DESC:FIELD OF THE INVENTION
The present invention relates to a stable pharmaceutical composition comprising
sumatriptan or a pharmaceutically acceptable salt thereof in the form of ready-to-use injection.
Further, the invention provides process of preparing such compositions and use thereof.
BACKGROUND OF THE INVENTION
Migraine is a common neurological disorder that greatly affects quality of life and increases work
disruption. An average of 6% and 17% of men and women, respectively, suffer from migraine
headache. The cause of migraine is uncertain but may be the result of vascular and/or neurological
dysfunction.
Sumatriptan is a selective 5-hydroxytryptamine 1D (5-HT1D) receptor agonist useful for treatment
of migraine. Sumatriptan succinate, a pharmaceutically acceptable salt of sumatriptan, is a white
to off-white free flowing powder with a molecular weight of 413.5. It is readily soluble in water
and in saline. Sumatriptan succinate is also known as 3-[2-(dimethylamino)ethyl]-N-methylindole-
5-methanesulfonamide succinate (1:1). Its empirical formula is C14H21N3O2S.C4H6O4 and it
has the following structural formula:
Sumatriptan has been approved for treatment of migraines and is available in various dosage
forms, such as subcutaneous injection, oral tablets and nasal spray and marketed in different
strengths (6 to 100 mg). The therapeutic activity of sumatriptan for the treatment of migraine is
thought to be due to the agonist effects at the 5-HT 1B/1D receptors on intracranial blood vessels
(including the arterio-venous anastomoses) and sensory nerves of the trigeminal system, which
result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release.
2
Pharmaceutical preparations containing sumatriptan or salts of sumatriptan are described in U.S.
Patent Nos. 4,816,470; 4,994,483; 5,037,845; 5,270,333; 5,288,498; 5,307,953; 5,393,773;
5,447,729; 5,554,639; 5,705,520; 5,863,559; 6,020,001; 6,255,502; 6,294,192; and 6,368,627 and
U.S. Patent Appl. Pub. Nos. 2003/0013753; 2003/0185761; and 2003/0190286; and the PCT pub.
Nos. WO 1998/02186; WO 2001/39836 and WO 2017/023361 and the German Patent No. DE
4314976.
The approved IMITREX® subcutaneous injection products for the acute treatment of migraine,
with or without aura, are available in 4 mg/0.5 mL and 6 mg/0.5 mL concentrations as single-dose
pre-filled syringes (PFSs) for use with an autoinjector pen (IMITREX® STATdose, NDA
020080), and as a single-dose vial of 6 mg/0.5 mL for SC injection (IMITREX®) and stored
between 2° and 30°C.
Surprisingly, inventors of the present invention found that stable composition of sumatriptan can
be prepared by controlling the dissolved oxygen content of the liquid composition. Particularly, by
controlling the dissolved oxygen (DO) content less than 0.5 ppm along with controlled cumulative
lethal thermal treatment.
SUMMARY OF THE INVENTION:
In one aspect of the present invention, there is provided a stable pharmaceutical composition
comprising sumatriptan or pharmaceutically acceptable salts thereof in the form of ready-to-use
injection, wherein the composition is substantially free of impurities such as (1-(3-(2-
(dimethylamino)ethyl)-1-((5-((N-methylsulfamoyl)methyl)-1H-indol-3-yl)methyl)-1H-indol-5-
yl)-N-methylmethanesulfonamide) and 5-hydroxymethyl-N, N –dimethyltryptamine.
In an embodiment, the pharmaceutical composition comprises sumatriptan succinate as an active
ingredient, sodium chloride as osmolality agent and water for injection as vehicle.
In another embodiment, the stable pharmaceutical composition of sumatriptan succinate has a
dissolved oxygen content of less than 0.5 ppm.
3
In another embodiment, the concentration of (1-(3-(2-(dimethylamino)ethyl)-1-((5-((Nmethylsulfamoyl)
methyl)-1H-indol-3-yl)methyl)-1H-indol-5-yl)-N-methylmethanesulfonamide)
and 5-hydroxymethyl-N, N –dimethyltryptamine impurities in the composition is controlled by
regulating the dissolved oxygen and autoclaving time respectively.
In another embodiment, the dissolved oxygen content of composition varies from 4ppm to less
than 0.5ppm.
In another embodiment, (1-(3-(2-(dimethylamino)ethyl)-1-((5-((N-methylsulfamoyl)methyl)-1Hindol-
3-yl)methyl)-1H-indol-5-yl)-N-methylmethanesulfonamide) impurity, which is an oxidative
cum thermal impurity, decreases by about 65 %, preferable by about 60%, more preferable by
about 58% as dissolved oxygen content of composition is reduced from about 4ppm to less than
0.5ppm.
In another embodiment, the terminal sterilization is done by autoclaving at 121°C for 8 minutes or
15 minutes or less.
In another embodiment, the 5-hydroxymethyl-N, N –dimethyltryptamine impurity, which is an
oxidative cum thermal impurity, decreases by about 45 %, preferably by about 40%, more
preferably by about 37% , when autoclaving time for composition decreases from about 15
minutes to about 8 minutes.
In another embodiment, following storage of the composition at 30oC and 65% relative humidity
for a period of 3 months, the amount of total impurities present in the composition is not more
than 1%.
In another aspect of the present invention, there is provided a stable liquid pharmaceutical
composition of sumatriptan succinate, wherein the composition is prepared by process comprising
steps of:
(a) purging nitrogen to reduce dissolved oxygen content in water for injection below 0.5 ppm.
(b) dissolving sodium chloride and sumatriptan succinate in water for injection of step (a) to form
a solution.
(c) filtering the solution of step (b) through 0.22 µm polyvinylidene difluoride (PVDF) filter and
filling in 1mL prefilled syringe, and
4
(d) terminally sterilizing the prefilled syringe of step (c) by autoclaving.
The pH of solution after step (b) was found to be 4.2 to 5.3.
In another aspect of the present invention, there is provided a stable ready to use pharmaceutical
composition of sumatriptan succinate for treatment of migraine, with or without aura in adults and
acute treatment of cluster headache in adult patients in need thereof.
DETAILED DESCRIPTION OF THE INVENTION:
The term "about", as used herein, refers to any value which lies within the range defined by a
number upto ± 10% of the value.
The term "substantially free of the impurity as used herein means the sumatriptan succinate
product contains an amount of (1-(3-(2-(dimethylamino)ethyl)-1-((5-((Nmethylsulfamoyl)
methyl)-1H-indol-3-yl)methyl)-1H-indol-5-yl)-N-methylmethanesulfonamide)
and 5-hydroxymethyl-N, N –dimethyltryptamine impurities is less than 1% w/w, preferably less
than 0.5% w/w and more preferably less than 0.3% w/w.
The impurities may be detected by suitable HPLC method. For example the impurities can be
measured by HPLC method as described in Sumatriptan succinate USP.
The impurities (1-(3-(2-(dimethylamino)ethyl)-1-((5-((N-methylsulfamoyl)methyl)-1H-indol-3-
yl)methyl)-1H-indol-5-yl)-N-methylmethanesulfonamide) and 5-hydroxymethyl-N, N –
dimethyltryptamine are detected at RRT 2.13 and RRT 0.78 respectively.
Regarding the specific RRT values of impurities disclosed herein, it is well known to a person
skilled in the art that the RRT values may vary from sample to sample due to, inter alia,
instrument errors (both instrument to instrument variation and the calibration of an individual
instrument) and differences in sample preparation. Thus, it has been generally accepted by those
skilled in the art that independent measurement of an identical RRT value can differ by amounts
of up to ±0.01. However, it also has been generally accepted by those skilled in the art that
independent measurement of an identical RRT value which is greater than 1 i.e. late eluting
impurity can differ by amounts of up to ±0.2.
5
The present invention relates to a ready to use, stable liquid composition comprising sumatriptan
or pharmaceutically acceptable salts thereof in the form of ready to use injection, wherein the
composition is substantially free of (1-(3-(2-(dimethylamino)ethyl)-1-((5-((Nmethylsulfamoyl)
methyl)-1H-indol-3-yl)methyl)-1H-indol-5-yl)-N-methylmethanesulfonamide)
and 5-hydroxymethyl-N, N –dimethyltryptamine impurities.
The term “stable composition” refers to any preparation of sumatriptan or pharmaceutically
acceptable salts thereof having sufficient physical and chemical stability to allow storage at a
convenient temperature, such as between about 2° C and about 30° C, for a commercially
reasonable period of time. The term “physical stability” refers to maintenance of color, and
absence of particulate matter and the term “chemical stability” relates to no or acceptable level of
drug-related impurities in terms of total impurity, maximum individual unknown impurity and
single maximum individual impurity. Further, a pharmaceutical composition of the invention is
“stable” or “stabilized” if one or more of the active agents therein exhibit good stability as
determined by a standard potency test. More specifically, such compositions exhibit a potency
loss of less than about 10%, preferably less than about 8%, more preferably less than about 5% as
determined by the test. Potency can be evaluated by one or a combination of strategies known in
the field.
Regulatory authorities worldwide require that drug manufacturers isolate, identify and
characterize the impurities in their products. Furthermore, it is required to control the levels of
these impurities in the final drug compound obtained by the manufacturing process and to ensure
that the impurity is present in the lowest possible levels, even if structural determination is not
possible.
Generally, impurities are identified spectroscopically and by other physical methods, and then the
impurities are associated with a peak position in a chromatogram (or a spot on a TLC plate).
Thereafter, the impurity can be identified by its position in the chromatogram, which is
conventionally measured in minutes between injection of the sample on the column and elution of
the particular component through the detector, known as the "retention time" ("Rt"). This time
period varies daily based upon the condition of the instrumentation and many other factors. To
mitigate the effect that such variations have upon accurate identification of an impurity,
practitioners use "relative retention time" ("RRT") to identify impurities. The RRT of an impurity
6
is its retention time divided by the retention time of a reference marker. In the current invention
the reference marker is sumatriptan base.
Water for injection (WFI) contain dissolved oxygen (DO). In certain embodiments dissolved
oxygen is controlled and with respect to the present invention this DO needs to be controlled. In
one embodiment the DO content of WFI is reduced below 0.50 ppm by purging of nitrogen (N2)
gas. Preferably, the DO content of WFI is reduced below 0.45 ppm, more preferably below 0.40
ppm, more preferably below 0.35 ppm, more preferably below 0.30 ppm.
In another embodiment, stable ready to use pharmaceutical composition of sumatriptan comprises
not more than about 2.0 % of total impurities and, more preferably not more than about 1.8 % of
total impurities.
In another embodiment, stable ready to use pharmaceutical composition of sumatriptan comprises
not more than about 0.5% of (1-(3-(2-(dimethylamino)ethyl)-1-((5-((N-methylsulfamoyl)methyl)-
1H-indol-3-yl)methyl)-1H-indol-5-yl)-N-methylmethanesulfonamide) impurity, preferably not
more than about 0.3%.
In another embodiment, stable ready to use pharmaceutical composition of sumatriptan comprises
not more than about 0.5% of 5-hydroxymethyl-N, N –dimethyltryptamine impurity, preferably
not more than about 0.3%.
In another aspect of the present invention, there is provided a stable liquid pharmaceutical
composition of sumatriptan succinate, wherein the composition is prepared by process comprising
steps of:
(a) purging nitrogen to reduce dissolved oxygen content in water for injection below 0.5 ppm.
(b) dissolving sodium chloride and sumatriptan succinate in water for injection of step (a) to form
a solution.
(c) filtering the solution through 0.22 µm polyvinylidene difluoride (PVDF) filter and filling in
1mL prefilled syringe,and
(d) terminally sterilizing the prefilled syringe of step (c) by autoclaving.
In another embodiment the pH of solution after step (b) was found to be 4.2 to 5.3.
7
In another aspect of the present invention, there is provided a stable liquid pharmaceutical
composition of sumatriptan succinate, wherein the composition is prepared by process comprising
steps of:
(a) purging nitrogen to reduce dissolved oxygen content in water for injection about 0.3 ppm.
(b) dissolving sodium chloride and sumatriptan succinate in water for injection of step (a) to form
a solution.
(c) filtering the solution through 0.22 µm polyvinylidene difluoride (PVDF) filter and filling in
1mL prefilled syringe, and
(d) terminally sterilizing the prefilled syringe of step (c) by autoclaving.
In another embodiment the pH of solution after step (b) was found to be 4.2 to 5.3.
In another embodiment, the terminal sterilization is by autoclaving at 121°C at 8 minutes, 12
minutes or 15 minutes cycle.
Further the present invention provide the stable ready to use pharmaceutical composition of
sumatriptan succinate for treatment of migraine, with or without aura in adults and acute treatment
of cluster headache in adult patients in need thereof.
In another embodiment, the composition retains at least 90 % its potency for about 3 months when
stored at 30? and 65% relative humidity.
In another embodiment, the (1-(3-(2-(dimethylamino)ethyl)-1-((5-((N-methylsulfamoyl)methyl)-
1H-indol-3-yl)methyl)-1H-indol-5-yl)-N-methylmethanesulfonamide) impurity, which is an
oxidative cum thermal impurity, decreases by about 65 %, preferable by about 60%, more
preferable by about 58% as dissolved oxygen content of composition is reduced from about 4ppm
to less than 0.5ppm.
In another embodiment, the 5-hydroxymethyl-N, N –dimethyltryptamine impurity, which is an
oxidative cum thermal impurity, decreases by about 45 %, preferable by about 40%, more
preferable by about 37%, when autoclaving time for composition decreases from about 15
minutes to about 8 minutes.
8
Examples:
The present invention can be described by way of following examples. It is to be recognized that
modifications falling within the scope and spirit of the description or claims, which would be
obvious to a person skilled in the art based upon the disclosure herein, are also considered to be
included within the scope of this disclosure.
Table 1: Composition of Sumatriptan injection 8 mg/mL & 12 mg/mL.
Material Purpose
8 mg/ml 12 mg/ml
Quantity/
0.5 mL
Quantity/
0.5 ml
Sumatriptan base as
succinate salt
Active Pharmaceutical
Ingredient
4 mg 6 mg
Sodium chloride Osmolality agent 3.8 mg 3.5 mg
Water for injection USP Vehicle 0.5 mL 0.5 mL
Manufacturing Process:
1. 80% of required volume of water for injection (WFI) previously nitrogen purged for 30
minutes, was collected in a SS vessel.
2. Dissolved oxygen of the WFI was checked and maintained below 0.5 ppm.
3. Dispensed quantity of sodium chloride was added to above-mentioned Water for Injection and
stirring was performed at 300-600 RPM for 5 minutes using overhead stirrer. Clear solution
was observed.
4. Dispensed quantity of sumatriptan succinate was added to above mentioned solution and
stirring was performed at 200 RPM for 30 minutes. Clear solution was observed.
5. pH of the solution was found to be 4.2- 5.3.
6. Made up the volume of solution with remaining quantity of WFI.
7. Solution was filtered through 0.2µm polyvinylidene difluoride (PVDF) filter.
8. Solution was filled in the 1 ml PFS and autoclaved at 8 min or 15 minutes cycle.
Effect of different concentrations of dissolved oxygen content on (1-(3-(2-
(dimethylamino)ethyl)-1-((5-((N-methylsulfamoyl)methyl)-1H-indol-3-yl)methyl)-1H-indol-
5-yl)-N-methylmethanesulfonamide) Impurity
Three compositions of sumatriptan injection 8mg/mL are prepared with same composition and
manufacturing procedure as given in table 1 but with different concentration of dissolved oxygen
9
(DO) content (DO < 4 ppm / DO< 1 ppm and DO< 0.5 ppm), wherein the autoclave time is about
15 minutes as shown in Table 2.
Table 2: Comparative data at different DO content for sumatriptan injection 8mg/mL
Example 1 Example 2 Example 3
DO in Composition DO < 4 PPM DO < 1 PPM DO <0.5 PPM
(1-(3-(2-(dimethylamino)ethyl)-1-((5-
((N-methylsulfamoyl)methyl)-1H-indol-
3-yl)methyl)-1H-indol-5-yl)-Nmethylmethanesulfonamide)
Impurity
(RRT 2.13)
0.192 0.142 0.080
From the above data it can be concluded that the impurity at RRT 2.13, which is an oxidative cum
thermal impurity shows the decreasing trends, as the dissolved oxygen content of composition
decreases from 4 ppm to 0.5 ppm.
Effect of autoclaving or cumulative lethality dose exposure time on 5-Hydroxymethyl-N,Ndimethyltryptamine
Impurity
Three compositions of sumatriptan injection 8mg/mL are prepared with same composition and
manufacturing procedure as given in table 1 but with different autoclave cycle time i.e. 8 min, 12
min or 15 min, wherein the dissolved oxygen content is less than <0.5 PPM as shown in table 3.
Table 3: Comparative data for different autoclave cycle time for sumatriptan injection 8mg/mL
Example 4 Example 5 Example 6
Autoclave Time 8 min 12 minute 15 minute
5-Hydroxymethyl-N,Ndimethyltryptamine
(RRT0.78)
0.135 0.190 0.215
From the above data it is concluded that impurity at RRT 0.78, which is an oxidative cum thermal
impurity, shows increasing trends as the autoclaving time of composition increase from 8 min to
15 min.
10
Stability Data of Example -5
Initial 3Months_30oC/65%
RH
9Months_30oC/65%
RH
Description Clear,
colourless to
pale yellow
solution
Clear, colourless to
pale yellow solution
Clear, colourless to
pale yellow solution
Assay (%) 101.6 100.60 101.70
Related Substances (%)
Sumatriptan Succinate
Related Compound A
(RRT 2.66)
0.132 0.160 0.270
Sumatriptan monomethyl
(Impurity B) (RRT 0.61)
ND ND ND
Related compound C
(RRT 0.89)
0.025 0.040 0.080
Sumatriptan N-oxide
Impurity-D (RRT 0.27)
0.015 ND ND
5-Hydroxymethyl-N,Ndimethyltryptamine
(RRT 0.78)
0.190 0.120 0.040
(1-(3-(2-
(dimethylamino)ethyl)-1-((5-
((Nmethylsulfamoyl)
methyl)-
1H-indol-3-yl)methyl)-1Hindol-
5-yl)-Nmethylmethanesulfonamide)
(RRT 2.13)
0.072 0.090 0.280
Max. unknown 0.012 0.080 0.117
Total Impurities 0.490 0.635 1.307

,CLAIMS:1. A stable pharmaceutical composition comprising sumatriptan or a pharmaceutically acceptable
salt thereof in the form of ready to use injection, wherein the composition is substantially free of
impurities (1-(3-(2-(dimethylamino)ethyl)-1-((5-((N-methylsulfamoyl)methyl)-1H-indol-3-
yl)methyl)-1H-indol-5-yl)-N-methylmethanesulfonamide) and 5-hydroxymethyl-N, N –
dimethyltryptamine.
2. The pharmaceutical composition of claim 1, wherein sumatriptan or a pharmaceutically
acceptable salt thereof is sumatriptan succinate.
3. The pharmaceutical composition of claim 1, comprises sumatriptan succinate as active
ingredient, sodium chloride as osmolality agent and water for injection as vehicle.
4. The pharmaceutical composition of claim 1, wherein the composition has a pH of from about
4.2 to about 5.3.
5. The pharmaceutical composition of claim 1, wherein the composition has a dissolved oxygen
content of less than about 0.5 ppm.
6. The pharmaceutical composition of claim 1, wherein the composition is terminally sterilized.
7. The pharmaceutical composition according to claim 6 is terminally sterilized by autoclaving
at 121°C for 12 minutes or less.
8. The pharmaceutical composition of claim 1, wherein following storage of the composition at
30oC and 65% relative humidity for a period of 3 months, the amount of total impurities present
in the composition is not more than 1%.
9. A stable liquid pharmaceutical composition of sumatriptan succinate, wherein the formulation
is prepared by process comprising steps of:
(a) Purging nitrogen to reduce dissolved oxygen of water for injection below 0.5 ppm.
(b) Dissolving sodium chloride and sumatriptan succinate thereof in water for injection of step
(a).
(c) Adjusting the pH of the solution of step (b) from about pH 4.2 to about 5.3.
(d) Solution of step (c) was filtered and filled in prefilled syringe.
(e) The prefilled syringe of step (d) is terminally sterilized by autoclaving at 121°C for about 12
minutes or less.
10. A stable liquid pharmaceutical composition of sumatriptan succinate, wherein the
formulation is prepared by process comprising steps of:
(a) Purging nitrogen to reduce dissolved oxygen of water for injection below about 0.5 ppm.
(b) Dissolving sodium chloride and sumatriptan succinate thereof in water for injection of step
(a).
(c) Adjusting the pH of the solution of step (b) from about pH 4.2 to about 5.3.
(d) Solution of step (c) was filtered and filled in prefilled syringe.
(e) The prefilled syringe of step (d) is terminally sterilized by autoclaving at 121°C for about 8
minutes or less.