Note: Descriptions are shown in the official language in which they were submitted.
CA 02571933 2014-02-27
TITLE: A DES CARBONYLETHOXYLORATADINE
CONTAINING
PHARMACEUTICAL COMPOSITION
The present invention relates to a pharmaceutical composition wherein the
pharmaceutically active ingredient (i.e. drug component) comprises
Descarbonylethoxyloratadine (or a pharmaceutically acceptable salt or polymoph
form
thereof). Descarbonylethoxyloratadine is also known as Desloratadine.
Desloratadine is a
derivative of loratadine and is chemically known as 8-chloro-6, 11 dihydro-11-
(4-
piperidylidene)-5H-benzo[5,6]-cyclohepta[1,2-b]pyridine. It is to be
understood herein
that Desloratadine may be referred to herein simply as DCL. DCL is known as a
long
acting tricyclic histamine antagonist. Pharmaceutical compositions comprising
DCL may
be used to treat allergic reactions in mammals and in particular is indicated
for the relief of
nasal and non nasal symptoms of allergic rhinitis.
Pharmaceutical compositions comprising DCL may additionally include one or
more
known pharmaceutically acceptable substances that is/are not a medicinally
active
constituent(s) such as for example, carrier or diluent elements. However it is
known that
some types of such medicinally inactive constituent(s) may induce or
facilitate
decomposition of DCL leading to its discoloration. The color instability in
the active
DCL ingredient may, for example, be attributed to a very minute amount of
degradation
product, such as the N-formyl impurity of desloratadine. The N-formyl impurity
of
desloratadine may be formed due to the presence of a wide variety of medically
inactive
substances commonly used in tablet formulations. Such instability may for
example be
brought on by the presence in the pharmaceutical composition of an acidic
medically
inactive substance such as for example an acidic substance; an acidic
substance may be an
acidic excipient(s) which may have a pH of less than 7 in water, (e.g. a pH in
range of 3
to 5). Acidic substances used in the formulation of pharmaceutical
compositions include
known substances such as for example, lactose, lactose monohydrate, sodium
benzoate,
microcrystalline cellulose, etc. Thus various formulations have been proposed
for the
purpose of providing a stable composition of Desloratadine which would
purportedly
avoid the incompatibility between Desloratadine and acidic substances; as
mentioned such
acidic substances may be acidic excipients such as lactose and other mono and
disaccharides. Proposed stabilized compositions are for example described for
example in
US patent no. 6,100,274, US patent application no 10/082,685 published under
no. US
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CA 02571933 2014-02-27
2002/0123504 as well as in PCT application no. PCT/IN2004/000399 published
under no.
WO 2005/065047.
It would be advantageous to be able to prepare alternate stabilized (e.g.
tablet)
formulation(s) comprising DCL such as for example a stabilized oral dosage
form of
Desloratadine. It would in particular be advantageous to have a DCL drug
formulation
which may inhibit the formation of DCL degradation materials and provide a
safe and
efficacious drug product for human consumption.
Thus the present invention provides a pharmaceutical composition for oral
administration
comprising a pharmaceutically active component and a pharmaceutically
acceptable
carrier component, wherein said pharmaceutically active component comprises a
DCL
element, wherein said pharmaceutically acceptable carrier component comprises
an acidic
element, and wherein said composition further comprises a DCL-protective
amount of a
pharmaceutically acceptable stabilizer element (i.e. member) selected from the
group
consisting of magnesium oxide, calcium oxide, aluminum oxide and mixtures
thereof.
It is to be understood herein that the expression pharmaceutically active
component
characterize the composition as comprising a therapeutically effective
amount" of the
DCL element. It is also to be understood herein that the expression "DCL
element"
includes DCL, a (suitable) pharmaceutically acceptable DCL salt, a (suitable)
pharmaceutically acceptable polymorphic form of DCL and the like, including
mixtures
thereof. In accordance with the present invention the DCL element may for
example
comprise (or consist of) DCL.
In accordance with the present invention a pharmaceutical composition, as
mentioned
above, comprises a DCL-protective amount of a stabilizer element (i.e.
member), i.e. any
predetermined amount may be used which is able to provide the desired effect
keeping in
mind, for example, the amount of DCL present in the composition. However, in
accordance with the present invention a pharmaceutical composition may, for
example,
comprise up to 10% (e.g. from 1% to 10%) by weight of said composition of said
stabilizer element In accordance with the present invention the stabilizer
element may,
for example, comprise from about 1% to about 5% (in particular from about 1%
to about
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CA 02571933 2014-02-27
2.65%; more particularly from about 1% to about 2.5%; e.g. from about 1% to
about
2.25%;) by weight of the composition.
In accordance with the present invention the a pharmaceutically acceptable
stabilizer
element (i.e. member) may comprise (or even consist) of magnesium oxide.
In accordance with the present invention a pharmaceutical composition may
comprise a
pharmaceutically acceptable acidic excipient element. An acidic excipient
element may,
for example, be selected from the group consisting of lactose,
microcrystalline cellulose
(MCC), silicified MCC and mixtures thereof.
A pharmaceutical composition of the present invention may be formulated in any
(known)
suitable, desired or necessary manner. A pharmaceutical composition in oral
dosage form
(e.g. tablet form) may for example be formulated by using direct compression
or wet
granulation processes which are known in the art of making solid oral dosage
forms.
A dosage form (e.g. tablet) of the invention may, for example, be produced in
the
following way: powders and/or granules may be mixed together using currently
known
production techniques. Thus as mentioned above a dosage form may be obtained
by
compression of a simple powder mixture comprising a matrix component and a
pharmaceutically active component in dry powder form. A dosage form may also
be
obtained by compression of a mixture of components wherein the mixture
comprises non-
drug components in dry powder form and granules, the granules having been
obtained
from the dry granulation, wet granulation, compaction or extrusion of a simple
mixture of
a dosage form component(s) and a pharmaceutically active component in dry
powder form
(e.g. a dosage form body may be a tablet made¨up of a single essentially
uniform body
(e.g. single layer)).
It is to be understood herein, that the reference to an "excipient" is a
reference to a
pharmaceutically acceptable ingredient or substance contained in a drug
formulation that
is not a medicinally active constituent and which may be a substance used as a
diluent or
vehicle for a drug.
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CA 02571933 2014-02-27
It is to be understood herein, that if a "class", "range", "group of
substances", etc. is
mentioned with respect to a particular characteristic (e.g. weight ratio,
concentration, time,
% by weight (e.g.%w/w), and the like) of the present invention, the present
invention
relates to and explicitly incorporates herein each and every specific member
and
combination of sub-classes, sub-ranges or sub-groups therein whatsoever. Thus,
any
specified class, range or group is to be understood as a shorthand way of
referring to each
and every member of a class, range or group individually as well as each and
every
possible sub-class, sub-range or sub-group encompassed therein; and similarly
with
respect to any sub-class, sub-ranges or sub-groups therein. Thus, for example,
as
mentioned herein
the mention that the composition comprises up to 10% by weight of the
composition of a
stabiliser element or member is to be understood herein as specifically
incorporating each
and every sub-range as well as each individual weight amount such as for
example 1% to
10%, up to 5% 5 % to 10%, .4%, 4.9%, 5%, 6%, 9% etc.;
and similarly with respect to any other parameters whatsoever.
It is in particular to be understood herein that for any group or range, no
matter how
defined, a reference thereto is a shorthand way of mentioning and including
herein each
and every individual member described thereby as well as each and every
possible class or
sub-group or sub-class of members whether such class or sub-class is defined
as positively
including particular members, as excluding particular members or a combination
thereof;
for example an exclusionary definition for a parameter or element may read as
follows:
"provided that when one of A and B is ¨Z and the other is W, - Z may not be
R".
DCL is for example described in U.S. patent no. 4,659,716.
It is to be understood herein that the expression "pharmaceutically acceptable
salt",
"pharmaceutically acceptable salts" and the like refers to a salt prepared
from
pharmaceutically acceptable non-toxic acid or base including inorganic acids
or bases or
organic acids or bases. Such DCL salts are for example described in U.S.
Patent numbers
4,659,716 and 5,595,997.
Examples of inorganic acids are hydrochloric acid, hydrobromic acid,
hydroiodic acid, sulfuric acid, and phosphoric acid. Organic acids may be
selected, for
example, from acids, such as formic acid, acetic acid, propionic acid,
succinic acid,
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CA 02571933 2014-02-27
glycolic acid, glucuronic acid, maleic acid, furoic acid, glutamic acid, etc..
U.S. patent
application no. 432387 published under no. 20050203116 provides a further
description of
salts of DCL.
Polymorphic forms of Desloratadine are for example described in U.S. patent
no.
6,506,767. U.S. patent 6962924 also describes salts and polymorphs of
Desloratadine
hemifumarate.
The phrase "therapeutically effective amount" is to be understood herein a
referring to an
amount of DCL element which provides a therapeutic benefit; for example, a
therapeutic
benefit in the treatment or management of allergic rhinitis.
The weight ratio, [namely X/(X+Y)], of the pharmaceutically active component
(X) to the
pharmaceutical composition (X+Y) as a whole (e.g. the whole tablet form) may
be from
0.01 to less than 0.8; a weight ratio of 0.01 being for low drug loading
medicaments and a
weight ration of 0.8 being for high drug loading medicaments. For example the
weight
ratio of pharmaceutically active component (i.e. drug) to tablet in particular
may be from
.01 to 0.5 (e.g. the weight ratio of drug to tablet may be from .05 to 0.5 and
more
particularly the weight ratio of drug to tablet may be 0.06). As may be
appreciated, in
the above equation X/(X+Y), X is the pharmaceutically active component
comprising a
DCL element and Y is the rest of the components of the composition including
the
stabiliser element.
In accordance with the present invention a pharmaceutical acceptable carrier
component
may comprise one or more excipients and as desired or necessary one or more
ancillary
additives.
As used herein, in relation to excipients as well as other additives, the term
"pharmaceutically acceptable" characterises the substances or compounds as
compounds
that are compatible with the other ingredients in a pharmaceutical formulation
and are
pharmaceutically acceptable to the subject when DCL is administered in
therapeutically
effective amounts.
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CA 02571933 2014-02-27
An excipient (or diluent) may for example be a substance such as, for example,
lactose,
microcrystalline cellulose, sugars such as mannitol, sorbitol etc.
A pharmaceutical composition (e.g. a dosage form) of the present invention may
for
example optionally contain a pharmaceutically acceptable additive component
comprising
one or more ancillary additive members selected from the group comprising
(e.g.
consisting of)
a lubricant or anti-adherent (such as, for example, magnesium stearate sodium
stearyl
fumarate, zinc stearate, stearic acid, glyceryl behenate, glyceryl
monostearate, etc.);
a glidant (such as, for example, talc, colloidal silicon dioxide, or any other
silica etc).;
a binder (such as, for example, polyvinylpyrrolidone (PVP), starch, gelatin,
ethyl
cellulose, sodium carboxy methyl cellulose);
and
a disintegrant (such as, for example, Croscannalose sodium, sodium starch
glycolate, cross linked PVP, starch etc.).
As mentioned above pharmaceutically acceptable glidants, lubricants and other
additives
such as are well known to those of skill in the art (i.e. including, for
example, those
mentioned herein), may also be included in the composition, i.e. any such
additive(s) may
for example be included in the formulation in an amount of from 0.01% to 10%
of the
weight of the dosage form. For example a glidant is a substance that may be
added
during the granulation process in order for the granules to flow from a hopper
onto a tablet
press to the dies and for consistent and uniform fill.
In any event, it is to be kept in mind that any such ancillary additive(s), if
present, is/are of
course to be chosen and to be incorporated into, for example, a dosage form in
amounts,
keeping in mind the purpose thereof.
In the following examples, a commercially available pharmaceutically
acceptable
Desloratadine (DCL) was used. Similarly, in the following examples
(commercially
available) pharmaceutically acceptable materials were used for the stabilizer
element and
the carrier component, namely:
Magnesium: Magnesium oxide is selected as a stabilizer. It is an inorganic
compound, which will provide basic pH (element) to the formulation.
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Microcrystalline Cellulose PH 101: Microcrystalline cellulose (grade PH 101)
was
selected as a filler in formulations herein (i.e. Avicel PH 101 ¨ from FMC
BioPolymer
U.S.A.). It was selected over other Microcrystalline cellulose grades because
of its good
compressability.
Microcrystalline Cellulose PH 112 : Microcrystalline cellulose (grade PH 112)
was
selected as a filler in formulations herein (i.e. Avicel PH 112¨ from FMC
BioPolymer
U.S.A.). It was selected over other Microcrystalline cellulose grades because
of its low
moisture content and desirable flow characteristics.
Starch 1500: Starch 1500 (a pregelatinized starch from Colorcon U.S.A,) was
selected as a binder.
Starch 1500 LM (a pregelatinized starch from Colorcon U.S.A.): Starch 1500 LM
(tow moisture) was selected as a disintegrant. It was preferred over Starch
1500 due to low
moisture content.
Hydroxypropyl Methylcellulose 2208 (i.e. Methocel K4M from Dow Chemicals
U.S.A.): was selected for controlling drug release; K refers to HPMC
(Hydroxypropyl
Methylcellulose) polymer of 2208 substitution as type per USP (US
Pharmacopia); 4M
refers to 4000 mPas viscosity range as per USP.
Zinc Stearate : Zinc stearate was selected as lubricant.
Lactose anhydrous: Lactose anhydrous was selected as an additional filler.
Example 1: tablets comprising Microcrystalline cellulose
The composition of the tablets is as follows wherein the percentages are given
as
percentage of the overall weight of the composition or blend:
Formulation I composition:
Ingredient Ingredient
no.
1 Desloratadine (DCL) 5.00
2 Magnesium Oxide 2.25
3 Microcrystalline cellulose PH 112 81.75
4 Starch 1500 LM 10.0
Trade-marks
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Zinc stearate 1.0
Total 100
As desired or necessary a tablet having a formulation composition in
accordance with the
present invention may further comprise a suitable (i.e. known) outer coating
surrounding
the compressed tablet core having a basic tablet formulation composition (e.g.
a
5 compressed tablet core wherein the basic tablet formulation composition
is the
Formulation I composition above may additionally include a coating). A
compressed
tablet core may for example, be coated with OPADRY Blue 03890819 (Supplied by
Colorcon) e.g. the coating may represent 2.5% w/w of the core tablet. The
OPADRY
13lue coating may, for example, be applied in known manner as for example as a
dispersion in purified water.
Process of preparation of coated Formulation I composition: Direct
Compression.
The process involved following steps:
Step 1 Mix Desloratadine and Magnesium oxide in Polyethylene bag,
Step 2 Place Microcrystalline cellulose PH 112 in a V blender and
add blend
of step 1. in to it. Add Starch 1500 LM (Low moisture) in the V
Blender.
Step 3 Mix the ingredients of step 2 in V blender.
Step 4 Lubricate the mixed blend of step 3 with Zinc stearate in V
Blender.
Step 5 Compress the final blend of step 4 on a rotary tablet press
(i.e.. a
Betapress from Manesty U.K.) with the target tablet weight of 85 mg
and target tablet hardness of 9.0 kp.
Step 6 Coat the compressed tablets with OPADRY Blue 03B90819
(Supplied by Colorcon) for 2.5% weight gain.
A stability study provided a stability profile of the above mentioned coated
Formulation I
composition product which indicated that the product is a stabilized
formulation. The
stabilization study was conducted by packaging tablets of the above coated
Formulation I
composition in high density polyethylene (HDPE) bottles in the presence of a
desiccant
(trisorb 1 g) and of cotton batton and stored at 40 C/75% RH . Neither known
nor
unknown impurities are more than 0.1% (by weight) when stored at 40 C/75% RH
for 1
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CA 02571933 2014-02-27
month. After one (1) month the above coated Formulation I composition product
(i.e.
20 tablets) were subjected to a High Performance Liquid Chromatographic assay
to
determine impurities; the solvent system comprised a Buffer pH 3.5 and
acetonitrile in
ratio of 75:25 v/v; column: US? L11 4.6 x 150 mm, 3 gm; and detector: 240 nm.
No
color change of the core tablets was observed at 1 month accelerated stability
time point.
In Table 1 (as well as Tables 2, 3 and 4) below the compound impurities are as
follows:
Compound 1:
11-(4-piperidinylidene)-6,11-dihydro-5H-benzo (5,6)cyclohepta(1,2-b)
pyridine
Compound 2:
8-Bromo-11-(4-piperidinylidene)-6,11-dihydro-5H-benzo(5,6)cyclo-
hepta(1,2-b)pyridine
Compound 3:
8-Chloro-11-(4-piperidinylidene)-benzo(5,6)cyclohepta(1,2-b)pyridine
Compound 4:
8-Chloro-11-(1-carboethoxy-4-piperidinylidene)-6,11-dihydro-5H-
benzo(5,6)cyclohepta(1,2-b)pyridine
Compound 5:
8-Chloro-6,11-dihydro-11-(N-methy1-4-piperidinylidene)-5H-
benzo(5,6)cyclohepta(1,2-b)pyridine
Compound 6:
8-Chloro-6,11-dihydro-11-(N-methy1-4-piperidiny1)-11-hydroxy-5H-
benzo(5,6)cyclohepta(1,2-b)pyridine
Compound 7:
8-Chloro-6,11-dihydro-5H-benzo(5,6)cyclohepta(1,2-b)pyridin-11-one
Compound 8:
4,8-Dichloro-6,11-dihydro-51-!-benzo(5,6)cyclohepta(1,2-b)pyridin-11-one
Compound 9:
4,8-Dichloro-6,11-dihydro-11-(N-ethoxycarbony1-4-piperidinylidene)-5H-
benzo(5,6)cyclohepta(1,2-b)pyridine
Compound 10:
8-Chloro-6,11-dihydro-11-(N-ethoxycarbony1-4-piperidiny1)-11-hydroxy-
5H-benzo(5,6)cyclohepta(1,2-b)pyridine
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CA 02571933 2014-02-27
The impurity results for Formulation I are set forth in Table 1 below:
TABLE 1: Stability compilation of the above coated Formulation I composition
product -
The percentage of impurities is expressed as percentage by weight of the
active ingredient
Desloratidine ; T=0 is the initial test date and 1 month refers to the
analysis time after
storage at 40 C/75% RH .
Im urities
T=0 1 Month
Compound 1 *
Compound 5 ' 0.002 *
Conlpound 2 *
Compound 3 0.005 *
Compound 6 *
Compound 7 , 0.005 *
Compound 8 0.005 *
Compound 4 *
Compound 9 ' *
Compound 10 . 0.02 *
Unknown Impurity
RRT :0.76
_ RRT :0.78
RRT :1.27
RRT :1.33 0.03
RRT :1.70
-
RRT :2.57 _
RRT :2.61
RRT :2.69 ' 0.04
RRT :2.71
RRT :2.74
RRT :2.73
RRT :3.33 .
Total unknown 0.00 0.07
Total related 0.04 0.07
*Impurities below 0.03% was not mentioned in results
Example 2 : tablets comprising Microcrystalline cellulose and Lactose anydrous
The composition of the tablets is as follows wherein the percentages are given
as percentage
of the overall weight of the composition:
Formulation II composition:
CA 02571933 2014-02-27
Ingredient no. Ingredient
1 Desloratadine (DCL) 5.88
- 2 Magnesium Oxide 2.65
3 Microcrystalline cellulose 79.41
PH 112 (Avicel PH 112)
4 Lactose anhydrous 5.29
Starch 1500 LM 5.59
6 Zinc stearate 1.18
Total 100
The Formulation II composition was prepared in a manner analogous to that for
the
preparation of the Formulation I composition above.
5
A stabilization study provided a stability profile of the above Formulation II
composition
product which indicated that the product is a stabilized formulation. The
stabilization
study was also conducted by packaging tablets of the above Formulation II
composition
in high density polyethylene (HDPE) bottles in the presence of a desiccant
(trisorb 1 g)
and of cotton batton and stored at 40 C/75% RH . Neither known nor unknown
impurities are more than 0.1% (by weight) when stored at 40 C/75% RH for 1
month.
After one (1) month the above Formulation II composition product (i.e. 20
tablets) were
subjected to a High Performance Liquid Chromatographic assay to determine
impurities;
the solvent system comprised a Buffer pH 3.5 and acetonitrile in ratio of
75:25 v/v;
column: USP Lll 4.6 x 150 mm, 3 uni; and detector: 240 nm. No color change of
the
core tablets was observed at 1 month accelerated stability time point.
The impurity results for Formulation II composition are set forth in Table 2
below:
TABLE 2: Stability compilation of Formulation II composition - The percentage
of
impurities is expressed as percentage by weight of the active ingredient
Desloratidine;
T=0 is the initial test date and 1 month refers to the analysis time after
storage at
40 C/75% RH
T=0 1 Month
Impurities
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CA 02571933 2014-02-27
1 Compound 1 0.00 0.00
Compound 5 0.00 0.00
Compound 2 0.00 0.00
Compound 3 0.00 0.00
Compound 6 0.00 0.00
Compound 7 0.00 0.00
Compound 8 0.00 0.00
Compound 4 0.00 0.00
Compound 9 0.00 0.00
Compound 10 0.00 0.00
Unknown Impurity
RRT:0.76 0.00 0.00
RRT:0.78 0.00 0.00
RRT:1.27 0.00 0.00
RRT:1.33 0.00 0.00
RRT:1.70 0.00 0.00
RRT:2.57 0.00 0.00
RRT:2.61 0.00 0.00
RRT:2.69 0.00 0.00
RRT:2.71 0.00 0.00
RRT:2.74 0.00 0.00
RRT:2.73 0.00 0.00
RRT:3.33 0.00 0.00
Total unknown 0.00 0.00
Total related 0.00 0.00
For the formulation compositions in examples 3 and 4 which follow, reference
is made in
the exemplified formulations III and IV to the additional presence of a OPADRY
Blue
coating in an amount of 2.5% w/w of the core tablet formulation. Reference(s)
is(are)
also made to the presence of a sufficient amount (q.s.) of water which is
mentioned in
relation to subsequently described the processes of making the respective
tablet
formulation compositions and not as an ingredient of the tablet formulation
composition
product.
Example 3: tablets comprising Microcrystalline cellulose and Lactose anydrous
The composition of the tablets is as follows wherein the percentages are given
as
percentage of the overall weight of the composition:
(coated) Formulation HI composition:
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Ingredient Ingredient
no.
Dry mix
1 Desloratadine (DCL) 5.88
2 Magnesium Oxide 2.65
3 Microcrystalline cellulose PH 101 34.71
(Avicel PH 101)
Binder
4 A Pregelatinized Starch (Starch 1500) 2.94
Purified Water q.s.
Lubrication
A Pregelatinized Starch (Starch 1500 2.65
LM)
6 Lactose anhydrous 5.29
7 Microcrystalline cellulose PH 112 44.71
(Avicel PH 112)
8 Zinc stearate 1.18
Total (of core tablet) 100
9 Opadry Blue 03B90819 2.5% w/w of core tablet
Purified Water q.s.
The Formulation III composition was prepared by wet granulation process as
described
below:
5 Manufacturing process of formulation III composition:
Step 1 Portion (apprx. 13.33% by weight of total core tablet weight) of
Microcrystalline cellulose PH 101 (of ingredient no. 3) was added in a high
shear granulator and mixed for 1 min at slow impeller speed (e.g. 300 rpm
impeller speed).
Step 2 Desloratidine and magnesium oxide was introduced in a Polyethylene
bag and
dispersed (i.e. mixed/blended) for 3 min. This blend was introduced in high
shear and mixed for 5 min at slow impeller speed(e.g. at 300 rpm impeller
speed).
Step 3 Remaining portion of Microcrystalline cellulose PH 101 (of
ingredient no. 3)
was passed through a 20 mesh (ASTM) screen then it was added in high shear
granulator of step 2 and mixed for 5 min at slow impeller speed (e.g. 300 rpm
impeller speed).
Step 4 Pregelatinized starch (starch 1500) was dissolved in Purified water
(15% starch
1500 in water) .
Step5 Step 3 blend was granulated in high shear granulator using
granulating solution
of step 4.
Step 6 Wet granules were dried using fluid bed dryer at 55 C inlet
temperature till the -
LOD (Loss On Drying) (105 C, 2g, 10 min) is achieved between 1.5 ¨ 2.5%.
Step 7 Dried granules were passed through co-mil equipped with 0.039"
screen and a
conventional standard impeller.
Step 8 Granules of step 7, Lactose Anhydrous, Microcrystalline cellulose PH
112 and -
Pregelatinized starch (Starch 1500 LM) were mixed in Polyethylene (PE) bag
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CA 02571933 2014-02-27
for 10 min.
Step 9 Zinc stearate was mixed with blend of step 8 for 60 seconds in
Polyethylene
PE bag.
Step 10 Final blend of step 11 was compressed using rotary tablet press (i.e..
a
, Betapress).
Step 11 Opadry Blue 03B90819 was dispersed in Purified water.
Step 12 Core tablets of step 10 were film coated up to 2.5%w/w weight gain
using
coating solution of step 11 in perforated coating pan.
Example 4 : tablets comprising Microcrystalline cellulose and Lactose
anhydrous and
prepared by wet granulation process
The composition of the tablets is as follows wherein the percentages are given
as
percentage of the overall weight of the composition:
Formulation IV composition:
Ingredient Ingredient %
no.
Dry mix
1 Desloratadine (DCL) 5.88
2 Microcrystalline cellulose PH 112 17.65
3 Magnesium Oxide 2.65
4 Microcrystalline cellulose PH 112 17.06
Binder
5 Pregelatinized starch (Starch 1500) 2.94
Purified Water q.s.
Lubrication
6 Pregelatinized starch (Starch 1500 LM) 2.65
7 Lactose anhydrous 5.29
8 Microcrystalline cellulose PH 112 42.70
9 Hydroxypropyl Methylcellulose 2208 2.00
Zinc stearate 1.18
Total (of core tablet) 100
11 Opadry Blue 03B90819 2.5%w/w of core tablet
Purified Water q.s.
The composition of Formulation IV composition was prepared by wet granulation
process
10 as detailed below:
Manufacturing process of formulation IV composition:
Step 1 Microcrystalline cellulose PH 112 (ingredient 2) was passed through
a 20
mesh (ASTM) screen then it was added in high shear granulator and mixed for
1 min at slow impeller speed.
Step 2 Desloratidine and magnesium oxide was introduced in a Polyethylene
bag and
dispersed for 3 min. This blend was passed through a 20 mesh (ASTM) screen,
introduced in high shear and mixed for 5 min at slow impeller speed.
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CA 02571933 2014-02-27
Step 3 Microcrystalline cellulose PH 112 (ingredient 4) was passed through
a 20
mesh (ASTM) screen then it was added in high shear granulator of step 2 and
mixed for 5 mm at slow impeller speed.
Step 4 Pregelatinized starch (starch 1500) was dissolved in Purified
water.
Step5 Step 3 blend was granulated in high shear granulator using
granulating solution
of step 4.
Step 6 Wet granules were dried using fluid bed dryer at 42 C inlet
temperature till the
LOD (105 C, 2g, 10 min) is achieved between 1.5 ¨ 2.5%.
Step 7 Dried granules were passed through co-mil equipped with 0.039"
screen and
standard impeller at slow speed (1200 rpm).
Step 8 Lactose Anhydrous, Microcrystalline cellulose PH 112 (ingredient
8),
Pre gelatinized starch (starch 1500 LM) and Hydroxypropyl Methylcellulose
2208 were passed through a 20 mesh (ASTM) screen.
Step 9 Granules of step 7 and powder of step 8 were mixed in Bin blender
for 1200
seconds at 14 rpm.
Step 10 Zinc stearate was passed through a 40 mesh (ASTM) screen and then it
was
dispersed in polyethylene bag with blend of step 9 for 30 seconds.
Step 11 Dispersion of step 10 and blend of step 9 were mixed in Bin blender
for 60
seconds then cover of bin blender were scrapped and again mixed for 60
seconds.
Step 12 Final blend of step 11 was compressed using rotary tablet press.
Step 13 Opadry Blue 03890819 was dispersed in Purified water.
Step 14 Core tablets of step 12 were film coated up to 2.5%w/w weight gain
using
coating solution of step 13 in perforated coating pan.
A stabilization study provided a stability profile of the above Formulation
III composition
product which indicated that the product is a stabilized formulation. The
stabilization
study was also conducted by packaging tablets of the above Formulation III
composition
in high density polyethylene (HDPE) bottles in the presence of a desiccant
(trisorb 1 g)
and of cotton batton and stored at 40 C/75% RH . Neither known nor unknown
impurities are more than 0.1% (by weight) when stored at 40 C/75% RH for 1
month.
After one (1) month the above Formulation III composition product (i.e. 20
tablets) were
subjected to a High Performance Liquid Chromatographic assay to determine
impurities;
the solvent system comprised a Buffer pH 3.5 and acetonitrile in ratio of
75:25 v/v;
column: USP L11 4.6 x 150 mm, 3 gm; and detector: 240 nm. No color change of
the
core tablets was observed at 1 month accelerated stability time point.
The impurity results for the above Formulation III composition are set forth
in Table 3
below:TABLE 3: Stability compilation of Formulation III composition - The
percentage
of impurities is expressed as percentage by weight of the active ingredient
desloratidine;
CA 02571933 2014-02-27
T=0 is the initial test date and 1 month refers to the analysis time after
storage at
40 C/75% RH
T=0 1 Month
Impurities
Compound 1 0.00 0.00
Compound 5 0.00 0.00
-Compound 2 0.00 0.00
Compound 3 0.00 0.00
Compound 6 0.00 0.00
Compound 7 0.00 0.00
Compound 8 0.00 0.00
Compound 4 0.00 0.00
Compound 9 0.00 0.00
Compound 10 0.00 0.00
Unknown Impurity
RRT:0.76 0.00 0.00
RRT:0.78 0.00 0.00
RRT:1.27 0.00 0.00
RRT:1.33 0.00 0.00
RRT:1.70 0.00 0.00
RRT:2.57 0.00 0.00
RRT:2.61 0.00 0.00
RRT:2.69 = 0.00 0.00
RRT:2.71 0.00 0.00
RRT:2.74 0.00 0.00
RRT:2.73 0.00 0.00
RRT:3.33 0.00 0.00
Total unknown 0.00 0.00
Total related 0.00 0.00
The stabilization study was also conducted by packaging tablets of the above
Formulation
IV composition in high density polyethylene (HDPE) bottles in the presence of
a
desiccant (trisorb 1 g) and of cotton batton and stored at 40 C/75% RI-! .
Neither known
nor unknown impurities are more than 0.1% (by weight) when stored at 40 C/75%
for 1 and 2 months. After one and two months the Formulation IV composition
product
(i.e. 20 tablets) were subjected to a High Performance Liquid Chromatographic
assay to
determine impurities; the solvent system comprised a Buffer pH 3.5 and
acetonitrile in
ratio of 75:25 v/v; column: USP L11 4.6 x 150 mm, 3 gm; and detector: 240 nm.
No
color change of the core tablets was observed at 1 and 2 months accelerated
stability time
point.
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CA 02571933 2014-02-27
The impurity results for Formulation IV composition are set forth in Table 3
below:TABLE 4:Stability compilation of Formulation IV composition - The
percentage of
impurities is expressed as percentage by weight of the active ingredient
Desloratidine;
T=0 is the initial test date and 1, 2 months refers to the analysis time after
storage at
40 C/75% RH.
I Month 2 Months
Assay (%) 99.0 97.4 981
Impurities <0.05% <0.05% <0.05%
Compound 1 <0.05% <0.05% <0.05%
Compound 5 <0.05% <0.05% <0.05%
Compound 2 <0.05% <0.05% <0.05%
Compound 3 <0.05% <0.05% <0.05%
Compound 6 <0.05% <0.05% <0.05%
Compound 7 <0.05% <0.05% <0.05%
Compound 8 <0.05% <0.05% <0.05%
Compound 4 <0.05% <0.05% <0.05%
Compound 9 <0.05% <0.05% <0.05%
Compound 10 <0.05% <0.05% <0.05%
Unknown Impurity
RRT: 2.26 <0.05% 0.05%
RRT:3.93 <0.05% 0.06%
Total unknown <0.05% 0.05% 0.06%
Total related <0.05% 0.05% 0.06%
Example 5: pH determinations for formulations with varying amounts of MgO
A number of test were conducted to determine the amount of MgO which was
needed to
obtain a solution pH in the range of from about 5 to about 9.5. Thus, for
the pH study,
a series of powder blends was prepared using Desloratadine (5 mg) ,
Microcrystalline
cellulose PH 112 (74 mg), Starch 1500 LM, (20 mg) , Zinc stearate(1 mg) and
with
varying amounts of Magnesium Oxide as set forth in table 2 below.
The pH investigation was carried out using by observing the pH change of 25 ml
of 0.001
N Hydrochloric Acid, before and after addition into it of formulations of the
present
invention.
The method for pH determination was carried out as follows::
17
CA 02571933 2014-02-27
(1) 25 ml of 0.001 N Hydrochloric acid was placed in glass beaker and the pH
determined using a pH meter.
(2) Thereafter one tablet or an equivalent amount of the composition was
admixed to the
acid in then glass beaker of step (1) and stirred with a glass rod until the
composition
was completely dispersed.
(3) the pH of the dispersion (obtained from step (2)) was then measured with
the pH
meter.
The results of the pH tests are set forth in the following table:
Formulation Amount of pH of 0.001 N pH of 0.001 N
composition Magnesium oxide Hydrochloric acid Hydrochloric acid
No. added before addition of after addition of
blend blend
1 0% w/w 2.961 4.047
2 1% w/w 3.041 5.193
3 2% w/w 2.993 6.572
4 2.5% w/w 2.996 9.091
5 5% w/w 2.953 9.427
As may be seen from the above table MgO may advantageously be used in amounts
of
from about 1% to about 5% (in particular from about 1% to about 2.65%; more
particularly from about 1% to about 2.5%; e.g. from about 1% to about 2.25%;)
by weight
of the composition.
18
