.01 to 13.0 % wt of malic acid, optionally one or more pharmaceutically acceptable excipient(s) and water, wherein the pH of the liquid pharmaceutical composition is from 4.5 to 8.0 and wherein the composition is obtainable according to a process comprising:(i) providing at least an alkalinizing agent in amount from 1.0 to 8.0 % wt, preferably dissolved in water to provide a first aqueous solution having a pH from 12.0 to 14.0,(ii) providing malic acid in amount from 0.01 to 13.0 % wt, contacting it with the at least an alkalinizing agent and with water, preferably contacting it with the first aqueous solution, and dissolving it to provide a second aqueous solution,(iii) adding citric acid to the previous second aqueous solution, in amount from 3.5 to 10.5 % wt, and dissolving it, to provide a third aqueous solution,(iv) adding magnesium oxide to the previous third aqueous solution, in amount from 1.0 to 3.0 % wt, dissolving it to provide a fourth aqueous solution,(v) optionally adding at least a preservative agent to the previous fourth aqueous solution, then at least an antioxidant and dissolving them to provide a fifth aqueous solution,(vi) adding sodium picosulfate in amount from 0.002 to 0.010 % wt and optionally other pharmaceutically acceptable excipients to the previous fourth or fifth aqueous solution, and dissolving them to provide a sixth aqueous solution, and(vii) if needed, adjusting the pH of the previous sixth aqueous solution at a value from 4.5 to 8.0, in which water is added in one or more of the previous steps in a preferred total amount from 70 to 95 % wt, all the percentages by weight being referred to the weight of the composition, to provide the liquid pharmaceutical composition.3) The composition according to claim 2 wherein the pH is higher than 5.0, preferably higher than 5.4 and lower than 7.6.4) The composition according to any one of the previous claims comprising from 0.003 to 0.009 % wt of sodium picosulfate, from 1.5 to 2.5 % wt of magnesium oxide, from 5.0 to 8.0 % wt of citric acid, from 3.0 to 8.0 % wt of malic acid, optionally one or more pharmaceutically acceptable excipient(s) and water.5) The composition according to any one of the previous claims comprising from 0.004 to 0.008 % wt of sodium picosulfate, from 1.8 to 2.2 % wt of magnesium oxide, from 5.5 to 7.0 % wt of citric acid, from 4.0 to 6.0 % wt of malic acid, optionally one or more pharmaceutically acceptable excipient(s) and water.6) The composition according to any one of the previous claims having a pH higher than 6.0, preferably higher than 6.4 or than 6.5.7) The composition according to any one of the previous claims wherein water is present in amount from 70 to 90 % wt, preferably from 75 to 85 % wt.8) The composition according to any one of the previous claims further comprising at least a preservative, preferably a paraben selected from methyl, ethyl, propyl, butyl esters, their salts and admixtures thereof, and at least an antioxidant, preferably selected from ascorbic acid, sodium ascorbate, sodium metabisulfite, potassium metabisulfite, sodium sulfite, sodium thiosulfate, sulfur dioxide erythorbic acid or propionic acid, more preferably sodium metabisulfite.9) The composition according to any one of the previous claims comprising less than 5%, preferably less than 4%, more preferably less than 3% wt of malic acid.10) The composition according to any one of the previous claims comprising:Malic acid 4.5 - 5.5 %Citric acid 6.0 - 6.5 %Magnesium oxide 1.9 - 2.1 %Parabens 0.07 - 0.12 %Sodium metabisulfite 0.4 - 0.6%Sodium picosulfate 0.004 - 0.008 %Purified water up to 100% and having a pH of about 6.5.11) A process for preparing the liquid pharmaceutical composition according to any one of claims 1 to 10 comprising:(i) providing at least an alkalinizing agent in amount from 1.0 to 8.0 % wt, preferably dissolved in water to provide a first aqueous solution having a pH from 12.0 to 14.0,(ii) providing malic acid in amount from 0.01 to 13.0 % wt, contacting it with the at least an alkalinizing agent and with water, preferably contacting it with the first aqueous solution, and dissolving it to provide a second aqueous solution,(iii) adding citric acid to the previous second aqueous solution, in amount from 3.5 to 10.5 % wt, and dissolving it, to provide a third aqueous solution,(iv) adding magnesium oxide to the previous third aqueous solution, in amount from 1.0 to 3.0 % wt, dissolving it to provide a fourth aqueous solution,(v) optionally adding at least a preservative agent to the previous fourth aqueous solution, then at least an antioxidant and dissolving them to provide a fifth aqueous solution,(vi) adding sodium picosulfate in amount from 0.002 to 0.010 % wt and optionally other pharmaceutically acceptable excipients to the previous fourth or fifth aqueous solution, and dissolving them to provide a sixth aqueous solution, and(vii) if needed, adjusting the pH of the previous sixth aqueous solution at a value from 4.5 to 8.0, preferably at a value higher than 5.0, more preferably higher than 5.4 and lower than 7.6, in which water is added in one or more of the previous steps in a preferred total amount from 70 to 95 % wt, all the percentages by weight being referred to the weight of the composition, to provide the liquid pharmaceutical composition.12) The process of claim 11 further characterized by one or more of the following features:- the alkalinizing agent is selected among sodium hydroxide, potassium hydroxide, sodium bicarbonate, ammonia, potassium citrate, triethanolamine and sodium citrate, preferably is sodium hydroxide, and it is dissolved in water providing a first aqueous solution (i);- malic acid, citric acid and magnesium oxide are added in solid form (ii, iii and vi);- in steps (iii) to (vii) the temperature of the solutions is kept lower than 40°C, preferably lower than 35°C;- in step (v) at least a paraben is added to the fourth aqueous solution, preferably in amount lower than 0.18% wt, followed, after dissolution, by addition of sodium metabisulfite as antioxidant;- about 90 % wt of the total amount of water is added in step (i).13) The process according to claim 11 or 12, which comprises:(i) providing a first aqueous solution having a pH from 13.0 to 14.0 and comprising sodium hydroxide in amount from 2.0 to 6.0 % wt,(ii) adding malic acid, preferably in solid form, to the first aqueous solution, in amount from 4.0 to 6.0 % wt, and dissolving it to provide a second aqueous solution,(iii) adding citric acid, preferably in solid form, to the previous second aqueous solution, at a temperature lower than 40°C, in amount from 5.5 to 7.0 % wt, and dissolving it, to provide a third aqueous solution,(iv) adding magnesium oxide, preferably in solid form, to the previous third aqueous solution, in amount from 1.8 to 2.2 % wt, and dissolving it to provide a fourth aqueous solution,(v) adding at least a paraben, preferably as an aqueous solution, in amount from 0.07 to 0.12 % wt, to the previous fourth aqueous solution, at a temperature lower than 40°C, then adding sodium metabisulfite in amount from 0.4 to 0.6 % wt, and dissolving them to provide a fifth aqueous solution,(vi) adding sodium picosulfate preferably in solid form, in amount from 0.004 to 0.008 % wt and optionally other pharmaceutically acceptable excipients to the previous fourth or fifthaqueous solution, at a temperature lower than 40°C, and dissolving them to provide a sixth aqueous solution, and(vii) if needed, adjusting the pH of the previous sixth aqueous solution at value from 6.0 to 7.0, in which water is added in total amount from 75 to 85 % wt, all the percentages by weight being referred to the weight of the composition, to provide the liquid pharmaceutical composition.14) The liquid pharmaceutical composition according to any one of claims 1 to 10 for use as a purgative or colon cleansing composition for the pre-treatment of patients undergoing surgery, colonoscopy or radiographic inspection of the colon.

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