Technical Field of the Invention
The present invention relates to an extended release tablet for oral administration comprising pregabalin and the process for the preparation thereof.
Background of the invention
Pregabalin, or (S)-3-(aminomethyl)-5-methylhexanoic acid, binds to the calcium channel alpha-2-delta (a25) subunit and is related to endogenous inhibitory neurotransmitter gamma-amino butyric acid (GABA), which is involved in brain neuronal activity. Pregabalin is indicated for the management of neuropathic pain associated with diabetic peripheral neuropathy or post herpetic neuralgia; as an adjunctive therapy for adult patients with partial onset seizures and for the treatment of generalized anxiety disorder in adults.
Currently, pregabalin is commercially available as conventional immediate release capsules in 25, 50, 75, 100, 150, 200, 225 and 300 mg strengths marketed by Pfizer, under the brand name LYRICA®, requiring two or three times a day dosing. Some epileptic patients need to take medication throughout their lives while others may only require it for a limited period. The importance of taking drugs at regular intervals cannot be overemphasized. However, it is not easy for everyone to remember to take the correct dose at the same time each day. Multiple dosing is not only inconvenient but also lowers patient compliance.
Advantages of extended release systems over conventional are well known. Extended release dosage forms not only increase patient compliance due to reduction in frequency of dosing, but they also reduce the severity and frequency of side effects, as they maintain substantially constant plasma levels by avoiding fluctuations of plasma levels of drug that are associated with dosing of the conventional immediate release formulations.
Pregabalin is disclosed in US Patent No. 6197819. Further, US Patent No. 6197819 also has generic disclosure of pharmaceutical compositions comprising pregabalin. US Patent No. 5563175 describes the use of pregabalin in the treatment of seizure disorders. US Patent No. 6117906 discloses the use of pregabalin in treating anxiety, while US patent No. 6001876 discloses its use in treating pain. US Patent No's. US 6663175, 5599973, 5608090, 5684189, 5710304, 5616793, 5629447, 5637767,

5840956, 6046353, 6028214 disclose processes for preparation of pregabalin and intermediates used in these processes.
WO 02/94220 discloses liquid pharmaceutical compositions of GABA analogs including pregabalin comprising atleast one polyhydric alcohol. WO 05/63229 discloses liquid oral pharmaceutical composition of pregabalin with a preservative, a taste masking agent, and optionally a viscosity controlling agent. WO 06/08640 discloses oil suspension for oral use comprising pregabalin and surfactant in an edible oil phase. WO 05/41927 describes composition comprising a complex of pregabalin and a transport moiety resulting in enhanced absorption of pregabalin in the gastrointestinal tract. WO 99/59573 and WO 05/51384 disclose stabilized pharmaceutical preparations comprising pregabalin and a-amino acids.
Extended release oral dosage forms for pregabalin are not known in the prior art. The benefits of extended release dosage forms are well realized. We, hereby, disclose novel oral extended release pharmaceutical compositions of pregabalin.
Summary of the Invention
In one general aspect it relates to an extended release tablet comprising pregabalin and at least one rate-controlling polymer; so that said tablet exhibits the following in vitro dissolution profile, when measured in a USP type II dissolution apparatus, at 50 rpm, at a temperature of 37±0.5°C in 900ml of 0.1 N hydrochloric acid;
- at most about 50% of the drug is released in 2 hours;
- at most about 70% of the drug is released in 4 hours and
- at most about 90% of the drug is released in 8 hours.
In another general aspect it relates to a process for the preparation of an extended release tablet of pregabalin wherein the process comprises granulating a mixture comprising pregabalin; at least one rate-controlling polymer and optionally other pharmaceutical excipients with water or binder solution; compressing the granules into a tablet.
In another general aspect it relates to a process for the preparation of an extended release tablet of pregabalin wherein the process comprises granulating a mixture

comprising pregabalin and at least one water-swellable cellulosic polymer; compressing the granules into a tablet.
In another general aspect it relates to a process for the preparation of an extended release tablet of pregabalin wherein the process comprises granulating a mixture comprising pregabalin and hydroxypropyl methylcellulose; compressing the granules into a tablet.
In another general aspect it relates to a process for the preparation of an extended release tablet of pregabalin wherein the process comprises granulating a mixture comprising pregabalin and a combination of hydroxypropyl methylcellulose and sodium carboxymethylcellulose; compressing the granules into a tablet.
In one general aspect it relates to an extended release tablet comprising pregabalin and at least one rate-controlling polymer wherein the tablet has relatively extended gastric residence time and the tablet provides for the extended release of pregabalin in the stomach environment over a prolonged period of time.
In another general aspect it relates to a extended release tablet comprising pregabalin and at least one rate controlling polymer wherein the tablet provides therapeutically effective plasma levels of pregabalin for a period of up to about 24 hours.
In another general aspect it relates to an extended release tablet comprising pregabalin and at least one water-swellable cellulosic polymer wherein the tablet provides therapeutically effective plasma levels of pregabalin for a period of up to about 24 hours.
Detailed Description of the Invention
The extended release tablet comprises pregabalin, atleast one rate controlling polymer and pharmaceutically acceptable excipients. The tablets described herein may be prepared by conventional processes using easily available excipients. The manufacturing facility requires conventional equipments.

Pregabalin is presently available as conventional immediate release capsules. In conventional oral dosage forms, there is little or no control over the release of the drug and an effective concentration can only be maintained by repeated administrations. Extended release systems provide a uniform concentration of drug at the absorption site for an extended period of time to allow for maintenance of plasma concentrations within a desired therapeutic range. The controlled absorption would help reduce the frequency of administration to once a day or twice a day. The present invention, therefore, relates to novel oral extended release tablets of pregabalin.
The term "extended release tablet" as used herein includes a tablet that achieves the slow release of drug over an extended period of time, and includes prolonged, controlled, extended and delayed release profiles. This includes matrix systems, osmotic systems and membrane-controlled systems. Particularly preferred are matrix systems.
"Pregabalin", as recited herein means pregabalin or a pharmaceutically acceptable form of pregabalin, including without limitation, its free form (zwitterion), and its pharmaceutically acceptable complexes, salts, enantiomer, solvates, hydrates, and polymorphs. Pregabalin may comprise from about 100mg to about 1000mg of the tablet weight.
The rate-controlling polymer may be either a hydrophilic or hydrophobic polymer;
particularly suitable are polymers that swell in aqueous media. The amount of polymer
in the tablet relative to pregabalin depends upon the rate of drug release required and
also upon the type and molecular weight of the polymer and other excipients present in
the formulation. Examples of suitable rate-controlling polymers include
polyvinylpyrrolidone; cellulosic polymers such as hydroxypropyl methylcellulose,
hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, sodium
carboxymethylcellulose; vinyl acetate copolymers; polysaccharides (such as alginate, xanthan gum, guar gum etc.), starch and starch based polymers, polyethylene oxide, methacrylic acid copolymers, maleic anhydride/methyl vinyl ether copolymers and derivatives and mixtures thereof. Particularly suitable is hydroxypropyl methylcellulose. Hydroxypropyl methylcellulose can be of different viscosity grades having viscosity from about 100cps to about 100,000cps. Suitable types are sold under the trade name Methocel by Dow Chemical Co. such as Methocel K4MCR, Methocel K15MCR and

Methocel K100MCR. Besides the above, cellulose derivatives such as ethyl cellulose or cellulose acetate, methacrylates, acrylic acid polymers and copolymers, high molecular weight polyvinyl alcohols and waxes such as fatty acids and glycerides are also included. The amount of the polymer in the dosage form may vary from about 5% to about 80% by weight of the composition, in particular from about 5 to about 70%, more particularly from about 5 to 50% by weight of the composition.
The pharmaceutically acceptable excipients may be one or more of diluent(s), binder(s), and lubricant(s) and glidants(s),
Suitable diluent(s) may be selected from one or more of any conventional diluents such as microcrystalline cellulose, lactose, mannitol, starch, calcium phosphate, calcium sulfate, sorbitol or mixtures thereof. The diluent may comprise from about 5% to about 40% by weight of the tablet. In one embodiment, the diluent may be microcrystalline cellulose.
Suitable binder(s) may be selected from one or more of polyvinylpyrrolidone, polyvinyl alcohol, cross-linked polyvinylpyrrolidone, cellulose gums (e.g. carboxymethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose), starch pregelatinized or mixtures thereof. The binder may be present in an amount ranging from about 2% to about 15% by weight of the tablet. In one embodiment, the binder may be polyvinylpyrrolidone.
Suitable glidants(s)/lubricant(s) may include one or more of magnesium stearate, stearic acid, talc, colloidal silicon dioxide, calcium stearate, zinc stearate or mixtures thereof. The lubricant may be added in a concentration varying from about 0.1% to about 2% by weight of the solid dosage form. In one embodiment, magnesium stearate is included as a lubricant.
Suitable solvent(s) for granulation process include one or more of water, ethanol, methanol, isopropyl alcohol, methylene chloride, acetone and the like, and combinations thereof.
Pregabalin extended release tablets may be prepared using the following steps:
1. Pregabalin is blended with rate-controlling polymer(s) and optionally with other excipients in a suitable mixer.

2. The blend of step 1 is granulated with water or a binder solution.
3. Granules are dried and sized.
4. Sized granules are mixed with other excipients such as lubricant, glidant and
compressed into a tablet.
Alternatively, non-aqueous granulation, direct compression or dry granulation techniques may also be used to prepare tablets. In direct compression the blend of pregabalin, rate-controlling polymer(s), diluent, binder, lubricant is prepared and compressed into a tablet. The dry granulation process can be carried out by compaction or by preparing slugs of a mixture of pregabalin, rate-controlling polymer(s) and optionally other excipients; sizing of the material/slugs so obtained and mixing with a lubricant and compressing into a tablet.
Tablets can additionally be coated with non-rate-controlling polymer(s) compositions like Opadry® sold by Colorcon to impart aesthetic appeal. Such a coating may comprise about 2% by weight of the tablet.
The extended release tablet of pregabalin disclosed herein is further illustrated by the following examples but it should not be construed as limiting the scope of the invention.

Example 1

Ingredients Qty (mg/tablet)
Intragranular
Pregabalin 606.05
Microcrystalline cellulose 153.95
Hydroxypropyl methyl cellulose 130.00
Polyvinylpyrrolidone 100.00
Purified water IP q.s.
Extragranular
Microcrystalline cellulose 100.00
Magnesium stearate 10.00
Total weight 1100.00
Process:
Pregabalin, microcrystalline cellulose and hydroxypropyl methylcellulose were mixed in rapid mixer granulator (RMG) for 10 minutes and granulated with aqueous polyvinylpyrrolidone solution. The resultant granules were dried in fluidized bed dryer (FBD) at 45-50°C. Extragranular microcrystalline cellulose and magnesium stearate were mixed with granules in a non-shear blender. The blend was then compressed into suitable sized tablets. The dissolution profile of tablets of Example 1 was determined in a USP type II apparatus in 900ml of 0.1 N HCI at 50rpm with 10 mesh basket used as sinkers. The dissolution profile is given in Table 1.
Table 1: In vitro release pattern of pregabalin from extended release tablets prepared as per composition of Example 1 in USP type II apparatus in 900ml_ of 0.1N HCI at 50 rpm with 10 mesh basket used as sinker

Time (hrs) % pregabalin released
1 27
2 42.92
4 59.62
6 74.05
8 85.62
10 94.03
12 102.42

Example 2

Ingredients Qty (mg/tablet)
Intragranular
Pregabalin 606.05
Microcrystalline cellulose 300.45
Hydroxypropyl methyl cellulose 30.00
Polyvinylpyrrolidone 20.00
Purified water IP q.s.
Extragranular
Hydroxypropyl methyl cellulose 80.00
Microcrystalline cellulose 150.00
Magnesium stearate 13.50
Total weight 1200.00
Process:
Pregabalin, microcrystalline cellulose and hydroxypropyl methylcellulose were mixed in RMG for 10 minutes and granulated with aqueous polyvinylpyrrolidone solution. The resultant granules were dried in FBD at 45-50°C. Extragranular hydroxypropyl methylcellulose, microcrystalline cellulose and magnesium stearate were mixed with granules in a non-shear blender. The blend was then compressed into suitable sized tablets. The dissolution profile of tablets of Example 2 was determined in a USP type II apparatus in 900mL of 0.1 N HCI at 50rpm with 10 mesh basket used as sinkers. The dissolution profile is given in Table 2.
Table 2: In vitro release pattern of pregabalin from extended release tablets prepared as per composition of Example 2 in USP type II apparatus in 900mL of 0.1N HCI at 50 rpm with 10 mesh basket used as sinker

Time (hrs) % pregabalin released
1 31.98
2 39.02
4 59.13
6 75.81
8 82.25
10 88.79
12 98.61
Example 3

Ingredients Qty (mg/tablet)

Intragranular
Pregabalin 606.05
Microcrystalline cellulose 243.95
Sodium carboxymethylcellulose 150.00
Hydroxypropyl methyl cellulose 110.00
Purified water IP q.s.
Extragranular
Microcrystalline cellulose 130.00
Magnesium stearate 10.00
Total weight 1250.00
Process:
Pregabalin, microcrystalline cellulose, sodium carboxymethylcellulose and hydroxypropyl methylcellulose were mixed in RMG for 10 minutes and granulated with purified water. The resultant granules were dried in FED at 45-50°C. Extragranular microcrystalline cellulose and magnesium stearate were mixed with granules in a non-shear blender. The blend was then compressed into suitable sized tablets. The dissolution profile of tablets of Example 3 was determined in a USP type II apparatus in 900ml of 0.1N HCI at 50rpm with 10 mesh basket used as sinkers. The dissolution profile is given in Table 3.
Table 3: In vitro release pattern of pregabalin from extended release tablets prepared as per composition of Example 3 in USP type II apparatus in 900mL of 0.1N HCI at 50 rpm with 10 mesh basket used as sinker

Time (hrs) % pregabalin released
1 31.09
2 43.32
4 59.98
6 66.66
8 75.95
10 81.78
12 82.83
10

Example 4

Ingredients Qty (mg/tablet)
Intragranular
Pregabalin 606.05
Microcrystalline cellulose 223.95
Sodium carboxymethylcellulose 150.00
Hydroxypropyl methyl cellulose 110.00
Polyvinylpyrrolidone 150.00
Purified water IP q.s.
Extragranular
Microcrystalline cellulose 150.00
Magnesium stearate 10.00
Total weight 1400.00
Process:
Pregabalin, microcrystalline cellulose, sodium carboxymethylcellulose and hydroxypropyl methylcellulose were mixed in RMG or 10 minutes and granulated with aqueous polyvinylpyrrolidone solution. The resultant granules were dried in FBD at 45-50°C. Extragranular microcrystalline cellulose and magnesium stearate were mixed with granules in a non-shear blender. The blend was then compressed into suitable sized tablets. The dissolution profile of tablets of Example 4 was determined in a USP type II apparatus in 900ml_ of 0.1 N HCI at 50rpm with 10 mesh basket used as sinkers. The dissolution profile is given in Table 4.
Table 4: In vitro release pattern of pregabalin from extended release tablets prepared as per composition of Example 4 in USP type il apparatus in 900ml of 0.1N HCI at 50 rpm with 10 mesh basket used as sinker

Time (hrs) % pregabalin released
1 30.3
2 40.23
4 53.93
6 68.00
8 81.88
10 89.09
12 97.56

WE CLAIM:
1. An extended release tablet comprising pregabalin and at least one rate-
controlling polymer and optionally other excipients, wherein the tablet exhibits
the following in vitro dissolution profile, when measured in a USP type II
dissolution apparatus, at 50rpm, at a temperature of 37±0.5°C in 900ml of 0.1N
hydrochloric acid;
at most about 50% of the drug is released in 2 hour; at most about 70% of the drug is released in 4 hours and at most about 90% of the drug is released in 8 hours.
2. The extended release tablet according to claim 1 wherein pregabalin comprises
from 10Omg to 10OOmg by weight of the tablet.
3. The extended release tablet according to claim 1 wherein the rate-controlling
polymer is from 5% to 80% by weight of the tablet.
4. The extended release tablet according to claim 1 wherein the rate-controlling
polymer comprises polyvinylpyrrolidone; cellulosic polymers; vinyl acetate
copolymers; alginate, xanthan gum, guar gum; starch and starch based
polymers, polyethylene oxide, methacrylic acid copolymers, maleic
anhydride/methyl vinyl ether copolymers and derivatives, ethyl cellulose,
cellulose acetate, methacrylates, acrylic acid polymers and copolymers, high
molecular weight polyvinyl alcohols, waxes and combinations thereof.
5. The extended release tablet according to claim 4 wherein the cellulosic polymer
is selected from hydroxypropyl methylcellulose and sodium
carboxymethylcellulose and combinations thereof.
6. The extended release tablet according to claim 1 wherein the other excipients
are selected from diluents, binders, lubricants and glidants as herein described.

7. A process for the preparation of an extended release tablet of pregabalin of
claim 1 wherein the process comprises granulating a mixture comprising
pregabalin; at least one rate-controlling polymer and optionally other
pharmaceutical excipients with water or binder solution; compressing the
granules into a tablet.
8. The process according to claim 7, wherein the process comprises granulating a
mixture of a therapeutically effective amount of pregabalin; about 5% to about
80% of rate-controlling polymer which is hydroxypropyl methylcellulose having
viscosity of from about 100 to about 100,000 cps and other pharmaceutical
excipients; compressing the granules into a tablet.
9. The extended release tablet of Claim 1, wherein the tablet provides
therapeutically effective plasma levels of pregabalin for a period of upto about 24
hours.
10. An extended release dosage form of pregabalin and process for the preparation
thereof substantially as described and illustrated by the examples herein.
Dated this the 15™ day of September, 2006.
For Ranbaxy Laboratories Limited


mar Patawari pany Secretary