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WO2025093697A1 - Composition pharmaceutique liquide laxative prête à l'emploi et son procédé de préparation - Google Patents

Composition pharmaceutique liquide laxative prête à l'emploi et son procédé de préparation Download PDF

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Publication number
WO2025093697A1
WO2025093697A1 PCT/EP2024/080863 EP2024080863W WO2025093697A1 WO 2025093697 A1 WO2025093697 A1 WO 2025093697A1 EP 2024080863 W EP2024080863 W EP 2024080863W WO 2025093697 A1 WO2025093697 A1 WO 2025093697A1
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Prior art keywords
aqueous solution
composition
previous
amount
sodium
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Pending
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PCT/EP2024/080863
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English (en)
Inventor
Susana RALLO BEL
Beatriz ROY GONZALEZ
Marta Bello Navarro
Vanesa MANERO LAMUELA
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Casen Recordati SL
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Casen Recordati SL
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Publication of WO2025093697A1 publication Critical patent/WO2025093697A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions

Definitions

  • 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.
  • 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.
  • 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.
  • KR Pharmabio's Picolight Powder®
  • RTU ready-to-use 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®.
  • 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.
  • 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.
  • Patent 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.
  • 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.
  • WO2018009761 A1 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).
  • 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.
  • 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.
  • 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.
  • an object of the present invention is a liquid pharmaceutical composition
  • 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.
  • This composition is physically and chemically more stable and less sour than similar compositions having pH of 5.4 or lower.
  • a further object of the present invention is a liquid pharmaceutical composition
  • 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:
  • a further object of the present invention is a process for preparing the liquid pharmaceutical composition of the invention as depicted above.
  • a further object of the present invention is the liquid pharmaceutical composition of the invention for use as a medicament.
  • 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.
  • 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.
  • 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).
  • Figure 3 shows the bar charts illustrating precipitate formation during stability studies on invention (dotted bar) vs comparative (white bar) compositions.
  • 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).
  • 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.
  • 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).
  • 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.
  • 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.
  • Figure 7 is a flow diagram illustrating a process for manufacturing a composition according to the present invention.
  • 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.
  • 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.
  • the present invention provides a liquid pharmaceutical composition
  • 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.
  • the present invention provides a liquid pharmaceutical composition
  • 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).
  • the present invention provides a liquid pharmaceutical composition
  • 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.
  • the present invention provides a liquid pharmaceutical composition
  • 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.
  • the composition according to the invention comprises less than 5%, preferably less than 4%, more preferably less than 3% wt of malic acid.
  • the present composition is more stable than previous compositions even in the presence of lower amounts of malic acid as stabilizer.
  • 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.
  • 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.
  • 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.
  • composition is characterized by an improved stability as shown in the present experimental section.
  • composition of the invention has a pH from 6.0 to 7.0 and comprises (% wt):
  • composition of the invention has a pH from 6.0 to 7.0 and comprises
  • composition of the invention has a pH of about 6.5 and comprises (% wt):
  • the above embodiments of the composition of the invention are prepared according to the process of the invention.
  • the present invention provides a liquid pharmaceutical composition
  • 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,
  • 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.
  • the above compositions preferably have a pH higher than 6.5 and lower than 8.0.
  • 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.
  • the malic acid used in the present composition may include l-malic acid and d-malic acid, however preferably racemic malic acid is used.
  • the citric acid used in the present composition may include hydrated forms, however preferably anhydrous citric acid is used.
  • the magnesium oxide used in the present composition may include light and heavy magnesium oxide, however preferably light magnesium oxide is used.
  • 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.
  • water is present in amount higher than 60%, more preferably higher than 70% wt, even more preferably higher than 75% wt.
  • water is preferably present in amount from 70 to 90 % wt, more preferably from 75 to 85 % wt.
  • water is the only solvent of the composition of the invention.
  • composition of the invention is a liquid composition, preferably is a solution, typically a transparent, colourless or slightly yellowish solution.
  • composition of the invention is a liquid composition suitable for oral administration.
  • 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.
  • 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.
  • composition of the invention may include other pharmaceutically acceptable excipients such as, for instance, preservative agents, sweeteners and flavours, stabilizers and pH adjusters.
  • 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.
  • 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.
  • 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.
  • composition of the invention may include sweeteners, flavours and taste modulators to increase the medication compliance.
  • composition of the present invention may contain less sweeteners and flavours compared to previous similar more acidic compositions.
  • 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.
  • composition of the invention may include stabilizers, for instance chelating agents such as ethylenediaminetetraacetic acid (EDTA) and the like.
  • chelating agents such as ethylenediaminetetraacetic acid (EDTA) and the like.
  • EDTA ethylenediaminetetraacetic acid
  • the composition of the present invention shows high stability even in the absence of chelating agents.
  • 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.
  • 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.
  • 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.
  • liquid composition according to the invention can be prepared according to a process comprising:
  • 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.
  • the addition of NaOH as a solid is less advantageous due to a slow dissolution and to the related possible carbonation problems.
  • 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.
  • 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.
  • 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.
  • 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.
  • malic acid and the alkalinizing acid may be added to water in any other order and therein dissolved.
  • malic acid is added as a solid to the first aqueous solution of the alkalinizing agent.
  • complete dissolution may be achieved in less than 20 minutes, preferably in less than 10 minutes, preferably under stirring.
  • malic acid is added in amount from 3.0 to 8.0 % wt, more preferably from 4.0 to 6.0 % wt.
  • a solution is obtained, with a pH ranging from about 12 to 13.
  • citric acid is added to the second aqueous solution, either as a solid or as a solution, such as an aqueous solution.
  • citric acid is added as a solid.
  • citric acid is added when the second solution temperature is lower than 40°C, more preferably lower than 35°C.
  • 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.
  • citric acid can be added in amount from 5.0 to 8.0 % wt, more preferably from 5.5 to 7.0 % wt.
  • 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.
  • magnesium oxide is added to the third aqueous solution, either as a solid or as a suspension, such as an aqueous suspension.
  • magnesium oxide is added as a solid.
  • magnesium oxide can be added in amount from 1 .5 to 2.5 % wt, more preferably from 1 .8 to 2.2 % wt.
  • a cooling step is then preferably applied to lower the temperature.
  • the final pH of the fourth solution upon magnesium oxide dissolution typically raises to a value between about 8.0 and 8.5.
  • 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.
  • the preservative agent is added when the fourth solution temperature is lower than 40°C, more preferably lower than 35°C.
  • the fourth solution can be cooled down as known in the art.
  • 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.
  • 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.
  • At least an antioxidant is added after complete dissolution of the at least a preservative agent.
  • 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.
  • the at least an antioxidant is sodium metabisulfite.
  • the final pH of the fifth solution may be typically from about 6.3 to 6.5.
  • sodium picosulfate is added to the fourth or fifth aqueous solution, either as a solid or as a solution, such as an aqueous solution.
  • sodium picosulfate is added as a solid.
  • 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.
  • 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.
  • compositions 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.
  • 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.
  • a pH adjuster such as an acidifying or an alkalinizing agent
  • also part of the water can be added herein.
  • steps of the process of the invention are carried out under stirring.
  • steps from iii) to vii) are carried out at a temperature lower than 40°C.
  • 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.
  • water may be added in one or more portions.
  • 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.
  • 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.
  • 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);
  • the temperature of the solutions is kept lower than 40°C, preferably lower than 35°C;
  • step (v) at least a paraben is added to the fourth aqueous solution followed, after dissolution, by addition of sodium metabisulfite as antioxidant;
  • step (i) about 90 % wt of the total amount of water is added in step (i).
  • the present process comprises:
  • pH and density of the aqueous liquid composition are checked using conventional methods.
  • 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.
  • 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.
  • 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.
  • 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 Example 4C
  • 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.
  • 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.
  • 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).
  • 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).
  • 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.
  • 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.
  • a suitable container e.g., bottles, vials etc
  • each bottle contains a single dose.
  • one or more botles may be packaged together, providing the patient with the doses required for an entire treatment.
  • 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.
  • 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).
  • composition of the invention is more stable than previous compositions (Ex. 4C, Ex. 4D).
  • 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.
  • 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.
  • the present composition at to (HPLC analysis just after manufacture) comprises Impurity A, derived from sodium picosulfate, in amount lower than 0.2 %.
  • 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%.
  • 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.
  • the present composition may thus increase the ease of storage and transport, the shelf life of the composition and even medication compliance.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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:
  • 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).
  • the mobile phase was a TFA (Trifluoroacetic acid) 0.05 % v/v solution with a pH around 2.
  • TFA Trifluoroacetic acid
  • instrument parameters were set as indicated in Table 1.
  • 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.
  • 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.
  • the presence of picosulfate and of related impurities was detected by HPLC.
  • 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.
  • 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.
  • Sodium picosulfate was quantitatively identified and analysed using a reversed-phase HPLC (high pressure chromatography) method and a PDA detector.
  • 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).
  • 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.
  • first mobile phase mobile phase A
  • second mobile phase mobile phase B
  • HPLC-grade water was used for the second mobile phase (mobile phase B)
  • third mobile phase mobile phase C
  • 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.
  • Magnesium Oxide was quantitatively analysed by volumetric titration with EDTA 0.1 M.
  • 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.
  • the mobile phase was: methanol 60% - Acetic Acid 1 mM 40%.
  • 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.
  • 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°.
  • 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).
  • 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.
  • the preservative agents parabens
  • sodium metabisulfite was added under stirring, bringing the pH at around 6.3 - 6.5.
  • 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.
  • 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.
  • 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.
  • 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:
  • compositions of the Examples 3.2, 3.4, 3.6 and 3.8 corresponds to the compositions claimed by EP’835.
  • compositions were prepared as illustrated below.
  • 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 TM 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.
  • 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 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).
  • 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 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.
  • 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:
  • 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.
  • 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.
  • Ex. 4C stability after freezing-thawing cycles: the compositions, packaged in 10 ml glass vials, were subjected to cycles of freezing-thawing as follows.
  • 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.
  • 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.
  • Example 1 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:
  • 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.
  • 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).
  • 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).
  • 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).
  • 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.
  • the height of the precipitate was always lower for the composition of the invention compared with the comparative composition.
  • 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.
  • 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.
  • compositions prepared according to the present process proved to be physically more stable than the compositions prepared according to WO’121 or WO’761 .
  • 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:
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • Parabens sol. solution of sodium methyl- and propyl-parabens
  • Modulator sweetness modulator
  • 5A included 0.09% wt of sodium methylparaben and 0.01% wt of sodium propylparaben.
  • 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.
  • 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.
  • Ex. 5A see process of Example 1 above
  • 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.
  • NaOH as aqueous solution was preferred and, when present, parabens were preferably added in low amount and before metabisulfite.
  • 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).
  • metabisulfite had to be preferably added after parabens as otherwise it would have decreased the pH below 8.0, making dissolution of parabens difficult;
  • 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;
  • 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 .
  • 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.
  • 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.

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Abstract

La présente invention concerne une composition pharmaceutique laxative liquide prête à l'emploi, de préférence destinée à être utilisée dans le nettoyage intestinal avant une chirurgie, une colonoscopie ou une inspection radiographique du côlon, et un procédé pour sa préparation. Par comparaison avec des compositions connues similaires, la composition pharmaceutique laxative de l'invention ayant un pH plus proche de la neutralité, présente une stabilité physique et chimique supérieure.
PCT/EP2024/080863 2023-11-03 2024-10-31 Composition pharmaceutique liquide laxative prête à l'emploi et son procédé de préparation Pending WO2025093697A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017031121A1 (fr) 2015-08-17 2017-02-23 Liang Alfred Chi-Yeh Préparations liquides contenant du picosulfate et du citrate de magnésium
US9827231B2 (en) 2014-03-19 2017-11-28 Ferring International Center S.A. Liquid pharmaceutical composition
WO2018009761A1 (fr) 2016-07-08 2018-01-11 Ferring B.V. Formulations liquides stabilisées contenant du picosulfate

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9827231B2 (en) 2014-03-19 2017-11-28 Ferring International Center S.A. Liquid pharmaceutical composition
EP3120835B1 (fr) 2014-03-19 2021-12-08 Ferring International Center S.A. Composition pharmaceutique liquide
WO2017031121A1 (fr) 2015-08-17 2017-02-23 Liang Alfred Chi-Yeh Préparations liquides contenant du picosulfate et du citrate de magnésium
WO2018009761A1 (fr) 2016-07-08 2018-01-11 Ferring B.V. Formulations liquides stabilisées contenant du picosulfate

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