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US20180015078A1 - Stabilized liquid formulations containing picosulfate - Google Patents

Stabilized liquid formulations containing picosulfate Download PDF

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Publication number
US20180015078A1
US20180015078A1 US15/643,727 US201715643727A US2018015078A1 US 20180015078 A1 US20180015078 A1 US 20180015078A1 US 201715643727 A US201715643727 A US 201715643727A US 2018015078 A1 US2018015078 A1 US 2018015078A1
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Prior art keywords
acid
picosulfate
formulation
sodium
liquid formulation
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US15/643,727
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Alfred Chi-Yeh Liang
Nipul Ghanshyambhai Patel
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Ferring BV
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Ferring BV
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Assigned to FERRING B.V. reassignment FERRING B.V. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LIANG, Alfred Chi-Yeh, PATEL, Nipul Ghanshyambhai
Publication of US20180015078A1 publication Critical patent/US20180015078A1/en
Priority to US17/555,277 priority patent/US12458634B2/en
Priority to US19/025,961 priority patent/US20260014128A1/en
Abandoned legal-status Critical Current

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    • 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
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • 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
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives 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

  • This disclosure relates to liquid formulations useful to treat constipation or for the clearance of the bowel prior to X-ray examination, endoscopy or surgery.
  • Picosulfate typically used in the form of its bis-sodium salt, sodium picosulfate (I), is a stimulant laxative.
  • Sodium picosulfate is a prodrug that itself has no physiological effect. It is metabolized by intestinal bacteria into the active compound, 4,4′-dihydroxydiphenyl-(2-pyridyl)-methane (DPM), which is the stimulant laxative and acts by increasing peristalsis in the intestine.
  • DPM 4,4′-dihydroxydiphenyl-(2-pyridyl)-methane
  • picosulfate in the form of sodium picosulfate can be used to treat constipation or for the clearance of the bowel prior to X-ray examination, endoscopy or surgery.
  • Picosulfate a stimulant laxative
  • osmotic laxative a stimulant laxative
  • Particularly useful are products that contain sodium picosulfate in combination with magnesium oxide and anhydrous citric acid, which together in solution form magnesium citrate, an osmotic laxative with a powerful cathartic effect. Examples of such formulations are sold under the trade names PICOPREP® and PREPOPIK®.
  • These products contain sodium picosulfate along with magnesium oxide and citric acid in the form of a solid that must be dissolved to be taken orally by the patient and provides a strong laxative that is easily palatable.
  • the products are particularly effective to prepare patients for colonoscopy.
  • the products include citric acid, magnesium oxide, and sodium picosulfate, as active ingredients, along with potassium bicarbonate, sodium saccharin, and flavoring (e.g., orange flavor).
  • the patient instruction sheet for the PREPOPIK® product instructs the patient to pour the solid contents of a packet of the preparation in 5 fluid ounces (150 mL) of water in a cup, and to stir the resulting mixture for 2-3 min. before drinking the entire contents of the cup. If the patient fails to follow the procedure precisely, e.g., by failing to stir the contents for the full 2-3 min. before consumption, there is a risk that the product will not be fully dissolved and that the patient will receive less than a full dose of the product, and that the product will therefore not be as effective as intended.
  • the liquid formulation can be stable for at least 10 days, such as for at least 60 days, or further such as for at least 1 year, at least 18 months, or at least 2 years, when stored at a temperature of about 20-25° C.
  • the present disclosure provides a liquid formulation comprising picosulfate and an antioxidant.
  • the liquid formulation comprises picosulfate, an antioxidant, and an osmotic laxative such as a magnesium salt.
  • the picosulfate is sodium picosulfate.
  • the picosulfate e.g., sodium picosulfate
  • the magnesium salt can be magnesium citrate.
  • the magnesium citrate can be formed by the reaction of a magnesium base, e.g., magnesium hydroxide, magnesium oxide or magnesium carbonate, such as magnesium oxide, with citric acid, e.g., anhydrous citric acid or citric acid monohydrate, such as anhydrous citric acid.
  • the magnesium citrate can include salts in which the magnesium and citrate components are present in a molar ratio in the range from about 1:1 to about 1.5:1, e.g., from about 1.1:1 to about 1.5:1, about 1.2:1 to about 1.5:1, about 1.3:1 to about 1.5:1, about 1.4:1 to about 1.5:1, about 1:1 to about 1.4:1, about 1.2:1 to about 1.4:1, about 1.3:1 to about 1.4:1, about 1:1 to about 1.3:1, about 1.1:1 to about 1.3:1, about 1.2:1 to about 1.3:1, or about 1:1 to about 1.2:1.
  • the magnesium and citric acid components can also be present in a molar ratio in the range from about 0.5:1 to about 1:1, about 0.6:1 to about 1:1, about 0.7:1 to about 1:1, about 0.8:1 to about 1:1, or about 0.9:1 to about 1:1.16.
  • the magnesium and citrate components can be present in a molar ratio of about 1.4:1.
  • the antioxidant can be acetone sodium bisulfate, ascorbic acid or a salt or ester thereof (such as ascorbyl palmitate or sodium ascorbate), butylated hydroxyanisole, butylated hydroxytoluene, dodecyl gallate, erythorbic acid, histidine, D-mannose, monothioglycerol, octyl gallate, propionic acid, potassium metabisulfite, propyl gallate, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium sulfite, sodium thiosulfate, sulfur dioxide, thymol, ⁇ -tocopherol, or tocopheryl polyethylene glycol succinate.
  • ascorbic acid or a salt or ester thereof such as ascorbyl palmitate or sodium ascorbate
  • butylated hydroxyanisole such ascorbyl palmitate or sodium ascorbate
  • butylated hydroxytoluene dodecyl
  • the antioxidant is a water-soluble antioxidant such as ascorbic acid, sodium ascorbate, sodium metabisulfite, potassium metabisulfite, sodium sulfite, sodium thiosulfate, sulfur dioxide, erythorbic acid or propionic acid.
  • the antioxidant is chosen from sodium metabisulfite, potassium metabisulfite, mannose, histidine, butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, and ⁇ -tocopherol.
  • the antioxidant is a water-insoluble antioxidant such as butylated hydroxyanisole, butylated hydroxytoluene, dodecyl gallate, octyl gallate, propyl gallate, thymol, ⁇ -tocopherol, or tocopheryl polyethylene glycol succinate.
  • the formulation when the antioxidant is water-insoluble, can further comprise a solubilizing agent, such as a surfactant.
  • a solubilizing agent such as a surfactant.
  • the solubilizing agent can be, e.g., propylene glycol, polysorbate or poloxamer.
  • the antioxidant can be present at a concentration in the range from about 0.002 M to about 0.1 M, e.g., about 0.005 M to about 0.02 M.
  • the formulation can include a magnesium salt, such as magnesium citrate.
  • the formulation can include magnesium citrate formed from magnesium oxide and citric acid.
  • the formulation can include magnesium and citrate in a molar ratio in the range from about 1:1 to about 1.5:1, such as a molar ratio of about 1.4:1.
  • the formulation can include a magnesium salt (e.g., magnesium citrate) at a concentration of magnesium in the range from about 0.2 to about 0.8 M, e.g., in the range from about 0.5 to about 0.6 M.
  • the formulation can include a carboxylic acid, such as acetic acid, arginine, ascorbic acid, asparagine, aspartic acid, cysteine, fumaric acid, formic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, glycolic acid, histidine, lactic acid, lysine, maleic acid, malic acid, malonic acid, methionine, oxalic acid, propionic acid, serine, succinic acid, tartaric acid, threonine, or tyrosine.
  • the formulation can include a carboxylic acid such as malic acid, malonic acid, or gluconic acid.
  • the carboxylic acid is malic acid (e.g., D-malic acid, L-malic acid, or DL-malic acid). In some embodiments, the carboxylic acid is malonic acid. In some embodiments the carboxylic acid can be in the form of a salt, e.g., a sodium or potassium salt, such as a sodium salt. In some embodiments, the carboxylic acid can be present at a concentration in the range from about 0.01 M to about 5 M, e.g., from about 0.1 M to about 1 M.
  • the formulation can include an ammonium salt, such as ammonium acetate, ammonium chloride, or ammonium sulfate.
  • the ammonium salt can be at a concentration in the range from about 1 g/L to about 40 g/L, e.g., from about 10 g/L to about 40 g/L.
  • the formulation can include a soluble anionic polymer, such as a polysaccharide polymer, such as a polysaccharide polymer that includes carboxylic acid groups.
  • soluble anionic polymers include alginic acid, carboxymethylcellulose (CMC), carrageenans, polyacrylic acid and copolymers thereof, and xanthan gum.
  • the formulation can include particularly carboxymethylcellulose (CMC).
  • the formulation can include an anionic polymer at a concentration in the range from about 0.5 g/L to about 25 g/L, e.g., a concentration in the range from about 1 g/L to about 10 g/L.
  • the formulation can include a preservative agent, such as methyl paraben, propyl paraben, sodium benzoate or potassium benzoate.
  • a preservative agent such as methyl paraben, propyl paraben, sodium benzoate or potassium benzoate.
  • the formulation can include a chelating agent, such as ethylenediaminetetraacetic acid (EDTA).
  • EDTA ethylenediaminetetraacetic acid
  • the pH of the formulation can be in the range from about 4.5 to about 5.2, e.g., about 4.7 to about 4.9.
  • the pH can be about 4.7.
  • the pH can be about 4.8.
  • the pH can be about 4.9.
  • the formulation is stable for at least 1 year when stored at a temperature of about 20-25° C. In some embodiments, when stored for 1 year at a temperature of 20-25° C., the formulation forms less than about 1% of the compound Picosulfate Benzyl Alcohol and less than about 0.2% of the unspecified impurity Compound RRT 1.35 as measured by HPLC analysis area percentage compared to sodium picosulfate.
  • the formulation when stored for 1 year at a temperature of 20-25° C., contains less than about 1% of the compound Picosulfate Related Compound A, less than about 1% of the compound Picosulfate Benzyl Alcohol, less than about 0.2% of the unspecified impurity Compound RRT 1.35, and less than about 0.2% of the unspecified impurity Compound RRT 1.94 as measured by HPLC analysis area percentage compared to sodium picosulfate.
  • the formulation when stored for 1 year at a temperature of 20-25° C., forms less than about 1% of the compound Picosulfate Related Compound A, less than about 0.2% of the compound Picosulfate Benzyl Alcohol, less than about 0.2% of the unspecified impurity Compound RRT 1.35, and less than about 0.2% of the unspecified impurity Compound RRT 1.94 as measured by HPLC analysis area percentage compared to sodium picosulfate.
  • FIG. 1 is a HPLC chromatogram of a sodium picosulfate-containing liquid formulation.
  • the term “about” means “approximately” (e.g., plus or minus approximately 10% of the indicated value).
  • alkali metal refers to a metal of group 1 (group IA) of the periodic table, including lithium, sodium, potassium and cesium.
  • carboxylic acid refers to an organic compound that contains one of more carboxylic acid groups (—C( ⁇ O)OH).
  • carboxylic acids in neutral (protonated) form, as well as carboxylic acids in salt (anionic or deprotonated) form.
  • identification threshold refers to a limit above which a degradation product should be “identified.”
  • identification refers to the process of obtaining structural characterization of the degradation product.
  • magnesium citrate refers to a magnesium salt of citric acid.
  • the magnesium citrate can be formed by the reaction of a magnesium base such as magnesium hydroxide, magnesium oxide or magnesium carbonate with citric acid, e.g., anhydrous citric acid or citric acid monohydrate.
  • pH refers to a numeric scale used to specify the acidity or basicity of an aqueous solution that is defined as being equal to the decimal logarithm of the reciprocal of the hydrogen ion activity in a solution.
  • a practical pH scale is defined by the equation:
  • E and E s are measured potentials of a galvanic cells containing a test solution and an appropriate buffer solution for standardization, and k is the change in potential per unit change in pH. Values that are obtained with solutions that are partially aqueous in character are considered apparent pH values.
  • related impurity in relation to impurities in a drug substance means an organic impurity sharing structural features with the drug substance formed, for example, during the synthesis of the drug substance (‘synthetic impurities’) and/or during storage (‘degradants’), excluding impurities derived from catalysts, solvents and reagents.
  • synthetic impurities organic impurity sharing structural features with the drug substance formed, for example, during the synthesis of the drug substance (‘synthetic impurities’) and/or during storage (‘degradants’), excluding impurities derived from catalysts, solvents and reagents.
  • degradation related impurity refers to an organic impurity sharing structural features with picosulfate.
  • soluble describes a compound that dissolves in solvent such as water or an aqueous solution.
  • insoluble describes a compound that does not dissolve in a solvent such as water, or that has low solubility, such that obtaining useful dissolved concentrations are typically not obtained unless additional substances that increase the solubility of the compound (e.g., solubilizers, surfactants) are included in the composition.
  • water soluble anionic polymer refers to a polymer that, when dissolved in water or an aqueous solution, contains acidic functional groups and that is therefore anionic at neutral pH.
  • stable when used to refer to liquid formulations 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 of time (during which the formulation is considered to be “stable.”). 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 precipitates, and/or the amount of the active ingredients that is chemically unchanged over the storage period.
  • the stability of formulation comprising picosulfate may be evaluated by, for example, whether a substantial proportion, e.g., at least 90% (such as at least about 95%, 96%, 97%, or 98%, and for example at least about 99%) of the picosulfate originally present in the solution (e.g., as determined by HPLC) remained in the formulation after the storage period.
  • the stability of the tested formulation can be evaluated under different conditions, such as, at controlled temperature of 25° C. ⁇ 2° C. (at about 60% relative humidity), 40° C. ⁇ 2° C. (at about 75% relative humidity), 55° C. (dry heat), or ambient temperature and humidity.
  • qualification threshold refers to a limit above which a degradation product should be “qualified.”
  • qualification refers to the process of acquiring and evaluating data that establishes the biological safety of an individual degradation product or a given degradation profile at the levels specified.
  • reporting threshold refers to a limit above which a degradation product should be reported to regulatory authority.
  • RRT relative retention time
  • t 1 is the retention time of a standard
  • t 2 is the retention time of the unknown.
  • RRT of a compound may vary within about ⁇ 0.05.
  • Unspecified compounds may be referred to or identified by their RRT.
  • Compound RRT 1.35 refers to an unspecified compound having RRT 1.35 ⁇ 0.05
  • Compound RRT 1.94 refers to an unspecified compound having RRT 1.94 ⁇ 0.05.
  • C 1-6 alkyl is specifically intended to individually disclose (without limitation) methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl and C 6 alkyl.
  • BHA butylated hydroxyanisole
  • BHT butylated hydroxytoluene
  • CMC carboxymethylcellulose
  • CRT controlled room temperature
  • d day(s)
  • EDTA ethylenediaminetetraacetic acid
  • Ex example
  • g gram(s)); h (hour(s)); HCl (hydrochloric acid);
  • HPMC hydroxypropylmethylcellulose
  • HPLC high-performance liquid chromatography
  • L liter(s)); M (molar); mg (milligram(s)) mL (milliliter); mM (millimolar); PET (polyethylene terephthalate); ppt (precipitate/precipitation); NaOH (sodium hydroxide); Na-saccharin (sodium saccharin); Na-CMC (sodium carboxymethylcellulose); RH (relative humidity); RT (retention
  • compositions comprising picosulfate and an antioxidant.
  • the formulations are useful to treat constipation or for the clearance of the bowel prior to X-ray examination, endoscopy or surgery.
  • the present disclosure also provides stable liquid formulations comprising picosulfate, magnesium citrate, and an antioxidant.
  • the formulations are useful to treat constipation or for the clearance of the bowel prior to X-ray examination, endoscopy or surgery.
  • Picosulfate is typically supplied in the form of a solid formulation that is dissolved to provide a liquid formulation for immediate use. This can be disadvantageous due to the need for the patient to prepare the liquid formulation by dissolving the solid before it is consumed. It would be more convenient and advantageous for the patient if the picosulfate could be provided in a pre-prepared liquid formulation. This requires that the liquid formulation be stable during transportation and storage since a pre-prepared liquid formulation would not be consumed immediately following preparation.
  • a suitable pre-prepared picosulfate liquid formulation should have a shelf life of about 3 months or greater, such as about 6 months or greater, about 9 months or greater, about 12 months or greater, about 18 months or greater, or about 2 years or greater, when stored under ambient conditions, e.g., when stored in a closed container at ambient temperature (typically about 20° C., about 25° C., or in the range from about 20° C. to about 25° C.).
  • the storage can be under an inert gas, e.g., nitrogen or argon, and the liquid formulation optionally can be purged with an inert gas prior to storage, and/or can optionally be prepared with water or an aqueous solvent that has been purged with an inert gas prior to use for preparing the formulation.
  • an inert gas e.g., nitrogen or argon
  • the liquid formulation optionally can be purged with an inert gas prior to storage, and/or can optionally be prepared with water or an aqueous solvent that has been purged with an inert gas prior to use for preparing the formulation.
  • a suitable pre-prepared picosulfate liquid formulation can be considered to have a shelf life of a particular period if, within the period defined for the shelf life, the formulation is stable. Stability of picosulfate formulation can be evaluated or indicated by, for example, the amount of degradation impurities arising from degradation of the picosulfate, the amount of visible precipitates formed, and/or the amount of picosulfate remained in the formulation after storage.
  • the amount of impurity that is considered significant can vary with the particular application.
  • ICH International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals
  • formulation comprising picosulfate is considered stable when it contains degradants such as picosulfate related impurities at a level of about 1% or less when stored for about 12 months under ambient conditions, e.g., in a closed container at ambient temperature.
  • formulation comprising picosulfate is considered stable when it contains degradants such as picosulfate related impurities at a level of about 1.5% or less when stored for about 18 months or greater, or about 2 years or greater, when stored under ambient conditions, e.g., in a closed container at ambient temperature.
  • the thresholds relate separately to each related impurity (including degradation products) and the percentage of the impurity is measured by HPLC analysis area percentage compared to sodium picosulfate.
  • formulation comprising picosulfate is considered stable when it (1) contains degradants such as picosulfate related impurities at a level of about 1% or less, about 0.5% or less, about 0.2% or less, about 0.15% or less, or about 0.10% or less, and (2) contains no visible precipitates (solution is clear and transparent), when stored for about 3 months or greater, such as about 6 months or greater, about 9 months or greater, about 12 months or greater, about 18 months or greater, or about 2 years or greater, when stored under ambient conditions, e.g., in a closed container at ambient temperature.
  • the thresholds relate separately to each related impurity (including degradation products) and the percentage of the impurity is measured by HPLC analysis area percentage compared to sodium picosulfate.
  • formulation comprising picosulfate is considered to be stable, when stored under controlled room temperature condition (25° C. ⁇ 2° C./60% ⁇ 5% relative humidity), it contains degradants such as picosulfate related impurities at a level of about 1% or less, or about 0.5% or less, about 0.2% or less, about 0.15% or less, or about 0.10% or less when stored for about 3 months or greater, such as about 6 months or greater, about 9 months or greater, about 12 months or greater, about 18 months or greater, or about 2 years or greater, when stored under ambient conditions, e.g., in a closed container at ambient temperature.
  • the thresholds relate separately to each related impurity (including degradation products) and the percentage of the impurity is measured by HPLC analysis area percentage compared to sodium picosulfate.
  • formulation comprising picosulfate is considered to be stable, after storing at about 55° C. for two weeks, it comprises one or more of the following (the percentage of the impurity is measured by HPLC analysis area percentage compared to sodium picosulfate):
  • formulation comprising picosulfate is considered to be stable, after storing at about 40° C./75% relative humidity for 3 months, it comprises one or more of the following (the percentage of the impurity is measured by HPLC analysis area percentage compared to sodium picosulfate):
  • formulation comprising picosulfate is considered to be stable, after storing at about 40° C./75% relative humidity for 6 months, it comprises one or more of the following (the percentage of the impurity is measured by HPLC analysis area percentage compared to sodium picosulfate):
  • formulation comprising picosulfate is considered to be stable, after storing at about 25° C./60% relative humidity for 1 year, it comprises one or more of the following (the percentage of the impurity is measured by HPLC analysis area percentage compared to sodium picosulfate):
  • the presence of picosulfate related impurities and unspecified impurities can be detected by a suitable analytical method that differentiates impurities from the picosulfate, e.g., HPLC.
  • a suitable analytical method that differentiates impurities from the picosulfate, e.g., HPLC.
  • the response factor of the impurity for structurally related unknown impurities can be 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 measures the relative amounts of the impurity and picosulfate.
  • the method uses ultra-high pressure chromatography (UPLC), on a Waters ACQUITY® UPLC HSS T3 2.1 ⁇ 100 mm chromatography column, which contains a C 18 reverse phase bonded silica (1.8 ⁇ m particle size), UV detection at 263 nm and a mobile phase gradient of 5-30% acetonitrile/95-70% aq. ammonium formate (25 mM; pH 3.45) at 0.2 mL/min. Under the analytical conditions used, sodium picosulfate has a retention time of about 7.4 min.
  • UPLC ultra-high pressure chromatography
  • the inventors have found that liquid formulations comprising picosulfate (e.g., sodium picosulfate) are not stable upon storage and form degradation products.
  • picosulfate e.g., sodium picosulfate
  • the inventors have surprisingly found that the formation of degradation products can be inhibited or reduced by including antioxidants in the formulation solution.
  • the impurities and degradation products can be characterized by the retention times and relative retention times shown in Table 2.
  • the inventors have found that the degradation products formed when picosulfate-containing (e.g., sodium picosulfate-containing) liquid formulations are stored include previously unknown oxidation products.
  • Picosulfate Related Compound A is identified as a picosulfate hydrolysis product of the structure (II):
  • Picosulfate Benzyl Alcohol is identified as a picosulfate oxidative product of the structure (IV):
  • the precipitates formed during the storage period may be resulted from the magnesium salt, e.g., magnesium citrate.
  • the amount of precipitates can be indirectly measured by assay of magnesium.
  • the present disclosure therefore provides a liquid formulation containing picosulfate and an antioxidant.
  • the picosulfate can be in the form of a salt and can be an alkali metal picosulfate, e.g., sodium picosulfate. In some embodiments, the picosulfate is sodium picosulfate.
  • the picosulfate can be present in the composition at a concentration in the range from about 0.10 mM to about 0.15 mM, e.g., about 0.11 mM to about 0.15 mM, about 0.12 mM to about 0.15 mM, about 0.13 mM to about 0.15 mM, about 0.14 mM to about 0.15 mM, about 0.11 mM to about 0.14 mM, about 0.12 mM to about 0.14 mM, 0.13 mM to about 0.14 mM, about 0.11 mM to about 0.13 mM, about 0.12 mM to about 0.13 mM, or about 0.11 mM to about 0.13 mM.
  • the concentration of picosulfate can be in the range from about 0.12 mM to about 0.14 mM, or from about 0.13 mM to about 0.15 mM, such as about 0.13 mM or about 0.14 mM.
  • the picosulfate salt can be present in an amount that provides a dose of sodium picosulfate, or a dose equivalent to a dose of sodium picosulfate, wherein the amount of sodium picosulfate in the dose is from about 5 mg to about 10 mg, such as from about 8 mg to about 12 mg, about 9 mg to about 11 mg, or about 10 mg, further such as 10 mg dose of sodium picosulfate.
  • the dose can be included in a volume in the range from about 50 mL to about 250 mL, e.g., from about 100 mL to about 200 mL, from about 150 mL to about 170 mL; e.g., about 100 mL, about 120 mL, about 125 mL, about 140 mL, about 150 mL, about 160 mL, about 175 mL, about 180 mL, or about 200 mL.
  • antioxidants examples include acetone sodium bisulfite, ascorbic acid or a salt or ester thereof (such as ascorbyl palmitate or sodium ascorbate), butylated hydroxyanisole, butylated hydroxytoluene, histidine, D-mannose, potassium metabisulfite, propyl gallate, sodium metabisulfite, sodium sulfite, sodium thiosulfate, sulfur dioxide, ⁇ -tocopherol.
  • acetone sodium bisulfite ascorbic acid or a salt or ester thereof (such as ascorbyl palmitate or sodium ascorbate), butylated hydroxyanisole, butylated hydroxytoluene, histidine, D-mannose, potassium metabisulfite, propyl gallate, sodium metabisulfite, sodium sulfite, sodium thiosulfate, sulfur dioxide, ⁇ -tocopherol.
  • antioxidants include dodecyl gallate, erythorbic acid, monothioglycerol, octyl gallate, propionic acid, sodium formaldehyde sulfoxylate, thymol, and tocopheryl polyethylene glycol succinate.
  • the antioxidant can be a sulfur(II) compound or sulfur(IV) compound, such as sulfur dioxide or a sulfur oxyanion containing one or more sulfur atoms in a sulfur(II) or sulfur(IV) oxidation state, or both.
  • Non-limiting examples include sulfite, bisulfite, disulfite, metabisulfate (dithionate), dithionite, thiosulfate (hyposulfite), or tetrathionate,
  • Such salts can be included as, e.g., ammonium, or alkali metal (e.g., sodium, potassium) salts.
  • the antioxidant can be a bisulfite, a sulfite, or a metabisulfite, e.g., ammonium bisulfite, ammonium sulfite, ammonium metabisulfite, sodium bisulfite, sodium sulfite, sodium metabisulfite, potassium bisulfite, potassium sulfite, or potassium metabisulfite.
  • the antioxidant can be sulfur dioxide.
  • the antioxidants can be present in the formulation at a concentration in the range from about 0.002 M to about 0.1 M, e.g., concentrations from about 0.002 M to 0.05 M, e.g., from about 0.002 M to about 0.03 M, e.g., from about 0.002 M to about 0.02 M, from about 0.002 M to about 0.01 M, from about 0.005 M to about 0.05 M, from about 0.005 M to about 0.03 M, from about 0.005 M to about 0.02 M, from about 0.01 M to about 0.02 M.
  • Suitable amounts of the antioxidant included in the formulations can include amounts in the range from about 0.5 g/L to about 5 g/L, e.g., from about 0.5 g/L to about 3 g/L, from about 0.5 g/L to about 2 g/L, from about 1 g/L to about 2 g/L.
  • the antioxidant is a water-soluble antioxidant.
  • suitable water-soluble antioxidants include ascorbic acid, sodium ascorbate, potassium ascorbate, sodium metabisulfite, potassium metabisulfite, sodium sulfite, sodium thiosulfate, and sulfur dioxide.
  • the antioxidant is a water-insoluble antioxidant.
  • suitable water-insoluble antioxidants include butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, thymol, and ⁇ -tocopherol.
  • the formulation can further include a solubilizing agent.
  • the solubilizing agent can increase the solubility of the water-insoluble oxidizing agent in water or an aqueous solvent.
  • the solubilizing agent can be a surfactant. Examples of suitable solubilizing agent include propylene glycol, polysorbate, and poloxamer.
  • Suitable amounts of the solubilizing agent included in the formulations can include amounts in the range from about 1 g/L to about 150 g/L, e.g., from about 1 g/L to about 100 g/L, from about 1 g/L to about 80 g/L, from about 1 g/L to about 50 g/L, from about 2 g/L to about 150 g/L, from about 2 g/L to about 100 g/L, from about 2 g/L to about 80 g/L, from about 2 g/L to about 50 g/L, from about 5 g/L to about 150 g/L, from about 5 g/L to about 100 g/L, from about 5 g/L to about 80 g/L, from about 5 g/L to about 50 g/L.
  • the formulations can include an osmotic laxative such as a magnesium salt or magnesium oxide.
  • the magnesium salt can be magnesium citrate.
  • the magnesium citrate can be formed by the reaction of a magnesium base, e.g., magnesium hydroxide, magnesium oxide or magnesium carbonate, such as magnesium oxide, with citric acid, e.g., anhydrous citric acid or citric acid monohydrate, such as anhydrous citric acid.
  • the magnesium citrate can include salts in which the magnesium and citrate components are present in a molar ratio in the range from about 1:1 to about 1.5:1, e.g., from about 1.1:1 to about 1.5:1, about 1.2:1 to about 1.5:1, about 1.3:1 to about 1.5:1, about 1.4:1 to about 1.5:1, about 1:1 to about 1.4:1, about 1.2:1 to about 1.4:1, about 1.3:1 to about 1.4:1, about 1:1 to about 1.3:1, about 1.1:1 to about 1.3:1, about 1.2:1 to about 1.3:1, or about 1:1 to about 1.2:1.
  • the magnesium and citric acid components can also be present in a molar ratio in the range from about 0.5:1 to about 1:1, about 0.6:1 to about 1:1, about 0.7:1 to about 1:1, about 0.8:1 to about 1:1, or about 0.9:1 to about 1:1.16.
  • the magnesium and citrate components can be present in a molar ratio of about 1.4:1.
  • the magnesium salt e.g., magnesium citrate
  • the magnesium salt can be present in the formulation at a concentration that provides a concentration of magnesium in the range from about 0.1 M to about 1 M, e.g., from about 0.2 M to about 0.8 M, or from about 0.5 M to about 0.6 M, e.g., about 0.1 M, about 0.2 M, about 0.3 M, about 0.4 M, about 0.5 M, about 0.6 M, about 0.7 M, about 0.8 M, about 0.9 M, or about 1 M.
  • the magnesium salt is present at a concentration that provides a concentration of magnesium in the range from about 0.5 M to about 0.6 M, or at a concentration of about 0.6 M.
  • the magnesium salt can be present in an amount per dose that is provided, or an amount that is equivalent to the amount that is provided, when the magnesium salt is prepared from magnesium oxide and the amount of magnesium oxide is in the range from about 1 g to about 6 g, e.g., from about 2 g to about 5 g, from about 2 g to about 4 g, from about 3 g to about 5 g, or from about 3 g to about 4 g, e.g., about 1 g, about 1.5 g, about 2 g, about 2.5 g, about 3 g, about 3.5 g, about 4 g, about 4.5 g, about 5 g, about 5.5 g, or about 6 g.
  • the magnesium salt is present in an amount per dose that is provided, or an amount that is equivalent to the amount that is provided, when the magnesium salt is prepared from magnesium oxide and the amount of magnesium oxide is about 3.5 g.
  • the magnesium salt can be present in an amount per dose that is provided by magnesium citrate when the magnesium citrate is prepared from magnesium oxide in the amounts specified above (or another magnesium base that provides magnesium in an equivalent amount to the amounts specified above) and citric acid.
  • the amount of citric acid per dose can be an amount of citric acid as specified by the molar ratios above.
  • the amount of citric acid per dose can be an amount that is provided by an amount of anhydrous citric acid (or an equivalent amount of hydrated citric acid) in the range from about 3 g to about 20 g, e.g., from about 5 g to about 15 g, from about 10 g to about 15 g, or about 9 g, about 10 g, about 11 g, about 12 g, about 13 g, about 14 g, or about 15 g, such as about 12 g.
  • the formulations can further include a carboxylic acid, an ammonium salt, and/or a soluble anionic polymer. While not being limited by any theory, it is considered that the carboxylic acid, and/or ammonium salt and/or soluble anionic polymer in an aqueous solution may help to increase the stability of formulation and/or inhibit, retard, or prevent the precipitation of salts, particularly magnesium salts, from the formulation. In some embodiments, one or more of a carboxylic acid, and/or ammonium salt and/or a soluble anionic polymer can be present in the formulation.
  • the formulation can include, e.g., a carboxylic acid and an ammonium salt (including an ammonium salt of a carboxylic acid), a carboxylic acid and a soluble anionic polymer, an ammonium salt and a soluble anionic polymer, or a carboxylic acid, an ammonium salt and a soluble anionic polymer.
  • the formulations can also include more than one of (e.g., two) of the carboxylic acid, the ammonium salt, and/or the soluble anionic polymer, including in combination with carboxylic acid(s), ammonium salt(s) and/or soluble anionic polymer(s).
  • the carboxylic acid(s), ammonium salt(s) and/or soluble anionic polymer(s) can be any one or any two or more of the carboxylic acids, ammonium salts and/or soluble anionic polymer described herein, and, when used in combination, they can be used in the amount specified for each component elsewhere in the present disclosure.
  • the carboxylic acids, ammonium salts and/or soluble anionic polymer described herein may also be used in a smaller amount than when used individually, and may be used, e.g., in about 25%, 50% or 75% of the amount specified for each individual component elsewhere in the present disclosure.
  • carboxylic acids that can be used in the formulations are water soluble.
  • carboxylic acids can be chosen from mono-, di- and tri-carboxylic acids.
  • carboxylic acids can be chosen from C 1-6 (or C 1-4 or C 1-3 ) alkanoic acids, including formic, acetic and propionic acid.
  • carboxylic acids can be chosen from C 1-6 (or C 1-4 or C 1-3 ) alkandioic or alkenedioic acids, including oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, fumaric acid, and maleic acid.
  • carboxylic acids can be chosen from hydroxy-substituted acids, including mono-, di- or tri-hydroxy-substituted mono-, di- or tricarboxylic acids, including glycolic acid, malic acid, lactic acid, citric acid, tartaric acid, 3-hydroxypropionic acid, and glyceric acid.
  • carboxylic acids can be chosen from amino-substituted acids, including ⁇ - and ⁇ -amino acids, including glycine, arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, methionine, proline, alanine, valine, isoleucine, leucine, phenylalanine, tyrosine, tryptophan, ⁇ -alanine, and homoserine.
  • amino-substituted acids including ⁇ - and ⁇ -amino acids, including glycine, arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, methionine, proline, alanine, valine, isoleucine, leucine, phenylalanine, tyrosine, trypto
  • each chiral center can be (R) or (S), and can be employed as a single isomer or mixture of isomers (e.g., a racemic mixture).
  • any of the a-amino acids arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, methionine, proline, alanine, valine, isoleucine, leucine, phenylalanine, tyrosine, tryptophan or homoserine can be in D- or L-configuration (or as mixtures).
  • hydroxy-substituted carboxylic acids can also be employed in the form of stereoisomers or mixtures thereof, e.g., glycolic acid, malic acid, lactic acid, citric acid, tartaric acid, 3-hydroxypropionic acid, and glyceric acid.
  • carboxylic acids examples include acetic acid, arginine, ascorbic acid, asparagine, aspartic acid, cysteine, fumaric acid, formic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, glycolic acid, histidine, lactic acid, lysine, maleic acid, malic acid, malonic acid, methionine, oxalic acid, propionic acid, serine, succinic acid, tartaric acid, threonine, and tyrosine.
  • Preferred carboxylic acids are those that are approved by the Food and Drug Administration for use as inactive ingredients in pharmaceutical products. Also preferred are carboxylic acids that are approved or recognized as safe for use in food products.
  • the citric acid when the carboxylic acid is citric acid, the citric acid can be an excess over the citric acid used to form magnesium citrate.
  • the carboxylic acid can be a carboxylic acid other than citric acid.
  • the carboxylic acid can also be a carboxylic acid other than any of the other acids identified above, e.g., an acid other than malic acid.
  • the carboxylic acid can be a carboxylic acid other than any of the following acids: acetic acid, aspartic acid, citric acid, fumaric acid, glutamic acid, lactic acid, maleic acid, malic acid, and succinic acid.
  • the carboxylic acid can be malic acid.
  • the carboxylic acid can be malonic acid.
  • the carboxylic acid can be tartaric acid. In some embodiments, the carboxylic acid can be D-tartaric acid. In some embodiments, the carboxylic acid can be L-tartaric acid. In some embodiments, the carboxylic acid can be DL-tartaric acid. In some embodiments, the carboxylic acid can be meso-tartaric acid.
  • the carboxylic acid can be malonic acid or tartaric acid when the formulation does not comprise an ammonium salt or a soluble anionic polymer.
  • the carboxylic acid can be gluconic acid (e.g., as sodium gluconate).
  • the carboxylic acid can be succinic acid.
  • the carboxylic acid can be included in the formulation in the form of a free acid, a salt, or a mixture of the acid one or more salts of the carboxylic acid, such as carboxylate salts.
  • suitable salts include ammonium salts and alkali metal salts, e.g., sodium or potassium carboxylate salts.
  • the carboxylic acids are in the form of sodium salts and/or potassium salts.
  • ammonium salts are included.
  • the carboxylic acid can also be used in the form of an acid addition salt, e.g., a hydrochloride salt, hydrogen sulfate salt, or a sulfate salt.
  • a mineral acid when the carboxylic acid is included in the formulation in the form of a salt, e.g., a carboxylate salt, a mineral acid can also be included in the formulation.
  • the mineral acid can react with a carboxylate salt to form the free acid.
  • Suitable mineral acids for this purpose include hydrochloric acid and sulfuric acid.
  • the amount of carboxylic acid included in the formulation can be any amount that is effective to stabilize the formulation.
  • Limits on the amount of carboxylic acid to be included in the formulation can include limits imposed by the solubility of the carboxylic acid, by the palatability of the carboxylic acid, or the toxicity or other undesirable properties of certain carboxylic acids.
  • the carboxylic acids can be present in the formulation at a concentration in the range from about 0.01 M to 5 M, e.g., concentrations from about 0.01 g/L to about 5 M, e.g., from about 0.01 M to about 3 M, from about 0.01 M to about 1 M, from about 0.05 M to about 5 M, from about 0.05 M to about 3 M, from about 0.05 M to about 1 M, from about 0.1 M to about 5 M, from about 0.1 M to about 3 M, or from about 0.1 M to about 1 M, e.g., about 0.1 M, about 0.2 M, about 0.3 M, about 0.4 M, about 0.5 M, about 0.6 M, about 0.7 M, about 0.8 M, about 0.9 M, about 1.0 M, about 1.2 M, about 1.4 M, about 1.5 M, about 2 M, about 3 M, about 4 M, or about 5 M.
  • concentrations from about 0.01 g/L to about 5 M, e.g., from about 0.01 M to about 3 M
  • Suitable amounts of the carboxylic acids included in the formulations can include amounts in the range from about 1 g/L to about 500 g/L, e.g., from about 1 g/L to about 300 g/L, from about 1 g/L to about 100 g/L, from about 5 g/L to about 500 g/L, from about 5 g/L to about 300 g/L, from about 5 g/L to about 100 g/L, from about 10 g/L to about 500 g/L, from about 10 g/L to about 300 g/L, or from about 10 g/L to about 100 g/L.
  • suitable amounts of the carboxylic acids can include amounts in the range from about 1 mL/L to about 500 mL/L, e.g., from about 1 mL/L to about 300 mL/L, from about 1 mL/L to about 100 mL/L, from about 5 mL/L to about 500 mL/L, from about 5 mL/L to about 300 mL/L, from about 5 mL/L to about 100 mL/L, from about 10 mL/L to about 500 mL/L, from about 10 mL/L to about 300 mL/L, or from about 10 mL/L to about 100 mL/L.
  • the soluble anionic polymer that can be used in the formulations include water soluble polymers containing carboxylic acid, sulfonic acid and sulfate groups. In one embodiment, water soluble polymers containing carboxylic acid groups are included. In some embodiments, the soluble anionic polymer is a polysaccharide polymer. Examples of suitable anionic polymers include alginic acid, carboxymethylcellulose, carageenans, polyacrylic acid and copolymers thereof, and xanthan gum.
  • the soluble anionic polymer can be included in the formulation in the form an acid, a salt form, in which the acidic functional groups have been deprotonated to anionic (or salt) form, or as a form in which the acidic functional groups have been partially deprotonated.
  • the soluble anionic polymers can be, e.g., sodium alginate or sodium carboxymethylcellulose.
  • the polymer is included in anionic form.
  • Suitable counter ions for the soluble anionic polymer include alkali metal counter ions, e.g., sodium or potassium, or ammonium counter ions.
  • the sodium salt forms of the soluble anionic polymer are chosen from the potassium salt forms.
  • the amount of the soluble anionic polymer included in the formulation can be any amount that is effective to stabilize the formulation.
  • Limits on the amount of the soluble anionic polymer to be included in the formulation can include limits imposed by the solubility of the soluble anionic polymer, by the palatability of the soluble anionic polymer, or the toxicity or other undesirable properties of certain soluble anionic polymer.
  • the presence of a soluble anionic polymer can also increase the viscosity of the liquid formulation, which can also impose limits on the amount of soluble anionic polymer included in the formulation.
  • the liquid formulation should be relatively free flowing so that it can be easily consumed orally by a patient.
  • the soluble anionic polymer can be alginic acid, e.g., as sodium alginate.
  • alginic acid e.g., as sodium alginate.
  • Examples include PROTANAL® CR 8133, PROTANAL® 8233, PROTANAL® LFR 5/60 or PROTACID® 120 NM.
  • the soluble anionic polymer can be carboxymethylcellulose, e.g., as sodium carboxymethylcellulose.
  • carboxymethylcellulose e.g., as sodium carboxymethylcellulose.
  • examples include AQUALON® CMC-7L2P, or AQUALON® CMC-7LF.
  • the soluble anionic polymer can be carrageenan, e.g., lambda-carrageenan.
  • carrageenan e.g., lambda-carrageenan.
  • examples include VISCARIN® GP 109F.
  • the soluble anionic polymer can be poly(acrylic) acid.
  • the soluble anionic polymer can be xanthan gum.
  • examples include XANTURAL® 75.
  • suitable amounts of the soluble anionic polymer included in the formulations can include amounts in the range from about 0.5 g/L to about 25 g/L, e.g., from about 0.5 g/L to about 20 g/L, from about 0.5 g/L to about 10 g/L, from about 0.5 g/L to about 5 g/L, from about 1 g/L to about 25 g/L, from about 1 g/L to about 20 g/L, from about 1 g/L to about 10 g/L, from about 1 g/L to about 5 g/L, from about 2 g/L to about 25 g/L, from about 2 g/L to about 20 g/L, from about 2 g/L to about 10 g/L, from about 2 g/L to about 5 g/L, from about 5 g/L to about 25 g/L, from about 5 g/L to about 20 g/L, from about 5 g/L to about 10 g/
  • the formulations can include both a carboxylic acid and a soluble anionic polymer.
  • the formulations can include both malic acid and alginic acid, e.g., as sodium alginate.
  • the formulations can include both malic acid and carboxymethylcellulose, e.g., as sodium carboxymethylcellulose.
  • the formulations can include both malic acid and carrageenan, e.g., lambda-carrageenan.
  • the formulations can include both malic acid and poly(acrylic) acid.
  • the formulations can include both malic acid and xanthan gum.
  • the malic acid can be, e.g., D-, L- or DL-malic acid.
  • the formulations can include both malonic acid and alginic acid, e.g., as sodium alginate. In some embodiments, the formulations can include both malonic acid and carboxymethylcellulose, e.g., as sodium carboxymethylcellulose. In some embodiments, the formulations can include both malonic acid and carrageenan, e.g., lambda-carrageenan. In some embodiments, the formulations can include both malonic acid and poly(acrylic) acid. In some embodiments, the formulations can include both malonic acid and xanthan gum.
  • the formulations can include both tartaric acid and alginic acid, e.g., as sodium alginate.
  • the formulations can include both tartaric acid and carboxymethylcellulose, e.g., as sodium carboxymethylcellulose.
  • the formulations can include both tartaric acid and carrageenan, e.g., lambda-carrageenan.
  • the formulations can include both tartaric acid and poly(acrylic) acid.
  • the formulations can include both tartaric acid and xanthan gum.
  • the tartaric acid can be, e.g., D-, L-, DL- or meso-tartaric acid.
  • the formulations can include both gluconic acid, e.g., as sodium gluconate, and alginic acid, e.g., as sodium alginate. In some embodiments, the formulations can include both gluconic acid, e.g., as sodium gluconate, and carboxymethylcellulose, e.g., as sodium carboxymethylcellulose. In some embodiments, the formulations can include both gluconic acid, e.g., as sodium gluconate, and carrageenan, e.g., lambda-carrageenan. In some embodiments, the formulations can include both gluconic acid, e.g., as sodium gluconate, and poly(acrylic) acid. In some embodiments, the formulations can include both gluconic acid, e.g., as sodium gluconate, and xanthan gum.
  • the formulations can include both succinic acid and alginic acid, e.g., as sodium alginate. In some embodiments, the formulations can include both succinic acid and carboxymethylcellulose, e.g., as sodium carboxymethylcellulose. In some embodiments, the formulations can include both succinic acid and carrageenan, e.g., lambda-carrageenan. In some embodiments, the formulations can include both succinic acid and poly(acrylic) acid. In some embodiments, the formulations can include both succinic acid and xanthan gum.
  • the ammonium salts that can be used in the formulations include water soluble salts of mineral acids or carboxylic acids.
  • the ammonium salts that can be used in the formulation include ammonium chloride, ammonium hydrogen sulfate, or ammonium sulfate.
  • the ammonium salts that can be used in the formulation also include ammonium carboxylate salts with any of the carboxylic acids identified above, e.g., ammonium formate, ammonium acetate, and ammonium propionate.
  • the ammonium salts that can be used in the formulation can be formed in situ by the reaction of ammonia with a suitable acid.
  • the amount of ammonium salt included in the formulation can be any amount that is effective to stabilize the formulation.
  • Limits on the amount of ammonium salt to be included in the formulation can include limits imposed by the solubility of the ammonium salt, by the palatability of the ammonium salt, or the toxicity or other undesirable properties of certain ammonium salts.
  • the ammonium salts included in the formulations can include amounts in the range from about 1 g/L to about 40 g/L, e.g., from about 1 g/L to about 20 g/L, from about 1 g/L to about 10 g/L, from about 1 g/L to about 5 g/L, from about 5 g/L to about 40 g/L, from about 5 g/L to about 20 g/L, from about 10 g/L to about 40 g/L, or from about 10 g/L to about 20 g/L.
  • the formulations can also include a preservative agent such as methyl paraben, propyl paraben, sodium benzoate or potassium benzoate.
  • a preservative agent such as methyl paraben, propyl paraben, sodium benzoate or potassium benzoate.
  • Suitable amounts of the preservative included in the formulations can include amounts in the range from about 0.1 g/L to about 2 g/L, e.g., from about 0.1 g/L to about 1.5 g/L, from about 0.1 g/L to about 1 g/L, from about 0.5 g/L to about 2 g/L, or from about 0.5 g/L to about 1 g/L.
  • the formulations can also include a chelating agent such as ethylenediaminetetraacetic acid (EDTA) (which can be in the form of a salt).
  • a chelating agent such as ethylenediaminetetraacetic acid (EDTA) (which can be in the form of a salt).
  • EDTA ethylenediaminetetraacetic acid
  • Suitable amounts of the chelating agent included in the formulations can include amounts in the range from about 0.1 g/L to about 5 g/L, e.g., from about 0.1 g/L to about 3 g/L, from about 0.1 g/L to about 2 g/L, from about 0.5 g/L to about 5 g/L, from about 0.5 g/L to about 3 g/L, from about 0.5 g/L to about 2 g/L, or from about 1 g/L to about 2 g/L.
  • EDTA ethylenediaminetetraacetic acid
  • the pH of the solution can be in the range from about 4.0 to about 6.5, such as from about 4.0 to about 5.5.
  • a low pH (below about 6.5, or below about 5.5) may be beneficial to help to stabilize the formulation and inhibit, retard, or prevent the precipitation of salts (e.g., magnesium salts) from the formulation; however, it is also understood that picosulfate can be unstable at a pH lower than about 4.0, and thus the pH of the formulation be in the range from about 4.0 to about 6.5, or, as an example, from about 4.0 to about 5.5.
  • the pH can be in a range, e.g., from about 4.0 to about 5.2, from about 4.0 to about 5.0, from about 4.0 to about 4.8, from about 4.0 to about 4.6, from about 4.0 to about 4.5, from about 4.0 to about 4.4, from about 4.0 to about 4.2, from about 4.2 to about 5.5, from about 4.2 to about 5.2, from about 4.2 to about 5.0, from about 4.2 to about 4.8, from about 4.2 to about 4.6, from about 4.2 to about 4.5, from about 4.2 to about 4.4, from about 4.4 to about 5.5, from about 4.4 to about 5.2, from about 4.4 to about 5.0, from about 4.4 to about 4.8, from about 4.4 to about 4.6, from about 4.5 to about 5.5, from about 4.5 to about 5.2, from about 4.5 to about 5.0, from about 4.5 to about 4.8, from about 4.6 to about 4.5, from about 4.5 to about 5.2, from about 4.5 to about 5.0, from about 4.5 to
  • the pH is in the range from about 4.5 to about 5.2.
  • the pH can be, e.g., about 4.0, about 4.1, about 4.2, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, or about 5.5.
  • the pH is about 4.9.
  • one or more acids or bases can be included in the formulation to adjust the pH.
  • one or more acids can be used, e.g., hydrochloric acid, sulfuric acid, a carboxylic acid (which can be one or more of the carboxylic acids described in greater detail above) or an ammonium salt (which can be one or more of the ammonium salts described in greater detail above).
  • one or more bases can be used, e.g., sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, or sodium or potassium salts of carboxylic acids (which can be one or more of the carboxylic acids described in greater detail above).
  • acids and bases can form salts that can be present as additional components of the formulation, e.g., sodium chloride, sodium sulfate, potassium sulfate, and potassium chloride.
  • the formulations are aqueous formulations containing water a solvent.
  • Additional water-soluble or water-miscible solvents can also be present in the formulation, including, e.g., alcohols, including C 2-4 alcohols such as ethanol, or glycols such as propylene glycol or polyethylene glycol.
  • additional ingredients that may be present in the formulation include sweetening and flavoring agents.
  • sweetening agent is aspartame and saccharin sodium.
  • flavoring agents include orange flavor containing acacia gum, lactose, ascorbic acid and butylated hydroxyanisole, and cranberry flavor containing maltodextrin, glyceryl triacetate (triacetin) and sodium octenyl succinated starch.
  • the sodium picosulfate, magnesium salts, carboxylic acids, ammonium salts and soluble anionic polymers, and other formulation components defined above are independent components of the composition and therefore any of the identified magnesium salts, carboxylic acids, ammonium salts and soluble anionic polymers, and other formulation components can be included in the formulation. Further, each of that the sodium picosulfate, magnesium salts, carboxylic acids, ammonium salts and soluble anionic polymers, and other formulation components can be included in the amounts described above.
  • liquid formulation described herein can be prepared by dissolving the ingredients of the formulation in a suitable liquid, such as water, to provide any of the liquid formulations as described above.
  • magnesium citrate when the formulation contains magnesium citrate, magnesium oxide and citric acid are used to provide the magnesium citrate.
  • the ingredients are used in amounts such that, the appropriate concentrations (such as those described above) are provided when the ingredients are dissolved in a given volume (e.g., as a non-limiting example, 150 mL may be used to provide a single unit dose) of the liquid.
  • the present disclosure thus provides a method of preparing a liquid formulation comprising dissolving ingredients comprising picosulfate, magnesium oxide, citric acid and an antioxidant to form a liquid formulation.
  • the ingredients further comprise a carboxylic acid, an ammonium salt or a soluble anionic polymer.
  • composition that includes sodium picosulfate, magnesium oxide, citric acid and an antioxidant.
  • the pharmaceutical composition can, for example, be a mixture of dry ingredients that forms a liquid formulation as described herein when it is dissolved.
  • liquid pharmaceutical composition prepared by, or obtainable by, the methods described herein.
  • the ingredients can be added to the formulation and/or dissolved in any suitable combination or order.
  • the ingredients (or a sub-set of the ingredients) can be mixed as a dry formulation, before dissolving, or any of the ingredients can be added sequentially.
  • heating can be used to dissolve some of the ingredients. In some embodiments, heating is not applied to a solution comprising sodium picosulfate. Suitable and non-limiting methods of preparing the formulations are described in the Examples.
  • the pH of the formulation can be adjusted to the range from about 4.0 to about 6.5, e.g., from about 4.0 to about 5.5, about 4.5 to about 5.2, from about 4.7 to about 4.9, or about 4.8.
  • the pH can be adjusted using a suitable acid and/or base (e.g., hydrochloric acid and/or sodium hydroxide).
  • the pH can be adjusted after all the ingredients have been dissolved or, e.g., following the addition of magnesium oxide, citric acid, and antioxidant, but prior to addition of sodium picosulfate.
  • the liquid formulation can be packaged in a suitable container (e.g., a bottle), which can include one or two doses of the formulation, and can be sealed with a closure.
  • a dose can be included in a volume of the liquid formulation in the range from about 50 mL to about 250 mL, e.g., from about 100 mL to about 200 mL, for example about 100 mL, about 120 mL, about 125 mL, about 140 mL, about 150 mL, about 160 mL, about 175 mL, about 180 mL, or about 200 mL, preferably about 160 mL.
  • the formulation can be stored at a temperature in the range from about 0° C. to about 30° C., e.g., about 4° C., about 5° C., about 10° C., about 15° C., about 20° C., about 21° C., about 22° C., about 23° C., about 24° C., or about 25° C.
  • the formulation is stable upon storage for at least about thirty days, about sixty days, about 90 days, at least about six months, at least about a year, at least about 18 months, or at least about two years.
  • liquid formulation described herein can be used to treat constipation or for the clearance of the bowel prior to X-ray examination, endoscopy or surgery.
  • the liquid formulation containing effective amounts of picosulfate (e.g., sodium picosulfate) and magnesium (e.g., magnesium citrate) is administered to a subject (e.g., a patient) in need of the treatment.
  • picosulfate e.g., sodium picosulfate
  • magnesium e.g., magnesium citrate
  • the picosulfate salt can be present in an amount that provides a dose of sodium picosulfate, or a dose equivalent to a dose of sodium picosulfate, wherein the amount of sodium picosulfate in the dose is from about 5 mg to about 15 mg, such as from about 8 mg to about 12 mg, about 9 mg to about 11 mg, or about 10 mg, further such as a 10 mg dose of sodium picosulfate.
  • the magnesium salt can be present in an amount per dose that is provided, or an amount that is equivalent to the amount that is provided, when the magnesium salt is prepared from magnesium oxide and the amount of magnesium oxide is in the range from about 1 g to about 6 g, e.g., from about 2 g to about 5 g, from about 2 g to about 4 g, from about 3 g to about 5 g, or from about 3 g to about 4 g, e.g., about 1 g, about 1.5 g, about 2 g, about 2.5 g, about 3 g, about 3.5 g, about 4 g, about 4.5 g, about 5 g, about 5.5 g, or about 6 g, such as about 3.5 g.
  • the magnesium salt can be present as the citrate salt wherein the amount of citric acid per dose can be an amount that is provided by an amount of anhydrous citric acid (or an equivalent amount of hydrated citric acid) in the range from about 3 g to about 20 g, e.g., from about 5 g to about 15 g, from about 10 g to about 15 g, or about 9 g, about 10 g, about 11 g, about 12 g, about 13 g, about 14 g, or about 15 g, such as about 12 g.
  • the dose can be included in a volume of the liquid formulation in the range from about 50 mL to about 250 mL, e.g., from about 100 mL to about 200 mL, for example about 100 mL, about 120 mL, about 125 mL, about 140 mL, about 150 mL, about 160 mL, about 175 mL, about 180 mL, or about 200 mL, such as about 160 mL.
  • the liquid formulation can further comprise an antioxidant.
  • the antioxidant can be sodium metabisulfite or potassium metabisulfite.
  • the liquid formulation can further comprise a carboxylic acid, such as malic acid or malonic acid.
  • the following procedures may be used:
  • the formulation can be given a split dose administration where a first dose of the formulation is taken the evening before the procedure (e.g., between about 5 pm and about 9 pm), which can be followed administration of clear liquid (e.g., five 150 mL glasses of clear liquid). Then, a second dose of the formulation can be taken the morning of the procedure (e.g., at least 1, 2, 3, 4, 5, 6, 7 or 8 hours prior to, but typically no more than 8, 9 or 10 hours prior to, the procedure), which can be followed by administration of clear liquid (e.g., three 150 mL glasses of clear liquid).
  • a first dose of the formulation is taken the evening before the procedure (e.g., between about 5 pm and about 9 pm)
  • administration of clear liquid e.g., five 150 mL glasses of clear liquid
  • a second dose of the formulation can be taken the morning of the procedure (e.g., at least 1, 2, 3, 4, 5, 6, 7 or 8 hours prior to, but typically no more than 8, 9 or 10 hours prior to, the procedure), which can be followed
  • the formulation can also be given a split dose administration where two doses of the formulation are taken the day before the procedure. For example, one dose of the liquid formulation can be taken in the afternoon (e.g., between about 4 pm and about 6 pm), which can be followed administration of clear liquid (e.g., five 150 mL glasses of clear liquid). Then, a second dose of the formulation can be taken in the late evening (e.g., approximately 6 h later, e.g., between about 10 pm and about 12 am), which can be followed by administration of clear liquid (e.g., three 150 mL glasses of clear liquid).
  • one dose of the liquid formulation can be taken in the afternoon (e.g., between about 4 pm and about 6 pm), which can be followed administration of clear liquid (e.g., five 150 mL glasses of clear liquid).
  • a second dose of the formulation can be taken in the late evening (e.g., approximately 6 h later, e.g., between about 10 pm and about 12 am), which can be followed by administration of clear liquid
  • Sodium picosulfate is quantitatively identified and analyzed using a reversed-phase UPLC method and UV detection.
  • first mobile phase 25 mM ammonium formate buffer, pH 3.45 is used.
  • second mobile phase mobile phase B
  • MILI-Q® water or equivalent used for dilution of all standards and samples.
  • Samples are prepared by transferring 5 mL of the bulk or drug product solution to a 10 mL volumetric flask and diluting to volume with water and filtered with a 0.45 ⁇ m PVDF filter.
  • the sodium picosulfate peak in the samples is identified by comparing the retention time of the sodium picosulfate peak to the sodium picosulfate peak in the working standard (approximately 7.4 min.)
  • the relative retention time and relative response factor for related substances is shown in Table 6.
  • the assay content of sodium picosulfate is calculated using the following equation:
  • the amount of each degradation product is calculated using following equation:
  • peaks in the sample solution with an area count greater or equal to sodium picosulfate peak area in the Sensitivity Solution is integrated. Peaks associated with blank diluent or the placebo are not integrated or reported.
  • FIG. 1 A typical chromatogram from the analysis is shown in FIG. 1 .
  • Liquid formulations containing sodium picosulfate and magnesium citrate were prepared as follows:
  • compositions of the formulations are shown in Table 7.
  • Formulations containing sodium picosulfate, magnesium citrate and sodium carboxymethylcellulose/sodium gluconate or malic acid were prepared having the compositions shown in Table 9.
  • Liquid formulations containing sodium picosulfate, magnesium citrate, sodium carboxymethylcellulose and sodium gluconate were prepared as follows:
  • Liquid formulations containing sodium picosulfate, magnesium citrate and malic acid were prepared as follows:
  • Formulations containing sodium picosulfate, magnesium citrate and sodium carboxymethylcellulose/sodium gluconate were prepared having the compositions shown in Table 11.
  • Liquid formulations containing sodium picosulfate, magnesium citrate, sodium carboxymethylcellulose and sodium gluconate were prepared as follows:
  • Formulations containing sodium picosulfate and magnesium citrate were prepared having the compositions shown in Table 13.
  • Liquid formulations containing sodium picosulfate, magnesium citrate and malic acid were prepared as follows:
  • Formulations containing sodium picosulfate, magnesium citrate and malic acid were prepared having the compositions shown in Table 15.
  • Liquid formulations containing a water-soluble antioxidant, sodium picosulfate, magnesium citrate and malic acid were prepared as follows.
  • a common base solution was prepared with 25% less purified water than theoretical weight and without sodium picosulfate and anti-oxidant. To accommodate different levels of anti-oxidants and solubilizers, the base solutions were prepared using 25% less purified water.
  • the final unit dose weight of all formulations was fixed to 177 g, by adjusting the quantity of water during preparation. Nitrogen was used to purge all solutions during preparations and bottle filling.
  • the base solution was prepared as follows:
  • Liquid formulations containing the water-soluble antioxidant, sodium picosulfate, magnesium citrate and malic acid were then prepared using the base solution as follows:
  • each anti-oxidant preparation was filled into PET bottles as below using a fill weight of 177 g.
  • Formulations containing sodium picosulfate, magnesium citrate and malic acid and various water-insoluble antioxidants were prepared having the compositions shown in Table 18.
  • Liquid formulations containing a water-insoluble antioxidants, sodium picosulfate, magnesium citrate and malic acid were prepared as follows.
  • a common base solution was prepared with 25% less purified water than theoretical weight and without sodium picosulfate and anti-oxidant. To accommodate different levels of anti-oxidants, and solubilizers the base solutions were prepared using 25% less purified water.
  • the final unit dose weight of all formulations was fixed to 177 g, by adjusting the quantity of water during preparation. Nitrogen was used to purge all solutions during preparations and bottle filling.
  • the base solution was prepared as follows:
  • Liquid formulations containing the water-insoluble antioxidant, sodium picosulfate, magnesium citrate and malic acid were then prepared using the base solution as follows:
  • each anti-oxidant preparation was filled into PET bottles as below using a fill weight of 177 g.

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CN116585261A (zh) * 2023-05-17 2023-08-15 深圳市贝美药业有限公司 药物液体组合物及其制备方法和应用
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CN117338709A (zh) * 2023-11-07 2024-01-05 浙江和沐康医药科技有限公司 一种复方匹可硫酸钠口服溶液及其制备方法

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