The present invention relates to pharmaceutical compositions of Pemetrexed containing
pharmaceutically acceptable organic amine and an inert gas. The pharmaceutical composition
may optionally include other pharmaceutically acceptable excipients which comprises any one
or combination of antioxidants/ chelating agents/ amino acids/ stabilizers/ preservatives/
bulking agents/ buffers/ organic solvents/ carriers/ diluents/ and solubilizers. The
pharmaceutical compositions of the present invention are stable and pharmaceutically
acceptable.
BACKGROUND OF THE INVENTION
Certain folic acid antimetabolites are known to be antineoplastic agents. These compounds
inhibit enzymatic conversion involving metabolic derivatives of folic acid. One such
compound described by U.S.Pat. No. 5,344,932, known as "Pemetrexed" represented by
Formula-! shown below, is currently formulated into a concentrated liquid for administration
as an infusion dosage form. This member of the folic acid family has been approved for
treatment of malignant pleural mesothelioma and for second-line treatment of non small cell
lung cancer. Pemetrexed disodium salt heptahydrate represented by Formula-11 is marketed by
Eli Lilly and Company under the trade name ALIMT A® as a sterile lyophilized powder for
intravenous administration. The commercial product is reported to be a lyophilized powder of
heptahydrate Pemetrexed disodium and mannitol. The lyophilized product is available in
strengths of 1 OOmg/vial and 500 mg/vial and is reconstituted with 0.9% sodium chloride at a
concentration of25mg/mL before its administration.
2
Formula I
Formula II
The formulation teachings of the US. Patent. No. 5,344,932 provides that the compounds
claimed therein can be administered parenterally.
It was found that a simple, isotonic saline solution of Pemetrexed is not pharmaceutically
acceptable for commercial purposes due to degradation of the solution to form unacceptable
related substances. The chemical instability of Pemetrexed is mainly attributed to their
oxidative and acidic degradation.
Bernd et al in US Patent No. 6,686,365 discloses a stable ready to use (RTU) formulation of
Pemetrexed which is developed by using antioxidants/amino acids like L-Cysteine,
Monothioglycerol and Thioglycolic acid. The preferred salt of the Pemetrexed is clearly
mentioned as Pemetrexed disodium and also atleast one antioxidant. The formulation
disclosed is aqueous one.
3
Yanling et al in CN Patent No. I 01081301, again discloses a RTU formulation of
Pemetrexed stabilized by using antioxidant like L-arginine, L-glutathione, Lmethionine
and L-tryptophan. The preferred salt of the Pemetrexed is clearly
mentioned as Pemetrexed disodium and also mentioned is atleast one antioxidant
Palepu et al in PCT Application No. W02012/015810, claims a RTU solution
formulation of Pemetrexed along with an antioxidant, a chelating agent and
dissolved in a pharmaceutically acceptable fluid. The Preferred salt is Pemetrexed
disodium and the composition mentioned is aqueous composition with chelating
agent and antioxidant.
Chandrasekhar et al in US Patent Application Publication No. 20110201631,
discloses lyophilized formulations of amorphous Pemetrexed and its salts and the
preferred one is disodium salt of Pemetrexed. The amorphous form of Pemetrexed is
particularly referred in this patent application.
It is indicated from all the above mentioned prior arts that all the pharmaceutical
compositions of Pemetrexed utilizes the preferred salt of Pemetrexed which is
Pemetrexed disodium. Antioxidants are also used in the prior art compositions.
Further all the abovementioned prior art compositions are aqueous based
formulations.
Further there is a prior art disclosure US 20080139810 that discloses a process for
preparing disodium salt of Pemetrexed, wherein the starting material is Pemetrexed
of formula I. The Pemetrexed thus utilized is converted to Pemetrexed disodium of
formula II during lyophilization process. Hence, there is in-situ formation of
Pemetrexed disodium during lyophilization and the final product contains
Pemetrexed disodium.
4
In light of the abovementioned prior arts there remains a need to develop stable
parenteral pharmaceutical compositions of Pemetrexed of formula I. In the present
invention it was surprisingly found that Pemetrexed according to formula I
containing pharmaceutically acceptable organic amines and an inert gas are
favorable in formulating pharmaceutical composition for medical use.
Further controlled oxygen content with inert gas purgmg and/or usmg
antioxidants/chelating agents/amino acids and maintaining higher pH values using
pharmaceutically acceptable organic amines is useful in controlling the oxidative and
acidic degradation of Pemetrexed respectively.
The formulation of the present invention provides the composition of Pemetrexed
with pharmaceutically acceptable organic amine which is free of sodium ions of
disodium salt of Pemetrexed released during the dilution of the pharmaceutical
composition of Pemetrexed disodium and uses pharmaceutically acceptable organic
amines to control the acidic degradation.
Against this backdrop of oxidative and acidic degradation the inventors of the
present Application have surprisingly found that stable pharmaceutical compositions
of Pemetrexed may be developed by utilizing Pemetrexed along with
pharmaceutically acceptable organic amine and may optionally contain some other
pharmaceutically acceptable excipients.
Object of the invention
It is an object of the present invention to overcome the drawbacks of the prior art.
It is another object of the present invention to provide a stable pharmaceutical
composition of Pemetrexed by utilizing Pemetrexed.
5
SUMMARY OF THE INVENTION
According to one aspect of the present invention there is provided a pharmaceutical
composition of Pemetrexed represented by formula I,
which is a ready to use solution composition or a lyophilized pharmaceutical
composition for parenteral administration comprising pharmaceutically acceptable
organic amine or their mixtures thereof, an inert gas and optionally containing at
least one or more pharmaceutically acceptable excipients.
According to another aspect of the present invention there is provided a process for
preparing ready to use pharmaceutical composition comprising the steps:
a. taking suitable quantity of water for injection in vessel and adding required
quantity of organic amine to the water for injection,
b. adding organic solvent to the above mixture and mixing uniformly,
c. purging inert gas into the solution to minimize the dissolved oxygen content,
d. adding Pemetrexed to the above mixture and dissolving and adjusting the pH to
about 6-8,
e. filtering the solution and filling in vials,
f. blanketing vial headspace with inert gas to achieve headspace oxygen content less
than 2% and more preferably less than 0.5%,
g. stoppering and sealing the vials.
6
According to yet another aspect of the present invention there is provided a process
for preparing lyophilized pharmaceutical composition comprising the steps:
a. taking suitable quantity of water for injection in vessel,
b. purging inert gas into the water for injection to minimize the dissolved oxygen
content,
c. adding required quantity of organic amine and bulking agent and dissolving in
water for injection,
d. adding Pemetrexed and dissolving and adjusting the pH to about 6-8,
e. making up the volume using water for injection,
f. filtering the solution and filling in vials,
g. stoppering the vials and lyophilizing by breaking the vacuum using inert gas.
DETAILED DESCRIPTION OF THE INVENTION
One aspect of the present invention IS the preparation of the pharmaceutical
composition of Pemetrexed in combination with a pharmaceutically acceptable
organic amine and an inert gas which is stable.
The term "pharmaceutical composition" in accordance with the present invention
refers to various dosage forms like ready to use and lyophilized pharmaceutical
compositions suitable for administration of a drug, such as parenteral, intravenous,
intraarterial, intramuscular, subcutaneous etc.
An organic amine is an organic compound which acts as a base. They usually contain
nitrogen atoms, which can easily be protonated. The preferred organic amines of the
present invention are selected from tromethamine and meglumine. The organic
amines may be present in amounts of about 40 to 90% by weight of Pemetrexed of
formula I.
7
The term "pharmaceutically acceptable" refers to an ingredient that is useful in
preparing a pharmaceutical composition that is generally safe, non-toxic, and neither
biologically nor otherwise undesirable, and includes those acceptable for veterinary
use as well as human pharmaceutical use.
In one embodiment of the present invention the pharmaceutical composition of the
present invention may optionally comprise other pharmaceutically acceptable
excipients which comprises any one or combination of antioxidants/ chelating
agents/ amino acids/ preservatives/ bulking agents/ buffers/ organic solvents/
carriers/ diluents/ and solubilizers.
The pharmaceutical compositions may further optionally include one or more
pharmaceutically acceptable excipients. These pharmaceutically acceptable
excipients may include one or more of: diluents or bulking agents such as dextrose,
sucrose, mannose, mannitol and the like; antibacterial preservatives, including one or
more of phenylmercuric nitrate, thiomersal, benzalkonium chloride, benzethonium
chloride, phenol, cresol and chlorobutanol; chelating agents such as ethylenediamine
tetraacetic acid (EDT A); buffers including one or more of acetate, citrate, tartarate,
phosphate, benzoate, And bicarbonate buffers, and amino acids such as glutamic acid
and histidine; tonicity contributors including one or more of hydrochloric acid,
dextrose, mannitol, sorbitol, and lactose. Antioxidants include monothioglycerol, !Cysteine,
and thioglycolic acid, sodium metabisulfite, ascorbic acid, sodium EDTA,
monoethanolamine gentisate, sodium formaldehyde sulfoxylate, sodium bisulfite.
The term "organic solvent" means an organic material, usually a liquid, capable of
dissolving other substances. Suitable solvents that can be used for preparing
pharmaceutical compositions of Pemetrexed include water and any organic solvents
from the various classes of solvents, such as, for example, alcohols, ketones, esters,
8
ethers, halogenated hydrocarbons, aromatic hydrocarbons, nitriles, aprotic polar
solvents, acidic solvents, and mixtures of any two or more thereof. Useful alcohols
include, for example, methanol, ethanol, denatured spirits, n-propanol, isopropanol,
n-butanol, isobutanol, t-butanol, polyhydroxy alcohols example ethylene glycol,
glycerin, propylene glycol, polyethylene glycol, diethylene glycol, diglycerin,
triethylene glycol, tetraethylene glycol, trimethylolpropane and the like. Useful
ketones include acetone, propanone, 2-butanone, and the like. Useful halogenated
hydrocarbons include, for example, dichloromethane, I ,2-dichloroethane,
chloroform, carbon tetrachloride, chlorobenzene, and the like. Useful esters include,
for example, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, t-butyl
acetate, and the like. Useful ethers include, for example, dimethyl ether, diethyl
ether, methyl t-butyl ether, ethyl methyl ether, diisopropyl ether, tetrahydrofuran,
dioxane, and the like. Useful aromatic hydrocarbons include, for example, toluene,
xylene, and the like. Useful nitriles include acetonitrile, propionitrile, and the like.
Useful aprotic polar solvents include N,N-dimethylformide (DMF),
dimethylsulfoxide (DMSO), N,N-dimethylacetamide (DMA), and the like. Useful
acidic solvents include formic acid, acetic acid, and the like. This listing is not
intended to be exhaustive, and combinations of solvents that are useful can include
more than one member of a class, and/or can be from different classes.
The above mentioned antioxidants/ chelating agents/ amino acids/ preservatives/
bulking agents/ buffers/ organic solvents/ carriers/ diluents/ and solubilizers may be
present in the compositions in pharmaceutically acceptable quantities.
The pharmaceutical compositions as developed by the Inventors of the present
invention are provided as lyophilized powder and ready to use solutions that are
suitable for parenteral administration after reconstitution with a suitable diluting
fluid.
9
In one embodiment of the present invention, pharmaceutical compositions of
Pemetrexed as per the present invention has a pH between about 4 and about I 0,
preferably between about 5 and 8 and more preferably in the range of about 6.0 and
about 8.
According to another aspect of the present invention "stability" is referred to both the
physical and chemical stability.
These formulations are presented as a single vial presentation having Pemetrexed
concentrations in the range of 2.5 to 50 mg/ml of which the preferred concentration
is 25 mg/ml. These pharmaceutical compositions are then administered via
intravenous infusion to treat patients suffering from malignant pleural mesothelioma
and for second-line treatment of non small cell lung cancer which is the approved
indication of Pemetrexed.
In another embodiment of the present invention, so as to minimize oxidation of the
sensitive material it is also desirable to remove headspace oxygen and moisture or
both from the sealable vessel as quickly as possible. This may be aided by, for
example, purging the sealable container with a gas which is substantially oxygenfree,
or substantially moisture free, or substantially oxygen and moisture free before,
during or after step, or any combination thereof. Purging can be expected to reduce
the oxygen level in the sealable container to a level of from about 0.1% to about
I 0%, typically about 5% or lower, depending on the efficiency of flushing and how
quickly the container is sealed after flushing.
The gas used for purging the sealable container may be any appropriate inert gas
known to those in the art, the most commonly used gases being argon, helium or
nitrogen, or mixtures thereof. However, the most preferred inert gas is nitrogen.
10
In another embodiment of the present invention, to control the acidic degradation of
the pharmaceutical composition of Pemetrexed, pharmaceutically acceptable organic
amine is used which maintains the pH of the solution more than 7, thereby reducing
the acidic degradation impurities. The preferred organic amines of the present
invention includes pharmaceutically acceptable organic amines such as
tromethamine and meglumine, of which tromethamine is the most preferred organic
am me.
In another embodiment of the present invention there is provided a process for
preparing ready to use pharmaceutical composition where the process comprises the
following steps:
a. taking suitable quantity of water for injection in vessel and adding required
quantity of organic amine to the water for injection,
b. adding organic solvent to the above mixture and mixing uniformly,
c. purging inert gas into the solution to minimize the dissolved oxygen content,
d. adding Pemetrexed to the above mixture and dissolving and adjusting the pH to
about 6-8,
e. filtering the solution and filling in vials,
f. blanketing vial headspace with inert gas to achieve headspace oxygen content less
than 2% and more preferably less than 0.5%,
g. stoppering and sealing the vials.
In a further embodiment of the present invention there is provided a process for
preparing lyophilized pharmaceutical composition comprising the steps:
a. taking suitable quantity ofwater for injection in vessel,
b. purging inert gas into the water for injection to minimize the dissolved oxygen
content,
11
c. adding required quantity of organic amine and bulking agent and dissolving in
water for injection,
d. adding Pemetrexed and dissolving and adjusting the pH to about 6-8,
e. making up the volume using water for injection,
f. filtering the solution and filling in vials,
g. stoppering the vials and lyophilizing by breaking the vacuum using inert gas.
The invention is further illustrated by way of the following examples, which in no
way should be construed as limiting the scope ofthe invention.
EXAMPLES
Various embodiments of the pharmaceutical compositions of Pemetrexed according
to the present invention were prepared and studied for their stability and impurity
profile when stored under accelerated stability conditions, which are illustrated
below:
The pharmaceutical compositions of Pemetrexed were prepared usmg orgamc
solvents along with ethanol and water without nitrogen purging or adjusting the pH
with organic amines. The pharmaceutical compositions were held for stability and
were found to be unacceptable.
Example 01
Pharmaceutical composition of Pemetrexed with Ethanol and Water
Sr. No. Ingredients Qty/mL Qty/mL
Composition with Composition with
Water Ethanol
1 Pemetrexed 25mg 25 mg
12
2 Dimethyl Acetamide 0.34 mL 0.34 mL
3 Propylene Glycol 0.33 mL 0.33 mL
4 Water 0.33 mL -
5 Ethanol - 0.33mL
The stability profile of the pharmaceutical composition of Pemetrexed with water
and ethanol according to Example 01 is summarized in Table I.
Table I: Stability profile of the pharmaceutical composition of Pemetrexed with
water and ethanol.
Results Results
Conditions (Total Impurity %) (Total Impurity%)
Composition with water Composition with ethanol
Initial 0.7 1.0
·-
60°C I 7days 9.5 19.5
40°C/75%RH/
4.3 3.4
14 days
25°C/60%RH/
3.5 5.5
1 Month
It is evident from the Example 01 and stability profile in Table I that there was an
extensive oxidative and acidic degradation which was unacceptable.
Example 02
In order to control the oxidative degradation nitrogen purging was used which to
some extent controlled the oxidative impurities.
13
Pharmaceutical composition ('A' and 'B') of Pemetrexed
Sr. No. Ingredients Qty/mL Qty/mL
Composition 'A' Composition 'B'
1 Pemetrexed 25mg 25 mg
2 Dimethyl Acetamide 0.28 mL 0.16 mL
3 Propylene Glycol 0.72 mL 0.84 mL
4 Nitrogen* q.s. q.s.
The pH of the pharmaceutical compositions 'A' and 'B' according to this example
was found to be between 4-5 which lead to the extensive hydrolytic degradation
which is unacceptable as per regulatory requirements. The stability profile of the
pharmaceutical composition of Pemetrexed according to Example 02 is summarized
in Table II.
Table II: Stability profile of the pharmaceutical composition of Pemetrexed
according to Example 02
Results (Total Impurity Results (Total Impurity
Conditions %) %)
Composition 'A' Composition 'B'
Initial 0.44 0.44
60°C I 7days 5.08 6.45
40°C/75%RH/
2.19 2.52
14 days
25°C/60%RH/
1.15 1.16
1 Month
14
It is evident from the above example that pharmaceutical compositions 'A' and '8'
the stability profile is not found to be acceptable but still found better than the
Example 01 hence to control the acidic impurities use of organic amines was
necessary in pharmaceutical composition of Pemetrexed.
In order to control oxidative as well as acidic degradation of Pemetrexed various
experiments were performed which are described below only for illustrative.
Example 03
Pharmaceutical composition of Pemetrexed:
Sr. No. Ingredients Qty/mL
1 Pemetrexed 25 mg
2 Tromethamine 15 mg
3 Hydrochloric acid, ifrequired q.s. to pH 6- 8
4 Water for Injection qs to 1mL
5 Nitrogen Nil
Table III: Stability profile of the pharmaceutical composition of Pemetrexed
according to Example 03
Related Substances %
Conditions
Total RS
Initial 0.61
40°C/75%RH/ 14 days 3.42
25°C/60%RH/ 1 Month 3.07
15
From the above table it is evident that using tromethamine alone is not sufficient, but
nitrogen purging is required for composing a stable composition. This is evident
from Example 04 where both nitrogen purging as well as tromethamine was used to
minimize the degradation due to oxidative as well as acidic factors.
Example 04
Pharmaceutical composition of Pemetrexed:
I Sr. No.I Ingredients Qty/mL
I Pemetrexed 25 mg
2 Tromethamine 15 mg
3 Hydrochloric acid, ifrequired q.s. to pH 6 - 8
4 Water for Injection qs to 1mL
5 Nitrogen* qs
* Nitrogen is used for purging in bulk solution and blanketing in vial headspace
The pharmaceutical composition according to Example 04 IS prepared by below
mentioned process.
Suitable quantity of water for injection in a manufacturing vessel is taken. Nitrogen
was purged into water for injection until dissolved oxygen content of water for
injection comes less than 7 mg/L, preferably less than 3 mg/L. Continue to bubble
nitrogen upto making up of the volume with water for injection. After nitrogen
bubbling added and dissolved required quantity of tromethamine in water for
injection. After addition of tromethamine Pemetrexed was added and dissolved. If
required, adjusted the pH to 6 - 8 with the help of I O%w/v tromethamine solution or
1 O%v/v hydrochloric acid solution. Volume was made up to 100% with water for
16
injection. Filtered the drug solution through a suitable 0.2fl filter. Filled the filtered
solution into vials. Blanket the vial headspace with nitrogen to achieve headspace
oxygen content less than 8%, preferably less than 2%. The vials were stoppered and
finally sealed.
Stabi I ity profile of the pharmaceutical composition as mentioned in Example 04 has
been summarized below in Table IV
Table-IV: Stability profile of the pharmaceutical composition as mentioned m
Example 04
Related Substances
Conditions Assay(%) pH o;o
Total impurity
Initial 103.8 6.9 0.37
60°C I 7days 103.6 6.9 0.79
40°C/75%RH/
105.0 7.1 0.54
14 days
25°C/60%RH/
106.9 7.1 0.46
1 Month
As evident from the Table IV stability profile of the pharmaceutical composition of
Example 04 is found to be superior as compared to the Example 01, 02 & 03.
Example 05
Pharmaceutical composition of Pemetrexed
Ingredients Qty/mL
17
I Pemetrexed 25 mg
2 Tromethamine 15 mg
3 Hydrochloric acid, if required q.s. to pH 6 - 8
4 Propylene glycol 50 %v/v
5 Water for Injection qs to I mL
6 Nitrogen* qs
* Nitrogen is used for purging in bulk solution and blanketing in vial headspace
The pharmaceutical composition according to Example 05 is prepared by below
mentioned process.
Suitable quantity of water for injection is taken in a manufacturing vessel. Required
quantity of tromethamine in water for injection was added and dissolved. Other
solvents i.e., propylene glycol was added and mixed uniformly. Nitrogen was purged
until dissolved oxygen content of solution comes less than 7 mg/L, preferably less
than 3 mg/L. Continue to bubble nitrogen upto the filteration of the solution.
Pemetrexed was added and dissolved. pH of the solution was adjusted if required to
6 - 8 with the help of l 0%w/v tromethamine solution or I 0%v/v hydrochloric acid
solution. Volume was made upto 100% with water for injection. Filtered the drug
solution through a suitable 0.2!J filter. The filtered solution was filled into vials.
Blanket the vial headspace with nitrogen to achieve headspace oxygen content less
than 8%, preferably less than 2%. The vials were stoppered and finally sealed.
Stability profile of the Formulation as mentioned m Example 05 has been
summarized below in Table V:
18
Table-V: Stability profile ofthe Formulation as mentioned in Example 05
Related Substances %
Conditions Assay(%) pH
Total impurity
Initial I 01.9 6.8 0.38
60°C /7days 100.9 6.9 1.08
40°C/75%RH/
102.0 6.8 0.60
14 days
25°C/60%RH/
I 03.7 7.0 0.48
I Month
Example 06
Pharmaceutical composition of Pemetrexed
Sr. No. Ingredients Qty/mL
I Pemetrexed 25 mg
2 Tromethamine 15 mg
3 Hydrochloric acid, if required q.s. to pH 6- 8
4 Dimethyl acetamide 16 o/ov/v
5 Propylene glycol 42 o/ov/v
6 Water for Injection qs to lmL
7 Nitrogen* qs
*Nitrogen is used for purging in bulk solution and blanketing in vial headspace
19
The pharmaceutical composition according to Example 06 ts prepared by below
mentioned process.
Suitable quantity of water for injection is taken in a manufacturing vessel. Required
quantity of tromethamine in water for injection was added and dissolved. Other
solvents i.e., PG and/or DMA were added and mixed uniformly. Nitrogen was
purged until dissolved oxygen content of solution comes less than 7 mg/L, preferably
less than 3 mg/L. Continue to bubble nitrogen upto the filteration of the solution.
Pemetrexed was added and dissolved. pH of the solution was adjusted if required to
6 - 8 with the help of I O%w/v tromethamine solution or 1 O%v/v hydrochloric acid
solution. Volume was made upto 100% with water for injection. Filtered the drug
solution through a suitable 0.2fl filter. The filtered solution was filled into vials.
Blanket the vial headspace with nitrogen to achieve headspace oxygen content less
than 8%, preferably less than 2%. The vials were stoppered and finally sealed.
Example 07
Pharmaceutical composition of Pemetrexed
Sr. No. Ingredients Qty/rnL
1 Pemetrexed 25 mg
2 Tromethamine 15 mg
3 Hydrochloric acid, ifrequired q.s. to pH 6- 8
4 Dimethyl acetamide 16 %v/v
5 Propylene glycol 42 %v/v
6 Ethanol qsto1mL
7 Nitrogen* qs
*Nitrogen is used for purging in bulk solution and blanketing in vial headspace
20
The pharmaceutical composition according to Example 07 IS prepared by below
mentioned process.
Suitable quantity of Ethanol is taken in a manufacturing vessel. Required quantity of
tromethamine in Ethanol was added and dissolved. Other solvents i.e., Propylene
glycol and/or Dimethylacetamide were added and mixed uniformly. Nitrogen was
purged until dissolved oxygen content of solution comes less than 7 mg/L, preferably
less than 3 mg/L. Continue to bubble nitrogen upto the filteration of the solution.
Pemetrexed was added and dissolved. pH of the solution was adjusted if required to
6 - 8 with the help of I O%w/v tromethamine solution or 1 O%v/v hydrochloric acid
solution. Volume was made upto 100% with ethanol. Filtered the drug solution
through a suitable 0.2fl filter. The filtered solution was filled into vials. Blanket the
vial headspace with nitrogen to achieve headspace oxygen content less than 8%,
preferably less than 2%. The vials were stoppered and finally sealed.
Example 08
Pharmaceutical composition of Pemetrexed
Sr. No. Ingredients Qty/mL
1 Pemetrexed 25 mg
2 Tromethamine 15 mg
3 Hydrochloric acid, if required q.s. to pH 6- 8
4 Dimethyl acetamide 33 %v/v
5 Propylene glycol 60 %v/v
6 Ethanol qs to 1 mL
7 Nitrogen* qs
* Nitrogen is used for purging in bulk solution and blanketing in vial headspace
21
The pharmaceutical composition according to Example 08 IS prepared by below
mentioned process.
Suitable quantity of Ethanol is taken in a manufacturing vessel. Required quantity of
tromethamine in Ethanol was added and dissolved. Other solvents i.e., Propylene
glycol and/or Dimethylacetamide were added and mixed uniformly. Nitrogen was
purged until dissolved oxygen content of solution comes less than 7 mg/L, preferably
less than 3 mg/L. Continue to bubble nitrogen upto the filteration of the solution.
Pemetrexed was added and dissolved. pH of the solution was adjusted if required to
6 - 8 with the help of I Oo/ow/v tromethamine solution or I Oo/ov/v hydrochloric acid
solution. Volume was made upto 100% with ethanol. Filtered the drug solution
through a suitable 0.2fl filter. The filtered solution was filled into vials. Blanket the
vial headspace with nitrogen to achieve headspace oxygen content less than 8%,
preferably less than 2%. The vials were stoppered and finally sealed.
Example 09
Pharmaceutical composition of Pemetrexed
Sr. No. Ingredients Qty/mL
1 Pemetrexed 25 mg
2 Tromethamine 15 mg
3 Hydrochloric acid, if required q.s. to pH 6- 8
4 Dimethyl acetamide 33 o/ov/v
5 Propylene glycol 60 o/ov/v
6 Water for Injection qs to 1mL
7 Nitrogen* qs
* Nitrogen is used for purging in bulk solution and blanketing in vial headspace
22
The pharmaceutical composition according to Example 09 IS prepared by below
mentioned process.
Suitable quantity of water for injection was taken in a manufacturing vessel.
Required quantity of tromethamine in water for injection was added and dissolved.
Other solvents i.e., Propylene glycol and/or Dimethylacetamide were added and
mixed uniformly. Nitrogen was purged until dissolved oxygen content of solution
comes less than 7 mg/L, preferably less than 3 mg/L. Continue to bubble nitrogen
upto the filteration of the solution. Pemetrexed was added and dissolved. pH of the
solution was adjusted if required to 6 - 8 with the help of 1 Oo/ow/v tromethamine
solution or I Oo/ov/v hydrochloric acid solution. Volume was made upto 100% with
water for injection. Filtered the drug solution through a suitable 0.211 filter. The
filtered solution was filled into vials. Blanket the vial headspace with nitrogen to
achieve headspace oxygen content less than 8%, preferably less than 2%. The vials
were stoppered and finally sealed.
Example 10
Pharmaceutical composition of Pemetrexed
Sr. No. Ingredients Qty/mL
I Pemetrexed 25 mg
2 Meglumine 22 mg
3 Hydrochloric acid, ifrequired q.s. to pH 6- 8
4 Dimethyl acetamide 33 o/ov/v
5 Propylene glycol 60 o/ov/v
6 Water for Injection qs to lmL
7 Nitrogen* qs
23
* Nitrogen is used for purging in bulk solution and blanketing in vial headspace
The pharmaceutical composition according to Example 10 is prepared by below
mentioned process.
Suitable quantity of water for injection was taken in a manufacturing vessel.
Required quantity of Meglumine in water for injection was added and dissolved.
Other solvents i.e., Propylene glycol and/or Dimethylacetamide were added and
mixed uniformly. Nitrogen was purged until dissolved oxygen content of solution
comes less than 7 mg/L, preferably less than 3 mg/L. Continue to bubble nitrogen
upto the filteration of the solution. Pemetrexed was added and dissolved. pH of the
solution was adjusted if required to 6 - 8 with the help of 1 Oo/ow/v meglumine
solution or 1 Oo/ov/v hydrochloric acid solution. Volume was made upto 100% with
water for injection. Filtered the drug solution through a suitable 0.2fl filter. The
filtered solution was filled into vials. Blanket the vial headspace with nitrogen to
achieve headspace oxygen content less than 8%, preferably less than 2%. The vials
were stoppered and finally sealed.
Various embodiments of the lyophilized pharmaceutical compositions of Pemetrexed
according to the present invention were prepared and studied for their stability and
impurity profile when stored under accelerated stability conditions, which are
illustrated below:
Example 11
Pharmaceutical composition of Pemetrexed
Sr. No. Ingredients Qty/lOOmg vial Qty/SOOmg
vial
1 Pemetrexed 100 mg 500 mg
24
2 Tromethamine 60 mg 300 mg
3 Hydrochloric acid, ifrequired q.s. to pH 6- 8 q.s. to pH 6- 8
4 Bulking Agent 100 mg 500 mg
5 Water for Injection# qs qs
6 Nitrogen* qs qs
* Nitrogen is used for purgmg m bulk solution and for vacuum break during
lyophilization
# Removed during Lyophilization
The pharmaceutical composition according to Example II 1s prepared by below
mentioned process.
Suitable quantity of water for injection was taken in a manufacturing vessel.
Nitrogen was purged into water for injection until dissolved oxygen content ofwater
for injection comes less than 7 mg/L, preferably less than 3 mg/L. Continue to
bubble nitrogen. The required quantity of tromethamine and bulking agent is added
and dissolved in water for injection of previous step. Pemetrexed was added and
dissolved. If required, pH was adjusted to 6 - 8 with the help of I 0%w/v
tromethamine solution or 1 O%v/v hydrochloric acid solution. Volume was made upto
100% by Water for Injection. The drug solution was filtered through a suitable 0.2fl
filter. The filtered solution was filled in vials. The vials were partially stoppered. The
vials were then loaded in lyophilizer. Run the pre-defined lyophilization recipe. After
lyophilization process is completed, partially break the vacuum with Nitrogen gas.
The vials were stoppered and unloaded and finally sealed and labelled.
Example 12
Pharmaceutical composition of Pemetrexed
25
Sr. No. Ingredients Qty/lOOmg vial Qty/500mg
vial
1 Pemetrexed 100 mg 500 mg
2 Tromethamine 60 mg 300 mg
3 Hydrochloric acid, ifrequired q.s. to pH 6- 8 q.s. to pH 6 - 8
4 Water for Injection# qs qs
5 Nitrogen* qs qs
* Nitrogen IS used for purging m bulk solution and for vacuum break during
lyophilization
#Removed during Lyophilization
The pharmaceutical composition according to Example 12 is prepared by below
mentioned process.
Suitable quantity of water for injection was taken in a manufacturing vessel.
Nitrogen was purged into water for injection until dissolved oxygen content of water
for injection comes less than 7 mg/L, preferably less than 3 mg/L. Continue to
bubble nitrogen. The required quantity of tromethamine is added and dissolved in
water for injection of previous step. Pemetrexed was added and dissolved. If
required, pH was adjusted to 6 - 8 with the help of 1 O%w/v tromethamine solution or
IO%v/v hydrochloric acid solution. Volume was made upto 100% by Water for
Injection. The drug solution was filtered through a suitable 0.211 filter. The filtered
solution was filled in vials. The vials were partially stoppered. The vials were then
loaded in lyophilizer. Run the pre-defined lyophilization recipe. After lyophilization
process is completed, partially break the vacuum with Nitrogen gas. The vials were
stoppered and unloaded and finally sealed and labelled.
26
Example 13
Pharmaceutical composition of Pemetrexed
Sr. No. Ingredients Qty/lOOmg vial Qty/500mg
vial
1 Pemetrexed 100 mg 500 mg
2 Meglumine 88 mg 440 mg
3 Hydrochloric acid, if required q.s. to pH 6- 8 q.s. to pH 6 - 8
4 Water for Injection# qs qs
5 Nitrogen* qs qs
* Nitrogen is used for purgmg m bulk solution and for vacuum break during
lyophilization
#Removed during Lyophilization
The pharmaceutical composition according to Example 13 IS prepared by below
mentioned process.
Suitable quantity of water for injection was taken in a manufacturing vessel.
Nitrogen was purged into water for injection until dissolved oxygen content of water
for injection comes less than 7 mg/L, preferably less than 3 mg/L. Continue to
bubble nitrogen. The required quantity of meglumine is added and dissolved in water
for injection of previous step. Pemetrexed was added and dissolved. If required, pH
was adjusted to 6 - 8 with the help of I Oo/ow/v meglumine solution or 1 Oo/ov/v
hydrochloric acid solution. Volume was made upto 100% by Water for Injection.
The drug solution was filtered through a suitable 0.2fl filter. The filtered solution
was filled in vials. The vials were partially stoppered. The vials were then loaded in
lyophilizer. Run the pre-defined lyophilization recipe. After lyophilization process is
27
completed, partially break the vacuum with Nitrogen gas. The vials were stoppered
and unloaded and finally sealed and labelled.
The presently marketed composition of Pemetrexed 'AI imta' was compared with the
formulation of the invention which is given below:
Table VI: Comparison of the stability profile of lyophilized composition of the
present invention with Alimta
Stability profile of lyophilized composition of present invention
Related Substances %
Condition Assay(%)
Total RS
Initial 97.7 0.14
40°C/75%RH 1 Month 104.0 0.26
40°C/75%RH 3Month 98.5 0.59
40°C/75%RH 6Month 98.5 1.29
25°C/60%RH 6Month 99.6 0.32
Stability data of Alimta
Initial 100.97 0.13
40°C/75%RH 1 Month - 0.10
40°C/75%RH 3Month - 0.16
28
40°C/75%RH 6Month - 0.18
25°C/60%RH 6Month - 0.12
From the above experimental data, it is apparent that lyophilized composition
according to the current invention is having the stability profile even better than the
currently available marketed composition Alimta.
According to the aspect of the present invention reconstitution stability of the
formulation is also an important aspect. The composition of the present invention is
to be injected into the body after reconstitution and further dilution. In order to verify
the stability and suitability of the lyophilized composition of the lyophilized
composition following experiments were conducted in various reconstituting fluids
at different temperatures. The results were then compared with the currently
marketed composition Alimta which are described in below Table:
Table VII: Comparison of Reconstituted injection stability of lyophilized
composition of the present invention with Alimta in 0.9% Saline at 2-8 oc
Reconstituted injection stability of lyophilized composition at 2-8 oc with
0.9% Saline solution
Related Substances %
Condition Assay(%)
Total RS
Initial 101.6 0.26
24 Hrs 102.6 0.25
29
Reconstituted injection stability of Alimta at 2-8 oc with 0.9% Saline
solution
Initial 102.4 0.14
24 Hrs 102.5 0.15
Table VIII: Comparison of Reconstituted injection stability of current
lyophilized composition of the present invention with Alimta in 0.9% Saline 25
oc
Reconstituted injection stability of lyophilized composition of present
invention at 25 oc with 0.9% Saline solution
Related Substances%
Condition
Total RS
Initial 0.26
24 Hrs 0.29
Reconstituted injection stability of Alimta at 25 oc with 0.9% Saline solution
Initial 0.14
24 Hrs 0.22
From the above experimental data it is apparent that injection reconstitution stability
of lyophilized composition of present invention is as good as Alimta in 0.9% saline.
The reconstituted stability of the lyophilized composition of present invention was
also checked in Dextrose 5% solution and found suitable (Table VII)
30
Table IX: Reconstituted injection stability of Lyophilized composition of
present invention with 5% Dextrose solution at 2-8 oc and 25 oc
Reconstituted injection stability of lyophilized composition with 5% Dextrose
solution at 2-8 oc
Related Substances %
Condition
Total RS
Initial 0.24
24 hours 0.28
48 hours 0.31
Reconstituted injection stability of lyophilized composition with 5% Dextrose
solution at 25 oc
-
Initial 0.24
24 hours 0.29
48 hours 0.33
Further the dilution stability of the lyophilized composition of the present invention
was also determined by using dextrose 5% solution with different concentration of 1
mg/mL and 9 mg/mL the results are articulated in Table VIII and Table IX.
Table X: Dilution Injection Stability data of Lyophilized composition of present
invention at 2-8 oc and 25 oc with 5% Dextrose at lmg/mL concentration
31
I
I
Dilution Injection Stability data of present composition at 2-8 oc with 5%
Dextrose at lmg/mL concentration
Related Substances %
Condition
Total RS
Initial 0.39
--·
24 hours 0.34
48 hours 0.31
Dilution Injection Stability data of present composition at 25 oc with 5%
Dextrose at lmg/mL concentration
Initial 0.40
24 hours 0.37
48 hours 0.38
-
Table XI: Dilution Injection Stability data of lyophilized composition of present
invention at 2-8 oc and 25 oc with 5% Dextrose at 9 mg/mL concentration
Dilution Injection Stability data of present composition at 2-8 oc with 5%
Dextrose at 9mg/mL concentration
Related Substances%
Condition
Total RS
32
Initial 0.24
24 hours 0.26
48 hours 0.29
Dilution Injection Stability data of present composition at 25 oc with 5%
Dextrose at 9mg/mL concentration
··----·~
Initial 0.27
24 hours 0.32
48 hours 0.39
From the above experiments it was found that the dilution stability of lyophilized
composition is found suitable in Dextrose 5% solution at I mg/mL and 9mg/mL
concentrations.

We Claim:

1. A pharmaceutical composition of Pemetrexed represented by formula I,
Formula I
for parenteral administration comprising a pharmaceutically acceptable organic
amine selected from tromethamine and rneglumine or mixture thereof, an inert gas
and optionally containing one or more pharmaceutically acceptable excipients;
wherein the composition is a liquid ready to use solution formulation or a lyophilized
pharmaceutical composition.
2. A pharmaceutical composition according to claim 1, wherein the inert gas is selected
from nitrogen, helium and argon.
3. A pharmaceutical composition according to claims 1 and 2, wherein the composition
is liquid and has a dissolved oxygen content of less than 7 mg/1, preferably less than
3 mg/1.
4. A pharmaceutical composition according to claim 1, wherein the excipients include
an organic solvent selected from the group comprising propylene glycol, N, Ndimethylacetamide
and ethanol.
34
5. A pharmaceutical composition according to claim I, wherein the pH of the ready to
use solution formulation is between 4 and 10, preferably between 5 and 8 and more
preferably in the range of 6 to 8.
6. A pharmaceutical composition according to claim 1, wherein the lyophilized
composition is reconstituted and diluted with 5% dextrose or 0.9% sodium chloride
solution before administering to a patient in need thereof.
7. A pharmaceutical composition produced by a method comprising the step of mixing
Pemetrexed of formula I,
Formula I
in a solvent with a pharmaceutically acceptable orgamc amme selected from
tromethamine and meglumine.
8. A pharmaceutical composition according to claim 7, wherein the solvent is purged
with an inert gas before, during or after mixing.
9. A process for preparing a ready to use solution formulation according to any of the
preceding claims comprising the steps:
35
a) taking a suitable quantity of water for injection in vessel and adding a required
quantity of organic amine to the water for injection;
b) adding organic solvent to the above mixture and mixing uniformly;
c) adding Pemetrexed to the above mixture and dissolving and adjusting the pH to
about 6-8;
d) filtering the solution and filling in vials;
e) stoppering and sealing the vials.
I 0. The process according to claim 9 comprises the step of purging inert gas into the
solution to minimize the dissolved oxygen content.
11. The process according to claims 9 and 10 comprises the step of blanketing vial
headspace with inert gas to achieve headspace oxygen content less than 2% and more
preferably less than 0.1 %.
12. A process for prepanng a lyophilized pharmaceutical composition of claim 1
comprising the steps:
a) taking a suitable quantity of water for injection in vessel;
b) adding required quantity of organic amine and bulking agent and dissolving in
water for injection;
c) adding Pemetrexed and dissolving and adjusting the pH to about 6-8;
d) making up the volume using water for injection;
e) filtering the solution and filling in vials;
f) stoppering the vials and lyophilizing by breaking the vacuum using inert gas.
13. The process according to claim 12 comprises the steps of purging inert gas into the
water for injection to minimize the dissolved oxygen content.
36
14. An injection for parenteral administration comprising Pemetrexed of formula I,
Formula I
pharmaceutically acceptable orgamc amme selected from tromethamine and
meglumine or mixture thereof, an inert gas and optionally containing at least one or
more pharmaceutically acceptable excipients.
15. Use of tromethamine and an inert gas for controlling oxidative and acidic
degradation of pemetrexed in a pharmaceutical composition, wherein pemetrexed is
represented by Formula I,
H}'~, _..,.. ..J , __., JJ1~})
H
( '-,'-.,_//-,,,_(~":::;:
0 I l ,, .-;:;- N, _..,...., _CC<:JH
"-..7 'l/ ---... (- "-....._._/
0 CC'C;'i--1
Formula I
16. Use according to claim 15, wherein the amount of tromethamine is 40 to 90% by
weight of Pemetrexed of formula I and the pharmaceutical composition is produced
37
by a method comprising the step of mixing Pemetrexed of formula I in a so lvent with
tromethamine and optionally one or more pharmaceutically acceptable excipients,
wherein the solvent is purged with an inert gas before, during or after mi xing.