PHARMACEUTICAL COMPOSITION COMPRISING PHENTERMINE AND
TOPIRAMATE
Field of the Invention
This invention relates to a pharmaceutical composition comprising a combination of
phenterrnine in an immediate release form and topiramate in an extended release form. Further. it
relates to processes for the preparation of the composition and the method of using the composition.
Background of the Invention
The prevalence of obesity in both children and adults is on the rise in first world countries,
especially in the United States, as well as in many developing countries such as China and India.
Many aspects of a person's life are affected by obesity, leading to physical problems such as knee
and ankle joint deterioration. The medical problems caused by obesity can be serious and often lifethreatening
and include diabetes, shortness of breath and other respiratory problems such as asthma
and pulmonary hypertension, gallbladder disease, dyslipidemia (for example, high cholesterol or
high levels of triglycerides) and dyslipidemic hypertension, osteoarthritis and other orthopedic
problems, reflux esophagitis (heartburn), snoring, sleep apnea, menstrual irregularities, infertility,
problems associated with pregnancy, gout, cardiovascular problems such as coronary artery disease
and other heart trouble, muscular dystrophy, and metabolic disorders such as
hypoalphalipoproteinemia, familial combined hyperlipidemia, and syndrome X, including insulinresistant
syndrome X. In addition, obesity has been associated with an increased incidence of certain
cancers, notably cancers of the colon, rectum, prostate, breast, uterus, and cervix.
Strategies for treating obesity and related disorders have included dietary restriction,
increased physical activity, pharmacological approaches, and even surgery, with the choice
depending, at least in part, on the degree of weight loss one is attempting to achieve as well as on the
severity of obesity exhibited by the subject.
Phentermine has been used as monotherapy in the treatment of obesity for about 30 years.
Phentermine acts on the hypothalamus, an appetite control center of the brain. Phentermine
monotherapy can increase weight loss when used in combination with diet and exercise, as compared
to diet and exercise alone. However, the drug loses effectiveness after about two weeks and, in fact,
is not approved by the FDA for use beyond six weeks. Moreover, weight loss may not be permanent,
especially after the drug is discontinued. Phentermine treatment is also associated with side effects
including nervousness, irritability, headache, sweating, dry-mouth, nausea and constipation.
The above listed shortcomings encouraged the use of phentermine in combination with other
agents. Various combination therapies that include phentermine as one of the agents have been
investigated and have met with mixed success. More recently, it has been suggested that phentermine
in combination with anti-convulsant is a potentially effective therapy for effecting weight loss.
Combination therapy for effecting weight loss and treating obesity with a sympathomimetic
agent (e.g., phentermine or a phentermine-like drug) and an anticonvulsant sulfamate derivative (e.g.
topiramate) is disclosed in U.S. Patent Nos. 7,674.776; 7,659,256; 7,553,818; and 7,056,890. A
disclosed preferred embodiment of pharmaceutical composition in these patents includes
phentermine in an immediate release formulation and further includes topiramate in a controlled
release formulation.
US Publication No. 2008101 13026 discloses a layered pharmaceutical formulation including
two or more pharmaceutical layers and an intermediate layer disposed between the two or more
pharmaceutical layers. A formulation wherein the first pharmaceutical layer comprises phentermine
and the second pharmaceutical layer comprises topiramate is disclosed.
US Publication No. 200810085306 discloses a delayedextended release formulation of
topirarnate for once-a-day administration.
US Publication Nos. 200910304789 and 200910304785 disclose a controlled release
composition for treating obesity, diabetes or a related condition in a subject comprising topiramate,
microcrystalline cellulose and methylcellulose. The patent applications also disclose a method for
treating obesity andor effecting weight loss by administering topiramate and optionally, in addition,
a sympathomimetic agent such as phentermine.
US Publication No. 2006/0 12 1 1 12 discloses a topirarnate formulation with an immediate
release component of topiramate and a delayed release component of topiramate.
US Publication No. 2008/0118557 discloses a sustained release topiramate formulation
comprising a topiramate containing enhanced immediate release (EIR) component and an extended
release (XR) component.
US Publication No. 201210003312 disclose multilayer minitablets comprising an immediate
release layer of phentermine and modified release layer of topiramate.
There is a need in the art to develop drug formulations in which phentermine is present in an
immediate release form and topiramate is present in an extended release form that involve simple
methods of production and are cost effective.
Summary of the Invention
The object of the present invention is to provide a pharmaceutical composition comprising
phentermine in an immediate release (IR) form and topiramate in an extended release (ER) form.
Accordingly in one aspect, the present invention relates to a pharmaceutical composition of
phentermine and topiramate comprising:
(i) an extended release portion comprising a therapeutically effective amount of topiramate
or its pharmaceutically acceptable salt, one or more rate-controlling agents and one or
more pharmaceutically acceptable excipients.
(ii) an immediate release portion comprising a therapeutically effective amount of
phentermine or its pharmaceutically acceptable salt and one or more pharmaceutically
acceptable excipients.
Embodiments of the composition may include one or more following features. For example,
the extended release topiramate portion and the immediate release phentermine portion may be
present as cores. The cores may be in the form of pellets, granules, beads, minitablets or tablets.
In one embodiment, the extended release topiramate portion is present as cores and the
immediate release phentermine portion is present as a coating over the extended release portion.
In another embodiment, the extended release topiramate cores are present as matrix cores
with an optional extended release polymer coating over the cores.
In another embodiment, the extended release topiramate cores are present as reservoir cores
produced by coating the immediate release topiramate cores with an extended release polymer
coating.
In another embodiment, the pharmaceutical composition of the present invention may be a
hard gelatin capsule or a tablet.
In another aspect, the present invention relates to a process of preparing a pharmaceutical
composition of phentermine and topiramate, wherein the process comprises the steps of:
(i) preparing extended release topiramate cores comprising a therapeutically effective amount
of topiramate or its pharmaceutically acceptable salt, one or more rate-controlling agents and
one or more pharmaceutically acceptable excipients,
(ii) preparing immediate release phentermine cores comprising a therapeutically effective
amount of phentermine or its pharmaceutically acceptable salt and one or more
pharmaceutically acceptable excipients, and
(iii) combining the extended release topiramate cores and the immediate release phentermine
cores.
In one embodiment the extended release topiramate cores are prepared by the processes
known in the art, such as, compaction, dry granulation. wet granulation, fluidized bed granulation
and extrusion-spheronization.
In another embodiment the extended release topiraillate cores are prepared by coating the
immediate release topiramate cores with a layer of one or more rate controlling agents.
In another embodiment, the immediate release topiramate cores are prepared by extrusionspheronization.
In another embodiment, the immediate release topiramate cores are prepared by layering
topiramate solution1 dispersion over the inert cores.
In another embodiment, the extended release topiramate cores and the immediate release
phentermine cores are blended and encapsulated into a hard gelatin capsule.
In another embodiment, the extended release topiramate cores and the immediate release
phentermine cores are blended and compressed into a tablet. The tablet may be a monolithic tablet,
bilayered tablet, inlay tablet or a compression coated tablet.
In another aspect, the present invention relates to a process of preparing a pharmaceutical
composition of phentermine and topiramate, wherein the process comprises the steps of:
(i) preparing extended release topiramate cores comprising a therapeutically effective amount
of topiramate or its pharmaceutically acceptable salt, one or more rate-controlling agents
and one or more pharmaceutically acceptable excipients,
(ii) dissolving or dispersing phentermine or its pharmaceutically acceptable salt and one or
more pharmaceutically acceptable excipients into a suitable solvent,
(iii) layering the extended release topiramate cores with the solution or dispersion of
phentermine, and
(iv) filling the cores prepared in step (iii) into a hard gelatin capsule or compressing the cores
to form a tablet.
In one embodiment, the solvents used for preparing the solution or dispersion of phentermine
include, but are not limited to, methylene chloride, isopropyl alcohol, acetone, methanol, ethanol,
water or mixtures thereof.
In another general aspect, the present invention relates to a method of treating obesity and
related disorders by administering to a person in need thereof a pharmaceutical composition of
phentermine and topiramate comprising:
(i) an extended release portion comprising a therapeutically effective amount of topiramate or
its pharmaceutically acceptable salt, one or more rate-controlling agents and one or more
pharmaceutically acceptable excipients,
(ii) an immediate release portion comprising a therapeutically effective amount of phentermine
or its pharmaceutically acceptable salt and one or more pharmaceuticallq acceptable
excipients.
The details of one or more embodiments of the invention are set forth in the description
below. Other features and objects of the invention will be apparent from the description and
examples.
Description of the invention
The object of the present invention is to provide a pharmaceutical composition comprising
phentermine in an immediate release (IR) form and topiramate in an extended release (ER) form.
The present invention relates to a pharmaceutical composition of phentermine and topiramate
comprising:
(i) an extended release portion comprising a therapeutically effective amount of topiramate
or its pharmaceutically acceptable salt, controlled release polymers and one or more
pharmaceutically acceptable excipients,
(ii) an immediate release portion comprising a therapeutically effective amount of
phentermine or its pharmaceutically acceptable salt and one or more pharmaceutically
acceptable excipients.
The term "therapeutically effective amount" of phentermine or topiramate refers to an
amount in which the agent is nontoxic but sufficient to provide the desired effect.
The term "pharmaceutically acceptable salt" include salts which are formed with inorganic
acids or organic acids or with bases. Suitable salts include salts formed with hydrochloric,
phosphoric, acetic, oxalic, tartaric or mandelic acids or those formed with bases such as sodium,
potassium, ammonium, calcium, or ferric hydroxides.
The term "topiramate" as used herein would encompass topiramate base and all its salts.
Topiramate or its salt is present in the composition in an amount of from about 2% to about 85% by
weight, more particularly from about 5% to about 75% by weight of the composition.
6
• The term "phentermine" as used herein would encompass phentermine base and all its salts.
In particular the pharmaceutical composition of the present invention comprises phentermine
hydrochloride. Phentermine or its salt is present in the composition in an amount of from about
0.001% to about 40% by weight of the composition, more particularly from about 0.1% to about
I I - 25% by weight of the composition.
The term "about", as used herein, when used along values assigned to certain measurements
and parameters means a variation of 10% from such values, or in case of a range of values. means a
1 0% variation from both the lower and upper limits of such ranges.
The extended release portion and the immediate release portion may be present as cores
which may be in the form of pellets, granules. beads, minitablets or tablets. Alternatively. the
extended release topiramate cores may be coated with an immediate release coating comprising a
therapeutically effective amount of phentermine or its pharmaceutically acceptable salt. Further the
extended release topiramate portion and immediate release phentennine portion may be encapsulated
in a hard gelatin capsule. Alternatively extended release topiramate portion and immediate release
phentermine portion may be compressed into a tablet. The tablet may be a monolithic tablet,
bilayered tablet, inlay tablet or a compression coated tablet
The extended release topiramate cores may be present as matrix cores. The matrix cores are
prepared by blending topiramate or its pharmaceutically acceptable salt with one or more ratecontrolling
agents and other pharmaceutically acceptable excipients, by the processes known in the
art, such as, compaction, dry granulation, wet granulation, fluidized bed granulation and extrusionspheronization.
The topiramate matrix cores may optionally be further coated with an extended
release polymer coating.
Alternatively, the extended release topiramate cores may be present as reservoir cores
produced by coating the immediate release topiramate cores with an extended release polymer
coating.
The blend comprising topiramate or its pharmaceutically acceptable salt and one or more
pharmaceutically acceptable excipients is layered onto inert cores as powder or as solution or
dispersion in a suitable solvent to form immediate release topiramate cores which are then further
coated with a layer of rate-controlling agents.
Alternatively, the immediate release topiramate cores are prepared by extrusionspheronization
which are then further coated with a layer of rate-controlling agents.
Alternatively, the blend comprising topiramate or its pharmaceutically acceptable salt and
one or more rate-controlling agents is layered onto inert cores as powder or as solution or dispersion
in a suitable solvent by techniques known to one skilled in the art, such as drug layering, powder
coating, roller compaction, granulation or extrusion-spheronization.
The inert core may be water-soluble, water swellable, water-insoluble or mixtures thereof.
The water-soluble or water swellable inert cores include one or more of sugar spheres. sugars
like dextrose, lactose, anhydrous lactose, spray-dried lactose, lactose monohydrate, mannitol.
starches. sorbitol, or sucrose. Tartaric acid pellets or the commercially available inert core materials
such as sugar sphere, non-pareil seed, and celphere may also be utilized.
Water-insoluble inert cores may include one or more of glass particlesheads or silicon
dioxide, calcium phosphate dihydrate, dicalcium phosphate, calcium sulfate dihydrate,
microcrystalline cellulose, cellulose derivatives, powdered cellulose, carnauba wax pellets or
mixtures thereof.
The extended release core comprising topiramate or its pharmaceutically acceptable salt can
be additionally coated with one or more non-rate controlling agents (seal layers) or rate-controlling
agents (rate-controlling layers) or combinations of both. The location of the seal layers in the core is
not critical. For example, the seal layers may be present over the inert core or may be present
between the core and a rate-controlling layer. Alternatively, the seal layer may be coated over the
rate-controlling layer.
The seal layers can be made of one or more polymers. Examples of polymers that can be used
include, but are not limited to, hydroxypropyl methylcellulose, hydroxypropyl cellulose,
methylcellulose, ethyl cellulose, polyvinyl alcohol, and polyethylene glycol. The seal layers may
additionally contain other excipients such as plasticizers, pigments, or opacifiers. Examples of
plasticizers that can be used include, but limited to, polyethylene glycol(s), glycerin, triacetin,
triethyl citrate, diethyl phthalate and mineral oils. Examples of pigmentslopacifiers that can be used
include, but are not limited to, water soluble dyes, pigments, and natural products.
The rate-controlling agents used in the present invention can be hydrophilic or hydrophobic
or combinations of both.
Suitable examples of hydrophilic rate-controlling agents include, but are not limited to,
cellulose derivatives such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl
cellulose, carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium carboxy
methylcellulose or combinations thereof; polyvinylpyrrolidone, polyvinyl acetate for example
Kollicoat@ SR, copolymer of vinylpyrrolidone and vinyl acetate, polysaccharides, polyalkylene
glycols, starch , gums and derivatives; or mixtures thereof.
Suitable examples of hydrophobic rate-controlling agents include, but are not limited to, ethyl
cellulose, ethyl cellulose aqueous dispersion (e.g. AquacoatBECD-30 and Surelease@), cellulose
acetate, cellulose acetate butyrate, poly (alkyl) methacrylate, hydroxypropyl methylcellulose
phthalate, and copolymers of acrylic or methacrylic acid esters , waxes. shellac, zein, castor oil,
hydrogenated vegetable oils or mixtures thereof.
The rate-controlling agents may additionally include, plasticizers selected from polyethylene
glycol. propylene glycol, triethylene glycol, ethyleneglycol monoleate. oleic acid, triethyl citrate,
acetyl triethyl citrate, acetyl tributyl citrate, triacetin. diethyl phthalate. glyceryl monostearate,
dibutyl sebacate. castor oil or mixtures thereof.
The rate-controlling agents may further include, pore-formers selected from polymers such as
polyethylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol, hydroxypropyl methyl cellulose,
Kollicoat IR (PVAIPEG copolymer 75:25 ratio), eudragits, carrageenan, alginates; salts such as
sodium chloride, sodium phosphate, calcium phosphate; and sugars such as sucrose, lactose,
mannitol.
The coating layers over the extended release core may be applied as solution/ dispersion of
coating ingredients using any conventional technique known in the art such as spray coating in a
conventional coating pan or fluidized bed processor or dip coating.
Example of solvents used for preparing a solutioddispersion of the coating ingredients
include, but are not limited to, methylene chloride, isopropyl alcohol, acetone, methanol, ethanol,
water or mixtures thereof.
The immediate release portion comprising phentermine may be present either in the form of
layer over the extended release topiramate cores or may be present as separate units.
The layer of phenterrnine can be coated on the extended release topiramate cores as powder
or as solution or dispersion in a suitable solvent, by any conventional technique known in the art
such as pan coating, spray coating, centrifugal fluidized coating and fluidized bed coating.
Alternatively, the immediate-release coating may be applied by press-coating, dry compression or
deposition over the extended-release core or seal-coated extended-release core.
Example of solvents used for preparing a solution or dispersion of phentermine include, but
are not limited to, methylene chloride, isopropyl alcohol, methanol, ethanol, acetone, water or
mixtures thereof.
Alternatively, the immediate release portion comprising phentermine may be present as
separate pellets, granules, beads, minitablets or tablets and may be prepared either by processes
known in the art, such as compaction, dry granulation, wet granulation, fluidized bed granulation or
extrusion-spheronization; or may be prepared by coating the phentermine solution or dispersion over
the inert cores by techniques known to one skilled in the an. such as drug layering. powder coating,
roller compaction, granulation or extrusion-spheronization.
The extended release and immediate release pellets, granules or beads are nlixed with one or
more pharmaceutically acceptable excipients and are either filled into a capsule or compressed into a
tablet for ease of administration.
Both the extended release core of topiramate and the immediate release portion comprising
phentermine may additionally contain suitable amounts of pharmaceutically acceptable excipients
that would be necessary for preparing appropriate dosage forms. Examples of pharmaceutically
acceptable excipients that can be used include, but are not limited to, diluents, binders, disintegrants,
lubricants/glidants, buffers, wetting agents, wicking agents, coloring agents and flavoring agents.
Suitable diluents may be selected from one or more of sugars, such as. dextrose, glucose,
sucrose, lactose; sugar alcohols, such as sorbitol, xylitol, mannitol; cellulose derivatives, such as
powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose; starches, such as
corn starch, pregelatinized starch, maize starch; magnesium salts, such as oxides, carbonates,
phosphates; calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium
sulfate, or mixtures thereof.
Suitable binders may be selected from one or more of starches, such as corn starch,
pregelatinized starch, maize starch; cellulose derivatives, such as hydroxypropyl methylcellulose,
hydroxypropyl cellulose, hydroxyethyl cellulose, methylcellulose; gums, such as xanthan gum, gum
acacia, gum arabic, tragacanth; water-soluble vinylpyrrolidone polymers, such as
polyvinylpyrrolidone, copolymer of vinylpyrrolidone vinyl acetate; sugars, such as sorbitol,
mannitol; sodium alginate, propylene glycol, methacrylates, or mixtures thereof.
Suitable disintegrants may be selected from one or more of alginic acid or alginates,
microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, crospovidone, sodium
starch glycolate, starch, pregelatinized starch, carboxymethyl starch, polyacrylates or mixtures
thereof.
Suitable lubricants/glidants/anti-adherentsm ay be selected from one or more of talc, aerosil,
magnesium stearate, stearic acid, glyceryl monostearate, glyceryl behenate, sodium stearyl fbmarate,
sodium starch fumarate, or mixtures thereof.
Suitable buffers may be selected from one or more of phosphate, acetate, citrate, succinate
and histidine buffers.
10
@ Suitable wetting agents may be selected from one or more of hydrophilic, hydrophobic
surfactants or mixtures thereof. The hydrophilic surfactants may be selected from one or more of
non-ionic surfactants, ionic surfactants or mixtures thereof.
Suitable wicking agents may be selected from one or more of silicon dioxide (syloidB 244FP
by Grace Davison Discovery Sciences). kaolin, titanium dioxide, alumina, niacinamide, sodium
lauryl sulfate, low molecular weight polyvinylpyrrolidone, m-pyrol, bentonite, magnesium aluminum
silicate, polyester, polyethylene or mixtures thereof.
Suitable coloring and flavoring agents may be selected from any FDA approved colors for
oral use.
Suitable solvents used in the preparation of the composition of the present invention include,
but are not limited to, methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water or
mixtures thereof.
The composition of the present invention may optionally be coated with one or more layers
comprising film forming agents andlor pharmaceutically acceptable excipients.
The pharmaceutical composition of the present invention may be used for treating obesity
and related disorders. The pharmaceutical composition of the present invention may contain an
additional therapeutic agent or may be administered in combination with other therapeutic agents.
The present invention is illustrated below by reference to the following example. However,
one skilled in the art will appreciate that the specific methods and results discussed are merely
illustrative of the invention, and not to be construed as limiting the invention.
0 EXAMPLE 1:
1 Lubrication 1
Procedure:
Preparation of Topiramate extended release spheroids
1. Topiramate and microcrystalline cellulose were sifted through suitable screen and mixture
was blended for 15 minutes.
2. A binder solution was prepared by dissolving hydroxypropyl methylcellulose in water.
3. The binder solution was added to the blend of step 1.
4. The wet mass of step 3 was transferred into extruder and extrudes were prepared and then
transferred into spheroniser and spheronised.
Magnesium stearate 0.5
@ 5. The spheroids of step 4 were dried at about 60°C till the loss on drying (at 105OC for 10
minutes) is between 1.0 - 3.0% w/w and then sifted through suitable screens to remove
oversize and fines.
Extended Release (ER) Coating
6. Ethyl cellulose was dispersed in isopropyl alcohol and purified water followed by
polyethylene glycol and hydroxypropyl nlethylcellulose under continuous stirring.
7. The spheroids of step 5 were coated with solution of step 6 till the target weight build up.
8. The spheroids of step 7 were dried till the loss on drying (at 105OC for 10 minutes) is between
1.0 - 3.0% w/w and then sifted through suitable screens to remove oversize and fines.
Phentermine Immediate Release (IR) Coating
9. To isopropyl alcohol1 purified water or combination of both, polyvinylpyrrolidone was
slowly added under stirring to ensure no lumps were formed.
10. Phentermine hydrochloride was added slowly to step 9 to ensure no lumps were formed and
stirring was continued for further 30 minutes. Lactose was added to the same dispersion and
stirred for 15-30 minutes to dissolve the lactose.
11. The topiramate extended release spheroids of step 8 were loaded in the wurster and layered
with phentermine solution of step 10 until target weight gain.
12. The pellets of step 1 1 were dried and sifted through suitable screens.
OpadryB film coating (Optional)
13. 12% w/w aqueous dispersion of opadryBwas prepared.
14. The phentermine layered pellets of step 12 were loaded in the wurster and the film coating
with opadryB dispersion was continued until target weight gain.
Lubrication
15. Magnesium stearate was sifted and the coated pellets of step 14 were lubricated.
Capsule Filling
16. The lubricated pellets of step 15 were filled into hard gelatin capsules using suitable capsule
filling equipment.
* EXAMPLE 2:
Percent wlw of
Ingredients formulation
Topiramate Pellets I
Topiramate 40
Microcrystalline cellulose 21.5
Hydroxypropyl methylcellulose 3.3
Purified water q. s.
ER Coating
Ethyl cellulose 4.5
Polyethylene glycol 0.9
Hydroxypropyl methylcellulose I 0.9 I
Isopropyl alcohol + Purified water q. s.
Phentermine IR pellets
Inert core (Seal coated with Hydroxypropyl
methylcellulose E5, optionally); Sugar spheres
14.5
Phentermine 6.2
I
Lactose 4.1
I
Croscarmellose sodium
Isopropyl alcohol1 Purified water or combination q. s.
of both
Procedure:
Preparation of Topiramate Extended release spheroids
Topiramate extended release spheroids were prepared in a similar way as described in example 1.
Preparation of Phentermine Immediate release pellets
1. To isopropyl alcohol1 purified water or combination of both, polyvinylpyrrolidone was
slowly added under stirring to ensure no lumps were formed.
2. Phentermine hydrochloride was added slowly to step 1 to ensure no lumps were formed and
stirring was continued for further 30 minutes. Lactose was added to the same dispersion and
stirred for 15-30 minutes to dissolve the lactose.
3. Sugar spheres (optionally seal coated with hydroxypropyl methylcellulose) were loaded in
the wurster and the drug layering process was continued until target weight gain.
4. The spheroids of step 3 were dries and sifted through suitable screens.
14
* Capsule Filling
The extended release pellets of topiramate and the immediate release pellets of phentermine
were filled into hard gelatin capsules using suitable capsule filling equipment.
Preparation of Phentermine Immediate release granules
1. Required quantities of phentermine hydrochloride, microcrystalline cellulose were weighed
and blended.
EXAMPLE 3:
Ingredients
Percent wlw of
formulation
Topiramate Pellets
Topiramate 46.0
I
Microcrystalline cellulose
Hydroxypropyl n~ethylcellulose
Purified water
25.0
4.0
q. s.
ER Coating
Ethyl cellulose
Polyethylene glycol
Hydroxypropyl methylcellulose
Isopropyl alcohol + Purified water
5.4
1.1
1.1
q. s.
Phentermine IR pellets/granules
Phentermine
Microcystalline cellulose
Croscarmellose sodium
Hydroxypropyl methylcellulose
Purified water
7.5
6.0
0.7
0.7
q. s.
Film coating (optional)
OpadryB coating
Purified water
2.0
q. s.
Lubrication
Magnesium stearate 0.5
Procedure:
Preparation of Topiramate extended release spheroids
Topiramate extended release spheroids were prepared in a similar way as described in example 1.
2. The blend of step 1 was granulated using hydroxypropyl methylcellulose in purified water as
the binder solution.
3. The granules were dried to a loss on drying of not more than 4-6% and blended with
croscarmellose sodium.
4. The blend of step 3 was lubricated using magnesium stearate.
OpadryB film coating (Optional)
5. 12% w/w aqueous dispersion of opadrya was prepared.
6. The phentermine layered pellets of step 12 were loaded in the wurster and the film coating
with opadrya dispersion was continued until target weight gain.
Lubrication
7. Magnesium stearate was sifted and the coated pellets of step 14 were lubricated.
Capsule Filling
1. The extended release pellets of topiramate and the immediate release granules of phentermine
were filled into hard gelatin capsules using suitable capsule filling equipment.
EXAMPLE 4:
Ingredients Percent w/w of
formulation
Topiramate Pellets
Inert core (Seal coated with hydroxypropyl
methylcellulose E5, optionally); Sugar spheres
Drug loading
Topiramate
Mannitol (optional)
Hydroxypropyl methylcellulose
Isopropyl alcohol/Purified water or combination of
both
38.8
32.4
6.3
q. s.
ER Coating
Ethyl cellulose
Polyethylene glycol
Hydroxypropyl methylcellulose
Isopropyl alcohol + Purified water
5.6
1.1
1.1
q. s.
Phentermine IR coating
Phentermine
Lactose
5.3
3.5
I Croscarmellose sodium
I
1 1
Film coating (optional) I
I
Polyvinylpyrrolidone
Isopropyl alcohol/Purified water or combination of
both
3.5
q. S. I
I
I
OpadryB coating
I
Lubrication
1.9 1
I
Purified water
Procedure:
q. s.
Magnesium stearate
Preparation of Topiramate Extended release pellets
t
0.5
1. A seal coating solution of hydroxypropyl methylcellulose in purified water was prepared.
Sugar spheres were loaded in the wurster and seal coated until target weight gain.
2. The pellets of step 1 were dried and sifted through suitable screens to remove oversize and
fines.
3. To isopropyl alcohol, hydroxypropyl methylcellulose was added slowly under stirring to
ensure no lumps were formed and stirring was continued for 10 minutes.
4. Topiramate was added to step 3 slowly to ensure no lumps were formed and stirring was
continued for further 30 minutes. Lactose was added to the same dispersion and stirred for
15-30 minutes to dissolve the lactose. The dispersion was passed through suitable screen.
5. The seal coated sugar spheres of step 3 were loaded in the wurster and the drug layering
process was continued until target weight gain.
6. The drug loaded pellets of step 5 were dried at about 6 0 ' ~ti ll the loss on drying (at 105OC for
10 minutes) was between 1.0 - 3.0% w/w and sifted through suitable screens to remove
oversize and fines.
Extended Release Coating
7. Ethyl cellulose was dispersed in isopropyl alcohol and purified water followed by
polyethylene glycol and hydroxypropyl methylcellulose under continuous stirring.
8. The pellets of step 6 were coated with solution of step 7 till the target weight build up.
9. The pellets of step 8 were dried till the loss on drying (at 105OC for 10 minutes) was between
1.0 - 3.0% w/w and then sifted through suitable screens to remove oversize and fines.
Phentermine IR coating
The topiramate extended release pellets were drug layered with phentermine solution in a
similar way as described in example 1.
Capsule Filling
The lubricated pellets were filled into hard gelatin capsules using suitable capsule filling
equipment
EXAMPLE 5:
I / Percent wlw of
Ingredients
I I formulation
1
Procedure:
Preparation of Topiramate Extended release pellets
Topiramate Pellets
Inert core (Seal coated with hydroxypropyl
methylcellulose E5, optionally); Sugar spheres
Drug loading
Topiramate
Lactose (Filler optional)
Hydroxypropyl methylcellulose
Isopropyl alcohol1 Purified water or combination of
both
38.0
28.0
5.4
q. s.
ER Coating
Ethyl cellulose
Polyethylene glycol
Hydroxypropyl methylcellulose
Isopropyl alcohol + Purified water
4.6
1 .O
1 .O
q. s.
Phentermine IR pellets
Inert core (Seal coated with hydroxypropyl
methylcellulose E5, optionally); Sugar spheres
9.2
Drug loading
Phentermine
Lactose
Croscarmellose sodium
Polyvinylpyrrolidone
Isopropyl alcohol1 Purified water or combination of
both
5.2
3.8
3.8
q. s.
Topiramate extended release pellets were prepared in a similar way as described in example 4.
Preparation of Phentermine Immediate release pellets
Phentermine immediate release pellets were prepared in a similar way as described in example 2.
Capsule Filling
The extended release pellets of topirarnate and the immediate release pellets of phentermine were
filled into hard gelatin capsules using suitable capsule filling equipment.
EXAMPLE 6:
Ingredients
Percent wlw of
formulation
Topiramate Pellets
Inert core (Seal coated with hydroxypropyl
methylcellulose E5, optionally); Sugar spheres
Drug looding
Topiramate
Lactose (optional)
Hydroxypropyl methylcellulose
Isopropyl alcohol/Purified water or combination of
both
38.0
31.4
5.8
q. s.
ER Coating
Ethyl cellulose
Polyethylene glycol
Hydroxypropyl methylcellulose
Isopropyl alcohol + Purified water
5.1
1.1
1.1
q. s.
Phentermine IR pellets/granules
Phentermine
Microcystalline cellulose
Croscarmellose sodium
Hydroxypropyl methylcellulose
Purified water
7.5
6.0
0.7
0.8
q. s.
Film coating (optional)
Opadry@ coating
Purified water
2.0
q. s.
Lubrication
Magnesium stearate 0.5
Procedure:
Preparation of Topiramate Extended release pellets
Topiramate extended release pellets were prepared in a similar way as described in example 4.
Preparation of Phentermine Immediate release granules
Phentermine immediate release granules were prepared in a similar way as described in example 3.
Capsule Filling
The extended release pellets of topiramate and the immediate release granules of phentermine
were filled into hard gelatin capsules using suitable capsule filling equipment.
EXAMPLE 7:
Ingredients
Percent wlw of
formulation
Topiramate-polymer matrix coating Pellets
-
Inert core (Seal coated with hydroxypropyl
methylcellulose E5, optionally); Sugar spheres
Drug polymer matrix loading
Topiramate
Lactose
Polyvinylpyrrolidone (optional)
Ethyl cellulose
Polyethylene glycol
Isopropyl alcohol + Purified water
39.7
26.8
6.6
5.3
1.1
q. s.
ER Coating (Optional)
Ethyl cellulose
Polyethylene glycol
Hydroxypropyl methylcellulose
Isopropyl alcohol + Purified water
5.7
1.1
1.1
q. s.
Phentermine IR coating
Phentermine
Lactose
Croscarmellose sodium
Polyvinylpyrrolidone
Isopropyl alcohol/Purified water or combination of
both
4.3
2.9
0.9
2.9
q. s.
Procedure:
Film coating (optional)
Preparation of To~iramate-polymer matrix coating. Pellets
OpadryB coating
Purified water
Preparation of Topiramate Drug layered pellets
2.0
q. s.
1. A seal coating solution of hydroxypropyl methylcellulose in purified water was prepared.
Sugar spheres were loaded in the wurster and seal coated until target weight gain.
2. The pellets of step 1 were dried and sifted through suitable screens to remove oversize and
fines.
3. To isopropyl alcohol, ethyl cellulose and polyvinylpyrrolidone were added slowly under
stirring to ensure no lumps were formed and stirring was continued for 10 minutes.
Lubrication
4. Topiramate was added to step 3 slowly to ensure no lumps were formed and stirring was
Magnesium stearate
continued for further 30 minutes. Lactose was added to the same dispersion and stirred for
0.5
15-30 minutes to dissolve the lactose. The dispersion was passed through suitable screen.
5. The seal coated sugar spheres of step 2 were loaded in the wurster and the drug layering
process was continued until target weight gain.
6. The drug loaded pellets of step 5 were dried at about 60°C till the loss on drying (at 105°C:
for 10 minutes) was between 1.0 - 3.0% wlw and sifted through suitable screens to remove
oversize and fines
Extended Release Coating (optional)
7. Ethyl cellulose was dispersed in isopropyl alcohol and purified water followed by
polyethylene glycol and hydroxypropyl methylcellulose under continuous stirring.
8. The pellets of step 6 were coated with solution of step 7 till the target weight build up.
9. The pellets of step 8 were dried till the loss on drying (at 10S°C for 10 minutes) was between
1.0 - 3.0% wlw and then sifted through suitable screens to remove oversize and fines.
Phentermine IR coating
The Topiramate-polymer matrix coating pellets were drug layered with phentermine solution
in a similar way as described in example 1.
0 Capsule Filling
The lubricated pellets were filled into hard gelatin capsules using suitable capsule filling
equipment.
EXAMPLE 8:
i Topiramate-polymer matrix coating Pellets
) Topiramate 1I 39.8
Ingredients
Microcrystalline cellulose 21.9
Percent wlw of
I
Polyvinylpyrrolidone , 3.5
I 1 formulation
1 Ethyl cellulose
Polyethylene glycol 1.6
I
Purified water q. s.
1 ER Coating (Optional)
Ethyl cellulose 5.6
Polyethylene glycol 1.1
I
I
Phentermine IR coating
Hydroxypropyl methylcellulose
I
1.1
Isopropyl alcohol + Purified water q. s.
Phentermine 6.5
1
Lactose
I
Film coating (optional)
3.5
Polyvinylpyrrolidone
Isopropyl alcohol1 Purified water or combination of
both
4.5
q. s.
I Purified water
OpadryQ coating
I Lubrication I
1.9
Procedure:
Magnesium stearate
Preparation of Topiramate-polvmer matrix coating Pellets
0.5
Preparation of Topiramate Drug layered pellets
1. Topiramate, microcrystalline cellulose, polyethylene glycol and ethyl cellulose were sifted
through suitable screen.
2. A binder solution was prepared by dissolving polyvinylpyrrolidone in purified water.
3. The binder solution was added to the blend of step 1 in rapid mixer granulator over a period
of 3-5 minutes.
4. The wet mass of step 3 was transferred into extruder and extrudes were prepared and then
transferred into spheroniser and spheronised.
5. The spheroids of step 4 were dried at about 60°C till the loss on drying (at 105°C for 10
minutes) Mas between 1.0 - 3.0% w/w and then sifted through suitable screens to remove
oversize and tines.
Extended Release Coating (optional)
6. Ethyl cellulose was dispersed in isopropyl alcohol and purified water followed by
polyethylene glycol and hydroxypropyl methylcellulose under continuous stirring.
7. The pellets of step 5 were coated with solution of step 6 till the target weight build up.
8. The pellets of step 7 were dried till the loss on drying (at 105°C for 10 minutes) was between
1.0 - 3.0% wlw and then sifted through suitable screens to remove oversize and fines.
Phentermine IR coating
The Topiramate-polymer matrix coating pellets were drug layered with phentermine solution
by a process as described in example 1.
Ca~suleF illing
The lubricated pellets were filled into hard gelatin capsules using suitable capsule filling
equipment.
EXAMPLE 9:
I Topiramate pellets I
Ingredients
Percent wlw of
formulation
Topiramate 18.15
I
Microcrystalline cellulose
I
I
Seal coating
25.85
Polyvinylpyrrolidone
I
Hydroxypropyl methylcellulose I 1.36 I
1.38
Purified water q.s.
I
Purified water q.s.
ER Coating
Ethyl cellulose
Pol yvinylpyrrolidone
Dibutyl sebacate
I Isopropyl alcohol+ Purified water
Talc
Procedure
Preparation of Topiramate extended release spheroids
1. Topiramate and microcrystalline cellulose were sifted through suitable screen and mixture
was blended.
2. A binder solution was prepared by dispersing polyvinylpyrrolidone in water under stirring.
3. The binder solution was added to the blend of step 1.
4. The wet mass of step 3 was transferred into extruder and extrudes were prepared and then
transferred into spheroniser and spheronised.
5. The spheroids of step 4 were dried at about 60°C till the loss on drying (at 105OC for 10
minutes) was not more than 2% wlw and then sifted through suitable screens to remove
oversize and fines.
2.19
1.46
0.55
q.s. I
0.53
I
Phentermine IR pellets
Seal Coating
/ Lubrication
Sugar beads
6. An aqueous binder solution was prepared by dispersing hydroxypropyl methylcellulose in
purified water under stirring.
7. The binder solution was sprayed over the spheroids of step 5 to weight gain of 2-4% and the
seal coated spheroids were dried.
43.41
Extended Release Coating
Drug loading
Phentermjne
Hydroxypropyl methylcellulose
Purified water
2.56
I
2.56
I q.s.
8. Polyvinylpyrrolidone was dispersed in isopropyl alcohol and purified water followed by
addition of ethyl cellulose and dibutyl sebacate under continuous stirring to get a clear
solution.
9. The spheroids of step 7 were coated with solution of step 8 till the target weight build up. - 10. The spheroids of step 9 were dried at about 50- 60°C till the loss on drying (at 105°C for 10
minutes) was not more than 2% wIw.
Lubrication
1 1. Talc was sifted and the coated pellets of step 10 were lubricated.
Preparation of Phentermine Immediate release pellets
1. Hydroxypropylmethylcellulose was dissolved in water followed by the addition of
Phentermine hydrochloride under continuous stirring.
2. Sugar spheres were loaded in the wurster and the drug layering process was continued until
target weight gain.
3. The spheroids of step 3 were dries and sifted through suitable screens.
Caast.de Filling
1. The extended release pellets of topiramate and the immediate release pellets of phentennine
were filled into hard gelatin capsules using suitable capsule filling equipment.
Dissolution Studies:
Table 1 provides the dissolution data of Topiramate capsules of 92mg strength prepared as
per Example 9.The dissolution was carried out using USP type I apparatus at 100 rpm at a
temperature of 37°C * 0.5OC wherein 500 mL of acetate buffer of pH 4.5 was used as the dissolution
medium.
Table 1
12
78
8
5 9
6
5 1
10
67
4
35
2
20
Time (hours)
Percent Drug Release
1
1 1
EXAMPLE 10:
I Sugar beads 1 40.82 1
Ingredients
I Drug loading 1
Percent w/w of
formulation
- -
~ydroxypropyml ethylcellulose I 2.41 I
Topiramate pellets
Phentermine
Topiramate
Microcrystalline cellulose
Polyvinylpyrrolidone
Purified water
2.4 1
Procedure
17.07
24.3 1
1.30
q.s.
1
Purified water
Preparation of To~iramatee xtended release s~heroids
q.s. I
Topiramate extended release spheroids were prepared by a process as described in example 9 except
for the extended release coating which comprise the following steps:
Seal coating
1. Ethyl cellulose aqueous dispersion and dibutyl sebacate were mixed in a container under
continuous stirring.
2. Polyvinylpyrrolidone was dissolved in water and the aqueous polyvinylpyrrolidone solution
was slowly added to the ethyl cellulose dispersion of step 1 under continuous stirring.
Hydroxypropyl methylcellulose
Purified water
1.28
q.s.
ER Coating
Ethyl cellulose aqueous dispersion
Purified water
Polyvinylpyrrolidone
Dibutyl sebacate
8.5 1
q.s.
0.64
0.77
-
Lubrication
Talc 0.48
Phentermine IR pellets
Preparation of Phentermine Immediate release pellets
Phentermine immediate release pellets were prepared by a process as described in example 9 .
Capsule Filling
* The extended release pellets of topiramate and the immediate release pellets of phentermine were
filled into hard gelatin capsules using suitable capsule filling equipment.
Dissolution Studies:
Table 2 provides the dissolution data of Topiramate capsules of 92mg strength prepared as
per Example 10. The dissolution was carried out using USP type I apparatus at 100 rpm at a
temperature of 37°C * 0.5"C wherein 500 mL of acetate buffer of pH 4.5 was used as the dissolution
medium.
Table 2
While several particular forms of the invention have been illustrated and described, it will be
apparent that various modifications and combinations of the invention detailed in the text can be
made without departing from the spirit and scope of the invention.

WECLAIM:
1. A pharmaceutical composition of phentermine and topiramate comprising:
(i) an extended release portion comprising a therapeutically effective amount of topiramate
*
or its pharmaceutically acceptable salt, one or more rate-controlling agents and one or
more pharmaceutically acceptable excipients.
( i i ) an immediate release portion comprising a therapeutically effective amount of
phentermine or its pharmaceutically acceptable salt and one or more pharmaceutically
acceptable excipients.
2. The pharmaceutical composition according to claim 1, wherein the extended release portion
and the immediate release portion are present as cores which may be in the form of pellets,
granules. beads, minitablets or tablets.
3. The pharmaceutical composition according to claim 1, wherein the extended release
topiramate portion is present as cores and the immediate release phentermine portion is
present as a coating over the extended release portion.
4. The pharmaceutical composition according to claim 1, wherein the extended release
topiramate cores are present as matrix cores with an optional extended release polymer
coating over the cores.
5. The pharmaceutical composition according to claim 1, wherein the extended release
topiramate cores are present as reservoir cores produced by coating the immediate release
topiramate cores with an extended release polymer coating.
6. The pharmaceutical composition according to claim 1, wherein the pharmaceutical
composition of the present invention is a hard gelatin capsule or a tablet.
7. A process of preparing a pharmaceutical composition of phentermine and topiramate
comprising the following steps:
(i) preparing extended release topiramate cores comprising a therapeutically effective
amount of topiramate or its pharmaceutically acceptable salt, one or more ratecontrolling
agents and one or more pharmaceutically acceptable excipients,
(ii) preparing immediate release phentermine cores comprising a therapeutically effective
amount of phentermine or its pharmaceutically acceptable salt and one or more
pharmaceutically acceptable excipients, and
(iii) combining the extended release topiramate cores and the immediate release
phentermine cores.
2 8
8. The process according to claim 7, wherein the extended release topiramate cores are prepared
by compaction, dry granulation, wet granulation, fluidized bed granulation or extrusion-
@ spheronization.
9. A process of preparing a pharmaceutical composition of phentermine and topiramate,
wherein the process comprises the steps of
(i) preparing extended release topiramate cores comprising a therapeutically effective
i amount of topiramate or its pharmaceutically acceptable salt, one or more ratecontrolling
agents and one or more pharmaceutically acceptable excipients,
(ii) dissolving or dispersing the phentermine or its pharmaceutically acceptable salt and one
or more pharmaceutically acceptable excipients into a suitable solvent.
(iii) layering the extended release topiramate cores with the solution or dispersion of
phentermine, and
(iv) filling the cores prepared in step (iii) into a hard gelatin capsule or compressing the
cores to form a tablet.
10. A method of treating obesity and related disorders by administering to a person in need
thereof a pharmaceutical composition of phentermine and topiramate comprising:
(i) an extended release portion comprising a therapeutically effective amount of topiramate,
one or more rate-controlling agents and one or more pharmaceutically acceptable excipients,
(ii) an immediate release portion comprising a therapeutically effective amount of
phentermine and one or more pharmaceutically acceptable excipients.