Pharmaceutical Composition
FIELD OF INVENTION:
The present invention relates to a pharmaceutical composition comprising an iron
chelating agent, and more particularly, relates to a pharmaceutical composition
comprising deferasirox or a pharmaceutically acceptable salt thereof, a process for
preparing such pharmaceutical composition, and its use in the treatment of chronic iron
overload.
BACKGROUND AND PRIOR ART:
One of the major obstacles to the development of highly potent pharmaceutical
formulations is the poor water solubility of many drugs. Approximately 40% of potential
drugs identified by pharmaceutical companies are poorly soluble in water, which greatly
hinders their clinical use. Low water solubility limits the bioavailability and absorption of
these agents.
Deferasirox has the chemical name 4-[3, 5-bis (2-hydroxyphenyl) - [1, 2, 4] triazol-l-yl]
enzoic acid, and is reported to have the following chemical structure.
Deferasirox is an orally active iron chelator, and has been approved for the treatment of
iron overload in transfusion dependent anemias (transfusion hemosiderosis), in particular
thalassemia major, thalassemia intermediate and in sickle cell disease to reduce ironrelated
morbidity and mortality, in patients having an age of two years and older.
Chronic iron overload is a result of regular blood transfusions used in the treatment of
several conditions including -thalassemia, sickle cell disease and myelodysplasia
syndromes.
Each unit of blood contains iron and as the human body has no physiological mechanism
to actively excrete excess iron, repeated blood transfusions result in excessive
accumulation of iron. This excess of iron deposited in body tissues can cause severe
damage to organs such as liver, heart, endocrine organs. This may lead to many
complications including cardiomyopathy, liver cirrhosis, diabetes mellitus and reduced
life expectancy.
Deferasirox mobilizes tissue iron by forming soluble stable complexes that are then
excreted in the feces. It is a tridentate iron chelator requiring two molecules of the drug to
form a stable complex. Iron is chelated both from the reticuloendothelial cells (RE cells)
as well as various parenchymal tissues. The chelated iron is cleared by the liver and
excreted through the bile. It also has the ability to prevent the myocardial cell iron uptake
by removing iron directly from myocardial cells.
Deferasirox is highly water-insoluble and is highly lipid-soluble, and is also observed to
possess good permeability. According to the Bio-pharmaceutics Classification System
(BCS), it has been classified as a Class II drug, implying that it is a poorly soluble, and a
highly permeable drug. Though deferasirox is highly water-insoluble, whatever limited
solubility it has, that too exhibits a high pH-dependent solubility. Though it is practically
insoluble in lower H, even at a pH of 6.8, it still remains insoluble, until the buffer
strength is altered to get optimal dissolution profile.
Deferasirox being practically insoluble in aqueous media exhibits a generally poor
dissolution profile and hence consequently poor bioavailability.
Several strategies and formulations have been employed to overcome these limitations of
solubility and poor bioavailability. Although existing strategies such as complexing drugs
with cyclodextrins, conjugation to dendrimers, salt formation of ionizable drugs and the
use of co-solvents have been shown to improve drug solubility, solubilization methods
that can improve the absorption of the drug are still highly desirable.
WO 2004035026 discloses a dispersible tablet of deferasirox wherein the active
ingredient is present in an amount of from 5% to 40% by weight based on total weight of
the tablet.
WO 2005097062 discloses a dispersible tablet of deferasirox wherein the active
ingredient is present in an amount of from 42% to 65% by weight based on total weight
of the tablet.
WO 2007045445 discloses a dispersible tablet of deferasirox or a pharmaceutically
acceptable salt thereof present in an amount of from 42% to 65% by weight based on
total weight of the tablet and at least one pharmaceutically acceptable excipient suitable
for the preparation of dispersible tablets and to process for making said dispersible tablet.
WO 2009067557 discloses a process of preparing deferasirox formulations having
sufficiently high dissolution rate and good bioavailability wherein said process comprises
co- milling deferasirox with at least two pharmaceutically acceptable excipients in the
absence of any solvent.
WO 2010035282 discloses oral pharmaceutical composition comprising deferasirox in
the form of a dispersible tablet wherein the active ingredient has a mean particle size less
than about and is present in an amount greater than 66% by weight based on total
weight of the tablet.
Deferasirox is commercially available as dispersible tablet (EXJADE ) for oral
administration. EXJADE is supplied as a dispersible tablet containing 125 g, 250 mg
and 500 mg of deferasirox per tablet. This tablet is dispersed in a glass of water or any
other suitable drink, and this resulting suspension is then administered to the patient.
Deferasirox is administered as a once daily oral iron chelator, which is prescribed as a
dispersible tablet, i.e., a tablet which needs to be dispersed in an aqueous medium prior to
administration.
Deferasirox is typically administered at an initial dose of about 20 mg/kg body weight,
and the dose is adjusted up to a maximum of 30 mg kg body weight.
Further, the recommended dosage of deferasirox is on the higher side in order to have a
clinical benefit. Due to its high dosage, the overall tablet weight and its volume including
its dimension makes it inconvenient to administer, in order to provide a
pharmacologically active daily dosage amount of deferasirox.
Hence, there is a need for an oral dosage form having a high drug content which would
be convenient for patient administration, which would exhibit acceptable dissolution and
absorption which leads to better bioavailability.
OBJECT OF THE INVENTION:
The object of the present invention is to provide a pharmaceutical composition
comprising nanosized deferasirox having improved surface area and solubility.
Another object of the present invention is to provide a process for preparing the
pharmaceutical composition comprising nanosized deferasirox.
Yet another object of the present invention is to provide a method for treatment of
chronic iron overload which comprises administering a pharmaceutical composition
comprising nanosized deferasirox.
SUMMARY OF THE INVENTION:
According to one aspect of the present invention there is provided a composition
comprising deferasirox in the form of particles, wherein substantially the particles have
an average particle size of less than or equal to about 2000nm.
According to another aspect of the present invention there is provided a pharmaceutical
composition comprising deferasirox and at least one excipient.
According to another aspect of the present invention there is provided a pharmaceutical
composition comprising deferasirox and a pharmaceutically acceptable carrier.
According to another aspect of the present invention there is provided a process for
preparing a pharmaceutical composition, which process comprising the steps of:
homogenizing deferasirox and at least one excipient to produce a homogenized
dispersion of the deferasirox in the excipient; and milling said homogenized dispersion to
produce a slurry of particles having an average particle size of less than or equal to about
2000nm.
According to another aspect of the present invention there is provided the use of a
composition according to present invention in the manufacture of a medicament for
treating chronic iron overload.
According to another aspect of the present invention there is provided a method of
treating chronic iron overload comprising administering a therapeutically effective
amount of a composition having deferasirox according to the present invention to a
patient in need thereof.
According to another aspect of the present invention there is provided a method of
treating chronic iron overload comprising administering a therapeutically effective
amount of deferasirox according to the present invention to a patient in need thereof.
According to one aspect of the present invention there is provided a pharmaceutical
composition comprising deferasirox or pharmaceutically acceptable salt, solvate,
derivatives, hydrate, enantiomer, polymorph, complex, or mixtures thereof.
According to another aspect of the present invention there is provided a pharmaceutical
composition comprising deferasirox or pharmaceutically acceptable salt, solvate,
derivatives, hydrate, enantiomer, polymorph, complex or mixtures thereof wherein the
deferasirox is in the nanosize range.
According to yet another aspect of the present invention there is provided a process for
preparing a pharmaceutical composition comprising deferasirox or pharmaceutically
acceptable salt, solvate, derivatives, hydrate, enantiomer, polymorph, complex or
mixtures thereof wherein the deferasirox is in the nanosize range.
According to a further aspect of the present invention there is provided a method of
treatment of chronic iron overload using a pharmaceutical composition comprising
deferasirox or pharmaceutically acceptable salt, solvate, derivatives, hydrate, enantiomer,
polymorph, complex or mixtures thereof wherein deferasirox is in the nanosize range.
DETAILED DESCRIPTION OF THE INVENTION:
In iron chelation therapy, a chelating drug binds with free or "labile" iron in the blood
and organs, which allows for removal of excess iron from the body. Thus if more of
deferasirox is available for chelation, there will be better removal of excess iron from the
body.
Also, where multiple transfusions are repeatedly needed and phlebotomy is not possible,
the chelation therapy provides a means of controlling the iron overload. The
bioavailability (the percentage of the drug absorbed compared to its initial dosage) is
limited by insolubility. Dissolution rate is a function of the surface area of the particles
and solubility. Dissolution rate is a direct function of total surface area for a dispersed
phase.
The recommended dosage of deferasirox is on the higher side, i.e., an initial dose of
about 20mg/kg body weight, and this dose is adjusted up to a maximum of 30mg/kg body
weight. Further, deferasirox has been classified as a Class II drug which exhibits poor
solubility.
Therefore, formulating a suitable formulation of deferasirox with desirable advantages
such as, easy to manufacture as well as which possess advantages such as patient
compliance is a challenge.
The inventors of the present invention have found that, the solubility properties of
deferasirox were improved by using nanosized deferasirox and thus leading to better
bioavailability of the drug.
Nanonization of hydrophobic or poorly water-soluble drugs generally involves the
production of drug nanocrystals through either chemical precipitation (bottom-up
technology) or disintegration (top-down technology). Different methods may be utilized
to reduce the particle size of the hydrophobic or poorly water soluble drugs. [Huabing
Chen et al, discusses the various methods to develop nanoformulations in "Nanonization
strategies for poorly water-soluble drugs," Drug Discovery Today, Volume 00, Number
00, March 2010].
The term "nanosizing" as used herein refers to the reduction of deferasirox particle size to
the sub-micron range. By submicron range, this suitably means having an average
particle size of less than or equal to about 2000nm.
Nanosizing leads to increase in the exposure of surface area of deferasirox particles
leading to an increase in the rate of dissolution.
The present invention thus provides a pharmaceutical composition comprising
deferasirox wherein deferasirox is in the nanosize range.
The term "nanosize" as used herein refers to deferasirox particles having an average
particle size of less than or equal to about 2000nm, preferably less than or equal to about
lOOOnm. The average particle size may, for example, be measured using laser based
particle size analyzer.
Preferably, substantially all particles have a particle size of less than or equal to about
2000 nm, preferably less than or equal to about 1000 nm.
The term "particles" as used herein refers to individual particle of deferasirox, or particles
of deferasirox or deferasirox granules or deferasirox compositions and/or mixtures
thereof.
The average particle size of the deferasirox is preferably above 1 nanometre.
The term "Deferasirox" is used in broad sense to include not only "Deferasirox" per se
but also their pharmaceutically acceptable salts, pharmaceutically acceptable solvates,
pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers,
pharmaceutically acceptable esters, pharmaceutically acceptable derivatives,
pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs,
pharmaceutically acceptable complexes etc.
The nanoparticles of the present invention can be obtained by any of the process such as
but not limited to milling, precipitation and homogenization.
According to one embodiment of the present invention, the process of milling comprises
dispersing deferasirox particles in a liquid dispersion medium in which deferasirox is
poorly soluble, followed by applying mechanical means in the presence of grinding
media like milling pearls to reduce the particle size of deferasirox to the desired average
particle size.
According to another embodiment of the present invention, the process of precipitation
involves the formation of crystalline or semi-crystalline deferasirox nanoparticles by
nucleation and the growth of drug crystals. In a typical procedure, drug molecules are
first dissolved in an appropriate organic solvent such as acetone, tetrahydrofuran or Nmethyl-
2-pyrrolidone at a super saturation concentration to allow for the nucleation of
drug seeds. Drug nanocrystals are then formed by adding the organic mixture to an
antisolvent like water in the presence of stabilizers such as Tween 80, Poloxamer 188 or
lecithin. The choice of solvents and stabilizers and the mixing process are key factors to
control the size and stability of the drug nanocrystals.
According to one another embodiment of the present invention, the process of
homogenization involves passing a suspension of crystalline deferasirox and stabilizers
through the narrow gap of a homogenizer at high pressure (for eg- 500-2000 bar). The
pressure creates powerful disruptive forces such as cavitation, collision and shearing,
which disintegrate coarse particles to nanoparticles.
According to one more embodiment of the present invention, the process of spray-freeze
drying involves the atomization of an aqueous deferasiorx solution into a spray chamber
filled with a cryogenic liquid (liquid nitrogen) or halocarbon refrigerant such as
chlorofluorocarbon or fluorocarbon. The water is removed by sublimation after the liquid
droplets solidify.
According to a still another embodiment of the present invention, the process of
supercritical fluid technology involves controlled crystallization of deferasiorx from
dispersion in supercritical fluids, carbon dioxide.
According to another embodiment of the present invention, the process of double
emulsion/solvent evaporation technique involves preparation of oil/water (o/w) emulsions
with subsequent removal of the organic phase through evaporation. The emulsions are
prepared by emulsifying an organic phase containing deferasirox, polymer and organic
solvent in an aqueous solution containing emulsifier. The organic solvent diffuses out of
the polymer phase and into the aqueous phase, and is then evaporated, forming
deferasirox-loaded polymeric nanoparticles.
According to a further embodiment of the present invention, the process of PRINT
(Particle replication in non-wetting templates) involves utilization of a low surface
energy fluoropolymeric mold that enables high-resolution imprint lithography, to
fabricate a variety of organic particles. PRINT can precisely manipulate particle size of
deferasirox ranging from 20 n to more than 100 .
According to one further embodiment of the present invention, the process of thermal
condensation involves use of capillary aerosol generator (CAG) to produce high
concentration condensation submicron to micron sized aerosols from a deferasirox
solution.
According to still further embodiment of the present invention, the process of
ultrasonication may be used for nano-sizing deferasirox. The process of ultrasonication
involves application of ultrasound during particle synthesis or precipitation, which leads
to smaller particles of deferasirox and increased size uniformity.
According to another embodiment of the present invention, the nano-sized deferasirox
may be prepared by spray drying. The process of spray drying involves supplying a feed
solution at room temperature and pumping it through the nozzle where it is atomized by a
nozzle gas. The atomized solution is then dried by preheated drying gas in a special
chamber to remove moisture from the system, thus forming dry particles of deferasirox.
According to a preferred embodiment of the present invention, the nanomilled
deferasirox may be obtained by nanomilling of deferasirox with at least one surface
stabilizer, at least one viscosity building agent and at least one polymer.
The present invention thus provides a pharmaceutical composition comprising nanosized
deferasirox particles, prefereably in the form of granules. The granules may comprise at
least one excipient. The excipient may comprise at least one of the following, but not
limited to, at least one surface stabilizers, at least one viscosity building agent and at least
one polymer and optionally other pharmaceutically acceptable carriers.
Surface stabilizer, according to the present inventions, means surfactants that are capable
of stabilizing the increased surfaced charge of the nanomilled drug. Suitable amphoteric,
non-ionic, cationic or anionic surfactants may be included as surface stabilizers in the
pharmaceutical composition of the present invention.
According to the present invention, surfactants may comprise one or more, but not
limited to Polysorbates, Sodium dodecyl sulfate (sodium lauryl sulfate), Lauryl dimethyl
amine oxide, Docusate sodium, Cetyl trimethyl ammonium bromide (CTAB)
Polyethoxylated alcohols, Polyoxyethylene sorbitan, Octoxynol, N, Ndimethyldodecylamine-
N-oxide, Hexadecyltrimethylammonium bromide, Polyoxyl 10
lauryl ether, Brij, Bile salts (sodium deoxycholate, sodium cholate), Polyoxyl castor oil,
Nonylphenol ethoxylate, Cyclodextrins, Lecithin, Methylbenzethonium chloride.
Carboxylates, Sulphonates, Petroleum sulphonates, alkylbenzenesulphonates,
Naphthalenesulphonates, Olefin sulphonates, Alkyl sulphates, Sulphates, Sulphated
natural oils & fats, Sulphated esters, Sulphated alkanolamides, Alkylphenols, ethoxylated
& sulphated, Ethoxylated aliphatic .alcohol, polyoxyethylene surfactants, carboxylic
esters Polyethylene glycol esters, Anhydrosorbitol ester & it's ethoxylated derivatives,
Glycol esters of fatty acids, Carboxylic amides, Monoalkanolamine condensates,
Polyoxyethylene fatty acid amides, Quaternary ammonium salts, Amines with amide
linkages, Polyoxyethylene alkyl & alicyclic amines, ,,,tetrakis substituted
ethylenediamines 2- alkyl 1- hydroxyethyl 2-imidazolines, N -coco 3-aminopropionic
acid/ sodium salt, N-tallow 3 -iminodipropionate disodium salt, N-carboxymethyl n
dimethyl n-9 octadecenyl ammonium hydroxide, n-cocoamidethyl n-hydroxyethylglycine
sodium salt etc.
Viscosity builders means, excipients that are capable of stabilizing the nanoparticles by
increasing the viscosity of the composition and thus preventing physical interaction of
nanoparticles under the operating conditions employed.
According to the present invention, viscosity builders, may comprise one or more, but not
limited to derivatives of sugars, such as lactose, saccharose, hydrolyzed starch
(maltodextrin) etc or mixtures thereof.
Polymers or polymers blends, according to the present invention, may comprise one or
more hydrophilic polymers, but not limited to cellulose derivates like
hydroxypropylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose,
methylcellulose polymers hydroxyethylcellulose, sodium carboxymethylcellulose,
carboxymethylene and carboxymethyl hydroxyethylcellulose; acrylics like acrylic acid,
acrylamide, and maleic anhydride polymers, acacia, gum tragacanth, locust bean gum,
guar gum, or karaya gum, agar, pectin, carrageenan, gelatin, casein, zein and alginates,
carboxypolymethylene, bentonite, magnesium aluminum silicate, polysaccharides,
modified starch derivatives and copolymers..
The deferasirox composition having nanosized particles of the invention can be
formulated into any suitable dosage form, including but not limited to liquid dispersions,
gels, aerosols, ointments, creams, controlled release formulations, lyophilized
formulations, tablets, capsules, delayed release formulations, extended release
formulations, pulsatile release formulations, and mixed immediate release and controlled
release formulations along with pharmaceutically acceptable carriers.
Solid oral dosage forms for administration include, but are not limited to, capsules,
tablets, pills, powders, and granules. In such solid dosage forms, the active agent is
admixed with at least one of the following carriers: (a) one or more inert excipients (or
carriers) (b) fillers or extenders (c) binders (d) humectants (e) disintegrating agents (f)
solution retarders (g) absorption accelerators (h) wetting agents (i) adsorbents and (j)
lubricants. For capsules, tablets, and pills, the dosage forms may also comprise buffering
agents.
The granules comprising nanosized deferasirox, according to the present invention, may
either be encapsulated in capsules or be compressed to form tablets or may be provided
as sachets or be provided as powders for reconstitution.
The solid dosage form, according to the present invention, may also optionally be coated.
More preferably, the formulation may be seal coated and then film coated.
According to an embodiment of the present invention, pharmaceutical composition may
be film coated with but not limited to Ready colour mix systems (such as Opadry colour
mix systems) and Kollicoat ® Protect.
According to the present invention, the seal coat comprises film forming polymeric
materials, such as but not limited to, hydroxypropylmethylcellulose,
hydroxypropylcellulose, polyvinylpyrrolidone, methylcellulose, carboxymethylcellulose,
hypromellose, acacia, gelatin to increase adherence and coherence of the seal coat.
n one aspect of the present invention there is provided a pharmaceutical composition
comprising deferasirox in the form of dispersible tablet, wherein deferasirox is in the
nanosize range.
In another aspect of the present invention there is provided a pharmaceutical composition
comprising deferasirox in the form of dispersible tablet, wherein deferasirox is in the
nanosize range of less than or equal to about 2000nm, preferably less than or equal to
about lOOOnm.
The term "dispersible tablet" as used herein refers to a tablet which normally disperses in
aqueous phase, e.g. in water, with or without external agitation.
Suitable carriers may be used for formulating the various dosage forms according to the
present invention.
According to the present invention, pharmaceutically acceptable opacifier for use in the
pharmaceutical composition of the present invention may comprise one or more, but is
not limited to titanium dioxide.
According to the present invention, pharmaceutically acceptable diluents or fillers for
use in the pharmaceutical composition of the present invention may comprise one or
more, but not limited to lactose (for example, spray-dried lactose, a-lactose, -lactose)
lactose available under the trade mark Tablettose, various grades of lactose available
under the trade mark Pharmatose or other commercially available forms of lactose,
lactitol, saccharose, sorbitol, mannitol, dextrates, dextrins, dextrose, maltodextrin,
croscarmellose sodium, microcrystalline cellulose (for example, microcrystalline
cellulose available under the trade mark Avicel), hydroxypropylcellulose, Lhydroxypropylcellulose
(low substituted), hydroxypropyl methylcellulose (HPMC),
methylcellulose polymers (such as, for example, Methocel A, Methocel A4C, Methocel
A15C, Methocel A4M), hydroxyethylcellulose, sodium carboxymethylcellulose,
carboxymethylene, carboxymethyl hydroxyethylcellulose and other cellulose derivatives,
starches or modified starches (including potato starch, corn starch, maize starch and rice
starch) and mixtures thereof.
According to the present invention, glidants, anti-adherents and lubricants may also be
incorporated in the pharmaceutical composition of the present invention, which may
comprise one or more, but not limited to stearic acid and pharmaceutically acceptable
salts or esters thereof (for example, magnesium stearate, calcium stearate, sodium stearyl
fumarate or other metallic stearate), talc, waxes (for example, microcrystalline waxes)
and glycerides, light mineral oil, PEG, silica acid or a derivative or salt thereof (for
example, silicates, silicon dioxide, colloidal silicon dioxide and polymers thereof,
crospovidone, magnesium aluminosilicate and/ or magnesium alumino metasilicate),
sucrose ester of fatty acids, hydrogenated vegetable oils (for example, hydrogenated
castor oil) , or mixtures thereof.
According to the present invention, suitable binders may also be present in the
pharmaceutical composition of the present invention, which may comprise one or more,
but not limited to polyvinyl pyrrolidone (also known as povidone), polyethylene
glycol(s), acacia, alginic acid, agar, calcium carragenan, cellulose derivatives such as
ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl
cellulose, sodium carboxymethylcellulose, dextrin, gelatin, gum arabic, guar gum,
tragacanth, sodium alginate, or mixtures thereof or any other suitable binder.
According to the present invention, suitable disintegrants may also be present in the
pharmaceutical composition of the present invention, which may comprise one or more,
but not limited to hydroxylpropyl cellulose (HPC), low density HPC,
carboxymethylcellulose (CMC), sodium CMC, calcium CMC, croscarmellose sodium;
starches exemplified under examples of fillers and also carboxymethyl starch,
hydroxylpropyl starch, modified starch; crystalline cellulose, sodium starch glycolate;
alginic acid or a salt thereof, such as sodium alginate or their equivalents and mixtures
thereof.
Further, the pharmaceutical composition according to the present invention may further
comprise at least one additional active ingredient such as but not limited to leukotriene,
probenecid, indomethacin, penicillin G, ritonavir, indinavir, saquinavir, furosemide,
methotrexate, sulfinpyrazone, interferon, ribavirin, viramidine, valopicitabine, aromatase
inhibitor, antiestrogen, anti-androgen, gonadorelin agonist, topoisomerase I inhibitor,
topoisomerase II inhibitor, microtubule active agent, alkylating agent, anti-neoplastic,
anti-metabolite, platin compound, anti-angiogenic compound, cyclooxygenase inhibitor,
bisphosphonate, heparanase inhibitor, telomerase inhibitor, protease inhibitor, matrix
metalloproteinase inhibitor, proteasome inhibitor, somatostatin receptor antagonist, anti¬
leukemic compound, ribonucleotide reductase inhibitor, S-adenosylmethionine
decarboxylase inhibitor; ACE inhibitor, antibiotics such as gentamicin, amikacin,
tobramycin, ciprofloxacin, levofloxacin, ceftazidime, cefepime, cefpirome, piperacillin,
ticarcillin, meropenem, imipenem, polymyxin B, colistin and aztreonam; cyclosporin A,
cyclosporin G, rapamycin.
There is also provided a process for preparing the pharmaceutical composition of the
present invention, which process comprises homogenizing deferasirox and at least one
excipient to produce a homogenized dispersion of the deferasirox in the excipient; and
milling said homogenized dispersion to produce a slurry of deferasirox particles having
an average particle size of less than or equal to about 2000 nm.
According to one embodiment the pharmaceutical composition of the present invention,
may be prepared by a process which comprises (a) preparing a dispersion of deferasirox
with Docusate sodium, HPMC, sodium lauryl sulphate and sucrose in purified water
under stirring conditions; (b) homogenizing the dispersion of step (a) and then
nanomilling the homogenized dispersion; (c) adsorbing the nanomilled drug by spraying
the nanomilled slurry on lactose monohydrate, microcrystalline cellulose and
crospovidone mixture in fluidized bed granulator; (d) drying and blending the granules
obtained in step (c). The granules may be lubricated and finally compressed into tablets.
The tablets obtained may be seal coated and then film coated.
The present invention further provides a method for treating chronic iron overload which
method comprises administering a therapeutically effective amount of a pharmaceutical
composition according to the present invention.
Furthermore, the present invention provides pharmaceutical compositions comprising
deferasirox for use in the treatment of chronic iron overload.
The following examples are for the purpose of illustration of the invention only and are
not intended in any way to limit the scope of the present invention.
Example 1
Sr. No. Ingredients Qty mg/tablet
Binder Solution
1. Deferasirox 500.00
2. Docusate Sodium IP 5.00
3. Hydroxypropylmethylcellulose 3cps IP 100.00
4. Sodium lauryl sulphate IP 14.00
5. Sucrose IP 150.00
6. Purified water IP q.s
Dry Mix
7. Lactose Monohydrate(200 mesh) IP 175.00
8. Microcrystalline Cellulose IP (Avicel PH 101) 152.00
9. Crospovidone IP 50.00
Lubrication
10. Crospovidone IP 36.00
11. Magnesium Stearate IP 6.00
Total 1188.00
Seal Coating
12. Hydroxypropylmethylcellulose 3cps IP 12.00
13. Isopropyl Alcohol IP q.s
14. Dichloromethane BP q.s
Total 1200.00
Film Coating
15. Opadry AMB White OY-B-28920 INH 25.00
16. Purified Water q.s.
Total 1225.00
Process:
1. Docusate sodium, HPMC, sodium lauryl sulphate and sucrose were solubalized in
water under stirring conditions.
2. Deferasirox was dispersed in the solution obtained in step (1).
3. Above dispersion was homogenized and then nanomilled .
4. Nanomilled drug slurry was adsorbed by spraying on lactose monohydrate,
microcrystalline cellulose and crospovidone mixture in a fluidized bed granulator.
5. Granules obtained were sized and lubricated.
6. Lubricated granules were finally compressed into tablets.
7. The tablets obtained were seal coated and then film coated.
Example 2
Sr. No. Ingredients Qty mg/tablet
Binder Solution
1. Deferasirox 500.00
2. Docusate Sodium IP 5.00
3. Hydroxypropylmethylcellulose 3cps IP 100.00
4. Sodium lauryl sulphate IP 14.00
5. Sucrose IP 150.00
6. Purified water IP q.s
Dry Mix
7. Lactose Monohydrate(200 mesh) IP 175.00
8. Microcrystalline Cellulose IP (Avicel PH 101) 152.00
9. Crospovidone IP 50.00
Lubrication
10. Crospovidone IP 36.00
11. Magnesium Stearate IP 6.00
Total 1188.00
Seal Coating
12. Hydroxypropylmethylcellulose 3cps IP 12.00
13. Isopropyl Alcohol IP q.s
14. Dichloromethane BP q.s
Total 1200.00
Film Coating
15. Kollicoat Protect 15.00
16. Talc IP 60.25
17. Titanium dioxide IP 3.75
18. Purified Water IP q.s.
19. Isopropyl Alcohol IP q.s.
Total 1225.00
Process:
1. Docusate sodium, HPMC, sodium lauryl sulphate and sucrose were solubalized in
water under stirring conditions;
2. Deferasirox was dispersed in the solution obtained in step (1);
3. Above dispersion was homogenized and then nanomiUed. 4. NanomiUed drug slurry
was adsorbed by spraying on lactose monohydrate, microcrystalline cellulose and
crospovidone mixture in a fluidized bed granulator;
5. Granules obtained were sized and lubricated;
6. Lubricated granules were finally compressed into tablets; and
7. The tablets obtained were seal coated and then film coated.
Example 3
Sr.No. Ingredients Qty mg/tablet
Binder Solution
1. Deferasirox 250.00
2. Docusate Sodium 5.00
3. Hydroxypropylmethylcellulose 15.00
4. Sodium lauryl sulphate 13.80
5. Sucrose 25.00
6. Purified water q.s.
Dry Mix
7. Lactose Monohydrate (200 mesh) 154.70
9. Crospovidone 50.00
Lubrication
10. Silicified Microcrystalline Cellulose 50.00
11. Crospovidone 40.00
12. Croscarmellose Sodium 20.00
13. Magnesium Stearate 1.50
14. Total 625.00
Process:
1. Docusate sodium, HPMC, sodium lauryl sulphate and sucrose were solubalized in
water under stirring conditions;
2. Deferasirox was dispersed in the solution obtained in step (1);
3. Above dispersion was homogenized and then nanomilled;
4. Nanomilled drug slurry was adsorbed by spraying on lactose monohydrate,
microcrystalline cellulose and crospovidone mixture in a fluidized bed granulator;
5. Granules obtained were sized and lubricated; and
6. Lubricated granules were finally compressed into tablets.
Example 4
Sr.No. Ingredients Qty nig/tablet
Binder Solution
1. Deferasirox 500.00
2. Docusate Sodium 10.00
3. Hydroxypropylmethylcellulose 30.00
4. Sodium lauryl sulphate 27.6
5. Sucrose 50.00
6. Purified water q.s
Dry Mix
7. Lactose Monohydrate (200 mesh) 309.40
9. Crospovidone 100.00
Lubrication
10. Silicified Microcrystalline Cellulose 100.00
11. Crospovidone 80.00
12. Croscarmellose Sodium 40.00
13. Magnesium Stearate 3.00
Total 1250.00
Process:
1. Docusate sodium, HPMC, sodium lauryl sulphate and sucrose were solubalized in
water under stirring conditions;
2. Deferasirox was dispersed in the solution obtained in step (1);
3. Above dispersion was homogenized and then nanomilled;
4. Nanomilled drug slurry was adsorbed by spraying on lactose monohydrate,
microcrystalline cellulose and crospovidone mixture in a fluidized bed granulator;
5. Granules obtained were sized and lubricated; and
6. Lubricated granules were finally compressed into tablets.
Example 5
Sr.No. Ingredients Qty mg/tablet
Binder Solution
1. Deferasirox 250.00
2. Docusate Sodium 5.00
3. Polyvinylpyrrolidone 15.00
4. Sodium lauryl sulphate 13.80
5. Sucrose 25.00
6. Purified water q.s.
Dry Mix
7. Lactose Monohydrate (200 mesh) 154.70
9. Crospovidone 50.00
Lubrication
10. Silicified Microcrystalline Cellulose 50.00
1 . Crospovidone 40.00
12. Croscarmellose Sodium 20.00
13. Magnesium Stearate 1.50
Total 625.00
Process:
1. Docusate sodium, PVP, sodium lauryl sulphate and sucrose were solubalized in water
under stirring conditions;
2. Deferasirox was dispersed in the solution obtained in step (1);
3. Above dispersion was homogenized and then nanomilled;
4. Nanomilled drug slurry was adsorbed by spraying on lactose monohydrate,
microcrystalline cellulose and crospovidone mixture in a fluidized bed granulator;
5. Granules obtained were sized and lubricated; and
6. Lubricated granules were finally compressed into tablets.
Example 6
Sr.No. Ingredients Qty mg/tablet
Binder Solution
1. Deferasirox 500.00
2. Docusate Sodium 10.00
3. Polyvinylpyrrolidone 30.00
4. Sodium lauryl sulphate 27.6
5. Sucrose 50.00
6. Purified water q.s
Dry Mix
7. Lactose Monohydrate (200 mesh) 309.40
9. Crospovidone 100.00
Lubrication
10. Silicified Microcrystalline Cellulose 100.00
11. Crospovidone 80.00
12. Croscarmellose Sodium 40.00
13. Magnesium Stearate 3.00
Total 1250.00
Process:
1. Docusate sodium, PVP, sodium lauryl sulphate and sucrose were solubalized in
purified water under stirring conditions;
2. Deferasirox was dispersed in the solution obtained in step (1);
3. Above dispersion was homogenized and then nanomilled;
4. Nanomilled drug slurry was adsorbed by spraying on lactose monohydrate,
microcrystalline cellulose and crospovidone mixture in a fluidized bed granulator;
5. Granules obtained were sized and lubricated; and
6. Lubricated granules were finally compressed into tablets.
It will be readily apparent to one skilled in the art that varying substitutions and
modifications may be made to the invention disclosed herein without departing from the
spirit of the invention. Thus, it should be understood that although the present invention
has been specifically disclosed by the preferred embodiments and optional features,
modification and variation of the concepts herein disclosed may be resorted to by those
skilled in the art, and such modifications and variations are considered to be falling
within the scope of the invention.
It is to be understood that the phraseology and terminology used herein is for the purpose
of description and should not be regarded as limiting. The use of "including,"
"comprising," or "having" and variations thereof herein is meant to encompass the items
listed thereafter and equivalents thereof as well as additional items.
It must be noted that, as used in this specification and the appended claims, the singular
forms "a," "an" and "the" include plural references unless the context clearly dictates
otherwise. Thus, for example, reference to "a propellant" includes a single propellant as
well as two or more different propellants; reference to a "cosolvent" refers to a single
cosolvent or to combinations of two or more cosolvents, and the like.
CLAIMS:
1. A pharmaceutical composition comprising deferasirox in the form of particles,
wherein the particles have an average particle size of less than or equal to about 2000 nm.
2. A pharmaceutical composition according to claim 1, wherein the particles have an
average particle size of less than or equal to about 1000 nm.
3. A pharmaceutical composition according to claim 1 or 2, comprising at least one
excipient.
4 . A pharmaceutical composition according to claim 1, 2 or 3, wherein the excipient
comprises at least one surface stabilizer.
5. A pharmaceutical composition according to any one of claims 1, 2 or 3, wherein
the excipient comprises at least one viscosity building agent.
6. A pharmaceutical composition according to any one of claims 1, 2 or 3, wherein
the excipient comprises at least one polymer.
7. A pharmaceutical composition according to any one of claims 4, wherein the
surface stabilizer is a surfactant.
8. A pharmaceutical composition according to claim 7, wherein the surfactant is an
amphoteric, non-ionic, cationic or anionic or combinations thereof.
9. A pharmaceutical composition according to claim 7 or 8, wherein the surfactant
comprises one or more of polysorbates; sodium dodecyl sulfate (sodium lauryl sulfate);
lauryl dimethyl amine oxide; docusate sodium; cetyl trimethyl ammonium bromide
(CTAB); a polyethoxylated alcohol; a polyoxyethylene sorbitan; Octoxynol; N,Ndimethyldodecylamine-
N-oxide; hexadecyltrimethylammonium bromide, polyoxyl 10
lauryl ether, brij, a bile salt, such as sodium deoxycholate or sodium cholate; a polyoxyl
castor oil; nonylphenol ethoxylate; a Cyclodextrin; lecithin; methylbenzethonium
chloride; a carboxylate; a sulphonate; a petroleum sulphonate; an
alkylbenzenesulphonates; a naphthalenesulphonate; and olefin sulphonate; a sulphate
surfactant; an alkyl sulphate; a sulphated natural oil or fat; a sulphated ester; a sulphated
alkanolamide; an alkylphenol, optionally ethoxylated and sulphated; an ethoxylated
aliphatic alcohol; polyoxyethylene; a carboxylic ester; a polyethylene glycol esters; an
anhydrosorbitol ester or an ethoxylated derivative therof; a glycol ester of a fatty acid; a
carboxylic amide; a monoalkanolamine condensate; a polyoxyethylene fatty acid amide;
a quaternary ammonium salt; an amine with amide linkages; a polyoxyethylene alkyl
amine; a polyoxyethylene alicyclic amine; a ,,,tetrakis substituted
ethylenediamine; a 2-alkyl-l-hydroxyethyl-2-imidazoline; N-coco-3-aminopropionic acid
or a sodium salt thereof; N-tallow-3-iminodipropionate disodium salt; N-carboxymethyln-
dimethyl-n-9 octadecenyl ammonium hydroxide; n-cocoamidethyl-nhydroxyethylglycine
sodium salt; or mixtures thereof.
10. A pharmaceutical composition according to claim 7, 8 or 9, wherein the surfactant
is docusate sodium and/or sodium lauryl sulphate.
11. A pharmaceutical composition according any one of claims 5, wherein the
viscosity building agent is lactose; sucrose; saccharose; a hydrolyzed starch, such as
maltodextrin; or a mixture thereof.
12. A pharmaceutical composition according to claim 11, wherein the viscosity
building agent is sucrose.
13. A pharmaceutical composition according any one of claims 6, wherein the
polymer is hydroxypropylcellulose; hydroxymethylcellulose;
hydroxypropylmethylcellulose; a methylcellulose polymer; hydroxyethylcellulose;
sodium carboxymethylcellulose; carboxymethylene hydroxyethylcellulose and/or
carboxymethyl hydroxyethylcellulose; an acrylic polymer, such as acrylic acid,
acrylamide, and maleic anhydride polymers and copolymers; or a mixture thereof.
14. A pharmaceutical composition according to claim 13, wherein the polymer is
hydroxypropylmethylcellulose.
15. A pharmaceutical composition according to any one of the preceding claims,
wherein substantially all the particles have an average particle size above 1 n .
16. A pharmaceutical composition comprising a composition according to any one of
claims 1to 15 and a pharmaceutically acceptable carrier.
17. A pharmaceutical composition according to claim 16, wherein the particles are
adsorbed on the surface of the carrier.
18. A pharmaceutical composition according to claim 16 or 17, wherein the carrier
comprises: one or more diluents or fillers; one or more binders; one or more lubricants;
one or more glidants; one or more disintegrants; one or more preservatives; one or more
humectants; one or more solution retarders; one or more absorption accelerators; one or
more wetting agents; one or more adsorbents; one or more buffering agents; or a mixture
thereof.
19. A pharmaceutical composition according to any one of claims 16, 17 or 18, which
is for oral administration.
20. A pharmaceutical composition according to any one of the claims 16 to 19, which
is a solid oral dosage form.
21. A pharmaceutical composition according to claim 19 or 20, which is in a form of
a tablet.
22. A pharmaceutical composition according to claim 21, wherein the tablet is a
dispersible tablet.
23. A pharmaceutical composition according to any one of claims 1 to 22 for use in
treating chronic iron overload.
24. A process for preparing a pharmaceutical composition, which process comprises
the steps of:
(1) homogenizing deferasirox and at least one excipient to produce a
homogenized dispersion of the deferasirox; and
(2) milling said homogenized dispersion to produce a slurry of deferasirox
particles having an average particle size of less than or equal to about 2000 nm.
25. A process according to claim 24, further comprising adsorbing the milled slurry
on a pharmaceutically acceptable carrier to form granules.
26. A process according to claim 25, wherein the granules are compressed to form
tablets.
27. A process according to claim 24, further comprises forming the slurring into a
liquid dispersions, gels or aerosols.
28. A process according to any one of claims 24 to 27, wherein the excipient is as
defined in any one of claims 4 to 1 .
29. The use of a pharmaceutical composition according to any one of claims 1 to 22
in the manufacture of a medicament for treating chronic iron overload.
30. A method of treating chronic iron overload comprising administering a
therapeutically effective amount of a pharmaceutical composition according to any one of
claims 1to 22 to a patient in need thereof.
31. A pharmaceutical composition according to any one of claims 1 to 22 further
comprising one or more active(s) selected from leukotriene, probenecid, indomethacin,
penicillin G, ritonavir, indinavir, saquinavir, furosemide, methotrexate, sulfinpyrazone,
interferon, ribavirin, viramidine, valopicitabine, aromatase inhibitor, antiestrogen, antiandrogen,
gonadorelin agonist, topoisomerase 1 inhibitor, topoisomerase inhibitor,
microtubule active agent, alkylating agent, anti-neoplastic, anti-metabolite, platin
compound, anti-angiogenic compound, cyclooxygenase inhibitor, bisphosphonate,
heparanase inhibitor, telomerase inhibitor, protease inhibitor, matrix metal loproteinase
inhibitor, proteasome inhibitor, somatostatin receptor antagonist, anti-leukemic
compound, ribonucleotide reductase inhibitor, S-adenosylmethionine decarboxylase
inhibitor; ACE inhibitor, antibiotics such as gentamicin, amikacin, tobramycin,
ciprofloxacin, levofloxacin, ceftazidime, cefepime, cefpirome, piperacillin, ticarcillin,
meropenem, imipenem, polymyxin B, colistin and aztreonam; cyclosporin A, cyclosporin
G, rapamycin or their pharmaceutically acceptable salts, solvates, tautomers, derivatives,
enantiomers, isomers, hydrates, prodrugs or polymorphs thereof.
32. A pharmaceutical composition substantially as herein described with reference to
the examples.