Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
CA 02457385 2004-02-06
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IMPROVED ENTERIC FORMULE1TION OF FLUOXETIN
FIELD OF THE INVENTION
The present invention belongs to the field of Pharmaceutical Sciences and
provides an industrially
advantageous improved formulation of Fluoxetin or a pharmaceutically
acceptable salt, solvate,
enantiomer or mixtures thereof including racemic mixture, which is designed
for once a week
dosing. The present invention teaches that active ingredient is in the formof
pluralities of particles as
spherical, cylindrical or elliptical units, pellets, minitablets, tablets or
capsules, which can be enteric
coated with enteric polymers with an optional smoothening layer. The enteric
polymer can be applied
in a manner, which does not require any neutralization or reduction of free
acidic groups.
BACKGROUND OF THE INVENTION
Fluoxetin, N-Methyl-3-phenyl-3-[(a,a,a,-trifluoro-4-tolyl) oxyl~ propylamine,
is an antidepressant
drug, which is disclosed in U.S. Patent No. 4,314,081, 4,626,549 and
5,847,217. The teaching for (S)
and (R) enantiomeric forms of Fluoxetin is found in U.S. Patent No. 5,889,186
and 5,708,035
respectively. Method and formulation for treating depression using optically
pure Fluoxetin is
disclosed in U.S. Patent No. 5,104,899. Published literature supports the fact
that Fluoxetin and its
active metabolite, NorFluoxetin show very long elimination half life and
eliminates slowly from the
body even after discontinuation of the dosing. Because of the long half life
of Fluoxetin, there has
not been any perceived need to actually prepare a Fluoxetin formulation
providing a longer payout.
While these higher doses of Fluoxetin have been shown to be~ efficacious,
there can be associated
side effects, such as nausea, presumably due to local irritation or the
increased plasma levels shortly
after dosing. Therefore, it has now been appreciated that a formulation having
higher doses of
Fluoxetin (e.g. 60mg to 120mg) which blunts the initial release of Fluoxetin
will have clinical
advantages, i.e. not only will such formulations provide convenient and
effective once per week
dosing, but will have an advantage of less side effects.
Enteric pharmaceutical fornmlation of Fluoxetin with a dose of 90 mg is
disclosed in U.S. Patent No.
5,985,322. Anderson et al. in U.S. Patent No. 5,985,322 discloses the enteric
Fluoxetin pellets
wherein, the Fluoxetin with one or more pharmaceutically acceptable excipients
is coated over the
inert non-pareil seeds made of sucrose and starch. The drug coated core is
then optionally coated
with a separating layer comprising of non reducing sugar, sucrose along with
one or more
pharmaceutically acceptable excipients and coated with
hydroxypropylmethylcellulose acetate
succinate as enteric coating polymer along with one or more pharmaceutically
acceptable excipients
and finally coated with finishing layer hydroxypropylmethylcellulose and talc.
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U.S. Patent No. 5,910,319 teaches that certain difficulties arose in preparing
conventional enteric
formulations of Fluoxetin. In particular, Fluoxetin was found to react with
many enteric coatings to
form a slowly--or even insoluble coating. Therefore it is important that the
separating layer should be
used to prevent such an interaction of enteric polymer and Fluoxetin. The
separating layer is also
used to provide smooth surface for the enteric coat, to improve the acid
resistance of the pellets. It
has been noted that the use of sucrose in separating layer has surprisingly
improved the acid
resistance of the pellets and successfully prevented the direct contact of
core pellets with enteric
polymer. One of the further objectives of the smoothening layer described in
U.S. Patent No.
5,910,319 is to improve the coverage of enteric layer and to avoid thin spots
in it caused by bumps
and irregularities on the core.
The U.S. Patent No. 5,985,322 discloses the use of
hydroxypropylmethylcellulose acetate succinate
as most preferred enteric polymer in view of 4% to 28 % of succinoyl groups,
which are the only free
carboxylic groups in the compound. It is disclosed that the enteric polymer
must be the one having
only small number of carboxylic acid groups per unit weight or repeating units
of the polymers so as
to decrease the chances of reaction of Fluoxetin and enteric polymer to form a
slowly dissolving or
even insoluble coating.
Specific teaching of U.S. Pat. No. 5,910,319 is directed towards the problem
that Fluoxetin can
precipitate in needle-like crystals during processing, which can be quite
large. Coating cores with
Fluoxetin in the large needle-like form can be difficult, and it is advisable
to mill or otherwise reduce
r the particle size of the Fluoxetin to less than about 50 pm before using it
in the present product and
process.
It should be noted that the teachings of U.S. Patent No. 5,910,319 and
5,985,322 are associated with
substantial problems like selection of enteric polymers having only small
number of carboxylic acid
groups per unit weight of repeating unit of polymer. The hydroxypropyl methyl
cellulose acetate
succinate, which is suggested by the said patent, has the amount of succinoyl
groups from 4% to 28%
which are the only free carboxylic acid groups present in the compound. The
other problems are the
incorporation of separating layer, which increases the processing steps and
reducing the particles size
of Fluoxetin to less than 50 p,m before using.
The present invention does not require the reduction of particle size of
Fluoxetin to less than 50 ~m
before using. Moreover Fluoxetin has a particle size wherein 90% particles are
of size less than 229
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microns, 50% particles are of size less than 90 microns and 10% particles are
of size less than 23
microns.
The smoothening coat is an optional feature of the invention. Particularly
when the formulation is in
the fore of capsule the gelatin capsule shell itself act as a separating layer
and avoids the extra
processing steps in the enteric formulation and enables the formulator to
incorporate enteric polymer
with substantially high number or free carboxylic acid groups.
Similarly the present invention also avoids the usual long processing time
required for the coating of
drug layer over non-pared seeds thus saving the processing time and production
cost. Likewise, the
15, usual problems of drug loss, which occurs during the coating of drug on
the inert non-pareil seeds
as described in U.S. Patent 5,95,322 and 5,910,319 are avoided.
SUMMARY OF THE INVENTION
It is an objective of the present invention to produce an improved enteric
formulation of Fluoxetin
without the use of hydroxypropyl methyl cellulose acetate succinate and
sucrose.
The formulation of the present invention comprises;
(a) a core comprising Fluoxetin or a pharmaceutically accepted salt, solvate,
enantiomers or
mixtures thereof including racemic mixture, in an amount of 90 mg base
equivalent of
Fluoxetin;
(b) an optional smoothening layer;
(c) an enteric coating layer comprising an at least one enteric coating
polymers selected from
the group consisting of Eudragit L100-55, Eudragit L 100, Eudragit S 100,
hydroxypropyl methyl cellulose pthalate, cellulose acetate pthalate, polyvinyl
acetate
pthalate; an at least one plasticisers selected from the group consisting of
triethyl citrate,
polyethylene glycol, diethyl phthalate or dibutyl phthalate; an at least one
lubricant or
glidants selected from the group consisting of talc, magnesium stearate,
kaolin or
colloidal silicon dioxide.
(d) an optional finishing layer.
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DETAILED DESCRIPTION OF THE INVENTION
The present invention is designed in the form of enteric formulations
manufactured in such a way
that the product passes unchanged through the stomach of the patient, and
dissolves and releases the
active ingredient quickly when it leaves the stomach and enters the small
intestine. The enteric
formulations of the present invention are in the form of tablet or capsule
wherein, the active
ingredient, Fluoxetin or a pharmaceutically accepted salts, solvates,
enantiomers or mixtures thereof
including racemic mixture, is in the inner part of the tablet, minitablets,
pellet or pluralities of
particles as spherical, elliptical or cylindrical units, enclosed with a film
or envelope called as the
"enteric coating", which is insoluble in acid environments, such as the
stomach, but is soluble in
near-neutral environments such as the small intestine. When the enteric
formulation is in the form of
capsule, the capsules are banded/sealed with gelatin solution followed by
enteric coating, such that
the capsule shell itself acts as separating layer to avoid the possible
reaction of the active ingredient
and the enteric polymer. Such a presence of natural separating coat avoids the
excess manufacturing
steps required in earlier inventions. Further it has been noted that the
capsules enteric coated in the
said manner are found to be therapeutically equivalent to the commercially
available product Prozac'~
Weekly 90 mg capsule and have acceptable stability as per ICH guidelines.
When used in this specification, the term "active ingredient" refers to
Fluoxetin or a
pharmaceutically accepted salts, solvates, enantiomers or mixtures thereof
including racemic
mixture. The invention contemplates the enteric formulations comprising
Fluoxetin preferably as
hydrochloride salts, however as will be appreciated by those skilled in the
art, other salt form or free
base form could be used to obtain the same beneficial feature of the
invention. Moreover, solvates of
Fluoxetin or its salts or free bases, salts, and/or solvates of the individual
isomers of Fluoxetin,
namely (R)-Fluoxetin and (S)-Fluoxetin, are contemplated by this invention
Throughout this
description, unless specified otherwise, the term "Fluoxetin" contemplates all
such forms, although
Fluoxetin hydrochloride is clearly the most preferred embodiment of this
invention. It should be
noted that there is no difference in the word Fluoxetin or Fluoxetine and can
be used interchangeably
in this specification without altering the scope and meaning of the invention.
The present invention utilizes Fluoxetin in the range of particle size wherein
90% particles are of size
less than 229 microns, 50% particles are of size less than 90 microns and 10%
particles are of size
less than 23 microns.
The present enteric coated formulations can be prepared by coating the enteric
polymer having
substantially high free carboxylic °acid, groups and does not require
to limit the free carboxylic acid
group in the range of from 4% to 28%.
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According to one of the embodiments of the present invention the active
ingredient is in the form of
pluralities of particles as spherical, elliptical or cylindrical units. The
delivery system in the form of
plurality of single units offers many clinical advantages. Each of the single
units act as a separate
entity therefore the chances of dose dumping or unpredictable transit across
the gastrointestinal tract
due to variable gastric or intestinal residence time is overcome by using
plurality of single units.
Preferably, the present invention describes the manufacturing of core of
active material in the form
of mini-tablets or pluralities of particles as spherical, elliptical or
cylindrical units, either by
compressing the active agent with one or more of the pharmaceutically
acceptable excipients on
tablet compression machine or by extrusion-spheronization technique. The
present invention
describes an improved enteric fornmlation containing Fluoxetin or
pharmaceutically accepted salts or
solvates thereof, in the dosage range of 60-120 mg, preferably 90-120 mg and
most preferably 90
mg base equivalent of Fluoxetin. The enteric formulations according to the
present invention are
designed for the treatment of various depressive disorders known in the art
with a dosing frequency
of once every seven days.
The formulation of the present invention is in the form of capsules or tablets
comprising pluralities of
particles as spherical, elliptical or cylindrical units or in the form of mini-
tablets. When the
formulation is in the form of pluralities of particles the size of such
particles ranges from O.Smm to
3.0 mm. When the formulation is in the form of minitablets the size of such
minitablets is in the
range of from O.Smm to 6 mm preferably 0.5 mm to 4 mm. When the formulation is
in the form of
tablets the size of such tablets is in the range of 6mm to 16 mm preferably 8
mm to 14 mm more
preferably 8mm to l lmm. These pluralities of particles as spherical,
elliptical or cylindrical units are
filled in the hard gelatin capsules of size ranging from 3 to 000. The hard
gelatin capsules are then
sealed with the gelatin solution in water in the concentration of 5-50% w/w at
temperature ranging
from 37°C to 70°C using hard gelatin capsule band sealing
machine known to the pharmaceutical
Industry. Alternately the sealing can be done using aqueous or nonaqueous
solution of any of the
polymers selected from hydroxypropylmethylcellulose, hydroxypropyl cellulose
or
hydroxyethylcellulose.
The word sealing and banding are used interchangeably in this description,
which means applying a
"band" of cohesive or polymeric materials as aqueous or non-aqueous solution
to fuse the cap and
the body of the capsule. Sealing of hard gelatin capsules with a band of
gelatin or other cellulosic
materials is known to the pharmaceutical industry since long and is very
common technique
employed in order to make the capsules tamperproof. However, the object of
applying such a sealing
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or banding of the capsules according to the present invention is to prevent
the migration of enteric
solution to the interior of the capsule thus avoiding the contact of active
ingredient with the enteric
coating. Further in the present invention the capsules are sealed to fuse the
cap and body of the
gelatin shell to provide uniform surface for subsequent coatings.
When the active ingredient is in the form of tablets it is preferred that
smoothening layer/coat is
applied. When applied, said smoothening- coat/layer is composed of cohesive or
polymeric material
with finely divided solid excipients, which constitute fillers. The polymeric
or cohesive materials can
be selected from any of the polymeric materials selected from
hydroxypropylmethylcellulose,
polyvinylpyrrolidone~ hydroxypropylcellulose, polyethylene glycol, sodium
alginate, Eudragit RD
100, combination of N-vinyl pyrollidone and vinyl acetate, combination of
microcrystalline cellulose
and carragenan etc. Hydroxypropylmethylcellulose and polyethylene glycol are
the preferred
material for smoothening layer as per present description. The fillers used
are those commonly used
in pharmaceutical industries like finely powdered talc, silicon dioxide etc.
The preferred aspect of the
present invention is to avoid the use of sucrose in said smoothening layer,
the use of which may be
detrimental to the patients having history of hyperglycemia.
When enteric formulation is in the form of capsule the smoothening layer may
be applied to facilitate
more even enteric coat. The capsule shell itself acts as separating barrier
(separating coat), which
prevents the interaction of acidic enteric polymer with the active ingredient
in the core. As used in.
this description the term "separating barrier" means a capsule shell with or
without a band.
The formulation of the present invention avoids the need of separating layer
between the enteric
layer and the core containing active ingredient (Fluoxetin it pharmaceutically
accepted salt, solvates,
enantiomers and mixtures thereof including racemic mixture) thus reduces the
extra processing steps
needed to manufacture such formulations containing separating layer. The
enteric layer is composed
of a water-insoluble polymer together with a plasticizer and one or more
pharmaceutically accepted
excipients. The polymers used for enteric coating as per the present invention
are selected from the
group consisting of Eudragit L100-55, Eudragit L 100, Eudragit S 100,
hydroxypropyl methyl
cellulose pthalate, cellulose acetate pthalate, polyvinyl acetate pthalate
etc. The preferred polymer is
Eudragit L100-55.
The coating process can be as follows. The Eudragit L 100-55 is dissolved in
solvent such as
isopropyl alcohol and triethyl citrate and magnesium stearate are added to it.
The resulting solution is
sprayed on the tablets or capsules using coating pan. Alternatively aqueous
dispersion of Eudragit L
100-55 (Spray dried Eudragit L30D-55 which can be reconstituted for aqueous
formulations) can
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also be used for coating. Eudragit L 100-55, Triethyl citrate or magnesium
stearate can be replaced
by the functionally equivalent ingredients as described in this specification.
The various components and layers of the enteric formulation of the present
invention are discussed
individually as follows.
Pluralities of particles:
The pluralities of particles as spherical, elliptical or cylindrical units are
prepared by using wet
granulation with or without use of binders lilce N-vinyl pyrollidone,
hydroxypropyl methyl cellulose
(5 cps-100 cps), hydroxypropylcellulose, pregelatinized starch, starch paste,
combination of N-vinyl
pyrollidone and vinyl acetate and gelatin in the concentration range of 2% to
20%.
The said formulation also contains one or more of the , pharmaceutically
accepted diluents like
sorbitol, mannitol, microcrystalline cellulose, dicalcium phosphate or
combination thereof .The
formulation of the present invention also contains surfactants like sodium
lauryl sulphate, poloxamer
407, Tween 20/40/60/80, Span 20/40/60/80, Cremophor RH 40 or combination
thereof.
The said formulation also contains one or more of the pharmaceutically
accepted disintegrants
selected from crosscarmellose sodium, crosspovidone, sodium
carboxymethylcellulose, sodium
starch glycolate or such like.
In the present formulation when water is used as granulating solution the
percentage of water with
respect to weight of powder mass ranges from 10% to 50% w/w. The moisture
content of the wet
mass ranges from 10% to 50%. The pluralities of particles are manufactured by
extrusion of wet
mass of Fluoxetin and one or more pharmaceutically acceptable excipients
followed by
spheronization.
Composition of Core Pellets
In redients Quantity
taken
Fluoxetin hydrochloride USP/NF 10-80 %
equivalent to w/w
Fluoxetin base 90 m
Mannitol USP 30-80 %
w/w
Microcrystalline cellulose (Avicel0-70 % w/w
PH 101) NF
Hydroxypropylmethyl cellulose NF, 2-10 % w/w
5 cps
Crosspovidone NF 1-10 % w/w
Sodium lauryl sulphate or Poloxamer0.1-2 %
407 NF w/w
Purified water I Qs
All the ingredients except hydroxypropyl methylcellulose (5 cps) were weighed
and blended together
for 15-30 minutes. The blend was then sifted through 40 # screen. The sifted
powder mass was then
granulated with hydroxypropylmethylcellulose solution in water. The wet mass
was then passed
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through extruder. The extrudes were then spheronized in spheronizer at speed
ranging from 200 rpm
to1500 rpm for the period of 2 minutes to 15 minutes. The pellets were then
dried for sufficient
period of time till the loss on drying of pellets was not more than 1.5 % wlw.
Example 1.
Core Pellet: (Plurality of particles as spherical, elliptical or cylindrical
units)
Quantity
Ingredients taken
in
m
Fluoxetin hydrochloride USP/NF 101
equivalent to
Fluoxetin base 90 m
Mannitol USP 345
Microcrystalline cellulose (Avicel32
PH 101) NF
Hydroxypropylmethyl cellulose 16
NF, 5 cps
Crosspovidone NF 8.5
Sodium lauryl sulphate or Poloxamer2.5
407 NF
Purified water qs
Optional smoothening layer:
Quantity
Ingredients taken
in m
Hydroxypropyl methyl 9
cellulose S cps
Polyethylene glycol 400 1.35
Talc 0.45
Purified water qs
Enteric coat:
Quantity
Ingredients taken
in m
EUDRAGIT~ L 100-5517.1
Triethyl citrate 1.71
Magnesium stearate1
Isopropyl alcoholqs
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Example 2.
Core pellet: (Plurality of particles as spherical, elliptical or cylindrical
units)
Quantity
Ingredients taken
in
m
Fluoxetin hydrochloride USP/NF 101
equivalent to
Fluoxetin base 90 m
Mannitol USP 345
Microcrystalline cellulose (Avicel32
PH 101) NF
Hydroxypropylmethyl cellulose 16
NF, 5 cps
Crosspovidone NF 8.5
Sodium lauryl sulphate or Poloxamer2.5
407 NF
Purified water qs
Optional smoothening layer:
Quantity
Ingredients taken
in m
Hydroxypropyl cellulose 9
5 cps
Polyethylene glycol 1.35
400
Colloidal silicon 0.45
dioxide
Purified water qs
Enteric coat:
Quantity
Ingredients taken
in m
Hydroxypropyl cellulose17
methyl 1
thalate ,
Dibutyl phthalate 1.71
Magnesium stearate 1
Isopropyl alcohol qs
Acetone qs
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Example 3.
Core pellet: (Plurality of particles as spherical, elliptical or cylindrical
units)
Ingredients
Quantity
taken in
m
Fluoxetin hydrochloride USP/NF101
equivalent to
Fluoxetin base 90 m
Mannitol USP 345
Hydroxypropylmethyl cellulose 16
NF, 5 cps
Crosspovidone NF 8.5
Sodium lauryl sulphate or Poloxamer2.5
407 NF
Purified water 106.6
Optional smoothening layer:
Ingredients Quantity
taken in
m
Hydroxypropyl methyl cellulose 9
5 cps
Polyethylene glycol 400 1.35
Talc 0.45
Purified water qs
Enteric coat:
Quantity
Ingredients taken
in m
Cellulose acetate17.1
pthalate
Triethyl citrate 1.71
Talc 1 ,
Isopropyl alcoholqs
Acetone qs
Mini-Tablets:
The mini-tablets are prepared either by using wet granulation or direct
compression or dry
granulation method with or without use of binders like N-vinyl pyrrolidone,
hydroxypropylmethyl
cellulose (5 cps to 100 cps) hydroxypropylcellulose, pregelatinized starch,
starch paste, combination
of N-vinyl pyrrolidone and vinyl acetate and gelatin in the concentration
range of 2% to 20 %. The
Said formulation also contains one or more of the pharmaceutically accepted
excipients like
mannitol, sorbitol, microcrystalline cellulose, dicalcium phosphate or
combination thereof as
diluents. Magnesium stearate, stearic acid, lubritab, talc and silicon dioxide
are used as lubricants
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and glidants. The said pharmaceutical excipients also contain disintegrants
like hydroxy propyl
cellulose, crosspovidone, sodium starch glycolate, crosscarmellose sodium or
combination thereof.
The said formulation also contains surfactants like sodium lauryl sulphate,
poloxamer 407,Tween
0/40/60/80, Span 20/40/60/80, Cremophor RH 40 or combination thereof.
Preparation of Mini-Tablets or Tablets
Ingredients Quantity
taken
Fluoxetin hydrochloride USP/NF
equivalent to
10-80 %
Fluoxetin base 90 m w/w
Microcrystalline cellulose NF
10 -90 %
Avicel PH 102 l 112 / 200 w/w
Polyvinylpyrollidone NF (PVP I~
30 / K 90)/ 2 -10 %
w/w
Plasdone S-630
Crosspovidone NF 2-10 % w/w
Magnesium stearate NF 0.1-3 %
w/w
Talc NF 0.1-3 %
w/w
Colloidal silicon dioxide NF 0.1-5 %
w/w
Sodium lauryl sulphate or Poloxamer0.1-5%
407 NF
All the ingredients except magnesium stearate and talc were weighed accurately
and sifted through
40 # screen. The sifted materials were then blended for 5-60 minutes in a
suitable blender.
Magnesium stearate and talc were weighed and sifted through 40 # screen and
added to other
ingredients and blended for 5-20 minutes before compressing into mini-tablets.
Alternatively all the
excipients except magnesium stearate, talc and polyvinyl pyrollidone were
weighed accurately and
sifted through 40 # screen and were granulated while polyvinylpyrrolidone
solution in water. The
wet mass was then optionally milled and dried or dried directly till the loss
on drying was 0.3% to
5 % w/w. The dried granules were again nulled and mixed with magnesium
stearate. Talc is weighed
and sifted separately. The lubricated granules were mixed for 5 minutes to 20
minutes and
compressed into tablets or mini-tablets.
The core of the present invention can be coated with film coating polymers
like N-vinyl pyrrolidone
(PVP I~ 30/I~ 90), polyethylene glycol, hydroxypropylmethylcellulose,
hydroxypropylcellulose,
hydroxyethylcellulose, sodium alginate, EUDRAGIT~ RD 100, combination of N-
vinyl pyrrolidone
and vinyl acetate along with one or more pharmaceutically acceptable
excipients like plasticisers,
glidants, anti adherent agents to improve the process of capsule filling
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Example 4.
Fluoxetin Mini-Tablets Formulation:
Quantity
Ingredients taken
In m
Fluoxetin hydrochloride USP/NF 101
equivalent to
Fluoxetin base 90 m
Microcrystalline cellulose NF 294
Avicel PH 102 / 112 / 200
Polyvinylpyrollidone NF (PVP K30/K90)27
/ Plasdone S - 630
Crosspovidone NF 18
Magnesium stearate NF 2
Talc NF 2
Colloidal silicon dioxide NF 6
Sodium lauryl sulphate or Poloxamer2
407 NF
Optional Smoothening Layer:
Quantity
Ingredients taken
in m
Hydroxypropyl methyl cellulose9
cps
Polyethylene glycol 400 1.35
Talc NF 0.45
Purified water qs
Enteric coat:
Quantity
Ingredients taken
in m
Eudragit L 17.1
100-55
Triethyl citrate1.71
Magnesium stearate1
Isopropyl alcoholqs
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Example 5. Fluoxetin Tablet Formulation
Quantity
Ingredients taken
In m
Fluoxetin hydrochloride USP/NF
equivalent to
101
Fluoxetin base 90 m
Microcrystalline cellulose NF
294
Avicel PH 102 / 112 / 200
Polyvinylpyrollidone NF (PVP K30/K90)
27
/ Plasdone S - 630
Crosspovidone NF 18
Magnesium stearate NF 2
Talc NF 2
Colloidal silicon dioxide NF . 6
Sodium lauryl sulphate or Poloxamer2
407 NF
Smoothening layer:
Quantity
Ingredients , taken
in m
Plasdone S-630 12.59
Triethyl citrate 1.89
Talc 1.26
Purified water qs
Enteric coat:
. Quantity
Ingredients taken
in m
Eudragit L 27.2
100-55
Triethyl citrate 2.72
Magnesium stearate 0.25
Isopropyl alcohol Qs
Example 6: Fluoxetin Tablets Formulation
Quantity
Ingredients . taken
In m
Fluoxetin hydrochloride USP/NF 101
equivalent to
Fluoxetin base 90 m
Microcrystalline cellulose NF 294
Avicel PH 102 l 112 l 200
Polyvinylpyrollidone NF (PVP K30/K90)
27
/ Plasdone S - 630
Crosspovidone NF 18
Magnesium stearate NF 2
Talc NF 2
Colloidal silicon dioxide NF 6
Sodium lauryl sulphate or Poloxamer2
407 NF
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Smoothening layer:
Quantity
Ingredients taken
in m
Hydroxypro y1 methyl cellulose12.59
5 c s
Polyethylene glycol 400 1.89
Talc 1.26
Purified water qs
Enteric coat:
Quantity
Ingredients taken
in m
Cellulose acetate 27.2
pthalate
Dibutyl phthalate 2.72
Colloidal silicon 0.25
dioxide
Isopropyl alcohol Qs
Acetone Qs
Hard Gelatin Capsule Sealing:
The core in the form of pluralities of particles as spherical, elliptical or
cylindrical units are filled in
hard gelatin capsules of size ranging from 3 to 000. The hard gelatin capsules
are then sealed with
gelatin solution in water in the concentration range of 5-50 % w/w at
temperature ranging from 37°C
to 70°C using hard gelatin capsule band sealing machine. The sealing of
capsules is done to fuse the
cap and body of capsules to provide uniform surface for the further functional
coating and also to
prevent the possible ingress of solvent during coating.
Optional Smoothening Coat/Layer:
The smoothening coat when applied is optional with an object of providing a
smooth surface for the
enteric coating. The optional smoothening coat can be applied using one or
more of the agents like
N-vinyl pyrrolidone (PVP I~ 30/K-90), polyethylene glycol,
hydroxypropylmethylcellulose,
hydroxypropylcellulose, hydroxyethylcellulose, sodium alginate, Eudragit
RD100, combination ofN-
vinyl pyrrolidone and vinyl acetate (Plasdone S-630), Opadry AMB along with
one or more
pharmaceutically acceptable excipients like plasticisers selected from
triethyl citrate, polyethylene
glycol, diethyl phthalate, dibutyl phthalate, glidants, antiadherents like '
talc, magnesium stearate,
kaolin, colloidal silicon dioxide, which are commonly known to those skilled
in the art. These
agents are applied in the range of 0.5 to 9 mg/cm Z surface area corresponding
to 0.5 to 7 % polymer
with respect to weight of core.
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Enteric/Site Specific Coating:
In the present invention the agents which inhibits the release of drug in
stomach and releases the
same once the pH in the body reaches 5.0 to 7.5 are sodium alginate, cellulose
acetate, copolymers
derived from methacrylic acid/ethyl acrylate, anionic methacrylic acid and
methacrylic acid esters,
cellulose acetate phthalate, polyvinyl acetate phthalate and
hydroxypropylmethylcellulose phthalate ,I
or combination thereof.
These agents are used in the range of 1 mg/cm2 to 20 mg/cm2 and are more
preferably from 2
mg/cmz to 12 mg/cm2 of surface area corresponding to about 2% to 20 % of the
enteric polymer with
respect to the weight of core. The coating solution/suspension also contains
excipients like
plasticisers selected from triethyl citrate, polyethylene glycol, diethyl
phthalate, dibutyl phthalate,
glidants, antiadherents like talc, magnesium stearate, kaolin or colloidal
silicon dioxide and such like.
Optional Finishing Coat:
The finishing coat can be optionally applied with an object to improve the
elegance of the product.
The agents which constitute the finishing coat includes various grades and
colours of commercial
product Opadry of M/s Colorcon which consists of hydroxy propyl
methylcellulose along with one
or more pharmaceutically acceptable excipients.
Stability Profile of the enteric formulations:
The assay and related substances show that the Fluoxetin 90 mg capsules and
tablets are substantially
stable over the storage period of 3 months and 6 months respectively at the
storage conditions of
40°C and 75% RH (relative humidity).
Assay and related substances for Fluoxetin 90 mg~capsules at storage condition
of 40°C and
75% RH.
InitialAfter 3 months
Assa 101.6%103.9%
Related substances0.03% ~ 0.07%
Assay and related substances Fluoxetin 90 mg Tablets at storage condition of
40°C and 75%
RH.
InitialAfter 6 months
Assa 98.20%103.3%
Related substances0.13% ~ 0.15%
The percent acid release of drug at pH 6.8 as well as gastric resistance is
not affected adversely even
after exposing the tablet to 40°C and 75% RH for 6 months and capsules
for 40°C and 75% RH for 3
months.
CA 02457385 2004-02-06
WO 03/013480 PCT/IB02/01268
Gastric resistance and dissolution profile of Fluoxetin 90 mg capsules at
storage condition of
40°C and 75% RH.
InitialAfter 3
months
acid release 0.0% 0.0%
in 0.1 N
HCL for 2 hours
using
USP apparatus
I at pH
6.8 at 100 RPM.
dissolution at
pH
6.8 using USP
apparatus I at
100
RPM
30 min 80% 67%
60 min 93% 87%
90 min 95% 89%
Gastric resistance and dissolution profile of Fluoxetin 90 mg tablet at
storage condition of 40°C
and 75% RH.
InitialAfter 6
months
acid release 0.0% 0.0%
in 0.1 N
HCL for 2 hours
using
USP apparatus
I at pH
6.8 at 100 RPM.
% dissolution
at pH
6.8 using USP
apparatus I at
100
RPM
30 min 68% 67%
60 min ~ 82% 79%
90 min 91% 88%
From the above data it is evident that gelatin shell acts as natural
separating barrier/coat to prevent
the interaction between Fluoxetin and enteric coating polymers (or polymers
used for site specific
coating as described in this specification), containing even substantially
high percentages of free
carboxylic acid groups.
The enteric Fluoxetin formulations of present invention was found to be
substantially stable and
therapeutically equivalent to the commercially available formulation Prozac~
Weekly 90 mg
capsules. The examples given above are for the purpose of illustration only
and not to be construed
as limitations thereon. Many variation of the present invention mentioned in
the detailed description
are obvious to those sleilled in the art and are contemplated to be within the
scope of the present
invention.
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