Claims:I/ We Claim:
1. Oral pharmaceutical composition comprising
i. etoricoxib or a pharmaceutically acceptable salt,
ii. a surfactant,
iii. a polymer, and
iv. one or more other pharmaceutically acceptable excipient,
wherein, the composition exhibits pH independent dissolution profile.
2. The pharmaceutical composition of claim 1, wherein the surfactant is selected from
selected from the group consisting of sodium lauryl sulphate, polyethylene glycol
having molecular weight in the range of about 2000 to 10000, Polysorbates, fatty acid
esters, esters of glycerol and fatty acids, esters of polyethylene glycol and fatty acids,
castor oil ethoxylate and mixtures thereof.
3. The pharmaceutical composition of claim 1, wherein the polymer is selected from
hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylalcohol,
Ethylcellulose, Hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl
cellulose acetate succinate, hydroxyethyl cellulose, polyvinylpyrrolidone and mixtures
thereof.
4. The pharmaceutical composition of claim 1, wherein the other pharmaceutically
acceptable excipient is selected from disintegrant, binder and mixtures thereof.
5. The pharmaceutical composition of claim 4, wherein the disintegrant is selected from
sodium starch glycolate, croscarmellose sodium and crospovidone and mixtures
thereof.
6. The pharmaceutical composition of claim 4, wherein the binder is selected from
polyvinyl pyrrolidone, polyvinyl alcohol, copovidone, hydroxy propyl methyl
cellulose, methyl cellulose, hydroxy propyl cellulose, powdered acacia, gelatin, guar
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gum, carbomer such as carbopol, polymethacrylates and pregelatinized starch and
mixtures thereof.
7. A method of preparing a pharmaceutical formulation comprising etoricoxib or a
pharmaceutically acceptable salt, the method comprising:
i. Preparation of drug dispersion by adding etoricoxib or a pharmaceutically
acceptable salt, a surfactant and one or more other pharmaceutically acceptable
excipient to a polymer solution and subjecting the same to homogenization to
obtain dispersion with desired particle size of etoricoxib,
ii. granulation by spray granulation technique by spraying drug dispersion on to
inert carrier to obtain granules,
iii. milling the granules and mixing them with extragranular excipients,
iv. mixing with a lubricant to obtain a lubricated blend,
v. compression of lubricated blend into tablets,
vi. optionally film coating the tablets.
8. The method of preparing a pharmaceutical formulation of claim 7, wherein the inert
carrier is selected from microcrystalline cellulose, silicified microcrystalline cellulose,
lactose monohydrate, spray dried lactose, and anhydrous lactose and mixtures thereof.
9. The method of preparing a pharmaceutical formulation of claim 7, wherein the
extragranular excipients are selected from disintegrant, binder, lubricant, glidant and
mixtures thereof.
10. The method of preparing a pharmaceutical formulation of claim 9, wherein the
disintegrant is selected from sodium starch glycolate, croscarmellose sodium and
crospovidone and mixtures thereof; binder is selected from polyvinyl pyrrolidone,
polyvinyl alcohol, copovidone, hydroxy propyl methyl cellulose, methyl cellulose,
hydroxy propyl cellulose, powdered acacia, gelatin, guar gum, carbomer such as
carbopol, polymethacrylates and pregelatinized starch and mixtures thereof; lubricant
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is selected from magnesium stearate and sodium stearyl fumarate and mixture thereof and glidant is selected from colloidal silica, hydrophobic colloidal silica, talc and mixtures thereof. , Description:The following specification describes the invention and the manner
in which it is to be performed
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PHARMACEUTICAL COMPOSITION OF ETORICOXIB
TECHNICAL FIELD OF THE INVENTION
The present specification relates to pharmaceutical formulation of etoricoxib
with rapid dissolution profile. Methods of preparing such formulations are also
provided.
BACKGROUND OF THE INVENTION
Etoricoxib is a highly selective cyclooxygenase-2 (COX-2) inhibitor that has
anti-inflammatory, antipyretic and analgesic effects, and is suitable for treating
symptoms and signs of osteoarthritis in acute and chronic stages, and acute gouty
arthritis. Chemically etoricoxib is 5-chloro-2- (6-methylpyridin-3-yl) -3- (4-
methylsulfonylphenyl) pyridine], having the following structural formula:
Etoricoxib is available in the United Kingdom & India as Arcoxia® film
coated tablet in 30mg, 60mg, 90mg and 120mg strengths and also as Nucoxia® film
coated tablets in India.
WO 2016/015776 discloses a pharmaceutical composition comprising
etoricoxib or a pharmaceutically acceptable salt thereof and at least one pH modifying
agent.
CN 105250231B discloses a pharmaceutical composition containing
etoricoxib and a preparation method thereof, the method adopts a dry granulation
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process, and a specific disintegrating agent is added, so that the drug disintegration is
effectively promoted, the dissolution is accelerated, the bioavailability is improved.
WO 2014/033526 describes pharmaceutical compositions of etoricoxib
prepared by dry granulation, whereby etoricoxib retains its initial polymorphic form.
Etoricoxib is a weakly basic drug (pKa 4.6) that has pH dependent solubility
and dissolution profile. It has a high solubility in the gastric media at low pH and
solubility decreases as the pH increases. Below represented is the solubility profile of
etoricoxib.
Table 1: Solubility profile of etoricoxib
S. No. pH (Buffer) Solubility
(mg/mL)
1 pH 2.0 (0.01 N hydrochloric acid) 25.10
2 pH 3.07 (0.1 M glycine buffer) 2.01
3 pH 3.54 (0.1 M glycine buffer) 0.70
4 pH 4.01 (0.1 M sodium acetate buffer) 0.30
5 pH 4.54 (0.1 M sodium acetate buffer) 0.14
6 pH 5.03 (0.1 M sodium acetate buffer) 0.09
7 pH 5.47 (0.1 M sodium acetate buffer) 0.08
8 pH 6.9 (water) 0.05
Accordingly, gastrointestinal transit of etoricoxib from gastric to intestinal
region results in precipitation of the drug. Hence, its oral absorption also displays high
fast-fed variability. A high fat meal results in a 36% reduction in the Cmax and increase
in Tmax by 2 h compared to that of the fasting state. Increase in Tmax in fed state results
in delayed absorption of the drug resulting in delayed onset of action. Due to the food
effect, inter subject variability is also high for etoricoxib. To overcome the food effect
of and achieve quicker onset of action, there is a need to develop robust formulation
with no variability irrespective of the prandial state.
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Accordingly, the present specification provides novel pharmaceutical
formulations of etoricoxib that has pH independent drug dissolution and does not have
food effect on the same. Also disclosed is the process of preparing such formulations.
Inventors of the present specification have surprisingly identified formulations and
methods of preparing the same that has pH independent drug dissolution and that does
not have food effect on the same.
OBJECT OF THE INVENTION
The present specification relates to pharmaceutical formulation of etoricoxib
with pH independent dissolution profile. Methods of preparing such formulations are
also provided.
In one aspect, the present specification relates to oral pharmaceutical
composition comprising etoricoxib or a pharmaceutically acceptable salt,
i. a surfactant,
ii. a polymer, and
iii. one or more other pharmaceutically acceptable excipient,
wherein, the composition exhibits pH independent dissolution profile.
In one aspect, the present specification relates to oral pharmaceutical
formulation of etoricoxib with pH independent dissolution profile.
In one another aspect, the oral pharmaceutical composition of the present
invention exhibits a ratio in the range from about 0.80 to about 1.2 for AUCo-t between
the oral pharmaceutical composition of present invention and a reference composition
with the 90% confidence interval under fed condition.
In one another aspect, the oral pharmaceutical composition of the present
invention exhibits a ratio in the range from about 0.80 to about 1.2 for AUCo-∞ between
the oral pharmaceutical composition of present invention and a reference composition
with the 90% confidence interval under fed condition.
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In one another aspect, the oral pharmaceutical composition of the present
invention exhibits a ratio in the range from about 0.80 to about 1.2 for Cmax between
the oral pharmaceutical composition of present invention and a reference composition
with the 90% confidence interval under fed condition.
In another aspect, the present specification relates to pharmaceutical
composition of the prepared by the steps of:
i. preparation of drug dispersion along with other excipients in a solvent,
ii. granulation by spray granulation technique by spraying drug dispersion on to
inert carrier,
iii. blending the obtained granules with extragranular excipients,
iv. compression of the granules into tablets,
v. optionally, film coating the tablets.
In another aspect, the present specification relates to method of preparing a
pharmaceutical formulation comprising etoricoxib or a pharmaceutically acceptable
salt, the method comprising:
i. preparation of drug dispersion by adding etoricoxib or a pharmaceutically
acceptable salt, a surfactant and one or more other pharmaceutically acceptable
excipient to a polymer solution and subjecting the same to homogenization to
obtain dispersion with desired particle,
ii. granulation by spray granulation technique by spraying drug dispersion on to
inert carrier to obtain granules,
iii. milling the granules and mixing them with extragranular excipients,
iv. mixing with a lubricant to obtain a lubricated blend,
v. compression of lubricated blend into tablets,
vi. optionally film coating the tablets.
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In a further embodiment, the composition of the present specification is suitable for
treating symptoms and signs of osteoarthritis in acute and chronic stages, and acute
gouty arthritis.
BRIEF DESCRIPTION OF FIGURES
Figure 1: Dissolution profile of formulation as per example 1 in multiple media
Figure 2: Dissolution profile of reference product Arcoxia® in multiple media
Figure 3: Dissolution profile of reference product Nucoxia® in multiple media
Figure 4: Comparative dissolution profile of Example 1 with reference products (0.1 N
HCL media)
Figure 5: Comparative dissolution profile of Example 1 with reference products
(Acetate buffer pH 4.5 media)
Figure 6: Comparative dissolution profile of Example 1 with reference products
(Acetate buffer pH 5.5 media)
Figure 7: Comparative dissolution profile of Example 1 with reference products
(FeSSIF pH 5.5 media)
Figure 8: Comparative dissolution profile of Example 1 with reference products
(Acetate buffer pH 5.5 + 0.2 M NaCl media)
Figure 9: Manufacturing method involving proprietary MISToxTM technology
DESCRIPTION OF INVENTION
The present specification relates to pharmaceutical formulation of etoricoxib
with pH independent dissolution profile. Methods of preparing such formulations are
also provided.
The term “pharmaceutical formulations” as used herein refers to oral dosage
forms preferably in the form of tablets, bilayer tablets, capsules, sachets and the like.
These solid dosage forms are generally prepared by using one or more suitable
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pharmaceutically acceptable excipients. The term composition or formulation are used
herein interchangeably.
The term “immediate release” as used herein refers to immediate or instant
release of drug from the compositions or formulations after administration.
The term “etoricoxib” as used in the context of the present specification
relates to the free base form, acid form, salt form, polymorphic crystalline or
amorphous form, solvates, ethers, esters, etc. The amount of etoricoxib or
pharmaceutically acceptable salts thereof are employed in the present composition is
in the range of 25-150 mg, e.g. 30 mg, 60 mg, 90 mg & 120 mg.
The term “homogenization” as used herein refers to process of reducing
pharmaceutical product particle sizes under high pressures, sheer, turbulence,
acceleration and impact, to make them more stable and clinically effective. Highpressure
homogenization in the pharmaceutical industry has proven its ability to make
more stable product, with better API dispersion. The average particle size of the
dispersion after subjecting to homogenization process as per the present specification
is in the range of from 0.5 μm to 15μm, preferably, from 1μm to 10μm.
The term “reference product” or “reference composition” as used herein refers
to Arcoxia® film coated tablets or Nucoxia® film coated tablets.
The term “spray granulation technique” as used herein refers to wet granulation
technique by fluid bed spray granulation method that involves top spraying or
tangential spraying of drug solution or dispersion on to inert carrier of mixture.
In one aspect, the present specification relates to oral pharmaceutical
composition comprising etoricoxib or a pharmaceutically acceptable salt,
i. a surfactant,
ii. a polymer, and
iii. one or more other pharmaceutically acceptable excipient,
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wherein, the composition exhibits pH independent dissolution profile.
In one aspect, the present specification relates to oral pharmaceutical
formulation of etoricoxib with pH independent dissolution profile.
In one aspect, the present specification relates to the pharmaceutical
formulation of etoricoxib that does not have food effect on the drug dissolution and
absorption.
In one aspect, the oral pharmaceutical composition of the present invention
exhibits same Tmax in both fed and fasting conditions.
In another aspect the present composition exhibits an absorption profile which
is improved compared to the absorption profile of the reference composition under fed
conditions.
In one another aspect, the oral pharmaceutical composition of the present
invention exhibits a ratio in the range from about 0.80 to about 1.2 for AUCo-t between
the oral pharmaceutical composition of present invention and a reference composition
with the 90% confidence interval under fed condition.
In one another aspect, the oral pharmaceutical composition of the present
invention exhibits a ratio in the range from about 0.80 to about 1.2 for AUCo-∞ between
the oral pharmaceutical composition of present invention and a reference composition
with the 90% confidence interval under fed condition.
In one another aspect, the oral pharmaceutical composition of the present
invention exhibits a ratio in the range from about 0.80 to about 1.2 for Cmax between
the oral pharmaceutical composition of present invention and a reference composition
with the 90% confidence interval under fed condition.
In another aspect, the present specification relates to pharmaceutical
composition of the prepared by the steps of:
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i. preparation of drug dispersion along with other excipients in a solvent,
ii. granulation by spray granulation technique by spraying drug dispersion on to
inert carrier,
iii. blending the obtained granules with extragranular excipients,
iv. compression of the granules into tablets,
v. optionally, film coating the tablets.
In another aspect, the present specification relates to method of preparing a
pharmaceutical formulation comprising etoricoxib or a pharmaceutically acceptable
salt, the method comprising:
i. preparation of drug dispersion by adding etoricoxib or a pharmaceutically
acceptable salt, a surfactant and one or more other pharmaceutically acceptable
excipient to a polymer solution and subjecting the same to homogenization to
obtain dispersion with desired particle size of etoricoxib,
ii. granulation by spray granulation technique by spraying drug dispersion on to
inert carrier to obtain granules,
iii. milling the granules and mixing them with extragranular excipients,
iv. mixing with a lubricant to obtain a lubricated blend,
v. compression of lubricated blend into tablets,
vi. optionally film coating the tablets.
Pharmaceutically acceptable excipients
The pharmaceutical formulations of the present inventions further comprises
one or more pharmaceutically acceptable excipients. The term “pharmaceutically
acceptable excipients” include, but not limited to, diluents, disintegrants, binders,
lubricants, polymers, glidants, acidifying agent, alkalizing agent, stabilizers,
surfactants, sweetener, film coating materials, plasticizers, pigments, opacifiers,
coloring agents and the like.
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Suitable diluents, may be selected from, but not limited to the group consisting
of different grades of starches, such as maize starch, potato starch, rice starch, wheat
starch, pregelatinised starch, fully pregelatinised starch; cellulose derivatives, such as
microcrystalline cellulose or silicified microcrystalline cellulose; sugar alcohols such
as mannitol, erythritol, sorbitol, xylitol; monosaccharides like glucose;
oligosaccharides like sucrose and lactose such as lactose monohydrate, lactose
anhydrous, spray dried lactose or anhydrous lactose; calcium salts, such as calcium
hydrogen phosphate; particularly preferably the fillers are selected from the group
consisting of, microcrystalline cellulose, silicified microcrystalline cellulose, lactose
monohydrate, spray dried lactose, and anhydrous lactose and the like and mixtures
thereof.
In an embodiment, the diluent as per the present specification is present in an
amount of from about 20% w/w to 85% w/w based on the total weight of the
composition. Preferably, diluent is present in an amount of from about 40% w/w to
75% w/w.
Suitable surfactant as component can be selected from, but not limited to the
group consisting of anionic surfactants, preferably sodium lauryl sulphate;
polyethylene glycol having molecular weight in the range of about 2000 to 10000;
Polysorbates; fatty acid esters, preferably propylene glycol caprylates such as Capmul
PG-8, Capryol 90; esters of glycerol and fatty acids, preferably glycerol oleates and
caprylates (Capmul MCM); esters of polyethylene glycol and fatty acids, castor oil
ethoxylate (glycerol polyethylene glycol ricinoleate). Preferably, surfactant is selected
from the group consisting of sodium lauryl sulphate; PEG 3350, PEG 4000, PEG 6000
or, PEG 8000, more preferably PEG 6000; Tween 20 or Tween 80; and esters of
polyethylene glycol and fatty acids; most preferably sodium lauryl sulphate.
In an embodiment, the surfactant as per the present specification is present
in an amount of from about 0.5% w/w to 5% w/w based on the total weight of the
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composition. Preferably, surfactant is present in an amount of from about 1% w/w to
3% w/w.
Suitable disintegrant may be selected from, but not limited to the group
consisting of carmellose calcium, carboxymethylstarch sodium, croscarmellose
sodium (cellulose carboxymethylether sodium salt, crosslinked), starch, modified
starch such as pregelatinized starch, starch derivatives such as sodium starch glycolate,
crosslinked polyvinylpyrrolidone (crospovidone), and low-substituted
hydroxypropylcellulose, and disintegrating aids such as magnesium aluminometasilicate
and ion exchange resins like polacrilin potassium; particularly preferably
the disintegrants are selected from the group consisting of sodium starch glycolate,
croscarmellose sodium and crospovidone and the like and mixtures thereof.
In an embodiment, the disintegrant as per the present specification is present
in an amount of from about 0.5% w/w to 10% w/w based on the total weight of the
composition. Preferably, disintegrant is present in an amount of from about 1% w/w to
7% w/w.
Suitable binder may be selected from, but not limited to the group consisting
of polyvinyl pyrrolidone (Povidone), polyvinyl alcohol, copolymers of
vinylpyrrolidone with other vinyl derivatives (Copovidone), hydroxy propyl methyl
cellulose, methyl cellulose, hydroxy propyl cellulose, powdered acacia, gelatin, guar
gum, carbomer such as carbopol, polymethacrylates and pregelatinized starch and the
like and mixtures thereof.
Suitable polymer include, but are not limited to hydroxypropyl methylcellulose
(Hypromellose), hydroxypropyl cellulose, polyvinylalcohol, Methylcellulose,
ethylcellulose, Hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl
cellulose acetate succinate, hydroxyethyl cellulose, polyvinylpyrrolidone, copolymers
of vinylpyrrolidone and vinylacetate, copolymers of acrylic and/or methacrylic acid
esters with trimethylammoniummethylacrylate, copolymers of
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dimethylaminomethacrylic acid and neutral methacrylic acid esters, polymers of
methacrylic acid or methacrylic acid esters, copolymers of acrylic acid ethylester and
methacrylic acid methyl ester, and copolymers of acrylic acid and acrylic acid
methylester and the like. Preferably, polymer is selected from hydroxypropyl
methylcellulose, hydroxypropyl cellulose, polyvinylalcohol, Ethylcellulose,
Hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate
succinate, hydroxyethyl cellulose, polyvinylpyrrolidone. The weight ratio of etoricoxib
and at least one polymer is from about 25:1 to about 1:25, preferably from about 20:1
to about 1:20.
In an embodiment, the polymer as per the present specification is present in an
amount of from about 0.5% w/w to 20% w/w based on the total weight of the
composition. Preferably, polymer is present in an amount of from about 1 % w/w to
10% w/w.
Suitable lubricant may be selected from, but not limited to the group consisting
of stearic acid, talc, glyceryl behenate, sodium stearyl fumarate and magnesium
stearate; particularly preferably the lubricant is magnesium stearate and sodium stearyl
fumarate and the like and mixtures thereof.
In an embodiment, the lubricant as per the present specification is present in an amount
of from about 0.5% w/w to 3% w/w based on the total weight of the composition.
Preferably, lubricant is present in an amount of from about 0.5% w/w to 2% w/w.
Suitable glidant, may be selected from, but not limited to the group consisting
of colloidal silica, hydrophobic colloidal silica and magnesium trisilicate, such as talc
and the like and mixtures thereof.
In an embodiment, the glidant as per the present specification is present in
an amount of from about 0.1% w/w to 5% w/w based on the total weight of the
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composition. Preferably, glidant is present in an amount of from about 0.3% w/w to
3% w/w.
Compositions as per the present specification are prepared by a method that
comprises the usage of proprietary Micronized Spray Dispersion Technology
(MISToxTM) that involves combination of drug dispersion preparation & spray
granulation technique. The drug dispersion is prepared by adding etoricoxib or a
pharmaceutically acceptable salt, a surfactant and one or more other pharmaceutically
acceptable excipient to a polymer solution and is subjected to homogenization to obtain
dispersion with desired particle size followed by spray granulation by spraying drug
dispersion on to inert carrier. Micronized Spray Dispersion Technology produces
dispersion with microencapsulated etoricoxib surrounded with hydrophilic polymer,
surfactant and one or more other pharmaceutically acceptable excipient that is sprayed
on to inert carrier.
In another aspect, the present specification relates to pharmaceutical
composition of the prepared by the steps of:
i. preparation of drug dispersion along with other excipients in a solvent,
ii. granulation by spray granulation technique by spraying drug dispersion on to
inert carrier,
iii. blending the obtained granules with extragranular excipients,
iv. compression of the granules into tablets,
v. optionally, film coating the tablets.
In another aspect, the present specification relates to method of preparing a
pharmaceutical formulation comprising etoricoxib or a pharmaceutically acceptable
salt, the method comprising:
i. preparation of drug dispersion by adding etoricoxib or a pharmaceutically
acceptable salt, a surfactant and one or more other pharmaceutically acceptable
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excipient to a polymer solution and subjecting the same to homogenization to
obtain dispersion with desired particle size,
ii. granulation by spray granulation technique by spraying drug dispersion on to
inert carrier to obtain granules,
iii. milling the granules and mixing them with extragranular excipients,
iv. mixing with a lubricant to obtain a lubricated blend,
v. compression of lubricated blend into tablets,
vi. optionally film coating the tablets.
The following examples will further describe certain specific aspects and
embodiments of the invention in greater details and are not intended to limit the scope
of invention.
EXAMPLES
Example 1: Immediate release formulation of etoricoxib.
Table 2: Immediate release formulation of etoricoxib
Ingredients
Example 1
(% w/w)
Drug dispersion
Etoricoxib 30
Hydroxy propyl methyl cellulose 2
Sodium lauryl sulfate 1.5
Croscarmellose sodium 2.5
Purified water q.s.
Inert carrier composition
Lactose monohydrate 25
Microcrystalline cellulose 35
Extra granular components
Magnesium stearate 1
Croscarmellose sodium 2.5
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Colloidal silicon dioxide 0.5
Total weight of composition 100
Manufacturing Process (using proprietary MISToxTM technology):
Drug dispersion preparation by homogenization:
1. Etoricoxib, Hydroxy propyl methyl cellulose, Sodium lauryl sulfate and
Croscarmellose sodium are dispensed, sifted & blended,
2. blend of step 1 is added into sufficient quantity of purified water to get 10%
solids build up and is subjected to homogenization to get drug dispersion,
Granulation:
3. lactose monohydrate, microcrystalline cellulose are dispensed, sifted &
blended,
4. load the inert carrier blend of step 3 into top spray granulator,
5. drug dispersion of step 2 is sprayed onto blend of step 4,
6. unload the granules obtained in step 5 and sift through desired mesh,
Tablet preparation:
7. extra granular components croscarmellose sodium, magnesium stearate &
colloidal silicon dioxide are dispensed and sifted,
8. sifted mixture of step 7 is added to sifted granules of step 6 and blended,
9. blend of step 8 is compressed into tablets,
10. tablets of step 9, are optionally film coated using desired film coating material.
Example 2: Immediate release formulation of etoricoxib.
Table 3: Immediate release formulation of etoricoxib
Ingredients
Example 2
(% w/w)
Drug dispersion
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Etoricoxib 30
Hydroxy propyl methyl cellulose 2
Croscarmellose sodium 2.5
Purified water q.s.
Inert carrier composition
Lactose monohydrate 25
Microcrystalline cellulose 36.5
Extra granular components
Magnesium stearate 1
Croscarmellose sodium 2.5
Colloidal silicon dioxide 0.5
Total weight of composition 100
Manufacturing Process (using proprietary MISToxTM technology):
Drug dispersion preparation:
1. Etoricoxib, Hydroxy propyl methyl cellulose and Croscarmellose sodium are
dispensed, sifted & blended,
2. blend of step 1 is added into sufficient quantity of purified water to get 10%
solids build up and is subjected to homogenization to get drug dispersion,
Granulation:
3. lactose monohydrate, microcrystalline cellulose are dispensed, sifted &
blended,
4. load the inert carrier blend of step 3 into top spray granulator,
5. drug dispersion of step 2 is sprayed onto blend of step 4,
6. unload the granules obtained in step 5 and sift through desired mesh,
Tablet preparation:
7. extra granular components croscarmellose sodium, magnesium stearate &
colloidal silicon dioxide are dispensed and sifted,
8. sifted mixture of step 7 is added to sifted granules of step 6 and blended,
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9. blend of step 8 is compressed into tablets,
10. tablets of step 9 are optionally film coated using desired film coating material.
Example 3- In-vitro dissolution study:
The release profile of the pharmaceutical formulation as per the present
specification was evaluated through in-vitro dissolution studies. The formulation
prepared according to the formula and process of example 1, and the reference products
Arcoxia® and Nucoxia® are subjected to an in vitro dissolution study at 50 rpm and
37°C using USP type II apparatus (paddle) in different media. Figure 1 & 2 represent
the dissolution profiles. Below are the results in various dissolution media:
Table 4: Dissolution profile of formulation prepared as per example 1
Time (in
minutes)
% drug release
0.1 N Hcl
Acetate
buffer pH 4.5
Acetate
buffer pH
5.5
FeSSIF
pH 5.5
Acetate buffer
pH 5.5 + 0.2 M
NaCl
0 0 0 0 0 0
10 93 80 86 69 63
15 98 88 91 84 79
30 101 94 95 96 88
45 101 97 96 98 92
60 - 97 97 99 94
90 - 98 97 99 94
120 - 98 98 100 97
FeSSIF- Fed State Simulated Intestinal Fluid
Table 5: Dissolution profile of reference product Arcoxia®
Time (in
minutes)
% drug release
0.1 N Hcl
Acetate
buffer pH 4.5
Acetate
buffer pH 5.5
FeSSIF
pH 5.5
Acetate buffer
pH 5.5 + 0.2 M
NaCl
0 0 0 0 0 0
10 94 37 25 32 19
15 96 48 32 42 26
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30 97 66 48 59 40
45 98 73 55 69 50
60 - 78 62 74 57
90 - 81 70 80 65
120 - 83 75 83 71
Table 6: Dissolution profile of reference product Nucoxia®
Time (in
minutes)
% drug release
0.1 N Hcl
Acetate buffer
pH 4.5
Acetate
buffer pH 5.5
FeSSIF
pH 5.5
Acetate buffer
pH 5.5 + 0.2 M
NaCl
0 0 0 0 0 0
10 93 68 59 44 37
15 97 73 60 56 44
30 99 80 66 68 54
45 - 84 69 73 58
60 - 86 71 80 62
90 - 89 74 85 65
120 - 90 76 87 66
The release profile demonstrates that formulations according to the present
specification shows improved dissolution profile and have superior and faster drug
release compared to reference products. Above study also shows that despite of pH of
the media, release of drug from the formulation of present invention is same i.e. the
drug release is independent of pH.
Example 4- Stability Study:
The stability of the pharmaceutical formulation as per the present specification
is evaluated through long term and accelerated stability studies. The composition was
prepared according to the formula and process of example 1, and is subjected to
stability study at 25±2°C/60%±5% RH and 40±2°C/75%±5% RH. All the samples
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were found to be stable and are within the limits of the specification. Below table
represents the study result data.
Table 7: Stability study of composition as per example 1
Characteristic Initial
40 °C /75 % RH 25 °C / 60 % RH
1 month 3 month 1 month 3 month
Assay (95.0 to 105.0%) 99.60% 100.53% 101.36% 100.51% 99.60%
RS
Unknown
NMT: 0.5 %
0.09 BQL 0.050 BQL BQL
Total
NMT: 2.0%
0.21 BQL 0.05 BQL BQL
Dissolution (%) 99 101 97 99.5 101
* BQL: below quantification limit; RS: Related substances (impurities); NMT: Not
More Than
Example 5- Pharmacokinetic study:
The pharmacokinetic parameters of pharmaceutical formulation as per the
present specification was evaluated in-vivo through comparative bioavailability studies
in fed state. The formulation was prepared according to the formula and process
example 1 and referred herein as test product (T). The reference product (R) used in
the study was Arcoxia®. The pharmacokinetic parameters of the test and the reference
products were assessed in an oral bioequivalence study in normal healthy, adult, human
subjects under fed conditions. The measured pharmacokinetic parameters are
summarized below. The study results demonstrate that test product is better when
compared to the reference product. Further, the test and reference products were well
tolerated by the subjects. No adverse event were reported after administration of test
products.
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Table 8: Pharmacokinetic study
Parameters (Units) Test Product
(T)
Reference Product
(R)
(T/R) %
Cmax (ng/mL) 1920.1782 1905.3221 100.78
AUC0-t (hr*ng/mL) 49033.1649 48486.1114 101.13
AUC0-∞ (hr*ng/mL) 67288.3090 63754.9150 105.54
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