EP4676487A1 - Injizierbare zusammensetzungen von metolazon - Google Patents

Injizierbare zusammensetzungen von metolazon

Info

Publication number
EP4676487A1
EP4676487A1 EP24796452.1A EP24796452A EP4676487A1 EP 4676487 A1 EP4676487 A1 EP 4676487A1 EP 24796452 A EP24796452 A EP 24796452A EP 4676487 A1 EP4676487 A1 EP 4676487A1
Authority
EP
European Patent Office
Prior art keywords
injectable composition
present
metolazone
invention comprises
surfactant
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP24796452.1A
Other languages
English (en)
French (fr)
Inventor
Pradeep Bhadauria
Arunprasath Kaliaperumal
Tushar RAJYAGURU
Harshad Harde
Sandip KHAIRNAR
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cipla Ltd
Original Assignee
Cipla Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cipla Ltd filed Critical Cipla Ltd
Publication of EP4676487A1 publication Critical patent/EP4676487A1/de
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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 an injectable pharmaceutical composition comprising metolazone.
  • the invention particularly relates to a ready-to-dilute composition comprising metolazone, and pharmaceutically acceptable excipients
  • the invention also particularly relates to a process of preparing the composition and its use in the treatment of salt and water retention.
  • Metolazone is a poorly aqueous soluble drug that has poor bioavailability and variable absorption. Metolazone is only sparingly soluble in water, but more soluble in alkali, and organic solvents. Solubility and stability are long identified factors hindering the development of therapeutic agents. Conventional delivery systems for very insoluble drugs typically use a combination of specialized excipients like cyclodextrins, extreme pH conditions, all of which are detrimental and toxic, when ingested in large amounts.
  • Metolazone is marketed as an oral immediate release tablet under the trademark ZaroxolynTM in the United States.
  • these metolazone oral tablet formulations are known to have a variable bioavailability and absorption which is erratic. This problem is particularly seen in patients with severe gastrointestinal edema. This gastrointestinal edema eventually causes structural and functional abnormalities of the gastrointestinal tract, which in turn results in reduction of rate of drug absorption and further delays the time to achieve an effective therapeutic dose. Further, such oral dosage forms cannot be administered in patients who are not conscious and have difficulty in swallowing (dysphagia). Hence there remains a need in the art for an injectable dosage form of metolazone, which can overcome the variable and erratic absorption and bioavailability issues observed with oral formulations.
  • Metolazone has limited solubility in aqueous solutions and formulation of an injectable composition is very complex. It is challenging to formulate an injectable composition of metolazone wherein the metolazone is in dissolved state and precipitation is prevented throughout the shelf of the product. Further, such injectable composition needs to be diluted in compatible admixture diluents before administration. Owing to the low aqueous solubility of metolazone, there is a high chance of precipitation of metolazone when diluted with compatible admixture diluents. It is of utmost challenge to prevent precipitation of metolazone at this stage, and this makes the formulation further challenging.
  • An object of the invention is to provide an injectable composition comprising metolazone.
  • Another object of the invention is to provide an injectable composition
  • an injectable composition comprising (a) metolazone, (b) at least one solvent, (c) at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • Another object of the invention is to provide a process for preparing stable injectable composition comprising metolazone.
  • One another object of the present invention is to provide safe, efficacious, and ready to dilute injectable composition comprising metolazone.
  • Another object of the present invention is to provide a method of treating salt and water retention by administering a ready-to-dilute injectable composition comprising metolazone.
  • the present invention relates to injectable pharmaceutical composition comprising metolazone.
  • the invention particularly relates to a ready-to-dilute composition comprising metolazone, and pharmaceutically acceptable excipients, process of preparing the composition, and its use in the treatment of salt and water retention.
  • Prior attempts on formulation of metolazone in an injectable composition have not led to a stable composition and especially such formulation were seen to precipitate upon dilution with compatible admixture diluents.
  • the present invention addresses the unmet need and provides an injectable composition of metolazone which can be administered to a patient in need thereof.
  • the injectable composition of the present invention also exhibits sufficient stability and prevents precipitation of metolazone even after dilution with compatible admixture diluents.
  • the present invention relates to an injectable composition of the present invention comprising (a) metolazone, (b) at least one solvent, (c) at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises metolazone in an amount of about 0.01 mg to about 50 mg.
  • the injectable composition of the present invention comprises metolazone in an amount of about 0.01 mg to about 20 mg.
  • the injectable composition of the present invention comprises metolazone in an amount of about 0.1 mg to about 10 mg.
  • the injectable composition of the present invention comprises metolazone in an amount of about 1 mg to about 10 mg.
  • the injectable composition of the present invention comprises metolazone an amount of about 5 mg.
  • the injectable composition of the present invention comprises metolazone in the unionized form.
  • the injectable composition of the present invention comprises metolazone as a pharmaceutically acceptable salt thereof.
  • the injectable composition of the present invention comprises solvent in an amount of about 1 mg to about 1500 mg. In one embodiment, the injectable composition of the present invention comprises solvent in an amount of about 1 mg to about 700 mg.
  • the injectable composition of the present invention comprises solvent in an amount of about 100 mg to about 600 mg.
  • the injectable composition of the present invention comprises solvent in an amount of about 200 mg.
  • the injectable composition of the present invention comprises solvent in an amount of about 300 mg.
  • the injectable composition of the present invention comprises solvent in an amount of about 400 mg.
  • the injectable composition of the present invention comprises solvent in an amount of about 800 mg.
  • the injectable composition of the present invention comprises solvent in an amount of about 1000 mg.
  • the injectable composition of the present invention comprises solvent in an amount of about 0.1% w/v to about 70% w/v.
  • the injectable composition of the present invention comprises solvent in an amount of about 10% w/v to about 60% w/v.
  • the injectable composition of the present invention comprises solvent in an amount of about 20% w/v.
  • the injectable composition of the present invention comprises solvent in an amount of about 30% w/v.
  • the injectable composition of the present invention comprises solvent in an amount of about 37.5% w/v.
  • the injectable composition of the present invention comprises solvent in an amount of about 40% w/v.
  • the injectable composition of the present invention comprises solvent in an amount of about 50 % w/v.
  • the injectable composition of the present invention comprises solvent in an amount of about 62.5% w/v. In a further embodiment, the injectable composition of the present invention comprises surfactant in an amount of about 1 mg to about 500 mg.
  • the injectable composition of the present invention comprises surfactant is present in an amount of about 100 mg.
  • the injectable composition of the present invention comprises surfactant is present in an amount of about 125 mg.
  • the injectable composition of the present invention comprises surfactant is present in an amount of about 150 mg.
  • the injectable composition of the present invention comprises surfactant is present in an amount of about 175 mg.
  • the injectable composition of the present invention comprises surfactant in an amount of about 200 mg.
  • the injectable composition of the present invention comprises surfactant in an amount of about 300 mg.
  • the injectable composition of the present invention comprises surfactant in an amount of about 400 mg.
  • the injectable composition of the present invention comprises surfactant in an amount of about 0.1% w/v to about 50% w/v.
  • the injectable composition of the present invention comprises surfactant in an amount of about 6.25% w/v.
  • the injectable composition of the present invention comprises surfactant in an amount of about 10% w/v.
  • the injectable composition of the present invention comprises surfactant in an amount of about 12.5% w/v.
  • the injectable composition of the present invention comprises surfactant in an amount of about 15 % w/v.
  • the injectable composition of the present invention comprises surfactant in an amount of about 17.5% w/v.
  • the injectable composition of the present invention comprises surfactant in an amount of about 18.75% w/v. In one more embodiment, the injectable composition of the present invention comprises surfactant in an amount of about 20% w/v.
  • the injectable composition of the present invention comprises surfactant in an amount of about 25% w/v.
  • the injectable composition of the present invention comprises surfactant in an amount of about 30% w/v.
  • the injectable composition of the present invention comprises (a) about 0.01 mg to about 20 mg of metolazone, (b) about 1 mg to about 700 mg of at least one solvent, (c) about 1 mg to about 500 mg of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 0.01 mg to about 20 mg of metolazone, (b) about 100 mg to about 600 mg of at least one solvent, (c) about 1 mg to about 500 mg of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 0.01 mg to about 20 mg of metolazone, (b) about 100 mg to about 600 mg of at least one solvent, (c) about 100 mg of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 0.01 mg to about 20 mg of metolazone, (b) about 100 mg to about 600 mg of at least one solvent, (c) about 125 mg of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 0.01 mg to about 20 mg of metolazone, (b) about 100 mg to about 600 mg of at least one solvent, (c) about 150 mg of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 0.01 mg to about 20 mg of metolazone, (b) about 100 mg to about 600 mg of at least one solvent, (c) about 175 mg of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 0.01 mg to about 20 mg of metolazone, (b) about 100 mg to about 600 mg of at least one solvent, (c) about 200 mg of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 0.01 mg to about 20 mg of metolazone, (b) about 100 mg to about 600 mg of at least one solvent, (c) about 300 mg of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 200 mg of at least one solvent, (c) about 100 mg of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 200 mg of at least one solvent, (c) about 125 mg of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 200 mg of at least one solvent, (c) about 150 mg of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 200 mg of at least one solvent, (c) about 175 mg of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 200 mg of at least one solvent, (c) about 200 mg of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 200 mg of at least one solvent, (c) about 300 mg of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 300 mg of at least one solvent, (c) about 100 mg of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 300 mg of at least one solvent, (c) about 125 mg of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 300 mg of at least one solvent, (c) about 150 mg of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 300 mg of at least one solvent, (c) about 175 mg of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 300 mg of at least one solvent, (c) about 200 mg of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 300 mg of at least one solvent, (c) about 300 mg of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 400 mg of at least one solvent, (c) about 100 mg of at least one surfactant, and (d) a pharmaceutically acceptable vehicle. In one more embodiment, the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 400 mg of at least one solvent, (c) about 125 mg of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 400 mg of at least one solvent, (c) about 150 mg of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 400 mg of at least one solvent, (c) about 175 mg of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 400 mg of at least one solvent, (c) about 200 mg of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 400 mg of at least one solvent, (c) about 300 mg of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 1000 mg of solvent, (c) about 100 mg of surfactant, and (d) a pharmaceutically acceptable vehicle. In one more embodiment, the composition has a volume of about 1.6 ml.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 800 mg of solvent, (c) about 300 mg of surfactant, and (d) a pharmaceutically acceptable vehicle. In one more embodiment, the composition has a volume of about 1.6 ml.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 600 mg of solvent, (c) about 400 mg of surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the composition has a volume of about 2 ml.
  • the injectable composition of the present invention comprises (a) about 0.01 mg to about 20 mg of metolazone, (b) about 0.1 % w/v to about 70 % w/v of at least one solvent, (c) about 0.1 % w/v to about 50 % w/v of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 0.01 mg to about 20 mg of metolazone, (b) about 10 % w/v to about 60 % w/v of at least one solvent, (c) about 0.1 % w/v to about 50 % w/v of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 0.01 mg to about 20 mg of metolazone, (b) about 10 % w/v to about 60 % w/v of at least one solvent, (c) about 10 % w/v of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 0.01 mg to about 20 mg of metolazone, (b) about 10 % w/v to about 60 % w/v of at least one solvent, (c) about 12.5 % w/v of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 0.01 mg to about 20 mg of metolazone, (b) about 10 % w/v to about 60 % w/v of at least one solvent, (c) about 15 % w/v of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 0.01 mg to about 20 mg of metolazone, (b) about 10 % w/v to about 60 % w/v of at least one solvent, (c) about 17.5 % w/v of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 0.01 mg to about 20 mg of metolazone, (b) about 10 % w/v to about 60 % w/v of at least one solvent, (c) about 20 % w/v of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 0.01 mg to about 20 mg of metolazone, (b) about 10 % w/v to about 60 % w/v of at least one solvent, (c) about 30 % w/v of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 20 % w/v of at least one solvent, (c) about 10 % w/v of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 20 % w/v of at least one solvent, (c) about 12.5 % w/v of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 20 % w/v of at least one solvent, (c) about 15 % w/v of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 20 % w/v of at least one solvent, (c) about 17.5 % w/v of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 20 % w/v of at least one solvent, (c) about 20 % w/v of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 20 % w/v of at least one solvent, (c) about 30 % w/v of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 30 % w/v of at least one solvent, (c) about 10 % w/v of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 30 % w/v of at least one solvent, (c) about 12.5 % w/v of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 30 % w/v of at least one solvent, (c) about 15 % w/v of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 30 % w/v of at least one solvent, (c) about 17.5 % w/v of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 30 % w/v of at least one solvent, (c) about 20 % w/v of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 30 % w/v of at least one solvent, (c) about 30 % w/v of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 40 % w/v of at least one solvent, (c) about 10 % w/v of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 40 % w/v of at least one solvent, (c) about 12.5 % w/v of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 40 % w/v of at least one solvent, (c) about 15 % w/v of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 40 % w/v of at least one solvent, (c) about 17.5 % w/v of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 40 % w/v of at least one solvent, (c) about 20 % w/v of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 40 % w/v of at least one solvent, (c) about 30 % w/v of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises solvent comprising at least one of polyethylene glycol, propylene glycol, and ethanol.
  • the injectable composition of the present invention comprises polysorbate as a surfactant.
  • the injectable composition of the present invention comprises PEG 35 Castor oil as a surfactant.
  • the injectable composition of the present invention comprises water as a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 0.1 mg to about 10 mg of metolazone, (b) about 0.1 % w/v to about 70 % w/v of at least one solvent, (c) about 0.1 % w/v to about 50 % w/v of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 0.1 mg to about 10 mg of metolazone, (b) about 30 % w/v to about 65 % w/v of at least one solvent, (c) about 5 % w/v to about 30 % w/v of at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 0.1 mg to about 10 mg of metolazone, (b) about 0.1 % w/v to about 70 % w/v of ethanol, (c) about 0.1 % w/v to about 50 % w/v of PEG 35 castor oil, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 0.1 mg to about 10 mg of metolazone, (b) about 30 % w/v to about 65 % w/v of ethanol, (c) about 5 % w/v to about 30 % w/v of PEG 35 castor oil, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 0.1 mg to about 10 mg of metolazone, (b) about 62.5 % w/v of ethanol, (c) about 6.25 % w/v of PEG 35 castor oil, and (d) water.
  • the injectable composition of the present invention comprises (a) about 0.1 mg to about 10 mg of metolazone, (b) about 50 % w/v of ethanol, (c) about 18.75 % w/v of PEG 35 castor oil, and (d) water.
  • the injectable composition of the present invention comprises (a) about 0.1 mg to about 10 mg of metolazone, (b) about 30 % w/v of ethanol, (c) about 20 % w/v of PEG 35 castor oil, and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 62.5 % w/v of solvent, (c) about 6.25 % w/v of surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 50 % w/v of solvent, (c) about 18.75 % w/v of surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 30 % w/v of solvent, (c) about 20 % w/v of surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention is stable for at least 1 hour after dilution with a compatible admixture diluent.
  • the injectable composition of the present invention is an aqueous composition.
  • the present invention relates to stable injectable pharmaceutical composition comprising metolazone.
  • the invention particularly relates to a ready- to-dilute composition comprising metolazone and pharmaceutically acceptable excipients, process of preparing the composition and its use in the treatment of salt and water retention.
  • Metolazone is designated chemically as 7-chloro-l, 2, 3, 4-tetrahydro-2- methyl-3-(2-methylphenyl)-4-oxo-6-quinazolinesulfonamide and a molecular weight of 365.83. Metolazone can exist in the unionized form, or as a pharmaceutically acceptable salt. The chemical structure in the unionized form is:
  • Metolazone has limited solubility in aqueous solutions and formulation of an injectable composition is complex. Metolazone is available as an oral dosage form viz. immediate release tablet, which is reported to have erratic absorption and variable bioavailability. There remains a need in the art for an injectable dosage form of metolazone, which can overcome the variable and erratic absorption and bioavailability issues observed with oral formulations. Further, it would be convenient to administer such injectable dosage forms to patients who are not conscious and who have difficulty in swallowing.
  • the present invention addresses this unmet need and provides an injectable composition of metolazone, which can be administered to a patient in need thereof.
  • the injectable composition of the present invention also exhibits sufficient stability and prevents precipitation of metolazone even after dilution with compatible admixture diluents.
  • the inventors of the present invention through rigorous experimentation have found out that a combination of surfactants and solvents imparts sufficient stability to the injectable composition of metolazone, and prevents precipitation of metolazone even after dilution with compatible admixture diluents.
  • the injectable composition of the present invention comprises metolazone, along with excipients.
  • the injectable composition of the present invention may include pharmaceutically acceptable salts of metolazone such as, sodium, maleate, sulphonate, succinate and hydrochloride.
  • the particle size is a critical attribute for improving the solubilization of metolazone.
  • the particle size of metolazone as per the present invention may have a D90 about 10 pm to about 200 pm, preferably from about 15 pm to about 100 pm. In some embodiments, the particle size of metolazone may have a D90 of at least about 10 pm 20 pm., 30 pm, 40 pm, 50 pm, 60 pm.
  • the composition contains at least about 0.01 mg to about 50 mg metolazone, preferably about 0.01 mg to about 20 mg metolazone, preferably about 0.1 mg to about 10 mg, more preferably about 5 mg.
  • the injectable composition of the present invention comprises about Img, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg metolazone or its pharmaceutically acceptable salt thereof.
  • the injectable composition of the present invention comprises about Img, about 2.5 mg, about 5 mg, about 7.5 mg or about 10 mg metolazone.
  • references to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se.
  • the term “about” includes the indicated amount ⁇ 10%.
  • the term “about” includes the indicated amount ⁇ 5%.
  • the term “about” includes the indicated amount ⁇ 1%.
  • to the term “about X” includes description of “X.”
  • the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise.
  • reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art.
  • the injectable composition of the present invention comprises (a) metolazone, (b) at least one solvent, (c) at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention is aqueous.
  • the injectable composition of the present invention comprises a combination of surfactants and solvents to allow for solubilization of metolazone as well as impart stability to the composition after dilution with compatible admixture diluents for infusion.
  • the injectable composition of the present invention comprises at least one solvent.
  • solvent are ethanol, pentane, 2-methylbutane (isopentane), heptane, hexane, cyclopentane and cyclohexane, methanol, 2- methoxyethanol, isopropanol, n-butanol, t-butyl alcohol, octanol, ethyl acetate, 2- methoxyethyl acetate, butyl acetate, benzyl benzoate, benzene, toluene, pyridine, xylene, diethyl ether, 2-ethoxyethyl ether, ethylene glycol dimethyl ether, methyl t- butyl ether, formaldehyde, glutaraldehyde, acetone, 3 -pentanone (diethyl ketone), ethylene glycol, propylene glycol, formic acid, acetic solvent,
  • the injectable composition of the present invention comprises a solvent comprising at least one of ethanol, propylene glycol, and polyethylene glycol.
  • the injectable composition of the present invention comprises solvent in an amount of about 1 mg to about 1500 mg.
  • the injectable composition of the present invention comprises solvent in an amount of about 1 mg to about 700 mg.
  • the injectable composition of the present invention comprises solvent in an amount of about 100 mg to about 600 mg.
  • the injectable composition of the present invention comprises solvent in an amount of about 200 mg.
  • the injectable composition of the present invention comprises solvent in an amount of about 300 mg. In another embodiment, the injectable composition of the present invention comprises solvent in an amount of about 400 mg.
  • the injectable composition of the present invention comprises solvent in an amount of about 800 mg.
  • the injectable composition of the present invention comprises solvent in an amount of about 1000 mg.
  • the injectable composition of the present invention comprises solvent in an amount of about 0.1% w/v to about 70% w/v.
  • the injectable composition of the present invention comprises solvent in an amount of about 10% w/v to about 60% w/v.
  • the injectable composition of the present invention comprises solvent in an amount of about 20% w/v.
  • the injectable composition of the present invention comprises solvent in an amount of about 30% w/v.
  • the injectable composition of the present invention comprises solvent in an amount of about 37.5% w/v.
  • the injectable composition of the present invention comprises solvent in an amount of about 40% w/v.
  • the injectable composition of the present invention comprises solvent in an amount of about 50 % w/v.
  • the injectable composition of the present invention comprises solvent in an amount of about 62.5% w/v.
  • the injectable composition of the present invention comprises at least one surfactant.
  • surfactant as used herein means agents that lower the surface tension (or interfacial tension) between two liquids or between a liquid and a solid.
  • Surfactants are usually organic compounds that are amphiphilic, i.e., they contain both hydrophobic groups (tails) and hydrophilic groups (heads). Therefore, a surfactant contains both a water-insoluble (or oil- soluble) component and a water- soluble component.
  • Surfactants can be classified according to polar head group.
  • a non-ionic surfactant has no charged groups in its head.
  • Non-ionic surfactants have covalently bonded oxygen-containing hydrophilic groups, which are bonded to hydrophobic parent structures.
  • the head of an ionic surfactant carries a net positive, or negative charge. If the charge is negative, the surfactant is more specifically called anionic; if the charge is positive, it is called cationic. If a surfactant contains a head with two oppositely charged groups, it is termed zwitterionic. An ideal interaction of hydrophilic and lipophilic group of surfactant with particle surface could be reason for obtaining appropriate suspension stability.
  • the surfactant can be a non-ionic surfactant, an ionic surfactant (anionic or cationic), or a zwitterionic surfactant. The surfactant reduces the interfacial tension between the solid particles and the liquid vehicle.
  • surfactant for this application include, but are not limited to, D-a-Tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS), polysorbate or polyethoxylated castor oil, Polyoxyl 20 stearate, Polyoxyl 35 castor oil, poloxamer, polyoxyethylene sorbitan monoisostearate, polyethylene glycol 40 sorbitan diisostearate, Polyoxyl 40 Hydrogenated castor oil, Polysorbate, Polysorbate 20, Polysorbate 40, Polyoxyl 60 stearate, Polysorbate 85, Polysorbate 60, poloxamer 331, polyoxyethylene fatty acid esters, Polyoxyl 40 castor oil, poloxamer 188, polyoxyethylene polyoxypropylene 1800, oleic acid, Sodium desoxycholate, Sodium lauryl sulfate, Sorbitan monolaurate, Sorbitan monooleate, Sorbitan monopalmitate, Sorbitan trioleate, N-Carbamoylated
  • the injectable composition of the present invention comprises a surfactant having an HLB value greater than about 8. In one embodiment, the surfactant has an HLB value of about 10 to about 30.
  • the injectable composition of the present invention comprises surfactant in an amount of about 1 mg to about 500 mg.
  • the injectable composition of the present invention comprises surfactant is present in an amount of about 100 mg.
  • the injectable composition of the present invention comprises surfactant is present in an amount of about 125 mg.
  • the injectable composition of the present invention comprises surfactant is present in an amount of about 150 mg.
  • the injectable composition of the present invention comprises surfactant is present in an amount of about 175 mg.
  • the injectable composition of the present invention comprises surfactant in an amount of about 200 mg.
  • the injectable composition of the present invention comprises surfactant in an amount of about 300 mg.
  • the injectable composition of the present invention comprises surfactant in an amount of about 400 mg.
  • the injectable composition of the present invention comprises surfactant in an amount of about 0.1% w/v to about 50% w/v.
  • the injectable composition of the present invention comprises surfactant in an amount of about 6.25% w/v.
  • the injectable composition of the present invention comprises surfactant in an amount of about 10% w/v.
  • the injectable composition of the present invention comprises surfactant is present in an amount of about 12.5% w/v. In one embodiment, the injectable composition of the present invention comprises surfactant is present in an amount of about 15 % w/v.
  • the injectable composition of the present invention comprises surfactant is present in an amount of about 17.5% w/v.
  • the injectable composition of the present invention comprises surfactant is present in an amount of about 18.75% w/v.
  • the injectable composition of the present invention comprises surfactant in an amount of about 20% w/v.
  • the injectable composition of the present invention comprises surfactant in an amount of about 25% w/v.
  • the injectable composition of the present invention comprises surfactant is present in an amount of about 30% w/v.
  • the injectable composition of the present invention comprises solvent in an amount of 30 % w/v, 30.25% w/v, 30.5% w/v, 30.75% w/v, 31% w/v, 31.25% w/v, 31.5% w/v, 31.75% w/v, 32% w/v, 32.25% w/v, 32.5% w/v, 32.75% w/v, 33% w/v, 33.25% w/v, 33.5% w/v, 33.75% w/v, 34% w/v, 34.25% w/v, 34.5% w/v, 34.75% w/v, 35 % w/v, 35.25 % w/v, 35.5 % w/v, 35.75 % w/v, 36 % w/v, 36.25 % w/v, 36.5 % w/v, 36.75 % w/v, 37 % w/v/v
  • the injectable composition of the present invention comprises ethanol in an amount of 30 % w/v, 30.25% w/v, 30.5% w/v, 30.75% w/v, 31% w/v, 31.25% w/v, 31.5% w/v, 31.75% w/v, 32% w/v, 32.25% w/v, 32.5% w/v, 32.75% w/v, 33% w/v, 33.25% w/v, 33.5% w/v, 33.75% w/v, 34% w/v, 34.25% w/v, 34.5% w/v, 34.75% w/v, 35 % w/v, 35.25 % w/v, 35.5 % w/v, 35.75 % w/v, 36 % w/v, 36.25 % w/v, 36.5 % w/v, 36.75 % w/v, 37 % w/v, 35
  • the injectable composition of the present invention comprises surfactant in an amount of 5 % w/v, 5.25 % w/v, 5.5% w/v, 5.75% w/v, 6% w/v, 6.25% w/v, 6.5% w/v, 6.75% w/v, 7% w/v, 7.25% w/v, 7.5% w/v, 7.75% w/v, 8% w/v, 8.25% w/v, 8.5% w/v, 8.75% w/v, 9% w/v, 9.25% w/v, 9.5% w/v, 9.75% w/v, 10% w/v, 10.25% w/v, 10.5% w/v, 10.75% w/v, 11% w/v, 11.25% w/v, 11.5% w/v, 11.75% w/v, 12% w/v, 12.25% w/v, 12.5% w/v, 12.7
  • the injectable composition of the present invention comprises PEG 35 castor oil in an amount of 5 % w/v, 5.25 % w/v, 5.5% w/v, 5.75% w/v, 6% w/v, 6.25% w/v, 6.5% w/v, 6.75% w/v, 7% w/v, 7.25% w/v, 7.5% w/v, 7.75% w/v, 8% w/v, 8.25% w/v, 8.5% w/v, 8.75% w/v, 9% w/v, 9.25% w/v, 9.5% w/v, 9.75% w/v, 10% w/v, 10.25% w/v, 10.5% w/v, 10.75% w/v, 11% w/v, 11.25% w/v, 11.5% w/v, 11.75% w/v, 12% w/v, 12.25% w/v, 12.5% w/w/v,
  • the injectable composition of the present invention may also contain a pharmaceutically acceptable vehicle, which allows for solubilization of the active and excipients and also aids in stabilization of the composition.
  • the injectable composition of the present invention contains water as a pharmaceutically acceptable vehicle.
  • the present invention relates to an injectable composition of the present invention comprising (a) metolazone, (b) at least one solvent, (c) at least one surfactant, and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises solvent comprising at least one of polyethylene glycol, propylene glycol, and ethanol.
  • the injectable composition of the present invention comprises a surfactant which is a non-ionic surfactant.
  • the injectable composition of the present invention comprises polysorbate as a surfactant.
  • the injectable composition of the present invention comprises PEG 35 Castor oil as a surfactant.
  • the injectable composition of the present invention comprises metolazone in an amount of about 0.01 mg to about 50 mg.
  • the injectable composition of the present invention comprises metolazone in an amount of about 0.01 mg to about 20 mg.
  • the injectable composition of the present invention comprises metolazone in an amount of about 1 mg to about 10 mg.
  • the injectable composition of the present invention comprises metolazone an amount of about 5 mg.
  • the injectable composition of the present invention comprises (a) about 0.01 mg to about 20 mg of metolazone, (b) about 1 mg to about 700 mg of at least one solvent, (c) about 1 mg to about 500 mg of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 0.01 mg to about 20 mg of metolazone, (b) about 100 mg to about 600 mg of at least one solvent, (c) about 1 mg to about 500 mg of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 0.01 mg to about 20 mg of metolazone, (b) about 100 mg to about 600 mg of at least one solvent, (c) about 100 mg of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 0.01 mg to about 20 mg of metolazone, (b) about 100 mg to about 600 mg of at least one solvent, (c) about 125 mg of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 0.01 mg to about 20 mg of metolazone, (b) about 100 mg to about 600 mg of at least one solvent, (c) about 150 mg of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 0.01 mg to about 20 mg of metolazone, (b) about 100 mg to about 600 mg of at least one solvent, (c) about 175 mg of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 0.01 mg to about 20 mg of metolazone, (b) about 100 mg to about 600 mg of at least one solvent, (c) about 200 mg of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 0.01 mg to about 20 mg of metolazone, (b) about 100 mg to about 600 mg of at least one solvent, (c) about 300 mg of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 200 mg of at least one solvent, (c) about 100 mg of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 200 mg of at least one solvent, (c) about 125 mg of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 200 mg of at least one solvent, (c) about 150 mg of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 200 mg of at least one solvent, (c) about 175 mg of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 200 mg of at least one solvent, (c) about 200 mg of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 200 mg of at least one solvent, (c) about 300 mg of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 300 mg of at least one solvent, (c) about 100 mg of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 300 mg of at least one solvent, (c) about 125 mg of at least one surfactant and (d) a pharmaceutically acceptable vehicle. In an embodiment, the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 300 mg of at least one solvent, (c) about 150 mg of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 300 mg of at least one solvent, (c) about 175 mg of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 300 mg of at least one solvent, (c) about 200 mg of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 300 mg of at least one solvent, (c) about 300 mg of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 400 mg of at least one solvent, (c) about 100 mg of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 400 mg of at least one solvent, (c) about 125 mg of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 400 mg of at least one solvent, (c) about 150 mg of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 400 mg of at least one solvent, (c) about 175 mg of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 400 mg of at least one solvent, (c) about 200 mg of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 400 mg of at least one solvent, (c) about 300 mg of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 1000 mg of solvent, (c) about 100 mg of surfactant and (d) a pharmaceutically acceptable vehicle.
  • the composition has a volume of about 1.6 ml.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 800 mg of solvent, (c) about 300 mg of surfactant and (d) a pharmaceutically acceptable vehicle.
  • the composition has a volume of about 1.6 ml.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 600 mg of solvent, (c) about 400 mg of surfactant and (d) a pharmaceutically acceptable vehicle.
  • the composition has a volume of about 2 ml.
  • the injectable composition of the present invention comprises (a) about 0.01 mg to about 20 mg of metolazone, (b) about 100 mg to about 600 mg of at least one solvent comprising at least one of ethanol, propylene glycol, and polyethylene glycol, (c) about 100 mg to about 300 mg of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 100 mg to about 600 mg of at least one solvent comprising at least one of ethanol, propylene glycol, and polyethylene glycol, (c) about 100 mg to about 300 mg of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 200 mg of at least one solvent comprising at least one of ethanol, propylene glycol, and polyethylene glycol, (c) about 100 mg to about 300 mg of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 300 mg of at least one solvent comprising at least one of ethanol, propylene glycol, and polyethylene glycol, (c) about 100 mg to about 300 mg of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 400 mg of at least one solvent comprising at least one of ethanol, propylene glycol, and polyethylene glycol, (c) about 100 mg to about 300 mg of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 200 mg of polyethylene glycol, (c) about 100 mg of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 200 mg of polyethylene glycol, (c) about 200 mg of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 200 mg of polyethylene glycol, (c) about 300 mg of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 300 mg of polyethylene glycol, (c) about 100 mg of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 300 mg of polyethylene glycol, (c) about 200 mg of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 300 mg of polyethylene glycol, (c) about 300 mg of polysorbate 80 and (d) water. In one embodiment, the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 400 mg of polyethylene glycol, (c) about 100 mg of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 400 mg of polyethylene glycol, (c) about 200 mg of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 400 mg of polyethylene glycol, (c) about 300 mg of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 200 mg of ethanol, (c) about 100 mg of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 200 mg of ethanol, (c) about 125 mg of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 200 mg of ethanol, (c) about 150 mg of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 200 mg of ethanol, (c) about 175 mg of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 200 mg of ethanol, (c) about 200 mg of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 200 mg of ethanol, (c) about 300 mg of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 300 mg of ethanol, (c) about 100 mg of polysorbate 80 and (d) water. In one embodiment, the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 300 mg of ethanol, (c) about 125 mg of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 300 mg of ethanol, (c) about 150 mg of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 300 mg of ethanol, (c) about 175 mg of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 300 mg of ethanol, (c) about 200 mg of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 300 mg of ethanol, (c) about 300 mg of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 400 mg of ethanol, (c) about 100 mg of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 400 mg of ethanol, (c) about 125 mg of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 400 mg of ethanol, (c) about 150 mg of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 400 mg of ethanol, (c) about 175 mg of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 400 mg ethanol, (c) about 200 mg of polysorbate 80 and (d) water. In one embodiment, the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 400 mg of ethanol, (c) about 300 mg of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 300 mg of propylene glycol, (c) about 300 mg of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 1000 mg of ethanol, (c) about 100 mg of PEG 35 Castor oil and (d) water. In an embodiment, the composition has a volume of about 1.6 ml.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 800 mg of ethanol, (c) about 300 mg of PEG 35 Castor oil and (d) water. In an embodiment, the composition has a volume of about 1.6 ml.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 600 mg of ethanol, (c) about 400 mg of PEG 35 Castor oil and (d) water.
  • the composition has a volume of about 2 ml.
  • the injectable composition of the present invention comprises (a) about 0.01 mg to about 20 mg of metolazone, (b) about 0.1 % w/v to about 70 % w/v of at least one solvent, (c) about 0.1 % w/v to about 50 % w/v of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 0.01 mg to about 20 mg of metolazone, (b) about 10 % w/v to about 60 % w/v of at least one solvent, (c) about 0.1 % w/v to about 50 % w/v of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 0.01 mg to about 20 mg of metolazone, (b) about 10 % w/v to about 60 % w/v of at least one solvent, (c) about 10 % w/v of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 0.01 mg to about 20 mg of metolazone, (b) about 10 % w/v to about 60 % w/v of at least one solvent, (c) about 12.5 % w/v of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 0.01 mg to about 20 mg of metolazone, (b) about 10 % w/v to about 60 % w/v of at least one solvent, (c) about 15 % w/v of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 0.01 mg to about 20 mg of metolazone, (b) about 10 % w/v to about 60 % w/v of at least one solvent, (c) about 17.5 % w/v of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 0.01 mg to about 20 mg of metolazone, (b) about 10 % w/v to about 60 % w/v of at least one solvent, (c) about 20 % w/v of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 0.01 mg to about 20 mg of metolazone, (b) about 10 % w/v to about 60 % w/v of at least one solvent, (c) about 30 % w/v of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 20 % w/v of at least one solvent, (c) about 10 % w/v of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 20 % w/v of at least one solvent, (c) about 12.5 % w/v of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 20 % w/v of at least one solvent, (c) about 15 % w/v of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 20 % w/v of at least one solvent, (c) about 17.5 % w/v of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 20 % w/v of at least one solvent, (c) about 20 % w/v of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 20 % w/v of at least one solvent, (c) about 30 % w/v of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 30 % w/v of at least one solvent, (c) about 10 % w/v of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 30 % w/v of at least one solvent, (c) about 12.5 % w/v of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 30 % w/v of at least one solvent, (c) about 15 % w/v of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 30 % w/v of at least one solvent, (c) about 17.5 % w/v of at least one surfactant and (d) a pharmaceutically acceptable vehicle. In one embodiment, the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 30 % w/v of at least one solvent, (c) about 20 % w/v of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 30 % w/v of at least one solvent, (c) about 30 % w/v of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 40 % w/v of at least one solvent, (c) about 10 % w/v of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 40 % w/v of at least one solvent, (c) about 12.5 % w/v of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 40 % w/v of at least one solvent, (c) about 15 % w/v of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 40 % w/v of at least one solvent, (c) about 17.5 % w/v of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 40 % w/v of at least one solvent, (c) about 20 % w/v of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 40 % w/v of at least one solvent, (c) about 30 % w/v of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 62.5 % w/v of solvent, (c) about 6.25 % w/v of surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 50 % w/v of solvent,
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 30 % w/v of solvent, (c) about 20 % w/v of surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 0.01 mg to about 20 mg of metolazone, (b) about 10 % w/v to about 60 % w/v of at least one solvent comprising at least one of ethanol, propylene glycol, and polyethylene glycol, (c) about 10 % w/v to about 30 % w/v of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 10 % w/v to about 60 % w/v of at least one solvent comprising at least one of ethanol, propylene glycol, and polyethylene glycol, (c) about 10 % w/v to about 30 % w/v of polysorbate 80 and
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 20 % w/v of at least one solvent comprising at least one of ethanol, propylene glycol, and polyethylene glycol, (c) about 10 % w/v to about 30 % w/v of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 30 % w/v of at least one solvent comprising at least one of ethanol, propylene glycol, and polyethylene glycol, (c) about 10 % w/v to about 30 % w/v of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 40 % w/v of at least one solvent comprising at least one of ethanol, propylene glycol, and polyethylene glycol, (c) about 10 % w/v to about 30 % w/v of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 20 % w/v of polyethylene glycol, (c) about 10 % w/v of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 20 % w/v of polyethylene glycol, (c) about 20 % w/v of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 20 % w/v of polyethylene glycol, (c) about 30 % w/v of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 30 % w/v of polyethylene glycol, (c) about 10 % w/v of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 30 % w/v of polyethylene glycol, (c) about 20 % w/v of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 30 % w/v of polyethylene glycol, (c) about 30 % w/v of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 40 % w/v of polyethylene glycol, (c) about 10 % w/v of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 40 % w/v of polyethylene glycol, (c) about 20 % w/v of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 40 % w/v of polyethylene glycol, (c) about 30 % w/v of polysorbate 80 and (d) water. In a further embodiment, the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 20 % w/v of ethanol, (c) about 10 % w/v of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 20 % w/v of ethanol, (c) about
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 20 % w/v of ethanol, (c) about 15 % w/v of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 20 % w/v of ethanol, (c) about
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 20 % w/v of ethanol, (c) about 20 % w/v of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 20 % w/v of ethanol, (c) about 30 % w/v of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 30 % w/v of ethanol, (c) about 10 % w/v of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 30 % w/v of ethanol, (c) about
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 30 % w/v of ethanol, (c) about 15 % w/v of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 30 % w/v of ethanol, (c) about 17.5 % w/v of polysorbate 80 and (d) water. In another embodiment, the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 30 % w/v of ethanol, (c) about 20 % w/v of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 30 % w/v of ethanol, (c) about 30 % w/v of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 40 % w/v of ethanol, (c) about 10 % w/v of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 40 % w/v of ethanol, (c) about 12.5 % w/v of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 40 % w/v of ethanol, (c) about 15 % w/v of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 40 % w/v of ethanol, (c) about 17.5 % w/v of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 40 % w/v of ethanol, (c) about 20 % w/v of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 40 % w/v of ethanol, (c) about 30 % w/v of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 30 % w/v of propylene glycol, (c) about 30 % w/v of polysorbate 80 and (d) water.
  • the injectable composition of the present invention comprises (a) about 0.1 mg to about 10 mg of metolazone, (b) about 0.1 % w/v to about 70 % w/v of at least one solvent, (c) about 0.1 % w/v to about 50 % w/v of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 0.1 mg to about 10 mg of metolazone, (b) about 30 % w/v to about 65 % w/v of at least one solvent, (c) about 5 % w/v to about 30 % w/v of at least one surfactant and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 0.1 mg to about 10 mg of metolazone, (b) about 0.1 % w/v to about 70 % w/v of ethanol, (c) about 0.1 % w/v to about 50 % w/v of PEG 35 castor oil and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 0.1 mg to about 10 mg of metolazone, (b) about 30 % w/v to about 65 % w/v of ethanol, (c) about 5 % w/v to about 30 % w/v of PEG 35 castor oil and (d) a pharmaceutically acceptable vehicle.
  • the injectable composition of the present invention comprises (a) about 0.1 mg to about 10 mg of metolazone, (b) about 62.5 % w/v of ethanol, (c) about 6.25 % w/v of PEG 35 castor oil and (d) water.
  • the injectable composition of the present invention comprises (a) about 0.1 mg to about 10 mg of metolazone, (b) about 50 % w/v of ethanol, (c) about 18.75 % w/v of PEG 35 castor oil and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 50 % w/v of ethanol, (c) about 18.75 % w/v of PEG 35 Castor oil and (d) water.
  • the injectable composition of the present invention comprises (a) about 5 mg of metolazone, (b) about 30 % w/v of ethanol, (c) about 20 % w/v of PEG 35 Castor oil and (d) water.
  • the injectable composition of the present invention is stable for at least 1 hour after dilution with a compatible admixture diluent.
  • the injectable composition of the present invention is aqueous.
  • the pH of the injectable composition of the present invention may be between about 6 to about 8.
  • the injectable composition of the present invention may demonstrate an osmolality between about 300 to about 350 osmole/kg upon dilution with compatible admixture diluents.
  • stable refers to an injection composition of present invention which is physically as well as chemically stable as demonstrated by compliance to acceptable specification when the composition is stored at convenient temperature, such as between about 0°C and about 60°C, for a commercially reasonable period of time, such as at least about 1 day, at least about 1 week, at least about 1 month, at least about 3 months, at least about 6 months, at least about 1 year, or at least about 2 years.
  • stable also refers to an injectable composition as per the present invention which exhibits physical stability for a sufficiently long time to allow for infusion of the product upon dilution with compatible admixture diluent such as sterile water for injection, saline or dextrose.
  • the injectable compositions of the present invention remain stable after dilution with a compatible admixture diluent for a sufficient time to allow for infusion to be completed.
  • the injectable composition of metolazone of present invention remains physically stable, with no precipitation or crystallization or color change upon storage and the shelf life period of 18-24 months when stored at 2-8° C.
  • the injectable composition of metolazone remains chemically stable when stored at 2-8° C., wherein various parameters such as the drug content (assay of metolazone) and content of related substances, i.e.
  • known and unknown impurities remains within specified limits such as those specified according to ICH guidelines, upon storage for prolonged period of time such as for at least 12 months, preferably for 18 months, more preferably 24 months or longer.
  • the injectable composition of the present invention remains stable for at least 1 hour after dilution with a compatible admixture diluent.
  • the said injectable compositions of metolazone prevent degradation of metolazone such that not more than 2 %, not more than 1%, not more than 0.4%, not more than 0.2% of metolazone impurity or impurities are formed over the storage period.
  • the value of assay of metolazone remains within the specified limit of 90-110% by weight of the label claim.
  • the ICH storage stability studies were performed on the injectable composition of the present invention packaged in the proposed commercial primary packaging and closure system.
  • the stability study samples were stored at 2-8°C, 25°C, 30°C, and 40°C.
  • the necessary parameters viz., assay, related substances, particle size distribution, pH, and osmolality were tested and found to be within specification at both stability conditions.
  • the stability data suggested long term stability at 2-8°C.
  • the time for which long term storage are contemplated include periods of at least about 24 months or longer with such that the composition is substantially free of impurities when stored at 2-8°C.
  • the injectable composition of the present invention can be prepared by a process comprising (a) preparing a mixture of at least one solvent and at least one surfactant; (b) dissolving metolazone in solution of step (a); (c) making up volume of solution of step (b) with water; (d) sterilizing the solution of step (c) followed by filling in appropriate container.
  • the injectable compositions of the present invention can be packaged in any suitable sterile vial or prefilled syringe or container fit for the sterile storage of pharmaceuticals.
  • the stable injectable composition of the present invention can be provided in a kit or package that includes a container enclosing the composition.
  • Suitable containers can be glass vials, i.e., Schott treated vials, molded glass vials, CZ resin vials, polypropylene or polyethylene vials or other special purpose containers.
  • Suitable containers can be prefilled syringes such as glass prefilled syringes, plastic prefilled syringes. Containers are of a size sufficient to hold one or more doses of metolazone.
  • the container may be part of a syringe or separate from the syringe.
  • the kit or package also includes a needle that can be suitably mounted to the syringe.
  • the size of the needle in some embodiments, is equal to or smaller than 18G, 19G, 20G, 21G, 22G, 23G, 24G, or 25G. In one embodiment, the needle has a size that is 20G or smaller. In one embodiment, the needle has a size that is 21G or smaller. In one embodiment, the needle has a size that is 22G or smaller. In one embodiment, the needle has a size that is 23G or smaller.
  • the injectable composition of the present invention may be administered without the need of an in-line filter during administration, demonstrating the absence of particulate matter throughout its shelf life.
  • the injectable composition of the present invention may be filtered by using an in-line filter before administration.
  • treatment of patient suffering from salt and water retention includes, but not limited to treatment of edema accompanying congestive heart failure; and edema accompanying renal diseases, including the nephrotic syndrome and states of diminished renal function.
  • the below table represents injectable composition using only solvents and without addition of any surfactant.
  • compositions prepared with only solvent did not show adequate stability and precipitated within 13 days and also did not exhibit sufficient stability upon dilution with compatible admixture diluents.
  • the below table represents injectable composition comprising a combination of polysorbate 80 in varying concentrations with fixed concentrations of ethanol
  • the below table represents injectable composition comprising a combination of ethanol in varying concentrations with fixed concentrations of polysorbate 80
  • step (b) Metolazone was dissolved in the solution of step (a)
  • step (b) Metolazone was dissolved in the solution of step (a)
  • the below table represents injectable composition with combination of polyethylene glycol and polysorbate 80
  • step (b) Metolazone was dissolved in the solution of step (a)
  • step (b) Metolazone was dissolved in the solution of step (a).

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EP24796452.1A 2023-04-27 2024-04-25 Injizierbare zusammensetzungen von metolazon Pending EP4676487A1 (de)

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US5124152A (en) * 1991-01-07 1992-06-23 Fisons Corporation Parenteral formulation of metolazone
US6383471B1 (en) * 1999-04-06 2002-05-07 Lipocine, Inc. Compositions and methods for improved delivery of ionizable hydrophobic therapeutic agents
EP3661487A4 (de) * 2017-09-12 2021-05-05 Academic Pharmaceuticals, Inc. Formulierung einer metolazonemulsion

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