Specification
FIELD OF THE INVENTION
This invention in general relates to high drug load pharmaceutical compositions
comprising iron chelating agents or their pharmaceutically acceptable salts, esters,
solvates, polymorphs, enantiomers or mixtures thereof In particular, the present
invention proposes a non-dispersibie, high drug load solid oral pharmaceutical
composition comprising Deferasirox and process for preparing the same.
BACKGROUND OF THE INVENTION
Deferasirox is an iron chelating agent and is indicated for treatment of chronic iron
overload due to blood transfusions (transfusional iron overload) and treatment of
chronic iron overload in non-transfusion-dependent thalassemia syndromes.
Deferasirox is chemically described as 4-[3,5-bis(2-hydroxyphenyl)-l H-l,2,4-triazoll-
yl]benzoic acid and is represented by the following formula:
- - - - -"-' 'OH-""""
N—N OH
Deferasirox was first approved in the US on Nov 02, 2005 as tablet for oral suspension
under the brand name EXJADE® in strengths of 125 mg, 250 mg and 500 mg. Inactive
ingredients in the EXJADE® tablet for suspension include lactose monohydrate,
crospovidone, povidone (K30), sodium lauryl sulphate, microcrystalline cellulose,
silicon dioxide, and magnesium stearate. Following patent and patent publications
pertain to dispersible tablet formulation of Deferasirox:
Patent publications US 8703203, US 2006/110446, US 2008/311 194, US
2008/312302, US 2011/046193, US 2011/319457 and US 2012/196909 disclose
dispersible tablet formulations of Deferasirox. As per the disclosure of US
201 1/319457, dispersible tablets have a drug load of about 29.4% (w/vv).
WO 2009/106824 discloses dispersible and effervescent oral dosage form of
Deferasirox having a drug load of 41.67% (w/w).
Patent publication WO 2010/035282 has a publication date of April 1, 2010 and
discloses dispersible oral pharmaceutical composition comprising Deferasirox or its
pharmaceutically acceptable salts wherein Deferasirox is present in an amount of at
least 66% by weight based on total weight of said composition.
WO 2014/067501 relates to dispersible tablets containing Deferasirox or its
pharmaceuticail-y acceptable salts and a combination of at least two disintegrants. The
disintegrants have different average size of particles and the total amount of the
disintegrant in a tablet is more than 35% by weight.
Another formulation of Deferasirox was approved in the US on March 30, 2015 under
the brand name JADENU® in strengths of 90 mg, 180 mg or 360 mg as an oral tablet.
Inactive ingredients in the JADENU® oral tablets are microcrystalline cellulose,
crospovidone, povidone (K30), magnesium stearate, colloidal silicon dioxide and
poloxamer (188). The film coating contains Opadry blue. Following patent and patent
publications pertain to oral tablet formulation of Deferasirox:
US 2015/0017241 discloses high drug load oral formulation comprising Deferasirox or
its pharmaceutically acceptable salt and at least one pharmaceutically acceptable
excipient prepared by wet granulation method. The tablets preferably used for clinical
pharmacokinetic (PK) study are disclosed to have a drug load of about 55.56 % (w/w)
in the composition.
Deferasirox is reported to be poorly soluble in water which leads to administration of
high dose of the drug to attain desired therapeutic effect. Poor aqueous solubility and
high dose of the drug also offer challenges to formulation scientist in developing a
suitable formulation. Recently, high drug load tablet formulation of Deferasirox
prepared by wet granulation and extrusion-spheronisation process have been disclosed
in US 2015/0017241. Extrusion-spheronisation process requires specialized
equipment, trained personnel and critical control of manufacturing steps as overwetting
of pellets may occur. There still remains a need for a high drug load oral dosage
form of Deferasirox produced by simple, economical and reproducible manufacturing
process which not only provides the prescribed daily dosage of the drug in a manner
which is convenient to administer but also circumvents solubility associated issues of
the drug. *
The present invention relates to a simple, reproducible, and cost-effective process for
delivering a high drug load of Deferasirox in a convenient manner. Further, the oral
pharmaceutical tablet composition prepared according to the manufacturing process
proposed in the present invention possesses desirable formulation characteristics.
SUMMARY OF THE INVENTION
One embodiment of the present invention relates to high drug load oral pharmaceutical
compositions comprising a pharmacologically effective amount of iron chelating
agents preferably Deferasirox or its pharmaceutically acceptable salt present in an
amount of more than 60% by weight. In particular, the amount of Deferasirox or its
pharmaceutical^ acceptable salt may vary from about 60% to about 85% by weight,
based on the total weight of the composition wherein, the composition exhibits a
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disintegration time of about 2 to about 10 minutes when measured by a standard USP
disintegration test.
In another embodiment, the present invention provides a process for the preparation of
high drug load oral pharmaceutical compositions comprising from about 60% to about
85% by weight of Deferasirox based on the total weight of the composition wherein,
the composition exhibits a disintegration time of about 2 to about 10 minutes when
measured by a standard USP disintegration test.
In yet another embodiment of the invention, the high drug load oral pharmaceutical
composition comprises from 50 to 800 mg of Deferasirox and exhibits a disintegration
time of about 2 to about 10 minutes when measured by a standard USP disintegration
test.
Another embodiment of the present invention encompasses a high drug load oral
pharmaceutical composition comprising from about 65% to about 85% by weight of
Deferasirox based on the total weight of the composition and a pharmaceutically
acceptable excipient selected from at least one of diluent, binder, disintegrant,
surfactant, lubricant, giidant and other pharmaceutical excipients. Combination of
excipients performing the same function may also be used to achieve desired
formulation characteristics. The composition exhibits a disintegration time of about 2
to about 10 minutes when measured by a standard USP disintegration test.
Another embodiment of the present invention includes a high drug load solid oral
pharmaceutical composition comprising from about 60% to about 85% by weight 0f
Deferasirox based on the total weight of the composition wherein, the composition
exhibits a disintegration time of about 2 to about 10 minutes when measured by a
standard USP disintegration test.
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In another embodiment, the present invention includes a high drug load solid oral
pharmaceutical composition comprising from about 65% to about 85% by weight of
Deferasirox based on the total weight of the composition wherein, the composition is
substantially free of other polymorphic forms and exhibits a disintegration time of
about 2 to about 10 minutes when measured by a standard USP disintegration test.
In another embodiment of the present invention, the non-dispersible oral dosage form
of the invention is prepared by wet or dry process to prepare a high drug load oral
pharmaceutical dosage form of Deferasirox. The wet and dry processes include, but are
not limited to, wet granulation, dry granulation, dry blending,and direct compression.
Other formulation techniques are also contemplated within the scope of the present
invention.
In another embodiment of the invention, the non-dispersible oral pharmaceutical
composition comprising Deferasirox..is prepared by co-milling of-the drug with the
excipient(s).
In another embodiment, the high drug load, non-dispersible oral pharmaceutical
composition of the present invention includes particle size of Deferasirox, wherein D90
is less than 100 jam.
Another embodiment of the present invention also provides a process for the
preparation of a high drug load oral pharmaceutical composition of Deferasirox,
comprising the steps of (a) blending a mixture of Deferasirox and at least one excipierit,
(b) wet granulation (aqueous or non-aqueous) of the mass, (c) drying the Wet granules
to obtain dried granules, (d) optionally milling of the dried granules, (e) adding at least
one lubricant and optionally other pharmaceutically acceptable excipients to the dried
milled granules, and compressing the lubricated granules into tablets or filling in
capsules.
In another embodiment, non-dispersible oral pharmaceutical composition of the present
invention exhibits a disintegration time of about 2 to about 10 minutes when measured
by a standard USP disintegration test.
In yet another embodiment, non-dispersible oral pharmaceutical composition of the
present invention exhibits a hardness of about 5 to about 20 kilopascals when measured
by a standard USP hardness test.
In another embodiment, non-dispersible oral pharmaceutical composition of the present
invention exhibits a dissolution profile whereby more than 85% of the drug is released
within 20 minutes.
In another embodiment, the non-dispersible oral pharmaceutical of the present
invention is stable for at least about six months at 40°C and 75% relative humidity.
In further embodiment, the present invention includes method of using the high drug
load, non-dispersible oral pharmaceutical composition comprising tablet of
Deferasirox in the treatment of chronic iron overload due to blood transfusions.
BRIEF DESCRIPTION OF THE DRAWNINGS
The above and other objects and features of the present invention will become apparent
from the following description of the invention, when taken in conjunction with the
accompanying drawing, in which:
FIG. 1 shows In vitro dissolution test of Deferasirox tablets
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 Deferasirox or its pharmaceutical^ acceptable
salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, and the other inert
ingredient(s) (pharmaceutical ly acceptable excipients). Such pharmaceutical
compositions are synonymous with "formulation" and "dosage form". Pharmaceutical
composition of the invention include, but is not limited to, granules, tablets (single
layered tablets, multilayered tablets, mini tablets, bioadhesive tablets, caplets, matrix
tablets, tablet within a tablet, mucoadhesive tablets, modified release tablets, pulsatile
release tablets, timed release tablets, delayed release, controlled release, extended
release and sustained release tablets), capsules (hard and soft or liquid filled soft gelatin
capsules), pills, troches,, sachets, powders, microcapsules, minitablets, tablets in
capsules and microspheres, matrix composition and the like. Preferably, the
pharmaceutical composition refers to tablets and capsules. More preferably, the
pharmaceutical composition refers to non-dispersible oral tablets.
"Deferasirox" as used here refers to the free acid form, its salts, esters, solvates,
polymorphs, enantiomers or mixtures thereof.
The term "high drug load" as used herein, refers from about 60% to about 85% by
weight of Deferasirox based on the total weight of the composition.
The term "excipient" means a pharmacologically inactive component such as a diluent,
lubricant, surfactant, carrier, or the like. The excipients that are useful in preparing a
pharmaceutical composition are generally safe, non-toxic and are acceptable for
veterinary as well as human pharmaceutical use. Reference to an excipient includes
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both one and more than one such excipient. Co-processed excipients are also covered
under the scope of present invention. The excipient(s) may be present intra-granularly
or extra-granu.ar.y or in both the phases. Further, excipient may be in the form of
powders or in the form of dispersion. Combination of excipients performing the same
function may also be used to achieve desired formulation characteristics.
"Substantially free" as used herein refers to the pharmaceutical composition of
Deferasirox, which does not contain binder and/or disintegrant. According to a
particularly preferred embodiment, the'pharmaceutical composition is substantially
free of binder and/or disintegrant. In particular, the pharmaceutical composition
comprises less than | * w/w of binder and/or disintegrant, by total weight of the
composition.
The term "non-dispersib.e tablet" as used herein, refers to a tablet which does not
d.sperse in aqueous phase, e.g. in water, before administration.
Unless otherwise stated the weight percentages expressed herein are based on the final
weight of the composition or formulation. -
In another embodiment the high drug load, non-dispersible oral pharmaceutical
g composition of the present invention includes particle size of Deferasirox or its salt.
wherein D9o is less than 100 |am.
In another embodiment the present invention includes particle size of free drug
particulate form of Deferasirox or its salt, wherein particle diameter at 90% cumulative
volume is less than about lOOum. Particle diameter at X% cumulative volume is a
method of designating volume-based particle size distribution such that X% by volume
of the particles have diameter equal to less than the stated value. Particle size reduction
can be performed by techniques including but not limited to fluid energy milling ball
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iii) Binder solution was prepared by dissolving Povidone in water.
iv) Step ii blend was granulated using step iii binder solution.
v) The granules of step iv were dried and the dried granules were sifted/milled
. through a suitable sieve/mill.
vi) Microcrystalline cellulose/ Lactose, Colloidal Silicon Dioxide and
Crospovidone were sifted through a suitable sieve and added to step v granules
and mixed for a suitable time.
vii) Magnesium stearate was sifted through a suitable sieve and mixed with step vi
blend for a suitable time.
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viii)The blend of step vii was compressed into tablets using suitable punches.
ix) The tablets of step viii were film coated.
Example III
Disintegration time of the tablet dosage form prepared using quantitative composition
as given in Example I and Example II was evaluated in a USP tablet disintegration
tester wherein the tablets were placed in a basket, which moves upward and downward
in a 1 L beaker of water at 37°C. Disintegration time of the tablet dosage form prepared
using quantitative composition as given in Example I and Example II was found to be
in range of 3 to 4 minutes.
Example IV
The standardized method and equipment for testing dissolution time is provided in
Office of Generic Drugs dissolution database. The dissolution profile of tablet dosage
form prepared using quantitative composition as given in Table 1 was measured in 900
ml of Phosphate Buffer, pH 6.8 having 0.5% Tween 20 (Office of Generic Drugs
dissolution database) using a USP II apparatus (paddle) at a temperature of 37*0.5°C
and a rotation speed of 75 revolutions per minute. The dissolution test was conducted
on the reference formulation JADENU®oral tablets in comparison to a tablet dosage
form as given in Example I. The dissolution data is provided in Table 3 and Fig. I.
TABLE 3
Time point
(min.)
5
10
15
20
30
45
60
% dru
JADENU®
51
80
87
90
92
95
96
g released
Example I
65
79
86
89
93
96
97
1.
19
Since, both commercially available JADENU® oral tablets and tablet dosage form
prepared using quantitative composition as given in Table 1 exhibited more than 85%
of drug release within 20 minutes, dissolution profiles of the two formulations were
found to be similar.
Many modifications of this invention can be made without departing from its spirit and
scope, as will be evident to those skilled in the art. The specific embodiments described
herein are provided by way of example only, and the invention is to be limited only by
the terms of the appended claims, along with the full scope "of equivalents to which
such claims are entitled.
WE CLAIM:
1. A non-dispersible, high drug load, solid oral pharmaceutical dosage form
comprising Deferasirox or its pharmaceutically acceptable salts, esters,
solvates, polymorphs, enantiomers or mixtures thereof wherein:
a) the dosage form comprises about 60% to about 85% (w/w) Deferasirox with
respect to total weight of the pharmaceutical dosage form;
b) the dosage form exhibits in vitro dissolution rate similar to JADENU® oral
tablets when the dosage form is placed in a dissolution vessel filled with
900 ml of Phosphate Buffer, pH 6.8 having 0.5% Tween 20 maintained at
37±0.5°C and stirred at a paddle speed of 75 rpm using a USP Type II
(paddle) apparatus.
c) at least 90% of Deferasirox present in the pharmaceutical dosage form has
a particle size less than about 50 |im
2. A non-dispersible, high drug load, solid oral pharmaceutical dosage form
comprising Deferasirox or its pharmaceutical ly acceptable salts, esters,
solvates, polymorphs, enantiomers or mixtures thereof wherein:
a) the dosage form comprises about 60% to about 85% (w/w) Deferasirox with
respect to total weight of the pharmaceutical dosage form;
b) the dosage form exhibits a disintegration time of about 2 to about 10 minutes
when measured by a standard USP disintegration test; and
d) Not less than 85% by weight of Deferasirox is released within 20 minutes
after the dosage form is placed in a dissolution vessel filled with 900 ml of
Phosphate Buffer, pH 6.8 having 0.5% Tween 20 maintained at 37±-0.5°C
and stirred at a paddle speed of 75 rpm using a USP Type II (paddle)
apparatus.
3. A non-dispersible, high drug load, solid oral pharmaceutical dosage form
comprising Deferasirox or its pharmaceutical ly acceptable salts, esters,
solvates, polymorphs, enantiomers or mixtures thereof wherein:
a) the dosage form comprises about 60% to about 85% (w/w) Deferasirox with
respect to total weight of the pharmaceutical dosage form; and
b) the dosage form exhibits a hardness of about 5 to about 20 kilopascals.
4. The pharmaceutical dosage form of claims 1-3, wherein the dosage form
comprises about 66% to about 85% of Deferasirox by weight with respect to
total weight of the pharmaceutical dosage form.
5. The pharmaceutical dosage form of claims 1-4, wherein the dosage form is
substantially free of other polymorphic forms.
6. The pharmaceutical dosage form of claims 1-5, wherein the dosage form is
prepared by dry blending or direct compression or granulation process.
7. The pharmaceutical dosage form of claim 1-5, wherein the dosage form
comprises pharmaceutically acceptable excipient selected from at least one of
diluent, binder, disintegrant, surfactant, lubricant, and glidant.
8. The pharmaceutical dosage form of claims 1-7, wherein Deferasirox or its
pharmaceutical^ acceptable salts, esters, solvates, polymorphs, enantiomers or
mixtures thereof is present in an amount ranging from about 50 to about 800
mg.
9. The pharmaceutical dosage form of claims 1-8, wherein Deferasirox or its
pharmaceutical ly acceptable salts, esters, solvates, polymorphs, enantiomers or
mixtures thereof has a particle size D90 less than about 100 (am.
10. A process for the preparation of a non-dispersible, solid oral pharmaceutical
dosage form comprising about 60% to about 85% (w/w) Deferasirox with
respect to total weight of the pharmaceutical dosage form, wherein the process
comprises:
(a) blending a mixture of Deferasirox and at least one' pharmaceutically
acceptable excipient;
(b) preparing binder solution by dissolving binder in water;
(c) granulating the blend of step (a) with binder solution of step (b);
(d) drying the wet granules to obtain dried granules;
(e) optionally milling the dried granules, followed by adding at least one
lubricant and optionally other pharmaceutically acceptable excipients to the
dried milled granules; and
(f) compressing the lubricated granules to form tablets.
(g) optionally coating the tablets of step (f).