WO2024121864A1

WO2024121864A1 - Ready-to-use injectable formulations of lurbinectedin

Info

Publication number: WO2024121864A1
Application number: PCT/IN2023/051141
Authority: WO
Inventors: Ravishanker Kovi; Prasad Vure; Kasu Raghu Rami REDDY; Venkata Sai Dheeraj MUNJULURY; Thupalli Ajey Kumar REDDY; Oshin BARBOZA
Original assignee: Rk Pharma Inc
Priority date: 2022-12-09
Filing date: 2023-12-07
Publication date: 2024-06-13

Abstract

The present invention relates to ready to use injectable formulation of Lurbinectedin. The invention makes it possible to administer Lurbinectedin without the need for reconstitution. The liquid formulation comprises Lurbinectedin and/ or its pharmaceutically acceptable salts and pharmaceutically acceptable excipients for parenteral administration. The present invention provides a polymer based dual or multi-chamber bag for the intravenous administration of Lurbinectedin wherein one chamber contains Lurbinectedin ready-to-use solution, and another chamber contains diluent or a multi-diluent system for parenteral administration. The present invention provides a polymer based dual or multi-chamber bag for the intravenous administration of Lurbinectedin wherein it contains Lurbinectedin ready- to-administer for parenteral administration.

Description

“READY-TO-USE INJECTABLE FORMULATIONS OF LURBINECTEDIN”

CROSS REFERENCE TO THE RELATED APPLICATIONS

This application claims priority benefits earlier of Indian provisional application no’s IN 202241071165 filed on Dec 09, 2022, and IN 202341052714 filed on Aug 05, 2023.

FIELD OF THE INVENTION

The present invention relates to ready to use injectable formulation of Lurbinectedin. The invention makes it possible to administer Lurbinectedin without the need for reconstitution. The liquid formulation comprises Lurbinectedin and/ or its pharmaceutically acceptable salts and pharmaceutically acceptable excipients for parenteral administration.

The present invention provides a polymer based dual or multi-chamber bag for the intravenous administration of Lurbinectedin wherein one chamber contains Lurbinectedin ready-to-use solution, and another chamber contains diluent or a multidiluent system for parenteral administration.

The present invention provides a polymer based dual or multi-chamber bag for the intravenous administration of Lurbinectedin wherein it contains Lurbinectedin ready- to-administer for parenteral administration.

BACKGROUND OF THE INVENTION

Lurbinectedin is a synthetic alkaloid analogue with antineoplastic activity. Lurbinectedin is derivative of the ecteinascidins, particularly ecteinascidin 736 (ET-736). Lurbinectedin (trade name Zepzelca®) is an antitumor chemotherapy drug distributed by Jazz Pharmaceuticals Inc. under license from Pharma Mar S.A. in US. In 2021, Lurbinectedin also received marketing authorization in the United Arab Emirates, Canada, Australia and Singapore.

The chemical name of ZEPZELCA® (Lurbinectedin) is (l’R,6R,6aR,7R, 13S, 14S,16R)-8,14-dihydroxy-6’,9-dimethoxy-4,10,23-trimethyl-19-oxo-2’,3’,4’,6,7,9’,12, 13,14,16-decahydro-6aH-spiro[7,13-azano-6,16-(epithiopropanooxymethano)[l,3] dioxo lo[7,8]isoquinolino[3,2-b][3]benzazocine-20,r-pyrido[3,4-b]indol]-5-yl acetate. The molecular formula is C41H44N4O10S. The molecular weight is 784.87g/mol, and the chemical structure is:

Figure A

ZEPZELCA® for injection 4 mg is supplied as a lyophilized powder in a singledose vial for reconstitution for intravenous use. The ZEPZELCA® lyophilized formulation is comprised of 4 mg Lurbinectedin, sucrose (800 mg), lactic acid (22.1 mg), and sodium hydroxide (5.1 mg). Before use, the lyophilizate is reconstituted by addition of 8 mL Sterile Water for Injection USP, yielding a solution containing 0.5 mg/ml Lurbinectedin (the calculated concentration is 0.47 mg/ml based on the final volume of 8.5 ml). Lurbinectedin is insoluble or practically insoluble in water but solubility increases at acidic pH. Lurbinectedin is administered by intravenous infusion over 60 minutes every 21 days until disease progression or unacceptable toxicity.

Lurbinectedin is covered by patent US 7763615 filed by Pharma Mar SA which covers ecteinascidin compounds for identification of new compounds with optimal features of cytotoxicity and selectivity toward the tumour and with a reduced systemic toxicity and improved pharmacokinetic properties.

The currently available lyophilized dosage form of Lurbinectedin for injection is costly to manufacture, distribute, store and inconvenient to use because it is not in a ready- to-use format. Reconstitution after lyophilization also requires adequate storage if not used immediately after reconstitution, the reconstituted solution can be stored prior to administration for up to 24 hours following reconstitution, including infusion time, at either room temperature/ ambient light or under refrigeration at 2°C-8°C (36°F-46°F) conditions. Therefore, an aqueous and ready-to-use Lurbinectedin solution formulation in affordable price is highly desirable for immediate use.

The present patent application relates to a polymer based dual or multi-chamber bag for the intravenous administration of Lurbinectedin formulation. The multi-chamber bags are made of a polypropylene-based film with a high oxygen barrier. This particular property protects amino acids against oxidation, the main factor in their degradation.

Multi-chamber bags for parenteral nutrition or for parenteral use offer many advantages. They enhance patient safety as they reduce handling and thus the risks of contamination of the nutritional mixture. They bring down the waiting time linked to the opening hours of manufacturing units (the solutions are prepared in hospital pharmacies). The drugs can therefore be dispensed by healthcare staff as soon as they are prescribed. The bags also come in more extensive ranges with simplified storage conditions. All these advantages have allowed the widespread use of these ready-to-use parenteral nutrition bags in hospitals.

Thus, the bag containing Lurbinectedin formulation surprisingly found according to the present disclosure allows to secure the preparation of the pharmacist, provide easy handling, secure the use by the caregiving personnel and guarantee the taking of the intended dose by the patient. The present invention provides a method for enabling hospitals or clinics to administer a dose of a drug to patients in need thereof while avoiding steps of manipulation, reconstitution, dilution, dispensing, sterilization, transfer, handling or compounding before intravenous administration.

SUMMARY OF THE INVENTION

The disclosed invention relates to administration of ready-to-use injectable formulation of Lurbinectedin via dual or multi-chamber bag. The formulation comprises Lurbinectedin with solvents or co-solvents like propylene glycol, ethanol, polyethylene glycol, dimethyl sulfoxide, water for injection; stabilizing agents like mannitol, sucrose, lactose, L-arginine or salts thereof and trehalose; pH adjusting agents like acetic acid, citric acid, lactic acid, fumaric acid, malic acid, succinic acid wherein pH of the solution is in the range of 2-6; wherein purity of Lurbinectedin is more than 90%. The present disclosure relates, in its broadest sense, to a bag for medical use having three compartments, preferably two compartments, more preferably atleast one chamber and having a compartment containing a diluent, a compartment containing a Lurbinectedin formulation and a compartment containing multiple diluents, the opening of which allows liquid to flow by gravity.

The bag comprising the Lurbinectedin composition is a dual or multi-chamber bag and is made up of polymers like polypropylene, polyethylene or ethylene vinyl alcohol or their copolymers with a high oxygen barrier.

The present application provides a composition comprising Lurbinectedin with multiple diluents, preferably 0.9% sodium chloride or 5% dextrose or mixtures thereof.

The present application provides an intravenous bag containing ready-to-use injectable formulation of Lurbinectedin comprising monosaccharide, lactic acid, pH adjusting agent, water for injection and optionally a complexing agent, stabilizing agent, preservative and oxidizing agent for parenteral administration.

The present application provides an intravenous bag containing ready-to-use injectable formulation of Lurbinectedin comprising monosaccharide, lactic acid, pH adjusting agent, water for injection and optionally a complexing agent, stabilizing agent, preservative and oxidizing agent for parenteral administration, preferably via central venous line or peripheral venous line or combinations thereof.

A dual or multi-chamber bag containing ready-to-use liquid parenteral formulation, comprising Lurbinectedin, at least one of a pharmaceutically acceptable solvent, and at least one pharmaceutically acceptable excipient or adjuvant in one chamber and diluent in another chamber.

The present invention discloses Lurbinectedin ready-to-use formulation having a concentration of Lurbinectedin from about 0.001% w/v to about 1% w/v.

The multi-chambered ready-to-use liquid parenteral formulation, comprising Lurbinectedin wherein the assay of Lurbinectedin is more than 99%.

A dual or multi-chamber bag containing ready-to-use liquid parenteral formulation, comprising Lurbinectedin, at least one of a pharmaceutically acceptable solvent, and at least one pharmaceutically acceptable excipient or adjuvant, optionally stabilizing agent in one chamber and diluent is selected from 0.9% of sodium chloride or 5% dextrose in another chamber.

A dual or multi-chamber bag containing ready-to-use liquid parenteral formulation, comprising Lurbinectedin, at least one of a pharmaceutically acceptable solvent, and at least one pharmaceutically acceptable excipient or adjuvant, optionally stabilizing agent, preferably at least one pH adjusting agent in one chamber and diluent selected from 0.9% of sodium chloride or 5% dextrose in another chamber, wherein the impurity deacetyl and dihydroxy of Lurbinectedin are lower than 0.5%.

A dual or multi-chamber bag containing ready-to-use liquid parenteral formulation, comprising Lurbinectedin is stable for a period of 1 month at 40°C.

A dual or multi-chamber bag containing ready-to-use liquid parenteral formulation, comprising Lurbinectedin is stable atleast for a period of 1 month at 40°C.

A dual or multi-chamber bag containing ready-to-use liquid parenteral formulation, comprising Lurbinectedin is stable for a period more than 6 months at 2- 8°C.

A dual or multi-chamber bag containing ready-to-use liquid parenteral formulation, comprising Lurbinectedin is stable throughout the shelf life at 2-8°C.

OBJECT OF THE INVENTION

The principle object of the invention is to provide a ready-to-use injectable Lurbinectedin formulation.

Another object of the invention is to provide a polymer-based bag for intravenous administration of ready-to-use injectable Lurbinectedin formulation, which is preferably easy to administer without need for reconstitution and has a desirable safety profile.

Another embodiment of the invention is to provide a polymer based dual or multichamber bag for the intravenous administration of Lurbinectedin formulation, wherein, the dual or multi-chamber bags are made up of polymers like ethylene vinyl alcohol, ethylene copolymers, butene- 1 copolymers, polypropylene-based or polyethylene film with a high oxygen barrier.

In one or more further embodiments, there is provided a ready-to-use or ready-to- administer, injectable liquid parenteral composition including Lurbinectedin and one or more pharmaceutically acceptable solvents, co-solvents, and/or solubilizing agents, pH stabilizing agents, osmotic agents, preservatives, complexing agents, antioxidants, alone or in combination.

In at least one embodiment, the pharmaceutically acceptable excipient or adjuvant comprises a pH adjuster selected from the group consisting of sodium phosphate, citric acid, acetic acid, lactic acid, gluconic acid, malic acid, fumaric acid alone or in combination.

In at least one embodiment, the pharmaceutically acceptable excipient or adjuvant comprises antioxidants selected from the group of ascorbic acid, acetylcysteine, sulfurous acid salts (bisulfite, metabisulfite), monothioglycerol, alone or in combination.

In at least one embodiment, the pharmaceutically acceptable excipient or adjuvant comprises osmotic agents like but not limited to dextrose, mannitol, glycerol, sodium chloride.

In at least one embodiment, the pharmaceutically acceptable excipient or adjuvant comprises preservatives include but are not limited to methyl paraben, propyl paraben, benzoic acid, sodium benzoate, sorbic acid, benzethonium chloride, benzalkonium chloride, etc. and any combinations thereof.

A further embodiment, the multi-chamber or dual chamber bag contains inlet to fill the two chambers with the Lurbinectedin formulation and diluent system respectively.

In at least one embodiment, after filling of a compartment, a filling tube is welded and cut in order to close off access to said compartment.

A further embodiment, the bag contains chambers separated by a seal that a person breaks without tearing the entire bag. Prior to use, the patient or caregiver breaks the seal between the two chambers and the solution from the two chambers are mixed and used for infusion.

In at least one embodiment, said bag further comprises an outlet tube for the administration of the treatment to a patient.

In at least one embodiment, the bags have been designed to allow different solutions that need mixing just before administration to the patient to be kept separate.

In at least one embodiment, the bags provide the advantages of accurate dosing, easy handling, seal integrity, high stability of the formulation. In at least one embodiment, the formulation has a concentration of Lurbinectedin of less than 10 mg/ml.

In at least one embodiment, the formulation has a concentration of Lurbinectedin of less than 7 mg/ml.

In at least one embodiment, the formulation has a concentration of Lurbinectedin of less than 5 mg/ml.

In at least one embodiment, the formulation has a concentration of Lurbinectedin of less than 0.5 mg/ml to Img/ml.

In at least one embodiment, the formulation has a concentration of Lurbinectedin of from about 0.001 % w/v to about 0.1 % w/v.

In at least one embodiment, the formulation has a concentration of Lurbinectedin of from about 0.1 % w/v to about 1 % w/v.

In at least one embodiment, the formulation has a concentration of Lurbinectedin of about 0.4 % w/v.

In at least one embodiment, at least 90% purity of the Lurbinectedin is retained after storage for 12 months at 5 °C ± 3 °C.

In at least one embodiment, the formulation has a pH from about 2 to about 9.

In at least one embodiment, the formulation has a pH from about 2 to about 8.

In at least one embodiment, the formulation has a pH from about 2 to about 6.

In at least one embodiment, the formulation has a pH from about 2 to about 5.

In at least one embodiment, the solvent comprises water for injection, ethanol, propylene glycol, polyethylene glycol, sorbitol, dimethyl sulfoxide, alone or in combination.

In at least one embodiment, the formulation comprises disaccharide selected from the group consisting of sucrose, trehalose or lactose, or a combination thereof.

In at least one embodiment, the formulation comprises amino acid, the amino acid is selected from the group consisting of arginine, histidine, lysine, phenylalanine and isoleucine, methionine, acetylcysteine, cysteine, citrulline, or any combination thereof.

In at least one embodiment, the formulation comprises monosaccharide selected from the group consisting of mannitol, galactose, glucose or a combination thereof. In another aspect, one chamber of the dual or multi-chamber bag contains Lurbinectedin ready-to-use liquid parenteral formulation that includes Lurbinectedin, sucrose, lactic acid, sodium hydroxide, water for injection and has pH in the range of 2- 9, more preferably 3-5.

In another aspect, one chamber of the dual or multi-chamber bag contains Lurbinectedin ready-to-use liquid parenteral formulation that includes Lurbinectedin, sucrose, citric acid, sodium hydroxide, water for injection and has pH in the range of 3- 5.

In another aspect, one chamber of the dual or multi-chamber bag contains Lurbinectedin ready-to-use liquid parenteral formulation that includes Lurbinectedin, mannitol, lactic acid, sodium hydroxide, water for injection and has pH in the range of 3- 5.

In another aspect, one chamber of the dual or multi-chamber bag contains Lurbinectedin ready-to-use liquid parenteral formulation that includes Lurbinectedin, citric acid, sodium hydroxide, water for injection and has pH in the range of 3-5.

In another aspect, a single dose vial of ready-to-use liquid parenteral formulation is provided that includes Lurbinectedin, ethanol, and sterile water for injection, and wherein the formulation has a pH about 2 to about 6.

A single dose vial of ready-to-use liquid parenteral formulation, comprising Lurbinectedin, dimethyl sulfoxide, sterile water for injection, wherein the formulation has a pH about 2 to about 6.

A further embodiment of the invention wherein, a pharmaceutical ready-to-use formulation of Lurbinectedin, wherein Lurbinectedin has purity more than 95% with deacetyl impurity not more than 1%, dehydroxy impurity not more than 1% and total impurity not more than 3.5% after storage at 5° C.±3° C, preferably total impurity not more than 3% after storage at lower than 5° C.±3° C.

A further embodiment of the invention wherein, a pharmaceutical ready-to-use formulation of Lurbinectedin, wherein Lurbinectedin has purity more than 95% with deacetyl impurity not more than 1%, dehydroxy impurity not more than 1%, any unspecified impurity not more than 0.5%, and total impurity not more than 3.5% after storage at 5° C.±3° C, preferably total impurity not more than 3% after storage at lower than 5° C.±3° C.

In at least one embodiment, more than 90% purity of Lurbinectedin is retained after storage for at least 30 days.

In at least one embodiment, more than 90% purity of Lurbinectedin is retained throughout the shelf-life period.

In at least one embodiment, more than 90% purity of Lurbinectedin is retained throughout the shelf life at 2- 8 °C.

The ready-to-use, injectable compositions of the present application are useful for the treatment of various types of cancer.

The details of one or more embodiments of the application are set forth in the description below. Other features, objects and advantages of the application will be apparent from the description and disclosures.

BRIEF DESCRIPTION OF THE DRAWINGS

The present disclosure will be better understood via the following description, made below purely for informational purposes, of an aspect of the present disclosure, in reference to the drawing in which:

Figure 1: illustrates the multichambered bag according to the present disclosure, wherein Chamber 1 contains Lurbinectedin solution and chamber 2 contains the diluent either 9% sodium chloride, 0.9% sodium chloride or 5 % dextrose solution. Connector is pushed to mix the contents of chamber 1 and 2 before administration via the opener.

Figure 2: illustrates the dual chambered bag according to the present disclosure, these 2-chamber bags allow the separation of different solutions that require admixing just before administration to the patient. The chambers are separated by a divisible connector or peelable welds. The solutions are mixed by simply squeezing one of the chambers manually. They provide good oxygen and water vapor barrier.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present application will now be described more fully hereinafter with reference to the accompanying examples and experiments, in which illustrative embodiments of the application are shown. This application may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the application to those skilled in the art.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. As used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.

As used herein, “bag” refers to dual or multi-chamber bag made up of polymers like polypropylene and/or polyethylene, ethylene vinyl alcohol or their copolymers with a high oxygen barrier.

As used herein, “Lurbinectedin” refers to Lurbinectedin and its pharmaceutically acceptable salts, solvates, hydrates, co-crystals and anhydrous forms thereof.

As used here in “ready-to-use” when used in connection with a Lurbinectedin formulation refers to a ready-to-administer formulation that includes Lurbinectedin in dissolved or solubilized form and/or is intended to be used as such or upon further dilution in intravenous diluents e.g., water for injection or other suitable diluent, before use by the designated route.

As used here in “ready-to-use” more often to be referred as ready to administer Lurbinectedin formulation to a patient without the need for reconstitution.

As used herein, a “single dose” refers to a sterile formulation packed in a container for parenteral administration (injection or infusion). A single-dose formulation is designed for use with a single patient as a single injection/infusion. Examples of containers or bags for use with single-dose formulations and for use with multi dose formulations, and for intravenous infusions include vials, ampules, bottles, intravenous bags, and pre-filled syringes or combinations thereof.

As used herein, and unless otherwise specified, the term “storage-stable” refers to any Lurbinectedin-containing composition or formulation having sufficient physical and chemical stability to allow storage at a convenient temperature, such as between about 0- 8° C and about 10°C, for a commercially reasonable period. The phrase “physical stability” refers to maintenance of color or colorless state, dissolved oxygen level, head space oxygen level and particulate matter, and the phrase “chemical stability” relates to formation assay of Lurbinectedin, Lurbinectedin-related impurities in terms of total impurities, single maximum individual impurity, or maximum individual unknown impurity. For pharmaceutical products, stability is required for commercially relevant times after manufacturing, such as for about 6, 12, 18, 24, 36 months or throughout the shelf life, during which time a product is kept in its original packaging under specified storage conditions.

As used herein, and unless otherwise specified, the term “about” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part, on how the value is measured or determined. In certain embodiments, the term about means within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05% or 0.01% of a given value or range.

The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all, alone or in combination, solvents, co-solvents, complexing agents, pH adjusting agents, solubilizing agents, isotonicity adjusting agents, preservatives, antioxidants, water for injection and stabilizing agents.

Suitable pharmaceutically acceptable diluents include but are not limited to 0.9% of sodium chloride solution, 5% of dextrose solution, mannitol solution, or mixtures thereof.

Suitable pharmaceutically acceptable solvents include but are not limited to water for injection, ethanol, propanol, butanol, polyethylene glycol, propylene glycol, N- methyl-2-pyrrolidone and the like. Preferred solvents are ethanol, propylene glycol, and more preferentially ethanol, more preferably water for injection. Pharmaceutically acceptable preservatives include but are not limited to methyl paraben, propyl paraben, benzoic acid, sodium benzoate, sorbic acid, benzethonium chloride, benzalkonium chloride, etc. and any combinations thereof.

Pharmaceutically acceptable stabilizing agent or agents include but are not limited to meglumine, cysteine, methionine, glucose, fructose, mannitol, glycine, sucrose, arginine, histidine etc. and combinations thereof.

Pharmaceutically acceptable pH adjusting agents include but are not limited to hydrochloric acid, lactic acid, boric acid, citric acid, acetic acid, orthophosphoric acid, succinic acid, sodium hydroxide, potassium hydroxide, ammonium hydroxide, magnesium oxide, calcium carbonate, magnesium carbonate, magnesium aluminum silicates, malic acid, potassium citrate, sodium phosphate, lactic acid, gluconic acid, alpha- ketoglutaric acid, aspartic acid, tartaric acid, fumaric acid, diethanolamine, monoethanolamine, sodium carbonate, sodium bicarbonate, triethanolamine, etc. and combinations thereof.

Pharmaceutically acceptable bulking agents include but are not limited to sucrose, mannitol, glycine, meglumine, dextrose or combinations thereof.

Pharmaceutically acceptable chelating agents may include, but are not limited to, citric acid or derivatives thereof, for example, anhydrous citric acid and the like, ethylenediaminetetraacetic acid (EDTA), disodium EDTA or derivatives thereof, or any combination thereof.

Pharmaceutically acceptable anti-oxidants may include, but are not limited to, ascorbic acid, sodium ascorbate, erythorbic acid, potassium metabisulfite, sodium metabisulfite, propionic acid, thiourea, cysteine, n-acetyl cysteine, methionine, sodium sulfite, or any combination thereof.

Examples of compositions may comprise pharmaceutically acceptable osmolarity or isotonicity adjusting agents but are not limited to dextrose, mannitol, glycerol, sodium chloride.

The formulations according to the present application may be in the form of clear injectable solution, suspension or emulsion. As used herein, the storage- stable ready-to-use injectable formulation may have a concentration of Lurbinectedin of lower than 10 mg/ml. In other embodiments, the injectable formulation may have a concentration of Lurbinectedin lower than 7 mg/ml.

In another embodiment, the injectable formulation may have a concentration of Lurbinectedin less than 5 mg/ml.

In still further embodiments, the injectable formulation may have a concentration of Lurbinectedin of from about 0.001% w/v to about 0.1% w/v.

In still further embodiments, the injectable formulation may have a concentration of Lurbinectedin of from about 0.1% w/v to about 1% w/v.

In still further embodiments, the injectable formulation may have a concentration of Lurbinectedin of from about 0.01% w/v to about 1% w/v.

In particular embodiments of the present application, the injectable formulation may have a concentration of Lurbinectedin of about 0.4% w/v.

In particular embodiments of the present application, the injectable formulation may have a concentration of Lurbinectedin of about 0.05% w/v.

The ready-to-use injectable Lurbinectedin containing formulations disclosed herein do not require any additional reconstitution step at the time of administration, instead the ready-to-use injectable Lurbinectedin containing formulations are for ready to administration in form of bags with a volume ranging from 100 to 500ml, 50ml to 500ml more preferably 100 to 250ml.

The formulations have a controlled impurity profile suitable for regulatory approval at various storage conditions. The storage -stable ready-to-use Lurbinectedin formulations may be stored at 2-8° C. The storage- stable, ready-to-use Lurbinectedin formulations for injection may retain at least 90% of the potency of Lurbinectedin throughout the shelf life after storage at 5°C±3°C, preferably for 12 months at 5°C±3°C.

The ready-to-use, injectable formulations may be formulated to provide single or multiple dosage administration. Formulation prepared by following the mentioned process may be further diluted in 500 ml 0.9% w/v sodium chloride or 5% w/v dextrose. Also, calculated volume of Lurbinectedin formulation prepared by mentioned process may be further diluted in 500 ml 0.9% w/v sodium chloride or 5% w/v dextrose. The single dosage formulation may be packaged in an ampoule, a vial, a syringe or bag. Multiple dosage formulations may be packaged in a vial. Multiple dosage formulations may preferably include at least one preservative.

The formulations have a pH value from about 2 to about 8. In some embodiments the pH range is from about 2.0 to about 7.0. In other embodiments the pH is about 2-6

Storage- stable ready-to-use, injectable formulations disclosed herein contain Lurbinectedin having a purity of from about 80% to about 120%.

In some embodiments the formulation contains Lurbinectedin having a purity of from about 90% to about 110%, preferably 95% to about 110%. In some embodiments the formulation contains Lurbinectedin having a purity of about 100%.

Dual chamber or multi-chamber bag consists of chamber 1 containing Lurbinectedin solution and chamber 2 containing the diluent either 0.9% sodium chloride or 5 % dextrose solution. Connector is pushed to mix the contents of chamber 1 and 2 before administration via the opener. Connector and opener are made up of polyethylene or polypropylene materials that are compatible with the Lurbinectedin ready-to-use formulation.

A polymer based dual or multi-chamber bag for the intravenous administration of Lurbinectedin formulation, wherein the dual or multi-chamber bags are made up of polymers like ethylene vinyl alcohol, ethylene copolymers, butene- 1 copolymers, polypropylene-based or polyethylene film with a high oxygen barrier.

An embodiment of Lurbinectedin formulation wherein the material used for the manufacture of dual or multi-chamber bags with use of Polyolefin, DEHP-Free, Latex- Free, polyvinylchloride (PVC), polypropylene (PP), polyethylene (PE) or polyolefin blend (PP+PE), Polyurethane (PU), polybutadiene (PBD), PVC, PP, PE, ethylene vinyl acetate (EVA), Fluorinated ethylene propylene (FEP) for Parenteral administration.

Examples of acceptable multichambered IV bags containing 0.9% Normal Saline and Lurbinectedin are also made from compatible material include the following: Polypropylene-polyethylene blend (PP-PE) (aka Polyolefin (PO) (eg, 100 to 500 mL), Polypropylene-polyethylene blend (PP-PE) (aka Polyolefin (PO) (eg, 1000 mL), Polyvinyl chloride (PVC) with DEHP (eg, 100 to 500 mL), Polyvinyl chloride (PVC) with DEHP (eg, 1000 mL). Examples of acceptable administration sets with 0.2-micron inline polyethersulfone (PES) filters and tubing made from compatible material include the following: PVC tubing with silicone segments, Polyethylene (PE) (0.2 p m PES filter), the intravenous infusion kit further contains injection port, drip chamber, roller clamp and side clamp which are the parts of the tubing used for infusion drug slow flow can be modulated. The standard sizes of these bags can range from 50 mL to 1000 mL.

Formulations disclosed herein is given in the examples below-

EXAMPLES

The following examples are for illustration only and are not intended in any way to limit the scope of the present application.

Example 1 & TABLE 1

Referring to Table 1, Lurbinectedin 4mg, 0.5 ml sterile water for injection, pH adjusted to 2-6 using acetic acid and 0.5 ml ethanol was added to the sterile water. Thereafter, the solution was stored at 2-8°C.

Example 2 & TABLE 2

Referring to Table 2, with Lurbinectedin, 0.5 ml glycine solution (125 mg glycine dissolved in 0.5 ml sterile water for injection) and pH adjusted to 2-6 using lactic acid and 0.5 ml ethanol was added to the solution and the solution was stored at 2-8° C. Example 3 & TABLE 3

Referring to Table 3, Lurbinectedin (4 mg) was weighed and dissolved in ethanol (3 ml, previously purged with nitrogen) and mixed gently until a clear solution is formed. The solution was filtered using either 0.22p PVDF or PES filter. 2 ml of sterile water for injection was added. pH was adjusted to 2-6 using acetic acid. Filtered solution was filled into vial/prefilled syringe (PFS). The solution was stored at room temperature.

Example 4 & TABLE 4

Referring to Table 4, Lurbinectedin (4mg) was weighed and dissolved in ethanol

(10 ml, previously purged with nitrogen) and mixed gently until a clear solution is formed. The solution was filtered using either 0.22p PVDF or PES filter. Sterile water for injection 10 ml was added. Filtered solution was filled into vial/prefilled syringe. The solution was stored at room temperature.

Example 5 & TABLE 5

Referring to Table 5, with Lurbinectedin was dissolved in 0.5 ml ethanol and 4.5ml of propylene glycol and pH adjusted to 2-6 using lactic acid and the solution was stored at 2-8° C. Example 6 & TABLE 6

Referring to Table 6, with Lurbinectedin, 3 ml ethanol and 2ml of dimethyl sulfoxide was taken and pH adjusted to 2-6 using succinic acid and the solution was stored at 2-8° C.

Example 7 & TABLE 7

Referring to Table 7, with Lurbinectedin, 2.5 ml polyethylene glycol and 2.5ml of propylene glycol was taken and pH adjusted to 2-6 using acetic acid and the solution was stored at 2-8° C.

Example 8 & TABLE 8

Example 9 & TABLE 9

Referring to Table 9, with Lurbinectedin, 5ml polyethylene glycol and 2.5mg of cyclodextrin was taken and dissolved, pH adjusted to 2-6 using acetic acid and the solution was stored at 2-8° C.

Example 10 & TABLE 10

Referring to Table 10, with Lurbinectedin, mannitol, lactic acid and sodium hydroxide was taken and dissolved, pH adjusted to 2-6 using lactic acid and the solution was stored at 2-8° C.

Example 11 & TABLE 11 - Lyophilized trial

Example 12 & TABLE 12

Example 13 & TABLE 13

Example 14 & TABLE 14

Stability data of Lurbinectedin in pharmaceutical formulation is summarized in Table 15 A. As can be seen, the purity of the Lurbinectedin formulation remained stable at more than 90% for at least thirty days.

Table 15A:

Impurity profile of Lurbinectedin is as below:

Procedure: Examples- 11 to 14:

Required quantity of Lurbinectedin was taken in suitable vessel and dissolved in the suitable solvent like buffer, water or TBA (tertiary butyl alcohol) or mixtures thereof, wherein the other excipients also dissolved in the suitable solvent like buffer, water or

TBA (tertiary butyl alcohol) or mixtures thereof, and further solution is aseptically filtered using 0.45-micron followed by 0.22-micron filter. The resulted solution is subjected to lyophilization and resulted lyophilizate is filled into the vial and a diluent into another vial. Example 15 and 16 Manufacturing Formula:

• Manufacturing Procedure:

Lactic acid solution was prepared by dissolving lactic acid in water for injection and stirred for 5 minutes. To that solution Lurbinectedin API was added and the solution was stirred well. The required quantity of sucrose was added and stirred. pH of 3.0 to 4.5 was adjusted by sodium hydroxide. The bulk solution was filtered with a 0.2micron filter. The filtered solution was filled in glass vials or pre-filled syringe. • Analysis:

Table 15 shows the analysis data of the Lurbinectedin solution Example 15

Example 17 and 18

• Manufacturing Formula:

5 • Manufacturing Procedure:

Lactic acid solution was prepared by dissolving lactic acid in water for injection and stirred for 5 minutes. To that solution Lurbinectedin API was added and the solution was stirred well. Required quantity of sucrose was added and stirred. pH of 3.0 to 4.5 was adjusted by sodium hydroxide. The bulk solution was filtered with 0.2micron filter. The 0 filtered solution was filled in polypropylene bags or polyethylene bags.

• Analysis:

Table 17 shows the analysis data of the Lurbinectedin solution Example 17-

Table 18 shows the analysis data of the Lurbinectedin solution Example 18-

Example 19 • Manufacturing Formula:

• Manufacturing Procedure:

Citric acid solution was prepared by dissolving citric acid in water for injection and stirred for 5 minutes. To that solution Lurbinectedin API was added and the solution was stirred well. Required quantity of sucrose was added and stirred and pH of 3.0 to 4.5 was adjusted using sodium hydroxide. The bulk solution was filtered with 0.2-micron filter. The filtered solution was filled in vials or PFS or polypropylene bags or polyethylene bags.

• Analysis: Table 19 shows the analysis data of the Lurbinectedin solution Example 19-

Example 20

• Manufacturing Formula:

• Manufacturing Procedure: Lactic acid solution was prepared by dissolving lactic acid in water for injection and stirred for 5 minutes. To that solution Lurbinectedin API was added and the solution was stirred well. Required quantity of mannitol was added and stirred and pH of 3.0 to 4.5 was adjusted using sodium hydroxide. The bulk solution was filtered with 0.2-micron filter. The filtered solution was filled in vials or PFS or polypropylene bags or polyethylene bags.

• Analysis:

Table 20 shows the analysis data of the Lurbinectedin solution Example 20-

Example 21:

• Manufacturing Formula:

• Manufacturing Procedure: Lactic acid solution was prepared by dissolving lactic acid in water for injection and stirred for 5 minutes. To that solution Lurbinectedin API was added and the solution was stirred well. Required quantity of lactose was added and stirred and pH of 3.0 to 4.5 was adjusted by sodium hydroxide. The bulk solution was filtered with 0.2 micron filter. The filtered solution was filled in vials or PFS or polypropylene bags or polyethylene bags.

• Analysis:

Table 21 shows the analysis data of the Lurbinectedin solution Example 21-

Example 22

Manufacturing Procedure:

Lactic acid solution was prepared by dissolving lactic acid in water for injection and stirred for 5 minutes. To that solution Lurbinectedin API was added and the solution was stirred well and pH of 3.0 to 4.5 was adjusted using sodium hydroxide. The bulk solution was filtered with 0.2 micron filter. The filtered solution was filled in vials or PFS or polypropylene bags or polyethylene bags.

Example 23

Manufacturing Procedure:

Lactic acid solution was prepared by dissolving lactic acid in water for injection and stirred for 5 minutes. To that solution Lurbinectedin API was added and the solution was

5 stirred well. Required quantity of sucrose, L-arginine was added and stirred and pH of 3.0 to 4.5 was adjusted using sodium hydroxide. The bulk solution was filtered with 0.2 micron filter. The filtered solution was filled in vials or PFS polypropylene bags or polyethylene bags.

10

Admixture study:

Study performed in both 0.9% NaCl and 5% Dextrose for Central venous line and peripheral venous line.

A dual or multi-chamber bag containing ready-to-administer liquid parenteral formulation, comprising Lurbinectedin, at least one of a pharmaceutically acceptable solvent, and at least one pharmaceutically acceptable excipient or adjuvant and optionally stabilizing agent in one chamber and diluent in another chamber as per the present invention. The material used for manufacturing of the bag is acceptable with US and EU Pharmacopoeia.

Without wishing to be bound to a theory, the process described in the present invention is believed to be a bag with multi-chamber compartment for the intravenous administration of a ready to use preparation of Lurbinectedin, which is commercially scalable, economical, stable and provides Lurbinectedin with improved yield along with high purity.

While the illustrative embodiments of the invention have been described with particularity, it will be understood that various other modifications will be apparent to and can be readily made by those skilled in the art without departing from the spirit and scope of the invention. Accordingly, it is not intended that the scope of the claims appended hereto be limited to the examples and descriptions set forth hereinabove but rather that the claims be construed as encompassing all the features of patentable novelty which reside in the present invention, including all features which would be treated as equivalents thereof by those skilled in the art to which the invention pertains.

Claims

We claim:

1. A ready-to-use liquid parenteral formulation, comprising Lurbinectedin, at least one of a pharmaceutically acceptable solvent, and at least one pharmaceutically acceptable excipient or adjuvant and optionally pharmaceutically acceptable stabilizing agent.

2. A ready-to-use liquid parenteral formulation as claimed in claim 1 can be vial, ampules, bottles, syringes, intravenous bags or multi chamber bag.

3. The formulation as claimed in claim 1, having a concentration of Lurbinectedin of from about 0.001% w/v to about 1% w/v.

4. The ready-to-use liquid parenteral formulation is having a pH value of about 2 to about 8, more preferably pH more than 3.

5. A multi-chamber bag containing ready-to-use liquid parenteral formulation, comprising Lurbinectedin, atleast one of a pharmaceutically acceptable solvent, and atleast one pharmaceutically acceptable excipient or adjuvant, optionally pharmaceutically acceptable stabilizing agent in one chamber and diluent in another chamber selected from 0.9% of sodium chloride or 5% dextrose.

6. The ready-to-use liquid parenteral formulation as claimed in claim 1 and 5, wherein the pharmaceutically acceptable solvent comprises water for injection, ethanol, propylene glycol, polyethylene glycol, sorbitol, dimethyl sulfoxide, alone or in combination.

7. The ready-to-use liquid parenteral formulation as claimed in claim 1 and 5, wherein the pharmaceutically acceptable excipient or adjuvant comprises a pH adjuster selected from the group consisting of acetic acid, lactic acid, succinic acid, malic acid, fumaric acid.

8. The ready-to-use liquid parenteral formulation as claimed in claim 1 and 5, wherein the stabilizing agents is selected from the group consisting of mannitol, sucrose, lactose, L-arginine or salts thereof and trehalose.

9. A multi-chamber bag used for the intravenous administration of Lurbinectedin formulation as claimed in claim 2 and 5, are made up of polymers like ethylene vinyl alcohol, ethylene copolymers, butene- 1 copolymers, polypropylene-based or polyethylene film with a high oxygen barrier.

10. A multi-chamber bag used for the intravenous administration of Lurbinectedin formulation as claimed in claim 2 and 5, wherein the material used for the manufacture of dual or multi-chamber bags with use of Polyolefin, DEHP-Free, Latex- Free, polyvinylchloride (PVC), polypropylene (PP), polyethylene (PE) or polyolefin blend (PP+PE), Polyurethane (PU), polybutadiene (PBD), PVC, PP or PE for Parenteral administration.

11. Storage- stable ready-to-use, injectable formulations containing Lurbinectedin is having a purity more than 90%, wherein deacetyl impurity (Impurity F), dihydroxy impurity (Impurity G), any unknown impurity of Lurbinectedin are lower than 0.5% or total impurities lower than 3.5%.

12. A pharmaceutical ready-to-use formulation of Lurbinectedin, wherein Lurbinectedin is having more than 99% purity and having impurity A lower than 0.1%, impurity B lower than 0.1%, impurity C lower than 0.1%, impurity D lower than 0.1%, impurity E lower than 0.1%, impurity F lower than 0.1%, impurity G lower than 0.1%, impurity H lower than 0.1% and total impurity not more than 3% after storage at 5° C±3° C.

13. A pharmaceutical ready to administer or ready to admixture of Lurbinectedin, wherein the formulation is stable for more than 4 days duration.