Technical Field of the Invention
The present invention relates to an extended release floating 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 further known that pregabalin does not have uniform absorption throughout the entire gastrointestinal tract. Pregabalin is absorbed in the small intestine and the ascending colon, but is poorly absorbed beyond the hepatic flexure. In order to overcome this decreased colonic absorption of pregabalin, the inventors have developed an extended release floating tablet of pregabalin that would not only provide sustained release of pregabalin but also retain the drug in the upper parts of the gastrointestinal tract for a long period of time.
Summary of the Invention
In one general aspect, it relates to an extended release floating tablet of pregabalin comprising pregabalin, a gas generating component, atleast one rate-controlling polymer and other pharmaceutical excipients.
In another general aspect, it relates to an extended release floating tablet of pregabalin comprising pregabalin, a gas generating component, atleast one rate-controlling polymer and other pharmaceutical excipients, wherein the gas generating component is sodium bicarbonate.
In another general aspect, it relates to an extended release floating tablet of pregabalin comprising pregabalin, a gas generating component, atleast one rate-controlling

polymer and other pharmaceutical excipients, wherein the rate-controlling polymer
comprises one or more of cross-linked polycryclic acid polymers,
hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose,
methylcellulose, alginate, xanthan gum, guar gum, polyethylene oxide, methacrylic acid copolymers, starch and starch based polymers.
In another general aspect it relates to a process for the preparation of an extended release floating tablet of pregabalin comprising pregabalin, a gas generating component, atleast one rate-controlling polymer and other pharmaceutical excipients, wherein the process comprises the conventional methods of wet granulation, dry granulation or direct compression.
In another general aspect, it relates to an extended release floating tablet of pregabalin comprising pregabalin, a gas generating component, 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 with 10 mesh basket used as sinker, at 50 rpm, at a temperature of 37±0.5°C in 900ml of 0.1 N hydrochloric acid;
- at most about 60% of the drug is released in 2 hours;
- at most about 90% of the drug is released in 4 hours;
- at most about 99% of the drug is released in 8 hours.
In another general aspect, it relates to an extended release floating tablet of pregabalin comprising pregabalin, a gas generating component, 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 further established that

pregabalin is not absorbed uniformly over the length of the gastrointestinal tract resulting in decreased rate and extent of absorption as it moves lower in the gastrointestinal tract. The inventors have therefore developed an extended release floating tablet of pregabalin, wherein upon administration, the tablet is retained in the stomach for a longer period of time and continuously releases pregabalin, thus improving the bioavailability of the drug. Eventually, the tablet passes out of the stomach and into the small intestine where it may continue to release pregabalin. Therefore, the extended release floating tablet of pregabalin keeps the drug in the region of absorption for a longer period of time and consequently improves the bioavailability of the drug.
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.
The term "extended release floating tablet" as used herein is a type of extended release tablet which has a bulk density less than gastric fluids and so remains buoyant in the stomach for a prolonged period of time. While the tablet is floating on the gastric contents, the drug is released slowly from the tablet.
"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. Pregabalin may comprise from about 100mg to about 1000mg of the tablet weight.
The rate-controlling polymer as used herein, 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. 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 gas generating component present in the extended release floating tablets, as described herein, may consist of a substance known to produce gas upon contact with gastric fluid and includes carbonates such as calcium carbonate or sodium glycine carbonate, bicarbonates such as sodium bicarbonate or potassium bicarbonate, sulfites such as sodium sulfite, sodium bisulfite or sodium metabisulfite, and the like. The gas generating component interacts with an acid source triggered by contact with water or simply with gastric fluid to generate carbon-dioxide or sulfur dioxide that gets entrapped within the hydrated gel matrix of the swelling tablet composition and allows them to float. The gas generating component may be present in an amount ranging from about 3% to about 30% by weight of the tablet. Particularly preferred gas generating component is sodium bicarbonate. These salts can be used alone or in combination with an acid source as a couple. Examples of acid source include citric acid or its salts such as sodium citrate or calcium citrate; malic acid, tartaric acid, succinic acid, fumaric acid,maleic acid or their salts, ascorbic acid or their salts and the like. 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 20% 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 solid dosage form.
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 polymers 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 floating tablet of pregabalin comprises pregabalin, a gas generating component, atleast one rate-controlling polymer and other pharmaceutical excipients.
In another embodiment, the extended release floating tablet of pregabalin comprises pregabalin, sodium bicarbonate, atleast one rate-controlling polymer selected from

Carbopol; hydroxypropylmethylcellulose, sodium alginate, xanthan gum or combinations thereof and other pharmaceutical excipients.
In another embodiment, the extended release floating tablet of pregabalin is prepared by the process comprising granulating a mixture comprising pregabalin; at least one rate-controlling polymer and optionally other pharmaceutical excipients with water or binder solution; adding gas generating component and optionally adding other rate-controlling polymers and other excipients and compressing the granules into a tablet using appropriate tooling.
In another embodiment, the extended release floating tablet of pregabalin is prepared by the process comprising granulating a mixture comprising pregabalin; at least one rate-controlling polymer and optionally other pharmaceutical excipients with water or binder solution; adding gas generating component, optionally adding other rate-controlling polymers and other excipients; re-granulating the resultant blend with the solution/dispersion of rate-controlling polymer; optionally adding other rate-controlling polymers and other excipients and finally compressing the granules into a 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: Extended release floating tablets of pregabalin
(Table Removed)

Process for Example 1:
Pregabalin and hydroxypropylmethylcellulose were sifted through a suitable screen and granulated with aqueous solution of polyvinylpyrrolidone. The resultant granules were dried and sifted through a suitable screen. Sodium bicarbonate was added to the granules. The resultant blend was lubricated with stearic acid and 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 and is given in Table 1.
Table 1: In vitro release pattern of pregabalin from extended release floating tablets prepared as per composition of Example 1 in USP type II apparatus in 900mL of 0.1 N HCI at 50 rpm with 10 mesh basket used as sinker
(Table Removed)

Example 2: Extended release floating tablets of pregabalin
(Table Removed)

Process for Example 2:
Pregabalin, lactose and hydroxypropylmethylcellulose were sifted through suitable screen and granulated with aqueous polyvinylpyrrolidone solution. The resultant granules were dried and sifted through suitable screen. Sodium bicarbonate and carbopol were added to the granules. The resultant blend was lubricated with magnesium stearate and 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 0.1N HCI at 50rpm with 10 mesh basket used as sinkers and is given in Table 2.

Table 2: In vitro release pattern of pregabalin from extended release floating tablets prepared as per composition of Example 2 in USP type II apparatus in 900mL of 0.1 N HCI at 50 rpm with 10 mesh basket used as sinker
(Table Removed)

Example 3: Extended release floating tablets of pregabalin
(Table Removed)

Process for Example 3:
Pregabalin and parts of cross-linked polyvinylpyrrolidone, lactose and hydroxypropylmethylcellulose were sifted through suitable screen, mixed and granulated with purified water. The resultant granules were dried and sifted through suitable screen. Xanthan gum, sodium alginate, carbopol, sodium bicarbonate and remaining part of cross-linked polyvinylpyrrolidone were added to the granules. The resultant blend was re-granulated with hydroxypropylmethylcellulose dispersion in water. The granules so obtained were dried and sifted through suitable screen and remaining lactose and hydroxypropylmethylcellulose were added to the said granules. The resultant blend was lubricated with magnesium stearate and compressed into suitable sized tablets. The dissolution profile of tablets of Example 3 was determined in a USP type II apparatus in 900mL of 0.1 N HCI at 50rpm with 10 mesh basket used as sinkers and is given in Table 3.

Table 3: In vitro release pattern of pregabalin from extended release floating tablets prepared as per composition of Example 3 in USP type II apparatus in 900mL of 0.1 N HCI at 50 rpm with 10 mesh basket used as sinker
(Table Removed)

WE CLAIM:
1) An extended release floating tablet of pregabalin comprising pregabalin, a gas generating component, atleast one rate-controlling polymer and other pharmaceutical excipients.
2) The extended release floating tablet of pregabalin according to Claim 1, wherein the gas generating component is sodium bicarbonate.
3) The extended release floating tablet of pregabalin according to Claim 2, wherein the rate-controlling polymer comprises one or more of hydroxypropylmethylcellulose, carbopol, sodium alginate, xanthan gum.
4) A process for the preparation of the extended release floating tablet of pregabalin according to Claim 1, wherein the process comprises the conventional methods of wet granulation, dry granulation or direct compression.
5) The extended release floating tablet of pregabalin 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 with 10 mesh basket used as a sinker, at 50 rpm, at a temperature of 37±0.5 C in 900ml of 0.1 N hydrochloric acid;

- at most about 60% of the drug is released in 2 hours;
- at most about 90% of the drug is released in 4 hours;
- at most about 99% of the drug is released in 8 hours.
6) The extended release floating 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 floating tablet of pregabalin and process for the preparation thereof substantially as described and illustrated by examples herein.