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NOVEL INJECTABLE COMPOSITIONS AND PROCESS OF PREPARATION
THEREOF
FIELD OF THE INVENTION,
The present invention relates to novel and highly stable injectable
pharmaceutical
compositions comprising at least one cyclooxygenase-II enzyme (COX-II)
inhibitor or
non-steroidal anti-inflammatory drug (NSAID) or COX/LOX inhibitor, or its
tautomeric forms, analogues, isomers, polymorphs, solvates, prodrugs or salts
thereof
as active ingredient suitable for parenteral administration preferably by
intramuscular
;
(IM) -on:intravenous (IV) route; process of preparing such compositions and
therapeutic
methods of using such compositions.
The analgesic and anti-inflammatory injectable compositions of the present
invention
are very useful in mammals particularly in humans for the treatment of acute
painful
conditions like one or more of post-operative trauma, pain associated with
cancer,
=l ~'1~I, ~ ,,,
sports injuries, migraine headache, neurological pain and pain associated with
sciatica
and spondylitis, and the like, and/or chronic painful conditions, and/or other
associated
.ll ,I1; disorders such as inflammation, fever, allergy, or the like.
BACKGROUND OF THE INVENTION
Non-steroidal anti-inflammatory drugs '(NSAIDs) and cyclooxygenase-II enzyme
(COX-TP) ''inhibitors 'are' 'iri general ' higliY~",liyd'rophobic~ compounds =
and readily
p'recipitate, even in''tli6 presence1 bf 'minor amounts of water. Hence it is
very difficult to
formulate a such compounds into injectable compositions for intramuscular or
intravenous use.
NSAIDs such as nimesulide, ketorolac, diclofenac, ibuprofen and naproxen, and
COX-
II ' inhibitors- in''parenteral formi''capable . of instant'therapeutic
action are extremely
desirable: 1 In' order''tio<<prepare parenteral formulatibhs 'of 'these
classes of compounds, a
suita~le,'safe' and non'-toxic 'carrier/vehiclei'is requif ed in which these
drugs are soluble.
Due to the physico-chemical properties of these groups of compounds, the
NSAIDs or
the COX-II inhibitors are poorly soluble in water hence presenting a
difficulty in
formulating these drugs in the parenteral fvrm. Attempts to provide NSAIDs and
COX-
Il inhibitory ctrugs or trieir analogs in parenteral torm using various
solvents such as
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alcohols, dimethyl sulphoxide, propylene glycol and glycerin were found to be
unsuccessful either due to problems of solubility or that when these drugs
dissolve in
solvents like isopropenol acid mixture, dimethyl sulphoxide and propylene
glycol, the
desired concentration range for the therapeutic administration of the above
drugs
particularly through intramuscular route does not permit the above solvent
usage as
they are found to be toxic. Due to such.problems, it has been extremely
difficult to
develop stable injectable formulation of such drugs.
Several efforts have been made in the past to inake injectable compositions
comprising
of NSAIDs such as nimesulide. An injectable formulation of nimesulide lias
been
reported in PCT Patent No. WO 95/34533 that discloses the utilization of a
salt form of
niniesulide with L-lysine which is in turn fiirther complexed with
cyclodextrins that
may be dissolved in water to give an injectable preparation. The maximum
solubility
achieved by this injectable co-nposition was reported to be 2.4 ing/ml, which
is not
sufficient for intraniuscular administration, as it would require very large
volumes to
administer therapeutic doses. Moreover, making a salt form of nimesulide and
then
combining with cyclodextrins not only makes the process cumbersome but also
increases the cost of the formulations. Another reference (Daffonehio, L. et
al.,
Inflaminatoiy Research, 45, 259-264, 1995), wherein nimesulide is dissolved in
saline
for intravenous adininistration for experimental studies in animals, also
describes only
very dilute solutions which cannot deliver therapeutic doses of nimesulide in
humans.
Nimesulide is a potent non-steroidal anti-inflammatory (NSAID) drug, presently
used
in the treatment of painful inflammatory conditions due to rheumatoid
arthritis, which
also possesses antipyretic activity. Compared to other NSAIDs, nimesulide has
a better
therapeutic ratio, low gastrotoxicity and generally good tolerability.
Nimesulide is a
strongly hydrophobic substance that is practically insoluble in water
(solubility in water
at room temperature being 0.01 mg/ml). Since nimesulide is insoluble in water
and in a
large number of non-toxic solvents specifically those which are approved for
parenteral
use, it becoines higllly difficult to formulate it into solutions suitable for
parenteral
administration via intramuscular or intravenous route. Other NSAIDs such as
diclofenac, ibuprofen, indomethacin, and naproxen also offer a lot of
difficulty in
making them into injectable ycompositions using approved excipients and the
permissible concentrations in which they are approved for parenteral use.
Parenteral
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compositions particularly comprising cyclooxygenase-II inhibitors sucli as
rofecoxib or
valdecoxib are highly unstable upon storage due to the tendency of such drugs
to
precipitate out, and hence it becomes difficult to obtain a homogeneous
solution for
parenteral administration during the shelf life of such products. It is known
and well
accepted that parenteral administration of drugs for the treatment of painful
inflammatoiy conditions, is more effective than other routes of
administration, since the
drug enters the circulation directly and promptly manifests its therapeutic
effect.
Seedher, Neelam et. al. (Indian Journal of Pharmaceutical Sciences, 65(1), 58-
61, 2003)
had described the solubility of niinesulide in various solvents and solvent-
cosolvent
mixtures in relation to the developinent of parenteral formulations. The said
publication
showed that the solubilization of nimesulide increased in semi-polar solvents
such as
polyethylene glycols (PEGs) and non-ionic surfactants such as Tweeng 80 and
Brij x
30. However, the concetitration of PEGs used to achieve the desired solubility
is too
hlgh i.e. 90% which is not recommended for parenteral use specifically meant
for IV
administration. US Patent Nos. 4,056,635 and 4,452,817 disclose compositions
containing propofol suitable for parenteral administration to produce
anesthesia in
warm-blooded animals as mixtures of propofol with surfactants such as
Gremophor u
RH40, Cremophor EL, and Tween(I 80 in an aqueous medium that may also contain
ethanol or other pharmaceutically acceptable ingredients. US Patent No.
4,794,1 17
claims a process for solubilizing indomethacin in water consisting essentially
of
dissolving an anti-inflammatory amount of indomethacin in a solubilizing
amount of at
least one polyethylene glycol having a molecular weight of 300 to 700 and
dissolving
the resulting solution in a solubilizing amount of an aqueous medium buffered
in a pH
range of 4.5 to 8 especially intended for the external use. US Patent No.
4,798,846
discloses sterile propofol compositions containing 1% to 2% propofol alone or
dissolved in oil such as arachis oil or ethyl oleate. These formulations are
stabilized
with surfactants. US Patent No. 5,858,999 discloses a sterile aqueous
pharmaceutical
composition for parenteral administration which comprises about 0.9 to about
90 mg/ml
of a lazaroid or a pharmaceutically acceptable salt thereof, about 0.002 to
about 2.OM
citrate, upto about 80% of a cosolvent selected from the group consisting of
propylene
glycol, polyethylene glycol, glycerol, ethanol, dimethylsulfoxide,
dimethylacetanlide,
diinethyl isosorbide, N-methyl-2-pyrrolidone and water at a pH of about 2.4 to
about
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3.5. These compositions use very high concentrations of cosolvents.
US Patent No. 5,688,829 assigned to the applicant of the present invention
discloses a
tllerapeutic injectable analgesic pharniaceutical composltion for intra-
muscular
administration comprising essentially nimesulide in a parenteral absorption
enhancing
base comprising dimethylacetamide, benzyl benzoate and etllyl oleate. The said
composition uses lipophilic solvents that are oily in nature to solubilize
nimesulide,
which does not allow administration of the injectable via the intravenous
route. Another
US Patent No. 6,451,302 assigned to the same applicant describes an injectable
water-
miscible composition comprising nimesulide; benzyl alcohol; a substance
selected fi=om
the group consisting of dimethylacctainide, dimethylformamide,
dimethylsulphoxide,
and N-methyl pyrrolidone; and a glycol selected from the group consisting of
polyethylene glycol (PEG 200 to 600), propylene glycol, hexylene glycol,
butylene
glycol, and polyethylene glycol 660 hydroxy stearate. The said patent
necessitates the
use of alkyl ainides/alkyl sulphoxides or pyrrolidones to solubilize
nimesulide.
US Patent No. 6,589,973 pertains to a clear, stable novel pharmaceutical
preparation of
selective COX-II inhibitors in the parenteral forin for the treatment of pain
and
inflammatory conditions arising because of cyclooxygenase-II activity. In
particular,
the pharmaceutical preparation of COX-II inhibitors comprise of selective COX-
lI
inhibitors such as celecoxib, rofecoxib and their analogs dissolved in a
selective
isosorbide type solvent. EP Patent No. 1228757 relates to stable phal-
maceutical
solutions suitable for parenteral administration of nimesulide consisting of
80%
glycerol forinal, 15% ethanol and 5% water and/or 75% glycerol formal, 10%
etllanol,
10% propylene glycol and 5% water. However the solvents and the concentrations
in
which they are used are not approved for parenteral administration. PCT
Publication
No. WO 2000072884 describes a novel pharmaceutical composition of nimesulide
and
2,5-di-O-methyl-1,4:3,6-dianhydro-D-glucitol with or without water, optionally
containing one or more diluents which can be used for IV/IM administration or
oral or
topical formulations. US Publication No. 20030078266 specifically relates to a
pharmaceutical composition comprising in powder forin, at least one water-
soluble
therapeutic agent selected from selective COX-2 inhibitory drugs and prodrugs
and
salts thereof, in a therapeutically effective total amount constituting about
30% to about
90% by weight, a parenterally acceptable buffering agent in an amount of about
5% to
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about 60% by weight, and other parenterally acceptable excipient ingredients
in a total
amount of zero to about 10% by weight, of the composition; said composition
being
reconstitutable in a parenterally acceptable solvent liquid to form an
injectable solution.
The solvents used to formulate compositions intended for parenteral use should
be non-
toxic and should be preferably present in low concentrations. Most of the
existing
patent and literature references describe parenteral compositions, which
comprise very
high concentrations of solvents that are primarily not approved for parenteral
use and
also are unstable during storage.
Hence, there still exists an unmet need for developing effective non-toxic
parenteral
compositions comprising COX-Il inhibitors or NSAIDs in which the latter are
substantially soluble, and compositions those are devoid of such
aforementioned
problems and which could remain stable throughout the shelf life of the
product.
The inventors of the present invention have done extensive research and
conducted
several experiments using different non-toxic solvents and discovered that
their
combination in various concentrations along with suitable buffers and
alkalizing agents
results in a highly solubilized system suitable for parenteral administration
in which the
COX-II inhibitors and/or NSAIDs are soluble and which are also stable during
the
storage of the product thus demonstrating a significant advancement over the
prior art.
SUMMARY OF THE INVENTION
It is an objective of the present invention to provide novel injectable
pharmaceutical
compositions comprising at least one COX-II inhibitor or NSAID or COX/LOX
inhibitor, or its tautomeric forms, analogues, isomers, polymorphs, solvates,
prodrugs,
or salts thereof as active ingredient and a solvent system comprising -a
mixtui-e of
glycols; optionally with other pharmaceutically acceptable excipients.
It is an objective of the present invention to provide novel injectable
pharmaceutical
compositions comprising at least one COX-II inhibitor or NSAID or COX/LOX
inhibitor, or its tautomeric forms, analogues, isomers, polymorphs, solvates,
prodrugs,
or salts thereof as active ingredient; a solvent system comprising a mixture
of glycols;
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at least one alkalizing agent; optionally with other pliarmaceutically
acceptable
excipients.
It is an objective of the present invention to provide novel injectable
pharmaceutical
compositions comprising at least one COX-Il inhibitor or NSAID or COX/LOX
inhibitor, or its tautomeric forms, analogues, isoiners, polymorphs, solvates,
prodrugs,
or salts thereof as active ingredient; a solvent system comprising a mixture
of glycols;
at least one alkalizing agent; at least one buffering agent; optionally with
other
pharmaceutically acceptable excipients.
It is also an objective of the present iiivention to provide novel injectable
pharmaceutical compositions comprising a NSAID preferably nimesulide as active
ingredient, a solvent system comprising a mixture of glycols, at least one
alkalizing
agent, at least one buffering agent, optionally with other pharmaceutically
acceptable
excipients.
It is another objective of the present invention to provide novel injectable
pharmaceutical compositions comprising at least one COX-II inhibitor or NSAID
or
COX/LOX inhibitor, or its tautomeric fonns, analogues, isomers, polymorphs,
solvates,
prodrugs, or salts thereof as active ingredient and a solvent system
comprising a
mixture of glycols; optionally with other pharmaceutically acceptable
excipients,
additionally comprising one or more other pharmaceutically acceptable active
ingredient(s).
It is another objective of the present invention to provide highly stable
injectable
pharmaceutical compositions suitable for intramuscular (IM) or intravenous
(IV)
administration.
It is yet another objective of the present invention to provide a process for
the
preparation of such novel injectable compositions.
It is yet another objective of the present invention to provide a process for
preparation
of a novel injectable pharmaceutical compositions comprising.at least one COX-
II
inhibitor or NSAID or COX/LOX inhibitor, or its tautomeric forrns, analogues,
isomers, polymorphs, solvates, prodrugs, or salts thereof as active ingredient
and a
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solvent system comprising a mixture of glycols; optionally witll other
pharmaceutically
acceptable excipients, which coinprises of the following steps:
i) adding the active ingredient(s) to the mixture of glycols followed by
mixing,
ii) optionally adding other pharmaceutically acceptable excipients and inixing
to
produce the injectable composition.
It is a still further objective of the present invention to provide a process
for preparation
of a novel injectable pharmaceutical coinpositions comprising at least one COX-
II
inhibitor or NSAID or COX/LOX inhibitor, or its tautomeric forms, analogues,
isomers, polymorphs, solvates, prodrugs, or salts thereof as active ingredient
and a
solvent system comprising a mixture of glycols; optionally with other
pharmaceutically
acceptable excipients, additionally comprising one or more buffering agent(s)
and/or
alkalizing agent(s), which comprises of the following steps:
i) -adding one or more buffering agent(s) to the mixture of glycols and mixing
to
obtain a hoinogeneous mixture,
ii) adding the active ingredient(s) to the mixture followed by mixing,
iii) adding alkalizing agent(s) followed by inixing,
'iv) adding the buffering agent(s) with mixing to obtain a homogeneous
mixture,
v) optionally adjusting the pH of the mixture to an alkaline pH by adding
alkalizing agent(s) to produce the injectable composition.
It is yet another objective of the present inv.ention to provide a method of
using such
composition which comprises administering to a patient in need thereof an
effective
amount of the composition.
The compositions of the present invention are particularly useful for the
treatment of
one or more acute painfiil conditions such as post-operative trauma, pain
associated
with cancer, sports injuries, migraine headache, neurological pain and pain
associated
with sciatica and spondylitis, or chronic painful conditions, and/or other
associated
disorders.
DETAILED DESCRIPTION OF THE INVENTION
The present invention describes novel injectable pharmaceutical compositions
comprising at least one COX-II inhibitor or NSAID or COX/LOX inhibitor, its
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tautomeric forms, analogues, isomers, polymorphs, solvates, prodrugs, or salts
thereof
as active ingredient. Preferably the active ingredient is a NSAID, more
preferably
nimesulide. The compositions of the present invention additionally comprise a
solvent
system comprising a mixture of glycols, optionally with other pharmaceutically
acceptable excipients.
In an embodiment, the novel injectable pharmaceutical compositions of the
present
invention comprise additionally at least one alkalizing agent(s) and/or at
least one
buffering agent(s).
In an embodiment, the novel injectable pharmaceutical composition comprises at
least
one COX-II inhibitor or NSAID or COX/LOX inhibitor or its tautomeric forms,
analogues, isomers, polymorphs, solvates, prodrugs, or salts or thereof as
active
ingredient from about 0.1% to about 80% w/v of the composition and a solvent
system
comprising a mixture of glycols from about 1% to about 80% v/v of the
composition;
optionally with other pharmaceutically acceptable excipients. In another
embodiment,
the composition of the present invention additionally comprise at least one
alkalizing
agent from about 0.2% to about 60% v/v of the composition and/or at least one
buffering agent from about 2% to about 80% v/v of the composition.
In an embodiment, the present invention provides novel injectable
pharmaceutical
compositions comprising nimesulide as active ingredient, a solvent system
comprising
a mixture of glycols, at least one alkalizing agent, at least one buffering
agent,
optionally with other pharmaceutically acceptable excipients.
According to an embodiment of the present invention, the injectable
compositions
comprising COX-II inhibitor or NSAID or COX/LOX inhibitor can be prepared
using a
mixture of different non-toxic solvents in various concentrations along with
suitable
buffers and alkalizing agents. These compositions are clear, odorless, highly
stable,
non-toxic and homogeneous and are therefore suitable for parenteral
administration. In
an embodiment of the present invention, the injectable compositions are
suitable
particularly for administration by intravenous (IV) or intramuscular (IM)
route.
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In the present invention, the solubilization techniques used to solubilize the
poorly
soluble COX-II inhibitors or NSAIDs or COX/LOX inhibitor are based on
cosolvation
and/or pH modification techniques. Particularly, the compositions of the
present
invention are highly stable, preferably in the pH range of about 7.5 to 11.5,
inore
preferably in the pH range of about 9.0 to 11Ø
The active ingredient useful in the present invention are preferably NSAIDs
selected
from but not limited to a group comprising nimesulide, nabumetone, tapoxalin,
diclofenac, flosulide ibuprofen, indomethacin, naproxen, and the like, their
tautomeric
forms, analogues, isomers, polymorphs, solvates, prodrugs, or salts tliereof
or COX-II
inhibitors selected from but not limited to a group comprising celecoxib,
rofecoxib,
valdecoxib, etoricoxib, parecoxib, itacoxib, deracoxib and the like or their
tautomeric
forms, analogues, isomers, polymorphs, solvates, prodrugs or salts thereof. In
an
embodiment, the active ingredient of the present invention belongs to the
category of
COX/LOX (cyclooxygenase/lipooxygenase) inhibitor such as licofelone. In an
embodiment of the preser-t invention, the active ingredient is present in the
micronized
form.
In an embodiment of the present invention, the novel injectable pharmaceutical
compositions comprising at least one COX-II inhibitor or NSAID or COX/LOX
inhibitor, or its tautomeric forms, analogues, isomers, polymorphs, solvates,
prodrugs,
or salts thereof as active ingredient and a solvent system compi-ising a
mixture of
glycols; optionally with other pharinaceutically acceptable excipients,
additionally
comprises one or more other pharmaceutically acceptable active ingredient(s).
Other
pharmaeeutically acceptable active ingredient(s) useful in the present
invention is any
active agent, which can be combined with a COX-II inhibitor or a NSAID or
COX/LOX inhibitor, known in the art such as acetaminophen, serratiopeptidase,
antibacterial agents, CNS agents, CVS agents, or the like.
In an embodiment of the present invention, the inixture of glycols used to
make the
solvent system is polyethylene glycol (PEG) selected from but not limited to a
group
comprising PEG 200, PEG 300, PEG 400, PEG 600 and PEG 700, or mixtures
thereof;
and propylene glycol. In a preferred embodiment, the solvent system comprises
a
mixture of PEG 400 and propylene glycol.
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In an embodiment of the present invention, the alkalizing agent used is an
inorganic
base or an organic base or a combination of both. In an embodiinent of the
present
invention, the alkalizing agent used is selected from but not limited to a
group
comprising inorganic bases such as sodium hydroxide, potassuun hydroxide,
calcium
hydroxide, magnesium hydroxide, calcium carbonate, magnesium carbonate,
magnesium oxide, and the like, or mixtures tllereof; and/or organic bases such
as
ineglumine, triethanolamine, diethanolamine and the like, or mixtures thereof.
In a
preferred embodiment, the alkalizing agent is an inorganic base suc(1 as
sodium
hydroxide or potassium 1lydroxide. The alkalizing agent is preferably used as
an
aqueous (water) solution, prepared by dissolving the said agent in water. The
quantity
of the said agent and volume of water in which the agent is dissolved is used
so as to
obtain desired concentration of the agent.
The bufferiilg agent used in the present invention is preferably an alkaline
buffering
agent selected froin but not limited to a group comprising glycine buffer,
lysine buffer,
phosphate buffer, acetate buffer, and the like, or mixtures thereof,
preferably having a
pH range of about 7.2 to about 12.5. In a preferred embodiment, glycine buffer
is used
as the buffering agent in the-compositions of the present invention. In a
still preferred
embodiment, glycine buffer having pH of about 8.3 to about 11.3 is used as the
buffering agent. The buffering agent is preferably used as an aqueous (water)
solution,
prepared by dissolving the desired compound(s) in water. The quantity of the
desired
compound(s) and volume of water in which the desired compound(s) is dissolved
is
used so as to obtain desired concentration and pH of the agent.
Pharmaceutically acceptable excipients used in the composition of the present
invention
are selected from but not limited to the group of excipients generally known
to persons
skilled in the art e.g. vehicles, bulking agents, stabilizers, preservatives,
surfactants,
hydrophilic polymers, solubility enhancing agents such as glycerine, various
grades of
polyethylene oxides, beta-cyclodextrins like sulfobutylether-beta-
cyclodextrin,
transcutol and glycofurol, tonicity adjusting agents, local anesthetics, pH
adjusting
agents, antioxidants, osmotic agents, chelating agents, viscosifying agents,
wetting
agents, emulsifying agents, acids, sugar alcohol, reducing sugars, non-
reducing sugars
and the like, or mixtures thereof. In an embodiment, the Pharmaceutically
acceptable
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excipient(s) is used in an amount of about 0.1% to about 70% w/v or v/v of the
composition.
The vehicles suitable useful in the present invention can be selected froin
but not
limited to a group comprising dimethylacetamide, dimethylforniainide,
dimethylsulphoxide, N-methyl pyrrolidone, benzyl benzoate, benzyl alcohol,
ethyl
oleate, polyoxyethylene glycolated castor oils (Cremophor EL), polyethylene
glycol
such as those having molecular weight of about 200 to 6000, propylene glycol,
hexylene glycols, butylene glycols and glycol derivatives such as polyethylene
glycol
660 hydroxy stearate (Solutrol@ HS15) and the like, or mixtures thereof.
In another embodiment of the present invention, the compositions additionally
comprises an antimicrobial preservative such as benzyl alcohol preferably at a
concentration of about 0.001% to about 5.0% w/w of the composition.
In yet another embodiment of the present invention, the composition
additionally
comprises a conventionally known antioxidant selected from but not limited to
a group
comprising ascorbyl palmitate, butyl hydroxy anisole, butyl hydroxy toluene,
propyl
gallate, a-tocopherol and the like, or mixtures thereof.
The compositions of the present invention are highly stable. In an embodiment,
the
novel compositions of the present invention may be diluted with suitable
diluting fluids
known to the art to prepare a solution or"dispersion or infusion before
administration.
The novel compositions of the present invention are highly stable and
compatible with
different diluting fluids such as demineralized (DM) water, dextrose 5% w/v,
sodium
chloride 0.9% w/v or mixtures thereof. These fluids can be employed during the
manufacture of the composition or can be used for diluting the composition
before
adininistration. For example, the composition is stable for 5 hrs upto 1:150
dilution and
for 48 hrs up to 1:5 dilution with DM water; for 2 hrs upto 1:150 dilution and
for 4 hrs
upto 1:3 dilution with dextrose 5.0% solution; and for 24 hrs upto 1:150
dilution and
for 48 hrs upto 1:100 dilution with 0.9% NaCI solution, particularly at room
temperature.
The compositions of the present inven,Iion are preferably filled into
ampoules.
Compatibility study on nimesulide injection (content of one ampoule) with
different
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infilsion solutions were perforined to study the physical stability (during
intravenous
infusion) of the injection after diluting with infusion solutions. Most of the
infusion
solutions possess pH in acidic range (e.g. Normal saline, about 6.2; Ringer
lactate
solution, about 6.5 and Dextrose 5% w/v, about 5.5). Admixing with infusion
solution
for known injections comprising a COX-II inhibitor or NSAID or COX/LOX
inhibitor
results into saturation and thus crystallization. This is not desirable for a
solution if
diluted as such since such solution is meant for parenteral administration.
Tllus,
particularly in case of nimesulide as the active ingredient, it is requu=ed to
maintain the
pH of final solution at alkaline side to stabilize the nilnesulide in infusion
solutloll.
Hence, compatibility studies were performed oll the Niillesulide in infilsion
solutions
already buffered with sodium bicarbonate to impart the alkalinity to the final
solution
and thus prevent recrystallization. The study showed that the illjectable
composition
was Iliglily stable and compatible witll different infusion solutions.
In a ful-tller embodiment, ethanol and/or dimethylacetamide (DMA) can also be
added
to the compositions of the present invention to furtller enhance tlle
solubility of the
active ingredient(s).
Stability study was conducted on the composition stated in Exalnple-I herein.
Long
term (at controlled room telnpetature i.e. 25 C), intermediate (at 30 C and
70% RH),
accelerated (at 40 C and 75% RH), and stress (at 60 C) stability studies were
performed on the product and samples were analyzed including the controlled
samples
kept at freezing conditions (at 2-8 C). The product was found to be stable for
lnore than
six months at each of the above conditions and it did not show any stability
issues
relating to physical changes like particulate matter, crystallization and
color change or
cllemical changes such as change in potency or presence of any degl-adation
product.
Furthermore, in order to assess the product stability, 'freeze-thaw cycle'
study was also
conducted and the product was found to be stable physically and chemically
even after
four freeze-thaw cycles (i.e. refrigeration of the product followed by keeping
the
product at 40 C and 75% RH for one day each).
In the present invention, the nimesulide injection is forlnulated preferably
as an
aqueous injection meant for dilution with infusion solutions particularly in
case of IV
administration. Nimesulide possess pH dependent solubility i.e. nimesulide is
soluble at
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alkaline pH and practically insoluble at acidic pH. Thus, preferably a solvent
system
comprising a mixture of solvents (particularly glycols) optionally along with
a pH
adjusting system has been adopted to prepare a stable formulation in the
present
invention.
Pharmacological Study
Acute toxicity study of nimesulide IV injection was carried in female Swiss
mice
weighing between 20-25 g (n = 6 per group). The samples used for the study
were
Nimesulide IV injection (Label claim: Each 3 ml contains 100 mg of nimesulide)
and
Placebo injection. 0.1 ml of injection equivalent to doses of 41.6, 50, 54.17,
58.3 and
83.3 mg of nimesulide per kg body weight were adininistered by IV route for 14
days.
Mice injected with 0.1 ml of injection equivalent to a dose of 50.0 mg/kg,
54.17 mg/kg,
and 83.3 mg/Icg showed toxic symptoms of decreased locomotor activity, stupor,
and
tremors. Mice injected at dose level of 41.6 mg/kg and 5inl/kg placebo did not
show
any toxic symptom. The mortality rate of 16.6 %, 50 %, and 100% was observed
at
dose levels of 54.17 mg/kg, 58.3 mg/kg, and 83.3 mg/kg respectively. The LD50
of the
nimesulide injection (IV) was found to be 57.54 mg/kg.
Acute toxicity study of nimesulide IM injection was carried out in female
Swiss mice
weighing between 20-25 g (n = 5 per group). The samples used for the study
were
Nimesulide IM injection (Label claim: Each 3 ml contains 100 mg of nimesulide)
and
Placebo injection. The dose given was 1.25, 2.5, 5, 6.25, and 7.5 m1/kg of
Nimesulide
IM injection equivalent to 41.6, 83.3, 166.67, 208.33, and 250 mg of
nimesulide per 1cg
body weight respectively by IM route for 14 days. No toxicity symptoms were
observed
at dose level of 41.6 mg/kg of nimesulide injection and with 2.5 m1/1cg
placebo
injection in mice. Mice injected with a dose of 83.3, 166.67, 208.33 or 250
mg/kg
showed toxicity symptoms. The' mortality rates of 40%, 80%, and 100% were
observed
at dose level of 166.67 mg/kg, 208.33 mg/kg, and 250 mg/kg respectively. The
LD50 of
the nimesulide injection when administered intramuscularly was found to be
173.78
mg/kg.
A study was conducted to compare the hemolytic potential of Nimesulide IV
injection
100 mg/ml of the present invention with that of commercially available IV/IM
injections on Rat whole blood (citrated) and Rat packed red blood cells
(citrated). The
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cominercially available IV/IM injections used for the study were Diazepam
injection 5
mg/ml (CALMPOSEO), Diclofenac sodium injection 25 mg/ml (VOVERANO),
Frusemide injection 10 mg/ml (LASIXO), Nimesulide injection 10% w/v
(NIMOVETO), and Pentazocin lactate injection 30 mg/ml (FORTWINO). The study
showed that Nimesulide IV injection of the present invention when tested (at
blood to
test sample ratio of 1:10) on Rat packed red blood cells (citrated) showed
comparative
fractions of healthy ce11s as compared to CALMPOSEO, FORTWINO, NIMOVETO
and VOVERANO. Nimesulide IV injection when tested (at blood to test sample
ratio
of 13:1) on Rat whole blood (citrated) showed coinparative fractions of
healthy cells as
compared to CALMPOSEO, FORTWINO, and LASIXO.
The perivenous tolerance following a single intravenous administration of
Nimesulide IV
injection 100 mg/3 ml of the present invention against a placebo composition
was studied in
rabbits. The study showed that the animals injected intravenously witli
Nimesulide IV
injection of the present invention or the placebo did not show any signs of
local
irritation at the site of injection in the right ears.
Pharmacokinetic study of Nimesulide IV injection of the present invention was
carr_ied
out in rabbits. Albino rabbits (1.9-2.1 kg) of either sex (n=4 rabbits) were
selected for
the study. Nimesulide IV injection, each 2 ml ampoule containing 75 mg
nimesulide,
was used. A dose of 3.75 mg/kg body weight of rabbit equivalent to human dose
of 75
mg/601cg were administered by IV route, via marginal ear vein of rabbits and
blood
sampling was done at 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24
hour intervals,
and the plasma samples were analyzed for nimesulide by LC-MS/MS. The
pharmacokinetic profile of Nimesulide injection in rabbits is presented below:
Table-1: Pharmacokinetic profile of Nimesulide injection in rabbits
S. No. Time (in hours) Average Plasma concentration
of Nimesulide (microgram/mi)
1 0 0.00
2 0.25 17.00
3 0.5 15.90
4 1 13.35
5 1.5 10.73
6 2 8.57
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7 2.5 8.18
8 3 7.83
9 4 6.26
6 3.10
5 11 8 1.41
12 10 0.62
13 12 0.24
14 24 0.00
In a further embodiment of the present invention, a process for the
preparation of such
10 novel injectable compositions is provided.
In an embodiment, the process for preparation of a novel injectable
pharinaceutical
compositions comprising at least one COX-II inhibitor or NSAID or COX/LOX
inhibitor, or its tautomeric forms, analogues, isomers, polymorphs, solvates,
prodrugs,
or salts thereof as active ingredient and a solveilt system coinprising a
mixture of
glycols; optionally with other pharmaceutically acceptable excipients, which
comprises
of the following steps:
i) adding the active ingredient(s) to the mixture of glycols followed by
mixing,
ii) optionally adding other pharmaceutically acceptable excipients and mixing
to
produce the injectable composition.
In another embodiment, the process for preparation of a novel injectable
pharmaceutical compositions comprising at least one COX-II inhibitor and/or
NSAID
or COX/LOX inhibitor, or its tautomeric forms, analogues, isomers, polymorphs,
solvates, prodrugs, or salts thereof as active ingredient and a solvent system
comprising
a mixture of glycols; optionally with other pharmaceutically acceptable
excipients,
additionally comprising one or more biuffering agent(s) and/or alkalizing
agent(s),
which comprises of the following steps:
i) adding one or more buffering agent(s) to the mixture of glycols and mixing
to
obtain a homogeneous mixture,
ii) adding the active ingredient(s) to the mixture followed by mixing,
iii) adding alkalizing agent(s) followed by mixing,
iv) adding the buffering agent(s) with mixing to obtain a homogeneous mixture,
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v) optionally adjusting the pH of the mixture to an alkaline pH by adding
alkalizing agent(s) to produce the injectable composition.
In another embodiment, the process as described herein comprises the active
ingredient
selected from a group comprising of at least one COX-II inhibitor or NSAID or
COX/LOX inhibitor, or its tautomeric forms, analogues, isomers, polymorphs,
solvates,
prodrugs, or salts thereof, optionally with one or more additional active
ingredient(s)
that can be combined with a COX-II inhibitor or NSAID known to art. Preferably
the
NSAID is nimesulide or its tautomeric forms, analogues, isomers, polymorphs,
solvates, prodrugs, or salts thereof.
In yet another embodiment of the present invention, therapeutic methods of use
of such
compositions are provided. The analgesic and anti-inflammatory injectable
compositions of the present invention are useful for the treatment of acute
painfiil
conditions like post-operative trauma, pain associated with cancer, sports
injuries,
migraine headache, neurological pain and pain associated with sciatica and
spondylitis,
and the like, in mammals particularly in humans and animals, more particularly
in
humans.
In a further embodiment, the present invention provides a method of using the
novel
injectable pharmaceutical composition, which comprises administering to a
patient in
need thereof an effective amount of the composition.
In a further embodiment, the present invention provides a method of using the
injectable pharmaceutical composition preferably for the treatment of acute
and/or
chronic painful conditions in mammals particularly mammals, including a
variety of
painful and inflammatory coilditions like postoperative pain, primary
dysmenorrhea
and painful osteoarthritisand/or other associated disorders such as
inflammation, fever,
allergy, or the like.
In a further embodiment, the present invention provides a method of using the
injectable pharmaceutical composition particularly for the treatment of acute
painful
conditions, wllerein such condition is one or more of post-operative trauma,
pain
associated with cancer, sports injuries, migraine headache, neurological pain
and pain
associated with sciatica and spondylitis.
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In a further embodiment is provided the use of the compositions of the present
iiivention for the preparation of medicament for the treatment of acute
painful
conditions, wherein such condition is one or more of post-operative trauma,
pain
associated with cancer, sports injuries, migraine headache, neurological pain
and pain
associated with sciatica and spondylitis, and/or chronlc painful conditions,
and/or
painful and inflammatory conditions like postoperative pain, primary
dysmenorrhea
and painful osteoarthritis and/or other associated disorders such as
inflammation, fever,
allergy, or the like.
Some typical examples illustrating embodiments of the present invention are
provided.
However, it should also be understood that the particular compositions,
processes and
methods illustrating the present invention are exemplary only and should not
be
regarded as limitations of the present invention.
EXAMPLES
Example-1: Nimesulide Injection (100 mg/3 ml)
S. No. Ingredients Quantity/ 100 ml
1. Polyethylene glycol (PEG-400) 30.00 ml
2. Propylene Glycol 20.00 ml
3. Glycine Buffer pH 11.3 36.00 ml
4. Nimesulide 3.34 gm
5. Sodium hydroxide (NaOH) solution 4.0% w/v 11.20 ml
Procedure:
i) Talce specified quantity (30-.00 m1)'of PEG-400 into a vessel.
ii) Add Propylene glycol (20.00 ml) to step (i) with continuous stirring using
mechanical stirrer.
iii) Add about 30.0 ml of the Glycine Buffer pH 11.3 to the step (ii) wath
continuous stirring to form a homogeneous mixture.
iv) Add weighed amount of Nimesulide (3.34 gm) passed through #60 mesli to the
step (iii) with continuous stirring.
v) Add specified quantity (11.20 ml) of NaOH 4.0% solution to the step (iv)
with
continuous stirring to form a homogeneous solution.
vi) Mix the solution for about 30 minutes by continuous stirring.
vii) Add remaining quantity of Glycine Buffer pH 11.3 to make up the volume to
100 ml.
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viii) Mix the solution for about 10 minutes by continuous stirring.
ix) Adjust final pH to 10.0 by adding NaOH 4.0% w/v solution.
x) Mix the solution for about 10 minutes by continuous stirring.
Example-2: Diclofenac Injection (75 mg/3 ml)
S. No. Ingredients Quantity/ 100 ml
1. Polyethylene glycol (PEG-300) 30.00 ml
2. Propylene Glycol 20.00 ml
3. Glycine Buffer pH 12.0 30.00 ml
4. Diclofenac 2.50 gm
5. Sodium hydroxide (NaOH) solution 4.0% w/v 10.00 ml
Pi=ocedure:
i) Take specified quantity (30.00 ml) of PEG-300 into a vessel.
ii) Add Propylene glycol (20.00 ml) to step (i) with continuous stirring.
iii) Add about 25.0 nil of the Glycine Buffer pH 12.0 to the step (ii) with
continuous stirring to form a homogeneous mixture.
iv) Add weighed amount of Diclofenac passed through #60 mesh to step (iii).
v) Add specified quantity (10.00 ml) of NaOH 4.0% solution to the step (iv)
with
continuous stirring to form a homogeneous solution.
vi) Mix the solution for about 30 minutes by continuous stirring.
vii) Add remaining quantity of Glycine Buffe-- to step (vi).
viii) Mix the solution for about 10 minutes by continuous stirring.
ix) Adjust final pH to 7.5 by adding NaOH 4.0% w/v solution.
x) Mix the solution for about 10 minutes by continuous stirring.
Example-3: Indomethacin Injection (25 mg/3 ml)
S. No. Ingredients Quantity/ 100 ml
1. Polyethylene glycol (PEG-400) 30.00 ml
2. Propylene Glycol 20.00 ml
3. Lysine Buffer pH 10 42.00 ml
4. Indomethacin 0.84 gm
5. Sodium hydroxide (NaOH) solution 4.0% w/v 11.20 ml
Procedure:
i) Take specified quantity (30.00 ml) of PEG-400 into a vessel.
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ii) Add Propylene glycol (20.00 ml) to step (i) with continuous stirring.
iii) Add about 36.0 ml of the Lysine Buffer to the step (ii) with continuous
stirring.
iv) Add weighed amount of Indomethacin passed through #60 mesh to step (iii).
v) Add specified quantity (11.20 ml) of NaOH 4.0% solution to the step (iv)
with
continuous stirring to form a homogeneous solution.
vi) Mix the solution for about 30 minutes by continuous stirring,
vii) Add remaining quantity of Lysine Buffer to step (vi).
viii) Mix the solution for about 10 minutes by continuous stirring.
ix) Adjust final pH to 11.5 by adding NaOH 4.0% w/v solution.
x) Mix the solution for about 10 minutes by continuous stirring.
Example-4: Rofecoxib Injection (25 mg/3 ml)
S. No. Ingredients Quantity/ 100 ml
l. Polyethylene glycol (PEG-400) 20.00 ml
2. Propylene Glycol 20.00 ml
3. Dimethylacetamide 10.00 ml
4: Glycine Buffer pH 11.3 36.00 ml
5. Rofecoxib 0.84 gm
6. Sodium hydroxide (NaOH) solution 4.0% w/v 12.00 nil
Procedure
i) Take specified quantity (20.00 ml) of PEG-400 into a vessel.
ii) Add Propylene glycol (20.00 ml) to step (i) with continuous stirring using
mechanical stirrer. Add 10.00 ml of Dimethylacetamide and mix.
iii) Add about 30.0 ml of the Glycine Buffer pH 11.3 to step (ii).
iv) Add weighed amount of Rofecoxib passed through #60 mesh to step (iii).
v) Add specified quantity (12.00 ml) of NaOH 4.0% solution to the step (iv)
with
continuous stirring to form a homogeneous solution.
vi) Mix the solution for about 30 minutes by continuous stirring.
vii) Add remaining quantity of Glycine Buffer pH 11.3 to make up the volume to
100 ml.
viii) Mix the solution for about 10 minutes by continuous stii-ring.
ix) Adjust final pH to 11.0 by adding NaOH 4.0% w/v solution.
x) Mix the solution for about 10 minutes by continuous stirring.
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Example-5: Licofelone Injection (100 mg/3 ml)
S. No. Ingredients Quantity/ 100 ml
1. Polyethylene glycol (PEG-400) 30.00 ml
2. Propylene Glycol 20.00 ml
3. Glycine Buffer pH 11.3 36.00 nzl
4. Licofeloile 3.34 gm
5. Sodium hydroxide (NaOH) solution 3.0% w/v 14.40 ml
Procedure
i) Take specified quantity (30.00 ml) of PEG-400 into a vessel.
ii) Add Propylene glycol (20.00 ml) to step (i) with continuous stirring,
iii) Add about 30.0 ml of the Glycine Buffer pH 11.3 to the step (ii) with
continuous stirring to form a homogeneous mixture.
iv) Add weighed amount of licofelone passed through #60 mesh to step (iii).
v) Add specified quantity (14.40 ml) of NaOH 3.0% solution to tlle step (iv)
with
continuous stirring to form a homogeneous solution.
vi) Mix the solution for about 30 minutes by continuous stirring.
vii) Add remaining quantity ofGlycine Buffer pH 11.3 to make up the volume to
100 ml.
viii) Mix the solution for about 10 ininutes by continuous stirring.
ix) Adjust final pH to 10.0 by adding NaOH 3.0% w/v solution.
x) Mix the solution for about 10 minutes by continuous stirring.
Example-6: Nimesulide Injection (100 mg/3 ml)
S. No. Ingredients Quantity/ 100 ml
1. Polyethylene glycol (PEG-400) , 30.00 ml
2. Propylene Glycol 20.00 ml
3. Glycine Buffer pH 11.3 36.00 ml
4. Nimesulide micronized 3.34 gm
5. Sodium hydroxide (NaOH) solution 5.0% w/v 11.00 ml
Procedure
i) Take specified quantity (30.00 ml) of PEG-400 into a vessel.
ii) Add Propylene glycol (20.00 ml) to step (i) with continuous stirring.
iii) Add about 30.0 ml of the Glycine Buffer pH 11.3 to the step (ii) with
continuous stirring to form a homogeneous mixture.
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iv) Add weighed amount of Nimesulide micronized passed through #60 mesh to the
step (iii) with continuous stirring.
v) Add specified quantity (11.00 ml) of NaOH 5.0% solution to the step (iv)
with
continuous stirring to form a homogeneous solution.
vi) Mix the solution for about 30 minutes by continuous stirring.
vii) Add remaining quantity of Glycine Buffer pH 11.3 to make up the vohIme to
100 ml.
viii) Mix the solution for about 10 minutes by continuous stirring.
ix) Adjust final pH to 10.0 by adding NaOH 5.0% w/v solution.
x) Mix the solution for about 10 minutes by continuous stirring.
Example-7: Nimesulide Injection (100 mg/3 ml)
S. No. Ingredients Quantity/ 100 ml
l. Polyethylene glycol (PEG-400) 30.00 ml
2: Propylene Glycol 20.00 ml
3. Glycine Buffer pH 11.3 36.00 ml
4. Nimesulide 3.34 gm
5. Potassium hydroxide (KOH) solution 5.6 % w/v 11.00 ml
Procedure
i) Take specified quantity (30.00 ml) of PEG-400 into a vessel.
ii) Add Propylene glycol (20.00 ml) to step (i) with continuous stirring.
iii) Add about 30.0 ml of the Glycine Buffer pH 11.3 to the step (ii) with
continuous stirring to form a homogeneous mixture.
iv) Add weighed amount of Nimesulide (3.34 gm) passed through #60 mesh to the
step (iii) with continuous stirring.
v) Add specified quantity (11.00 ml) of KOH 5.6% solution to the step (iv)
with
continuous stirring to form a homogeneous solution.
vi) Mix the solution for about 30 minutes by continuous stirring.
vii) Add remaining quantity of Glycine Buffer pH 11.3 to make up the volume to
100 ml.
viii) Mix the solution for about 10 minutes by continuous stirring.
ix) Adjust final pH to 11.0 by adding KOH 5.6% w/v solution.
x) Mix the solution for about 10 minutes by continuous stirring.
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Example-8: Nimesulide Injection (100 mg/3 ml)
S. No. Ingredients Quantity/ 100 ml
1. Polyethylene glycol (PEG-400) 30.00 ml
2. Propylene Glycol 10.00 ml
3. Glycine Buffer pH 11.3 46.00 ml
4. Nimesulide 3.34 gm
5. Potassium llydroxide (KOH) solution 4.0 % w/v 13.80 ml
Procedure
i) Take specified quantity (30.00 ml) of PEG-400 into a vessel.
ii) Add Propylene glycol (10.00 ml) to step (i) with continuous stirring.
iii) Add about 40.0 ml of the Glycine Buffer pH 11.3 to the step (ii) with
continuous stirring to form a homogeneous mixture.
iv) Add weighed amount of Nimesulide (3.34 gm) passed through #60 mesh to the
step (iii) with continuous stirring.
v) Add specified quantity (13.80 ml) of KOH 4.0% solution to the step (iv)
with
continuous stirring to form a homogeneous solution.
vi) Mix the solution for about 30 minutes by continuous stirring.
vii) Add remauling quantity of Glycine Buffer pH 11.3 to make up the volunle
to 100 ml.
viii) Mix the solution for about 10 minutes by continuous stirring.
ix) Adjust final pH to 11.0 by adding KOH 4.0% w/v solution.
x) Mix the solution for about 10 minutes by continuous stirring.
Example-9: Nimesulide Injection (100 mg/3 ml)
S. No. Ingredients Quantity/ 100 ml
1. Polyethylene glycol (PEG-600) 20.00 ml
2. Propylene Glycol 10.00 ml
3. Phosphate Buffer pH 7.2 56.00 ml
4. Nimesulide 3.34 gm
5: Potassium hydroxide (KOH) solution 5.6 % w/v 11.20 ml
Procedure
i) Take specified quantity (20.00 ml) of PEG-600 into a vessel.
iij Add Propylene glycol (10.00 ml) to sten (i) with continuous stirring.
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iii) Add about 50.0 ml of the Phosphate Buffer pH 7.2 to the step (ii) with
continuous stirring to form a homogeneous mixture.
iv) Add weighed amount of Nimesulide (3.34 gm) passed through 960 mesh to the
step (iii) with continuous stirring.
v) Add specified quantity (11.20 ml) of KOH 4.0% solution to the step (iv)
with
continuous stirring to form a homogeneous solution.
vi) Mix the solution for about 30 minutes by continuous stirring.
vii) Add remaining quantity ofPhosphate Buffer pH 7.2 to make up volume to 100
inl.
viii) Mix the solution for about 10 minutes by continuous stirring.
ix) Adjust final pH to 11.0 by adding KOH 5.6% w/v solution.
x) Mix the solution for about 10 minutes by continuous stirring.
Example-10: Nimesulide Injection (100 mg/3 ml)
S. No. Ingredients ' Quantity/ 100 ml
1. Polyethylene glycol (PEG-300) 30.00 ml
2. Glycine Buffer pH 11.3 56.00 ml
3. Nimesulide micronized 3.34 gm
4. Potassium hydroxide (KOH) solution 6.5 % w/v 9.50 ml
Procedure
i) Take specified quantity (30.00 inl) of PEG-300 into a vessel.
ii) Add about 40.0 ml of the Glycine Buffer pH 11.3 to the step (i) with
continuous
stirring to form a homogeneous mixture.
iii) Add weighed amount of Nimesulide micronized passed through #60 mesh to
the
step (ii) with continuous stirring.
iv) Add specified quantity (9.50 ml) =of KOH 6.5% solution to the step (iii)
with
continuous stirring to form a homogeneous solution.
v) Mix the solution for about 30 minutes by continuous stirring.
vi) Add remaining quantity of Glycine Buffer pH 11.3 to make up the volume to
100 ml.
vii) Mix the solution for about 10 minutes by continuous stirring.
viii) Adjust final pH to 9.5 by adding KOH 6.5% w/v solution.
ix) Mix the solution for about 10 minutes by continuous stirring.
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Example-11: Nimesulide injection (75mg/2m1):
S. No. Ingredients Quantity/ 100 -nl
1. Nimesulide micronized 3.77 (Y-
2. Polyethylene Glycol (PEG 400) 30.00 m1
3. Propylene Glycol 20.00 ml
4. Glycine Buffer pH 11.3 35.00 ml
5. NaOH solution 4.0% 13.00 ml
Procedure
i) Take specified quantity (30.00 ml) of PEG-400 into a vessel.
ii) Add Propylene glycol (20.00 ml) to step (i) with continuous stirring.
iii) Add about 30.00 ml of the Glycine Buffer pH 11.3 to the step (ii) with
continuous stirring to form a llomogeneous mixture.
iv) Add weighed amount of Nimesulide (3.75 g) passed through #60 mesh to the
step (iii) with continuous stirring.
v) Add specified quantity (13.00 ml) of NaOH 4.0% solution to the step (iv)
with
continuous stirring to form a homogeneous solution.
vi) Mix the solution for about 30 minutes by continuous stirring.
vii) Add remaining quantity of Glycine Buffer pH 11.3 to make up the volume to
100 -nl.
viii) Mix the solution for about 10 minutes by continuous stirring.
ix) Adjust final pH to 10.0 by adding NaOH 4.0% w/v solution.
x) Mix the solution for about 10 minutes by continuous stirring.
Example-12: Licofelone injection (100 mg/3 ml):
S. No. Ingredients Quantity/ 100 ml
1. Licofelone 3.34 g
2. Polyethylene Glycol (PEG-400) 30.00 ml
3. Propylene Glycol 20.00 ml
4. Glycine Buffer pH 11.3 30.00 ml
5. NaOH solution 4.0% . 15.00 ml
Procedure
i) Take specified quantity (30.00 ml) of PEG-400 into a vessel.
ii) Add Propylene glycol (20.00 ml) to step (i) with continuous stirring using
mechanical stirrer.
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iii) Add about 28.00 ml of the Glycine Buffer pH 11.3 to the step (ii) with
continuous stirring to form a homogeneous mixture.
iv) Add weighed amount of Licofelone (3.34 g) passed through #60 mesh to the
step (iii) with continuous stirring.
v) Add specified quantity (15.00 ml) of NaOH 4.0% solution to the step (iv)
with
continuous stirring to form a homogeneous solution.
vi) Mix the solution for about 30 minutes by continuous stirring.
vii) Add remaining quantity of Glycine Buffer pH 11.3 to make up the volLune
to 100 ml.
viii) Mix the solution for about 10 ininutes by continuous stirring.
ix) Adjust final pH to 10.0 by adding NaOH 4.0% w/v solution.
x) Mix the solution for about 10 minutes by contuluous stirring.
Example-13: Parecoxib injection (50 mg/2 ml):
S. No. Ingredients Quantity/ 100 ml
1. Parecoxib 2.50 g
2. Polyethylene Glycol (PEG-400) 30.00 ml
3. Propylene Glycol 20.00 ml
4. Glycine Buffer pH 11.3 34.00 ml
5. NaOH solution 4.0% 14.00 ml
Procedure
i) Take specified quantity (30.00 ml) of PEG-400 into a vessel.
ii) Add Propylene glycol (20.00 ml) to step (i) with continuous stirring using
mechanical stirrer.
iii) Add about 30.00 ml of the Glycine Buffer pH 11.3 to the step (ii) with
continuous stirring to form a homogeneous mixture.
iv) Add weighed amount of Parecoxib (2.50 g) passed through #60 mesh to the
step
(iii) with continuous stirring.
v) Add specified quantity (14.00 ml) of NaOH 4.0% solution to the step (iv)
with
continuous stirring to form a homogeneous solution.
vi) Mix the solution for about 30 minutes by continuous stirring.
vii) Add remaining quantity of Glycine Buffer pH 11.3 to make up the volume to
100 ml.
viii) Mix the solution for about 10 minutes by continuous stirring.
ix) Adjust final pH to 10.0 by adding NaOH 4.0% w/v solution.
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x) Mix the solution for about 10 minutes by continuous stirring.
Example-14: Diclofenac Sodium injection (75 mg/2 ml):
S. No. Ingredients Quantity/ 100 nil
1. Diclofenac Sodium 3.77 g
2. Polyethylene Glycol (PEG-400) 30.00 ml
3. Propylene Glycol 20.00 ml
4. Glycine Buffer pH 11.3 35.00 ml
5. NaOH solution 4.0% 13.00 ml
Procedure
i) Take specified quantity (30.00 ml) of PEG-400 into a vessel.
ii) Add Propylene glycol (20.00 ml) to step (i) with continuous stirring using
mechanical stirrer.
iii) Add about 30:00 ml of the Glycine Buffer pH 11.3 to the step (ii) with
continuous stirring to form a homogeneous mixture.
iv) Add weighed amount of Diclofenac sodium (3.77 g) passed tllrough #60 mesh
to the step (iii) with continuous stirring.
v) Add specified quantity (13.00 ml) of NaOH 4.0% solution to the step (iv)
with
continuous stirring to form a homogeneous solution.
vi) Mix the solution for about 30 minutes by continuous stirring.
vii) Add remaining quantity ofGlycine Buffer pH 11.3 to make up the volume to
100 inl.
viii) Mix the solution for about 10 minutes by continuous stirring.
ix) Adjust final pH to 10.0 by adding NaOI-i 4.0% w/v solution.
x) Mix the solution for about 10 minutes by contimious stirring.
Example-15: Ibuprofen injection (200 n1g/2 ml):
S. No. Ingredients Quantity/ 100 ml
1. Ibuprofen 10 g
2. Polyethylene Glycol (PEG-400) 30.00 ml
3. Propylene Glycol 20.00 ml
4. Glycine Buffer pH 11.3 25.00 ml
5. NaOH solution 4.0% 18.00 ml
Procedure
i) Take specified quantity (30.00 ml) of PEG-400 into a vessel.
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WO 2006/126214 PCT/IN2006/000177
ii) Add Propylene glycol (20.00 ml) to step (i) with continuous stirring.
iii) Add about 22.00 ml of the Glycine Buffer pH 11.3 to the step (ii) with
continuous stirring to form a homogeneous mixture.
iv) Add weighed amount of Ibuprofen (10.00 g) passed through #60 mesh to the
step (iii) with continuous stirring.
v) Add specified quantity (18.00 ml) of NaOH 4.0% solution to the step (iv)
with
continuous stirring to form a homo=geneous solution.
vi) Mix the solution for about 30 minutes by continuous stirring.
vii) Add remaining quantity of Glycine Buffer pH 11.3 to make up the volume to
100 ml.
viii) Mix the solution for about 10 minutes by continuous stirring.
ix) Adjust final pH to 10.0 by adding NaOH 4.0% w/v solution.
x) Mix the solution for about 10 minutes by continuous stirring.
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