Description: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-pyridinedicarboxylate. The product is a racemic mixture, each enantiomer has equipotent antihypertensive activity. The molecular formula is C21H23Cl2NO6 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.

US10010537 discloses a composition comprising Clevidipine butyrate, EDTA, soybean oil, purified egg yolk phospholipids, glycerin, and water. The composition disclosed in the US10010537 is an emulsion.

US11103490 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. CN102665413 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. WO2022160970 discloses a concentrated solution comprising an insoluble drug and a carrier, which helps to form a micelle, wherein the carrier is composed of a composite emulsifier and a co-solvent.

As per the Australian public assessment report the states marketed formulation Cleviprex® needs to be administered within 4 hours after puncture/spike.

Accordingly, it can be concluded that the prior arts disclose either emulsion dosage forms or microspheres or liposome or lipid nanosuspension or nanoparticles, or micelle composition and the marketed formulation is an emulsion which involves a complex manufacturing process and needs to be stored at 2 – 8 °C.

Therefore, there is a need to have a room temperature stable aqueous solution for the injection of Clevidipine which overcomes the limitations of the currently marketed formulation.

OBJECT OF THE INVENTION

The principal object of this invention is to provide 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.

Another object of this invention is to provide 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 at room temperature.

A further object of this invention is to provide 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, and wherein the solution for injection is devoid of any oily material.

Another object of this invention is to provide 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, and wherein the solution for injection is not an emulsion.

Another object of this invention is to provide 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, and wherein pH of the solution is 6-8.

Another object of this invention is to provide 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, wherein pH of the solution is 6-8 and wherein the solution is a clear, colorless, and transparent solution.

Another object of this invention is to provide 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 at room temperature, and wherein pH of the solution is 6-8.

Another object of this invention is to provide 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 at room temperature, and wherein pH of the solution is 6-8 and wherein the solution is a clear, colorless, and transparent solution.

Another object of this invention is to provide a room temperature stable aqueous solution for injection comprising Clevidipine and vitamin E polyethylene glycol succinate, wherein the solution is stable for at least 6 months at 40°C temperature and 75% relative humidity.

Another object of this invention is to provide a room temperature stable aqueous solution for injection comprising Clevidipine and vitamin E polyethylene glycol succinate, wherein the solution is stable at room temperature.

Another object of this invention is to provide a room temperature stable aqueous solution for injection comprising Clevidipine and vitamin E polyethylene glycol succinate, wherein the amount of Vitamin E polyethylene glycol succinate is more than 0.75 % to 20 % w/w of the composition and wherein the solution is stable for at least 6 months at 40°C temperature and 75% relative humidity.

Another object of this invention is to provide a room temperature stable aqueous solution for injection comprising Clevidipine and vitamin E polyethylene glycol succinate, wherein the amount of Clevidipine is 0.25 mg/ml to 5 mg/ml, and the amount of Vitamin E polyethylene glycol succinate is more than 0.75 % to 20 % w/w and wherein the solution is stable for at least 6 months at 40°C temperature and 75% relative humidity.

Another object of this invention is to provide a room temperature stable aqueous solution for injection comprising Clevidipine and vitamin E polyethylene glycol succinate, wherein the amount of Clevidipine is 0.5 mg/ml, and the amount of Vitamin E polyethylene glycol succinate is more than 0.75 % to 20 % w/w and wherein the solution is stable for at least 6 months at 40°C temperature and 75% relative humidity.

Another object of this invention is to provide 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, and wherein the total impurities in the solution is not more than 2% and single impurity is not more than 0.5% throughout shelf-life of the product.

Another object of this invention is to provide 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 at room temperature, and wherein the total impurities in the solution is not more than 2% and single impurity is not more than 0.5% throughout shelf-life of the product.

Another object of this invention is to provide 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 up to 48 hours after the stopper is punctured.

Another object of this invention is to provide 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 can be infused up to 48 hours after the stopper is punctured.

SUMMARY OF THE INVENTION

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 0.75 % to 20 % w/w of the composition, wherein the solution is stable for at least 6 months at 40°C 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 at room temperature which overcomes the limitations of the currently marketed formulation.

DETAILED DESCRIPTION OF THE INVENTION

The detailed description and the examples provided herein are exemplary and any modification or variation within the scope of the invention will be apparent to a person skilled in the art. Further, unless otherwise defined, all the technical and scientific terms used herein shall bear the meaning as understood by a person who is ordinarily skilled in the art.

The term “aqueous solution” refers to a solution that contains water.

The term “stable aqueous solution” refers to an aqueous solution of present invention that is physically and chemically stable at room temperature throughout shelf-life. The room temperature has the same meaning as known to the person skilled in the art and as mentioned in the official compendium like USP or IP.

The term “room temperature stable” or stable at room temperature refers to a solution of the present invention which is to be stored at room temperature and the solution is physically and chemically stable. The room temperature has the same meaning as known to the person skilled in the art and as mentioned in the official compendium like USP or IP.

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, wherein the solution is stable for at least 6 months at 40°C temperature and 75% relative humidity.

In one of the embodiment, 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, wherein the solution is stable at room temperature.

According to the present invention, the amount of Clevidipine in the room temperature stable aqueous solution is 0.25 mg/ml to 5 mg/ml, 0.25 mg/ml to 4 mg/ml, 0.25 mg/ml to 3 mg/ml, 0.25 mg/ml to 2 mg/ml, 0.25 mg/ml to 1 mg/ml, 0.25 mg/ml to 0.75 mg/ml, 0.25 mg/ml, 0.50 mg/ml, 0.75 mg/ml, 1.00 mg/ml, 1.25 mg/ml, 1.50 mg/ml, 1.75 mg/ml, 2.00 mg/ml, 2.50 mg/ml, 3.00 mg/ml, 3.50 mg/ml, 4.00 mg/ml, 4.50 mg/ml or 5.00 mg/ml.

According to the present invention, the amount of solubilizer selected from vitamin E polyethylene glycol succinate, propylene glycol, polyethylene glycol, or a mixture thereof is more than 0.75 % to 20 % w/w, 1 % to 18 % w/w, 1 % to 16 % w/w, 1 % to 14 % w/w, 1 % to 13 % w/w, 1 % to 12 % w/w, 1 % to 10 % w/w, 1 % to 8 % w/w, 1 % to 6 % w/w, 1 % to 5 % w/w, 1 % to 4 % w/w, 1 % to 3 % w/w, 1 % to 2 % w/w.

According to the present invention, a room temperature stable aqueous solution for injection of Clevidipine is devoid of any oily material.

According to the present invention, a room temperature stable aqueous solution for the injection of Clevidipine is not an emulsion.

According to the present invention, a room temperature stable aqueous solution for the injection of Clevidipine is a clear, colorless, and transparent solution.

According to the present invention, a room temperature stable aqueous solution for the injection of Clevidipine has a pH in the range of 6-8. Preferably the pH is around 7.

According to the present invention, a room temperature stable aqueous solution for the injection of Clevidipine, wherein the total impurities of the solution is not more than 2 % and the single maximum impurity is not more than 0.5 % throughout self-life.

According to the present invention, the active ingredient is Clevidipine, and pharmaceutically acceptable salt thereof like Clevidipine butyrate.

According to the present invention, the solubilizer is selected from vitamin E polyethylene glycol succinate, propylene glycol, polyethylene glycol, or a mixture thereof. The amount of solubilizer selected from vitamin E polyethylene glycol succinate, propylene glycol, polyethylene glycol, or a mixture thereof is more than 0.75 % to 20 % w/w.

According to the handbook of pharmaceutical excipients 6th edition, Vitamin E polyethylene glycol succinate is also known as tocofersolan, tocophersolan, tocopherol polyethylene glycol succinate, D-a-tocopheryl polyethylene glycol 1000 succinate, TPGS, vitamin E polyethylene glycol 1000 succinate, vitamin E TPGS. The Vitamin E polyethylene glycol succinate is available as a white to light-brown, waxy solid. Chemically, Vitamin E polyethylene glycol succinate is a mixture of monoesterified polyethylene glycol 1000, the diesterified polyethylene glycol 1000, free polyethylene glycol 1000, and free tocopherol. The room temperature stable aqueous solution of Clevidipine according to the present invention comprises more than 0.75 % to 20 % w/w Vitamin E polyethylene glycol succinate.

Propylene glycol is also known as 1,2-Dihydroxypropane, E1520, 2-hydroxypropanol, methyl ethylene glycol, methyl glycol, propane-1,2-diol, and propylenglycolum. The room temperature stable aqueous solution of Clevidipine according to the present invention comprises more than 0.75 % to 20 % w/w Propylene glycol.

Polyethylene Glycol (PEG), PEG is available as a different grade like PEG 200, 300, 400, 600, 800, 1000, 4000, 6000, 8000, and 20000. The PEG is also known as macrogols, carbowax, macrogola, PEG, polyoxyethylene glycol. The room temperature stable aqueous solution of Clevidipine according to the present invention comprises more than 0.75 % to 20 % w/w polyethylene glycol.

The present invention further comprises edetate disodium glycerine, sodium hydroxide, and water for injection.

In another embodiment, the present invention provides a room temperature stable aqueous solution comprising Clevidipine, Vitamin E polyethylene glycol succinate, wherein the solution is stable for at least 6 months at 40°C temperature and 75% relative humidity.

In another embodiment, the present invention provides a room temperature stable aqueous solution comprising Clevidipine and Vitamin E polyethylene glycol succinate, edetate disodium, glycerine, and water for injection, wherein the solution is stable for at least 6 months at 40°C temperature and 75% relative humidity.

According to the present invention, the amount of vitamin E polyethylene glycol succinate is more than 0.75 % to 20 % w/w, 1 % to 18 % w/w, 1 % to 16 % w/w, 1 % to 14 % w/w, 1 % to 13 % w/w, 1 % to 12 % w/w, 1 % to 10 % w/w, 1 % to 8 % w/w, 1 % to 6 % w/w, 1 % to 5 % w/w, 1 % to 4 % w/w, 1 % to 3 % w/w, 1 % to 2 % w/w.

In another embodiment, the present invention provides a room temperature stable aqueous solution comprising Clevidipine and propylene glycol, wherein the solution is stable for at least 6 months at 40°C temperature and 75% relative humidity.

In another embodiment, the present invention provides a room temperature stable aqueous solution comprising Clevidipine, propylene glycol, edetate disodium, glycerine, and water for injection, wherein the solution is stable for at least 6 months at 40°C temperature and 75% relative humidity.

According to the present invention, the amount of propylene glycol is more than 0.75 % to 20 % w/w, 1 % to 18 % w/w, 1 % to 16 % w/w, 1 % to 14 % w/w, 1 % to 13 % w/w, 1 % to 12 % w/w, 1 % to 10 % w/w, 1 % to 8 % w/w, 1 % to 6 % w/w, 1 % to 5 % w/w, 1 % to 4 % w/w, 1 % to 3 % w/w, 1 % to 2 % w/w.

In another embodiment, the present invention provides a room temperature stable aqueous solution comprising Clevidipine and polyethylene glycol, wherein the solution is stable for at least 6 months at 40°C temperature and 75% relative humidity.

In another embodiment, the present invention provides a room temperature stable aqueous solution comprising Clevidipine, polyethylene glycol, edetate disodium, glycerine, and water for injection, wherein the solution is stable for at least 6 months at 40°C temperature and 75% relative humidity.

According to the present invention, the amount of polyethylene glycol is more than 0.75 % to 20 % w/w, 1 % to 18 % w/w, 1 % to 16 % w/w, 1 % to 14 % w/w, 1 % to 13 % w/w, 1 % to 12 % w/w, 1 % to 10 % w/w, 1 % to 8 % w/w, 1 % to 6 % w/w, 1 % to 5 % w/w, 1 % to 4 % w/w, 1 % to 3 % w/w, 1 % to 2 % w/w.

In another of the embodiment, 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, wherein the solution is stable for at least 6 months at 40°C temperature and 75% relative humidity, and wherein the solution for injection is devoid of any oily material.

In another of the embodiment, 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, wherein the solution is stable for at least 6 months at 40°C temperature and 75% relative humidity, and wherein the solution for injection is not an emulsion.

In another of the embodiment, 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, wherein the solution is stable for at least 6 months at 40°C temperature and 75% relative humidity, and wherein pH of the solution is 6-8.

In another of the embodiment, 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, wherein the solution is stable for at least 6 months at 40°C temperature and 75% relative humidity, wherein pH of the solution is 6-8 and wherein the solution is a clear, colorless, and transparent solution.

In another of the embodiment, 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, wherein the solution is stable at room temperature, and wherein pH of the solution is 6-8.

In another of the embodiment, 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, wherein the solution is stable at room temperature, and wherein pH of the solution is 6-8 and wherein the solution is a clear, colorless, and transparent solution.

In another of the embodiment, the present invention provides a room temperature stable aqueous solution for injection comprising Clevidipine and vitamin E polyethylene glycol succinate, wherein the solution is stable for at least 6 months at 40°C temperature and 75% relative humidity.

In another of the embodiment, the present invention provides a room temperature stable aqueous solution for injection comprising Clevidipine and vitamin E polyethylene glycol succinate, wherein the solution is stable at room temperature.

In another of the embodiment, the present invention provides a room temperature stable aqueous solution for injection comprising Clevidipine and vitamin E polyethylene glycol succinate, wherein the amount of Vitamin E polyethylene glycol succinate is more than 0.75 % to 20 % w/w of the composition and wherein the solution is stable for at least 6 months at 40°C temperature and 75% relative humidity.

In another of the embodiment, the present invention provides a room temperature stable aqueous solution for injection comprising Clevidipine and vitamin E polyethylene glycol succinate, wherein the amount of Clevidipine is 0.25 mg/ml to 5 mg/ml, and the amount of Vitamin E polyethylene glycol succinate is more than 0.75 % to 20 % w/w and wherein the solution is stable for at least 6 months at 40°C temperature and 75% relative humidity.

In another of the embodiment, the present invention provides a room temperature stable aqueous solution for injection comprising Clevidipine and vitamin E polyethylene glycol succinate, wherein the amount of Clevidipine is 0.5 mg/ml, and the amount of Vitamin E polyethylene glycol succinate is more than 0.75 % to 20 % w/w and wherein the solution is stable for at least 6 months at 40°C temperature and 75% relative humidity.

In another of the embodiment, 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, wherein the solution is stable for at least 6 months at 40°C temperature and 75% relative humidity, and wherein the total impurities in the solution is not more than 2% and single impurity is not more than 0.5% throughout shelf-life of the product.

In another of the embodiment, 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, wherein the solution is stable at room temperature, and wherein the total impurities in the solution is not more than 2% and single impurity is not more than 0.5% throughout shelf-life of the product.

In another embodiment, the present invention provides a room temperature stable aqueous solution comprising Clevidipine in the amount of 0.25 mg/ml to 5 mg/ml, solubilizer selected from Vitamin E polyethylene glycol succinate, propylene glycol, polyethylene glycol, or a mixture thereof in the amount of 17 mg/ml to 230 mg/ml, Edetate Disodium in the amount of 0.03 mg/ml to 0.7 mg/ml, Glycerine in the amount of 15 mg/ml to 250 mg/ml, Sodium hydroxide for pH adjustment and Water for Injection, wherein the solution is stable for at least 6 months at 40°C temperature and 75% relative humidity.

In another embodiment, the present invention provides a room temperature stable aqueous solution comprising Clevidipine in the amount of 0.25 mg/ml to 5 mg/ml, Vitamin E polyethylene glycol succinate in the amount of 17 mg/ml to 230 mg/ml, edetate disodium in the amount of 0.03 mg/ml to 0.7 mg/ml, glycerine in the amount of 15 mg/ml to 250 mg/ml, Sodium hydroxide for pH adjustment and Water for Injection, wherein, pH of the solution is 6 to 8, the solution is a clear, colorless, and transparent solution and the solution is stable for at least 6 months at 40°C temperature and 75% relative humidity.

In another embodiment, the present invention provides a room temperature stable aqueous solution comprising Clevidipine in the amount of 0.25 mg/ml to 5 mg/ml, Vitamin E polyethylene glycol succinate in the amount of 17 mg/ml to 230 mg/ml, edetate disodium in the amount of 0.03 mg/ml to 0.7 mg/ml, glycerine in the amount of 15 mg/ml to 250 mg/ml, sodium hydroxide for pH adjustment and water for injection, wherein, pH of the solution is 6 to 8, the solution is a clear, colorless, and transparent solution and the solution is stable for at least 6 months at 40°C temperature and 75% relative humidity and the solution does not contain oily substance and the solution is not in a form of emulsion or liposome or dispersion.

In another embodiment, the present invention provides a room temperature stable aqueous solution comprising Clevidipine in the amount of 0.25 mg/ml to 5 mg/ml, Solubilizer selected from Vitamin E polyethylene glycol succinate, propylene glycol, polyethylene glycol, or a mixture thereof in the amount of more than 0.75 % to 20 % w/w, wherein, pH of the solution is 6 to 8, the solution is a clear, colorless, and transparent solution, the solution is stable for at least 6 months at 40°C temperature and 75% relative humidity and total impurities in the solution are not more than 2 % and the single maximum impurity is not more than 0.5 % throughout shelf-life when stored at room temperature.

In another embodiment, 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, wherein the solution is stable up to 48 hours after the stopper is punctured.

The solution of the present invention does not contain any excipient which can promote microbial growth. Once, punctured or spiked, the solution of the present invention remains stable for 48 hours and can be administered to the patient in need thereof within 48 hours.

The solution of the present invention can be administered alone and can be co-administered with water for injection, sodium chloride (0.9%) injection, dextrose (5%) injection, dextrose (5%) in sodium chloride (0.9%) injection, dextrose (5%) in ringers lactate injection and lactated ringers injection.

The solution of the present invention is stable for up to 48 hours with water for injection, 0.9% sodium chloride injection, 5% dextrose injection, dextrose (5%) in sodium chloride (0.9%) injection, and lactated ringers injection.

In another embodiment, 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, wherein the solution can be infused up to 48 hours after the stopper is punctured.

In another embodiment, the present invention provides a room temperature stable aqueous solution for injection comprising; Clevidipine or pharmaceutically acceptable salt thereof and 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.

In another embodiment, 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, wherein a process for the preparation of the solution comprises following steps;
1. vitamin E polyethylene glycol succinate, propylene glycol, polyethylene glycol, or a mixture thereof was melted and Clevidipine butyrate was added in the same and stirred.
2. Water for injection was added in step 1 and the temperature was maintained at 40 to 60° C and stirred till complete dissolution. After complete dissolution, the solution was cooled below 30° C.
3. Remaining amount of water for injection, edetate disodium, and glycerine were mixed till complete dissolution.
4. Solution of step 2 was added to the solution of step 3 under stirring.
5. pH of the solution was adjusted between 6 to 8 with 0.5 % w/v sodium hydroxide.
6. The solution was filtered through 0.2 µ nylon/pes capsule filter.
7. The filtered solution was filled in the USP type I clear glass vial.

EXAMPLES

The present invention has been described by way of example only, and it is to be recognized that modifications thereto filling within the scope and spirit of appended claims, and which would be obvious to a person skilled in the art based upon the disclosure herein, are also considered to be within the scope of this invention.

Example 1: According to the present invention

S. No. Ingredients Quantity in
mg/ ml
1 Clevidipine butyrate 0.5
2 Vitamin E Polyethylene Glycol Succinate (Vitamin E TPGS) 20.00
3 Edetate Disodium 0.05
4 Glycerine 22.50
5 0.5% w/v Sodium hydroxide solution q.s. to adjust pH
6 Water for Injection q.s. to 1 ml

Example 2: 50 ml fill volume (According to the present invention)

S. No. Ingredients Quantity for 50 ml fill volume (mg)
1 Clevidipine butyrate 25.00
2 Vitamin E Polyethylene Glycol Succinate (Vitamin E TPGS) 1000.00
3 Edetate Disodium 2.50
4 Glycerine 1125.00
5 0.5% w/v Sodium hydroxide solution q.s. to adjust pH
6 Water for Injection q.s. to 50 ml

Example 3: 100 ml fill volume (According to the present invention)

S. No. Ingredients Quantity for 100 ml fill volume (mg)
1 Clevidipine butyrate 50.00
2 Vitamin E Polyethylene Glycol Succinate (Vitamin E TPGS) 2000.00
3 Edetate Disodium 5.00
4 Glycerine 2250.00
5 0.5% w/v Sodium hydroxide solution q.s. to adjust pH
6 Water for Injection q.s. to 100 ml

Process for preparation for example 1 – 3:

1. Vitamin E polyethylene glycol succinate was melted and maintained at 40 to 60° C temperature and Clevidipine butyrate was added in the same and stirred.
2. Water for injection was added in step 1 and the temperature was maintained at 40 to 60° C and stirred till complete dissolution. After complete dissolution, the solution was cooled below 30° C.
3. Remaining amount of water for injection, edetate disodium, and glycerine were mixed till complete dissolution.
4. Solution of step 2 was added to the solution of step 3 under stirring.
5. pH of the solution was adjusted between 6 to 8 with 0.5 % w/v sodium hydroxide.
6. The volume was made to 100% with water for injection.
7. The solution was filtered through 0.2 µ nylon/pes capsule filter.
8. The filtered solution was filled in the USP type I clear glass vial.
9. The filled vials were autoclaved at 121° C for 15 min at 15 lbs pressure.

Example 4: According to the present invention

Batch number B-4
API concentration 0.5 mg/mL
S. No. Ingredients
1 Clevidipine butyrate 0.5 mg
2 Vitamin E Polyethylene Glycol Succinate (Vitamin E TPGS) 15.00 mg
3 Edetate Disodium 0.05 mg
4 Glycerine 22.50 mg
5 0.5% w/v Sodium hydroxide solution Qs to adjust pH
6 Water for Injection QS to 1 ml

Example 5: According to the present invention

Batch number B-5
API concentration 2.0 mg/mL
S. No. Ingredients
1 Clevidipine butyrate 2.0 mg
2 Vitamin E Polyethylene Glycol Succinate (Vitamin E TPGS) 60.00 mg
3 Edetate Disodium 0.20 mg
4 Glycerine 22.50 mg
5 0.5% w/v Sodium hydroxide solution Qs to adjust pH
6 Water for Injection QS to 1 ml

Example 6: According to the present invention

Batch number B-6
API concentration 0.5 mg/mL
S. No. Ingredients
1 Clevidipine butyrate 0.5 mg
2 Vitamin E Polyethylene Glycol Succinate (Vitamin E TPGS) 20.00 mg
3 Edetate Disodium 0.05 mg
4 Glycerine 22.50 mg
5 0.5% w/v Sodium hydroxide solution Qs to adjust pH
6 Water for Injection QS to 1 ml

Example 7: According to the present invention

Batch number B-7
API concentration 5.0 mg/mL
S. No. Ingredients
1 Clevidipine butyrate 5.0 mg
2 Vitamin E Polyethylene Glycol Succinate (Vitamin E TPGS) 200.00 mg
3 Edetate Disodium 0.50 mg
4 Glycerine 22.50 mg
5 0.5% w/v Sodium hydroxide solution Qs to adjust pH
6 Water for Injection QS to 1 ml

Example 8: Not according to the present invention

Batch number B-3
API concentration 0.5 mg/mL
S. No. Ingredients
1 Clevidipine butyrate 0.5 mg
2 Vitamin E Polyethylene Glycol Succinate (Vitamin E TPGS) 7.50 mg
3 Edetate Disodium 0.05 mg
4 Glycerine 22.50 mg
5 0.5% w/v Sodium hydroxide solution Qs to adjust pH
6 Water for Injection QS to 1 ml

Process for preparation for examples 4 to 9:

Examples 4 to 9 were prepared as per the process mentioned above for examples 1 - 3.

The room temperature stable aqueous solution for injection of Examples 1, and example 4 - 8 were evaluated for their physical and chemical characteristics.

Following are the study results:

S. No. Batch number / Example Example 1 Example 8 Example 4 Example 5 Example 6 Example 7
1 Description CCTS* Hazy solution CCTS* CCTS* CCTS* CCTS*
2 pH 6.79 6.45 6.45 6.49 6.13 6.32
3 Assay 101.3 99 105.7 99.63 99.13 100.32
4 Related Substances (Before Autoclave)
Impurity A ND Not Performed ND Not Performed 0.02 0.03
Impurity B 0.05 Not Performed 0.05 Not Performed 0.02 0.02
Single maximum 0.09 Not Performed 0.23 Not Performed 0.04 0.05
Total impurities 0.21 Not Performed 0.86 Not Performed 0.14 0.16
5 Related Substances (After Autoclave)
Impurity A Not Performed Not Performed ND 0.01 0.02 0.03
Impurity B Not Performed Not Performed 0.08 0.14 0.12 0.1
Single maximum Not Performed Not Performed 0.27 0.13 0.04 0.05
Total impurities Not Performed Not Performed 0.47 0.31 0.23 0.25
* - CCTS: Clear colourless transparent solution

Further the room temperature stable aqueous solution for injection of Examples 1, and example 4 - 7 were subject to stability study at 40°C temperature 75% relative humidity for 6 months.

Stability study (40°C/75% RH)
3 Months
S. No. Ingredients Example 1 Example 8 Example 4 Example 5 Example 6 Example 7
1 Description CCTS* Not Performed CCTS* CCTS* CCTS* CCTS*
2 pH 6.81 Not Performed 6.58 6.35 6.26 6.41
3 Assay 100.31 Not Performed 101.2 98.63 98.13 99.86
4 Related Substances
Impurity A ND Not Performed ND 0.02 0.04 0.02
Impurity B 0.05 Not Performed 0.05 0.13 0.1 0.08
Single maximum 0.1 Not Performed 0.39 0.14 0.09 0.12
Total impurities 0.34 Not Performed 1.53 0.43 0.31 0.53
6 Months
S. No. Ingredients Example 1 Example 8 Example 4 Example 5 Example 6 Example 7
1 Description CCTS* Not Performed CCTS* CCTS* CCTS* CCTS*
2 pH 6.51 Not Performed 6.53 6.43 6.23 6.42
3 Assay 98.85 Not Performed 98.63 99.63 100.2 98.63
4 Related Substances
Impurity A ND Not Performed ND 0.03 0.04 0.03
Impurity B 0.06 Not Performed 0.04 0.15 0.13 0.09
Single maximum 0.1 Not Performed 0.42 0.15 0.06 0.1
Total impurities 0.36 Not Performed 1.66 0.61 0.56 0.63

Stability study (30°C/75% RH)
3 Months
S. No. Ingredients Example 1 Example 8 Example 4 Example 5 Example 6 Example 7
1 Description CCTS* Not Performed CCTS* CCTS* CCTS* CCTS*
2 pH 6.72 Not Performed 6.43 6.45 6.36 6.44
3 Assay 99.56 Not Performed 99.85 99.86 99.63 99.13
4 Related Substances
Impurity A ND Not Performed ND 0.02 0.03 0.04
Impurity B 0.06 Not Performed 0.09 0.15 0.11 0.09
Single maximum 0.10 Not Performed 0.32 0.15 0.06 0.06
Total impurities 0.26 Not Performed 0.72 0.61 0.43 0.36
6 Months
S. No. Ingredients Example 1 Example 8 Example 4 Example 5 Example 6 Example 7
1 Description CCTS* Not Performed CCTS* CCTS* CCTS* CCTS*
2 pH 6.59 Not Performed 6.42 6.33 6.23 6.61
3 Assay 98.53 Not Performed 99.86 99.13 99.86 99.31
4 Related Substances
Impurity A ND Not Performed ND 0.02 0.02 0.05
Impurity B 0.06 Not Performed 0.08 0.16 0.12 0.10
Single maximum 0.11 Not Performed 0.29 0.14 0.08 0.08
Total impurities 0.29 Not Performed 0.61 0.71 0.56 0.43
* - CCTS: Clear colourless transparent solution

The stability study data indicated that the aqueous solution for injection of Examples 1, and example 4 – 7 are stable.

Example 9: According to the present invention

Qty. in mg
S. No. Ingredients Ex. 9a Ex. 9b Ex. 9c Ex. 9d
1 Clevidipine butyrate 0.25 5 0.25 5
2 Vitamin E Polyethylene Glycol Succinate (Vitamin E TPGS) 5 20 5 20
3 Polyethylene Glycol 200 0.1 - -
4 Propylene glycol - - 300 0.1
5 Edetate Disodium 0.5 0.05 0.5 0.05
6 Glycerine 25 0.1 25 0.1
7 0.5% w/v Sodium hydroxide solution Qs to adjust pH Qs to adjust pH Qs to adjust pH Qs to adjust pH
8 Water for Injection QS to 1 ml QS to 1 ml QS to 1 ml QS to 1 ml

Physical and chemical analysis of example 9a – 9d (at initial time)

S. No. Ex. 9a Ex. 9b Ex. 9c Ex. 9d
1 Description CCTS* CCTS* CCTS* CCTS*
2 pH 6.46 6.85 6.82 6.36
3 Assay 99.53 100.63 98.52 99.39
4 Related Substances
Impurity A ND ND ND 0.01
Impurity B 0.03 0.05 0.04 0.09
Single maximum 0.09 0.23 0.23 0.22
Total impurities 0.36 0.31 0.39 0.46
* - CCTS: Clear colourless transparent solution

Example 10: Stability of the solution of the present invention with other injectable solutions (to evaluate stability after puncture).

Solution of Example 4 (batch B4) with other injectable solution (i.e., stability in case of co-administration):

Related Substance
Combination Condition pH Impurity-A Impurity-B SMUI Total Impurities
B4+WFI (1:1) Initial 6.19 ND 0.10% 0.34% 0.96%
B4+NS (1:1) Initial 6.25 ND 0.09% 0.10% 0.22%
B4+DNS (1:1) Initial 5.64 ND 0.10% 0.10% 0.24%
B4+RL (1:1) Initial 6.1 ND 0.09% 0.10% 0.23%
B4+5% DS (1:1) Initial 5.89 ND 0.09% 0.10% 0.23%
B4+WFI (1:1) After 48 Hours 6.12 ND 0.09% 0.06% 0.20%
B4+NS (1:1) After 48 Hours 6.14 ND 0.09% 0.06% 0.20%
B4+DNS (1:1) After 48 Hours 5.55 ND 0.10% 0.07% 0.22%
B4+RL (1:1) After 48 Hours 5.98 ND 0.09% 0.05% 0.19%
B4+5% DS (1:1) After 48 Hours 5.96 ND 0.10% 0.07% 0.22%

Solution of Example 5 (batch B5) with other injectable solution (i.e., stability in case of co-administration):

Related Substance
Batch No Condition pH Impurity-A Impurity-B SMUI Total Impurities
B5+WFI (1:1) Initial 5.65 ND 0.13% 0.09% 0.26%
B5+NS (1:1) Initial 5.88 ND 0.13% 0.14% 0.31%
B5+DNS (1:1) Initial 4.93 ND 0.13% 0.09% 0.26%
B5+RL (1:1) Initial 6.1 ND 0.14% 0.11% 0.30%
B5+5% DS (1:1) Initial 5.4 ND 0.13% 0.11% 0.28%
B5+WFI (1:1) After 48 Hours 5.72 ND 0.12% 0.06% 0.22%
B5+NS (1:1) After 48 Hours 5.86 ND 0.11% 0.05% 0.20%
B5+DNS (1:1) After 48 Hours 4.97 ND 0.12% 0.05% 0.22%
B5+RL (1:1) After 48 Hours 6.12 ND 0.12% 0.06% 0.23%
B5+5% DS (1:1) After 48 Hours 5.38 ND 0.12% 0.05% 0.21%

NS: Sodium chloride (0.9%) injection, 5%DS: Dextrose (5%) injection, DNS: Dextrose (5%) in sodium chloride (0.9%) injection, RL: Lactated ringers injection
WFI: Water for Injection

From the above examples and study results, it can be concluded 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. The solution of the present invention can be infused/administered up to 48 hours after the stopper is punctured. 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.
I / We claim,

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. 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. 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. 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. The room temperature stable aqueous solution as claimed in claim 1, wherein pH of the solution is 6 to 8.

6. The room temperature stable aqueous solution as claimed in claim 1, wherein the solution is stable at room temperature throughout shelf-life.

7. The room temperature stable aqueous solution as claimed in claim 1, wherein the solution is a clear, colorless, and transparent solution.

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. 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. The room temperature stable aqueous solution as claimed in claim 1, wherein a process for the preparation of the solution comprises following steps;
1. Melt vitamin E polyethylene glycol succinate, propylene glycol or polyethylene glycol, or a mixture thereof, and add Clevidipine butyrate in the same.
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.
3. Mix the remaining amount of water for injection, edetate disodium, and glycerine till complete dissolution.
4. Add the solution of step 2 to the solution of step 3 under stirring.
5. Adjust pH of the solution between 6 to 8 with 0.5 % w/v sodium hydroxide.
6. Filter the solution through a 0.2 µ nylon/pes capsule filter.
7. The filtered solution was filled in the USP type I clear glass vial. , Claims:I / We claim,

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. 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. 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. 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. The room temperature stable aqueous solution as claimed in claim 1, wherein pH of the solution is 6 to 8.

6. The room temperature stable aqueous solution as claimed in claim 1, wherein the solution is stable at room temperature throughout shelf-life.

7. The room temperature stable aqueous solution as claimed in claim 1, wherein the solution is a clear, colorless, and transparent solution.

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. 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. The room temperature stable aqueous solution as claimed in claim 1, wherein a process for the preparation of the solution comprises following steps;
1. Melt vitamin E polyethylene glycol succinate, propylene glycol or polyethylene glycol, or a mixture thereof, and add Clevidipine butyrate in the same.
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.
3. Mix the remaining amount of water for injection, edetate disodium, and glycerine till complete dissolution.
4. Add the solution of step 2 to the solution of step 3 under stirring.
5. Adjust pH of the solution between 6 to 8 with 0.5 % w/v sodium hydroxide.
6. Filter the solution through a 0.2 µ nylon/pes capsule filter.
7. The filtered solution was filled in the USP type I clear glass vial.