EP4401727A1 - A stable ready to dilute injectable pharmaceutical formulation of mitomycin - Google Patents

A stable ready to dilute injectable pharmaceutical formulation of mitomycin

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Publication number
EP4401727A1
EP4401727A1 EP22869512.8A EP22869512A EP4401727A1 EP 4401727 A1 EP4401727 A1 EP 4401727A1 EP 22869512 A EP22869512 A EP 22869512A EP 4401727 A1 EP4401727 A1 EP 4401727A1
Authority
EP
European Patent Office
Prior art keywords
mitomycin
pharmaceutical formulation
injectable pharmaceutical
pharmaceutically acceptable
dimethylacetamide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP22869512.8A
Other languages
German (de)
French (fr)
Other versions
EP4401727A4 (en
Inventor
Nisarg Pravinkumar SHAH
Maheshkumar Parasmalji SONI
Dhavalkumar Vallabhadas DADHANIYA
Ajeet Kumar Singh
Ashish Sehgal
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Intas Pharmaceuticals Ltd
Original Assignee
Intas Pharmaceuticals Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Intas Pharmaceuticals Ltd filed Critical Intas Pharmaceuticals Ltd
Publication of EP4401727A1 publication Critical patent/EP4401727A1/en
Publication of EP4401727A4 publication Critical patent/EP4401727A4/en
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions

Definitions

  • the present invention relates to a stable ready to dilute (RTD) injectable pharmaceutical formulation of Mitomycin or a pharmaceutically acceptable salt thereof.
  • the said formulation further comprises N, N - Dimethylacetamide (DMAC), Polyethylene glycol (PEG) and optionally other pharmaceutically acceptable excipients. Further, the present invention discloses process for the preparation of the said formulation.
  • Mitomycin is blue-violet crystalline powder. Mitomycin has an empirical formula of C 15 H 18 N 4 O 5 , a molecular weight of 334.33, and the following structural formula:
  • Mitomycin Mitomycin is marketed as topical and injectable dosage forms.
  • the injectable dosage forms are available as lyophilized powder for injection.
  • the marketed injectable dosage form is available in the form of lyophilized powder under the brand name MUTAMYCIN by Bristol Myers Squibb, MITOZYTREX by Supergen and MITOMYCIN by Medac.
  • the marketed formulation of MUTAMYCIN contains Mitomycin as active pharmaceutical ingredient and mannitol as pharmaceutically acceptable excipients.
  • MUTAMYCIN are available as three dosage strengths i.e., 5 mg per vial, 20 mg per vial, and 40 mg per vial.
  • marketed formulation of MITOZYTREX contains mitomycin as active pharmaceutical ingredient and hydroxypropyl ⁇ cyclodextrin (HP ⁇ CD) as pharmaceutically acceptable excipients.
  • MITOZYTREX is available as one dosage strengths i.e., 5 mg per vial. Furthermore, marketed formulation of MITOMYCIN by Medac contains mitomycin as active pharmaceutical ingredient and urea as pharmaceutically acceptable excipients. MITOMYCIN by Medac are available as four dosage strengths i.e., 2 mg per vial, 10 mg per vial, 20 mg per vial, and 40 mg per vial. All lyophilized products require reconstitution of the powder prior to administration to the patient in need thereof.
  • US10688049 discloses a lyophilized powder composition for parenteral administration comprising Mitomycin, which are characterized by high stability and can be rapidly reconstituted to form solutions. Further, it discloses a solution comprising a mixture of tert-butanol and water, and urea as additives.
  • US6048845 discloses a composition comprising an anti -ulceration effective amount of a substituted cyclodextrin compound, a cytotoxic drug i.e. Mitomycin, and mannitol as bulking agent.
  • Mitomycin has issues related to stability, solubility, reconstitution and their final concentration prior to administration when manufactured in the form of lyophilized powder formulation.
  • the previously available lyophilized product was facing the problems associated with longer reconstitution time and difficulty in making final concentration within the limit prior to administration.
  • the object of present invention is to provide a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof.
  • Another object of present invention is to provide a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof, N, N-Dimethylacetamide and Polyethylene glycol.
  • Another object of present invention is to provide a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof, N, N-Dimethylacetamide, Polyethylene glycol and optionally other pharmaceutically acceptable excipients.
  • Another object of present invention is to provide a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof, N, N-Dimethylacetamide, Polyethylene glycol and optionally other pharmaceutically acceptable excipients, which is diluted with either 0.45 % Sodium chloride injection, 0.9 % Sodium chloride Injection or Sodium lactate Injection to make desired final solution before administration.
  • Another object of present invention is to provide a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof, N, N-Dimethylacetamide, Polyethylene glycol and optionally other pharmaceutically acceptable excipients, which is diluted with either 0.45 % Sodium chloride injection, 0.9 % Sodium chloride Injection or Sodium lactate Injection to make desired final solution before administration, and further administered by intravenous and/or intravesical route of administration.
  • Another object of present invention is to provide a process for the preparation of a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof, N, N- Dimethylacetamide, Polyethylene glycol and optionally other pharmaceutically acceptable excipients.
  • the present invention provides a stable ready to dilute injectable pharmaceutical formulation of Mitomycin or a pharmaceutically acceptable salt thereof.
  • the said formulation further comprises N, N-Dimethylacetamide, Polyethylene glycol and optionally other pharmaceutically acceptable excipients. Further, the present invention discloses process for the preparation of the said formulation.
  • RTD ready to dilute
  • a formulation which is a sterile and stable injectable formulation that is not reconstituted from a solid by a healthcare provider prior to use, and it is further diluted with either 0.45 % Sodium chloride injection, 0.9 % Sodium chloride Injection or Sodium lactate Injection to make desired final solution before administration.
  • a RTD formulation is supplied by a pharmaceutical manufacturer in a suitable container (e.g., vial, syringe, bag, and container) in liquid form.
  • stable ready to dilute injectable pharmaceutical formulation refers to a stable ready to dilute injectable pharmaceutical formulation, which comprises Mitomycin, N, N-Dimethylacetamide, Polyethylene glycol and optionally other pharmaceutically acceptable excipients, wherein impurity D and total impurity in the formulation individually are not more than (NMT) 1.0 % w/w when stored at 2-8 °C temperature for at least 3 months and 25 °C temperature / 60 % RH for at least 1 month; wherein the pH of the formulation is about 5 to 7.
  • total impurity refers to all the defined (i.e., Albomitomycin C (Impurity D), 1,2 cis 1 -hydroxy 2, 7-diaminomitosene, and 1,2 trans 1- hydroxy 2, 7-diaminomitosene) and other uncharacterized impurities.
  • the present invention provides a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof and process for the preparation of said formulation.
  • the present invention provides a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof, N, N-Dimethylacetamide and Polyethylene glycol.
  • the present invention provides a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof, N, N-Dimethylacetamide, Polyethylene glycol and optionally other pharmaceutically acceptable excipients.
  • a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof, N, N-Dimethylacetamide, Polyethylene glycol and optionally other pharmaceutically acceptable excipients; wherein N, N-Dimethylacetamide is present in an amount of about 0.1 ml to 0.5 ml.
  • a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof, N, N-Dimethylacetamide, Polyethylene glycol and optionally other pharmaceutically acceptable excipients; wherein Mitomycin or a pharmaceutically acceptable salt thereof is present in a concentration of about 1 mg/ml to 50 mg/ml.
  • a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof, N, N-Dimethylacetamide, Polyethylene glycol and optionally other pharmaceutically acceptable excipients; wherein Mitomycin or a pharmaceutically acceptable salt thereof is present in a concentration of about 1 mg/ml to 50 mg/ml, N, N-Dimethylacetamide is present in an amount of about 0.1 ml to 0.5 ml and Polyethylene glycol is present in an amount to make the volume up to 1 ml; and the said formulation has pH of about 5.0 to 7.0.
  • a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof, N, N-Dimethylacetamide, Polyethylene glycol and optionally other pharmaceutically acceptable excipients; wherein Mitomycin or a pharmaceutically acceptable salt thereof is present in a concentration of about 1 mg/ml to 50 mg/ml, N, N-Dimethylacetamide is present in an amount of about 0.1 ml to 0.5 ml and Polyethylene glycol is present in an amount to make the volume up to 1 ml; and the said formulation has pH of about 5.0 to 7.0; which is diluted with either 0.45 % Sodium chloride injection, 0.9 % Sodium chloride Injection or Sodium lactate Injection to make desired final solution before administration.
  • a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof, N, N-Dimethylacetamide, Polyethylene glycol and optionally other pharmaceutically acceptable excipients; wherein Mitomycin or a pharmaceutically acceptable salt thereof is present in a concentration of about 1 mg/ml to 50 mg/ml, N, N-Dimethylacetamide is present in an amount of about 0.1 ml to 0.5 ml and Polyethylene glycol is present in an amount to make the volume up to 1 ml; and the said formulation has pH of about 5.0 to 7.0; which is diluted with either 0.45 % Sodium chloride injection, 0.9 % Sodium chloride Injection or Sodium lactate Injection to make desired final solution before administration, and further administered by intravenous and/or intravesical route of administration.
  • a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof, N, N-Dimethylacetamide, Polyethylene glycol and optionally other pharmaceutically acceptable excipients; wherein Mitomycin or a pharmaceutically acceptable salt thereof is present in a concentration of about 1 mg/ml to 50 mg/ml, more specifically Mitomycin or a pharmaceutically acceptable salt thereof is present in a concentration of about 2 mg/ml, 5 mg/ml, 10 mg/ ml, 20 mg/ml, or 40 mg/ml.
  • a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof, N, N-Dimethylacetamide, Polyethylene glycol and optionally other pharmaceutically acceptable excipients; wherein N, N-Dimethylacetamide is present in an amount of about 0.1 ml to 0.5 ml, more specifically N, N- Dimethylacetamide is present in an amount of about 0.1 ml, 0.15 ml, 0.2 ml, 0.25 ml, 0.3 ml, 0.35 ml, 0.4 ml, 0.45 ml, or 0.5 ml.
  • a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof
  • Polyethylene glycol is present in an amount to make the volume up to 1 ml; more specifically Polyethylene glycol is present in an amount of about 0.05 ml, 0.1 ml, 0.15 ml, 0.2 ml, 0.25 ml, 0.3 ml,
  • Polyethylene glycol is Polyethylene glycol 300.
  • a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof in a concentration of about 2 mg/ml, N, N-Dimethylacetamide is present in an amount of about 0.4 ml, Polyethylene glycol, and optionally other pharmaceutically acceptable excipients, wherein Polyethylene glycol is present in an amount to make the volume up to 1 ml; and the said formulation has pH of about 5.0 to 7.0; which is diluted with either 0.45 % Sodium chloride injection, 0.9 % Sodium chloride Injection or Sodium lactate Injection to make desired final solution before administration, and further administered by intravenous and/or intravesical route of administration.
  • a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof in a concentration of about 5 mg/ml, N, N-Dimethylacetamide in an amount of about 0.4 ml, Polyethylene glycol, and optionally other pharmaceutically acceptable excipients, wherein Polyethylene glycol is present in an amount to make the volume up to 1 ml; and the said formulation has pH of about 5.0 to 7.0; which is diluted with either 0.45 % Sodium chloride injection, 0.9 % Sodium chloride Injection or Sodium lactate Injection to make desired final solution before administration, and further administered by intravenous and/or intravesical route of administration.
  • a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof at a concentration of about 10 mg/ml, N, N-Dimethylacetamide in an amount of about 0.4 ml, Polyethylene glycol, and optionally other pharmaceutically acceptable excipients, wherein Polyethylene glycol is present in an amount to make the volume up to 1 ml; and the said formulation has pH of about 5.0 to 7.0; which is diluted with either 0.45 % Sodium chloride injection, 0.9 % Sodium chloride Injection or Sodium lactate Injection to make desired final solution before administration, and further administered by intravenous and/or intravesical route of administration.
  • a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof at a concentration of about 20 mg/ml, N, N-Dimethylacetamide in an amount of about 0.4 ml, Polyethylene glycol, and optionally other pharmaceutically acceptable excipients, wherein Polyethylene glycol is present in an amount to make the volume up to 1 ml; and the said formulation has pH of about 5.0 to 7.0; which is diluted with either 0.45 % Sodium chloride injection, 0.9 % Sodium chloride Injection or Sodium lactate Injection to make desired final solution before administration, and further administered by intravenous and/or intravesical route of administration.
  • a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof at a concentration of about 20 mg/ml, N, N-Dimethylacetamide at an amount of about 0.2 ml, Polyethylene glycol, and optionally other pharmaceutically acceptable excipients, wherein Polyethylene glycol is present in an amount to make the volume up to 1 ml; and the said formulation has pH of about 5.0 to 7.0; which is diluted with either 0.45 % Sodium chloride injection, 0.9 % Sodium chloride Injection or Sodium lactate Injection to make desired final solution before administration, and further administered by intravenous and/or intravesical route of administration.
  • a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof at a concentration of about 40 mg/ml, N, N-Dimethylacetamide in an amount of about 0.4 ml, Polyethylene glycol, and optionally other pharmaceutically acceptable excipients, wherein Polyethylene glycol is present in an amount to make the volume up to 1 ml; and the said formulation has pH of about 5.0 to 7.0; which is diluted with either 0.45 % Sodium chloride injection, 0.9 % Sodium chloride Injection or Sodium lactate Injection to make desired final solution before administration, and further administered by intravenous and/or intravesical route of administration.
  • a stable ready to dilute injectable pharmaceutical formulation can comprise N, N-Dimethylacetamide and Polyethylene glycol are in a weight ratio ranging from about 1 :9 to about 9: 1.
  • the weight ratio of the N, N-Dimethylacetamide and Polyethylene glycol can range from about 1 :9 to about 9: 1.
  • the other pharmaceutically acceptable excipients may comprise of antioxidants.
  • the antioxidants can be selected from but not limited to methionine, monothioglycerol, L-cysteine, Thioglycolic acid, Butylated Hydroxy Anisole (BHA), Butylated Hydroxy Toluene (BHT) and mixtures thereof.
  • the present invention provides a process for the preparation of a stable ready to dilute injectable pharmaceutical formulation comprising, Mitomycin, N, N-Dimethylacetamide, Polyethylene glycol and optionally other pharmaceutically acceptable excipients, wherein the formulation is prepared by process comprising the following steps: a. Take required quantity of N, N-Dimethylacetamide in a manufacturing vessel and sparge inert gas (e.g., nitrogen) with stirring, b. Optionally add other pharmaceutically acceptable excipients into step a, c. Add required quantity of Mitomycin into step b with stirring, d. Add Polyethylene glycol to solution of step c to make up the volume up to batch size with stirring for proper mixing; e. Filter the bulk solution obtained in step d; and f. Fill the filtered bulk solution into glass vials. Stopper the vials with rubber stopper and seal the vials.
  • a stable ready to dilute injectable pharmaceutical formulation comprises, Mitomycin, N, N-Dimethylacetamide, Polyethylene glycol, and optionally other pharmaceutically acceptable excipients, wherein impurity D and total impurity in the formulation individually are not more than (NMT) 1.0 % w/w when stored at 2-8 °C temperature for at least 3 months and 25 °C temperature / 60 % RH for at least 1 month; wherein the pH of the formulation is about 5 to 7.
  • Example 1 a-d Ready to dilute injectable pharmaceutical formulation
  • Example 2 a-d Ready to dilute injectable pharmaceutical formulation (2 mg/ml)
  • Example 3 a-d Ready to dilute injectable pharmaceutical formulation (5 mg/ml)
  • Example 4 a-d Ready to dilute injectable pharmaceutical formulation (10 mg/ml)
  • Example 5 a-d Ready to dilute injectable pharmaceutical formulation (20 mg/ml)
  • Example 6 a-d Ready to dilute injectable pharmaceutical formulation (40 mg/ml)
  • Example 7 a-d Ready to dilute injectable pharmaceutical formulation (20 mg/ml)
  • Process for preparation of formulation of example la and 2-7 a a. Take required quantity of N, N-Dimethylacetamide in a manufacturing vessel and sparge nitrogen gas with stirring; b. Add required quantity of Mitomycin into step a; and stir with nitrogen sparging to dissolve it; c. Add Polyethylene glycol to solution of step b to make up the volume up to batch size and stir with nitrogen sparging for proper mixing; d. Filter the above bulk solution; and e. Fill the filtered solution into amber glass vial. Stopper the vials with rubber stopper and seal the vials.
  • Process for preparation of formulation of example lb and 2-7b a. Take required quantity of N, N-Dimethylacetamide in a manufacturing vessel and sparge nitrogen gas with stirring; b. Add required quantity of Butylated Hydroxy Anisole into step a and stir with nitrogen sparging to dissolve it; c. Add required quantity of Butylated Hydroxy Toluene into step b and stir with nitrogen sparging to dissolve it; d. Add required quantity of Mitomycin into step c and stir with nitrogen sparging to dissolve it; e. Add Polyethylene glycol to solution obtained in step d to make up the volume up to batch size and stir with nitrogen sparging for proper mixing; f. Filter the above bulk solution; g. Fill the filtered solution into amber glass vial. Stopper the vials with rubber stopper and seal the vials.
  • Process for preparation of formulation of example 1 c and 2-7 c a. Take required quantity of N, N-Dimethylacetamide in a manufacturing vessel and sparge nitrogen gas with stirring; b. Add required quantity of Butylated Hydroxy Anisole into step a and stir with nitrogen sparging to dissolve it; c. Add required quantity of Mitomycin into step b and stir with nitrogen sparging to dissolve it;
  • step d Add Polyethylene glycol to solution obtained in step c to make up the volume up to batch size and stir with nitrogen sparging for proper mixing; e. Filter the above bulk solution; f. Fill the filtered solution into amber glass vial. Stopper the vials with rubber stopper and seal the vials.
  • Process for preparation of formulation of example Id and 2-7 d a. Take required quantity of N, N-Dimethylacetamide in a manufacturing vessel and sparge nitrogen gas with stirring;
  • step b Add required quantity of Butylated Hydroxy Toluene into step a and stir with nitrogen sparging to dissolve it; c. Add required quantity of Mitomycin into step b and stir with nitrogen sparging to dissolve it; d. Add Polyethylene glycol to solution obtained in step c to make up the volume
  • N, N- Dimethylacetamide and Polyethylene glycol can be used in preparation of a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin.

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Abstract

The present invention relates to a stable ready to dilute (RTD) injectable pharmaceutical formulation of Mitomycin or a pharmaceutically acceptable salt thereof. The said formulation further comprises N, N - Dimethylacetamide (DMAC), Polyethylene glycol (PEG) and optionally other pharmaceutically acceptable excipients. Further, the present invention discloses process for the preparation of the said formulation.

Description

A stable ready to dilute injectable pharmaceutical formulation of Mitomycin
RELATED APPLICATIONS
This application is related to Indian Provisional Application IN202121042020 filed 17th September, 2021 and is incorporated herein in its entirety.
FILED OF THE INVENTION
The present invention relates to a stable ready to dilute (RTD) injectable pharmaceutical formulation of Mitomycin or a pharmaceutically acceptable salt thereof. The said formulation further comprises N, N - Dimethylacetamide (DMAC), Polyethylene glycol (PEG) and optionally other pharmaceutically acceptable excipients. Further, the present invention discloses process for the preparation of the said formulation.
BACKGROUND OF THE INVENTION
Mitomycin is blue-violet crystalline powder. Mitomycin has an empirical formula of C15H18N4O5, a molecular weight of 334.33, and the following structural formula:
(Mitomycin) Mitomycin is marketed as topical and injectable dosage forms. The injectable dosage forms are available as lyophilized powder for injection.
Historically, due to stability issue of Mitomycin, currently, the marketed injectable dosage form is available in the form of lyophilized powder under the brand name MUTAMYCIN by Bristol Myers Squibb, MITOZYTREX by Supergen and MITOMYCIN by Medac. The marketed formulation of MUTAMYCIN contains Mitomycin as active pharmaceutical ingredient and mannitol as pharmaceutically acceptable excipients. MUTAMYCIN are available as three dosage strengths i.e., 5 mg per vial, 20 mg per vial, and 40 mg per vial. Further, marketed formulation of MITOZYTREX contains mitomycin as active pharmaceutical ingredient and hydroxypropyl β cyclodextrin (HPβCD) as pharmaceutically acceptable excipients. MITOZYTREX is available as one dosage strengths i.e., 5 mg per vial. Furthermore, marketed formulation of MITOMYCIN by Medac contains mitomycin as active pharmaceutical ingredient and urea as pharmaceutically acceptable excipients. MITOMYCIN by Medac are available as four dosage strengths i.e., 2 mg per vial, 10 mg per vial, 20 mg per vial, and 40 mg per vial. All lyophilized products require reconstitution of the powder prior to administration to the patient in need thereof.
US10688049 discloses a lyophilized powder composition for parenteral administration comprising Mitomycin, which are characterized by high stability and can be rapidly reconstituted to form solutions. Further, it discloses a solution comprising a mixture of tert-butanol and water, and urea as additives.
US6048845 discloses a composition comprising an anti -ulceration effective amount of a substituted cyclodextrin compound, a cytotoxic drug i.e. Mitomycin, and mannitol as bulking agent.
From the prior-art literature, it can be concluded that Mitomycin has issues related to stability, solubility, reconstitution and their final concentration prior to administration when manufactured in the form of lyophilized powder formulation. The previously available lyophilized product was facing the problems associated with longer reconstitution time and difficulty in making final concentration within the limit prior to administration.
Considering the prior efforts as disclosed in the background, a need exists which would addresses the issue of solubility, stability and improved reconstitution time of formulation of Mitomycin and provides an alternative as a stable ready to dilute injectable pharmaceutical formulation of Mitomycin.
OBJECT OF THE INVENTION
It is therefore, the object of present invention is to provide a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof.
Another object of present invention is to provide a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof, N, N-Dimethylacetamide and Polyethylene glycol.
Another object of present invention is to provide a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof, N, N-Dimethylacetamide, Polyethylene glycol and optionally other pharmaceutically acceptable excipients.
Another object of present invention is to provide a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof, N, N-Dimethylacetamide, Polyethylene glycol and optionally other pharmaceutically acceptable excipients, which is diluted with either 0.45 % Sodium chloride injection, 0.9 % Sodium chloride Injection or Sodium lactate Injection to make desired final solution before administration. Another object of present invention is to provide a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof, N, N-Dimethylacetamide, Polyethylene glycol and optionally other pharmaceutically acceptable excipients, which is diluted with either 0.45 % Sodium chloride injection, 0.9 % Sodium chloride Injection or Sodium lactate Injection to make desired final solution before administration, and further administered by intravenous and/or intravesical route of administration.
Another object of present invention is to provide a process for the preparation of a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof, N, N- Dimethylacetamide, Polyethylene glycol and optionally other pharmaceutically acceptable excipients.
SUMMARY OF THE INVENTION
The present invention provides a stable ready to dilute injectable pharmaceutical formulation of Mitomycin or a pharmaceutically acceptable salt thereof. The said formulation further comprises N, N-Dimethylacetamide, Polyethylene glycol and optionally other pharmaceutically acceptable excipients. Further, the present invention discloses process for the preparation of the said formulation.
DETAILED DESCRIPTION OF THE INVENTION
All terms as used herein in this application, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. Other more specific definitions for certain terms as used in the present application are as set forth below and are intended to apply uniformly throughout the specification and claims unless an otherwise expressly set out definition provides a broader definition. For the purposes of the present invention, any range given includes both the lower and the upper end points of the range. Range given should be considered approximate, unless specifically stated.
The term “ready to dilute (RTD)” refers to a formulation which is a sterile and stable injectable formulation that is not reconstituted from a solid by a healthcare provider prior to use, and it is further diluted with either 0.45 % Sodium chloride injection, 0.9 % Sodium chloride Injection or Sodium lactate Injection to make desired final solution before administration. Further, a RTD formulation is supplied by a pharmaceutical manufacturer in a suitable container (e.g., vial, syringe, bag, and container) in liquid form.
The term “about” refers to within plus or minus 10 % of a stated value.
The term “stable ready to dilute injectable pharmaceutical formulation” refers to a stable ready to dilute injectable pharmaceutical formulation, which comprises Mitomycin, N, N-Dimethylacetamide, Polyethylene glycol and optionally other pharmaceutically acceptable excipients, wherein impurity D and total impurity in the formulation individually are not more than (NMT) 1.0 % w/w when stored at 2-8 °C temperature for at least 3 months and 25 °C temperature / 60 % RH for at least 1 month; wherein the pH of the formulation is about 5 to 7.
The term “total impurity” refers to all the defined (i.e., Albomitomycin C (Impurity D), 1,2 cis 1 -hydroxy 2, 7-diaminomitosene, and 1,2 trans 1- hydroxy 2, 7-diaminomitosene) and other uncharacterized impurities.
The present invention provides a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof and process for the preparation of said formulation. In another embodiment the present invention provides a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof, N, N-Dimethylacetamide and Polyethylene glycol.
In another embodiment the present invention provides a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof, N, N-Dimethylacetamide, Polyethylene glycol and optionally other pharmaceutically acceptable excipients.
According to present invention, a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof, N, N-Dimethylacetamide, Polyethylene glycol and optionally other pharmaceutically acceptable excipients; wherein N, N-Dimethylacetamide is present in an amount of about 0.1 ml to 0.5 ml.
According to present invention, a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof, N, N-Dimethylacetamide, Polyethylene glycol and optionally other pharmaceutically acceptable excipients; wherein Polyethylene glycol is present in an amount to make the volume up to 1 ml.
According to present invention, a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof, N, N-Dimethylacetamide, Polyethylene glycol and optionally other pharmaceutically acceptable excipients; wherein Mitomycin or a pharmaceutically acceptable salt thereof is present in a concentration of about 1 mg/ml to 50 mg/ml.
According to present invention, a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof, N, N-Dimethylacetamide, Polyethylene glycol and optionally other pharmaceutically acceptable excipients; wherein Mitomycin or a pharmaceutically acceptable salt thereof is present in a concentration of about 1 mg/ml to 50 mg/ml, N, N-Dimethylacetamide is present in an amount of about 0.1 ml to 0.5 ml and Polyethylene glycol is present in an amount to make the volume up to 1 ml; and the said formulation has pH of about 5.0 to 7.0.
According to present invention, a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof, N, N-Dimethylacetamide, Polyethylene glycol and optionally other pharmaceutically acceptable excipients; wherein Mitomycin or a pharmaceutically acceptable salt thereof is present in a concentration of about 1 mg/ml to 50 mg/ml, N, N-Dimethylacetamide is present in an amount of about 0.1 ml to 0.5 ml and Polyethylene glycol is present in an amount to make the volume up to 1 ml; and the said formulation has pH of about 5.0 to 7.0; which is diluted with either 0.45 % Sodium chloride injection, 0.9 % Sodium chloride Injection or Sodium lactate Injection to make desired final solution before administration.
According to present invention, a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof, N, N-Dimethylacetamide, Polyethylene glycol and optionally other pharmaceutically acceptable excipients; wherein Mitomycin or a pharmaceutically acceptable salt thereof is present in a concentration of about 1 mg/ml to 50 mg/ml, N, N-Dimethylacetamide is present in an amount of about 0.1 ml to 0.5 ml and Polyethylene glycol is present in an amount to make the volume up to 1 ml; and the said formulation has pH of about 5.0 to 7.0; which is diluted with either 0.45 % Sodium chloride injection, 0.9 % Sodium chloride Injection or Sodium lactate Injection to make desired final solution before administration, and further administered by intravenous and/or intravesical route of administration.
According to present invention, a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof, N, N-Dimethylacetamide, Polyethylene glycol and optionally other pharmaceutically acceptable excipients; wherein Mitomycin or a pharmaceutically acceptable salt thereof is present in a concentration of about 1 mg/ml to 50 mg/ml, more specifically Mitomycin or a pharmaceutically acceptable salt thereof is present in a concentration of about 2 mg/ml, 5 mg/ml, 10 mg/ ml, 20 mg/ml, or 40 mg/ml.
According to present invention, a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof, N, N-Dimethylacetamide, Polyethylene glycol and optionally other pharmaceutically acceptable excipients; wherein N, N-Dimethylacetamide is present in an amount of about 0.1 ml to 0.5 ml, more specifically N, N- Dimethylacetamide is present in an amount of about 0.1 ml, 0.15 ml, 0.2 ml, 0.25 ml, 0.3 ml, 0.35 ml, 0.4 ml, 0.45 ml, or 0.5 ml.
According to present invention, a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof,
N, N-Dimethylacetamide, Polyethylene glycol and optionally other pharmaceutically acceptable excipients; wherein Polyethylene glycol is present in an amount to make the volume up to 1 ml; more specifically Polyethylene glycol is present in an amount of about 0.05 ml, 0.1 ml, 0.15 ml, 0.2 ml, 0.25 ml, 0.3 ml,
O.35 ml, 0.4 ml, 0.45 ml, 0.5 ml, 0.55 ml, 0.6 ml, 0.65 ml, 0.7 ml, 0.75 ml, 0.8 ml, 0.85 ml, 0.9 ml, 0.95 ml, or 1.0 ml.
More specifically, according to present invention Polyethylene glycol is Polyethylene glycol 300.
According to present invention, a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof in a concentration of about 2 mg/ml, N, N-Dimethylacetamide is present in an amount of about 0.4 ml, Polyethylene glycol, and optionally other pharmaceutically acceptable excipients, wherein Polyethylene glycol is present in an amount to make the volume up to 1 ml; and the said formulation has pH of about 5.0 to 7.0; which is diluted with either 0.45 % Sodium chloride injection, 0.9 % Sodium chloride Injection or Sodium lactate Injection to make desired final solution before administration, and further administered by intravenous and/or intravesical route of administration.
According to present invention, a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof in a concentration of about 5 mg/ml, N, N-Dimethylacetamide in an amount of about 0.4 ml, Polyethylene glycol, and optionally other pharmaceutically acceptable excipients, wherein Polyethylene glycol is present in an amount to make the volume up to 1 ml; and the said formulation has pH of about 5.0 to 7.0; which is diluted with either 0.45 % Sodium chloride injection, 0.9 % Sodium chloride Injection or Sodium lactate Injection to make desired final solution before administration, and further administered by intravenous and/or intravesical route of administration.
According to present invention, a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof at a concentration of about 10 mg/ml, N, N-Dimethylacetamide in an amount of about 0.4 ml, Polyethylene glycol, and optionally other pharmaceutically acceptable excipients, wherein Polyethylene glycol is present in an amount to make the volume up to 1 ml; and the said formulation has pH of about 5.0 to 7.0; which is diluted with either 0.45 % Sodium chloride injection, 0.9 % Sodium chloride Injection or Sodium lactate Injection to make desired final solution before administration, and further administered by intravenous and/or intravesical route of administration.
According to present invention, a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof at a concentration of about 20 mg/ml, N, N-Dimethylacetamide in an amount of about 0.4 ml, Polyethylene glycol, and optionally other pharmaceutically acceptable excipients, wherein Polyethylene glycol is present in an amount to make the volume up to 1 ml; and the said formulation has pH of about 5.0 to 7.0; which is diluted with either 0.45 % Sodium chloride injection, 0.9 % Sodium chloride Injection or Sodium lactate Injection to make desired final solution before administration, and further administered by intravenous and/or intravesical route of administration.
According to present invention, a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof at a concentration of about 20 mg/ml, N, N-Dimethylacetamide at an amount of about 0.2 ml, Polyethylene glycol, and optionally other pharmaceutically acceptable excipients, wherein Polyethylene glycol is present in an amount to make the volume up to 1 ml; and the said formulation has pH of about 5.0 to 7.0; which is diluted with either 0.45 % Sodium chloride injection, 0.9 % Sodium chloride Injection or Sodium lactate Injection to make desired final solution before administration, and further administered by intravenous and/or intravesical route of administration.
According to present invention, a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin or a pharmaceutically acceptable salt thereof at a concentration of about 40 mg/ml, N, N-Dimethylacetamide in an amount of about 0.4 ml, Polyethylene glycol, and optionally other pharmaceutically acceptable excipients, wherein Polyethylene glycol is present in an amount to make the volume up to 1 ml; and the said formulation has pH of about 5.0 to 7.0; which is diluted with either 0.45 % Sodium chloride injection, 0.9 % Sodium chloride Injection or Sodium lactate Injection to make desired final solution before administration, and further administered by intravenous and/or intravesical route of administration. According to present invention, a stable ready to dilute injectable pharmaceutical formulation can comprise N, N-Dimethylacetamide and Polyethylene glycol are in a weight ratio ranging from about 1 :9 to about 9: 1. For example, in the formulation, the weight ratio of the N, N-Dimethylacetamide and Polyethylene glycol can range from about 1 :9 to about 9: 1.
The other pharmaceutically acceptable excipients may comprise of antioxidants.
The antioxidants can be selected from but not limited to methionine, monothioglycerol, L-cysteine, Thioglycolic acid, Butylated Hydroxy Anisole (BHA), Butylated Hydroxy Toluene (BHT) and mixtures thereof.
In another embodiment the present invention provides a process for the preparation of a stable ready to dilute injectable pharmaceutical formulation comprising, Mitomycin, N, N-Dimethylacetamide, Polyethylene glycol and optionally other pharmaceutically acceptable excipients, wherein the formulation is prepared by process comprising the following steps: a. Take required quantity of N, N-Dimethylacetamide in a manufacturing vessel and sparge inert gas (e.g., nitrogen) with stirring, b. Optionally add other pharmaceutically acceptable excipients into step a, c. Add required quantity of Mitomycin into step b with stirring, d. Add Polyethylene glycol to solution of step c to make up the volume up to batch size with stirring for proper mixing; e. Filter the bulk solution obtained in step d; and f. Fill the filtered bulk solution into glass vials. Stopper the vials with rubber stopper and seal the vials.
According to the present invention, a stable ready to dilute injectable pharmaceutical formulation comprises, Mitomycin, N, N-Dimethylacetamide, Polyethylene glycol, and optionally other pharmaceutically acceptable excipients, wherein impurity D and total impurity in the formulation individually are not more than (NMT) 1.0 % w/w when stored at 2-8 °C temperature for at least 3 months and 25 °C temperature / 60 % RH for at least 1 month; wherein the pH of the formulation is about 5 to 7. EXAMPLES
The present invention has been described by the way of example only, and it is to be recognized that modifications thereto falling 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 1a-d: Ready to dilute injectable pharmaceutical formulation
Example 2a-d: Ready to dilute injectable pharmaceutical formulation (2 mg/ml) Example 3a-d : Ready to dilute injectable pharmaceutical formulation (5 mg/ml)
Example 4a-d : Ready to dilute injectable pharmaceutical formulation (10 mg/ml)
Example 5a-d : Ready to dilute injectable pharmaceutical formulation (20 mg/ml) Example 6a-d: Ready to dilute injectable pharmaceutical formulation (40 mg/ml) Example 7a-d : Ready to dilute injectable pharmaceutical formulation (20 mg/ml)
Process for preparation of formulation of example la and 2-7a: a. Take required quantity of N, N-Dimethylacetamide in a manufacturing vessel and sparge nitrogen gas with stirring; b. Add required quantity of Mitomycin into step a; and stir with nitrogen sparging to dissolve it; c. Add Polyethylene glycol to solution of step b to make up the volume up to batch size and stir with nitrogen sparging for proper mixing; d. Filter the above bulk solution; and e. Fill the filtered solution into amber glass vial. Stopper the vials with rubber stopper and seal the vials.
Process for preparation of formulation of example lb and 2-7b: a. Take required quantity of N, N-Dimethylacetamide in a manufacturing vessel and sparge nitrogen gas with stirring; b. Add required quantity of Butylated Hydroxy Anisole into step a and stir with nitrogen sparging to dissolve it; c. Add required quantity of Butylated Hydroxy Toluene into step b and stir with nitrogen sparging to dissolve it; d. Add required quantity of Mitomycin into step c and stir with nitrogen sparging to dissolve it; e. Add Polyethylene glycol to solution obtained in step d to make up the volume up to batch size and stir with nitrogen sparging for proper mixing; f. Filter the above bulk solution; g. Fill the filtered solution into amber glass vial. Stopper the vials with rubber stopper and seal the vials.
Process for preparation of formulation of example 1c and 2-7c: a. Take required quantity of N, N-Dimethylacetamide in a manufacturing vessel and sparge nitrogen gas with stirring; b. Add required quantity of Butylated Hydroxy Anisole into step a and stir with nitrogen sparging to dissolve it; c. Add required quantity of Mitomycin into step b and stir with nitrogen sparging to dissolve it;
5 d. Add Polyethylene glycol to solution obtained in step c to make up the volume up to batch size and stir with nitrogen sparging for proper mixing; e. Filter the above bulk solution; f. Fill the filtered solution into amber glass vial. Stopper the vials with rubber stopper and seal the vials.
10
Process for preparation of formulation of example Id and 2-7d: a. Take required quantity of N, N-Dimethylacetamide in a manufacturing vessel and sparge nitrogen gas with stirring;
15 b. Add required quantity of Butylated Hydroxy Toluene into step a and stir with nitrogen sparging to dissolve it; c. Add required quantity of Mitomycin into step b and stir with nitrogen sparging to dissolve it; d. Add Polyethylene glycol to solution obtained in step c to make up the volume
20 up to batch size and stir with nitrogen sparging for proper mixing; e. Filter the above bulk solution; f. Fill the filtered solution into amber glass vial. Stopper the vials with rubber stopper and seal the vials.
25 Stability study of the formulation of examples:
For the stability study, the formulation obtained in example 6a-d and 7d were stored at 2-8 °C temperature. The stability study results are tabulated below:
30 Stability study of the formulation of example 6a:
Stability study of the formulation of example 6b:
Stability study of the formulation of example 6C:
Stability study of the formulation of example 6d:
Stability study of the formulation of example 7d:
5 ND: Not detected; BQL: Below quantification level; BDL: Below disregard limit From the above stability study results, it can be concluded that N, N- Dimethylacetamide and Polyethylene glycol can be used in preparation of a stable ready to dilute injectable pharmaceutical formulation comprising Mitomycin.

Claims

We Claim:
1. A stable ready to dilute injectable pharmaceutical formulation comprising, a. Mitomycin; b. N, N-Dimethylacetamide; c. Polyethylene glycol; d. Optionally other pharmaceutically acceptable excipients; and e. the pH of the formulation is about 5 to 7; wherein the impurity D and total impurity in the formulation individually are not more than 1.0 % w/w, when stored at 2-8 °C for at least 3 months.
2. The stable ready to dilute injectable pharmaceutical formulation according to claim 1, wherein Mitomycin is in a concentration of about 1 mg/ml to 50 mg/ml.
3. The stable ready to dilute injectable pharmaceutical formulation according to claim 1, wherein Mitomycin is in a concentration of about 20 mg/ml and N, N-Dimethylacetamide is in an amount of about 0.1 to 0.5 ml.
4. The stable ready to dilute injectable pharmaceutical formulation according to claim 1, wherein Mitomycin is in a concentration of about 40 mg/ml and N, N-Dimethylacetamide is in an amount of about 0.1 to 0.5 ml.
5. The stable ready to dilute injectable pharmaceutical formulation according to claim 1, wherein N, N-Dimethylacetamide and Polyethylene glycol are in a weight ratio ranging from about 1 :9 to about 9: 1.
6. The stable ready to dilute injectable pharmaceutical formulation according to claim 1, wherein other pharmaceutically acceptable excipients may comprise of antioxidants, which are selected from methionine, monothioglycerol, L- cysteine, Thioglycolic acid, Butylated Hydroxy Anisole (BHA), Butylated Hydroxy Toluene (BHT) and mixtures thereof.
7. The stable ready to dilute injectable pharmaceutical formulation according to claim 1, which is diluted with either 0.45 % Sodium chloride injection, 0.9 % Sodium chloride Injection or Sodium lactate Injection to make desired final solution before administration. The stable ready to dilute injectable pharmaceutical formulation according to claim 1, which is administered by intravenous and/or intravesical route of administration. A process for the preparation of a stable ready to dilute injectable pharmaceutical formulation comprising, Mitomycin, N, N- Dimethylacetamide; Polyethylene glycol and optionally other pharmaceutically acceptable excipients, wherein the formulation is prepared by process comprising following steps; i. Take required quantity of N, N-Dimethylacetamide in a manufacturing vessel and sparge nitrogen gas with stirring; ii. Optionally add required quantity of other pharmaceutically acceptable excipients into step i and stir with nitrogen sparging to dissolve it; iii. Add required quantity of Mitomycin into step ii; and stir with nitrogen sparging; iv. Add Polyethylene glycol to solution of step iii to make up the volume up to batch size and stir with nitrogen sparging for proper mixing; v. Filter the above bulk solution; and vi. Fill the filtered solution into amber glass vial. Stopper the vials with rubber stopper and seal the vials.
EP22869512.8A 2021-09-17 2022-09-15 Stable, ready-to-use, injectable, pharmaceutical formulation of mitomycin Pending EP4401727A4 (en)

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US5216011A (en) * 1989-09-01 1993-06-01 Bristol-Myers Squibb Co. Stable solutions of mitomycin c
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