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EP-4734991-A1 - A ROOM TEMPERATURE STABLE AQUEOUS SOLUTION FOR INJECTION OF CLEVIDIPINE

EP4734991A1EP 4734991 A1EP4734991 A1EP 4734991A1EP-4734991-A1

Abstract

The present invention provides a room temperature stable aqueous solution for injection comprising Clevidipine and solubilizer selected from Vitamin E polyethylene glycol succinate, propylene glycol, polyethylene glycol, or a mixture thereof in an amount of 075 % to 20 % w/w of the composition, wherein the solution is stable at room temperature and wherein the solution is a clear, colorless, and transparent solution. Further, the present invention provides a process for the preparation of the said solution. The invention provides a simple aqueous solution that is easy to prepare, and stable which overcomes the limitations of the currently marketed formulation.

Inventors

  • PATEL, BHAVESH NAGINBHAI
  • Saurabh, Surendra Singh
  • Kesarkar, Dnyanadeo Jotiba
  • Shah, Viral Harishbhai

Assignees

  • Precise Biopharma Pvt Ltd

Dates

Publication Date
20260506
Application Date
20240305

Claims (17)

  1. 1. A room temperature stable aqueous solution for injection comprising; (a) Clevidipine or pharmaceutically acceptable salt thereof and (b) Solubilizer selected from Vitamin E polyethylene glycol succinate, propylene glycol, polyethylene glycol, or a mixture thereof, wherein the solution is stable at room temperature.
  2. 2. The room temperature stable aqueous solution as claimed in claim 1, wherein the amount of Clevidipine is 0.25 mg/ml to 5 mg/ml.
  3. 3. The room temperature stable aqueous solution as claimed in claim 1, wherein the amount solubilizer is more than 0.75 % to 20 % w/w.
  4. 4. The room temperature stable aqueous solution as claimed in claim 1, wherein the total impurities of the solution is not more than 2 % and the single maximum impurity is not more than 0.5 % after 6 months when stored at 40 °C temperature and 75 % relative humidity.
  5. 5. The room temperature stable aqueous solution as claimed in claim 1, wherein pH of the solution is 6 to 8.
  6. 6. The room temperature stable aqueous solution as claimed in claim 1, wherein the solution is stable at room temperature throughout shelf-life.
  7. 7. The room temperature stable aqueous solution as claimed in claim 1, wherein the solution is a clear, colorless, and transparent solution.
  8. 8. The room temperature stable aqueous solution as claimed in claim 1, wherein the solution is stable up to 48 hours after the stopper is punctured.
  9. 9. A room temperature stable aqueous solution for injection comprising; (a) Clevidipine or pharmaceutically acceptable salt thereof and (b) Solubilizer selected from Vitamin E polyethylene glycol succinate, propylene glycol, polyethylene glycol, or a mixture thereof, wherein at least one solubilizer is Vitamin E polyethylene glycol succinate, wherein the solution is stable for at least 6 months at 40°C temperature and 75% relative humidity.
  10. 10. The room temperature stable aqueous solution as claimed in claim 1, wherein a process for the preparation of the solution comprises following steps;
  11. 1. Melt vitamin E polyethylene glycol succinate, propylene glycol or polyethylene glycol, or a mixture thereof, and add Clevidipine butyrate in the same.
  12. 2. Add water for injection in step 1 and maintain the temperature at 40 to 60° C and stir till complete dissolution. After complete dissolution, cool the solution below 30° C.
  13. 3. Mix the remaining amount of water for injection, edetate disodium, and glycerine till complete dissolution.
  14. 4. Add the solution of step 2 to the solution of step 3 under stirring.
  15. 5. Adjust pH of the solution between 6 to 8 with 0.5 % w/v sodium hydroxide.
  16. 6. Filter the solution through a 0.2 p nylon/pes capsule filter.
  17. 7. The filtered solution was filled in the USP type I clear glass vial.

Description

A ROOM TEMPERATURE STABLE AQUEOUS SOLUTION FOR INJECTION OF CLEVIDIPINE RELATED APPLICATIONS The present application claims benefit of the Indian Complete Application No. IN202321036811 filed on, May 28th, 2023 the entire contents of which are hereby incorporated by reference. FIELD OF THE INVENTION This invention provides a room temperature stable aqueous solution for injection comprising Clevidipine and solubilizer selected from Vitamin E polyethylene glycol succinate, propylene glycol, polyethylene glycol, or a mixture thereof, wherein the solution is stable for at least 6 months at 40°C temperature and 75% relative humidity. Further, the present invention provides a process for the preparation of the said solution. The invention provides a simple aqueous solution that is easy to prepare, and stable at room temperature which overcomes the limitations of the currently marketed formulation. BACKGROUND OF THE INVENTION Clevidipine is a dihydropyridine calcium channel blocker. Chemically, the active substance, clevidipine, is butyroxymethyl methyl 4-(2',3 'dichlorophenyl)- 1,4- dihydro-2,6-dimethyl-3,5-pyridinedi carboxylate. The product is a racemic mixture, each enantiomer has equipotent antihypertensive activity. The molecular formula is C21H23Q2NO6 and the molecular weight is 456.3 g/mol. The chemical structure of Clevidipine is as follows: Clevidipine as a compound was disclosed in US patent US5856346. Clevidipine is practically insoluble in water. The currently marketed composition is formulated in an oil-in-water emulsion and its brand name is Cleviprex® in the USA. Currently, Clevidipine is marketed as Cleviprex® in the USA. The Cleviprex® injection is supplied as a sterile, milky white liquid emulsion product in single-use glass vials at a concentration of 0.5 mg/mL of Clevidipine. The Cleviprex® contains Clevidipine, soybean oil, glycerin, purified egg yolk phospholipids, oleic acid, disodium edetate, and sodium hydroxide to adjust pH. The Cleviprex® is a ready-to-use emulsion. The Cleviprex® is stored at 2-8°C (36-46°F). The Cleviprex® product vials in cartons can be transferred to 25°C (i.e., room temperature) for not exceeding 2 months. The Cleviprex® is a registered trademark of Chiesi Farmaceutici S.p.A. US5739152 discloses an emulsion for intravenous administration which comprises a short-acting dihydropyridine compound having a half-life in plasma of less than 30 minutes, a lipid phase, emulsifier and water or a buffer. US8658676 discloses a composition comprising Clevidipine, an antimicrobial agent EDTA, a lipid, an emulsifier, a tonicity modifier, and water. The composition disclosed in the US8658676 is an emulsion. US 10010537 discloses a composition comprising Clevidipine butyrate, EDTA, soybean oil, purified egg yolk phospholipids, glycerin, and water. The composition disclosed in the US 10010537 is an emulsion. SUBSTITUTE SHEET (RULE 26) US 11103490 discloses a composition comprising Clevidipine, an antimicrobial agent, a lipid, an emulsifier, a tonicity modifier, a co-emulsifier, water, and an antioxidant selected from the list. The composition disclosed in the US11103490 is an emulsion. WO2020151444 discloses a composition comprising a Clevidipine butyrate fat emulsion injection and a preparation process therefor. WO2019123221 discloses an injectable oil in water pharmaceutical composition comprising effective amount of Clevidipine or a pharmaceutically acceptable salt or ester as an active agent and the process of preparation thereof. WO2022160971 discloses a concentrate, characterized in that the concentrate contains a poorly soluble drug and a self-emulsifying carrier. The concentrate can be used to prepare an intravenous injection emulsion. The patent literatures CN101766568, CN101791311, CN102000027, CN102228434, CN102319212, CN102525918, CN103110580, CN103126986, CN103169672, CN103211760, CN103520104, CN104146958, CN104523590, CN104490777, CN105456189, CN105853353, CN105878182, CN107362139, CN107661294, CN107982215, CN107998488, CN112168778, CN113197853 are discloses emulsion composition or composition having oily components. CN105497909 discloses a composition comprising Clevidipine butyrate and hydroxypropyl-beta-cyclodextrin.CN107343876 discloses a Clevidipine lipid microsphere injection. The CN102228443 discloses a method for preparing Clevidipine butyrate microspheres. The CN101780036 discloses a lipid microsphere injection of butyrate Clevidipine. CN102335134 discloses a Clevidipine butyrate liposome preparation. CN 102665413 discloses Clevidipine or nicardipine in aerosol dry powder form. CN103479577 discloses a lipid nanosuspension containing Clevidipine butyrate, and a freeze-drying preparation of the lipid nanosuspension. WO2015179334 discloses a composition comprising Clevidipine in a sterile, ready to use, physically stable, aqueous dispersion of nanoparticles. W02022160970 discloses a concentrated solution comprising an insoluble drug and a carrier, which helps