PHARMACEUTICAL GASTRO-RETENTIVE SOLID ORAL DOSAGE FORM OF
NILOTINIB
Field of the Invention
The present invention relates to a pharmaceutical gastro-retentive solid oral dosage
form comprising nilotinib as the active ingredient. The invention is further related to
methods of preparing said solid oral dosage form.
Background of the Invention
Nilotinib was first disclosed in U.S. Patent No. 7,169,791. It is chemically
described as 4-methyl-N-[3-(4-methyl-lH-imidazol-l-yl)-5-(trifluoromethyl)phenyl]-3-
[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide and is an inhibitor of the protein
tyrosine kinase (TK) activity of BCR-ABL.
U.S. Patent No. 8,293,756 discloses pharmaceutical compositions of nilotinib
prepared by wet granulation.
Nilotinib is characterized as a Class IV compound according to t e
Biopharmaceutical Classification System (BCS), which means that it has low/moderate
aqueous solubility and low permeability. The solubility of nilotinib at 25°C in aqueous
solutions decreases strongly with increasing pH and it is practically insoluble at pH 4.5
and higher. This decrease in the solubility of nilotinib in environments with a pH of more
than 1 leads to a decrease in the absorption of nilotinib. The poor water-solubility of
nilotinib and its salts mean that they are difficult to formulate as oral delivery dosage
forms with good bioavailability. Hence, there is a need to develop a pharmaceutical solid
oral dosage form of nilotinib which has better solubility and bioavailability. In the present
invention, the inventors have developed such a pharmaceutical oral solid dosage form of
nilotinib.
Summary of the Invention
In one general aspect, the present invention provides a gastro-retentive solid oral
dosage form which comprises nilotinib or a salt thereof, at least one rate controlling
polymer, and other pharmaceutically acceptable excipients.
In an embodiment of the above aspect, the rate controlling polymer is a swelling
agent.
In another embodiment of t e above aspect, t e dosage form may further comprise
an acidifying agent.
In another embodiment of the above aspect, the dosage form may be administered
once daily or twice daily.
In another embodiment of the above aspect, the dosage form is a tablet. The
gastro-retentive action of the tablet is based on one or more mechanisms, for example,
floatation, gas generation, or swelling.
In another embodiment of the above aspect, the dosage form may further comprise
one or more osmogen agents.
In another embodiment of the above aspect, the other pharmaceutically acceptable
excipients are selected from the group comprising diluents, matrix forming agents,
disintegrants, binding agents, gas-generating agents, semi-permeable film-forming agents,
glidants, and lubricants.
The details of the various embodiments of the invention are set forth in the
description below. Other features and advantages of the invention will also be apparent
from the description.
Detailed Description of the Invention
The term "gastro-retentive", as used herein, refers to a pharmaceutical dosage form
which is capable of staying in the stomach for a prolonged period of time, preferably for a
period longer than that of food, and therefore is capable of releasing the active ingredient
in the stomach for a time period longer than when delivered as a conventional dosage
form. The gastro-retentive time may be characterized by retention of the dosage form in
the stomach for a period that is longer than the normal emptying time of the stomach, /.e.,
longer than about 2 hours.
Several mechanisms for gastro-retentive action of the oral solid dosage form may
be designed and developed by applying approaches which include low-density floating
systems that cause buoyancy in gastric fluid; high-density sinking systems that are
retained in the bottom of the stomach; mucoadhesive systems that cause bioadhesion to
stomach mucosa; gas generation by the dosage form that causes buoyancy in gastric fluid;
swelling of the dosage form beyond the size which can pass through the human pyloric
sphincter of the stomach; and large sized dosage forms per se which may limit passing of
the dosage form through t e pyloric sphincter. The diameter of the human pyloric
sphincter is on an average 12 mm (± 7mm) and therefore a dosage form larger than the
pyloric diameter cannot pass through the stomach.
The term "solid oral dosage form", as used herein, includes tablets, mini-tablets,
capsules, caplets, granules, beads, pellets, multiparticulates, spheroids, or combinations
thereof. If the solid form is a tablet, the tablet can be of any suitable shape, such as round,
spherical, oval, concave, bi-concave, hemispherical, or any polygonal shape, such as
square, rectangular, pentagonal, hexagonal, and the like. The tablet may have a
monolithic or a multilayer structure.
The term "rate-controlling polymer", as used herein, refers to polymers which are
capable of controlling the release of the active ingredient from the dosage form. The
polymer can control the release of the active ingredient by any mechanism, such as
swelling, matrix forming, or film forming.
The term "swelling agent", as used herein, refers to polymers which are capable of
absorbing water, resulting in physical swelling and expansion. The swelling of the
polymer can be characterized by an increase in the dimensions of the dosage form in one
or more directions. Preferred examples of swelling agents include, but are not limited to,
hypromellose, methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose,
carboxymethyl cellulose, guar gum, xanthan gum, tragacanth gum, carrageenan, pectin,
egg albumin, chitosan, pectin, bovine serum albumin, microcrystalline cellulose, crosslinked
carboxymethyl cellulose, cross-linked polyvinyl pyrrolidone, or a starch.
The term "acidifying agent", as used herein, refers to substances which are able to
create an acidic pH environment within and around the dosage form and therefore increase
the solubility and dissolution of the active ingredients which are soluble in acidic pH.
Preferred examples of acidifying agents include, but are not limited to, fumaric acid, citric
acid, tartaric acid, amino acid, or lactic acid.
Preferred examples of osmogen agents include, but are not limited to, organic and
inorganic compounds such as salts, acids, bases, chelating agents, sodium chloride, lithium
chloride, magnesium chloride, magnesium sulfate, lithium sulfate, potassium chloride,
sodium sulfite, calcium bicarbonate, sodium sulfate, calcium sulfate, calcium lactate, dmannitol,
urea, tartaric acid, raffinose, sucrose, alpha-d-lactose monohydrate, glucose,
sorbitol, other similar or equivalent materials, and combinations thereof.
Preferred examples of diluents include, but are not limited to, calcium phosphate -
dibasic, calcium carbonate, lactose, glucose, microcrystalline cellulose, cellulose
powdered, silicified microcrystalline cellulose, calcium silicate, starch, starch
pregelatinized, and polyols such as mannitol, sorbitol, xylitol, maltitol, and sucrose.
The term "matrix forming agent", as used herein, refers to the pharmaceutical
agents which impart structural integrity and provide mechanical strength to the dosage
form, among other functions. Preferred examples of matrix forming agents include, but
are not limited to, hydroxypropyl methylcellulose (HPMC), acrylic acid polymers,
polyvinyl acetate (PVA), polyvinylpyrrolidone (PVP), cross-linked polyvinylpyrrolidone,
ethylcellulose, carbomer homopolymer (type A), and combinations thereof.
Preferred examples of disintegrants include, but are not limited to, cross-linked
cellulose, cross-linked polyvinylpyrrolidone (crospovidone), sodium starch glycolate,
polyvinylpyrrolidone (polyvidone, povidone), sodium carboxymethylcellulose, crosslinked
sodium carboxymethylcellulose (croscarmellose sodium), hydroxypropyl cellulose,
hydroxypropyl methylcellulose, xanthan gum, alginic acid, and soy polysaccharides.
Preferred examples of binding agents include, but are not limited to, starch,
pregelatinized starch, carboxymethyl cellulose, sodium cellulose, microcrystalline
cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone,
crospovidone, and combinations thereof.
Preferred examples of gas-generating agents include, but are not limited to, alkali
metal carbonates and bicarbonates such as sodium bicarbonate and calcium carbonate.
When gas-generating agents come in contact with water or stomach acid, they generate
gas bubbles which help keep the dosage form in a buoyant state and hence avoid its
passage through the stomach.
The term "semi-permeable film", as used herein, refers to a film allowing water or
solvent to pass through it, but is impermeable to the dissolved active ingredient and other
excipients, thereby preventing the passage of dissolved active ingredient and other
excipients through it. The semi-permeable film may include film-forming agents, for
example, polyvinylalcohol, hydroxypropyl starch, hydroxyethyl starch, hydroxypropyl
cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methylcellulose phthalate,
hydroxypropyl methylcellulose acetate succinate, methyl cellulose, cellulose acetate, and
polyacrylic resin; pore-forming agents such as polyethylene glycol, hydroxypropyl
cellulose, micronized sugar, sodium chloride, mannitol, and sorbitol; or plasticizers such
as triethyl citrate, castor oil, dibutyl sebacate, phthalates, polyethylene glycol, glycerol,
and poloxamer; and combinations thereof.
Preferred examples of solvents used for preparing the coating solution of the semi
permeable film may include, but are not limited to, methylene chloride, isopropyl alcohol,
acetone, propylene glycol, methanol, ethanol, chloroform, ether, water, and combinations
thereof.
Preferred examples of glidants and lubricants may include, but are not limited to,
sodium lauryl sulfate, talc, magnesium stearate, sodium stearyl fumarate, stearic acid,
glyceryl behenate, hydrogenated vegetable oil, zinc stearate, and colloidal silicon dioxide.
The gastro-retentive solid oral dosage form of the present invention may be
prepared by conventional processes of wet granulation, dry granulation, or direct
compression. The processes may also involve coating of the dosage form with functional
coatings such as a semi-permeable film coating.
The invention may be further illustrated by the following examples, which are for
illustrative purposes only and should not be construed as limiting the scope of the
invention in any way.
EXAMPLES
Example 1: Density Based Gastro-Retentive Tablets
Manufacturing Procedure:
1) Sift nilotinib, the acidifying agent, microcrystalline cellulose, hypromellose,
polyvinylpyrrolidone, carbomer homopolymer type A, and colloidal silicon dioxide
through a BSS #18 sieve.
2) Sift magnesium stearate through a BSS # 60 sieve.
3) Blend t e materials of step 1 in a low shear blender for 15 minutes.
4) Blend t e materials of step 2 and step 3 in a low shear blender for 10 minutes.
5) Compress the blend of step 4 into tablets using suitable tooling.
Example 2 : Gas Generating Gastro-Retentive Tablets
Manufacturing Procedure:
1) Sift nilotinib, the acidifying agent, sodium bicarbonate, microcrystalline cellulose,
lactose anhydrous, xanthan gum, and colloidal silicon dioxide through a BSS #18
sieve.
2) Sift magnesium stearate through a BSS #60 sieve.
3) Blend the materials of step 1 in a low shear blender for 15 minutes.
4) Blend the materials of step 2 and step 3 in a low shear blender for 10 minutes.
5) Compress the blend of step 4 into tablets using a suitable tooling.
Example : Size Based Gastro-Retentive Osmotic Tablets
Manufacturing Procedure:
1) Sift nilotinib, the acidifying agent, sodium chloride, lactose monohydrate, and
colloidal silicon dioxide through a BSS #18 sieve.
2) Sift magnesium stearate through a BSS #60 sieve.
3) Blend the materials of step 1 in a low shear blender for 15 minutes.
4) Blend the materials of step 2 and step 3 in a low shear blender for 10 minutes.
5) Compress the blend of step 4 into tablets using a suitable tooling.
6) Dissolve hypromellose in water.
7) Coat the tablets of step 5 with the solution of step 6 .
8) Dissolve cellulose acetate and polyethylene glycol in an acetone and water mixture.
9) Coat the tablets of step 7 with the solution of step 8.
10) Cure the tablets of step 9 for a period of 24 hours at 40°C.
11) Drill the tablets of step 10 with one hole on one side or one hole on both sides using
a laser beam to a particular diameter and depth.
Example 4 : Gastro Floating Capsules
Manufacturing Procedure:
Preparation of Capsules:
1) Capsules may be prepared by any one of the following methods:
a . Capsules may be filled with nilotinib.
b. Capsules may be filled with nilotinib and lactose as granules or powder.
c . Nilotinib and lactose mini-tablets may be filled into the capsules.
2) Prepare gelatin solution and use it to band seal the capsules of step 1.
Coating of Capsules:
3) Coat the capsules of step 2 with cellulose acetate or ethyl cellulose solution
containing polyethylene glycol.

We Claim:
1. A gastro-retentive solid oral dosage form which comprises nilotinib or a salt
thereof, at least one rate-controlling polymer, and other pharmaceutically acceptable
excipients.
2 . The gastro-retentive solid dosage form of claim 1, wherein the rate-controlling
polymer is a swelling agent.
3 . The gastro-retentive solid oral dosage form of claim 1, wherein t e dosage form
further comprises an acidifying agent.
4 . The gastro-retentive solid oral dosage form of claim 1, wherein the dosage form is
administered once daily or twice daily.
5 . The gastro-retentive solid dosage form of claim 1, wherein t e dosage form is a
tablet.
6 . The gastro-retentive tablet of claim 5, wherein the gastro-retentive action of the
tablet is based on one or more mechanisms of floatation, gas generation, and swelling.
7 . The gastro-retentive solid dosage form of claim 1, wherein the dosage form further
comprises one or more osmogen agents.
8. The gastro-retentive solid dosage form of claim 1, wherein the other
pharmaceutically acceptable excipients are selected from diluents, matrix forming agents,
disintegrants, binding agents, gas-generating agents, semi-permeable film-forming agents,
glidants, and lubricants.