FIELD OF THE INVENTION
This invention in general relates to a pharmaceutical composition of Oseltamivir or its
pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or
mixtures thereof. In particular, the present invention proposes a stable pharmaceutical
composition for constitution into solution or suspension comprising Oseltamivir or its
pharmaceutical^ acceptable salts, esters, solvates, polymorphs, enantiomers or
mixtures thereof and process for preparing the same.
BACKGROUND OF THE INVENTION
Oseltamivir phosphate is an influenza neuraminidase inhibitor. It shows potent
inhibitory activity against neuraminidase of influenza virus and has been widely used
for the treatment and prophylaxis of influenza. Oseltamivir phosphate is chemically
known as (3R,4R,5S)-4-acetylamino-5-amino-3(l-ethylpropoxy)-l-cyclohexene-lcarboxylicacid,
ethyl ester, phosphate (1:1), having the following structure:
NH2- H3PO,
Oseltamivir phosphate is marketed in the United States under the brand name
TAMIFLU® capsules and TAMIFLU® powder for oral suspension for the treatment
and prophylaxis of influenza by Hoffmann LA Roche. Inactive ingredients in
TAMIFLU® powder for oral suspension include monosodium citrate, saccharin
sodium, sodium benzoate, sorbitol, titanium dioxide, tutti-frutti flavoring, and xanthan
gum.
U.S. Patent No. 5,763,483, assigned to Gilead Sciences, discloses various carbocyclic
compounds including Oseltamivir phosphate and use of this compound in the treatment
of influenza.
U.S. Patent No. 8,334,319, assigned to Roche, discloses various polymorphic forms of
(3R,4R,5S)-5-amino-4-acetylamino-3-(l-ethyl-propoxy)-cyclohex-l-ene-carboxylic
acid ethyl ester phosphate (Oseltamivir phosphate) including crystalline form A, B, C
and amorphous form. This patent publication further discloses that the active
pharmaceutical ingredient of the commercially available medicament Tamiflu® is
crystalline form A.
U.S. Patent No. 9,012,499, assigned to Roche, discloses dry syrup pharmaceutical
composition of Oseltamivir phosphate comprising sugar alcohol(s) like erythritol, Dmannitol,
and sucrose, wherein amount of each of glucose and mannose contained in
the sugars and sugar alcohols as impurities is 0.01% by weight or less. This patent
publication highlights various formulation stability issues associated with powder for
suspension dosage form of Oseltamivir phosphate. The patent publication further
highlights that presence of amine group in Oseltamivir phosphate compound can react
with sugar alcohol(s) which leads to discoloration of Oseltamivir phosphate powder for
suspension formulation during storage.
U.S. Patent No. 9,034,382, assigned to Institute of Pharmacology and Toxicology
Academy of Military Medical Sciences China, discloses single population of
Oseltamivir phosphate granule composition and process for preparing thereof.
Oseltamivir phosphate granules composition as per the publication comprises at least
one diluent (such as sucrose) and at least one binder (such as povidone,
carboxymethylcellulose sodium and methylcellulose sodium). The granules are
reported to be water soluble
PCT Patent publication No. WO 2016/088010 discloses powder for suspension
composition of Oseltamivir phosphate comprising two different population, wherein
first population comprises Oseltamivir phosphate and one or more pharmaceutical^
3
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acceptable excipients and second population comprises one or more pharmaceutically
acceptable excipients, wherein second population is free from Oseltamivir phosphate.
There is a need in the art to provide new compositions of Oseltamivir for suspension
with desirable technical attributes such as viscosity, reconstitution time, content
uniformity and dissolution and which are free from discoloration during storage.
The present invention relates to a pharmaceutical composition of Oseltamivir or its
pharmaceutically acceptable salts, esters, solvates, polymorphs- enantiomers or
mixtures thereof and process of preparation thereof for extemporaneous reconstitution
into a homogeneous liquid suspension. Further, the pharmaceutical compositions of the
present invention exhibits technical attributes comparable to the commercially
marketed formulation of Oseltamivir phosphate such as viscosity, reconstitution time,
and dissolution and is also free from any discoloration during storage.
SUMMARY OF THE INVENTION
A first aspect of the present invention provides a pharmaceutical composition for
constitution into a suspension comprising a) first population comprising from about
0.5% to about 90% w/w Oseltamivir or its pharmaceutically acceptable salt, from about
0.1%o to about 45% w/w sorbitol and one or more pharmaceutically acceptable
excipients and b) second population comprising from about 0.1% to about 60% w/w
Oseltamivir or its pharmaceutically acceptable salt, from about 20% to about 70% w/w
sorbitol and one or more pharmaceutically acceptable excipients.
A second aspect of the present invention provides a pharmaceutical composition for
constitution into a suspension comprising a) first population comprising from about
0.5% to about 50% w/w Oseltamivir or its pharmaceutically acceptable salt, from about
0.1% to about 30% w/w sorbitol and one or more pharmaceutically acceptable
excipients and b) second population comprising from about 0.1% to about 30% w/w
Oseltamivir or its pharmaceutically acceptable salt, from about 20%) to about 50% w/w
sorbitol and one or more pharmaceutically acceptable excipients.
4
A third aspect of the present invention provides a pharmaceutical composition for
constitution into a suspension comprising a) first population comprising from about
0.5% to about 90% w/w Oseltamivir or its pharmaceutical^ acceptable salt and one or
more pharmaceutical!)/ acceptable excipients and b) second population comprising
from about 0.1% to about 60% w/w Oseltamivir or its pharmaceutical^ acceptable salt
and one or more pharmaceutical^ acceptable excipients, wherein the composition is
substantially free from binder.
A fourth aspect of the present invention provides a pharmaceutical composition for
constitution into a suspension comprising a) first population comprising from about
0.5% to about 90% w/w Oseltamivir or its pharmaceutical^ acceptable salt and one or
more pharmaceutically acceptable excipients and b) second population comprising
from about 0.1% to about 60% w/w Oseltamivir or its pharmaceutical^ acceptable salt
and one or more pharmaceutical^ acceptable excipients, wherein the composition is
substantially free from disintegrant.
A fifth aspect of the present invention provides a pharmaceutical composition for
constitution into a suspension comprising a) first population comprising from about
0.5% to about 90% w/w Oseltamivir or its pharmaceutical^ acceptable salt and one or
more pharmaceutical^ acceptable excipients and b) second population comprising
from about 0.1% to about 60% w/w Oseltamivir or its pharmaceutical^ acceptable salt
and one or more pharmaceutical^ acceptable excipients, wherein the composition is
substantially free from binder and/or disintegrant.
According to one embodiment of the above aspects, the first population is in the form
of powder and second population is in the form of granules.
According to another embodiment of the above aspects, the first population is in the
form of granules and second population is in the form of granules.
According to another embodiment of the above aspects, the first population is in the
form of powder and second population is in the form of powder.
5
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A sixth aspect of the present invention provides a pharmaceutical composition for
constitution into a suspension comprising a) first population in the form of granules or
powder comprising from about 0.5% to about 90% w/w Oseltamivir or its
pharmaceutically acceptable salt and one or more pharmaceutically acceptable
excipients, b) second population in the form of granules or powder comprising from
about 0.1% to about 60% w/w Oseltamivir or its pharmaceutical^ acceptable salt and
one or more pharmaceutically acceptable excipients and c) third population in the form
of granules or powder optionally comprising Oseltamivir or its pharmaceutically
acceptable salt and one or more pharmaceutically acceptable excipients.
According to one embodiment of the above aspects, one or more pharmaceutically
acceptable excipients are selected from the group comprising diluent, gelling agent,
pH-regulating agent, buffering agent, sweetening agent, flavoring agent, glidant,
surfactant, binder, preservative, and optionally a binder and/or disintegrant.
A seventh aspect of the present invention provides a process of preparing
pharmaceutical composition for constitution into a suspension comprising preparing
powder or granules of Oseltamivir phosphate and pharmaceutically acceptable
excipients by using formulation techniques selected from the group consisting of
blending, wet granulation, dry granulation to form one population and preparing
powder or granules of Oseltamivir phosphate and pharmaceutically acceptable
excipients by using formulation techniques selected from the group consisting of
blending, wet granulation, dry granulation to form the second population and optionally
preparing powder or granules of Oseltamivir phosphate and pharmaceutically
acceptable excipients by using formulation techniques selected from the group
consisting of blending, wet granulation, dry granulation to form the third population.
An eighth aspect of the present invention provides a method of using the
pharmaceutical composition for constitution into a suspension comprising Oseltamivir
or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or
mixtures thereof in the treatment and prophylaxis of influenza.
6
A ninth aspect of the present invention provides a pharmaceutical composition of
Oseltamivir for constitution into a suspension wherein the composition exhibits a
dissolution profile comparable to the TAMIFLU® powder for suspension.
DETAILED DESCRIPTION OF THE INVENTION
The present invention can be more readily understood by reading the following detailed
description of the invention and study of the included examples.
As used herein, the term "composition", as in pharmaceutical composition, is intended
to encompass a drug product comprising Oseltamivir or its pharmaceutical^
acceptable salts, esters, solvates; polymorphs, stereoisomers or mixtures thereof, and
other inert ingredient(s) (pharmaceutically acceptable excipients). Such pharmaceutical
compositions are synonymous with "formulation" and "dosage form". Pharmaceutical
compositions of the invention include, but are not limited to, powder, granules,
capsules (soft or liquid filled soft gelatin capsules), sachets, microcapsules and the like.
Preferably, the pharmaceutical composition refers to powder and granules. More
preferably, the pharmaceutical composition refers to powder and granules for
constitution into solution or suspension.
"Oseltamivir" as used herein refers to the base form, its salts, esters, solvates,
polymorphs, enantiomers or mixtures thereof. Preferably, the salt of Oseltamivir is
Oseltamivir phosphate.
The term "excipient" means a pharmacologically inactive component such as a diluent,
binder, disintegrant, alkaline agent, surfactant, glidants, gelling agent, pH-regulating
agent, sweeteners, flavoring agents, preservative, colouring agent, carrier, or the like.
The excipients useful in preparing the pharmaceutical composition of the present
invention are generally safe, non-toxic and are acceptable for veterinary as well as
human pharmaceutical use. Reference to an excipient includes both one and more than
one such excipient. Co-processed excipients are also covered under the scope of the
present invention. Further, excipient may be in the form of powders or in the form of
7
dispersion. Combination of excipients performing the same function may also be used
to achieve desired formulation characteristics.
Unless otherwise stated the weight percentages expressed herein are based on the final
weight of the composition or formulation.
"Substantially free" as used herein refers to the pharmaceutical composition of
Oseltamivir or its pharmaceutically acceptable salts, esters, solvates, polymorphs,
enantiomers or mixtures thereof, which may not contain a binder and/or disintegrant.
In particular, the pharmaceutical composition comprise 1 % w/w or less of binder and/or
1% w/w or less of disintegrant by total weight of the composition
As used herein, the term "about" means ± approximately 20% of the indicated value,
such that "about 10 percent" indicates approximately 08 to 12 percent.
Bulk density, as used herein, refers to the ratio of the mass of an untapped powder
sample and its volume including the contribution of the interparticulate void volume.
Bulk density indicates mass of a powder material that can be filled in per unit volume.
Tapped density, as used herein, refers to the ratio of the mass of a tapped powder sample
and its volume. Tapped density of granules is determined using Electrolab tap density
tester
One embodiment of the present invention relates to a stable, pharmaceutical
composition of Oseltamivir or pharmaceutically acceptable salt, esters, solvates,
polymorphs, enantiomers or mixtures thereof and process of preparing such
-^ composition.
!* Another embodiment of the present invention relates to a stable, pharmaceutical Q .
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composition comprising a pharmacologically effective amount of Oseltamivir or
N pharmaceutically acceptable salt, esters, solvates, polymorphs, enantiomers or mixtures
o thereof, wherein the pharmaceutical composition is preferably a composition for
constitution into suspension or solution. CO
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g Another.embodiment of the present invention relates to a pharmaceutical composition
5 for constitution into a suspension comprising a) first population comprising
d Oseltamivir or its pharmaceutically acceptable salt and one or more pharmaceutically
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8
acceptable excipients and b) second population comprising Oseltamivir or its
pharmaceutically acceptable salt and one or more pharmaceutically acceptable
excipients.
Another embodiment of the present invention relates to a pharmaceutical composition
for constitution into a suspension comprising a) first population in the form of powder
comprising Oseltamivir or its pharmaceutically acceptable salt and one or more
pharmaceutically acceptable excipients and b) second population in the form of
granules comprising Oseltamivir of its pharmaceutically acceptable salt and one or
more pharmaceutically acceptable excipients.
Another embodiment of the present invention relates to a pharmaceutical composition
for constitution into a suspension comprising a) first population in the form of granules,
comprising Oseltamivir or its pharmaceutically acceptable salt and one or more
pharmaceutically acceptable excipients and b) second population in the form of
granules, comprising Oseltamivir or its pharmaceutically acceptable salt and one or
more pharmaceutically acceptable excipients.
Yet another embodiment of the present invention relates to a pharmaceutical
composition for constitution into a suspension comprising a) first population in the
form of granules or powder comprising Oseltamivir or its pharmaceutically acceptable
salt and one or more pharmaceutically acceptable excipients, b) second population in
the form of granules or powder comprising Oseltamivir or its pharmaceutically
acceptable salt and one or more pharmaceutically acceptable excipients and c) third
population in the form of granules or powder optionally comprising Oseltamivir or its
pharmaceutically acceptable salt and one or more pharmaceutically acceptable
excipients.
Another embodiment of the present invention relates to a pharmaceutical composition
for constitution into a suspension comprising a) first population in the form of powder
comprising Oseltamivir or its pharmaceutically acceptable salt and one or more
pharmaceutically acceptable excipients and b) second population in the form of powder
9
T 1 0 - 1 1 - 2 Q 1 7 -1 7 : 52
comprising Oseltamivir or its pharmaceutically acceptable salt and one or more
pharmaceutically acceptable excipients.
Another embodiment of the present invention relates to a pharmaceutical composition
for constitution into a suspension comprising a) first population comprising
Oseltamivir or its pharmaceutically acceptable salt and one or more pharmaceutically
acceptable excipients and b) second population comprising Oseltamivir or its
pharmaceutically acceptable salt and one or more pharmaceutically acceptable
excipients, wherein the ratio of first population to second population is in the range of
0.1:99.9 to 99.9:0.1 based on total weight of the composition.
Another embodiment of the present invention relates to a pharmaceutical composition
for constitution into a suspension comprising a) first population comprising from about
0.5% to about 90% w/w Oseltamivir or its pharmaceutically acceptable salt and one or
more pharmaceutically acceptable excipients and b) second population comprising
from about 0.1% to about 60% w/w Oseltamivir or its pharmaceutically acceptable salt
and one or more pharmaceutically acceptable excipients.
Another embodiment of the present invention relates to a pharmaceutical composition
for constitution into a suspension comprising a) first population comprising from
about 0.5% to about 90% w/w Oseltamivir or its pharmaceutically acceptable salt,
from about 0.1% to about 45% w/w sorbitol and one or more pharmaceutically
acceptable excipients and b) second population comprising from about 0.1% to about
60% w/w Oseltamivir or its pharmaceutically acceptable salt, from about 20% to
about 70% w/w sorbitol and one or more pharmaceutically acceptable excipients.
Another embodiment of the present invention relates to a pharmaceutical composition
for constitution into a suspension comprising a) first population comprising from
about 0.5% to about 50% w/w Oseltamivir or its pharmaceutically acceptable salt,
from about 0.1% to about 30% w/w sorbitol and one or more pharmaceutically
10
X 1 G - 1 1 - 2 G 1 7 1 7 : 52
acceptable excipients and b) second population comprising from about 0.1 % to about
30% w/w Oseltamivir or its pharmaceutically acceptable salt, from about 20% to
about 50% w/w sorbitol and one or more pharmaceutically acceptable excipients.
Another embodiment of the present invention relates to a pharmaceutical composition
for constitution into a suspension comprising a) first population comprising from about
0.5% to about 90% w/w Oseltamivir or its pharmaceutically acceptable salt and one or
more pharmaceutically acceptable excipients and b) second population comprising
from about 0.1% to about 60% w/w Oseltamivir or its pharmaceutically acceptable salt
and one or more pharmaceutically acceptable excipients, wherein the composition is
substantially free from binder and/or disintegrant.
Another embodiment of the present invention relates to a pharmaceutical composition
for constitution into a suspension comprising a) first population comprising
Oseltamivir or its pharmaceutically acceptable salt and one or more pharmaceutically
acceptable excipients and b) second population comprising Oseltamivir or its
pharmaceutically acceptable salt and one or more pharmaceutically acceptable
excipients, wherein the content of glucose and mannose in sugar alcohol(s) is at least
0.02% by weight and wherein the composition is free from any discoloration.
Another embodiment of the present invention relates to a pharmaceutical composition
for constitution into a suspension comprising a) first population comprising
Oseltamivir or its pharmaceutically acceptable salt and one or more pharmaceutically
acceptable excipients including one or more sugar alcohol and b) second population
comprising Oseltamivir or its pharmaceutically acceptable salt and one or more
pharmaceutically acceptable excipients including one or more sugar alcohol, wherein
the sugar alcohol(s) used in composition contains water content of more than 1% and
wherein the composition is free from any discoloration.
Another embodiment of the present invention relates to a process of preparing
pharmaceutical composition for constitution into a suspension comprising: preparing
powder or granules of Oseltamivir phosphate and pharmaceutically acceptable
11
excipients by using convention formulation techniques like blending, wet granulation,
dry granulation to form first population and preparing powder or granules of
Oseltamivir phosphate and pharmaceutically acceptable excipients by using convention
formulation techniques like blending, wet granulation, dry granulation to form second
population.
Another embodiment of the present invention relates to a process of preparing
pharmaceutical composition for constitution into a suspension comprising: preparing
powder or granules of Oseltamivir phosphate and pharmaceutically acceptable
excipients by using convention formulation techniques like blending, wet granulation,
dry granulation to form one population and preparing powder or granules of
Oseltamivir phosphate and pharmaceutically acceptable excipients by using convention
formulation techniques like blending, wet granulation, dry granulation to form second
population and preparing powder or granules of pharmaceutically acceptable excipients
and optionally Oseltamivir phosphate by using convention formulation techniques like
blending, wet granulation, dry granulation to form third population.
Another embodiment of the present invention relates to a stable pharmaceutical
composition for constitution into a suspension comprising Oseltamivir phosphate and
pharmaceutically acceptable excipients, wherein the composition exhibits technical
attributes such as pH, viscosity, viscoelasticity, reconstitution time, and dissolution that
is comparable to the commercially available counterpart (Tamiflu® powder for oral
suspension).
In yet another embodiment of the invention, the pharmaceutical composition comprises
from about 1 to about 100 mg of Oseltamivir or its pharmaceutically acceptable salts,
esters, solvates, polymorphs, enantiomers or mixtures thereof.
Another embodiment of the present invention encompasses a pharmaceutical
composition for constitution into a suspension comprising from about 1 % to about 95%
by weight of Oseltamivir or its pharmaceutically acceptable salts, esters, solvates,
polymorphs, enantiomers or mixtures thereof and a pharmaceutically acceptable
excipient selected from at least one of diluent, binder, disintegrant, surfactant, alkaline
12
H I i Q - i I - 2 a I 7 17 : 5 2
agent, glidant, gelling agent, pH-regulating agent, preservative, sweeteners, flavoring
agents, coloring agent and other pharmaceutical excipients. Combination of excipients
performing the same function may also be used to achieve desired formulation
characteristics.
In another embodiment, pharmaceutical composition for constitution into a suspension
comprises Oseltamivir or its pharmaceutically acceptable salts, esters, solvates,
polymorphs, enantiomers or mixtures thereof wherein, particle size of Oseltamivir or
its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or
mixtures thereof is such that D90 is less than about 100 (am.
In a further embodiment of the present invention, particle size reduction may be
performed by using a hammer mill, air jet mill, ball mill or any other milling equipment
known in the art.
In another embodiment of the present invention, the pharmaceutical composition for
constitution into a suspension comprising Oseltamivir or its pharmaceutically
acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof has
desirable bulk and tapped density.
In further embodiment, the present invention includes method of using the
pharmaceutical composition for constitution into a suspension comprising Oseltamivir
or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or
mixtures thereof in the treatment and prophylaxis of influenza.
In another embodiment, the present invention includes a pharmaceutical composition
for constitution into a suspension comprising a) first population comprising
Oseltamivir or its pharmaceutically acceptable salt and one or more pharmaceutically
acceptable and b) second population comprising Oseltamivir or its pharmaceutically
acceptable salt and one or more pharmaceutically acceptable excipients, wherein the
composition is substantially free of other polymorphic forms.
13
r i n - 1 1 - 2G-17 17 : 5:2
In yet another embodiment, pharmaceutical composition for constitution into a
suspension of the present invention can be prepared by using convention formulation
techniques like blending, wet granulation (Rapid mixer granulator or fluidized bed
processor), dry granulation, or any other techniques known in the art.
In yet another embodiment, granules can be prepared by using convention formulation
techniques like blending, wet granulation, dry granulation, fluidized bed process or any
other techniques known in the art. Granulation liquid can be aqueous or non- aqueous
or mixture thereof.
The pharmaceutical compositions of the present invention are reconstituted with a
suitable vehicle such as water, juices, non-aqueous liquids, or mixtures thereof into a
solution or suspension. Particularly, the compositions are reconstituted with water.
One embodiment of the invention encompasses a pharmaceutical composition for
constitution into a suspension comprising Oseltamivir or a salt thereof and a
pharmaceutically acceptable excipient selected from at least one of diluent, binder,
disintegrant, surfactant, alkaline agent, glidant, gelling agent, pH-regulating agent,
preservative, sweeteners, flavoring agents, coloring agents and other pharmaceutical
excipients.
Diluents or fillers are substances which usually provide bulk to the composition.
Various useful fillers or diluents include, but are not limited to calcium carbonate,
calcium phosphate, dibasic anhydrous, calcium phosphate, dibasic dihydrate, calcium
phosphate tribasic, calcium sulphate, cellulose powdered, silicified microcrystailine
cellulose, cellulose acetate, lactitol, lactose, magnesium carbonate, magnesium oxide,
maltodextrin, mannitol, microcrystailine cellulose, polydextrose, sodium alginate,
sodium chloride, sugar alcohol, sorbitol, xylitol, erythritol, starch, pregelatinized starch
and or mixtures thereof. Particularly, the diluent is sorbitol. The amount of diluent in
the composition ranges from about 5% to about 95% w/w.
Binders impart cohesiveness to formulation. Various useful binders include, but are not
limited to hypromellose, hydroxypropyl cellulose, acacia, alginic acid, carbomer,
carboxymethylcellulose sodium, dextrin, dextrose, gelatin, guar gum, hydroxyethyl
14
I 1 Q - 1 1 - 2 Q 1 7 1 7 : 52
cellulose, hydroxyethyhnethyl cellulose, low substituted hydroxypropyl cellulose,
magnesium aluminium silicate, maltodextrin, maltose, methylceilulose, polydextrose,
polyethylene oxide, polymethacrylates, povidone, sodium alginate, starch,
pregelatinized starch, stearic acid, sucrose and zein, or mixtures thereof. The amount
of binder in the composition ranges from about 0% to about 40% w/w.
Various useful disintegrants include, but are not limited to, alginic acid, calcium
phosphate, tribasic, carboxymethylcellulose calcium, carboxymethylcellulose sodium,
colloidal silicon dioxide, croscarmellose sodium; crospovidone, guar gum, low
substituted hydroxypropyl cellulose, magnesium aluminun silicate, methylceilulose,
microcrystalline cellulose, povidone, sodium alginate, sodium starch glycolate,
polacrilin potassium, silicified microcrystalline cellulose, starch or pre- gelatinized
starch, or mixtures thereof. The amount of disintegrant in the composition ranges from
about 0% to about 25% w/w.
Glidants improve flowability and accuracy of dosing. Since the present invention
relates to an oral pharmaceutical composition, it is imperative to use glidant(s) to
achieve desirable flowability of the active. Glidants used in the composition include,
but are not limited to, tribasic calcium phosphate, calcium silicate, cellulose, powdered,
colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, starch and talc or
mixtures thereof.
Surfactants or surface-active agents improve wettability of the dosage form and/or
^ enhance its dissolution. Surfactants contemplated in the present invention include but
ro are not limited to anionic surfactants, amphoteric surfactants, non-ionic surfactants and
CD macromolecular surfactants. Suitable examples of anionic surfactants include, but are
*nr I T I T - c-->
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15
monostearate, polyoxyethylene fatty acid esters such as polyoxyl 40 stearate,
polyoxyethylene fatty alcohol ethers such as polyoxyl 10 oleyl ether, glycerol fatty acid
esters such as glycerol monostearate, commercially available SEPITRAP® 80 or
SEPITRAP® 4000.
Various useful gelling agents include, but are not limited to, xanthan gum, guar gum,
locust bean gum, tragacanth, cellulose derivatives, acacia, agar, alginic acid, sodium
carboxymethyl cellulose, sorbitol, fucoidan, furcellaran, laminaran or similar gel
forming agents. Particularly, the gelling agent is xanthan gum. The amount of gelling
agent in the composition ranges from about 0.05% to about 8% w/w.
Various useful pH-regulating agent include, but are not limited to, citric acid, tartaric
acid, succinic acid, malic acid, lactic acid, benzoic acid, sorbic acid and ascorbic acid.
Various useful buffering agents include, but are not limited to, monosodium citrate,
trisodium citrate, sodium phosphate, disodium phosphate, sodium acetate, sodium
bicarbonate, calcium carbonate, calcium formate, magnesium hydroxide, aluminum,
aluminum hydroxide/magnesium hydroxide co-precipitate, aluminum
hydroxide/sodium bicarbonate co-precipitate, calcium acetate, calcium bicarbonate,
calcium borate, calcium bicarbonate, calcium citrate, calcium gluconate, calcium
glycerophosphate, calcium hydroxide, calcium lactate, calcium phthalate, calcium
phosphates, calcium succinate, calcium tartrate, calcium propionate, , dipotassium
hydrogen phosphate, dipotassium phosphate, disodium hydrogen phosphate, disodium
^ succinate, dry aluminum hydroxide gel, L-arginine, magnesium acetate, magnesium
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ro aluminate, magnesium borate, magnesium bicarbonate, magnesium carbonate,
CD magnesium citrate, magnesium gluconate, magnesium lactate, magnesium metasilicate
CNT aluminate, magnesium oxide, magnesium phthalate, magnesium phosphate,
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o magnesium silicate, magnesium succinate, magnesium tartrate, potassium acetate,
potassium carbonate, potassium bicarbonate, potassium borate, potassium CO citrate,
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g potassium metaphosphate, potassium phthalate, potassium phosphate, potassium
S polyphosphate, potassium pyrophosphate, potassium succinate, potassium tartrate,
o
C! sodium borate, sodium carbonate, sodium citrate, sodium gluconate, sodium hydrogen
CO
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16
phosphate, sodium hydroxide, sodium lactate, sodium phthalate, , sodium
polyphosphate, sodium pyrophosphate, sodium sesquicarbonate, sodium succinate,
sodium tartrate, sodium tripolyphosphate, synthetic hydrotalcite, tetrapotassium
pyrophosphate, tetrasodium pyrophosphate, tripotassium phosphate, trisodium
phosphate, trometamol, and mixtures thereof. Particularly, the buffering agent is
monosodium citrate. The ratio of oseltamivir to monosodium citrate is in the range of
1:20 to 20:1% w/w based on the total weight of the composition.
Various useful sweetening agents include, but are not limited to, acesulfame potassium
(acesulfame K), alitame, aspartame, cyclamate, cylamate, dextrose, isomalt,
MagnaSweet®' maltitol, mannitol, neohesperidine DC, neotame, Prosweet® powder,
saccharin, sorbitol, stevia, sucralose, sucrose, tagatose, thaumatin, xylitol, and the like.
Various useful flavoring agents, sweetening agents, and/or colorants include, but are
not limited to, tutti fruitti, acacia syrup, alitame, anise, apple, aspartame, banana,
bavarian cream, berry, blackcurrant, butter, butter pecan, butterscotch, calcium citrate,
camphor, caramel, cherry, cherry cream, chocolate, cinnamon, citrus, citrus punch,
citrus cream, cocoa, coffee, cola, cool cherry, cool citrus, cyclamate, cylamate,
amaranth, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate,
glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon
cream, maltol, mannitol, Titanium dioxide, maple, tartarazine, menthol, mint, mint
cream, mixed berry, nut, orange, peanut butter, pear, peppermint, peppermint cream,
Prosweet® Powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint,
spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, Swiss
cream, tagatose, tangerine, thaumatin, vanilla, walnut, watermelon, wild cherry,
wintergreen, xylitol, and combinations thereof, for example, anise-menthol, cherryanise,
cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime,
lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint.
Various useful preservative include, but are not limited to, sodium benzoate,
benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol,
bronopol, butyl paraben, chlorobutanol, chlorocresol, chlorhexidine, cresol,
17
ethylenediaminetetraacetic acid, ethyl paraben, imidurea, methyl paraben, phenol,
phenylmercuric salts, potassium sorbate, propylene glycol, propyl paraben, sodium
citrate, sodium propionate, sorbic acid, thiomerosol, cetylpyridinium chlorideand
mixtures thereof.
The dissolution study can be carried out using a suitable method such as by using USP
apparatus type-II (paddle) apparatus at a rotation speed of 25 rpm with 900 mL of 0.1N
HCI as dissolution medium at 37±0.5°C.
EXAMPLES
The following examples are intended to further illustrate certain preferred
embodiments of the invention and are not limiting in nature.
Examples 1
Ingredients
First Population (Granules)
Oseltamivir phosphate
Sorbitol
Sodium benzoate
Second Population (Granules)
Oseltamivir phosphate
Sorbitol
Monosodium citrate
Saccharin sodium
Titanium dioxide
Extragranular
Tutti frutti flavor
Xanthan gum
% w/w
3.00
0.1-45
0.18
0.97
20-70
7.00
LOO
1.19
1.00
1.50
Procedure:
First population and second population of Oseltamivir phosphate was prepared was
using dry blending/dry granulation/wet granulation. In case of wet granulation, mixture
of water and isopropyl alcohol was used.
18
T i n - i i - 2 0 1 7 1 7 : 5 2
Examples 2-6
TABLE 2
Example No. 2 3 4 5 6
First Population (% range w/w)
Ingredients
Oseltamivir
phosphate
Sorbitol
Xanthan gum
Granulation
Solvent
Granules | Powder
0.1-10%
0.1-45%
0-5%
q.s.
0.1-10%
0.1-45
0-5%
-
Powder
0.1-10%
0.1 -45
0-5%
-
Granules
0.1-10%
0.1-45
0-5%
q.s.
Powder
0.1-10%
0.1-45
0-5%
-
Second Population (% range w/w)
Ingredients
Oseltamivir
phosphate
Sorbitol
Sodium Citrate
Saccharin sodium
Titanium Dioxide
Granulation
Solvent
Sodium Benzoate
Flavor
Granules
0.1-10%
20-70
0-5%
0-3%
0-3%
q.s.
0-3%
0-3%
Granules
0.1-10%
20-70
0-5%
0-3%
0-3%
q.s.
0-3%
0-3%
Powder
0.1-10%
20-70
0-5%
0-3%
0-3%
-
0-3%
0-3%
Granules
0.1-10%
20-70
0-5%
0-3%
0-3%
q.s.
0-3%
0-3%
Granules
0.1-10%
20-70
0-5%
0-3%
0-3%
q.s.
0-3%
0-3%
Third Population (% range w/w)
Ingredients
Oseltamivir
phosphate
Mannitol
Xanthan gum
Granulation
Solvent
-
-
-
-
-
. -
-
. -
-
-
-
-
-
-
-
Granules
0.1-10%
0-90%
0-5%
q.s.
Granules
0.1-10%
0-90%
0-5%
q.s.
Procedure:
First population and second population of Oseltamivir phosphate is prepared by Dry
blending/Dry granulation/Wet granulation. Third population is prepared by dry
granulation/wet granulation, In case of wet granulation, mixture of water and isopropyl
alcohol is used.
In-Vitro Dissolution Study
Dissolution tests were performed with composition of Example 1 and TAMIFLU®
powder for oral suspension using USP apparatus type-11 (paddle) apparatus at a rotation
speed of 25 rpm with 900 mL of 0.1N HCl as dissolution medium at 37±0.5°C. The
results are illustrated in Table 2
TABLE 2
Time (minutes)
5
10
15
20
30
% Oseltamivir release
Example 1
95
101
103
103
.104
TAMIFLU® powder for
suspension
90
95
95
96
97
Viscosity and pH study
The viscosity and pH of composition of Example 1 and TAMIFLU® powder for
suspension were determined after reconstitution with 55 mL of water (Table 3).
Viscosity was determined with Brookfield viscometer with spindle # SC4-18 at a speed
of4rpmat25°C.
TABLE 3
Composition
Example 1
TAMIFLU®
powder for
suspension
Viscosity
511
491
PH
3.8
3.7

We claim:
1. A pharmaceutical composition for constitution into a suspension comprising a) first
population comprising from about 0.5% to about 90% w/w Oseltamivir or its
pharmaceutically acceptable salt, from about 0.1% to about 45% w/w sorbitol and one
or more pharmaceutically acceptable excipients and b) second population comprising
from about 0.1% to about 60% w/w Oseltamivir or its pharmaceutically acceptable
salt, from about 20% to about 70% w/w sorbitol and one or more pharmaceutically
acceptable excipients.
2. A pharmaceutical composition for constitution into a suspension comprising a) first
population comprising from about 0.5% to about 50% w/w Oseltamivir or its
pharmaceutically acceptable salt, from about 0.1% to about 30% w/w sorbitol and one
or more pharmaceutically acceptable excipients and b) second population comprising
from about 0.1% to about 30% w/w Oseltamivir or its pharmaceutically acceptable
salt, from about 20% to about 50% w/w sorbitol and one or more pharmaceutically
acceptable excipients.
3. A pharmaceutical composition for constitution into a suspension comprising a) first
population comprising from about 0.5% to about 90% w/w Oseltamivir or its
pharmaceutically acceptable salt and one or more pharmaceutically acceptable
excipients and b) second population comprising from about 0.1% to about 90% w/w
Oseltamivir or its pharmaceutically acceptable salt and one or more pharmaceutically
acceptable excipients, wherein the composition is substantially free from binder and/or
disintegrant.
4. The.composition for constitution into a suspension of claims 1-3, wherein the first
population is in the form of powder and second population is in the form of granules.
5. The composition for constitution into a suspension of claims 1- 3, wherein the first
population is in the form of granules and second population is in the form of granules.
6. The composition for constitution into a suspension of claims 1 - 3 wherein the first
population is in the form of powder and second population is in the form of powder.
7. A pharmaceutical composition for constitution into a suspension comprising a) first
population in the form of granules or powder comprising from about 0.5% to about
90% w/w Oseltamivir or its pharmaceutically acceptable salt and one or more
pharmaceutically acceptable excipients, b) second population in the form of granules
or powder comprising from about 0.1% to about 90% w/w Oseltamivir or its
pharmaceutically acceptable salt and one or more pharmaceutically acceptable
excipients and c) third population in the form of granules or powder optionally
comprising Oseltamivir or its pharmaceutically acceptable salt and one or more
pharmaceutically acceptable excipients.
8. The composition for constitution into a suspension of claims 1-3 and 7, wherein
the one or more pharmaceutically acceptable excipients are selected from the group
comprising diluent, gelling agent, pH-regulating agent, buffering agent, sweetening
agent, flavoring agent, glidant, surfactant, binder, preservative, and optionally a
binder and/or disintegrant.
9. A process of preparing pharmaceutical composition for constitution into a
suspension of claims 1- 3 and 7 comprising preparing powder or granules of
Oseltamivir phosphate and pharmaceutically acceptable excipients by using
formulation techniques selected from the group consisting of blending, wet
granulation, dry granulation to form one population and preparing powder or granules
of Oseltamivir phosphate and pharmaceutically acceptable excipients by using
formulation techniques selected from the group consisting of blending, wet
granulation, dry granulation to form the second population and optionally preparing
powder or granules of Oseltamivir phosphate and pharmaceutically acceptable
excipients by using formulation techniques selected from the group consisting of
blending, wet granulation, dry granulation to form the third population.
10. The composition for constitution into a suspension of claims 1-3, wherein the
composition exhibits a dissolution profile comparable to the TAMIFLU® powder for
suspension.