The present invention relates to a modified release tablet comprising pregabalin with pharmaceutically acceptable excipients, wherein the modified release tablet substantially maintains its hydrodynamic balance and physical integrity for the time period during which the drug is released into the stomach. Further it relates to a process for the preparation of the modified release tablet.

BACKGROUND OF THE INVENTION

Pregabalin is an analogue of the physiologically important endogenous neurotransmitter [gamma] -amino butyric acid (GABA), which is involved in the regulation of neural processes. The lUPAC name of pregabalin [.INN] is (S)-3-(aminomethyl)-5-methyl hexanoic acid. The chemical structure of pregabal in is shown in formula below:

¾N

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Pregabalin is disclosed in U.S. Patent Nos. 6,197,819 and 5,563,175, which describe its use in the treatment of seizure disorders. U.S. Patent No. 6,1 17,906 discloses the use of pregabalin in treating anxiety, while U.S. Patent No. 6,001 ,876 discloses its use in treating pain. Currently, pregabalin is available as conventional immediate-release capsules marketed by CP Pharms/Pfizer under the brand name Lyrica ^® . The marketed product Lyrica ^® Capsules requires two or three times a day dosing. In order to improve patient compliance and to reduce the severity and frequency of side effects by reducing peak blood levels along with an increase in drug efficacy by increasing minimum plasma concentration, a once-daily tablet is desirable.

However, the development of a suitable once-daily formulation is rendered more difficult by the fact that pregabalin cannot be absorbed in the entire gastrointestinal tract (GIT). Pregabalin is only absorbed in the upper sections of the gut. It is therefore desirable to have a dosage form which has a longer retention time in the upper GIT and which, during that time, releases the active agent continuously over a longer period of time.

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The U.S. Publication Application No. 2007/026951 1 discloses a pregabalin formulation containing matrix forming agent and a swelling agent, wherein the matrix forming agent is polyvinyl acetate and polyvinylpyrrolidone, and the swelling agent is cross-linked polyvinylpyrrolidone.

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The U.S. Publication Application No. 2010/0255067 describes pharmaceutical compositions comprising pregabalin, a hydrophobic release controlling agent, and other pharmaceutically acceptable excipients. The U.S. Publication Application No. 2013/149253 describes oral dosage form for the modified release of pregabalin, comprising pregabalin in a matrix comprising a swelling agent, a matrix former and a buoyancy agent or alternatively a sedimentation agent. Therefore, a modified release tablet that retains in the upper parts of the gastrointestinal tract would be an ideal dosage form for pregabalin. The objective of the present invention is to develop a modified release tablet of pregabalin.

OBJECTS OF THE INVENTION

The primary object of the invention is to provide a modified release tablet comprising pregabalin with pharmaceutically acceptable excipients, wherein the modified release tablet substantially maintains its hydrodynamic balance and physical integrity for the time period during which the drug is released into the stomach.

Another object of the invention is to provide a modified release tablet comprising pregabalin with at least one low-density excipient, at least one swelling agent, at least one gelling agent, and optionally a bubble-generating mixture, wherein the modified release tablet substantially maintains its hydrodynamic balance and physical integrity for the time period during which the drug is released into the stomach.

Another object of the invention is to provide a process for the preparation of a modified release tablet of pregabalin.

SUMMARY OF THE INVENTION

In a first embodiment, the invention relates to a modified release tablet comprising pregabalin with pharmaceutically acceptable excipients, wherein the modified release tablet substantially maintains its hydrodynamic balance and physical integrity for the time period during which the drag is released into the stomach.

In another embodiment, the invention relates to a modified release tablet comprising pregabalin with at least one low-density excipient, at least one swelling agent, at least one gelling agent, and optionally a bubble-generating mixture, wherein the modified release tablet substantially maintains its hydrodynamic balance and physical integrity for the time period during which the drug is released into the stomach.

In a preferred embodiment, the invention relates to a modified release tablet comprising pregabalin with colloidal silicon dioxide as a low-density excipient, croscarmellose sodium as swelling agent and hydroxy ethyl cellulose (HEC) as gelling agent.

In a preferred embodiment, the invention relates to a modified release tablet comprising pregabalin with ethyl cellulose (EC 20 cps) as a low-density excipient, sodium starch glycolate as swelling agent, polyvinyl pyrrolidone (PVP) as gelling agent, and additionally a bubble-generating mixture.

In another embodiment, the invention relates to a process for the preparation of a modified release tablet of pregabalin, preferably direct compression method.

DETAILED DESCRIPTION

The present invention relates to a modified release tablet comprising pregabalin with pharmaceutically acceptable excipients, wherein the modified release tablet substantially maintains its hydrodynamic balance and physical integrity for the time period during which the drug is released into the stomach.

The "modified release tablet" remains in the patient's stomach following oral administration, which is substantially longer than the average residence time of a corresponding immediate release dosage form.

Not bound to any theory, the term "hydrodynamic balance" for the purpose of the invention means that the tablet maintains its balance within the stomach such that it does not sink or passes away through the pylorus, but the tablet remains suspended on the surface of the gastric fluid during which the drug is released into the stomach.

Not bound to any theory, the term "physical integrity" for the purpose of the invention refers to the tablet strength that maintains the tablet structure in an intact form and thus it does not rupture into smaller units, during which the drug is released into the stomach.

The present invention may employ any pharmaceutically acceptable form of pregabalin, including its free form (zwitter ion), and its pharmaceutically acceptable complexes, acid addition salts, base . addition salts solvates, hydrates, and polymorphs.

The present invention relates to a modified release tablet comprising pregabalin with at least one low-density excipient, at least one swelling agent, at least one gelling agent, and optionally a bubble-generating mixture, wherein the modified release tablet substantially maintains its hydrodynamic balance and physical integrity for the time period during which the drug is released into the stomach. The "low-density excipient" of the present invention includes microcrystalline cellulose (MCC) PH 105 grade, colloidal silicon dioxide (commonly known as Aerosil 200), ethyl cellulose (EC 20 cps) or combinations or copolymers thereof.

The excipient MCC PH 105 grade here refers to micro crystalline cellulose having mean particle size of 20 microns and bulk density of 0.2 to 0.3 gm/cc.

The excipient Aerosil ΖΌΌ grade here refers to colloidal silicon dioxide having mean particle size of 12-16 nm and tapped density of 0.05gm/cc.

The excipient EC 20 cps grade here refers to ethyl cellulose having mean particle size of 5-60 microns and bulk density of 0.2gm/cc.

The "swelling agent" of the present invention includes croscarmellose sodium, sodium starch glycolate (SSG), microcrystalline. cellulose (MCC), starch, cross- linked homopolymers of l-vinyl-pyrrolidin-2-one (Crospovidone) or combinations or copolymers thereof.

The swelling agent absorbs water from the gastric fluid and thereby the tablet expands in size larger than the pylorus. The swelling agent is generally used in an amount ranging from about 5% to about 30% by weight of the tablet composition.

The "gelling agent" of the present invention includes polyvinyl pyrrolidone (PVP), polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol such as carbomers (carbopols), alginates, preferably sodium alginate, hydroxyalkyl cellulose, especially hydroxyethyl cellulose (HEC), xanthan gum or combinations or copolymers thereof. The gelling agent includes excipient that forms a gel when in contact with gastric fluid and thereby modifies the drug release characteristics of the tablet. The gelling agent is generally used in an amount ranging from about 0.5% to about 40% by weight of the tablet composition.

The "bubble-generating mixture" of the present invention includes, non-limiting examples, such as bicarbonate/ascorbic acid, bicarbonate/tartaric acid, bicarbonate/citric acid, carbon ate/tartaric acid, carbonate/citric acid and/or carbonate/ascorbic acid.

The modified release tablet of the present invention when comes in contact with gastric fluid it readily forms bubbles that get entrapped within the well-defined tablet structure such that the tablet maintains its hydrodynamic balance and physical integrity for the time period during which pregabalin is released into the stomach.

In addition to the above-mentioned ingredients, the modified release tablet may also comprise further pharmaceutically acceptable excipients such as diluents, binders, rate-controlling agents, lubricants, wetting agent, glidants and coating excipients.

The present invention may employ the rate controlling agents, preferably hydroxy propyl methyl cellulose (HPMC) or other pharmaceutically acceptable excipients.

The modified release tablet of pregabalin is designed for once-daily administration and achieves bioequivalence with immediate release dosage form of pregabalin that is taken two- or three-times daily.

In another embodiment, the invention relates to a process for the preparation of a modified release tablet of pregabalin. It can be prepared by routine tableting method including direct compression, granulation and pelletization methods. Preferably, the process for the preparation is direct compression method.

In order to further illustrate the present invention, the following examples are provided for the purpose of clarity of understanding. However, it is not intended in any way to limit the scope of present invention and it is readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the scope of the invention.

Example 1: Modified Release Tablet of Pregabalin.

The modified release tablet of the present invention is prepared by Direct Compression method in the procedural steps as described below.

Manufacturing Process:

(i) Sift all ingredients through appropriate sieves,

(ii) Blend the sifted ingredients for an appropriate time,

(iii) Compressed the blend into tablets

(iv) Optionally film coat the compressed tablets.

Dissolution Studies of Modified release tablet formulation (F3) as representative example: