U.S. patent application number 15/073708 was filed with the patent office on 2016-07-14 for 3'-[(2z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4h-pyrazol-4-y- lidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid bis-(monoethanolamine).
This patent application is currently assigned to NOVARTIS AG. The applicant listed for this patent is NOVARTIS AG. Invention is credited to Shivakumar Kapsi, Francis X. Muller.
Application Number | 20160199353 15/073708 |
Document ID | / |
Family ID | 39343460 |
Filed Date | 2016-07-14 |
United States Patent
Application |
20160199353 |
Kind Code |
A1 |
Kapsi; Shivakumar ; et
al. |
July 14, 2016 |
3'-[(2Z)-[1-(3,4-DIMETHYLPHENYL)-1,5-DIHYDRO-3-METHYL-5-OXO-4H-PYRAZOL-4-Y-
LIDENE]HYDRAZINO]-2'-HYDROXY-[1,1'-BIPHENYL]-3-CARBOXYLIC ACID
BIS-(MONOETHANOLAMINE)
Abstract
Disclosed are novel pharmaceutical compositions containing
3'-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4--
ylidene]hydrazinol-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid
bis-(monoethanolamine) (eltrombopag olamine) and processes for
preparing the same.
Inventors: |
Kapsi; Shivakumar; (Jurong
Island, SG) ; Muller; Francis X.; (Collegeville,
PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
NOVARTIS AG |
Basel |
|
CH |
|
|
Assignee: |
NOVARTIS AG
Basel
CH
|
Family ID: |
39343460 |
Appl. No.: |
15/073708 |
Filed: |
March 18, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14851497 |
Sep 11, 2015 |
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15073708 |
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14450569 |
Aug 4, 2014 |
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14851497 |
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13272367 |
Oct 13, 2011 |
8828430 |
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14450569 |
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12607284 |
Oct 28, 2009 |
8071129 |
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13272367 |
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PCT/US2007/074918 |
Aug 1, 2007 |
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12607284 |
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60915761 |
May 3, 2007 |
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60947731 |
Jul 3, 2007 |
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Current U.S.
Class: |
424/465 |
Current CPC
Class: |
A61K 9/2077 20130101;
A61P 7/04 20180101; A61P 7/00 20180101; A61K 47/26 20130101; A61P
7/06 20180101; A61K 9/19 20130101; Y10T 428/2982 20150115; A61K
31/4152 20130101; A61K 47/34 20130101; A61P 43/00 20180101; C07D
231/46 20130101; A61P 7/02 20180101; A61K 9/20 20130101; A61K
9/2095 20130101 |
International
Class: |
A61K 31/4152 20060101
A61K031/4152; A61K 9/20 20060101 A61K009/20 |
Claims
1. The pharmaceutical tablet comprising: a) a drug, which is
3'-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4--
ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid
bis-(monoethanolamine); wherein, b) 90% of the drug particles have
a particle size greater than 10 micron but less than 90 micron.
2. A method of treating thrombocytopenia in a human in need thereof
which comprises administering to such human a therapeutically
effective amount of a pharmaceutical tablet according to claim
1.
3. A process for preparing pharmaceutical tablets containing the
compound of claim 1, which process comprises the steps of; a)
admixing: the compound
3'-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-p-
yrazol-4-ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic
acid bis-(monoethanolamine), wherein 90% of the compound particles
have a particle size of greater than 10 micron but less than 90
micron; and one or more excipients; to form a mixture; and b)
compressing the mixture into tablets.
4. The pharmaceutical tablet comprising: a) a drug, which is
3'-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4--
ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid
bis-(monoethanolamine); wherein, b) 90% of the drug particles have
a particle size greater than 20 micron but less than 50 micron.
5. A method of treating thrombocytopenia in a human in need thereof
which comprises administering to such human a therapeutically
effective amount of a pharmaceutical tablet according to claim
4.
6. A process for preparing pharmaceutical tablets containing the
compound of claim 4, which process comprises the steps of; a)
admixing: the compound
3'-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-p-
yrazol-4-ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic
acid bis-(monoethanolamine), wherein 90% of the drug particles have
a particle size greater than 20 micron but less than 50 micron; and
one or more excipients; to form a mixture; and b) compressing the
mixture into tablets.
7. The pharmaceutical tablet comprising: a) a drug, which is
3'-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4--
ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid
bis-(monoethanolamine); wherein, b) 50% of the drug particles have
a particle size greater than 5 micron but less than 50 micron.
8. A method of treating thrombocytopenia in a human in need thereof
which comprises administering to such human a therapeutically
effective amount of a pharmaceutical tablet according to claim
7.
9. A process for preparing pharmaceutical tablets containing the
compound of claim 7, which process comprises the steps of; a)
admixing: the compound
3'-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-p-
yrazol-4-ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic
acid bis-(monoethanolamine), wherein 50% of the drug particles have
a particle size greater than 5 micron but less than 50 micron; and
one or more excipients; to form a mixture; and b) compressing the
mixture into tablets.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to granules and solid oral
pharmaceutical dosage forms, suitably tablets, suitably capsules,
comprising
3'-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4--
ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid
bis-(monoethanolamine) represented by the following formula (I) and
hereinafter referred to as "eltrombopag olamine" or Compound B:
##STR00001##
BACKGROUND OF THE INVENTION
[0002]
3'-{N'[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-y-
lidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid (hereinafter
Compound A) is a compound which is disclosed and claimed, along
with pharmaceutically acceptable salts, hydrates, solvates and
esters thereof, as being useful as an agonist of the TPO receptor,
particularly in enhancing platelet production and particularly in
the treatment of thrombocytopenia, in International Application No.
PCT/US01/16863, having an International filing date of May 24,
2001; International Publication Number WO 01/89457 and an
International Publication date of Nov. 29, 2001; which has United
States Publication Number US2004/0019190 A1, having a United States
Publication date of Jan. 29, 2004; now U.S. Pat. No. 7,160,870,
issued Jan. 9, 2007, the disclosure of which is hereby incorporated
by reference.
[0003] The bis-(monoethanolamine) salt of this compound is
disclosed (disclosed as
3'-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4--
ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid,
which also describes Compound A) in International Application No.
PCT/US03/16255, having an International filing date of May 21,
2003; International Publication Number WO 03/098002 and an
International Publication date of Dec. 4, 2003; which has United
States Publication Number US2006/0178518 A1, having a United States
Publication date of Aug. 10, 2006; the disclosure of which is
hereby incorporated by reference.
[0004] Compound A is disclosed for the treatment of degenerative
diseases/injuries in International Application No. PCT/US04/013468,
having an International filing date of Apr. 29, 2004; International
Publication Number WO 04/096154 and an International Publication
date of Nov. 11, 2004; which has United States Publication Number
US2007/0105824 A1, having a United States Publication date of May
10, 2007; the disclosure of which is hereby incorporated by
reference.
[0005] Compositions that may contain Compound A and/or Compound B
are disclosed in International Application No. PCT/US01/16863,
International Application No. PCT/US03/16255 and International
Application No. PCT/US04/013468.
[0006] Solid oral pharmaceutical dosage forms are popular and
useful forms of medications for dispensing pharmaceutically active
compounds. A variety of such forms are known, including tablets,
capsules, pellets, lozenges, and powders.
[0007] However, the formulation of an acceptable solid oral
pharmaceutical dosage form on a commercial scale is not always
straightforward. The formula and process of manufacture must be
such as to provide an integral solid dosage form that maintains its
integrity until used. The solid dosage form must also possess
acceptable dissolution and disintegration properties so as to
provide the desired profile in use. Pharmaceutically active
compounds with low solubility and/or that can react with commonly
used excipients can present particular challenges in preparing high
quality solid dosage forms, since the physical properties of the
drug influence the properties of the solid dosage form. The
formulator must balance the drug's unique properties with the
properties of each excipient in order to prepare a safe,
efficacious and easy to use solid dosage form.
[0008] Eltrombopag olamine presents the formulator with unique
concerns when attempting to formulate this compound into a suitable
solid oral pharmaceutical dosage form, suitably a tablet, suitably
a capsule, with a desirable pharmacokinetic profile, particularly
on a commercial scale. Such concerns include, but are not limited
to; the tendency of the compound to form insoluble metal complexes
when contacted with excipients that contain a coordinating metal,
slow dissolution of the compound from solid dosage forms and the
tendency of the compound to under go a Maillard reaction when
contacted with excipients that contain reducing sugars. Significant
realization of these concerns will have an adverse effect on the in
vivo administration of eltrombopag olamine.
[0009] It would be desirable to provide eltrombopag olamine in a
solid oral pharmaceutical dosage form on a commercial scale with a
desirable pharmacokinetic profile.
[0010] The present invention is directed to granules and solid oral
pharmaceutical dosage forms that contain eltrombopag olamine,
suitably the solid dosage form is a tablet, suitably the solid
dosage form is a capsule, suitably these solid dosage forms are
produced on a commercial scale.
SUMMARY OF THE INVENTION
[0011] The present invention relates to granules and solid oral
pharmaceutical dosage forms comprising a therapeutically effective
amount of eltrombopag olamine. The invention also relates to a
process for making granules and solid oral pharmaceutical dosage
forms comprising eltrombopag olamine.
[0012] Another aspect of this invention relates to granules and
solid oral pharmaceutical dosage forms, suitably tablets, suitably
capsules, comprising eltrombopag olamine that are formulated using
diluents that are substantially free of reducing sugars, which as
used herein and in the claims includes diluents that are free of
reducing sugars, and that are substantially free of coordinating
metals, which as used herein and in the claims includes diluents
that are free of coordinating metals. Such granules and solid oral
pharmaceutical dosage forms exhibit improved properties. Such
improved properties help to ensure safe and effective
treatment.
[0013] Another aspect of this invention relates to film coated
pharmaceutical tablets comprising eltrombopag olamine, wherein the
film coat contains no coordinating metals, or only an amount of
coordinating metal approximately equal to or less than 0.025 parts
of Compound B. Such tablets exhibit improved properties. Such
improved properties help to ensure safe and effective
treatment.
[0014] Another aspect of this invention relates to granules and
solid oral pharmaceutical dosage forms comprising eltrombopag
olamine that are formulated with a defined drug particle size range
where about 90% of drug particle size is in the range of 10 to 90
microns. Such tablets exhibit improved properties. Such improved
properties help to ensure safe and effective treatment.
[0015] Another aspect of this invention relates to granules and
solid oral pharmaceutical dosage forms containing eltrombopag
olamine comprising a high percentage of disintegrant, suitably an
amount equal to or greater than 4%. Such tablets exhibit improved
properties. Such improved properties help to ensure safe and
effective treatment.
[0016] Another aspect of this invention relates to a method of
treating thrombocytopenia, which method comprises administering to
a subject in need thereof a therapeutically effective amount of
granules or a solid oral pharmaceutical dosage form of the present
invention.
[0017] Another aspect of this invention relates to a method of
agonizing the TPO receptor, which method comprises administering to
a subject in need thereof a therapeutically effective amount of
granules or a solid oral pharmaceutical dosage form of the present
invention.
[0018] Also included in the present invention are methods of
co-administering granules or a solid oral pharmaceutical dosage
form of the present invention with further active ingredients.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] FIG. 1 depicts the dissolution comparison of tablets
containing eltrombopag and a metal containing diluent with tablets
containing eltrombopag and a non-metal containing diluent.
[0020] FIG. 2 depicts the effect of API particle size on the
dissolution of eltrombopag from 75 mg tablets.
DETAILED DESCRIPTION OF THE INVENTION
[0021] By the term "coordinating metal" and "coordinating metals"
and derivatives thereof, as used herein is meant a metal or a metal
containing excipient, suitably a diluent, or metal containing
tablet coating material, which forms a complex, such as a chelate
complex, in the presence of eltrombopag olamine. Examples of such
metals include: [0022] aluminum, calcium, copper, cobalt, gold,
iron, magnesium, manganese and zinc.
[0023] By the term "reducing sugar" as used herein is meant a sugar
or sugar containing excipient, suitably a diluent, which reacts
with eltrombopag olamine to form a Maillard product when admixed
together. Examples of such reducing sugars include:
[0024] lactose, maltose, glucose, arabinose and fructose.
[0025] The term Maillard reaction is well known in the art and is
utilized herein as to its standard meaning. Generally, the term
Maillard reaction is used herein to mean the reaction of a reducing
sugar, as defined herein, in a formulation, suitably granules or
solid dosage forms, with eltrombopag olamine that produces a
pigment or pigments, suitably a brown pigment. The pigments are
referred to herein as Maillard products. The production of such
Maillard products is an indication of chemical instability.
[0026] As used herein, the term "improved properties" and
derivatives thereof, contemplates several advantages to the
pharmacokinetic profile of the in vivo release of Compound B from a
formulation, suitably granules or a solid oral pharmaceutical
dosage form, that utilizes an aspect of the present invention when
compared to a formulation that does not utilize that aspect of the
present invention, suitably the formulation is produced on a
commercial scale, and will vary depending on the particular aspect
of the invention being utilized. Examples of improved properties
include: increased oral bioavailability, reduced formation of
insoluble metal complexes, improved chemical stability, a
consistent pharmacokinetic profile and a consistent dissolution
rate.
[0027] As used herein, the term "drug" or "active ingredient" and
derivatives thereof, means Compound B or eltrombopag olamine.
[0028] By the term "commercial scale" and derivatives thereof, as
used herein is meant, preparation of a batch scale greater than
about 20 kg of granulation mix, suitably greater than 50 kg,
suitably greater than 75 kg or a batch size suitable to prepare at
least about 50,000 tablets, suitably at least 75,000 tablets,
suitably at least 100,000 tablets.
[0029] When indicating that the diluents for use herein and in the
claims are substantially free of coordinating metals and/or that
are substantially free of reducing sugars, it is contemplated that
minor amounts, for example: about 5% or less, of the diluent
component could contain a coordinating metal or metals and/or a
reducing sugar or reducing sugars. In this aspect of the invention,
it is believed that very minor amounts of coordinating metals
and/or reducing sugars can be incorporated into the diluent
component without adversely effecting tablet performance.
[0030] The term "effective amount" and derivatives thereof, means
that amount of a drug or active ingredient that will elicit the
biological or medical response of a tissue, system, animal or human
that is being sought, for instance, by a researcher or clinician.
Furthermore, the term "therapeutically effective amount" means any
amount which, as compared to a corresponding subject who has not
received such amount, results in improved treatment, healing,
prevention, or amelioration of a disease, disorder, or side effect,
or a decrease in the rate of advancement of a disease or disorder.
The term also includes within its scope amounts effective to
enhance normal physiological function.
[0031] As used herein, the term "formulation" and derivatives
thereof, unless otherwise defined refers to granules and/or solid
oral pharmaceutical dosage forms of the invention that contain
eltrombopag olamine.
[0032] By the term "co-administering" and derivatives thereof as
used herein is meant either simultaneous administration or any
manner of separate sequential administration of granules and/or a
solid oral pharmaceutical dosage form of the present invention and
a further active ingredient or ingredients, known to treat
thrombocytopenia, including chemotherapy-induced thrombocytopenia
and bone marrow transplantation and other conditions with depressed
platelet production. The term further active ingredient or
ingredients, as used herein, includes any compound or therapeutic
agent known to or that demonstrates advantageous properties when
administered with TPO or a TPO mimetic. Preferably, if the
administration is not simultaneous, the compounds are administered
in a close time proximity to each other. Furthermore, it does not
matter if the compounds are administered in the same dosage form,
e.g. one compound may be administered topically and another
compound may be administered orally.
[0033] Examples of a further active ingredient or ingredients for
use in combination with the presently invented formulations include
but are not limited to: chemoprotective or myeloprotective agents
such as G-CSF, BB10010 (Clemons et al., Breast Cancer Res.
Treatment, 1999, 57, 127), amifostine (Ethyol) (Fetscher et al.,
Current Opinion in Hemat., 2000, 7, 255-60), SCF, IL-11, MCP-4,
IL-1-beta, AcSDKP (Gaudron et al., Stem Cells, 1999, 17, 100-6),
TNF-.alpha., TGF-b, MIP-1a (Egger et al., Bone Marrow Transpl.,
1998, 22 (Suppl. 2), 34-35), and other molecules identified as
having anti-apoptotic, survival or proliferative properties.
[0034] By the term "granules" and derivatives thereof, as used
herein refers to formulated particles that comprise eltrombopag
olamine, diluents that are substantially free of coordinating
metals and/or that are substantially free of reducing sugars, and
suitably also binders and/or lubricants and/or disintegrants such
that the particles are suitable for utilization in preparing solid
oral pharmaceutical dosage forms. It is also possible to administer
the granules directly to a subject in need thereof as a medicament.
However, it is anticipated that the granules are most appropriately
utilized in the preparation of solid oral pharmaceutical dosage
forms as indicated above.
[0035] By the term "solid oral pharmaceutical dosage form" and
"solid dosage form" and derivatives thereof, as used herein refers
to a final pharmaceutical preparation that comprises eltrombopag
olamine, such tablets, capsules, pellets, lozenges and powders
(including coated versions of any of such preparations) that are
suitable for in vivo administration.
[0036] Suitably, the granules and solid oral pharmaceutical dosage
forms of the present invention comprise eltrombopag olamine, a
diluent (also known as filler or bulking agent), and suitably also
a binder and/or a lubricant and/or a disintegrant. Those skilled in
the art will recognize that a given material may provide one or
more functions in the tablet formulation, although the material is
usually included for a primary function. The percentages of
diluent, binder, lubricant and disintegrant provided herein and in
the claims are by weight of the tablet.
[0037] Diluents provide bulk, for example, in order to make the
tablet a practical size for processing. Diluents may also aid
processing, for example, by providing improved physical properties
such as flow, compressibility, and tablet hardness. Because of the
relatively high percentage of diluent and the amount of direct
contact between the diluent and the active compound in the typical
pharmaceutical formulation, the interaction of the diluent with the
active compound is of particular concern to the formulator.
Examples of diluents suitable for general use include:
water-soluble fillers and water-insoluble fillers, such as calcium
phosphate (e.g., di and tri basic, hydrated or anhydrous), calcium
sulfate, calcium carbonate, magnesium carbonate, kaolin, spray
dried or anhydrous lactose, cellulose (e.g., microcrystalline
cellulose, powdered cellulose), pregelatinized starch, starch,
lactitol, mannitol, sorbitol, maltodextrin, powdered sugar,
compressible sugar, sucrose, dextrose, and inositol. The diluents
that do not contain coordinating metals and diluents that are
non-reducing sugars are suitable for tablets of the current
invention. Suitable diluents for use in this invention include
microcrystalline cellulose, powdered cellulose, pregelatinized
starch, starch, lactitol, mannitol, sorbitol, and maltodextrin.
Unsuitable diluents include calcium phosphate (e.g., di and tri
basic, hydrated or anhydrous), calcium sulfate, calcium carbonate,
magnesium carbonate, kaolin, and spray dried or anhydrous lactose.
In one embodiment of the present invention, the diluent is composed
of one or both of Mannitol and microcrystalline cellulose.
[0038] The granules and solid oral pharmaceutical dosage forms of
the present invention typically comprise from about 25% to about
89%, of one or more diluents.
[0039] One aspect of the present invention comprises granules
wherein the granules are formulated using a diluent or diluents
that are substantially free of coordinating metals and/or that are
substantially free of reducing sugars.
[0040] One aspect of the present invention comprises solid oral
pharmaceutical dosage forms wherein the solid dosage forms are
formulated using a diluent or diluents that are substantially free
of coordinating metals and/or that are substantially free of
reducing sugars.
[0041] One aspect of the present invention comprises pharmaceutical
tablets, wherein the tablets are formulated using a diluent or
diluents that are substantially free of coordinating metals and/or
that are substantially free of reducing sugars.
[0042] One aspect of the present invention comprises pharmaceutical
capsules, wherein the capsules are formulated using a diluent or
diluents that are substantially free of coordinating metals and/or
that are substantially free of reducing sugars.
[0043] Binders impart cohesive properties to the powdered material.
Examples of binders suitable for use in the present invention
include: starch (e.g., paste, pregelatinized, mucilage), gelatin,
sugars (e.g., sucrose, glucose, dextrose, molasses, lactose,
dextrin, xylitol, sorbitol), polymethacrylates, natural and
synthetic gums (e.g., acacia, alginic acids and salts thereof such
as sodium alginate, gum tragacanth, Irish moss extract, panwar gum,
ghatti gum, guar gum, zein), cellulose derivatives [such as
carboxymethyl cellulose and salts thereof, methyl cellulose (MC),
hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose
(HPC), hydroxyethyl cellulose (HEC) and ethyl cellulose (EC)],
polyvinylpyrrolidone, Veegum, larch arabogalactan, polyethylene
glycol, waxes, water, alcohol, magnesium aluminum silicate, and
bentonites. In one embodiment of the present invention, the binder
comprises polyvinylpyrrolidone (PVP).
[0044] The granules and solid oral pharmaceutical dosage forms of
the present invention typically comprise up to about 8% binder. The
formulations suitably comprise up to about 5%, suitably up to about
2% binder.
[0045] Lubricants are generally used to enhance processing, for
example, to prevent adhesion of the formulation material to
manufacturing equipment, reduce interparticle friction, improve
rate of flow of the formulation, and/or assist ejection of the
formulations from the manufacturing equipment. Examples of
lubricants suitable for use in the present invention include: talc,
stearates (e.g., magnesium stearate, calcium stearate, zinc
stearate, palmitostearate), stearic acid, hydrogenated vegetable
oils, glyceryl behanate, polyethylene glycol, ethylene oxide
polymers (e.g., CARBOWAXes), liquid paraffin, sodium lauryl
sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl
fumarate, DL-leucine, and silica derivatives (e.g., colloidal
silicon dioxide, colloidal silica, pyrogenic silica, and hydrated
sodium silicoaluminate). In one embodiment of the present
invention, the lubricant comprises magnesium stearate.
[0046] The granules and solid oral pharmaceutical dosage forms of
the present invention typically comprise up to about 2% lubricant.
The formulations suitably comprise up to about 1.5%, suitably up to
about 1% lubricant.
[0047] Disintegrants are employed to facilitate breakup or
disintegration of the formulation after administration. Examples of
disintegrants suitable for use in the present invention include:
starches, celluloses, gums, crosslinked polymers, and effervescent
agents, such as corn starch, potato starch, pregelatinized starch,
modified corn starch, croscarmellose sodium, crospovidone, sodium
starch glycolate, Veegum HV, methyl cellulose, microcrystalline
cellulose, cellulose, modified cellulose gum (e.g., Ac-Di-Sol R),
agar, bentonite, montmorillonite clay, natural sponge, cation
exchange resins, ion exchange resins (e.g., polyacrin potassium),
alginic acid and alginates, guar gum, citrus pulp,
carboxymethylcellulose and salts thereof such as sodium lauryl
sulfate, magnesium aluminum silicate, hydrous aluminum silicate,
sodium bicarbonate in admixture with an acidulant such as tartaric
acid or citric acid. In one embodiment of the present invention,
the disintegrant is sodium starch glycolate.
[0048] The granules and solid oral pharmaceutical dosage forms of
the present invention typically comprise an amount from 4% to about
12% disintegrant. The formulations suitably comprise from about 6%
to about 10%, suitably from about 7% to 9% disintegrant.
[0049] The solid oral pharmaceutical dosage forms, suitably
tablets, suitably capsules, of the present invention will typically
be sized up to 1 gram, e.g., from about 0.01 gram to about 0.8
gram. These solid dosage forms typically comprise from about 5 mg
to about 900 mg of eltrombopag olamine per dosage form. In suitable
embodiments, the solid dosage forms comprise from about 5 to about
200 mg eltrombopag olamine (e.g., in an about 100-800 mg dosage
form). Tablet formulations of the invention may have a variety of
shapes, including diamond, modified capsule, modified oval, and
hexagonal, and may optionally have a tilt.
Tablets
[0050] The choice of particular types and amounts of excipients,
and tabletting technique employed depends on the further properties
of eltrombopag olamine and the excipients, e.g., compressibility,
flowability, particle size, compatibility, and density. The tablets
may be prepared according to methods known in the art, including
direct compression, dry granulation, fluid bed granulation, and wet
granulation, and the type of excipients used will vary accordingly.
It has been found that wet granulation is particularly suitable for
providing high strength, low breakage tablets comprising relatively
high concentrations of eltrombopag olamine (e.g., about 40% or
more), on a scale suitable for commercial production. Suitable wet
granulated tablets of the invention comprise granules comprising
eltrombopag olamine and one or more of fillers, binders and
disintegrants, wherein the granules are mixed with additional
filler, binder, disintegrant and/or lubricant to form a compression
mixture that is compressed to form tablets.
[0051] Included in the present invention are pharmaceutical
compositions in tablet form, suitably prepared on a commercial
scale, that comprise eltrombopag olamine, wherein the tablet is
made by a wet granulation process using a diluent or diluents that
are substantially free of coordinating metals and/or that are
substantially free of reducing sugars. Also included in the present
invention are such pharmaceutical compositions that contain a film
coat, wherein the film coat contains no coordinating metals, or
only an amount of coordinating metal approximately equal to or less
than 0.025 parts of Compound B.
[0052] Also included in the present invention are pharmaceutical
compositions that comprise eltrombopag olamine, wherein the tablet
is made by a wet granulation process, suitably on a commercial
scale, using a diluent or diluents that are substantially free of
coordinating metals and/or that are substantially free of reducing
sugars, and about 90% of the eltrombopag olamine particles have a
particle size greater than 10 micron but less than 90 micron.
[0053] Also included in the present invention are pharmaceutical
compositions that comprise eltrombopag olamine, wherein the tablet
is made by a wet granulation process, suitably on a commercial
scale, using a diluent or diluents that are substantially free of
coordinating metals and/or that are substantially free of reducing
sugars, and about 90% of the eltrombopag olamine particles have a
particle size greater than 10 micron but less than 90 micron,
suitably greater than 20 micron but less than 50 micron.
[0054] Also included in the present invention are pharmaceutical
compositions that comprise eltrombopag olamine, wherein the tablet
is made by a wet granulation process, suitably on a commercial
scale, using a diluent or diluents that are substantially free of
coordinating metals and/or that are substantially free of reducing
sugars, and about 50% of the eltrombopag olamine particles have a
particle size greater than 5 micron but less than 50 micron,
suitably greater than 5 micron but less than 20 micron.
[0055] In one embodiment of the present invention, the tablets of
the present invention comprise: [0056] (i) from about 2% to about
65% eltrombopag olamine; [0057] (ii) from about 25% to about 89% of
diluent; [0058] (iii) up to about 8% binder, suitably up to about
5%, suitably up to about 4%; [0059] (iv) up to about 2% lubricant,
suitably up to about 1.5%, suitably up to about 1%; and [0060] (v)
from 4% to about 12% disintegrant, suitably 6% to 10%, suitably
from 7% to 9%.
[0061] Suitable wet granulated tablets comprise, by weight of the
tablet, from about 10% to about 95% of eltrombopag olamine active
intragranules and from about 5% to about 90% of external
excipients; wherein the eltrombopag olamine active intragranules
comprise, by weight of the intragranules: [0062] (i) from about 2%
to about 88% eltrombopag olamine; [0063] (ii) from about 10% to
about 96% diluent; [0064] (iii) from about 2% to about 5% binder;
and [0065] (iv) optionally from 0% to about 4% disintegrant; and
wherein the external excipients comprise, by weight of the tablet:
[0066] (i) from 0% to about 70% diluent; [0067] (ii) from about
0.25% to about 2%, suitably from about 0.25% to about 1.25%
lubricant; and [0068] (iii) from 4% to about 10% disintegrant.
[0069] In the foregoing embodiments, the diluent is suitably a
combination of mannitol and microcrystalline cellulose, the
non-reducing sugar is suitably mannitol, the binder is suitably
polyvinylpyrolidone, the lubricant is suitably magnesium stearate,
and the disintegrant is suitably sodium starch glycolate. Suitably,
the intragranule filler is a mixture of mannitol and
microcrystalline cellulose and the external filler is
microcrystalline cellulose.
[0070] In one embodiment of the current invention, tablets are
coated with a film coat formed from an aqueous film coat
composition. Aqueous film coat compositions suitable for use in the
present invention comprise a film-forming polymer, water as a
vehicle, and optionally one or more adjuvants such as are known in
the film-coating art. When the film coat contains a coordinating
metal, as used herein, the amount of coordinating metal is
approximately equal to or less than 0.025 parts of Compound B.
[0071] The film-forming polymer is selected to form coatings with
mechanical properties (e.g., mechanical strength, flexibility)
suitable to meet performance requirements, such as those required
by the intended use environment (e.g., dissolution profile in
gastrointestinal fluids), and/or use (e.g. solution viscosity).
Examples of suitable film-forming polymers include cellulosic
polymers (e.g., cellulose ethers such as HPMC, HPC, MC, EC, HEC,
CAP, sodium ethyl cellulose sulfate, carboxymethyl cellulose and
the like); polyvinylpyrolidone; zein; and acrylic polymers (e.g.,
methacrylic acid/methacrylic acid ester copolymers such as
methacrylic acid/methylmethacrylate copolymers and the like).
Cellulosic polymers are preferred in the present invention,
especially cellulosic ethers and more especially HPMC and HPC. The
polymers are typically provided in either aqueous or organic
solvent based solutions or aqueous dispersions. However, the
polymers may be provided in dry form, alone or in a powdery mixture
with other components (e.g., a plasticizer and/or colorant), which
is made into a solution or dispersion by the user by admixing with
the aqueous vehicle.
[0072] The aqueous film coat composition further comprises water as
a vehicle for the other components, to facilitate their delivery to
the tablet surface. The vehicle may optionally further comprise one
or more water soluble solvents, e.g., alcohols (e.g., methanol,
isopropanol, propanol) and ketones (e.g., acetone). The skilled
artisan can select appropriate vehicle components to provide good
interaction between the film-forming polymer and the vehicle to
ensure good film properties. In general, polymer--vehicle
interaction is designed to yield maximum polymer chain extension to
produce films having the greatest cohesive strength and thus
mechanical properties. The components are also selected to provide
good deposition of the film-forming polymer onto the tablet
surface, such that a coherent and adherent film is achieved.
[0073] The aqueous film coating composition may optionally comprise
one or more adjuvants known in the art, such as plasticizers,
colorants, detackifiers, secondary film-forming polymers, flow
aids, surfactants (e.g., to assist spreading), maltodextrin, and
polydextrose.
[0074] Plasticizers provide flexibility to the film, which may
reduce film cracking and improve adhesion to the tablet. Suitable
plasticizers will generally have a high degree of compatibility
with the film-forming polymer and sufficient permanence such that
the coating properties are generally stable. Examples of suitable
plasticizers include glycerin, propylene glycol, polyethylene
glycols (e.g., molecular weight from 200 to 20,000, including Union
Carbide's PEG 400, 4000, 6000, 8000, and 20,000), glycerin
triacetate (aka triacetin), acetylated monoglyceride, citrate
esters (e.g., triethyl citrate, acetyl triethyl citrate, tributyl
citrate, acetyl tributyl citrate), phthalate esters (e.g., diethyl
phthalate), mineral oil and hydrogenated glucose syrup. In one
embodiment of the present invention, the plasticizer is chosen from
polyethylene glycols, triacetin, propylene glycol, glycerin, and
mixtures thereof
[0075] The aqueous film coat composition suitably comprises one or
more colorants. In addition to enhancing esthetic appeal, the
colorant provides product identification. Suitable colorants
include those approved and certified by the FDA, including FD&C
and D&C approved dyes, lakes, and pigments, and titanium
dioxide, provided that the film coat contains no coordinating
metals, or only an amount of coordinating metal approximately equal
to or less than 0.025 parts of Compound B.
[0076] Suitably, the colorant comprises one or more coloring agents
selected from the group consisting of red iron oxides, red dyes and
lakes, yellow iron oxides, yellow dyes and lakes, titanium dioxide,
and indigo carmine. For example, the colorant may be selected to
provide a light beige shade, for example consisting essentially of
a) red iron oxide, red dye, and/or red lake, b) yellow iron oxide,
yellow dye, and/or yellow lake, and c) titanium dioxide.
Alternatively, the colorant may be selected to provide a pink shade
(e.g., consisting essentially of titanium dioxide and red iron
oxide, red dye and/or red lake); a light green shade (e.g.,
consisting essentially of yellow iron oxide, yellow dye and/or
yellow lake, indigo carmine, and titanium dioxide); a light blue
shade (e.g., consisting essentially of titanium dioxide and indigo
carmine); or an orange shade (e.g., consisting of essentially of
titanium dioxide and sunset yellow).
[0077] The above mentioned colorants that contain a coordinating
metal are acceptable at a level approximately equal to or less than
0.025 parts of Compound B.
[0078] In suitable alternative embodiments, the aqueous film
coating composition for use in the current invention comprises:
[0079] a cellulosic film-forming polymer; and [0080] (ii) a
plasticizer.
[0081] Suitably, such compositions further comprise a colorant.
Such compositions may optionally further comprise one or more
additional adjuvants such as a detackifier, flow aid, surfactant,
and secondary film-forming polymer.
[0082] Examples of optional detackifiers include lecithin, stearic
acid, mineral oil, modified derivatized starch, tapioca dextrin,
and polyethylene glycol. Examples of optional secondary
film-forming polymers include sodium alginate, propylene glycol
alginate, and polyvinylpyrrolidone. Examples of optional
surfactants include dioctyl sodium sulfosuccinate and polysorbate
80. Examples of optional flow aids include talc, fumed silica,
bentonite, hydrogenated vegetable oils, stearines, and waxes.
[0083] The aqueous film coat composition will typically comprise
from about 5% to about 25%, suitably about 5% to about 20%, coating
solids in the vehicle. In suitable embodiments, the solids
typically comprise from about 25% to about 70%, suitably about 60%
to about 70% film-forming polymer, about 5% to about 10%, suitably
about 6% to about 8%, plasticizer, and about 20% to about 35%
colorant, by weight.
[0084] A number of suitable aqueous film coating compositions are
commercially available. The aqueous film coat composition may be
provided in the form of a solution or dispersion. Alternatively,
the composition may be provided in a dry form that can be combined
with the vehicle components according to supplier instructions
prior to coating the tablet. Suitably, aqueous film coating
compositions are those commercially available from Colorcon, Inc.
of West Point, Pa., under the trade name OPADRY and OPADRY II
(nonlimiting examples include Opadry YS-1-7706-G white, Opadry
Yellow 03B92357, Opadry Blue 03B90842). These compositions are
available as dry film coating compositions that can be diluted in
water shortly before use. OPADRY and OPADRY II formulations
comprise a cellulosic film forming polymer (e.g., HPMC and/or HPC),
and may contain polydextrose, maltodextrin, a plasticizer (e.g.,
triacetin, polyethylene glycol), polysorbate 80, a colorant (e.g.,
titanium dioxide, one or more dyes or lakes), and/or other suitable
film-forming polymers (e.g., acrylate-methacrylate copolymers).
Suitable OPADRY or OPADRY II formulations may comprise a
plasticizer and one or more of maltodextrin, and polydextrose
(including but not limited to a) triacetin and polydextrose or
maltodextrin or lactose, or b) polyethylene glycol and polydextrose
or maltodextrin).
[0085] The tablets are also suitably coated to provide a uniform
coating without speckling. The tablets are typically coated to
provide a dry tablet weight gain of from about 2 to about 5%,
suitably about 3 to 4%.
[0086] The uncoated tablet cores are coated with the aqueous film
coating composition by methods well known in the art using
commercially available equipment (e.g., Thomas Accela-Cota, Vector
Hi-Coater, Compu-Lab 36). In general, the process usually involves
rolling or tumbling the tablets in a pan, or suspending the tablets
on a cushion of air (fluidized bed), and intermittently or
continuously (preferably continuously) spraying a fine mist of
atomized droplets of the coating composition onto the tablets, the
droplets wetting, spreading and coalescing on the surface of the
tablets to form an adherent and coherent film coating. The tablets
are typically heated to about 40 to 50.degree. C., suitably about
45 to 50.degree. C., e.g., by air having a temperature of up to
about 75.degree. C., suitably about 65 to 70.degree. C.
Process of Making the Tablet
[0087] Pharmaceutical tablets of the invention that are
wet-granulated can be prepared by a process comprising the steps
of:
I) preparing the granules; which comprises the steps of: [0088] a)
mixing together the dry materials comprising eltrombopag olamine, a
diluent, a binder, and optionally a disintegrant for a time
sufficient to homogenize the materials; [0089] b) adding a
granulating fluid to the mixture of dry materials, preferably while
mixing; [0090] c) mixing the granulating fluid with the mixture of
dry materials for a granulating time sufficient to generally
uniformly wet the dry materials, so as to form wet granules; [0091]
d) wet-milling the wet granules; [0092] e) drying the wet-milled
granules to form dry granules; and [0093] f) dry milling the dry
granules to form granules of desired size; II) preparing the
tablet; which comprises the steps of: [0094] a) mixing the granules
prepared in step I) f) with external excipients comprising a
filler, a lubricant and a disintegrant for a time sufficient to
homogenize the granules and external excipients; and [0095] b)
compressing the mixture comprising the granules and external
excipients to form a tablet.
[0096] Suitably, the tablets are further film-coated, especially
aqueous film-coated.
[0097] In preparing wet-granulated granules, the dry materials may
be mixed with suitable equipment such as known in the art (e.g.,
Niro-Fielder Blender/Granulator, Bear Varimixer, Key High Shear
Mixer/Granulator) for a time sufficient to homogenize the
materials, e.g., for about 3 minutes.
[0098] The granulating fluid is then added to the dry mixture,
preferably while mixing. The granulating fluid is suitably water,
although may alternatively be comprised of water in admixture with
one or more of binders such as PVP and HPMC, from about 10 v/w % to
about 30 v/w % of the granulating fluid, based on the total wet
granulation mixture, is suitably used. The granulating fluid and
dry materials may be mixed using suitable equipment such as known
in the art (e.g., Niro-Fielder Blender/Granulator, Bear Varimixer,
Key High Shear Mixer/Granulator) for a total time sufficient to
generally uniformly wet the dry material so as to form wet
granules, suitably for about 3 to about 15 minutes. Typically the
fluid is added to the dry material with mixing over a period of
about 1 to about 15 minutes, then the total batch is mixed for an
additional time (post-granulating fluid-addition time), of about
0.5 minutes to about 6 minutes.
[0099] In a suitable embodiment, about 10 v/w % to about 30 v/w %
granulating fluid and a post-granulating fluid-addition granulating
time of about 6 minutes or less is used. Suitably, about 24 v/w %
granulating fluid and a post-granulating fluid-addition granulating
time of less than 3 minutes is used, e.g., about 2.5 minutes.
Suitably, about 16 v/w % granulating fluid and a post-granulating
fluid-addition granulating time of more than 2.5 minutes is used,
e.g., about 4 minutes.
[0100] The wet granules are then wet-milled by methods such as are
known in the art for providing a generally uniformly sized wet mass
(such that the granules dry relatively evenly). Suitable
wet-milling techniques may involve screening (e.g., manual
screens), comminuting mills (such as a Co-mil, including but not
limited to a 0.375'' screen), or extruders.
[0101] The wet-milled granules are dried by methods such as are
known in the art for providing generally uniform drying, to a low
residual amount of granulating fluid (preferably about 0.5% to
about 1.0%). Fluid bed dryers are suitable drying equipment.
[0102] The dried granules are then dry-milled using known methods
to provide generally uniformly sized granules (unimodal
distribution), suitably having a mean particle diameter of less
than 240 microns (found to provide improved content uniformity).
Suitable dry-milling equipment includes Co-mils, including but not
limited to having a 0.094'' screen.
[0103] Suitably the granules and the dry materials of the
compression mix are generally unimodal in size distribution, in
order to facilitate formation of a homogeneous mix and to mitigate
possible segregation of the mix after blending. If necessary, the
dry materials may be pre-screened to provide the desired particle
size distribution. Screening of the lubricant may be particularly
useful to deagglomerate the lubricant.
[0104] In preparing the compression mixture, the granules, filler,
and disintegrant are mixed over a suitable period of time, about 5
to 15 minutes. Lubricant is then added and mixed for a suitable
period of time, about 1 to 4 minutes. The mixture is then
compressed into tablets using presses such as are known in the art
(e.g., rotary tablet press).
[0105] It has been found that the above granulating fluid levels,
granulating times, and excipients provide improved processing.
Capsules
[0106] The choice of particular types and amounts of excipients,
and capsulation technique employed depends on the further
properties of eltrombopag olamine and the excipients, e.g.,
compressibility, flowability, particle size, compatibility, and
density. The capsules may be prepared according to methods known in
the art, suitably filling a standard two piece hard gelatin capsule
with eltrombopag olamine admixed with excipients, suitably filling
a standard two piece hard gelatin capsule with granules prepared
according to this invention, suitably on a scale suitable for
commercial production. Suitable capsules of the invention comprise
granules comprising eltrombopag olamine and one or more of fillers,
binders and disintegrants, wherein the granules are mixed with
additional filler, binder, disintegrant and/or lubricant to form a
granular mixture that is filled into capsules.
[0107] Included in the present invention are pharmaceutical
compositions in capsule form, suitably prepared on a commercial
scale, that comprise eltrombopag olamine, wherein the capsule is
made using a diluent or diluents that are substantially free of
coordinating metals and/or that are substantially free of reducing
sugars.
[0108] Also included in the present invention are pharmaceutical
compositions that comprise eltrombopag olamine, wherein the capsule
is made, suitably on a commercial scale, using a diluent or
diluents that are substantially free of coordinating metals and/or
that are substantially free of reducing sugars, and about 90% of
the eltrombopag olamine particles have a particle size greater than
10 micron but less than 90 micron.
[0109] Also included in the present invention are pharmaceutical
compositions that comprise eltrombopag olamine, wherein the capsule
is made, suitably on a commercial scale, using a diluent or
diluents that are substantially free of coordinating metals and/or
that are substantially free of reducing sugars, and about 90% of
the eltrombopag olamine particles have a particle size greater than
10 micron but less than 90 micron, suitably greater than 20 micron
but less than 50 micron.
[0110] Also included in the present invention are pharmaceutical
compositions that comprise eltrombopag olamine, wherein the capsule
is made, suitably on a commercial scale, using a diluent or
diluents that are substantially free of coordinating metals and/or
that are substantially free of reducing sugars, and about 50% of
the eltrombopag olamine particles have a particle size greater than
5 micron but less than 50 micron, suitably greater than 5 micron
but less than 20 micron.
[0111] The invented granules and solid oral pharmaceutical dosage
forms may be administered in therapeutically effective amounts to
treat or prevent a disease state, e.g., as described in the above
referenced International Applications Nos. PCT/US01/16863,
PCT/US03/16255 and PCT/US04/013468, the disclosures of which are
herein incorporated by reference. It will be recognized by one of
skill in the art that the optimal quantity and spacing of
individual dosages of eltrombopag olamine formulations of the
invention will be determined by the nature and extent of the
condition being treated and the particular patient being treated,
and that such optimums can be determined by conventional
techniques. It will also be appreciated by one of skill in the art
that the optimal course of treatment, i.e., the number of doses of
eltrombopag olamine given per day for a defined number of days, can
be ascertained by those skilled in the art using conventional
course of treatment determination tests.
[0112] A method of this invention of inducing TPO agonist activity
in humans comprises administering to a subject in need of such
activity a therapeutically effective amount of a solid oral
pharmaceutical dosage form of the present invention.
[0113] The invention also provides for the use of eltrombopag
olamine in the manufacture of a solid oral pharmaceutical dosage
form of the present invention.
[0114] The invention also provides for the use of eltrombopag
olamine in the manufacture of a solid oral pharmaceutical dosage
form of the present invention for use in enhancing platelet
production.
[0115] The invention also provides for the use of eltrombopag
olamine in the manufacture of a solid oral pharmaceutical dosage
form of the present invention for use in treating
thrombocytopenia.
[0116] The invention also provides for a solid oral pharmaceutical
dosage form for use as a TPO mimetic which comprises eltrombopag
olamine and a pharmaceutically acceptable carrier of the present
invention.
[0117] The invention also provides for a solid oral pharmaceutical
dosage form for use in the treatment of thrombocytopenia which
comprises eltrombopag olamine and a pharmaceutically acceptable
carrier of the present invention.
[0118] The invention also provides for a solid oral pharmaceutical
dosage form for use in enhancing platelet production which
comprises eltrombopag olamine and a pharmaceutically acceptable
carrier of the present invention.
[0119] The invention also provides a process for preparing solid
oral pharmaceutical dosage forms containing a diluent or diluents
that are substantially free of coordinating metals and/or that are
substantially free of reducing sugars and a therapeutically
effective amount of eltrombopag olamine, which process comprises
bringing eltrombopag olamine into association with the diluent or
diluents.
[0120] No unacceptable toxicological effects are expected when the
compound of the invention is administered in accordance with the
present invention.
[0121] Without further elaboration, it is believed that one skilled
in the art can, using the preceding description, utilize the
present invention to its fullest extent. The following Examples,
therefore, are to be construed as merely illustrative and not a
limitation of the scope of the present invention.
[0122] All the excipients utilized herein are standard
pharmaceutical grade excipients available from numerous
manufacturers well known to those in the art.
EXAMPLES
Examples 1 to 7
Tablet Preparation
[0123] Wet granulated, tablets comprising eltrombopag olamine and
the ingredients in Table 1 were prepared.
TABLE-US-00001 TABLE 1 Tablet Strength Component 12.5 mg 25 mg 25
mg 50 mg 50 mg 75 mg 100 mg Granules 40% Drug-loaded (39.9) (79.7)
(79.7) (159.4) (159.4) (239.1) (318.8) eltrombopag olamine, milled
15.95 31.9 31.9 63.8 63.8 95.7 127.6 Microcrystalline cellulose
7.45 14.9 14.9 29.8 29.8 44.7 59.6 Mannitol 14.9 29.7 29.7 59.5
59.5 89.2 118.9 Povidone 1.6 3.2 3.2 6.4 6.4 9.6 12.8 Purified
water -- -- -- -- Extra-granular components Microcrystalline
cellulose 119.4 238.8 238.8 159.1 159.1 79.3 NA Sodium starch
glycolate 14.0 28.0 28.0 28.0 28.0 28.0 27.6 Magnesium Stearate
1.75 3.5 3.5 3.5 3.5 3.5 3.5 Film-coating components Purified water
-- -- -- -- Opacity .RTM. white 8.9 14.0 14.0 14.0 Opadry Orange
14.0 Opadry Brown 14.0 Opadry Blue 14.0 Total tablet weight
(mg/tablet) 183.9 364 364 364 364 364 364
[0124] Granules were prepared by separately weighing and screening
mannitol, microcrystalline cellulose and povidone.
[0125] As a general procedure, the ingredients were blended with
the active ingredient and then wet-granulated (in a high-shear
wet-granulator) with purified water. The wet-granule mass was
wet-milled, then dried in a fluid-bed dryer and the dried granules
were milled.
[0126] Then extragranular ingredients (microcrystalline cellulose,
if needed, and sodium starch glycolate) were separately weighed,
screened and blended with the granules. Magnesium stearate was
added and blended with the mixture. The blend was compressed and
the tablet cores were then film coated. The tablets were film
coated with an aqueous suspension of OPADRY film coating
preparation.
Example 8
Tablet Preparation
[0127] Eltrombopag olamine tablets containing diluents with the
coordinating metal calcium phosphate dibasic anhydrous were
manufactured in a similar manner as described above. Tablet
composition for the tablet coordinating metal diluent is provided
in table 2.
TABLE-US-00002 TABLE 2 Tablet Strength Component 50 mg Granules 40%
Drug-loaded (159.4) eltrombopag olamine, milled 63.8 Calcium
Phopshate dibasic anhydrous 89.3 Povidone 6.4 Purified water --
Extra-granular components Microcrystalline cellulose 159.1 Sodium
starch glycolate 28.0 Magnesium Stearate 3.5 Film-coating
components Purified water -- Opadry .RTM. white 14.0 Total tablet
weight (mg/tablet) 364
[0128] In FIG. 1, the tablet prepared with no coordinating metal
diluent (indicated as "with non-coordinating metal diluent") is a
eltrombopag 50 mg tablet generally prepared as described in Table 1
above and the tablet prepared with the coordinating metal
diluent--Calcium Phopshate dibasic anhydrous--(indicated as "with
coordinating metal diluent") is a eltrombopag 50 mg tablet
generally prepared as described in Table 2 above. Dissolution
comparison was performed using USP Apparatus II, 50 rpm, in
phosphate buffer pH 6.8 containing 0.5% Tween 80.
Example 9
[0129] FIG. 2 depicts the effect of API particle size distribution
on eltrombopag olamine dissolution. Eltrombopag olamine 75 mg
tablets were generally prepared in the manner described in Example
5, using different particle sizes. The particle size refers to the
particle size of the drug granules used in the formulation.
[0130] Dissolution comparison was performed using USP Apparatus II,
50 rpm, in phosphate buffer pH 6.8 containing 0.5% Tween 80.
* * * * *