DESC:FIELD OF INVENTION
Disclosed herein is a pharmaceutical composition for injection comprising selexipag or a
salt thereof and a pharmaceutically acceptable excipient.
BACKGROUND
Selexipag is a prostacyclin receptor agonist. Selexipag indicated for the treatment of
pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression and
reduce the risk of hospitalization for PAH.
The chemical name for selexipag is 2-{4-[(5,6-diphenylpyrazin-2-yl) (isopropyl)amino]
butoxy}-N-(methylsulfonyl) acetamide. Its empirical molecular formula is C26H32N4O4S.
The average molecular mass is 496.62. The structural formula is:
US Patent No. 7,205,302 discloses selexipag and its use in the treatment of PAH. US
Patent Nos. 8,791,122, 9,284,280, 9,340,516 and 9,440,931 disclose polymorphic
crystalline forms of selexipag. US patent publication 2020/0129506 discloses an aqueous
injection composition of selexipag which includes an aqueous phosphate buffer as well as
a lyophilized form of the composition.
There is need to develop a stable injection composition of selexipag and disclosed herein
is a stable pharmaceutical composition for injection comprising selexipag or a salt thereof
and a pharmaceutically acceptable excipient.
SUMMARY
3
In first embodiment, disclosed is a pharmaceutical composition for injection comprising
selexipag or a salt thereof, and a pharmaceutically acceptable excipient. The composition
is administered intravenously, intramuscularly or subcutaneously. The composition is in
the form of a solution, suspension or a lyophilized powder. The composition is ready to
use (e.g. a solution or suspension), or ready to dilute or reconstitute (e.g., a lyophilized
powder) using a pharmaceutically acceptable diluent.
In a second embodiment, disclosed is a pharmaceutical composition for injection
comprising selexipag or a salt thereof, and a pharmaceutically acceptable excipient,
wherein the pharmaceutically acceptable excipient is selected from group consisting of a
bulking agent, a surfactant, a buffer, a pH adjusting agent, a solvent, and combinations
thereof.
In another embodiment, disclosed is a pharmaceutical composition for injection
comprising: (a) selexipag or a salt thereof, (b) glycine as a bulking agent in an amount of
about 2% to about 10% by weight of the composition, (c) succinic acid, acetic acid, or
methane sulphonic acid as a buffer in an amount of about 0.01% to about 5% by weight
of the composition, (d) polysorbate 20 as a surfactant in an amount of about 0.05% to
about 2% by weight of the composition, and (e) sodium hydroxide as a pH adjusting
agent.
In further embodiment of, disclosed is a process of preparing a lyophilized
pharmaceutical composition for injection comprising: (a) selexipag or a salt thereof, (b)
glycine as bulking agent in an amount of about 2% to about 10% by weight of the
composition, (c) succinic acid, acetic acid, or methane sulphonic acid as a buffer in an
amount of about 0.01% to about 5% by weight of the composition, (d) polysorbate 20 as
a surfactant in an amount of about 0.05% to about 2% by weight of the composition, and
(e) sodium hydroxide as a pH adjusting agent, wherein said process comprises the steps
of: (i) adjusting the pH of water for injection to 7.5 with sodium hydroxide , (ii) adding
and dissolving the selexipag in the solution of (i) to provide a mixture, (iii) adding and
dissolving the bulking agent, buffer, and surfactant to the mixture of step (ii), (iv)
4
adjusting a total volume, filtering the solution and filling the solution into a container
followed by sealing the container, and (v) lyophilizing the solution in the sealed container
to obtain the lyophilized pharmaceutical composition.
In another embodiment, disclosed is a pharmaceutical composition for injection
comprising: (a) selexipag or a salt thereof, (b) glycine as a bulking agent in an amount of
about 2% to about 10% by weight of the composition, (c) polysorbate 20 as a surfactant
in an amount of about 0.05% to about 2% by weight of the composition, and (d) sodium
hydroxide as a pH adjusting agent, wherein the composition is devoid of any buffer. Also
disclosed is a process of preparing the pharmaceutical composition, which is devoid of
any buffer, wherein the composition is ready to use, ready to dilute or in lyophilized
form.
In an aspect, the pharmaceutical compositions described herein have a pH which ranges
between 4 to 8, or 6 to 8, or 7.5.
DETAILED DESCRIPTION
Unless defined otherwise, all technical and scientific terms used herein have the same
meaning as is commonly understood by one of ordinary skill in the art to which this
invention belongs. If there is a plurality of definitions for a term herein, those in this
section prevail unless stated otherwise.
It must be noted that, as used in this specification and the appended claims, the singular
forms “a" " an,” and " the " include plural referents unless the context clearly dictates
otherwise. Thus, for example, reference to " a container " includes one or more of such
containers and reference to the agent” includes reference to one or more of such agents.
In describing and claiming the present invention, the following terminology will be used
in accordance with the definitions set forth below.
Selexipag has been shown to be beneficial in the treatment of pulmonary arterial
hypertension (PAH). In a phase III clinical trial, among patients with PAH, the risk of the
5
primary composite end point of death or a complication related to PAH was significantly
lower among patients who received selexipag than among those who received placebo.
Selexipag received market approval, e.g., in the United States and is indicated for the
treatment of PAH (WHO Group I) to delay disease progression and reduce the risk of
hospitalization for PAH. Approved film-coated tablet formulations of selexipag intended
for twice daily oral administration have been used (UPTRAVI®), wherein excipients
include D-mannitol, cornstarch, low substituted hydroxypropylcellulose,
hydroxypropylcellulose, and magnesium stearate. The tablets are film coated with a
coating material containing hypromellose, propylene glycol, titanium dioxide, carnauba
wax along with a mixture of iron oxides.
In certain instances, the use of an oral formulation of selexipag may be inappropriate or
impossible (e.g., in urgent care, or in case a patient is for some reason unable to swallow
a tablet). UPTRAVI® is also available as selexipag for injection, a lyophilized form
including glycine, phosphoric acid, polysorbate 20, and sodium hydroxide for pH
adjustment. UPTRAVI® for injection is sold in 10mL vials to which sodium chloride for
injection is added to provide 225 µg/mL of selexipag. There is a need to develop
alternative intravenously administered formulations of selexipag.
In first embodiment, disclosed is a pharmaceutical composition for injection comprising
selexipag or a salt thereof, and a pharmaceutically acceptable excipient. The composition
is administered intravenously, intramuscularly or subcutaneously. The composition is in
the form of a solution, suspension or lyophilized powder. The composition is ready to use
(e.g., a solution or suspension) or ready to dilute or ready to reconstitute (e.g., a
lyophilized powder) using a suitable diluent.
In second embodiment, disclosed is a pharmaceutical composition for injection
comprising selexipag or a salt thereof and a pharmaceutically acceptable excipient,
wherein the pharmaceutically acceptable excipient is selected from group consisting of a
bulking agent, a surfactant, a buffer, a pH adjusting agent, a solvent, and combinations
thereof.
6
In a specific aspect, the pharmaceutical composition comprises a bulking agent which is
selected from group consisting of mannitol, sorbitol, glycine, glucose, maltose, sucrose,
lactose, polyvinylpyrrolidone, dextran, and combinations thereof. The bulking agent is
present in a concentration ranging from about 2% to about 10% by weight of the
pharmaceutical composition. More preferably, the bulking agent is present in a
concentration of about 5% by weight of the pharmaceutical composition.
The pharmaceutical composition comprises a surfactant which is selected from the group
consisting of polysorbate 20, lecithin (phosphatides), cholesterol, tragacanth, stearic acid,
calcium stearate, glyceryl monostearate, cetostearyl alcohol, cetomacrogol emulsifying
wax, sorbitan esters, polyoxyethylene alkyl ethers, e.g., macrogol ethers such as
cetomacrogol 1000, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan
fatty acid esters, e.g., the commercially available TWEENS™ (Tween™ 20 and
Tween™ 80), and combinations thereof. The surfactant is present in a concentration
ranging from about 0.05% to about 2% by weight of the pharmaceutical composition.
More preferably the surfactant is present at a concentration of about 0.3% by weight of
the pharmaceutical composition.
The pharmaceutical composition may comprise a buffer which is selected from the group
consisting of succinic acid, acetic acid, boric acid, tartaric acid, adipic acid, ascorbic acid,
citric acid, lactic acid, malic acid, methane sulphonic acid, and combinations thereof. The
buffer is present in a concentration ranging from about 0.01% to about 5% by weight of
the pharmaceutical composition. More preferably, the buffer is present in a concentration
of about 0.02%, or about 0.06%, or about 0.09%, or about 0.11% by weight of the
pharmaceutical composition. In an aspect, the buffer does not include phosphoric acid,
sodium phosphate, or any phosphate buffer.
The pharmaceutical composition may comprise a pH adjusting agent selected from
sodium hydroxide, hydrochloric acid, and a combination thereof.
7
In an aspect, when the pharmaceutical composition is in aqueous form, the
pharmaceutical composition has a pH which ranges between 4 to 8, or 6 to 8, or is 7.5.
The pharmaceutical composition may comprise an aqueous or nonaqueous solvent,
preferably an aqueous solvent such as water for injection is used in the composition.
Suitable non-aqueous solvents include but not limited to ethanol, polyethylene glycol,
propylene glycol and combination thereof.
In an embodiment, the pharmaceutical composition of invention is devoid of any buffer.
In another embodiment, disclosed is an aqueous pharmaceutical composition for injection
comprising: (a) 500 µg to 2000 µg of selexipag or a salt thereof, (b) glycine as a bulking
agent in an amount of about 2% to about 10% by weight of the pharmaceutical
composition, (c) succinic acid, acetic acid or methane sulphonic acid as a buffer in an
amount of about 0.01% to about 5% by weight of the pharmaceutical composition, (d)
polysorbate 20 as a surfactant in an amount of about 0.05% to about 2% by weight of the
pharmaceutical composition, and sodium hydroxide as a pH adjusting agent.
In another embodiment, disclosed is an aqueous pharmaceutical composition for injection
comprising: (a) about 0.01 to about 1% or about 0.05% by weight of selexipag or a salt
thereof, (b) glycine as a bulking agent in an amount of about 2% to about 10% by weight
of the pharmaceutical composition, (c) succinic acid, acetic acid or methane sulphonic
acid as a buffer in an amount of about 0.01% to about 5% by weight of the
pharmaceutical composition, (d) polysorbate 20 as a surfactant in an amount of about
0.05% to about 2% by weight of the pharmaceutical composition, and sodium hydroxide
as a pH adjusting agent.
In another embodiment, disclosed is an aqueous pharmaceutical composition for injection
comprising: (a) 500 µg to 2000 µg of selexipag or a salt thereof, (b) glycine as a bulking
agent in an amount of about 2% to about 10% by weight of the pharmaceutical
composition, (c) succinic acid as a buffer in an amount of about 0.11% by weight of the
8
pharmaceutical composition, (d) polysorbate 20 as a surfactant in an amount of about
0.05% to about 2% by weight of the pharmaceutical composition, and (e) sodium
hydroxide as a pH adjusting agent.
In another embodiment, disclosed is an aqueous pharmaceutical composition for injection
comprising: (a) 500 µg to 2000 µg of selexipag or a salt thereof, (b) glycine as a bulking
agent in an amount of about 2% to about 10% by weight of the pharmaceutical
composition, (c) acetic acid as a buffer in an amount of about 0.024% or 0.06% by
weight of the pharmaceutical composition, (d) polysorbate 20 as a surfactant in an
amount of about 0.05% to about 2% by weight of the pharmaceutical composition, and
(e) sodium hydroxide as a pH adjusting agent.
In another embodiment, disclosed is an aqueous pharmaceutical composition for injection
comprising: (a) selexipag or a salt thereof, (b) glycine as a bulking agent in an amount of
about 2% to about 10% by weight of the pharmaceutical composition, (c) methane
sulphonic acid as a buffer in an amount of about 0.09% by weight of the pharmaceutical
composition, (d) polysorbate 20 as a surfactant in an amount of about 0.05% to about 2%
by weight of the pharmaceutical composition, and (e) sodium hydroxide as a pH
adjusting agent.
In still another embodiment, disclosed is an aqueous pharmaceutical composition for
injection comprising: (a) 1800 µg of selexipag or a salt thereof, (b) glycine as a bulking
agent in an amount of about 5% by weight of the pharmaceutical composition, (c)
succinic acid as a buffer in an amount of about 0.11% by weight of the pharmaceutical
composition, (d) polysorbate 20 as a surfactant in an amount of about 0.3% by weight of
the pharmaceutical composition, and (e) sodium hydroxide as a pH adjusting agent.
In still another embodiment, disclosed is an aqueous pharmaceutical composition for
injection comprising: (a) 1800 µg of selexipag or a salt thereof, (b) glycine as a bulking
agent in an amount of about 5% by weight of the pharmaceutical composition, (c) acetic
acid as buffer in an amount of about 0.024% or 0.06% by weight of the pharmaceutical
9
composition, (d) polysorbate 20 as a surfactant in an amount of about 0.3% by weight of
the pharmaceutical composition, and (e) sodium hydroxide as a pH adjusting agent.
In yet another embodiment, disclosed is an aqueous pharmaceutical composition for
injection comprising: (a) 1800 µg of selexipag or a salt thereof, (b) glycine as a bulking
agent in an amount of about 5% by weight of the pharmaceutical composition, (c)
methane sulphonic acid as a buffer in an amount of about 0.09% by weight of the
composition, (d) polysorbate 20 as a surfactant in an amount of about 0.3% by weight of
composition, and (e) sodium hydroxide as a pH adjusting agent.
In alternate embodiment, disclosed is an aqueous pharmaceutical composition for
injection comprising: (a) 1800 µg of selexipag or a salt thereof, (b) glycine as a bulking
agent in an amount of about 2% to about 10% by weight of the pharmaceutical
composition, (c) polysorbate 20 as a surfactant in an amount of about 0.05% to about 2%
by weight of the pharmaceutical composition, and (d) sodium hydroxide as a pH
adjusting agent, wherein the pharmaceutical composition is devoid of any buffer.
In further embodiment of the invention, disclosed is a process of preparing a lyophilized
pharmaceutical composition for injection comprising: (a) selexipag or a salt thereof, (b)
glycine as a bulking agent in an amount of about 2% to about 10% by weight of the
composition, (c) succinic acid, acetic acid or methane sulphonic acid as a buffer in an
amount of about 0.01% to about 5% by weight of the composition, (d) polysorbate 20 as
a surfactant in an amount of about 0.05% to about 2% by weight of the composition, and
(e) sodium hydroxide as a pH adjusting agent, wherein said process comprises the steps
of: (i) adjusting the pH of water for injection with sodium hydroxide to pH 7.5, (ii)
adding and dissolving selexipag in the solution of (i) to provide a mixture, (iii) adding
and dissolving the bulking agent, the buffer, and the surfactant to the mixture of step (ii,)
(iv) adjusting the volume, filtering the solution and filling the solution into a container
followed by sealing the containier, and (v) lyophilizing the solution in the sealed
container to obtain the lyophilized pharmaceutical composition.
10
In further embodiment, disclosed is a process of preparing a lyophilized pharmaceutical
composition for injection comprising: (1) preparing an aqueous comprising (a) 1800 µg
of selexipag or a salt thereof, (b) glycine as a bulking agent in an amount of about 2% to
about 10% by weight of the aqueous composition, (c) succinic acid, acetic acid or
methane sulphonic acid as a buffer in an amount of about 0.01% to about 5% by weight
of the aqueous composition, (d) polysorbate 20 as a surfactant in an amount of about
0.05% to about 2% by weight of the aqueous composition, and (e) sodium hydroxide as a
pH adjusting agent, ii) adjusting the pH of water for injection with sodium hydroxide to
pH 7.5, (ii) adding and dissolving 1800 µg of selexipag in the solution of (i) to provide a
mixture, (iii) adding and dissolving a bulking agent, a buffer, a surfactant and water to the
mixture of step (ii) to provide an aqueous pharmaceutical composition, (iv) filtering the
aqueous pharmaceutical composition if step (iii) and filling the filtered composition into a
container followed by sealing the container, and (v) lyophilizing the filtered composition
in the sealed container to obtain the lyophilized pharmaceutical composition; wherein
glycine is the bulking agent in an amount of about 2% to about 10% by weight of the
aqueous composition; succinic acid, acetic acid or methane sulphonic acid is the buffer in
an amount of about 0.01% to about 5% by weight of the aqueous composition; and
polysorbate 20 is the surfactant in an amount of about 0.05% to about 2% by weight of
the aqueous composition.
The following examples serve to provide further appreciation of the invention but are not
meant in any way to restrict the effective scope of the invention.
11
EXAMPLES
Example 1: Selexipag for Injection with succinate buffer.
Name of Ingredient
A B
Quantity per vial
(prior to reconstitution)
Quantity per vial
(prior to reconstitution)
mg/vial % mg/vial %
Selexipag 1800 µg 0.05 1800 µg 0.05
Glycine 180 mg 5 180 mg 5
Polysorbate 20 10.8 mg 0.3 10.8 mg 0.3
Succinic acid 4.24 mg 0.118 1.7 mg 0.047
NaOH q.s. to pH 7.5 q.s. to pH 7.5
Water for Injection* q.s. to 3.6 mL q.s. to 100 mL q.s. to 3.6 mL q.s. to 100 mL
Example 2: Selexipag for Injection with acetate buffer.
Name of Ingredient
C D
Quantity per vial
(prior to reconstitution)
Quantity per vial
(prior to reconstitution)
mg/vial % mg/vial %
Selexipag 1800 µg 0.05 1800 µg 0.05
Glycine 180 mg 5 180 mg 5
Polysorbate 20 10.8 mg 0.3 10.8 mg 0.3
Glacial acetic acid 2.16 mg 0.06 0.865 mg 0.02402
NaOH q.s. to pH 7.5 q.s. to pH 7.5
Water for Injection* q.s. to 3.6 ml q.s. to 100 mL q.s. to 3.6 ml q.s. to 100 mL
12
Example 3: Selexipag for Injection with methane sulfonic acid buffer.
Name of Ingredient
E
Quantity per vial
(prior to reconstitution)
mg/vial %
Selexipag 1800 µg 0.05
Glycine 180 mg 5
Polysorbate 20 10.8 mg 0.3
Methane sulfonic acid 3.45 mg 0.096
Sodium Hydroxide q.s. to pH 7.5
Water for Injection* q.s. to 3.6 mL q.s. to 100 mL
Example 4: Selexipag for Injection without buffer.
Name of Ingredient
F
Quantity per vial
(prior to reconstitution)
mg/vial %
Selexipag 1800 µg 0.05
Glycine 180 mg 5
Polysorbate 20 10.8 mg 0.3
Sodium Hydroxide q.s. to pH 7.5
Water for Injection* q.s. to 3.6 mL q.s. to 100 mL
Manufacturing process for Examples 1 to 4:
Selexipag is practically insoluble in water. The drug product is sensitive to light and
temperature, hence entire manufacturing is performed under subdued light at a controlled
temperature of 2°C- 8°C. Initially, a selexipag slurry is prepared in a first part of 1%w/v
sodium hydroxide solution at 2°C- 8°C. The selexipag slurry is then added to a second
quantity of sodium hydroxide solution. Glycine, polysorbate 20 and buffer such as
succinic acid (Example 1) or glacial acetic acid (Example 2) or methane sulfonic acid
13
(Example 3) or no buffer (Example 4) were added subsequently to the above bulk and the
pH was adjusted to about 7.5 using the remaining quantity of 1% w/v sodium hydroxide
solution. The volume was made up to the mark using water for injection. The bulk
solution was filtered through Durapore®, PVDF (0.22µ absolute rated sterilizing grade
membrane filter) capsule type with filter part number: KVGLS04TT3 and filled into glass
vials at 2°C-8°C with partial stoppering. The vials were then subjected to a lyophilization
cycle. The vials containing lyophilized cake/powder were then fully stoppered and sealed
with flip off aluminum seals.
Example 5: Stability study results of Example 1B, 2D and 4F formulations.
The lyophilized vials of above examples were kept on stability as per ICH at different
time intervals and at conditions 2°C-8°C and at 25°C/60%RH. Note that the pH of bulk
was measured during the manufacturing process, prior to lyophilization. pH of finished
drug is of Reconstituted solution. The degradation products were measured by HPLC
method where the lyophilized vials were reconstituted with solution and then analyzed by
using HPLC method known in the art.
14
Example 1B Results
1B (Batch with 4 mM Succinic acid buffer)
Parameters Initial
2°C-8°C 25°C/60%RH
1 month 3 month 6 month 1 month 3 month 6 month
Description * * * * * * *
pH of Reconstituted
solution
6.98 7.22 7.15 7.16 7.16 NP 7.02
Water Content 0.60% 0.87% 0.80% 0.92% 1.01% 0.79% 0.71%
Assay 98.4 100.7 98.1 98.9 99.2 97.4 100.9
Degradation products (%)
Diphenyl pyrazine
Impurity /Alcohol
Impurity
ND <0.1 <0.1 <0.1 <0.1 <0.1 <0.1
Acid Impurity 0.105 <0.1 0.103 0.127 0.159 0.31 0.455
Ethyl ester Impurity ND N.D. <0.1 ND N.D. ND ND
Tertiary Butyl Ester
IMP
ND N.D. <0.1 ND N.D. <0.1 <0.1
Single Max 0.128 0.133 0.12 <0.1 0.411 0.285 0.417
Total Impurity 0.34 0.133 0.22 0.178 0.57 0.87 1.246
*White to almost white lyophilized cake or powdered material
15
Example 2D Results
2D (Batch With 4mM Glacial Acetic Acid)
Parameters Initial
2°C-8°C 25°C/60%RH
1 month 3 month 6 month 9 month 12 month 1 month 3 month 6 month
Description * * * * * * * * *
pH of
Reconstituted
solution
7.07 7.04 7.19 7.30 7.09 7.26 7.05 7.14 7.21
Water
Content
1.04% 0.37% 0.42% 0.60% 1.05% 0.59% 0.61% 0.3% 0.004468
Assay 97.6 97.7 97.1 98.3 99.0 98.5 97.0 97.0 97.4
Degradation products (%)
Diphenyl
pyrazine
Impurity
/Alcohol
Impurity
<0.1 <0.1 <0.1 <0.1 <0.1 <0.1 0.027 <0.1 <0.1
Acid
Impurity
<0.1 <0.1 <0.1 <0.1 0.106 <0.1 <0.1 0.122 0.372
Ethyl ester
Impurity
ND ND ND <0.1 ND ND ND ND <0.1
Tertiary
Butyl Ester
IMP
ND ND <0.1 ND ND <0.1 ND <0.1 ND
Single Max <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 0.176
Total
Impurity
<0.1 <0.1 <0.1 <0.1 0.11 <0.1 <0.1 0.122 0.565
*White to almost white lyophilized cake or powdered material
16
Example 4F results
4F (Batch without buffer)
Parameters Initial
2°C-8°C 25°C/60%RH
1 month 3 month 6 month 1 month 3 month 6 month
Description * * * * * * *
pH of
Reconstituted
solution
7.35 7.45 NP 7.54 7.40 NP 7.29
Water Content 0.70% 0.96% 0.71% 0.99% 1.41% 0.68 0.64%
Assay 98.7 99.8 98.7 98.8 99.5 97.6 97.7
Degradation products (%)
Diphenyl
pyrazine Impurity
/Alcohol Impurity
<0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1
Acid Impurity 0.103 <0.1 0.101 0.118 0.136 0.323 0.615
Ethyl ester
Impurity
ND N.D. ND ND N.D. ND ND
Tertiary Butyl
Ester IMP
ND N.D. <0.1 ND N.D. <0.1 ND
Single Max 0.032 <0.1 <0.1 <0.1 0.176 0.337 0.286
Total Impurity <0.1 < 0.1 0.1 0.118 0.312 0.66 1.153
*White to almost white lyophilized cake or powdered material
As the above three tables, all the formulation were found to be stable at 2-8°C as well as at accelerated conditions with suitable
impurity profile. ,CLAIMS:A pharmaceutical composition for injection comprising selexipag or salt thereof
and a pharmaceutically acceptable excipient.
2. The pharmaceutical composition of claim 1, wherein the composition is
administered intravenously, intramuscularly or subcutaneously.
3. The pharmaceutical composition of claim 1, wherein the composition is in the
form of a solution or suspension or lyophilized powder.
4. The pharmaceutical composition of claim 1, wherein the composition is ready to
use or ready to dilute or reconstitution using suitable diluent.
5. The pharmaceutical composition of claim 1, wherein the pharmaceutically
acceptable excipients are selected from group consisting of a bulking agent, a
surfactant, a buffer, a pH adjusting agent and a suitable solvent.
6. The pharmaceutical composition of claim 1, wherein the bulking agent is
selected from group consisting of mannitol, sorbitol, glycine, glucose, maltose,
sucrose, lactose, polyvinylpyrrolidone and dextran.
7. The pharmaceutical composition of claim 1, wherein the pH adjusting agent is
sodium hydroxide, hydrochloric acid or combination thereof.
8. The pharmaceutical composition of claim 1, wherein the solvent is aqueous or
nonaqueous, preferably aqueous such as water for injection.
9. The pharmaceutical composition of claim 8, wherein the bulking agent is present
in a concentration ranging from about 2% to about 10% by weight of
composition.
10. The pharmaceutical composition of claim 8, wherein the bulking agent is
present in a concentration is about 5% by weight of composition.
11. The pharmaceutical composition of claim 8, wherein the surfactant is present
in a concentration ranging from about 0.05% to about 2% by weight of
composition.
18
12. The pharmaceutical composition of claim 8, wherein the surfactant is present
in a concentration of about 0.3% by weight of composition.
13. The pharmaceutical composition of claim 1, wherein the composition is
devoid of buffer.
14. A lyophilized pharmaceutical composition for injection comprising: (a) 500
µg to 2000 µg of selexipag or salt thereof, (b) glycine as bulking agent in about
2% to about 10% by weight of composition, (c) succinic acid or acetic acid or
methane sulphonic acid as buffer in about 0.01% to about 5% by weight of
composition, (d) polysorbate 20 as surfactant in about 0.05% to about 2% by
weight of composition and (e) sodium hydroxide as a pH adjusting agent to
provide a pH of 4 to 8.
15. A pharmaceutical composition for injection comprising: (a) 500 µg to 2000 µg
of selexipag or salt thereof, (b) glycine as bulking agent in about 2% to about
10% by weight of composition, (c) succinic acid as buffer in about 0.04% by
weight of composition, (d) polysorbate 20 as surfactant in about 0.05% to about
2% by weight of composition and (e) sodium hydroxide as a pH adjusting agent
to provide a pH of 4 to 8.
16. A pharmaceutical composition for injection comprising: (a) 500 µg to 2000 µg
of selexipag or salt thereof, (b) glycine as bulking agent in about 2% to about
10% by weight of composition, (c) acetic acid as buffer in about 0.024% or
0.06% by weight of composition, (d) polysorbate 20 as surfactant in about 0.05%
to about 2% by weight of composition and (e) sodium hydroxide as a pH
adjusting agent to provide a pH of 4 to 8.
17. A pharmaceutical composition for injection comprising: (a) 500 µg to 2000 µg
of selexipag or salt thereof, (b) glycine as bulking agent in about 2% to about
10% by weight of composition, (c) methane sulphonic acid as buffer in about
0.09% by weight of composition, (d) polysorbate 20 as surfactant in about 0.05%
to about 2% by weight of composition and (e) sodium hydroxide as a pH
adjusting agent to provide a pH of 4 to 8.
19
18. A pharmaceutical composition for injection comprising: (a) 500 µg to 2000 µg
of selexipag or salt thereof, (b) glycine as bulking agent in about 5% by weight
of composition, (c) succinic acid as buffer in about 0.11% by weight of
composition, (d) polysorbate 20 as surfactant in about 0.3% by weight of
composition and (e) sodium hydroxide as a pH adjusting agent to provide a pH of
4 to 8.
19. A pharmaceutical composition for injection comprising: (a) 500 µg to 2000 µg
of selexipag or salt thereof, (b) glycine as bulking agent in about 5% by weight
of composition, (c) acetic acid as buffer in about 0.024% or 0.06% by weight of
composition, (d) polysorbate 20 as surfactant in about 0.3% by weight of
composition and (e) sodium hydroxide as a pH adjusting agent to provide a pH of
4 to 8.
20. A pharmaceutical composition for injection comprising: (a) 500 µg to 2000 µg
of selexipag or a salt thereof, (b) glycine as bulking agent in about 5% by weight
of composition, (c) methane sulphonic acid as buffer in about 0.09% by weight
of composition, (d) polysorbate 20 as surfactant in about 0.3% by weight of
composition and (e) sodium hydroxide as a pH adjusting agent to provide a pH of
4 to 8.
21. The pharmaceutical composition of any of above claims, wherein the pH of
the composition ranges between 4 to 8, or 6 to 8, or 7.5.
22. A process of preparing a pharmaceutical composition for injection
comprising: (a) selexipag or salt thereof, (b) glycine as bulking agent in about
2% to about 10% by weight of composition, (c) succinic acid or acetic acid or
methane sulphonic acid as buffer in about 0.01% to about 5% by weight of
composition, (d) polysorbate 20 as surfactant in about 0.05% to about 2% by
weight of composition and (e) sodium hydroxide as a pH adjusting agent,
wherein said process comprise steps of: (i) collecting water for injection and
adjusting the pH using sodium hydroxide to 7.5, (ii) adding and dissolving
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selexipag to water for injection from first step, (iii) adding and dissolving
bulking agent, buffer, surfactant to mixture of step ii, (iv) making up the volume
and filtering bulk solution and filling into suitable container followed by sealing,
and (v) lyophilizing the sealed container to obtain the pharmaceutical
composition.