DESC: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 ß cyclodextrin (HPßCD) 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, 0.35 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

Sr. No. Ingredients 2–40 mg/ml
(Qty./ml) – 1a 2–40 mg/ml
(Qty./ml) – 1b 2–40 mg/ml
(Qty./ml) – 1c 2–40 mg/ml
(Qty./ml) – 1d
1 Mitomycin 2–40 mg/ml 2–40 mg/ml 2–40 mg/ml 2–40 mg/ml
2 N, N-Dimethylacetamide 0.1 – 1 mL 0.1 – 1 mL 0.1 – 1 mL 0.1 – 1 mL
3 Polyethylene glycol q. s. to 1 mL q. s. to 1 mL q. s. to 1 mL q. s. to 1 mL
4 Butylated Hydroxy Anisole - 0.001 – 0.010 mg 0.001 – 0.010 mg -
5 Butylated Hydroxy Toluene - 0.01 – 0.10 mg - 0.01 – 0.10 mg
6 Nitrogen gas q. s. q. s. q. s. q. s.
pH: 5.0 - 7.0

Example 2a-d: Ready to dilute injectable pharmaceutical formulation (2 mg/ml)

Sr. No. Ingredients 2 mg/mL (Qty./mL) - 2a 2 mg/mL (Qty./mL) – 2b 2 mg/mL (Qty./mL) – 2c 2 mg/mL (Qty./mL) – 2d
1 Mitomycin 2.0 mg 2.0 mg 2.0 mg 2.0 mg
2 N, N-Dimethylacetamide 0.4 mL 0.4 mL 0.4 mL 0.4 mL
3 Polyethylene glycol 300 q. s. to 1 mL q. s. to 1 mL q. s. to 1 mL q. s. to 1 mL
4 Butylated Hydroxy Anisole - 0.006 mg 0.006 mg -
5 Butylated Hydroxy Toluene - 0.04 mg - 0.04 mg
6 Nitrogen gas q. s. q. s. q. s. q. s.
pH: 5.0 - 7.0

Example 3a-d: Ready to dilute injectable pharmaceutical formulation (5 mg/ml)

Sr. No. Ingredients 5 mg/mL (Qty./mL) - 3a 5 mg/mL (Qty./mL) – 3b 5 mg/mL (Qty./mL) – 3c 5 mg/mL (Qty./mL) – 3d
1 Mitomycin 5.0 mg 5.0 mg 5.0 mg 5.0 mg
2 N, N-Dimethylacetamide 0.4 mL 0.4 mL 0.4 mL 0.4 mL
3 Polyethylene glycol 300 q. s. to 1 mL q. s. to 1 mL q. s. to 1 mL q. s. to 1 mL
4 Butylated Hydroxy Anisole - 0.006 mg 0.006 mg -
5 Butylated Hydroxy Toluene - 0.04 mg - 0.04 mg
6 Nitrogen gas q. s. q. s. q. s. q. s.
pH: 5.0 - 7.0

Example 4a-d: Ready to dilute injectable pharmaceutical formulation (10 mg/ml)

Sr. No. Ingredients 10 mg/mL (Qty./mL) - 4a 10 mg/mL (Qty./mL) – 4b 10 mg/mL (Qty./mL) – 4c 10 mg/mL (Qty./mL) – 4d
1 Mitomycin 10.0 mg 10.0 mg 10.0 mg 10.0 mg
2 N, N-Dimethylacetamide 0.4 mL 0.4 mL 0.4 mL 0.4 mL
3 Polyethylene glycol 300 q. s. to 1 mL q. s. to 1 mL q. s. to 1 mL q. s. to 1 mL
4 Butylated Hydroxy Anisole - 0.006 mg 0.006 mg -
5 Butylated Hydroxy Toluene - 0.04 mg - 0.04 mg
6 Nitrogen gas q. s. q. s. q. s. q. s.
pH: 5.0 - 7.0

Example 5a-d: Ready to dilute injectable pharmaceutical formulation (20 mg/ml)

Sr. No. Ingredients 20 mg/mL (Qty./mL) - 5a 20 mg/mL (Qty./mL) – 5b 20 mg/mL (Qty./mL) – 5c 20 mg/mL (Qty./mL) – 5d
1 Mitomycin 20.0 mg 20.0 mg 20.0 mg 20.0 mg
2 N, N-Dimethylacetamide 0.4 mL 0.4 mL 0.4 mL 0.4 mL
3 Polyethylene glycol 300 q. s. to 1 mL q. s. to 1 mL q. s. to 1 mL q. s. to 1 mL
4 Butylated Hydroxy Anisole - 0.006 mg 0.006 mg -
5 Butylated Hydroxy Toluene - 0.04 mg - 0.04 mg
6 Nitrogen gas q. s. q. s. q. s. q. s.
pH: 5.0 - 7.0

Example 6a-d: Ready to dilute injectable pharmaceutical formulation (40 mg/ml)

Sr. No. Ingredients 40 mg/mL (Qty./mL) - 6a 40 mg/mL (Qty./mL) – 6b 40 mg/mL (Qty./mL) – 6c 40 mg/mL (Qty./mL) – 6d
1 Mitomycin 40.0 mg 40.0 mg 40.0 mg 40.0 mg
2 N, N-Dimethylacetamide 0.4 mL 0.4 mL 0.4 mL 0.4 mL
3 Polyethylene glycol 300 q. s. to 1 mL q. s. to 1 mL q. s. to 1 mL q. s. to 1 mL
4 Butylated Hydroxy Anisole - 0.006 mg 0.006 mg -
5 Butylated Hydroxy Toluene - 0.04 mg - 0.04 mg
6 Nitrogen gas q. s. q. s. q. s. q. s.
pH: 5.0 - 7.0

Example 7a-d: Ready to dilute injectable pharmaceutical formulation (20 mg/ml)

Sr. No. Ingredients 20 mg/mL (Qty./mL) - 7a 20 mg/mL (Qty./mL) – 7b 20 mg/mL (Qty./mL) – 7c 20 mg/mL (Qty./mL) – 7d
1 Mitomycin 20.0 mg 20.0 mg 20.0 mg 20.0 mg
2 N, N-Dimethylacetamide 0.2 mL 0.2 mL 0.2 mL 0.2 mL
3 Polyethylene glycol 300 q. s. to 1 mL q. s. to 1 mL q. s. to 1 mL q. s. to 1 mL
4 Butylated Hydroxy Anisole - 0.006 mg 0.006 mg -
5 Butylated Hydroxy Toluene - 0.04 mg - 0.04 mg
6 Nitrogen gas q. s. q. s. q. s. q. s.
pH: 5.0 - 7.0

Process for preparation of formulation of example 1a 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 1b 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;
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 1d and 2-7d:

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 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 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.

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:

Stability study of the formulation of example 6a:
Specification Impurities
Condition Description Assay Impurity D 1,2 cis 1-hydroxy 2,7-diaminomitosene 1,2 trans 1-hydroxy 2,7-diaminomitosene Any other impurity Total Impurity pH
Clear blue violet color solution 90-110% NMT 2.5% NMT 1.2% NMT 1.2% NMT 0.5% NMT 5.0% To be recorded
Initial Clear blue color solution 102.1 0.472 ND ND 0.028 0.500 6.07
2-8°C,
1 month, Inverted Clear blue color solution 98.3 0.560 ND ND ND 0.560 6.15
25°C/60% RH,
1 month, Inverted Clear blue color solution 97.3 0.571 BQL ND 0.229 0.800 6.05
2-8°C,
3 month, Inverted Clear blue violet color solution 97.8 0.519 ND ND BQL 0.519 6.05
25°C/60% RH,
3 month, Inverted Clear blue color solution 95.9 0.477 ND ND 0.631 1.605 5.80
2-8°C,
6 month, Inverted Clear blue color solution 97.2 0.448 ND ND 0.147 0.595 6.10
25°C/60% RH,
6 month, Inverted Clear blue color solution 93.1 0.437 0.206 ND 0.547 1.675 6.20

Stability study of the formulation of example 6b:
Specification Impurities
Condition Description Assay Impurity D 1,2 cis 1-hydroxy 2,7-diaminomitosene 1,2 trans 1-hydroxy 2,7-diaminomitosene Any other impurity Total Impurity pH
Clear blue violet color solution 90-110% NMT 2.5% NMT 1.2% NMT 1.2% NMT 0.5% NMT 5.0% To be recorded
Initial Clear blue violet color solution 97.1 0.435 ND ND ND 0.435 6.13
2-8°C,
3 month, Inverted Clear blue violet color solution 98.1 0.532 ND ND 0.050 0.582 6.18
25°C/60% RH,
3 month, Inverted Clear blue violet color solution 97.3 0.459 BDL ND 0.188 0.787 6.22
2-8°C,
6 month, Inverted Clear blue violet color solution 98.8 0.449 ND ND 0.067 0.516 6.18
25°C/60% RH,
6 month, Inverted Clear blue violet color solution 98.1 0.432 0.079 ND 0.179 0.834 6.23

Stability study of the formulation of example 6c:
Specification
Impurities
Condition Description Assay Impurity D 1,2 cis 1-hydroxy 2,7-diaminomitosene 1,2 trans 1-hydroxy 2,7-diaminomitosene Any other impurity Total Impurity pH
Clear blue violet color solution 90-110% NMT 2.5% NMT 1.2% NMT 1.2% NMT 0.5% NMT 5.0% To be recorded
Initial Clear blue violet color solution 97.1 0.443 ND ND ND 0.443 6.16
2-8°C,
3 month, Inverted Clear blue violet color solution 98.2 0.451 ND ND 0.044 0.451 6.18
25°C/60% RH,
3 month, Inverted Clear blue violet color solution 96.8 0.463 0.086 ND 0.398 1.098 6.13
2-8°C,
6 month, Inverted Clear blue violet color solution 98.9 0.444 ND ND 0.175 0.619 6.18
25°C/60% RH,
6 month, Inverted Clear blue violet color solution 97.7 0.422 0.145 ND 0.300 1.129 6.22

Stability study of the formulation of example 6d:
Specification Impurities
Condition Description Assay Impurity D 1,2 cis 1-hydroxy 2,7-diaminomitosene 1,2 trans 1-hydroxy 2,7-diaminomitosene Any other impurity Total Impurity pH
Clear blue violet color solution 90-110% NMT 2.5% NMT 1.2% NMT 1.2% NMT 0.5% NMT 5.0% To be recorded
Initial Clear blue violet color solution 97.1 0.466 ND ND ND 0.466 6.18
2-8°C,
3 month, Inverted Clear blue violet color solution 98.2 0.45 BDL ND 0.060 0.510 6.12
25°C/60% RH,
3 month, Inverted Clear blue violet color solution 97.5 0.5 0.122 ND 0.110 0.811 6.11
2-8°C,
6 month, Inverted Clear blue violet color solution 98.7 0.436 ND ND 0.056 0.492 6.12
25°C/60% RH,
6 month, Inverted Clear blue violet color solution 96.6 0.454 0.211 ND 0.454 1.894 6.20

Stability study of the formulation of example 7d:
Specification Impurities
Condition Description Assay Impurity D 1,2 cis 1-hydroxy 2,7-diaminomitosene 1,2 trans 1-hydroxy 2,7-diaminomitosene Any other impurity Total Impurity pH
Clear blue violet color solution 90-110% NMT 2.5% NMT 1.2% NMT 1.2% NMT 0.5% NMT 5.0% To be recorded
Initial Clear blue violet color solution 100.2 0.553 ND ND ND 0.553 6.58
2-8°C,
3 month, Inverted Clear blue violet color solution 98.2 0.493 ND ND 0.044 (BDL) 0.493 6.56
25°C/60% RH,
3 month, Inverted Clear blue violet color solution 96.3 0.493 ND ND 0.219 0.898 6.55
2-8°C,
6 month, Inverted Clear blue violet color solution 98 0.821 ND ND 0.036 (BQL) 0.821 6.20
25°C/60% RH,
6 month, Inverted Clear blue violet color solution 95.3 0.807 0.126 ND 0.144 1.153 6.30
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.

8. The stable ready to dilute injectable pharmaceutical formulation according to claim 1, which is administered by intravenous and/or intravesical route of administration.

9. 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.