WO2023181077A1 - Stable liquid composition comprising obeticholic acid or salts thereof - Google Patents

Stable liquid composition comprising obeticholic acid or salts thereof Download PDF

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Publication number
WO2023181077A1
WO2023181077A1 PCT/IN2023/050284 IN2023050284W WO2023181077A1 WO 2023181077 A1 WO2023181077 A1 WO 2023181077A1 IN 2023050284 W IN2023050284 W IN 2023050284W WO 2023181077 A1 WO2023181077 A1 WO 2023181077A1
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Prior art keywords
acid
sodium
agent
oil
group
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PCT/IN2023/050284
Other languages
French (fr)
Inventor
Venkata Sivakumar Bobba
Girish Kumar Jain
Shankar POL
Sunil POPHALE
Dhiraj NIKAM
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Zenvision Pharma Llp
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Publication of WO2023181077A1 publication Critical patent/WO2023181077A1/en

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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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions

Definitions

  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising obeticholic acid or its salts, its process of preparation and method of use of said pharmaceutical composition.
  • the present invention relates to a stable liquid composition for oral administration comprising obeticholic acid or its salts, its process of preparation and its indication for the treatment of adult patients with primary biliary cholangitis (PBC).
  • PBC primary biliary cholangitis
  • PBC Primary biliary cirrhosis
  • ALP alkaline phosphatase
  • Obeticholic acid is a semi- synthetic bile acid analogue which is a farnesoid X receptor (FXR) agonist.
  • FXR farnesoid X receptor
  • obeticholic acid is 3a, 7a-dihydroxy-6a-ethyl-5P-cholan-24-oic acid. It is a white to off-white powder. It is soluble in methanol, acetone and ethyl acetate. Its solubility in water is pH dependent. It is slightly soluble at low pH and very soluble at high pH.
  • Obeticholic acid Tablet, Oral was first approved by U.S. FDA on May 27, 2016 under the brand name OCALIVA for Intercept Pharmaceuticals Inc. it is available in 5mg and lOmg strength. The product is indicated for the treatment of adult patients with primary biliary cholangitis (PBC)
  • PBC primary biliary cholangitis
  • U.S. Patent No. RE48,286 discloses compound Obeticholic acid generically, further U.S. Patent No. 7,138,390, U.S. Patent No. 8,058,267, U.S. Patent No. 8,377,916 also discloses compound generically and method of treating cholestatic liver disease by using compound generically.
  • U.S. Patent No. 9,238,673 discloses composition comprising obeticholic acid Form 1 and a pharmaceutically acceptable carrier.
  • U.S. Patent No. 10,047,117 discloses a method of treating an FXR mediated disease or condition in a subject comprising administering to the subject a pharmaceutical formulation comprising an effective amount of a substantially pure solid form of obeticholic acid, wherein the solid form of obeticholic acid comprises less than 1% of chenodeoxy cholic acid, and wherein the formulation comprises about 1 mg to about 30 mg of obeticholic acid.
  • U.S. Patent No. 10,174,073 discloses a pharmaceutical composition comprising crystalline or non-crystalline obeticholic acid (OCA).
  • U.S. Patent No. 10,052,337, U.S. Patent No. 10,751,349 and U.S. Patent No. 10,758,549 discloses a pharmaceutical composition and a method of treating primary biliary cholangitis (PBC) by using said composition respectively.
  • PBC primary biliary cholangitis
  • Obeticholic acid is a BCS Class II compound which has low solubility and soluble in the organic solvents like ethanol, methanol, acetone and ethyl acetate.
  • compositions of Obeticholic acid which are tedious, expensive or technologically demanding to prepare or are unlikely to remain stable over the shelf life of the product. Still, there is a need to prepare alternate compositions of Obeticholic acid that are stable, cost effective, easy to administer and provides the desired bioavailability.
  • Obeticholic acid is presently marketed only in solid dosage forms, i.e., Tablet.
  • solid dosage forms are not suitable for some patients who have difficulty in swallowing solid dosage forms, e.g., pediatric patients or older patients or incapacitated patients.
  • a drug administered in liquid dosage form is immediately available for absorption from gastrointestinal tract and can be absorbed faster than the same amount of the drug administered in a tablet dosage form.
  • solid dosage forms may not be convenient, when chronic therapy is needed. Therefore, there exists a clear need in the art for stable oral liquid compositions of Obeticholic acid.
  • the present stable liquid composition for oral administration comprising Obeticholic acid or salt thereof can be manufactured without using costly and tedious formulation manufacturing instruments.
  • the present stable liquid composition for oral administration comprising Obeticholic acid or salt thereof exhibit properties such as but not limited to storage stability, ready to use composition, easy administration, minimum side effects, high therapeutic efficiency, better patient compliance, functionally reproducible and significant advancement over the available solid dosage forms of Obeticholic acid.
  • the stable oral liquid compositions described herein are also provided with a pleasant mouth feel thereby further enhancing patient compliance and ease of administration.
  • Another object of the present invention to provide a stable liquid pharmaceutical composition, comprising: a) Obeticholic acid or its salts; b) Buffering agent; c) Preservative or Antimicrobial preservative; d) Flavor enhancer; e) Co-solvent; f) Sweetening agent; g) Flavouring agent; and h) Solvent.
  • step (c) Stirring solution of step (b) after addition of every excipient and API until it’s become clear;
  • step (e) Filling the solution of step (d) into suitable bottle or container.
  • step (b) Adding buffering agent in solution of step (a) under continuous stirring, till solution becomes clear;
  • step (c) Adding sweetening agent in solution of step (b) under continuous stirring, till solution becomes clear;
  • step (d) Adding co-solvent in solution of step (c) under continuous stirring, till solution becomes clear;
  • step (e) Adding sweetening agent in solution of step (d) under continuous stirring, till solution becomes clear;
  • step (f) Adding active pharmaceutically ingredient (API) in solution of step (e) under continuous stirring, till solution becomes clear;
  • step (g) Adding flavoring agent in solution of step (f) under continuous stirring, till solution becomes clear;
  • step (h) Adding flavor enhancer in solution of step (g) under continuous stirring, till solution becomes clear;
  • step (j) Filling the solution of step (i) into suitable bottle or container.
  • the further object of the present invention to provide a method of using a stable liquid pharmaceutical composition comprising Obeticholic acid or its salts and one or more pharmaceutically acceptable excipients for the treatment of adult patients with primary biliary cholangitis (PBC).
  • PBC primary biliary cholangitis
  • the present invention discloses a liquid pharmaceutical composition, comprising: a) Obeticholic acid or its salts; and b) One or more pharmaceutically acceptable excipients.
  • the present invention discloses a stable liquid pharmaceutical composition for oral administration, comprising: a) Obeticholic acid or its salts and b) One or more pharmaceutically acceptable excipients.
  • the present invention provides a stable liquid pharmaceutical composition, comprising: a) Obeticholic acid or its salts; b) Buffering agent; c) Preservative or Antimicrobial preservative; d) Flavor enhancer; e) Co-solvent; f) Sweetening agent; g) Flavoring agent; and h) Solvent.
  • the present invention provides a stable liquid pharmaceutical composition, comprising: a) 0.01-100 mg/ml of the Obeticholic acid or its salts; b) 0.01-150 mg/ml of the buffering agent; c) 0.001-50 mg/ml of the preservative or antimicrobial preservative; d) 0.01- 600 mg/ml of the flavor enhancer; e) 1-1200 mg/ml of the co-solvent; f) 0.1-6000 mg/ml of the sweetening agent; g) 0.001-10 mg/ml of the flavoring agent; and h) q.s.to the solvent.
  • the present invention relates to a stable liquid pharmaceutical composition, comprising: a) 0.01-100 mg/ml of the Obeticholic acid or its salts; b) 0.01-150 mg/ml of the sodium citrate; c) 0.001-50 mg/ml of the benzoic acid; d) 0.01- 600 mg/ml of the citric acid anhydrous; e) 1-1200 mg/ml of the glycerin; f) 0.1-6000 mg/ml of the sucrose; g) 0.01- 450 mg/ml of the saccharin sodium dihydrate h) 0.001-10 mg/ml of the flavoring agent; and i) q.s.to the Solvent.
  • the present invention provides a process for the preparation of a stable liquid pharmaceutical composition, comprises steps of:
  • step (c) Stirring solution of step (b) after addition of every excipient and API until it’s become clear;
  • step (e) Filling the solution of step (d) into suitable bottle or container.
  • the present invention provides a process for the preparation of a stable liquid pharmaceutical composition, comprises steps of:
  • step (b) Adding buffering agent in solution of step (a) under continuous stirring, till solution becomes clear;
  • step (c) Adding sweetening agent in solution of step (b) under continuous stirring, till solution becomes clear;
  • step (d) Adding co-solvent in solution of step (c) under continuous stirring, till solution becomes clear;
  • (e) Adding sweetening agent in solution of step (d) under continuous stirring, till solution becomes clear;
  • step (f) Adding active pharmaceutically ingredient (API) i.e., Obeticholic acid or its salts in solution of step (e) under continuous stirring, till solution becomes clear;
  • API active pharmaceutically ingredient
  • step (g) Adding flavoring agent in solution of step (f) under continuous stirring, till solution becomes clear;
  • step (h) Adding flavor enhancer in solution of step (g) under continuous stirring, till solution becomes clear;
  • step (j) Filling the solution of step (i) into suitable bottle or container.
  • the present invention provides a method of using a stable liquid pharmaceutical composition comprising Obeticholic acid or its salts and one or more pharmaceutically acceptable excipients for the treatment of adult patients with primary biliary cholangitis (PBC).
  • PBC primary biliary cholangitis
  • compositions or “pharmaceutical composition” or “liquid composition” or “liquid pharmaceutical composition” or “stable liquid pharmaceutical composition” or “stable liquid composition for oral administration” as used herein synonymously include dosage forms such as a solution, a suspension, a syrup, a concentrate, an elixir or an emulsion or the like.
  • the composition of the invention is a stable liquid pharmaceutical composition for oral administration.
  • composition as in pharmaceutical composition, is intended to encompass a drug product comprising Obeticholic acid or salt thereof and other inert ingredient(s) (pharmaceutically acceptable excipients).
  • the present invention relates to a stable liquid pharmaceutical composition
  • a stable liquid pharmaceutical composition comprising Obeticholic acid or its salts and one or more pharmaceutically acceptable excipient.
  • stable refers to any composition comprising a drug having sufficient physical and chemical stability at the time of manufacturing of the composition and during shelf life.
  • liquid composition includes ready-to-use liquid composition or reconstituted liquid composition.
  • the ready-to-use liquid composition comprises a solution, a suspension, a syrup, a concentrate, an elixir or an emulsion or the like.
  • the reconstituted liquid compositions comprise solution and/or suspension reconstituted from dry powder comprising pellets, granules, beads or the like.
  • Oleticholic acid is used in broad sense to include not only “Obeticholic acid” per se but also its pharmaceutically acceptable salts, solvates, hydrates, enantiomers, derivatives, isomers, polymorphs, stereoisomers, diastereoisomers, metabolites, prodrugs thereof, also its various crystalline and amorphous forms or mixtures thereof.
  • the Obeticholic acid is present in an amount from about 0.01 mg/ml to about 100 mg/ml, preferably in a range from about 0.1 mg/ml to about 75 mg/ml, more preferably in a range from about 0.1 mg/ml to about 50 mg/ml by total volume of composition.
  • “Pharmaceutically acceptable salts” or “salt thereof’ or “its salt” as used herein includes those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, which are well known in the art.
  • Pharmaceutically acceptable salts include, but are not limited to, any of the salts or cocrystals of Obeticholic acid selected from acid salts, base salts, amino acid salts, such as but not limited to sodium, potassium, citrate, hydrochloride, hydrobromide, sulphate, phosphate, maleate, formate, acetate, nitrate, mesylate, succinate, benzoate, L-arginine salt, L-lysine salt, Tris (hydroxymethyl) aminomethane salt, or the like.
  • amino acid salts such as but not limited to sodium, potassium, citrate, hydrochloride, hydrobromide, sulphate, phosphate, maleate, formate, acetate, nitrate, mesylate, succinate, benzoate, L-arginine salt, L-lysine salt, Tris (hydroxymethyl) aminomethane salt, or the like.
  • treating refers to obtaining desired pharmacological and/or physiological effect.
  • the effect can be therapeutic, which includes achieving, partially or substantially, one or more of the following results: partially or totally reducing the extent of the disease, disorder or syndrome; ameliorating or improving a clinical symptom or indicator associated with the disorder or delaying, inhibiting or decreasing the likelihood of the progression of the disease, disorder or syndrome.
  • compositions are components that are added to the pharmaceutical composition other than the active ingredient.
  • “Pharmaceutically acceptable excipient(s)” are components that are added to the pharmaceutical composition other than the active ingredient Obeticholic acid or its salts. Excipients may be added to facilitate manufacture, enhance stability, enhance product characteristics, enhance patient acceptability etc.
  • Pharmaceutically acceptable excipient(s) includes, but not limited to, solvent(s), vehicle, co-solvents, buffer or buffering agent or pH adjusting agent, preservatives or antimicrobial preservative, flavor enhancer, sweeteners or sweetening agent, flavor or flavoring agent, surface- active agents or surfactant or solubilizer, antioxidant, coloring agent, antifoaming agent, taste-masking agents, suspending agent, emulsifying agent, stabilizers, diluents, resin, anticaking agent, chelating agent, acidifying agent, viscosity modifier, one or more lipid, pharmaceutical-grade dyes/pigments and any other excipient known to the art for making pharmaceutical composition.
  • solvents according to the present invention include but not limited to group comprising water, purified water, glycerin, acetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, butyl alcohol, ethylene glycol monoethyl ether, ethyl acetate, monoethyl acetate, cyclohexane, benzene, toluene, naphtha, 1,4-dioxane, tetrahydrofuran, hydrochloric acid (HC1), sodium chloride, calcium chloride, acetone and water, acetone and methanol, acetone and ethyl alcohol, methylene dichloride and methanol, and ethylene dichloride and methanol and combination thereof.
  • the solvent is purified water.
  • the solvent according to present invention may be present in an amount to make up volume to quantity sufficient.
  • co-solvent examples include but not limited to group comprising of glycerin or glycerol, maltitol, sorbitol and propylene glycol and combination thereof.
  • the co-solvent is glycerin.
  • the co-solvent is present in an amount of from about 1 mg/ml to about 1200 mg/ml of the composition, preferably from about 10 mg/ml to about 800 mg/ml; more preferably from about 10 mg/ml to about 600 mg/ml based on the total volume of the composition.
  • buffer or buffering agents or pH adjusting agents include but not limited to a group comprising citrate buffers, phosphate buffers, monosodium dibasic phosphate, gluconic acid, lactic acid, citric acid, trisodium citrate, acetic acid, maleic acid, tartaric acid, fumaric acid, sodium phosphate, sodium gluconate, sodium lactate, sodium citrate, sodium acetate, potassium citrate, sodium bicarbonate, potassium bicarbonate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, Potassium, sodium, ammonium salt of acetic acid and combinations thereof.
  • the buffering agent is sodium citrate.
  • the buffering agents or pH adjusting agents are present in an amount of from about 0.01 mg/ml to about 150 mg/ml of the composition, preferably from about 0.01 mg/ml to about 125 mg/ml; more preferably from about 0.01 mg/ml to about 100 mg/ml based on the total volume of the composition.
  • preservatives or antimicrobial preservative include but not limited to group comprising alcohol, benzyl alcohol, bronopol, methylparaben, propylparaben, butylparaben, boric acid and borate salts, sorbic acid, sodium sorbate, potassium sorbate, calcium sorbate, benzoic acid, sodium benzoate, potassium benzoate, calcium benzoate, phenol, methylhydroxybenzoate, ethyl parahydroxybenzoate, sodium ethyl para-hydroxybenzoate, sodium metabisulphite, chlorbutol, chlorocresol, chlorhexidine, diazolidinyl urea, sodium citrate, chlorbutanol, butylated hydroxyl toluene (BHT), butylated hydroxyl anisole (BHA), tocopherol, ethylenediamine tetraacetic acid, propyl gallate, quaternary compounds, e.g.
  • preservatives and antimicrobial preservative are similar reference in the context of describing the invention.
  • the preservatives or antimicrobial preservative is benzoic acid.
  • the preservatives or antimicrobial preservative are present in an amount of from about 0.001 mg/ml to about 50 mg/ml of the composition, preferably from about 0.001 mg/ml to about 45 mg/ml; more preferably from about 0.001 mg/ml to about 40 mg/ml based on the total volume of the composition.
  • sweeteners or sweetening agent or first sweetening agent or second sweetening agent include but not limited to a group comprising sucrose, glucose, dextrose, fructose, lactose, maltose, invert sugar, sorbitol, mannitol, xylitol, lactitol, erythritol, maltodextrin, maltitol, isomaltitol, isomalt, maltulose, isomaltulose, lactulose, threitol, arabitol, ribitol, galactitol, thaumatin, saccharin sodium, saccharin sodium dihydrate, aspartame, acesulfame, and sucralose, and combinations thereof.
  • the sweetening agent is sucrose and saccharin sodium dihydrate.
  • the sweeteners or sweetening agent are present in an amount of from about 0.1 mg/ml to about 6000 mg/ml of the composition, preferably from about 0.1 mg/ml to about 4000 mg/ml; more preferably from about 0.1 mg/ml to about 3000 mg/ml based on the total volume of the composition.
  • flavor enhancer include but not limited to a group comprising citric acid anhydrous, alanine, threonine, proline, serine, sucrose, fructose, dextrose, maltose, trehalose, glucose, stevia, glycerin, lactitol, maltitol, xylitol, sorbitol and mannitol, sucralose, saccharin, acesulfame potassium, aspartame, ethyl maltol, ethyl vanillin, fumaric acid, malic acid, maltol, menthol, monosodium glutamate, sodium chloride, stevia, tartaric acid, and vanillin, cherry, orange, peppermint, strawberry, apple, pineapple, anise fruit, peach, raspberry, orange cream and combinations thereof.
  • the flavor enhancer is citric acid anhydrous.
  • the flavor enhancer is present in an amount of from about 0.01 mg/ml to about 600 mg/ml, preferably about 0.1 mg/ml to 100 mg/ml; more preferably about 0.5 mg/ml to 50 mg/ml based on the total volume of the composition.
  • flavors or flavoring agent include but not limited to a group comprising banana, lemon, xylitol, lemon and xylitol, orange, grape, lime and grapefruit, vanilla, butterscotch, bubble gum, peppermint, fantasy fruit flavor, tutti-frutti, apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot, plant leaves, flowers, fruits, cinnamon oil, oil of wintergreen, peppermint oils, clove oil, citrus oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, oil of bitter almonds, and cassia oil; maltol, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid and combinations thereof.
  • flavouring or flavoring also known as flavor (or flavour) or flavorant.
  • the flavouring agent is lemon or
  • the flavoring agent are present in an amount of from about 0.001 mg/ml to about 10 mg/ml of the composition, preferably about 0.001 mg/ml to about 9 mg/ml; more preferably from about 0.01 mg/ml to 8 mg/ml based on the total volume of the composition.
  • stabilizers according to the present invention include but not limited to a group comprising of EDTA disodium salt, amino acids such as glutamic acid and combination thereof.
  • emulsifying agent examples include but not limited to a group comprising of gun acacia, tragacanth and combination thereof.
  • diluent(s) or filler include but not limited to a group comprising of Emdex/dextrates, citric acid, mannitol, sorbitol, sucrose, microcrystalline cellulose, carboxymethyl cellulose (carmellose), sodium carboxymethyl cellulose (carmellose sodium), corn starch, potato starch, anhydrous lactose, lactose monohydrate and combination thereof.
  • antioxidant examples include but not limited to a group comprising of butylated hydroxyl toluene, butylated hydroxyl anisole, DL-alpha-tocopherol, propyl gallate, octylgallate, ascorbyl palmitate, acetyl cysteine, L- cysteine hydrochloride, vitamin E acetate, ascorbic acid, Monothio glycerol, sodium ascorbate, fumaric acid, lecithin, sodium metabisulfite, sodium sulfite and combination thereof.
  • viscosity modifier include but not limited to a group comprising of methylcellulose, sodium carboxy methylcellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, sodium alginate, carbomer, povidone, acacia, guar gum, xanthan gum, Tragacanth, crosscaremellose sodium, microcrystalline cellulose, ethyl cellulose, magnesium aluminum silicate and combination thereof.
  • pH modifier/adjusting agent include but not limited to a group comprising of sodium hydroxide, potassium hydroxide, hydrochloric acid carbonic acid, phosphoric acid, succinic acid, tartaric acid, lactic acid, and their sodium, potassium, calcium, ammonium salts and combination thereof.
  • solubilizers according to the present invention include but not limited to a group comprising of polysorbate and combination thereof.
  • coloring agent according to the present invention include but not limited to a group comprising of titanium dioxide, carotene, ferric oxide, erythrosine, tetrazine and combination thereof.
  • acidic agents or acidifying agents include but not limited to a group comprising of citric acid maleic acid, tartaric acid, fumaric acid, adipic acid, succinic acid, lactic acid, glycolic acid, alpha-hydroxy acids, ascorbic acid and amino acids, anhydrides, salts and derivatives of these acids and combination thereof.
  • the present invention provides a liquid pharmaceutical composition, comprising: a) Obeticholic acid or its salts; and b) One or more pharmaceutically acceptable excipients.
  • the present invention provides a stable liquid pharmaceutical composition for oral administration, comprising: a) Obeticholic acid or its salts and b) One or more pharmaceutically acceptable excipients.
  • the present invention provides a stable liquid pharmaceutical composition, comprising: a) Obeticholic acid or its salts; b) Buffering agent; c) Preservative or Antimicrobial preservative; d) Flavor enhancer; e) Co-solvent; f) Sweetening agent; g) Flavoring agent; and h) Solvent.
  • the present invention provides a stable liquid pharmaceutical composition, comprising: a) 0.01-100 mg/ml of the Obeticholic acid or its salts; b) 0.01-150 mg/ml of the buffering agent; c) 0.001-50 mg/ml of the preservative or antimicrobial preservative; d) 0.01- 600 mg/ml of the flavor enhancer; e) 1-1200 mg/ml of the co-solvent; f) 0.1-6000 mg/ml of the sweetening agent; g) 0.001-10 mg/ml of the flavoring agent; and h) q.s.to the solvent.
  • the present invention provides a stable liquid pharmaceutical composition, comprising: a) 0.01-100 mg/ml of the Obeticholic acid or its salts; b) 0.01-150 mg/ml of the sodium citrate; c) 0.001-50 mg/ml of the benzoic acid; d) 0.01- 600 mg/ml of the citric acid anhydrous; e) 1-1200 mg/ml of the glycerin; f) 0.1-6000 mg/ml of the sucrose; g) 0.01- 450 mg/ml of the saccharin sodium dihydrate h) 0.001-10 mg/ml of the flavoring agent; and i) q.s.to the Solvent.
  • the present invention also relates to a process of preparation of a liquid pharmaceutical composition comprising Obeticholic acid or its salts and one or more pharmaceutically acceptable excipient.
  • the present invention also relates to a process of preparation of a stable liquid pharmaceutical composition, comprise steps of:
  • step (b) Adding and dissolving one or more pharmaceutically acceptable excipients and active pharmaceutically ingredient (API) sequentially under continuous stirring to a solvent of step (a);
  • step (c) Stirring solution of step (b) after addition of every excipient and API until it’s become clear;
  • step (d) Finally make up the volume with solvent; and (e) Filling the solution of step (d) into suitable bottle or container.
  • the present invention also relates to a process of preparation of a stable liquid pharmaceutical composition, comprise steps of:
  • step (b) Adding buffering agent in solution of step (a) under continuous stirring, till solution becomes clear;
  • step (c) Adding sweetening agent in solution of step (b) under continuous stirring, till solution becomes clear;
  • step (d) Adding co-solvent in solution of step (c) under continuous stirring, till solution becomes clear;
  • step (e) Adding sweetening agent in solution of step (d) under continuous stirring, till solution becomes clear;
  • step (f) Adding active pharmaceutically ingredient (API) i.e., Obeticholic acid or its salts in solution of step (e) under continuous stirring, till solution becomes clear;
  • API active pharmaceutically ingredient
  • step (g) Adding flavoring agent in solution of step (f) under continuous stirring, till solution becomes clear;
  • step (h) Adding flavor enhancer in solution of step (g) under continuous stirring, till solution becomes clear;
  • step (j) Filling the solution of step (i) into suitable bottle or container.
  • the present invention provides a method of using a liquid pharmaceutical composition comprising Obeticholic acid or its salts and one or more pharmaceutically acceptable excipients for the treatment of adult patients with primary biliary cholangitis (PBC)
  • PBC primary biliary cholangitis
  • the stable liquid pharmaceutical composition comprising Obeticholic acid or its salts according to present invention can be used in combination with other medicines for prophylaxis and treatment of adult patients with primary biliary cholangitis (PBC).
  • the stable liquid pharmaceutical composition comprising Obeticholic acid or its salts can be prepared into single dose or multi dose pharmaceutical composition having immediate release or modified release or controlled release or delayed release or any combination thereof.
  • the stable liquid pharmaceutical composition comprising Obeticholic acid or its salts can be packaged in a suitable pack/container such as amber-colored polyethylene terephthalate (PET) bottle, glass bottle, vials, high-density polyethylene (HDPE) bottle, low- density polyethylene (LDPE) bottle, polypropylene (PP) bottle, vial, packets, pouches, sachets and the like.
  • a suitable pack/container such as amber-colored polyethylene terephthalate (PET) bottle, glass bottle, vials, high-density polyethylene (HDPE) bottle, low- density polyethylene (LDPE) bottle, polypropylene (PP) bottle, vial, packets, pouches, sachets and the like.
  • dispensing and/or dosing syringe (Marked in mL)
  • a measuring cup for administering the composition can be included in the package with container.
  • the stable liquid pharmaceutical composition comprising Obeticholic acid or its salts of the present invention is expected to have suitable organoleptic properties in terms of taste, after taste, odor, flavor, and acceptability.
  • the stable liquid pharmaceutical composition comprising Obeticholic acid or its salts of the present invention is exhibit desirable technical attributes such as appearance, pH, assay, specific gravity/density, relative standard (RS), viscosity, physical stability, microbiological stability, preservative efficacy test (PET) and storage stability.
  • desirable technical attributes such as appearance, pH, assay, specific gravity/density, relative standard (RS), viscosity, physical stability, microbiological stability, preservative efficacy test (PET) and storage stability.
  • Example No 1 and 2 Manufacturing process for Example No 1 and 2: 1. In suitable Stainless-Steel container of purified water and under stirring add accurately weighed quantity of Benzoic acid, under continuous stirring, keep stirring till solution becomes clear;

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Abstract

The present invention relates to a stable liquid pharmaceutical composition comprising Obeticholic acid or its salts and one or more pharmaceutically acceptable excipients and its process of preparation and its use for the treatment of adult patients with primary biliary cholangitis (PBC).

Description

STABLE LIQUID COMPOSITION COMPRISING OBETICHOLIC ACID OR SALTS THEREOF
FIELD OF THE INVENTION
The present invention relates to a pharmaceutical composition comprising obeticholic acid or its salts, its process of preparation and method of use of said pharmaceutical composition.
More particularly, the present invention relates to a stable liquid composition for oral administration comprising obeticholic acid or its salts, its process of preparation and its indication for the treatment of adult patients with primary biliary cholangitis (PBC). BACKGROUND OF THE INVENTION
Primary biliary cirrhosis (PBC) is a rare, serious, life-threatening liver disease characterized by cholestasis with progressive impairment of bile flow in the liver that results in increased hepatocellular bile acid concentrations. Bile acids at elevated hepatocellular concentrations can be toxic to the liver. Such hepatocellular injury results in a local inflammatory response and is signalled early on by the secretion of alkaline phosphatase (ALP). In patients with an inadequate response to therapy, the disease frequently progresses to hepatic fibrosis and eventual cirrhosis, hepatic decompensation, and death unless a patient receives a liver transplant.
Obeticholic acid (OCA) is a semi- synthetic bile acid analogue which is a farnesoid X receptor (FXR) agonist. The structural formula is as follows:
Figure imgf000002_0001
(Formula I)
The empirical formula is C26H44O4. The molecular weight is 420.63 g/mol. Chemically, obeticholic acid is 3a, 7a-dihydroxy-6a-ethyl-5P-cholan-24-oic acid. It is a white to off-white powder. It is soluble in methanol, acetone and ethyl acetate. Its solubility in water is pH dependent. It is slightly soluble at low pH and very soluble at high pH.
Obeticholic acid Tablet, Oral was first approved by U.S. FDA on May 27, 2016 under the brand name OCALIVA for Intercept Pharmaceuticals Inc. it is available in 5mg and lOmg strength. The product is indicated for the treatment of adult patients with primary biliary cholangitis (PBC)
• without cirrhosis or
• with compensated cirrhosis who do not have evidence of portal hypertension, either in combination with ursodeoxycholic acid (UDCA) with an inadequate response to UDCA or as monotherapy in patients unable to tolerate UDCA.
U.S. Patent No. RE48,286 discloses compound Obeticholic acid generically, further U.S. Patent No. 7,138,390, U.S. Patent No. 8,058,267, U.S. Patent No. 8,377,916 also discloses compound generically and method of treating cholestatic liver disease by using compound generically.
U.S. Patent No. 9,238,673 discloses composition comprising obeticholic acid Form 1 and a pharmaceutically acceptable carrier.
U.S. Patent No. 10,047,117 discloses a method of treating an FXR mediated disease or condition in a subject comprising administering to the subject a pharmaceutical formulation comprising an effective amount of a substantially pure solid form of obeticholic acid, wherein the solid form of obeticholic acid comprises less than 1% of chenodeoxy cholic acid, and wherein the formulation comprises about 1 mg to about 30 mg of obeticholic acid.
U.S. Patent No. 10,174,073 discloses a pharmaceutical composition comprising crystalline or non-crystalline obeticholic acid (OCA).
U.S. Patent No. 10,052,337, U.S. Patent No. 10,751,349 and U.S. Patent No. 10,758,549 discloses a pharmaceutical composition and a method of treating primary biliary cholangitis (PBC) by using said composition respectively.
Obeticholic acid is a BCS Class II compound which has low solubility and soluble in the organic solvents like ethanol, methanol, acetone and ethyl acetate.
The prior-art documents only provided compositions of Obeticholic acid, which are tedious, expensive or technologically demanding to prepare or are unlikely to remain stable over the shelf life of the product. Still, there is a need to prepare alternate compositions of Obeticholic acid that are stable, cost effective, easy to administer and provides the desired bioavailability.
Hence due to the chemical nature of the drug, Obeticholic acid is presently marketed only in solid dosage forms, i.e., Tablet. However, solid dosage forms are not suitable for some patients who have difficulty in swallowing solid dosage forms, e.g., pediatric patients or older patients or incapacitated patients. Also, a drug administered in liquid dosage form is immediately available for absorption from gastrointestinal tract and can be absorbed faster than the same amount of the drug administered in a tablet dosage form. Further, solid dosage forms may not be convenient, when chronic therapy is needed. Therefore, there exists a clear need in the art for stable oral liquid compositions of Obeticholic acid.
To date, no liquid compositions of Obeticholic acid or salt thereof are known. In view of this, stable liquid compositions for oral administration of Obeticholic acid or salt thereof are desirable over presently available solid dosage forms, as they would offer better patient compliance, convenience and flexible dosing regimen.
However, a prime concern with any liquid formulation is the stability of the active ingredient, both short term and over the time. Inventors of the present application have for the first time developed oral liquid compositions of Obeticholic acid or salt thereof. The oral liquid compositions are stable both during manufacturing and shelf life.
The present stable liquid composition for oral administration comprising Obeticholic acid or salt thereof can be manufactured without using costly and tedious formulation manufacturing instruments.
The present stable liquid composition for oral administration comprising Obeticholic acid or salt thereof exhibit properties such as but not limited to storage stability, ready to use composition, easy administration, minimum side effects, high therapeutic efficiency, better patient compliance, functionally reproducible and significant advancement over the available solid dosage forms of Obeticholic acid.
The stable oral liquid compositions described herein are also provided with a pleasant mouth feel thereby further enhancing patient compliance and ease of administration.
OBJECTS OF THE INVENTION
It is an object of the present invention to provide a liquid pharmaceutical composition, comprising: a) Obeticholic acid or its salts; and b) One or more pharmaceutically acceptable excipients.
It is an object of the present invention to provide a stable liquid pharmaceutical composition for oral administration, comprising: a) Obeticholic acid or its salts; and b) One or more pharmaceutically acceptable excipients.
Another object of the present invention to provide a stable liquid pharmaceutical composition, comprising: a) Obeticholic acid or its salts; b) Buffering agent; c) Preservative or Antimicrobial preservative; d) Flavor enhancer; e) Co-solvent; f) Sweetening agent; g) Flavouring agent; and h) Solvent.
It is another object of the invention to provide a process for the preparation of a liquid pharmaceutical composition, comprises steps of:
(a) Taking solvent in stainless-steel container;
(b) Adding and dissolving one or more pharmaceutically acceptable excipients and active pharmaceutically ingredient (API) sequentially under continuous stirring to a solvent of step
(a);
(c) Stirring solution of step (b) after addition of every excipient and API until it’s become clear;
(d) Finally make up the volume with solvent; and
(e) Filling the solution of step (d) into suitable bottle or container.
It is another object of the present invention to provide a process for the preparation of a stable liquid pharmaceutical composition, comprises steps of:
(a) Adding a solvent in suitable stainless-steel container and adding accurately weighed quantity of a preservative, under continuous stirring till solution becomes clear;
(b) Adding buffering agent in solution of step (a) under continuous stirring, till solution becomes clear;
(c) Adding sweetening agent in solution of step (b) under continuous stirring, till solution becomes clear;
(d) Adding co-solvent in solution of step (c) under continuous stirring, till solution becomes clear;
(e) Adding sweetening agent in solution of step (d) under continuous stirring, till solution becomes clear;
(f) Adding active pharmaceutically ingredient (API) in solution of step (e) under continuous stirring, till solution becomes clear;
(g) Adding flavoring agent in solution of step (f) under continuous stirring, till solution becomes clear; (h) Adding flavor enhancer in solution of step (g) under continuous stirring, till solution becomes clear;
(i) Finally make up the volume with solvent; and
(j) Filling the solution of step (i) into suitable bottle or container.
The further object of the present invention to provide a method of using a stable liquid pharmaceutical composition comprising Obeticholic acid or its salts and one or more pharmaceutically acceptable excipients for the treatment of adult patients with primary biliary cholangitis (PBC).
SUMMARY OF THE INVENTION
In one aspect, the present invention discloses a liquid pharmaceutical composition, comprising: a) Obeticholic acid or its salts; and b) One or more pharmaceutically acceptable excipients.
In one aspect, the present invention discloses a stable liquid pharmaceutical composition for oral administration, comprising: a) Obeticholic acid or its salts and b) One or more pharmaceutically acceptable excipients.
In another aspect, the present invention provides a stable liquid pharmaceutical composition, comprising: a) Obeticholic acid or its salts; b) Buffering agent; c) Preservative or Antimicrobial preservative; d) Flavor enhancer; e) Co-solvent; f) Sweetening agent; g) Flavoring agent; and h) Solvent.
In another aspect, the present invention provides a stable liquid pharmaceutical composition, comprising: a) 0.01-100 mg/ml of the Obeticholic acid or its salts; b) 0.01-150 mg/ml of the buffering agent; c) 0.001-50 mg/ml of the preservative or antimicrobial preservative; d) 0.01- 600 mg/ml of the flavor enhancer; e) 1-1200 mg/ml of the co-solvent; f) 0.1-6000 mg/ml of the sweetening agent; g) 0.001-10 mg/ml of the flavoring agent; and h) q.s.to the solvent.
In another aspect, the present invention relates to a stable liquid pharmaceutical composition, comprising: a) 0.01-100 mg/ml of the Obeticholic acid or its salts; b) 0.01-150 mg/ml of the sodium citrate; c) 0.001-50 mg/ml of the benzoic acid; d) 0.01- 600 mg/ml of the citric acid anhydrous; e) 1-1200 mg/ml of the glycerin; f) 0.1-6000 mg/ml of the sucrose; g) 0.01- 450 mg/ml of the saccharin sodium dihydrate h) 0.001-10 mg/ml of the flavoring agent; and i) q.s.to the Solvent.
In another aspect, the present invention provides a process for the preparation of a stable liquid pharmaceutical composition, comprises steps of:
(a) Taking solvent in stainless- steel container;
(b) Adding and dissolving one or more pharmaceutically acceptable excipients and active pharmaceutically ingredient (API) sequentially under continuous stirring to a solvent of step
(a);
(c) Stirring solution of step (b) after addition of every excipient and API until it’s become clear;
(d) Finally make up the volume with solvent; and
(e) Filling the solution of step (d) into suitable bottle or container.
In another aspect, the present invention provides a process for the preparation of a stable liquid pharmaceutical composition, comprises steps of:
(a) Adding a solvent in suitable stainless-steel container and adding accurately weighed quantity of a preservative, under continuous stirring till solution becomes clear;
(b) Adding buffering agent in solution of step (a) under continuous stirring, till solution becomes clear;
(c) Adding sweetening agent in solution of step (b) under continuous stirring, till solution becomes clear;
(d) Adding co-solvent in solution of step (c) under continuous stirring, till solution becomes clear; (e) Adding sweetening agent in solution of step (d) under continuous stirring, till solution becomes clear;
(f) Adding active pharmaceutically ingredient (API) i.e., Obeticholic acid or its salts in solution of step (e) under continuous stirring, till solution becomes clear;
(g) Adding flavoring agent in solution of step (f) under continuous stirring, till solution becomes clear;
(h) Adding flavor enhancer in solution of step (g) under continuous stirring, till solution becomes clear;
(i) Finally make up the volume with solvent; and
(j) Filling the solution of step (i) into suitable bottle or container.
In another aspect, the present invention provides a method of using a stable liquid pharmaceutical composition comprising Obeticholic acid or its salts and one or more pharmaceutically acceptable excipients for the treatment of adult patients with primary biliary cholangitis (PBC).
DETAILED DESCRIPTION OF THE INVENTION
The term "composition" or "pharmaceutical composition" or “liquid composition” or "liquid pharmaceutical composition" or “stable liquid pharmaceutical composition” or "stable liquid composition for oral administration" as used herein synonymously include dosage forms such as a solution, a suspension, a syrup, a concentrate, an elixir or an emulsion or the like.
Preferably, the composition of the invention is a stable liquid pharmaceutical composition for oral administration.
The term “composition”, as in pharmaceutical composition, is intended to encompass a drug product comprising Obeticholic acid or salt thereof and other inert ingredient(s) (pharmaceutically acceptable excipients).
The present invention relates to a stable liquid pharmaceutical composition comprising Obeticholic acid or its salts and one or more pharmaceutically acceptable excipient.
The term “stable” as used herein, refers to any composition comprising a drug having sufficient physical and chemical stability at the time of manufacturing of the composition and during shelf life.
The term “liquid composition,” includes ready-to-use liquid composition or reconstituted liquid composition. The ready-to-use liquid composition comprises a solution, a suspension, a syrup, a concentrate, an elixir or an emulsion or the like. The reconstituted liquid compositions comprise solution and/or suspension reconstituted from dry powder comprising pellets, granules, beads or the like.
The term “Obeticholic acid” is used in broad sense to include not only “Obeticholic acid” per se but also its pharmaceutically acceptable salts, solvates, hydrates, enantiomers, derivatives, isomers, polymorphs, stereoisomers, diastereoisomers, metabolites, prodrugs thereof, also its various crystalline and amorphous forms or mixtures thereof.
The Obeticholic acid is present in an amount from about 0.01 mg/ml to about 100 mg/ml, preferably in a range from about 0.1 mg/ml to about 75 mg/ml, more preferably in a range from about 0.1 mg/ml to about 50 mg/ml by total volume of composition.
The term “Pharmaceutically acceptable salts” or “salt thereof’ or “its salt” as used herein, includes those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, which are well known in the art.
Pharmaceutically acceptable salts include, but are not limited to, any of the salts or cocrystals of Obeticholic acid selected from acid salts, base salts, amino acid salts, such as but not limited to sodium, potassium, citrate, hydrochloride, hydrobromide, sulphate, phosphate, maleate, formate, acetate, nitrate, mesylate, succinate, benzoate, L-arginine salt, L-lysine salt, Tris (hydroxymethyl) aminomethane salt, or the like.
The term "treating" or "treatment" refers to obtaining desired pharmacological and/or physiological effect. The effect can be therapeutic, which includes achieving, partially or substantially, one or more of the following results: partially or totally reducing the extent of the disease, disorder or syndrome; ameliorating or improving a clinical symptom or indicator associated with the disorder or delaying, inhibiting or decreasing the likelihood of the progression of the disease, disorder or syndrome.
The term "Pharmaceutically acceptable excipient(s)" or suitable pharmaceutically acceptable excipients are components that are added to the pharmaceutical composition other than the active ingredient.
"Pharmaceutically acceptable excipient(s)" are components that are added to the pharmaceutical composition other than the active ingredient Obeticholic acid or its salts. Excipients may be added to facilitate manufacture, enhance stability, enhance product characteristics, enhance patient acceptability etc. Pharmaceutically acceptable excipient(s) includes, but not limited to, solvent(s), vehicle, co-solvents, buffer or buffering agent or pH adjusting agent, preservatives or antimicrobial preservative, flavor enhancer, sweeteners or sweetening agent, flavor or flavoring agent, surface- active agents or surfactant or solubilizer, antioxidant, coloring agent, antifoaming agent, taste-masking agents, suspending agent, emulsifying agent, stabilizers, diluents, resin, anticaking agent, chelating agent, acidifying agent, viscosity modifier, one or more lipid, pharmaceutical-grade dyes/pigments and any other excipient known to the art for making pharmaceutical composition.
The examples of solvents according to the present invention include but not limited to group comprising water, purified water, glycerin, acetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, butyl alcohol, ethylene glycol monoethyl ether, ethyl acetate, monoethyl acetate, cyclohexane, benzene, toluene, naphtha, 1,4-dioxane, tetrahydrofuran, hydrochloric acid (HC1), sodium chloride, calcium chloride, acetone and water, acetone and methanol, acetone and ethyl alcohol, methylene dichloride and methanol, and ethylene dichloride and methanol and combination thereof. Preferably, the solvent is purified water. The solvent according to present invention may be present in an amount to make up volume to quantity sufficient.
The examples of co-solvent according to the present invention include but not limited to group comprising of glycerin or glycerol, maltitol, sorbitol and propylene glycol and combination thereof. Preferably, the co-solvent is glycerin. The co-solvent is present in an amount of from about 1 mg/ml to about 1200 mg/ml of the composition, preferably from about 10 mg/ml to about 800 mg/ml; more preferably from about 10 mg/ml to about 600 mg/ml based on the total volume of the composition.
The examples of buffer or buffering agents or pH adjusting agents according to the present invention include but not limited to a group comprising citrate buffers, phosphate buffers, monosodium dibasic phosphate, gluconic acid, lactic acid, citric acid, trisodium citrate, acetic acid, maleic acid, tartaric acid, fumaric acid, sodium phosphate, sodium gluconate, sodium lactate, sodium citrate, sodium acetate, potassium citrate, sodium bicarbonate, potassium bicarbonate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, Potassium, sodium, ammonium salt of acetic acid and combinations thereof. Preferably, the buffering agent is sodium citrate.
The buffering agents or pH adjusting agents are present in an amount of from about 0.01 mg/ml to about 150 mg/ml of the composition, preferably from about 0.01 mg/ml to about 125 mg/ml; more preferably from about 0.01 mg/ml to about 100 mg/ml based on the total volume of the composition.
The examples of preservatives or antimicrobial preservative according to the present invention include but not limited to group comprising alcohol, benzyl alcohol, bronopol, methylparaben, propylparaben, butylparaben, boric acid and borate salts, sorbic acid, sodium sorbate, potassium sorbate, calcium sorbate, benzoic acid, sodium benzoate, potassium benzoate, calcium benzoate, phenol, methylhydroxybenzoate, ethyl parahydroxybenzoate, sodium ethyl para-hydroxybenzoate, sodium metabisulphite, chlorbutol, chlorocresol, chlorhexidine, diazolidinyl urea, sodium citrate, chlorbutanol, butylated hydroxyl toluene (BHT), butylated hydroxyl anisole (BHA), tocopherol, ethylenediamine tetraacetic acid, propyl gallate, quaternary compounds, e.g. benzalkonium chloride and cetylpyridinium chloride, phenyl ethyl alcohol and combinations thereof. The use of the term’s “preservatives” and “antimicrobial preservative” are similar reference in the context of describing the invention. Preferably, the preservatives or antimicrobial preservative is benzoic acid.
The preservatives or antimicrobial preservative are present in an amount of from about 0.001 mg/ml to about 50 mg/ml of the composition, preferably from about 0.001 mg/ml to about 45 mg/ml; more preferably from about 0.001 mg/ml to about 40 mg/ml based on the total volume of the composition.
The examples of sweeteners or sweetening agent or first sweetening agent or second sweetening agent according to the present invention include but not limited to a group comprising sucrose, glucose, dextrose, fructose, lactose, maltose, invert sugar, sorbitol, mannitol, xylitol, lactitol, erythritol, maltodextrin, maltitol, isomaltitol, isomalt, maltulose, isomaltulose, lactulose, threitol, arabitol, ribitol, galactitol, thaumatin, saccharin sodium, saccharin sodium dihydrate, aspartame, acesulfame, and sucralose, and combinations thereof. Preferably, the sweetening agent is sucrose and saccharin sodium dihydrate.
The sweeteners or sweetening agent are present in an amount of from about 0.1 mg/ml to about 6000 mg/ml of the composition, preferably from about 0.1 mg/ml to about 4000 mg/ml; more preferably from about 0.1 mg/ml to about 3000 mg/ml based on the total volume of the composition.
The examples of flavor enhancer according to the present invention include but not limited to a group comprising citric acid anhydrous, alanine, threonine, proline, serine, sucrose, fructose, dextrose, maltose, trehalose, glucose, stevia, glycerin, lactitol, maltitol, xylitol, sorbitol and mannitol, sucralose, saccharin, acesulfame potassium, aspartame, ethyl maltol, ethyl vanillin, fumaric acid, malic acid, maltol, menthol, monosodium glutamate, sodium chloride, stevia, tartaric acid, and vanillin, cherry, orange, peppermint, strawberry, apple, pineapple, anise fruit, peach, raspberry, orange cream and combinations thereof. Preferably, the flavor enhancer is citric acid anhydrous. The flavor enhancer is present in an amount of from about 0.01 mg/ml to about 600 mg/ml, preferably about 0.1 mg/ml to 100 mg/ml; more preferably about 0.5 mg/ml to 50 mg/ml based on the total volume of the composition.
The examples of flavors or flavoring agent according to the present invention include but not limited to a group comprising banana, lemon, xylitol, lemon and xylitol, orange, grape, lime and grapefruit, vanilla, butterscotch, bubble gum, peppermint, fantasy fruit flavor, tutti-frutti, apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot, plant leaves, flowers, fruits, cinnamon oil, oil of wintergreen, peppermint oils, clove oil, citrus oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, oil of bitter almonds, and cassia oil; maltol, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid and combinations thereof. The term flavouring or flavoring also known as flavor (or flavour) or flavorant. Prefarably, the flavouring agent is lemon or xylitol or lemon and xylitol.
The flavoring agent are present in an amount of from about 0.001 mg/ml to about 10 mg/ml of the composition, preferably about 0.001 mg/ml to about 9 mg/ml; more preferably from about 0.01 mg/ml to 8 mg/ml based on the total volume of the composition.
The examples of stabilizers according to the present invention include but not limited to a group comprising of EDTA disodium salt, amino acids such as glutamic acid and combination thereof.
The examples of emulsifying agent according to the present invention include but not limited to a group comprising of gun acacia, tragacanth and combination thereof.
The examples of diluent(s) or filler according to the present invention include but not limited to a group comprising of Emdex/dextrates, citric acid, mannitol, sorbitol, sucrose, microcrystalline cellulose, carboxymethyl cellulose (carmellose), sodium carboxymethyl cellulose (carmellose sodium), corn starch, potato starch, anhydrous lactose, lactose monohydrate and combination thereof.
The examples of antioxidant according to the present invention include but not limited to a group comprising of butylated hydroxyl toluene, butylated hydroxyl anisole, DL-alpha-tocopherol, propyl gallate, octylgallate, ascorbyl palmitate, acetyl cysteine, L- cysteine hydrochloride, vitamin E acetate, ascorbic acid, Monothio glycerol, sodium ascorbate, fumaric acid, lecithin, sodium metabisulfite, sodium sulfite and combination thereof.
The example of viscosity modifier according to the present invention include but not limited to a group comprising of methylcellulose, sodium carboxy methylcellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, sodium alginate, carbomer, povidone, acacia, guar gum, xanthan gum, Tragacanth, crosscaremellose sodium, microcrystalline cellulose, ethyl cellulose, magnesium aluminum silicate and combination thereof.
The example of pH modifier/adjusting agent according to the present invention include but not limited to a group comprising of sodium hydroxide, potassium hydroxide, hydrochloric acid carbonic acid, phosphoric acid, succinic acid, tartaric acid, lactic acid, and their sodium, potassium, calcium, ammonium salts and combination thereof.
The examples of solubilizers according to the present invention include but not limited to a group comprising of polysorbate and combination thereof.
The examples of coloring agent according to the present invention include but not limited to a group comprising of titanium dioxide, carotene, ferric oxide, erythrosine, tetrazine and combination thereof.
The examples of acidic agents or acidifying agents according to the present invention include but not limited to a group comprising of citric acid maleic acid, tartaric acid, fumaric acid, adipic acid, succinic acid, lactic acid, glycolic acid, alpha-hydroxy acids, ascorbic acid and amino acids, anhydrides, salts and derivatives of these acids and combination thereof.
In one embodiment, the present invention provides a liquid pharmaceutical composition, comprising: a) Obeticholic acid or its salts; and b) One or more pharmaceutically acceptable excipients.
In one embodiment, the present invention provides a stable liquid pharmaceutical composition for oral administration, comprising: a) Obeticholic acid or its salts and b) One or more pharmaceutically acceptable excipients.
In one embodiment, the present invention provides a stable liquid pharmaceutical composition, comprising: a) Obeticholic acid or its salts; b) Buffering agent; c) Preservative or Antimicrobial preservative; d) Flavor enhancer; e) Co-solvent; f) Sweetening agent; g) Flavoring agent; and h) Solvent.
In one embodiment, the present invention provides a stable liquid pharmaceutical composition, comprising: a) 0.01-100 mg/ml of the Obeticholic acid or its salts; b) 0.01-150 mg/ml of the buffering agent; c) 0.001-50 mg/ml of the preservative or antimicrobial preservative; d) 0.01- 600 mg/ml of the flavor enhancer; e) 1-1200 mg/ml of the co-solvent; f) 0.1-6000 mg/ml of the sweetening agent; g) 0.001-10 mg/ml of the flavoring agent; and h) q.s.to the solvent.
In one embodiment, the present invention provides a stable liquid pharmaceutical composition, comprising: a) 0.01-100 mg/ml of the Obeticholic acid or its salts; b) 0.01-150 mg/ml of the sodium citrate; c) 0.001-50 mg/ml of the benzoic acid; d) 0.01- 600 mg/ml of the citric acid anhydrous; e) 1-1200 mg/ml of the glycerin; f) 0.1-6000 mg/ml of the sucrose; g) 0.01- 450 mg/ml of the saccharin sodium dihydrate h) 0.001-10 mg/ml of the flavoring agent; and i) q.s.to the Solvent.
In one embodiment, the present invention also relates to a process of preparation of a liquid pharmaceutical composition comprising Obeticholic acid or its salts and one or more pharmaceutically acceptable excipient.
In one embodiment, the present invention also relates to a process of preparation of a stable liquid pharmaceutical composition, comprise steps of:
(a) Taking solvent in stainless-steel container;
(b) Adding and dissolving one or more pharmaceutically acceptable excipients and active pharmaceutically ingredient (API) sequentially under continuous stirring to a solvent of step (a);
(c) Stirring solution of step (b) after addition of every excipient and API until it’s become clear;
(d) Finally make up the volume with solvent; and (e) Filling the solution of step (d) into suitable bottle or container.
In one embodiment, the present invention also relates to a process of preparation of a stable liquid pharmaceutical composition, comprise steps of:
(a) Adding a solvent in suitable stainless-steel container and adding accurately weighed quantity of a preservative, under continuous stirring till solution becomes clear;
(b) Adding buffering agent in solution of step (a) under continuous stirring, till solution becomes clear;
(c) Adding sweetening agent in solution of step (b) under continuous stirring, till solution becomes clear;
(d) Adding co-solvent in solution of step (c) under continuous stirring, till solution becomes clear;
(e) Adding sweetening agent in solution of step (d) under continuous stirring, till solution becomes clear;
(f) Adding active pharmaceutically ingredient (API) i.e., Obeticholic acid or its salts in solution of step (e) under continuous stirring, till solution becomes clear;
(g) Adding flavoring agent in solution of step (f) under continuous stirring, till solution becomes clear;
(h) Adding flavor enhancer in solution of step (g) under continuous stirring, till solution becomes clear;
(i) Finally make up the volume with solvent; and
(j) Filling the solution of step (i) into suitable bottle or container.
In another embodiment, the present invention provides a method of using a liquid pharmaceutical composition comprising Obeticholic acid or its salts and one or more pharmaceutically acceptable excipients for the treatment of adult patients with primary biliary cholangitis (PBC)
• without cirrhosis or
• with compensated cirrhosis who do not have evidence of portal hypertension, either in combination with ursodeoxycholic acid (UDCA) with an inadequate response to UDCA or as monotherapy in patients unable to tolerate UDCA.
The stable liquid pharmaceutical composition comprising Obeticholic acid or its salts according to present invention can be used in combination with other medicines for prophylaxis and treatment of adult patients with primary biliary cholangitis (PBC). The stable liquid pharmaceutical composition comprising Obeticholic acid or its salts can be prepared into single dose or multi dose pharmaceutical composition having immediate release or modified release or controlled release or delayed release or any combination thereof.
The stable liquid pharmaceutical composition comprising Obeticholic acid or its salts can be packaged in a suitable pack/container such as amber-colored polyethylene terephthalate (PET) bottle, glass bottle, vials, high-density polyethylene (HDPE) bottle, low- density polyethylene (LDPE) bottle, polypropylene (PP) bottle, vial, packets, pouches, sachets and the like.
Further, dispensing and/or dosing syringe (Marked in mL), a measuring cup for administering the composition can be included in the package with container.
The stable liquid pharmaceutical composition comprising Obeticholic acid or its salts of the present invention is expected to have suitable organoleptic properties in terms of taste, after taste, odor, flavor, and acceptability.
The stable liquid pharmaceutical composition comprising Obeticholic acid or its salts of the present invention is exhibit desirable technical attributes such as appearance, pH, assay, specific gravity/density, relative standard (RS), viscosity, physical stability, microbiological stability, preservative efficacy test (PET) and storage stability.
EXAMPLES
The following examples serve to illustrate the embodiments of the present invention. However, they do not intend to limit the scope of the present invention.
Example 1: Obeticholic acid oral solution (5mg/5ml)
Figure imgf000016_0001
q.s.: Quantity sufficient
Example 2: Obeticholic acid oral solution (10mg/5mL)
Figure imgf000017_0001
q.s.: Quantity sufficient
Manufacturing process for Example No 1 and 2: 1. In suitable Stainless-Steel container of purified water and under stirring add accurately weighed quantity of Benzoic acid, under continuous stirring, keep stirring till solution becomes clear;
2. Add Sodium Citrate under continuous stirring, keep stirring till solution becomes clear;
3. Add Sodium saccharin dihydrate under continuous stirring, keep stirring till solution becomes clear;
4. Add Glycerin under continuous stirring, keep stirring till solution becomes clear;
5. Add sucrose under continuous stirring, keep stirring till solution becomes clear;
6. Add Obeticholic acid under continuous stirring, keep stirring till solution becomes clear;
7. Add flavor under continuous stirring, keep stirring till solution becomes clear; 8. Add citric acid anhydrous under continuous stirring, keep stirring till solution becomes clear; and
9. Finally make up the volume with purified water.
Example 3: Obeticholic acid oral solution
Figure imgf000017_0002
Figure imgf000018_0001
q.s.: Quantity sufficient
Manufacturing process for Example 3A, 3B & 3C: Same as mentioned under example number 1 and 2.

Claims

We claim:
1. A stable liquid pharmaceutical composition, comprising: a) Obeticholic acid or its salts; and b) One or more pharmaceutically acceptable excipients.
2. The composition as claimed in claim 1, wherein the stable liquid pharmaceutical composition is administered via oral route and is used for treatment of adult patients with primary biliary cholangitis (PBC).
3. The composition as claimed in claim 1, wherein the Obeticholic acid or its salts is present in an amount of from about 0.01 mg/ml to about 100 mg/ml based on the total volume of the composition.
4. The composition as claimed in claim 1, wherein the pharmaceutically acceptable excipient is selected from a group comprising of one of more solvent(s), vehicle, co-solvent, buffer or buffering agent or pH adjusting agent, preservative or antimicrobial preservative, flavor enhancer, sweetener or sweetening agent, flavor or flavoring agent, surface-active agent or surfactant or solubilizer, antioxidant, coloring agent, antifoaming agent, tastemasking agent, suspending agent, emulsifying agent, stabilizers, diluents, resin, anticaking agent, chelating agent, acidifying agent, viscosity modifier, one or more lipid, pharmaceutical grade dye or pigment, and combination thereof.
5. The composition as claimed in claim 4, wherein the buffering agent is present in a range of 0.01-150 mg/ml; the preservative or antimicrobial preservative is present in a range of 0.001-50 mg/ml; the flavor enhancer is present in a range of 0.01- 600 mg/ml; the co-solvent is present in a range of 1-1200 mg/ml; the sweetening agent is present in a range of 0.1-6000 mg/ml; and the flavoring agent is present in a range of 0.001-10 mg/ml.
6. The composition as claimed in claim 5, wherein the buffering agent is selected from a group comprising of citrate buffers, phosphate buffers, monosodium dibasic phosphate, gluconic acid, lactic acid, citric acid, trisodium citrate, acetic acid, maleic acid, tartaric acid, fumaric acid, sodium phosphate, sodium gluconate, sodium lactate, sodium citrate, sodium acetate, potassium citrate, sodium bicarbonate, potassium bicarbonate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, Potassium, sodium, ammonium salt of acetic acid and combinations thereof; preservative or antimicrobial preservative is selected from a group comprising of alcohol, benzyl alcohol, bronopol, methylparaben, propylparaben, butylparaben, boric acid and borate salts, sorbic acid, sodium sorbate, potassium sorbate, calcium sorbate, benzoic acid, sodium benzoate, potassium benzoate, calcium benzoate, phenol, methylhydroxybenzoate, ethyl parahydroxybenzoate, sodium ethyl para- hydroxybenzoate, sodium metabisulphite, chlorbutol, chlorocresol, chlorhexidine, diazolidinyl urea, sodium citrate, chlorbutanol, butylated hydroxyl toluene, butylated hydroxyl anisole, tocopherol, ethylenediamine tetraacetic acid, propyl gallate, benzalkonium chloride, cetylpyridinium chloride, phenyl ethyl alcohol and combinations thereof; the flavor enhancer is selected from a group comprising of citric acid anhydrous, alanine, threonine, proline, serine, sucrose, fructose, dextrose, maltose, trehalose, glucose, stevia, glycerin, lactitol, maltitol, xylitol, sorbitol and mannitol, sucralose, saccharin, acesulfame potassium, aspartame, ethyl maltol, ethyl vanillin, fumaric acid, malic acid, maltol, menthol, monosodium glutamate, sodium chloride, stevia, tartaric acid, and vanillin, cherry, orange, peppermint, strawberry, apple, pineapple, anise fruit, peach, raspberry, orange cream and combinations thereof; the co-solvent is selected from a group comprising of glycerol or glycerin, maltitol, sorbitol, propylene glycol and combination thereof; the sweetening agent is selected from a group comprising of sucrose, glucose, dextrose, fructose, lactose, maltose, invert sugar, sorbitol, mannitol, xylitol, lactitol, erythritol, maltodextrin, maltitol, isomaltitol, isomalt, maltulose, isomaltulose, lactulose, threitol, arabitol, ribitol, galactitol, thaumatin, saccharin sodium, saccharin sodium dihydrate, aspartame, acesulfame, and sucralose, and combinations thereof; the flavoring agent is selected from a group comprising of banana, lemon, xylitol, orange, grape, vanilla, butterscotch, bubble gum, peppermint, fantasy fruit, tutti-frutti, apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot, plant leaves, cinnamon oil, oil of wintergreen, peppermint oils, clove oil, citrus oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, oil of bitter almonds, cassia oil, maltol, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid and combinations thereof; and the solvent is selected from a group comprising of water, purified water, glycerin, acetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, butyl alcohol, ethylene glycol monoethyl ether, ethyl acetate, monoethyl acetate, cyclohexane, benzene, toluene, naphtha, 1,4-dioxane, tetrahydrofuran, hydrochloric acid, sodium chloride, calcium chloride, acetone and water, acetone and methanol, acetone and ethyl alcohol, methylene dichloride and methanol, and ethylene dichloride and methanol and combination thereof.
7. The composition as claimed in claim 1, wherein the composition is formulated into a dosage form selected from a group comprising of a liquid solution, a solution, a suspension, a syrup, a concentrate, an elixir and an emulsion.
8. A process for preparation of a stable liquid pharmaceutical composition, comprising: (a) Charging a solvent in a stainless-steel container and adding accurately weighed quantity of a preservative, under continuous stirring, till solution becomes clear;
(b) Adding buffering agent in the solution of step (a) under continuous stirring, till the solution becomes clear;
(c) Adding first sweetening agent in the solution of step (b) under continuous stirring, till the solution becomes clear;
(d) Adding co-solvent in the solution of step (c) under continuous stirring, till the solution becomes clear;
(e) Adding second sweetening agent in the solution of step (d) under continuous stirring, till the solution becomes clear;
(f) Adding Obeticholic acid or its salts in the solution of step (e) under continuous stirring, till the solution becomes clear;
(g) Adding flavoring agent in the solution of step (f) under continuous stirring, till the solution becomes clear;
(h) Adding flavor enhancer in the solution of step (g) under continuous stirring, till solution becomes clear;
(i) Finally make up the volume with the solvent; and
(j) Filling the solution of step (i) into a suitable bottle or container.
9. The process as claimed in claim 8, wherein the buffering agent is present in a range of 0.01-150 mg/ml; the preservative or antimicrobial preservative is present in a range of 0.001-50 mg/ml; the flavor enhancer is present in a range of 0.01- 600 mg/ml; the co-solvent is present in a range of 1-1200 mg/ml; the sweetening agent is present in a range of 0.1-6000 mg/ml; and the flavoring agent is present in a range of 0.001-10 mg/ml.
10. The process as claimed in claim 8, wherein the buffering agent is selected from a group comprising of citrate buffers, phosphate buffers, monosodium dibasic phosphate, gluconic acid, lactic acid, citric acid, trisodium citrate, acetic acid, maleic acid, tartaric acid, fumaric acid, sodium phosphate, sodium gluconate, sodium lactate, sodium citrate, sodium acetate, potassium citrate, sodium bicarbonate, potassium bicarbonate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, Potassium, sodium, ammonium salt of acetic acid and combinations thereof; preservative or antimicrobial preservative is selected from a group comprising of alcohol, benzyl alcohol, bronopol, methylparaben, propylparaben, butylparaben, boric acid and borate salts, sorbic acid, sodium sorbate, potassium sorbate, calcium sorbate, benzoic acid, sodium benzoate, potassium benzoate, calcium benzoate, phenol, methylhydroxybenzoate, ethyl parahydroxybenzoate, sodium ethyl para- hydroxybenzoate, sodium metabisulphite, chlorbutol, chlorocresol, chlorhexidine, diazolidinyl urea, sodium citrate, chlorbutanol, butylated hydroxyl toluene, butylated hydroxyl anisole, tocopherol, ethylenediamine tetraacetic acid, propyl gallate, benzalkonium chloride, cetylpyridinium chloride, phenyl ethyl alcohol and combinations thereof; the flavor enhancer is selected from a group comprising of citric acid anhydrous, alanine, threonine, proline, serine, sucrose, fructose, dextrose, maltose, trehalose, glucose, stevia, glycerin, lactitol, maltitol, xylitol, sorbitol and mannitol, sucralose, saccharin, acesulfame potassium, aspartame, ethyl maltol, ethyl vanillin, fumaric acid, malic acid, maltol, menthol, monosodium glutamate, sodium chloride, stevia, tartaric acid, and vanillin, cherry, orange, peppermint, strawberry, apple, pineapple, anise fruit, peach, raspberry, orange cream and combinations thereof; the co-solvent is selected from a group comprising of glycerol or glycerin, maltitol, sorbitol, propylene glycol and combination thereof; the sweetening agent is selected from a group comprising of sucrose, glucose, dextrose, fructose, lactose, maltose, invert sugar, sorbitol, mannitol, xylitol, lactitol, erythritol, maltodextrin, maltitol, isomaltitol, isomalt, maltulose, isomaltulose, lactulose, threitol, arabitol, ribitol, galactitol, thaumatin, saccharin sodium, saccharin sodium dihydrate, aspartame, acesulfame, and sucralose, and combinations thereof; the flavoring agent is selected from a group comprising of banana, lemon, xylitol, orange, grape, vanilla, butterscotch, bubble gum, peppermint, fantasy fruit, tutti-frutti, apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot, plant leaves, cinnamon oil, oil of wintergreen, peppermint oils, clove oil, citrus oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, oil of bitter almonds, cassia oil, maltol, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid and combinations thereof; and the solvent is selected from a group comprising of water, purified water, glycerin, acetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, butyl alcohol, ethylene glycol monoethyl ether, ethyl acetate, monoethyl acetate, cyclohexane, benzene, toluene, naphtha, 1,4-dioxane, tetrahydrofuran, hydrochloric acid, sodium chloride, calcium chloride, acetone and water, acetone and methanol, acetone and ethyl alcohol, methylene dichloride and methanol, and ethylene dichloride and methanol and combination thereof.
PCT/IN2023/050284 2022-03-24 2023-03-24 Stable liquid composition comprising obeticholic acid or salts thereof WO2023181077A1 (en)

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WO2016176208A1 (en) * 2015-04-27 2016-11-03 Intercept Pharmaceuticals, Inc. Compositions of obeticholic acid and methods of use
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WO2016176208A1 (en) * 2015-04-27 2016-11-03 Intercept Pharmaceuticals, Inc. Compositions of obeticholic acid and methods of use
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