STABILIZED GASTRORETENTIVE TABLETS OF PREGABALIN
Field of the Invention
The present invention relates to stabilized gastroretentive tablets comprising pregabalin,
one or more swellable polymers, a pH modifier, and other pharmaceutically acceptable
excipients. It also relates to processes for the preparation of said stabilized gastroretentive
tablets of pregabalin.
Background of the Invention
Pregabalin, as disclosed in U.S. Patent No. 6,197,819, is chemically designated as (S)-3-
(aminomethyl)-5-methylhexanoic acid.
Pregabalin is not uniformly absorbed throughout the gastrointestinal tract, and is
predominantly absorbed from the stomach and the upper part of the intestine. In such instances,
it is beneficial to develop gastroretentive tablets that are retained in the upper parts of the
gastrointestinal tract for prolonged periods of time.
Several attempts have been made in the prior art to provide gastroretentive dosage forms
of pregabalin. U.S. Publication No. 2007/0269511 discloses a pharmaceutical composition
comprising pregabalin, a matrix forming agent comprising polyvinyl acetate and
polyvinylpyrrolidone, and a swelling agent comprising cross-linked polyvinylpyrrolidone,
wherein the pharmaceutical composition is adapted for once-daily dosing.
PCT Publication No. WO 2010/143052 discloses a gastroretentive floating tablet of
pregabalin comprising one or more water insoluble components, wherein the water insoluble
component is preferably a combination of ethyl cellulose and hydrogenated castor oil.
However, one major problem with pregabalin formulations is the tendency to form an
undesired cyclic lactam during manufacture and/or shelf life. Several attempts have been made
in the prior art to reduce this tendency of pregabalin to form the corresponding lactam and
provide stable formulations thereof.
U.S. Patent No. 7,309,719 discloses a stabilized pharmaceutical composition consisting
of gabapentin or pregabalin and a neutral a-amino acid as a stabilizer.
U.S. Publication No. 2009/0156677 discloses the use of a humectant as a stabilizer in
pharmaceutical compositions containing pregabalin,
D E L H I " 2 9 - Q & - 2 G 1 6 1 6 : 4 12
In view of the aforesaid, it is necessary to provide stabilized gastroretentive tablets of
pregabalin that are substantially free of the lactam impurity. The present inventors have
surprisingly found_ that the^ addition_-of a suitable pH modifier to :gastroretentive tablets of
pregabalin substantially reduces the formation of the undesired lactam impurity, thereby
resulting in improved stability.
Summary of the Invention
The present invention relates to stabilized gastroretentive tablets comprising pregabalin
that are substantially free of the lactam impurity. The stabilized gastroretentive tablets comprise
pregabalin, one or more swellable polymers, a pH modifier, and other pharmaceutically
acceptable excipients.
Detailed Description of the Invention
A first aspect of the present invention provides a stabilized gastroretentive tablet
comprising pregabalin, one or more swellable polymers, a pH modifier, and other
pharmaceutically acceptable excipients.
According to one embodiment of the above aspect, the swellable polymers are selected
from the group comprising cellulosic polymers, polyalkylene oxides, polysaccharides, acrylic
acid polymers, vinyl pyrrolidone polymers, and combinations thereof.
According to another embodiment of the above aspect, the pH modifier is selected from
the group comprising magnesium oxide, sodium acetate, trisodium citrate, meglumine, trisodium
orthophosphate, sodium bicarbonate, sodium hydroxide, and combinations thereof.
According to another embodiment of the above aspect, the pharmaceutically acceptable
excipients are selected from the group comprising diluents, binders, disintegrants,
lubricants/glidants, and combinations thereof.
According to another embodiment of the above aspect, the tablet is substantially free of
the lactam impurity.
According to another embodiment of the above aspect, the tablets are prepared by the
processes of direct compression, dry granulation, or wet granulation.
The term "pregabalin," as used herein, includes pregabalin and salts, polymorphs,
hydrates, solvates, prodrugs, chelates, and complexes thereof.
The term "gastroretentive tablet," as used herein, refers to a tablet which is capable of
staying in the stomach for a prolonged period of time, and therefore is capable of releasing
pregabalin in the stomach for a time period longer than when delivered as a conventional tablet.
The term "stabilized," as used herein, implies that the tablet is substantially free of the
lactam impurity.
The term "lactam," as used herein, refers to the undesired degradation product produced
by intramolecular condensation reaction of the y-amino group and the carboxylic acid group of
pregabalin. This cyclic lactam of pregabalin is chemically 4-isobutyl-pyrrolidin-2-one.
The term "substantially free of lactam," as used herein, implies that the lactam content
does not exceed 0.6% by weight of lactam, preferably 0.4% by weight of lactam, more
preferably 0.2% by weight of pregabalin.
The term "swellable polymers," as used herein, refers to polymers that swell in the
presence of gastric fluids. This swelling increases the size of the tablet to such an extent so as to
provide retention of the tablet in the stomach of a patient. The swellable polymers that may be
used in the present invention are selected from the group comprising cellulosic polymers,
polyalkylene oxides, polysaccharides, acrylic acid polymers, vinyl pyrrolidone polymer, and
combinations thereof. Cellulosic polymers include methyl cellulose, hydroxymethyl cellulose,
hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl
cellulose, sodium carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose,
calcium carboxymethyl cellulose, and combinations thereof. Polyalkylene oxides include
polyethylene oxide, such as that available under the trade name Polyox®. Polysaccharides
include starch and starch-based polymers, chitosan, agar, alginates, carrageenan, furcellaran,
guar gum, gum arabic, gum tragacanth, karaya gum, locust bean gum, pectin, dextran, gellan
gum, rhamsan gum, welan gum, xanthan gum, propylene glycol alginate, hydroxypropyl guar,
and combinations thereof. Vinyl pyrrolidone polymers include cross-linked
polyvinylpyrrolidone and crospovidone.
Suitable pH modifiers are selected from the group comprising magnesium oxide, sodium
acetate, trisodium citrate, meglumine, trisodium orthophosphate, sodium bicarbonate, sodium
hydroxide, and combinations thereof.
The tablets of the present invention comprise other pharmaceutically acceptable
excipients that are routinely used and are selected from the group comprising diluents, binders,
disintegrants, lubricants/glidants, and combinations thereof.
D E L H I. 2:9 - O & - 2 0 I 6 16 : 4 Suitable diluents are selected from the group comprising microcrystalline cellulose;
silicified microcrystalline cellulose; lactose; glucose; natural, modified, or pregelatinized starch;
mannitol; sorbitol; and combinations thereof.
Suitable binders are selected from the group comprising povidone, methyl cellulose,
ethyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methyl cellulose,
acacia, guar gum, alginic acid, dextrin, maltodextrin, polyvinyl alcohol, gelatin, starch, and
combinations thereof.
Suitable disintegrants are selected from the group comprising sodium carboxymethyl
cellulose; low-substituted hydroxypropyl cellulose; carboxymethyl cellulose; calcium
carboxymethyl cellulose; cross-linked polyvinyl pyrrolidone; microcrystalline cellulose; natural,
modified, or pregelatinized starch; gums; and combinations thereof.
Suitable lubricants/glidants are selected from the group comprising colloidal silicon
dioxide, talc, stearic acid, magnesium stearate, zinc stearate, calcium stearate, sodium stearyl
fumarate, hydrogenated castor oil, and combinations thereof.
The tablets described herein may be prepared by conventional processes using
commonly available equipment. The process may comprise direct compression, wet
granulation, or dry granulation.
The tablets of the present invention may be further coated with one or more nonfunctional
coatings. The coating may comprise one or more film-forming polymers and coating
additives.
Examples of film-forming polymers include ethyl cellulose, hydroxypropyl methyl
cellulose, hydroxypropyl cellulose, methylcellulose, carboxymethyl cellulose, hydroxymethyl
cellulose, hydroxyethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose phthalate,
cellulose acetate phthalate, cellulose acetate trimellitate, waxes, and methacrylic acid polymers
such as Eudragit®. Alternatively, commercially available coating compositions comprising filmforming
polymers marketed under various trade names, such as Opadry®, may also be used.
Coating additives may be selected from the group comprising binders, plasticizers,
opacifiers, coloring agents, and lubricants.
Examples of plasticizers include acetylated triacetin, triethyl citrate, tributyl citrate,
glycerol tributyrate, diacetylated monoglyceride, polyethylene glycols, propylene glycol, sesame
oil, acetyl tributyl citrate, acetyl triethyl citrate, diethyl oxalate, diethyl phthalate, diethyl
D'ELHX 29-08 - 201S 16 : 4%
maleate, diethyl nimarate,- dibutyl succinate, diethyl malonate, dioctyl phthalate, dibutyl
sebacate, and combinations thereof.
Examples of opacifiers include titanium dioxide, talc, calcium carbonate, behenic acid,
cetyl alcohol, and combinations thereof.
Coloring agents include any FDA approved color for oral use.
Specific examples of solvents for granulation or coating include water, acetone, ethanol,
methanol, isopropyl alcohol, methylene chloride, and combinations thereof.
Coating may be performed by applying the coating composition as a solution,
suspension, or blend using any conventional coating technique known in the art such as spray
coating in a conventional coating pan or fluidized bed processor, dip coating, or compression
coating.
The tablets may be dispensed in packs made with usual packaging materials like highdensity
polyethylene (HDPE) bottles or blister packs. The package may additionally contain a
desiccant.
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 1-5
Ingredients
Pregabalin
Crospovidone
Hydroxypropyl
methyl cellulose
Kollidon® SR
Polyethylene oxide
Maltodextrin
Acrylic acid
polymer
Magnesium oxide
Sodium acetate
Tri sodium citrate
Magnesium stearate
Quantity (% w/w)
Example 1
26.72
25.02
22.83
20.00
-
4.94
-
-
-
0.49
Example 2
33.00
25.00
25.00
-
-
10.00
6.00
-
-
-
1.00
Example 3
33.00
31.00
29.00
-
-
-'
6.00
-
-
-
1.00
Example 4
33.00
30.88
28.87
-
-
-
6.00
0.25
-
-
1.00
Example 5
33.00
30.75
28.75
-
-
-
6.00
0.50
-
-
1.00
D E L H I 2.9 - 08 - 2 8 1 6 16 : 4%
Examples 6-11
Ingredients
Pregabalin
Crospovidone
Hydroxypropyl
methyl cellulose
Kollidon® SR
Polyethylene oxide
Maltodextrin
Acrylic acid
polymer
Magnesium oxide
Sodium acetate
Trisodium citrate
Magnesium
stearate
Quantity {% w/w)
Example
6
33.00
30.63
28.62
-
-
-
6.00
0.75
-
-
1.00
Example
7
33.00
30.50
28.50
-
-
-
6.00
1.00
-
-
1.00
Example
8
33.00
29.50
27.50
-
-
-
6.00
3.00
-
-
1.00
Example
9
33.00
28.50
26.50
-
-
-
6.00
5.00
-
-
1.00
Example :
10
33.00
30.50
28.50
-
-
-
6.00
-
1.00
-
1.00
Example
11
33.00
30.50
28.50
-
-
-
6.00
-
-
1.00
1.00
Procedure:
1. Each ingredient was sifted through mesh #20.
2. All the ingredients of step 1, except magnesium stearate, were blended together for
15 minutes.
3. The mixture of step 2 was blended with magnesium stearate for 5 minutes.
Blends prepared as per the above procedure were kept for 21 days at 40°C/75% RH and
tested for lactam formation. The resultant stability data is provided in Table 1.
Table 1: Stability Data of Blends Prepared as per Examples 1-11
Example
1
2
3
4
5
6
7
8 ;
9
10
11
Percentage of Lactam
Initial
0.0040
0.0036
0.0100
ND*
ND*
ND*
0.0026
0.0010
0.0100
ND*
ND*
21 days (40°C/75% RH)
0.240
0.280
0.260
0.080
0.060
0.030
0.014
0.016
0.050
0.190
0.190
(* Not detectable)
I P O DELHI' 2 9 - 0 8 - 2 0 1 6 1 6 : 41
<
The formulas of Examples 1, 2 and 3 do not include a pH modifier, and therefore serve
as reference examples. The stability data demonstrates the addition of a pH modifier reduces the
lactam formation.
Examples 12-15
Ingredients
Pregabalin
Crospovidone
Hydroxypropyl methyl cellulose
Acrylic acid polymer
Meglumine
Trisodium orthophosphate
Magnesium stearate
Opadry® pink
Purified water
Quantity (°
Example
12
32.04
30.10
30.58
3.88
-
-
0.49
2.91
q.s.
/o w/w)
Example
13
32.04
29.-13
28.15
3.88
3.40
-
0.49
2.91
q.s.
Example
14
32.04
30.10
29.12
4.76
-
0.58
0.49
2.91
q.s.
Example
15
33.00
29.00
29.00
4.00
-
4.50
0.50
- '
-
Procedure for Examples 12,13, and 14:
CD
G)
co
Q.
CD
CN
E
o
LL
CN
O
CN
o
CO
o
CN
CO
CN
CO
O
CO
CO
o
CN
G)
1.
2.
3.
4.
5.
6.
All the ingredients, except magnesium stearate, were sifted through sieve #20 and
blended for 15 minutes.
Magnesium stearate was sifted through sieve #25.
The blend of step 1 was blended with the material of step 2 for 5 minutes.
The blend of step 3 was compressed into a tablet using appropriate tooling.
Opadry® pink was dispersed in purified water and stirred for 45 minutes.
The tablets of step 4 were coated with the dispersion of step 5 in a perforated
coating pan.
Procedure for Example 15:
1,
2.
3.
4.
5.
6.
1
Trisodium orthophosphate was dissolved in purified water.
The solution of step 1 was sprinkled on hydroxypropyl methyl cellulose to
uniformly adsorb on it.
The material of step 2 was dried in a tray dryer at 40°C.
The remaining ingredients, except magnesium stearate, were sifted through sieve
#20 and blended with material of step 3 for 15 minutes.
Magnesium stearate was sifted through sieve # 25.
The blend of step 4 was blended with the material of step 5 for 5 minutes.
Xte blend of step 6 was cpmpresged into a tablet using appropriate tooling.
. ;g— =
CN
The tablets thus obtained were kept in HDPE bottles at 40°C/75% RH for 6 months and
tested for lactam formation. The resultant stability data is provided in Table 2.
Table 2: Stability Data of Tablets Prepared as per Examples 12-15
Examples
12
13
14
15
Percentage of Lactam
Initial
0.01
0.01
0.01
-
1 month
0.11
0.10
0.10
0.11
2 months
0.20
0.19
0.18
0.19
3 months
0.31
0.28
0.27
0.19
6 months
0;55
0.41
0.44
0.36
Example 12 is a reference example that does not contain a pH modifier. From the above
data, it is evident that the tablets containing a pH modifier have reduced levels of lactam as
compared to tablets without a pH modifier.
2 9 - 0 8 - 2 Q1

WE CLAIM:
1. A stabilized gastroretentive tablet comprising pregabalin, one or more swellable
polymers, a pH modifier, and other pharmaceuticaily acceptable excipients.
2. The stabilized gastroretentive tablet according to claim 1, wherein the swellable
polymers are selected from the group -comprising cellulosic polymers, polyalkylene
oxides, polysaccharides, acrylic acid polymer, vinyl pyrrolidone polymer, and
combinations thereof.
3. The stabilized gastroretentive tablet according to claim 1, wherein the pH modifier is
selected from the group comprising magnesium oxide, sodium acetate, trisodium citrate,
meglumine, trisodium orthophosphate, sodium bicarbonate, sodium hydroxide, and
combinations thereof.
4. The stabilized gastroretentive tablet according to claim 1, wherein the other
pharmaceuticaily acceptable excipients are selected from the group comprising diluents,
binders, disintegrants, lubricants/glidants, and combinations thereof.
5. The stabilized gastroretentive tablet according to claim 1, wherein the tablet is
substantially free of the lactam impurity.
6. The stabilized gastroretentive tablet according to claim 1, wherein the tablet is prepared
'ST by direct compression, dry granulation, or wet granulation.