FIELD OF THE INVENTION
The invention relates to pharmaceutical composition comprising 15-30 % w/w of
clomiphene citrate, 2-5% w/w of binder and 0.5-5% w/w of disintegrant. The
clomiphene citrate is having the particle size ranges less than 10 microns.
The invention also relates to pharmaceutical compositions comprising an
oral composition of clomiphene citrate and processes for preparation thereof.
BACKGROUND OF THE INVENTION
Clomiphene citrate (I) is chemically known as 2-[4-(2-chloro-1,2-
diphenylethenyl) phenoxy]-N,N-diethylethanamine-2-hydroxypropane-1,2,3-
tricarboxylic acid and its chemical structure is as follows:
Clomiphene citrate is a white to pale yellow, essentially odorless, crystalline
powder with a pKa of 9.31. Clomiphene citrate is freely soluble in methanol, soluble
in ethanol, slightly soluble in acetone, water, and chloroform and insoluble in ether.
Clomiphene citrate is the citrate salt form of clomiphene, a
triphenylethylene nonsteroidal ovulatory stimulant evaluated for both estrogenic
and anti-estrogenic activities that compete with estrogen for binding at estrogen
receptor sites in target tissues. This agent causes the release of the pituitary
gonadotropins follicle stimulating hormone (FSH) and luteinizing hormone (LH),
leading to ovulation. Clomiphene citrate has approved by The United States Food
and Drug Administration (FDA) on February 1, 1967 and it sold under the
tradename CLOMID® for the treatment of ovulatory dysfunction in women desiring
pregnancy. In India, Clomiphene citrate was approved by Central Drugs Standard
Control Organization on February 1974 as a fertility drug- induction of ovulation
in patients with persistant ovulatory dysfunction who desire pregnancy.
2
Clomiphene is a synthetic estrogen agonist antagonist which has been
widely used for the induction of ovulation in anovulatory women for many years
(Greenblatt et al (1961); J. Am. Med. Ass. 178:101-104)
Clomiphene composition and its salts have been disclosed in US2914563
(Robert E. Allen et al.). US ‘563 discloses the derivatives of triphenylethylene
which indicated for the anti-estrogenic activity. Example 3, disclosed the
preparation of citrate form of said compound. Other examples also disclosed the
tablet, capsule, injectable, oral suspension, and syrups as finished form with other
derivatives of triphenylethylene.
Clomiphene is a racemic mixture of cis and trans isomers. The original cis
and trans isomers were called isomer-B and isomer-A respectively. In 1976, it was
revealed that the cis and trans nomenclature had been mistakenly reversed (Ernst et
al. (1976); J. Pharm. Sci 65 : 148-150).
Currently the authentic cis and trans isomers are called Zuclomiphene (with
oestrogenic activity) and Enclomiphene (with antioestrogenic activity).
Ismagilov Iskandar et al. in RU2570383 covers the anti-estrogenic tablet
composition as clomiphene citrate (1: 1) and lactose moistened mass of 5.5%
aqueous gelatin solution using granulation in a fluidized followed by drying and
granules are subjected to dry granulation through a mesh having granules dusted
starch, talc and magnesium stearate and compressed into tablets.
Joseph S. Podolski et. al. in WO2014031177 discloses the pharmaceutical
compositions using trans -clomiphene or pharmaceutically acceptable salts and
solvates having a specified size range of and their use in treating disorders including
secondary hypogonadism, type 2 diabetes, elevated cholesterol, elevated
triglycerides, wasting, lipodystrophy, female and male infertility, benign prostate
hypertrophy, prostate cancer, breast cancer, ovarian cancer and endometrial cancer.
Despite several formulations reported in the prior art however, due to
unsuitable tableting properties of clomiphene citrate and its reported formulations
itself, still there remains need for the composition/formulation, which are scalable
3
on industrial scale and results in stable pharmaceutical composition with enhance
dissolution profile.
SUMMARY OF INVENTION
Provided herein are simple and easily scalable oral unit solid pharmaceutical
compositions of clomiphene citrate with improved granulating, tabletting
properties, and the process of preparing such composition. The present invention
provides a tablet containing clomiphene citrate, which provides high stability of
clomiphene citrate within the compositions.
In one aspect of the present invention it relates an oral pharmaceutical composition
of clomiphene citrate comprising 15-30% w/w of clomiphene citrate, 2-5% w/w of
binder and 0.5-5% w/w of disintegrant, wherein disintegrant is selected from
polyvinyl-n-pyrrolidone and at least 90% particles of active pharmaceutical
ingredient is having a size of less than 10 microns.
In another aspects of the present invention, it relates to a pharmaceutical
composition of clomiphene citrate comprising 15-25 % w/w of clomiphene citrate,
2-5% w/w of binder and 0.5-5% w/w of disintegrant, wherein the composition is
prepared using binder as povidone in aqueous solution.
In yet another aspects of the present invention, it relates to a process of
preparing pharmaceutical composition of clomiphene citrate wherein the process
comprising the steps of:
a) shifting diluent and glidant followed by pre-mixing with povidone
aqueous binder solution for 10-20 min.
b) perform fluidization using premixed material at 50-60°C.
c) drying and sifting the granules to prepare intragranular part.
d) adding extragranular part comprising with clomiphene citrate and other
pharmaceutical acceptable excipients, followed by blending.
4
In yet another aspects of the present invention, it relates to preparing
pharmaceutical compositions for oral administration comprising a step of admixing
the clomiphene citrate extragranular and intragranular part followed by blending
with pharmaceutically acceptable excipients, optionally, comprising a step of
compressing the composition into tablets, and optionally followed by a film-coating
or directly encapsulating in desired capsule size.
In further another aspects of the present invention, it relates to process of
preparing pharmaceutical composition, wherein the addition of
polyvinylpyrrolidone in extragranular part alone or with intragranular part or both.
The solid oral pharmaceutical composition of clomiphene citrate according
to present invention may be useful in for the treatment of infertility in women.
Various other specific aspects of the invention are further detailed in the
description part of the specification, wherever appropriate.
DETAILED DESCRIPTION
The present invention provides novel pharmaceutical composition of
clomiphene citrate which are useful in the treatment of infertility in women.
In one embodiment according to present invention, it provides an oral
pharmaceutical composition of clomiphene citrate comprising 15-30% w/w of
clomiphene citrate, 2-5% w/w of binder and 0.5-5% w/w of disintegrant, wherein
disintegrant is selected from polyvinyl-n-pyrrolidone and at least 90% particles of
active pharmaceutical ingredient is having a size of less than 10 microns.
Clomiphene citrate as an orally administered, nonsteroidal, ovulatory
stimulant active substance, typically prescribed with a low dose, 50 mg daily (1
tablet) for 5 days. The dose should be increased only in those patients who do not
ovulate in response to cyclic 50 mg of dose. It is a white to pale yellow, essentially
odorless, crystalline powder with slightly soluble in acetone, water, and chloroform;
and insoluble in ether. Clomiphene citrate shown to be readily absorbed orally in
5
humans and excreted principally in the faeces. The two clomiphene isomers have
been found to have mixed estrogenic and antiestrogenic effects, which may vary
from one species to another. Some data suggest that zuclomiphene has greater
estrogenic activity than enclomiphene. It is pharmaceutically compatible with most
of the reported adjuvants/excipients. Thus, in view of the dosage desired for the
therapy and the nature of the active ingredient, there is a further need to optimize
the pharmaceutical dosage forms comprising clomiphene citrate so that it is
convenient to manufacture, administer, and simultaneously provide the requisite
daily dosage of clomiphene.
It is also required that the said pharmaceutical dosage forms exhibit stability
upon storage, as this is essential to ensure an adequate shelf life of the final dosage
form. Further there is an apparent need to develop an optimized stable
pharmaceutical dosage form that contains an appropriate dosage amount of
clomiphene citrate and also exhibits stability throughout the shelf life with enhance
dissolution profile. The particle size of the clomiphene citrate is having a
significantly impact on dissolution profile.
The present invention particularly provides a pharmaceutical composition
of clomiphene citrate and active pharmaceutical ingredient (API) in the
composition of clomiphene citrate according to present invention may be isomer or
racemic mixture physically crystalline powdered material.
The mean particle size of clomiphene citrate according to the present
invention is less than about 15 microns, preferably between about 04 and about 06
microns. Further, the invention encompasses clomiphene citrate with at least 90%
of the particles having a particle size of less than about 15 microns. More preferably,
at least 90% of the particles having a size of less than about 10 microns.
The invention also provides pharmaceutical compositions comprising or
formulated using clomiphene citrate with a particle size within the specified narrow
range and one or more pharmaceutically acceptable carriers.
6
Trans-clomiphene is characterized for size using an instrument adapted to
measure equivalent spherical volume diameter, such as a Malvern Mastersizer 2000
laser diffraction particle size analyzer or equivalent instrument. After being
characterized for size, the clomiphene is then milled, if necessary, preferably using
a pin mill under suitable conditions of mill rotation rate and feed rate, to bring the
particle size value within the above mentioned limits according to the invention.
The efficiency of milling is checked by sampling using a Malvern Mastersizer 2000
laser diffraction particle size analyzer and the final particle size is checked in a
similar manner.
In one of the specific embodiment, racemic mixture was utilized to prepare
the composition.
In pharmaceutical excipients, “binders” are compounds which cause
agglomeration of drug and excipient particles during the manufacturing process and
act to control the release of drug from the dosage form. The agglomeration can be
in the form of a granulation or a powder. The present invention provides the
pharmaceutical composition of clomiphene citrate comprising binder selected from
cellulose derivatives e.g. ethyl cellulose, methyl cellulose, guar gum, blende guar
gum and other cellulose e.g. cellulose gums (carboxymethyl cellulose,
hydroxypropyl methylcellulose, and hydroxypropyl cellulose),
polyvinylpyrrolidone (povidone), cross-linked polyvinylpyrrolidone,
pregelatinized starch, acacia, alginic acid, carbomer, dextrin, maltodextrin.
In a specific embodiment according to present invention the binder used in
the pharmaceutical composition was povidone.
The present invention also provides the pharmaceutical composition of
clomiphene citrate comprising disintegrant wherein disintegrant is selected from
mannitol, alginic acid, carboxymethylcellulose, hydroxypropylcellulose,
microcrystalline cellulose, croscarmellose sodium, povidone, polyvinyl-npyrrolidone
(crospovidone), magnesium aluminum silicate, methylcellulose,
7
sodium alginate, starches or modified starches such as sodium starch glycolate, corn
starch, potato starch or pregelatinized starch.
The pharmaceutical composition of clomiphene citrate comprising the
addition of disintegrant in intragranular or extragranular part of composition.
Inventors of present invention successfully optimized the addition of
disintegrant in intragranular or extragranular part of the composition or both.
It is required that the pharmaceutical composition of the present invention
provide adequate compaction with desired disintegration time. Inventors of the
present invention surprisingly found that disintegrant play a major role and impact
on pharmaceutical composition when disintegrant is distributed as intragranular or
extragranular or both part of process for preparing the composition.
Present invention also provides the pharmaceutical composition of
clomiphene citrate comprising disintegrant as polyvinyl-n-pyrrolidone wherein the
total weight of disintegrant is to distribute as intragranular or extragranular or both.
In one embodiment according to present invention, it provides a
pharmaceutical composition of clomiphene citrate comprising 15-25 % w/w of
clomiphene citrate, 2-5% w/w of binder and 0.5-5% w/w of disintegrant, wherein
the composition is prepared using binder as povidone in aqueous solution.
The invention, provides a process for preparing pharmaceutical composition
comprising clomiphene citrate, the process particularly comprises wetting
extragranular part with a granulation liquid, which is aqueous containing binder,
and granulating the mixture in a suitable granulator, e.g. high shear (Rapid mixer
granulator/RMG) or fluid bed granulator (FBG or FBP), followed by drying, and
optionally, sieving and/or milling, slugging.
Present invention also provides a process for preparing pharmaceutical
composition comprising clomiphene citrate whereas the granules further followed
by drying, and optionally, sieving and/or milling.
8
Further step of present invention involves addition of extragranular part of
excipients and blending to make final blend for tablet compression, or filling into
hard gelatin capsules.
In yet another embodiment of the present invention, it provides to a process
of preparing pharmaceutical composition of clomiphene citrate wherein the process
comprising the steps of:
a) shifting diluent and glidant followed by pre-mixing with povidone
aqueous binder solution for 10-20 min.
b) perform fluidization using premixed material at 50-60°C.
c) drying and sifting the granules to prepare intragranular part.
d) adding extragranular part comprising with clomiphene citrate and other
pharmaceutical acceptable excipients, followed by blending.
The step a) of sifting the diluent and glidant according to the present
invention, carried out in a shifter by conventional method however it was found that
sifting carried out using mesh size of ranging between 35#-45# at temperature
ranging between 15-30° C.
Premixing of both sifted material is carried out for 5-15 min using fluidized
bed processor. However, it is preferred that a time of 5-10 min premixing is
necessary.
Furthermore, the step b) of premixed material is added in binder solution of
povidone and performed fluidization using premixed mixture using fluidized bed
granulator for 20-30 min.
The step c) of drying according to the present invention, the fluidized
material is dried using trey drier at 50-60° C for 20-30 min and sifted using the mesh
size ranging between 20#-30#. As advantage of sifting inventors of the present
application found that this kind of step has satisfactory outcome and betterment of
further step.
9
Further process carried out in step d), clomiphene citrate passed through the
mesh size ranging 50#-70# and blend with the material prepared in step c) as
intragranular part of the for 10-20min using blender.
In further the pharmaceutical acceptable excipients as extragranular part of
the composition, disintegrant and filler passed by using the mesh size ranging
between 50#-70# and mixed with the part of the composition prepared in step d) for
5-20 min.
The inventors of the present invention found that the addition of disintegrant
in intragranular and extragranular part of the composition gives satisfactory
response in dissolution profile and the sifting of materials also gives better flow
property of the granules and easier for further step.
The prepared mixture as per above mixed with lubricant, glidant and as per
present invention further processed for compression and/or encapsulating in
capsules shell.
In yet another embodiment of the present invention, it provides to prepare
pharmaceutical compositions for oral administration comprising a step of admixing
the clomiphene citrate granulate with pharmaceutically acceptable excipients,
optionally, comprising a step of compressing the composition into tablets, and
optionally followed by a film-coating or directly encapsulating in desired capsule
size.
The granulate composition according to the present invention may be use
for making the solid oral composition which may be further film coated. However,
inventors of the present application have surprisingly found the advantages of
admixing extragranular component more particularly a combination of disintegrant
and lubricant. This extragranular component addition in granulate composition
provides improved dissolution profile. Besides additional advantages in trouble
from compression and subsequent coating process.
The pharmaceutical composition of clomiphene citrate according to present
invention involves necessarily use of lubricant, wherein lubricant is selected from
10
magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl
fumarate, vegetable oil, mineral oil.
Inventors of the present application additionally found the advantage of
addition of lubricant as magnesium stearate which upon addition as extragranular
component give the improved flow of granules in hopper while performing the
compression or filling in capsule shells.
It has been observed by present inventors that various composition
discussed in prior art suffer a disadvantage of either not meeting dissolution profile
parameters or making coating process non-uniform and difficult which may results
as blistering, chipping, picking, blushing, cracking (splitting) or the like.
The inventors of the present invention of pharmaceutical composition of
clomiphene citrate gives the advantages over aforementioned difficulties while
preparing for pharmaceutical composition by admixing an optimized lubricant,
glidant and fillers.
Present invention, provides a process for making the pharmaceutical
composition for oral administration comprising a step of admixing
pharmaceutically acceptable excipients and clomiphene citrate, comprising a step
of compressing the composition into tablets, optionally followed by a non-aqueous
film-coating.
The term "oral" administration means that the active agent is in a
formulation designed to be ingested, i.e. designed to be delivered to the
gastrointestinal system for absorption.
The term "oral solid composition" or "oral pharmaceutical composition"
comprises capsule, tablet (film coated tablet, controlled release tablet, modified
release tablet, delayed release etc.), micro tablet, powder, granule and pellets.
Capsules used as oral dosage form can be soft or hard capsules, though oral dosage
form of the present invention is tablet or capsule.
The term "about" is a value that can be considered ±5% of the given value.
11
Based on context of discussion, the term "% w/w" refers to the relative value
to total weight of granules or to total weight of pharmaceutical composition and “%
v/v” refer to volume by total volume percentage.
In one of embodiments, the application provides pharmaceutical dosage
forms of clomiphene citrate having content uniformities (CU) from about 90% to
about 110% by weight, with relative standard deviations (RSD) of not more than
about 5%. In embodiments, the invention relates to pharmaceutical formulations
having a disintegration time of less than about 15 minutes. In embodiments, the
invention relates to pharmaceutical formulations having friability not more than
about 1 % w/w.
Usage of the terms "a" and "an" and "the" and similar referents in the context
of describing the invention (especially in the context of the following claims) are to
be construed to cover both the singular and the plural, unless otherwise indicated
herein or clearly contradicted by context. The terms "comprising," "having,"
"including," and "containing" are to be construed as open-ended terms (i.e.,
meaning "including, but not limited to,") unless otherwise noted. Recitation of
ranges of values herein are merely intended to serve as a shorthand method of
referring individually to each separate value falling within the range, unless
otherwise indicated herein, and each separate value is incorporated into the
specification as if it were individually recited herein. The term wt % refers to
percent by weight. All methods described herein can be performed in any suitable
order unless otherwise indicated herein or otherwise clearly contradicted by
context. The use of any and all examples or exemplary language (e.g. "such as")
provided herein, is intended merely to better illuminate the invention and does not
pose a limitation on the scope of the invention unless otherwise claimed. No
language in the specification should be construed as indicating any non-claimed
element as essential to the practice of the invention.
The terms “pharmaceutically acceptable excipients”, “pharmaceutically
compatible excipients”, and “excipients” are used interchangeably in this
disclosure. They refer to non-API substances such as disintegrators, binders, fillers,
12
and lubricants used in formulating pharmaceutical composition. They are generally
safe for administering to humans according to established governmental standards,
including those promulgated by the United States Food and Drug Administration.
The term "mean particle size" is defined as equivalent spherical diameter as
determined by laser light diffraction scattering.
Particular embodiments of this invention are described herein, including the
best mode known to the inventors for carrying out the invention. Variations of those
particular embodiments may become apparent to those of ordinary skill in the art
upon reading the foregoing description. The inventors expect skilled artisans to
employ such variations as appropriate, and the inventors intend for the invention to
be practiced otherwise than as specifically described herein. Accordingly, this
invention includes all modifications and equivalents of the subject matter recited in
the claims appended hereto as permitted by applicable law. Moreover, any
combination of the above-described elements in best possible variations thereof is
encompassed by the invention unless otherwise indicated herein or otherwise
clearly contradicted by context.
While the forgoing pages provide a detailed description of the preferred
embodiments of the invention, it is being understood that the summary, description
and examples are illustrative only of the core of the invention and non-limiting.
Furthermore, as many changes can be made to the invention without departing from
the scope of the invention, it is intended that all material contained herein be
interpreted as illustrative of the invention and not in a limiting sense.
13
EXAMPLE 01-04
Tablet 01: Composition of Clomiphene citrate
INGREDIENTS
Intragranular
Clomiphene
Citrate
polyvinyl-npyrrolidone
(PVNP)
Maize starch
Microcrystalline
cellulose
Quantity (mg/ tablet)
Example 1
PVNP 0.5%
50.85
1.25
8.75
160.53
Example 2
PVNP 1.0%
50.85
2.5
8.75
158.03
Granulating fluid
Povidone
Aqueous
Extragranular
Talc
Silicon di-oxide
Maize starch
(dried)
Magnesium
stearate
Core tablet
weight
10.0
q.s
PVNP 1.5%
2.5
2.5
7.99
1.875
250.0
10.0
q.s
PVNP 2.0%
2.5
2.5
7.99
1.875
250.0
Example 3
PVNP 1.5%
50.85
3.75
8.75
155.53
10.0
q.s
PVNP 2.5%
2.5
2.5
7.99
1.875
250.0
Example 4
PVNP 2.0%
50.85
5.0
8.75
153.03
10.0
q.s
PVNP 3.0%
2.5
2.5
7.99
1.875
250.0
Manufacturing process for preparation of clomiphene citrate tablet composition
using wet granulation:
1. Microcrystalline cellulose sifted using sieve #40
2. Maize starch and polyvinyl-n-pyrrolidone sifted separately using sieve #100
14
3. Prepared granulating fluid using povidone in aqueous medium at temperature not
more than 50°C.
4. Step 01 and 02 materials a loaded into Mass mixture and pre-mix step carried for
5-10 min and the granulating part of step 03 into the pre-mix material with proper
mixing for 20 minutes.
5. The wet granules are dried at 50-60°C and passed through sieve #24. After
sieving the mixture processed for blending.
6. Clomiphene citrate passed through sieve #60 added blend for 10- 15 min in
blender.
7. Polyvinyl-n-pyrrolidone as extragranular and maize starch passed through sieve
#60 added in above blend and mixed for 5 min.
8. Step 7 followed with lubrication stage and blending with sifted talc, silicon dioxide
and magnesium stearate through sieve # 60.
9. The final blend is compressed with appropriate punch size.
Tablets prepared of Examples is packaged in closed HOPE containers,
together with desiccant canister, and stored at three different conditions: 25°C and
60% relative humidity (Condition 1), 30°C and 65% RH (Condition 2) or 40°C and
75% RH (Condition 3) for one month. Dissolution testing results of initial and
stored samples are shown in Table 2. The dissolution study is conducted in 900 ml
of aqueous medium, using BP type 2 (basket) apparatus, while stirred at 100 rpm
for 45 minutes.
Dissolution testing results of tablets of Examples 01-04 are shown in Table 02
Table 02:
Time (Minutes)
5
Cumulative% of Drug Dissolved
Trial-01
Avg.
15.5
%
RSD
4.51
Trial-02
Avg.
18.9
%
RSD
2.33
Trial-03
Avg.
45.9
% RSD
2.95
Trial-04
Avg.
85
% RSD
4.12
15
10
15
20
30
45
20.4
30.2
50.9
61.1
68.2
3.93
4.82
2.21
5.65
3.22
26.6
41.8
56.2
68.4
73.52
5.48
4.35
3.86
2.98
4.36
59.3
65.4
65.8
77.2
79.8
2.56
3.65
2.75
3.48
2.69
95
91
91
93
97
11.27
2.92
7.14
6.57
8.22
The abovementioned examples, which are provided by way of illustration,
should not be construed as limiting the scope of the invention with respect to
parameter/s, ingredient/s and quantities used in any manner.

We Claims,
01. An oral pharmaceutical composition of clomiphene citrate comprising 15-30%
w/w of clomiphene citrate, 2-5% w/w of binder and 0.5-5% w/w of disintegrant,
wherein disintegrant is selected from polyvinyl-n-pyrrolidone and at least 90%
particles of active pharmaceutical ingredient is having a size of less than 10
microns.
02. An oral pharmaceutical composition of clomiphene citrate according to claim
1, comprising 15-30% w/w of clomiphene citrate, 2-5% w/w of binder and 0.5-5%
w/w of disintegrant, wherein the composition is prepared using binder as povidone
in aqueous solution.
03. A process for preparing oral pharmaceutical composition according to the claim
1, wherein the solid oral composition is tablet or capsule.
04. A process of preparing pharmaceutical composition of clomiphene citrate
wherein the process comprising the steps of:
a) shifting diluent and glidant followed by pre-mixing with povidone
aqueous binder solution for 10-20 min.
b) perform fluidization using premixed material at 50-60°C.
c) drying and sifting the granules to prepare intragranular part.
d) adding extragranular part comprising with clomiphene citrate and other
pharmaceutical acceptable excipients, followed by blending.
05. A process for preparing the pharmaceutical composition according to the claim
4 wherein the addition of polyvinyl-n-pyrrolidone in extragranular part alone or
with intragranular part or both.
06. A process for preparing the pharmaceutical composition according to the claim
4 wherein step d) of adding extragranular composition comprising pharmaceutical
acceptable excipients selected from maize starch, silicone di-oxide and magnesium
stearate.
17
07. A process for preparing the pharmaceutical composition according to the claim
5, wherein the ratio of polyvinyl-n-pyrrolidone in extragranular part and
intragranular part is 1-5:1.