Technical Field of the Invention
The present invention relates to an extended release bi-layer 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, management of post herpetic neuralgia; management of fibromyalgia, 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 CP Pharms, 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 dosage forms 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 06/008640 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.
The benefits of extended release dosage forms over conventional dosage forms are therefore, well realized. It is even more desirable to achieve both immediate release and extended release of the drug from a single tablet. Hence, the inventors have developed extended release bi-layer tablets of pregabalin so that the administration of a single tablet provides the immediate release of an amount of drug that promptly produces the desired therapeutic effect and also a gradual and continual release of additional amounts of drug to maintain this level of effect over an extended period of time to overcome frequent or multiple dosing.
Summary of the Invention
In one general aspect, it relates to an extended release bi-layer tablet of pregabalin comprising (a) an immediate release layer comprising pregabalin and other pharmaceutical excipients and (b) an extended release layer comprising pregabalin, atleast one rate-controlling polymer and other pharmaceutical excipients.

In another general aspect, it relates to an extended release bi-layer tablet of pregabalin comprising (a) an immediate release layer comprising pregabalin and other pharmaceutical excipients and (b) an extended release layer comprising pregabalin, atleast one rate-controlling polymer and other pharmaceutical excipients, wherein the rate-controlling polymer in the extended release layer is a cellulosic polymer.
In another general aspect it relates to a process for the preparation of an extended bi-layer release tablet of pregabalin, wherein the process comprises granulating pregabalin and other pharmaceutical excipients to form immediate release granules; separately granulating pregabalin, atleast one rate-controlling polymer and other pharmaceutical excipients to form extended release granules; lubricating the respective granules and compressing them into a bi-layer tablet using appropriate tooling.
In another general aspect, it relates to an extended release bi-layer tablet of pregabalin comprising (a) an immediate release layer comprising pregabalin and other pharmaceutical excipients and (b) an extended release layer comprising pregabalin, atleast one rate-controlling polymer and other pharmaceutical excipients, wherein the 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 70% of the drug is released in 1 hour;
- at most about 80% of the drug is released in 2 hours;
- at most about 95% of the drug is released in 4 hours.
In another general aspect, it relates to an extended release bi-layer tablet of pregabalin comprising (a) an immediate release layer comprising pregabalin and other pharmaceutical excipients and (b) an extended release layer comprising pregabalin, atleast one rate-controlling polymer and other pharmaceutical excipients, wherein the said tablet provides therapeutically effective plasma levels of pregabalin for a period of upto about 24 hours.

Detailed Description of the Invention
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. It is even more advantageous to develop simple and economical tablets that would provide a pulsatile delivery system (i.e. immediate release followed by sustained release), thereby providing immediate therapeutic effect, followed by sustained release for over 24 hours from a single administration.
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, enantiomers, solvates, hydrates, and polymorphs. Total pregabalin in both the layers may comprise from about 100mg to about 1000mg of the tablet weight.
The rate-controlling polymer as used herein, in the extended release layer of the bi-layer tablet may either be a hydrophilic or hydrophobic polymer; particularly suitable are polymers that swell and/or gel 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 cross-linked polyacrylic acid polymers such as is available under the brand name Carbopol; cellulosic derivatives such as hydroxypropylmethylcellulose, hydroxypropylcellulose,

hydroxyethylcellulose, methylcellulose, vinyl acetate copolymers; polysaccharides
such as sodium alginate, potassium alginate, xanthan gum, guar gum etc.; starch
and starch based polymers; polyethylene oxide; methacrylic acid copolymers; maleic
anhydride/methyl vinyl ether copolymers and derivatives; or combinations thereof.
Particularly preferred polymer is hydroxypropylmethylcellulose.
Hydroxypropylmethylcellulose can be of different viscosity grades having the viscosity from about 100 cps to about 100,000 cps and are available, for example, under the trade name Methocel® by the Dow Chemical Company. Hydroxypropylmethylcellulose of a specific grade providing the desired release profile may be used such as Methocel® K100MCR, Methocel® K4M, Methocel® K15M and the like. The amount of the polymer in the dosage form may vary from about 2% to about 80% by weight of the tablet, in particular from about 2 to about 60%, more particularly from about 2 to 50% by weight of the tablet.
The pharmaceutically acceptable excipients may be one or more of diluents, binders, glidants, lubricants, disintegrants and colouring agents.
Suitable diluents 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 be present in an amount ranging from about 0% to about 50% by weight of the tablet.
Suitable binders may be selected from one or more of polyvinylpyrrolidone, polyvinyl alcohol, cross-linked polyvinylpyrrolidone, cellulose gums (e.g. carboxymethyl cellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose), starch pregelatinized or mixtures thereof. The binder may be present in an amount ranging from about 0% to about 15% by weight of the tablet.
Suitable glidants/lubricants may include one or more of magnesium stearate, stearic acid, talc, colloidal silicon dioxide, calcium stearate, zinc stearate or mixtures thereof. The glidant/lubricant may be present in an amount ranging from about 0.05% to about 2% by weight of the tablet.

Suitable disintegrants may include one or more of cross-linked carboxymethylcellulose sodium or cross-linked polyvinylpyrrolidone. The disintegrant may be present in an amount ranging from about 0% to about 10% by weight of the tablet.
Suitable colouring agents include those approved for use by the United States Food and Drug Administration (FDA) such as iron oxide and are well known to those skilled in the art.
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.
Tablets can additionally be coated with non-rate-controlling polymer compositions like Opadry® sold by Colorcon to impart aesthetic appeal. Such a coating may comprise about 2% by weight of the tablet.
The compositions described herein may be prepared by conventional processes using commonly available equipments. The process may comprise involving wet granulation, dry granulation or direct compression processes.
Preferred pharmaceutical compositions of the present invention may take form of several different embodiments.
In one embodiment, the extended release bi-layer tablet of pregabalin comprises (a) an immediate release layer comprising pregabalin and other pharmaceutical excipients and (b) an extended release layer comprising pregabalin, atleast one rate-controlling polymer and other pharmaceutical excipients.
In another embodiment, the extended release bi-layer tablet of pregabalin comprises (a) an immediate release layer comprising pregabalin and other pharmaceutical excipients and (b) an extended release layer comprising pregabalin, atleast one rate-

controlling polymer which is a cellulosic polymer and other pharmaceutical excipients.
In one of the above embodiment, the cellulosic polymer is hydroxypropylmethylcellulose.
In another embodiment, the extended release bi-layer tablet is prepared by the process comprising granulating pregabalin and other pharmaceutical excipients to form immediate release granules; separately granulating pregabalin, atleast one rate-controlling polymer and other pharmaceutical excipients to form extended release granules; lubricating the respective granules and compressing them into a bilayer tablet using appropriate tooling.
The following examples are given for purpose of illustrating the present invention and not intended to limit the scope in any way.
Example 1 (1a-1c): Extended release bi-layer tablets of pregabalin
(Table Removed)

Process for Example 1 (1a-1c):
Immediate release layer: Pregabalin and part of microcrystalline cellulose were sifted through suitable screen. Sifted iron oxide red was added to it and this blend was

granulated with aqueous solution of polyvinylpyrrolidone. The granules were dried and sifted through appropriate sieve and mixed with remaining microcrystalline cellulose, croscarmellose sodium and magnesium stearate to form immediate release blend.
Extended Release Layer: Pregabalin, hydroxypropylmethylcellulose and part of microcrystalline cellulose were sifted through suitable screen and granulated with the aqueous solution of polyvinylpyrrolidone. The granules were dried and sifted through appropriate sieve and mixed with remaining microcrystalline cellulose and magnesium stearate to form the extended release blend.
Compression: The respective immediate release and extended release blends were compressed on a bilayer compression machine using appropriate tooling. The dissolution profiles of tablets of Example 1 (1a-1c) was determined in a USP type II apparatus in 900mL of 0.1 N HCI at 50rpm and are given in Table 1.
Table 1: In vitro release pattern of pregabalin from extended release bi-layer tablets prepared as per compositions of Example 1 (1a-1c) in USP type II apparatus in 900mL of 0.1 N HCI at 50 rpm
(Table Removed)

WE CLAIM:
1) An extended release bi-layer tablet of pregabalin comprising (a) an immediate release layer comprising pregabalin and other pharmaceutical excipients and (b) an extended release layer comprising pregabalin, atleast one rate-controlling polymer and other pharmaceutical excipients.
2) The extended release bi-layer tablet of pregabalin according to Claim 1, wherein the rate-controlling polymer in the extended release layer is a cellulosic polymer.
3) The extended release bi-layer tablet of pregabalin according to Claim 2, wherein the rate-controlling polymer in the extended release layer is hydroxypropylmethylcellulose.
4) A process for the preparation of extended release bi-layer tablet of pregabalin according to Claim 1, wherein the process comprises granulating pregabalin and other pharmaceutical excipients to form immediate release granules; separately granulating pregabalin, atleast one rate-controlling polymer and other pharmaceutical excipients to form extended release granules; lubricating the respective granules and compressing them into a bi-layer tablet using appropriate tooling.
5) The extended release bi-layer tablet according to the Claim 1, wherein the 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 0.1N hydrochloric acid

- at most about 70% of the drug is released in 1 hour;
- at most about 80% of the drug is released in 2 hours;
- at most about 95% of the drug is released in 4 hours.
6) The extended release bi-layer tablet of pregabalin according to Claim 1, wherein
the said tablet provides therapeutically effective plasma levels of pregabalin for a
period of upto about 24 hours.

7) The extended release bi-layer tablet of pregabalin and process for the preparation thereof substantially as described and illustrated by examples herein.