FIELD OF THE INVENTION
The present invention relates to gastro-retentive multiparticulate pharmaceutical composition comprising pregabalin. It also relates to a process for the preparation of said composition.

BACKGROUND OF THE INVENTION
Pregabalin is an analogue of the endogenous neurotransmitter ?-amino butyric acid (GABA) which is involved in the regulation of brain neuronal activity. Chemically, it is known as (S)-(+)-3-(amino methyl)-5-methylhexanoic acid.
Pregabalin is marketed in the form of capsule, oral solution and extended release tablets under the trade name Lyrica® in the USA by innovator PF Prism CV (Pfizer). It is approved for use in the treatment of neuropathic pain associated with diabetic peripheral neuropathy (DPN), postherpetic neuralgia, fibromyalgia and as an adjunctive treatment for partial onset seizures in adults.

Marketed immediate release capsules of pregabalin (Lyrica®) are available in strengths of 25, 50, 75, 100, 150, 200, 225, and 300 mg and are administered to patients two or three times daily. Immediate release oral solution of pregabalin is also available in strength of 20 mg/mL but it also has to be administered multiple times daily, which may lead to decreased patient compliance. To facilitate patient compliance, Pfizer has introduced pregabalin extended release tablet (Lyrica CR®) in strengths of 82.5, 165 and 330 mg, which are to be administered once daily. However, tablet and capsule formulation is not suitable for patients with swallowing difficulties including geriatric patents.
Development of once daily dosing of pregabalin is beset with numerous challenges. Pregabalin is not absorbed uniformly in the gastrointestinal tract. It is mainly absorbed in the small intestine and in the ascending colon in humans and is poorly absorbed beyond the hepatic flexture. It is desirable to have a dosage form which has a longer dwell time in the upper gastrointestinal tract (GIT) and releases pregabalin continuously over a prolong period of time. Further, pregabalin is freely soluble in water which makes the development of an extended release formulation more challenging.
Various approaches have been attempted for developing a sustained release dosage form of pregabalin.
U.S. Patent Nos. 8,945,620, 9,144,559, 10,022,447, assigned to Pfizer, discloses pharmaceutical composition comprising pregabalin, a matrix forming agent comprising polyvinyl acetate, polyvinylpyrrolidone and a swelling agent comprising cross-linked polyvinylpyrrolidone, wherein the pharmaceutical composition is adapted for once-daily oral dosing.
U.S. Patent No. 9,393,205, assigned to Ranbaxy, discloses gastroretentive tablet comprising pregabalin, at least one swellable polymer and pharmaceutically acceptable excipients.
U.S. Patent No. 8,454,993, assigned to Lupin, discloses a controlled release pharmaceutical composition comprising pregabalin, a hydrophobic release controlling agent consisting essentially of ethyl cellulose. It also discloses a controlled release pharmaceutical composition wherein the hydrophobic release controlling agent consisting essentially of hydrogenated vegetable oil. The disclosed compositions are not gastro-retentive compositions.
U.S. Patent No. 9,028,865, assigned to Lupin, discloses a controlled release pharmaceutical composition comprising pregabalin, a hydrophobic release controlling agent(s) additionally containing a wicking agent selected from the group consisting of a hydrophilic, organic, polymeric, fusible substance or a particulate soluble or particulate insoluble inorganic material. The disclosed composition is not a gastro-retentive composition.

U.S. Publication No. 2013/0149253, assigned to Ratiopharm, discloses a modified release tablet of pregabalin, comprising pregabalin in a matrix comprising a swelling agent, a matrix former and a buoyancy agent or a sedimentation agent.
The prior art discloses single unit compositions such as extended release tablets of pregabalin. It is possible that a single unit preparation might migrate into the duodenum in a short period of time after administration and thereby fail to exhibit desired retention in the stomach. There is a need of gastro-retentive multiparticulate pharmaceutical composition of pregabalin capable of remaining in the stomach for a prolonged period of time.
The inventors of the present invention propose gastro-retentive multiparticulate pharmaceutical composition of pregabalin. The compositions are convenient for administering to patients including geriatrics and are expected to improve patient convenience and adherence to therapy. The proposed gastro-retentive multiparticulate pharmaceutical compositions can be administered directly into the patient's mouth or sprinkled onto food or dispersed into a liquid medium to form a suspension and then administered. The multiparticulate pharmaceutical compositions are expected to exhibit desired technical attributes such as dissolution and stability and bioequivalent to a commercially marketed extended release tablet (Lyrica CR®)
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a gastro-retentive multiparticulate pharmaceutical composition of pregabalin which releases pregabalin for an extended period of time.
One embodiment of the present invention relates to a gastro-retentive multiparticulate pharmaceutical composition of pregabalin comprising:
(a) an inert core coated with pregabalin;
(b) a gas generating layer coated over the pregabalin core; and
(c) a release controlling layer coated on the gas generating layer comprising a release controlling agent.

Another embodiment of the present invention relates to a gastro-retentive multiparticulate pharmaceutical composition of pregabalin comprising:
(a) an inert core coated with pregabalin;
(b) optionally a seal coat over the pregabalin core;
(c) a gas generating layer coated over the pregabalin core or seal coated pregabalin core; and
(d) a release controlling layer coated on the gas generating layer comprising a release controlling agent.

Another embodiment of the present invention relates to a gastro-retentive multiparticulate pharmaceutical composition of pregabalin comprising:
(a) an inert core;
(b) seal coat over the inert core;
(c) pregabalin layer over the seal coat;
(d) a seal coat over the pregabalin layer;
(e) a gas generating layer coated over the seal coated pregabalin layer; and
(f) a release controlling layer coated on the gas generating layer comprising a release controlling agent.

Another embodiment of the present invention relates to a gastro-retentive multiparticulate pharmaceutical composition of pregabalin comprising:
(a) an inert core;
(b) optionally a seal coat over the inert core;
(c) pregabalin layer over the inert core or seal coated seal coat;
(d) optionally a seal coat over the pregabalin layer;
(e) a gas generating layer coated over the pregabalin layer or seal coated pregabalin layer; and
(f) a release controlling layer coated on the gas generating layer comprising a release controlling agent.

Another embodiment of the present invention relates to a gastro-retentive multiparticulate pharmaceutical composition of pregabalin comprising:
(a) a core comprising pregabalin and one or more pharmaceutically acceptable excipients;
(b) a gas generating layer coated over the pregabalin core; and
(c) a release controlling layer coated on the gas generating layer comprising a release controlling agent.

Another embodiment of the present invention relates to a gastro-retentive multiparticulate pharmaceutical composition of pregabalin comprising:
(a) a core comprising pregabalin and one or more pharmaceutically acceptable excipients;
(b) optionally a seal coat over the pregabalin core;
(c) a gas generating layer over the pregabalin core or seal coated pregabalin core;
(d) optionally a seal coat over the gas generating layer; and
(e) a release controlling layer coated on the gas generating layer or the seal coated gas generating layer comprising a release controlling agent.

Another embodiment of the present invention relates to a gastro-retentive multiparticulate pharmaceutical composition of pregabalin comprising:
(a) an inert core coated with pregabalin;
(b) a gas generating layer coated over the pregabalin core;
(c) a release controlling layer coated on the gas generating layer comprising a release controlling agent; and
(d) a pharmaceutically acceptable carrier.
Another embodiment of the present invention relates to a gastro-retentive multiparticulate pharmaceutical composition of pregabalin comprising:
(a) an inert core coated with pregabalin;
(b) a gas generating layer coated over the pregabalin core; and
(c) a release controlling layer coated on the gas generating layer comprising a release controlling agent;
wherein the composition is reconstituted with a pharmaceutically acceptable carrier before administration.
Another embodiment of the present invention relates to a process for the preparation of a gastro-retentive multiparticulate pharmaceutical composition of pregabalin comprising:
(i) preparing a core comprising pregabalin;
(ii) optionally coating a seal coat over the pregabalin core;
(iii) coating the pregabalin core or seal coated pregabalin core with a gas generating layer;
(iv) optionally coating a seal coat over the gas generating layer; and
(v) coating the gas generating layer of step (iii) or seal coated core of step (iv) with a release controlling layer.

DETAILED DESCRIPTION OF THE INVENTION
The term “composition” or “formulation” or “dosage form”, as in pharmaceutical composition, is intended to encompass a drug product comprising pregabalin or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, and other inert ingredient(s) (pharmaceutically acceptable excipients). Such pharmaceutical compositions are synonymous with “formulation” and “dosage form”. Pharmaceutical composition of the invention include, but is not limited to, multiparticulate composition of pregabalin. The multiparticulate composition can be in the form of gastro-retentive suspension powder for reconstitution and ready to use gastro-retentive suspension.
The term “multiparticulate”, as used herein, refers to a plurality of discrete or aggregated particles, pellets, beads, granules, spheroids, spheres, microspheres, microcapsules, microparticles, minitablets, powder or mixture thereof.
The term “pregabalin”, as used herein, means pregabalin or a pharmaceutically acceptable form of pregabalin, including its free form (zwitterion) and its pharmaceutically acceptable complexes, salts, enantiomers, solvates, hydrates, and polymorphs. The multiparticulate composition of the present invention comprises pregabalin in an amount from about 0.01% w/w to about 90% w/w of the total composition.
The term “core”, as used herein refers to particulate such as bead, pellet, granule comprising pregabalin and one or more pharmaceutically acceptable excipients. Pregabalin may be present in the core or layered over inert particle to form the core.
The term “inert particle,” as used herein, refers to a particle made from a sugar sphere also known as a non-pareil seed, a microcrystalline cellulose sphere, a dibasic calcium phosphate bead, a mannitol bead, a silica bead, glass bead, a tartaric acid pellet, a wax based pellet and the like.
The term “excipient” means a pharmacologically inactive component such as a diluent, glidant, lubricant, disintegrant, binder, surfactant or the like. Co-processed excipients are also covered under the scope of present invention. Combination of excipients performing the same function may also be used to achieve desired formulation characteristics.
The term “gastro-retentive”, as used herein, refers to a pharmaceutical composition which remain in the stomach exceeding the usual period, for example, the pharmaceutical composition remains in the stomach for at least two hours. Particularly, the composition remains in the stomach for at least two hours, three hours, four hours, five hours or more.
The term “gas generating layer”, as used herein, refers to a layer which evolves a gas such as carbon dioxide upon contact with the gastric juice. The gas generating layer may include a single component that generates gas upon contact with gastric fluid or may include a gas generating couple. Gas generating components that may be used in the present invention include 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. These salts may be used alone or in combination with an acid source as a gas generating couple. The acid source may be an edible organic acid, a salt of an edible organic acid, or mixture thereof. Examples of organic acids that may be used include citric acid, malic acid, succinic acid, tartaric acid, fumaric acid, ascorbic acid, glutamic acid and their salts, and mixtures thereof.
The gas generating layer can be present as single layer or can include two layers with an inner layer comprising a bicarbonate and an outer layer comprising an organic acid. However, the order of these layer is not strictly limited.
The term “extended release” as used herein, refers to a release profile to effect delivery of pregabalin over an extended period of time, as being between about 4 hour to about 6, 8, 12 or 24 hours.
The term “plasticizer” as used herein, refers to the group of compounds having plasticizing property and helps in forming film with polymers. The plasticizer may be used alone or in combination with other plasticizers.
The term “about”, as used herein, refers to any value which lies within the range defined by a variation of up to ±10% of the value.
One embodiment of the present invention relates to a gastro-retentive multiparticulate pharmaceutical composition of pregabalin comprising:
(a) an inert core coated with pregabalin;
(b) a gas generating layer coated over the pregabalin core; and
(c) a release controlling layer coated on the gas generating layer comprising a release controlling agent.

Another embodiment of the present invention relates to a gastro-retentive multiparticulate pharmaceutical composition of pregabalin comprising:
(a) an inert core coated with pregabalin;
(b) optionally a seal coat over the pregabalin core;
(c) a gas generating layer coated over the pregabalin core or seal coated pregabalin core; and
(d) a release controlling layer coated on the gas generating layer comprising a release controlling agent.

Another embodiment of the present invention relates to a gastro-retentive multiparticulate pharmaceutical composition of pregabalin comprising:
(a) an inert core;
(b) seal coat over the inert core;
(c) pregabalin layer over the seal coat;
(d) a seal coat over the pregabalin layer;
(e) a gas generating layer coated over the seal coated pregabalin layer; and
(f) a release controlling layer coated on the gas generating layer comprising a release controlling agent.

Another embodiment of the present invention relates to a gastro-retentive multiparticulate pharmaceutical composition of pregabalin comprising:
(a) an inert core;
(b) optionally a seal coat over the inert core;
(c) pregabalin layer over the inert core or seal coated inert core;
(d) optionally a seal coat over the pregabalin layer;
(e) a gas generating layer coated over the drug core; and
(f) a release controlling layer coated on the gas generating layer comprising a release controlling agent.

Another embodiment of the present invention relates to a gastro-retentive multiparticulate pharmaceutical composition of pregabalin comprising:
(a) a core comprising pregabalin and one or more pharmaceutically acceptable excipients;
(b) a gas generating layer coated over the pregabalin core; and
(c) a release controlling layer coated on the gas generating layer comprising a release controlling agent.

Another embodiment of the present invention relates to a gastro-retentive multiparticulate pharmaceutical composition of pregabalin comprising:
(a) a core comprising pregabalin and a pharmaceutically acceptable excipient;
(b) optionally a seal coat over the pregabalin core;
(c) a gas generating layer over the pregabalin core or seal coated pregabalin core;
(d) optionally a seal coat over the gas generating layer; and
(e) a release controlling layer coated on the gas generating layer or the seal coated gas generating layer comprising a release controlling agent.

Another embodiment of the present invention relates to a gastro-retentive multiparticulate pharmaceutical composition of pregabalin comprising:
(a) an inert core coated with pregabalin;
(b) a gas generating layer coated over the pregabalin core;
(c) a release controlling layer coated on the gas generating layer comprising a release controlling agent; and
(d) a outer layer comprising a mucoadhesive agent.

Another embodiment of the present invention relates to a gastro-retentive multiparticulate pharmaceutical composition of pregabalin comprising:
(a) an inert core coated with pregabalin;
(b) a gas generating layer coated over the pregabalin core;
(c) a release controlling layer coated on the gas generating layer comprising a release controlling agent; and
(d) a pharmaceutically acceptable carrier.
Another embodiment of the present invention relates to a gastro-retentive multiparticulate pharmaceutical composition of pregabalin comprising:
(a) an inert core coated with pregabalin;
(b) a gas generating layer coated over the pregabalin core; and
(c) a release controlling layer coated on the gas generating layer comprising a release controlling agent; wherein the composition is reconstituted with a pharmaceutically acceptable carrier before administration.
Another embodiment of the present invention relates to a gastro-retentive multiparticulate pharmaceutical composition of pregabalin comprising:
(a) a core comprising pregabalin and one or more pharmaceutically acceptable excipients;
(b) a gas generating layer coated over the pregabalin core; and
(c) a release controlling layer coated on the gas generating layer comprising a release controlling agent; and
(d) a pharmaceutically acceptable carrier.
Another embodiment of the present invention relates to a gastro-retentive multiparticulate pharmaceutical composition of pregabalin comprising:
(a) a core comprising pregabalin and one or more pharmaceutically acceptable excipients;
(b) a gas generating layer coated over the pregabalin core; and
(c) a release controlling layer coated on the gas generating layer comprising a release controlling agent;
wherein the composition is reconstituted with a pharmaceutically acceptable carrier before administration.
In yet another embodiment of the present invention, the gas generating layer comprises a carbonate or a bicarbonate.
In yet another embodiment of the present invention, the gas generating layer further comprises an organic acid.

Another embodiment of the present invention relates to a gastro-retentive multiparticulate pharmaceutical composition of pregabalin, wherein the composition is free of ethylcellulose.

In yet another embodiment of the present invention, the release controlling layer does not contain ethyl cellulose.
In yet another embodiment of the present invention, the release controlling agent is not ethyl cellulose.
In yet another embodiment of the present invention, the release controlling layer comprises a plasticizer.
Another embodiment of the present invention relates to a gastro-retentive multiparticulate pharmaceutical composition of pregabalin comprising pregabalin in complexed form e.g., ion-exchange resin.

Another embodiment of the present invention relates to a process for the preparation of a gastro-retentive multiparticulate pharmaceutical composition of pregabalin comprising:
(i) preparing a core comprising pregabalin;
(ii) optionally coating a seal coat over the pregabalin core;
(iii) coating the pregabalin core or seal coated pregabalin core with a gas generating layer;
(iv) optionally coating a seal coat over the gas generating layer; and
(v) coating the gas generating layer of step (iii) or seal coated core of step (iv) with a release controlling layer.

Another embodiment of the present invention provides a process for the preparation of a unit dose pack of gastro-retentive multiparticulate pharmaceutical composition of pregabalin comprising the steps of:
(i) preparing a gastro-retentive multiparticulate pharmaceutical composition of pregabalin;
(ii) filling the composition into a unit dose pack; and
(iii) sealing the pack.

Another embodiment of the present invention relates to a gastro-retentive multiparticulate pharmaceutical composition of pregabalin comprising microspheres of pregabalin.

Another embodiment of the present invention relates to a gastro-retentive multiparticulate pharmaceutical composition of pregabalin comprising microcapsules of pregabalin.

Suitable pharmaceutically acceptable excipients are selected from the group comprising diluent, glidant, binder, disintegrant, lubricant, release controlling polymer, surfactant, colorants, organic acid, suspending agents, anti-caking agents, pH adjusting agents/buffering agents and other pharmaceutical excipients.

Diluents are selected from the group comprising mannitol, microcrystalline cellulose, calcium carbonate, calcium phosphate, dibasic anhydrous, calcium phosphate, calcium phosphate tribasic, calcium sulphate, cellulose powdered, cellulose acetate, compressible sugar, confectioner’s sugar, dextrates, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, polydextrose, sodium alginate, sorbitol, starch, pregelatinized starch, sucrose, trehalose and xylitol, or mixtures thereof. Diluents are present in the range from about 10% to about 95% by weight based on the total weight of the composition.

Glidants are selected from the group comprising colloidal silicon dioxide, tribasic calcium phosphate, calcium silicate, cellulose, powdered, magnesium silicate, magnesium trisilicate, starch and talc or mixtures thereof. Glidants are present in the range from about 0% to about 15% by weight based on the total weight of the composition, particularly in the range of 0.05% to about 5% by weight based on the total weight of the composition.

Binders are selected from the group comprising hypromellose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, acacia, alginic acid, carbomer, dextrin, ethylcellulose, gelatin, glucose, guar gum, maltose, methylcellulose, povidone (polyvinylpyrrolidone), copovidone, starch, polyvinyl alcohol or polyethylene oxide, or mixtures thereof. Binders are present in the range from about 0% to about 40% by weight based on the total weight of the composition, particularly in the range of 0.1% to about 30% by weight based on the total weight of the composition.

Disintegrants are selected from the group comprising pregelatinized starch, crospovidone, alginic acid, croscarmellose sodium, carmellose calcium, potassium polacrilin, sodium starch glycolate, low substituted hydroxypropyl cellulose and starch, or mixtures thereof. Disintegrants are present in the range from about 0% to about 40% by weight based on the total weight of the composition.

Lubricants are selected from the group comprising magnesium stearate, calcium stearate, stearic acid, zinc stearate, sucrose stearate, hydrogenated vegetable oil, talc, poloxamer, adipic acid, glyceryl palmitostearate, glycerine monostearate, medium-chain triglycerides, sodium stearyl fumarate, glyceryl behenate, sodium lauryl sulphate, sodium stearyl fumarate, magnesium lauryl sulphate and polyethylene glycol. Lubricants are present in the range from about 0% to about 10% w/w based on the total weight of the composition, particularly in the range of 0.1% to about 3% by weight based on the total weight of the composition.

Surfactants or surface-active agents improve wettability of the dosage form and/or enhance its dissolution. Surfactants contemplated in the present invention include but are not limited to anionic surfactants, amphoteric surfactants, non-ionic surfactants and macromolecular surfactants. Suitable examples of anionic surfactants include but are not limited to sodium lauryl sulphate, sodium cetyl stearyl sulphate or sodium dioctyl sulphosuccinate etc. Suitable example of an amphoteric surfactant include but is not limited to lecithin. Suitable examples of non-ionic surfactants include but is not limited to cetyl alcohol, stearyl alcohol, cetyl stearyl alcohol, cholesterol, sorbitan fatty acid esters such as sorbitan mono-oleate, polyoxyethylene sorbitan fatty acid esters such as polysorbate 80, polysorbate 20, polyoxyethylene fatty acid glycerides such as macrogol 1000 glycerol monostearate, polyoxyethylene fatty acid esters such as polyoxyl 40 stearate, polyoxyethylene fatty alcohol ethers such as polyoxyl 10 oleyl ether, glycerol fatty acid esters such as glycerol monostearate commercially available as Sepitrap® 80 or Sepitrap® 4000 etc.

Various water-soluble polymers are used to form a barrier/seal or film over the core. Examples include but are not limited to cellulose derivatives such as soluble alkyl- or hydroalkylcellulose derivatives such as methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxymethylethyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, etc., acidic cellulose derivatives, dextrins, starches and starch derivatives, polymers based on carbohydrates and derivatives thereof, natural gums such as gum arabic, xanthans, alginates, polyacrylic acid, polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone, chitosan and derivatives thereof, shellac and derivatives thereof, waxes and fat substances.

Colorants include but are not limited to iron oxides such as red ferric oxide, yellow ferric oxide and black iron oxide; titanium oxide; beta-carotene and food blue No. 2 aluminium lake.

Organic acids are selected from the group comprising citric acid, malic acid, succinic acid, tartaric acid, fumaric acid, ascorbic acid, glutamic acid, and their salts, and mixtures thereof. Organic acids are present in the range of 0% to about 10% by weight based on the total weight of the composition, particularly in the range of 0.01% to about 5% by weight based on the total weight of the composition.

Release controlling agents can be hydrophobic or hydrophilic release controlling agents. Release controlling agents are present in the release controlling layer over the pregabalin core. They can also be present inside the pregabalin core.

Hydrophobic release controlling agents are selected from the group consisting of polyvinyl acetate, hydroxypropyl methylcellulose acetate succinate, shellac, zein, acrylic acid and methacrylic acid polymers, copolymers and esters thereof, cellulose acetate, cellulose acetate phthalate, cellulose acetate propionate, cellulose acetate butyrate, cellulose triacetate, poly (methyl methacrylate), poly (ethyl methacrylate), poly (butyl methacrylate), poly (isobutyl methacrylate), and poly (hexyl methacrylate), poly (isodecyl methacrylate), poly (lauryl methacrylate), poly (phenyl methacrylate), poly (methyl acrylate), poly (isopropyl acrylate), poly (isobutyl acrylate), poly (octadecyl acrylate), waxes such as beeswax, camauba wax, paraffin wax, microcrystalline wax, and, ozokerite; fatty alcohols such as cetostearyl alcohol, stearyl alcohol, cetyl alcohol and myristyl alcohol, and fatty acid esters such as glyceryl monostearate; glycerol monooleate, acetylated monoglycerides, tristearin, tripalmitin, cetyl esters wax, glyceryl palmitostearate, glyceryl behenate, hydrogenated castor oil; and mixtures thereof.

Hydrophilic release controlling agents are selected from the group consisting of cellulose and its derivatives such as carboxymethyl cellulose, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose; polyalkylene oxides e.g. polyethylene oxide; polyvinyl alcohol; polyvinylpyrrolidone; gums e.g. carrageenan, xanthan gum, guar gum; chitosan and its derivatives; carbomers, alginic acid and its derivatives e.g., sodium alginate, polyglycolized glycerides, polyethylene glycol and mixtures thereof.

The release controlling agents are present in the range from about 0.1% to about 80% by weight based on the total weight pellets. Particularly, the release controlling agents are present in the range from about 0.1% to about 60% by weight based on the total weight of the pellets.

Mucoadhesive agents have the property of adhering to the gastrointestinal mucus membranes for an extended period of time. Mucoadhesive agents are selected from the group comprising polyacrylic polymers, such as carbomer and its derivatives, or cellulose derivatives, such as hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and sodium carboxymethylcellulose, chitosan, diethylaminoethyldextran, lectin, and mixtures thereof.

Plasticizers are selected from the group consisting of phthalates e.g., dibutyl phthalate, citrates e.g., triethyl citrate, castor oil and polyethylene glycol, and combinations thereof. Plasticizers are present in the range from about 0.01% to about 5% by weight based on the total weight of the gastro-retentive pellets.

Suspending agents are selected from the group consisting of cellulose derivatives such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methylcellulose, carboxymethyl cellulose and its salts/derivatives, microcrystalline cellulose, and co-processed spray dried forms of microcrystalline cellulose and carboxymethyl cellulose sodium (such as Avicel® RC-501, Avicel® RC-581, Avicel® RC-591, and Avicel®CL-611); carbomers (such as those available under the trade name Carbopol); gums such as xanthan gum, locust bean gum, tragacanth gum, arabinogalactan gum, agar gum, gellan gum, guar gum, apricot gum, karaya gum, sterculia gum, acacia gum, gum arabic, and carrageenan; pectin; dextran; gelatin; polyethylene glycols; polyvinyl compounds such as polyvinyl acetate, polyvinyl alcohol, and polyvinyl pyrrolidone; sugar alcohols such as xylitol and mannitol; colloidal silica; maltodextrin, starch; and mixtures thereof. Suspending agents are present in the range from about 0.1% to about 5% by weight based on the total weight of the composition.

Anti-caking agents are selected from the group consisting of colloidal silicon dioxide, tribasic calcium phosphate, powdered cellulose, magnesium trisilicate, starch, or mixtures thereof. Anti-caking agents are present in the range from about 0.01% to about 5% by weight based on the total weight of the composition.
pH adjusting agents/buffering agents are selected from the group consisting of citric acid, sodium citrate, sodium phosphate, potassium citrate, gluconic acid, lactic acid, acetic acid, sodium gluconate, sodium lactate, acetate buffer, sodium acetate, potassium citrate, sodium bicarbonate, potassium bicarbonate, sodium dihydrogen phosphate and potassium dihydrogen phosphate, and combinations thereof.
Agent used to form seal coat/barrier coat are selected from the group consisting of cellulose derivatives such as methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose; dextrins, starch and its derivatives, polymers based on carbohydrates and their derivatives, polyvinyl alcohol, shellac, waxes, and combinations thereof. Agent used to form seal coat/barrier coat is present in the range from about 0.01% to about 10% by weight based on the total weight of the gastro-retentive pellets.
Carrier is selected from the group consisting of water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, glycerin, buffers, liquid glucose, glycerol, aqueous solutions of sugar alcohols (such as sorbitol, mannito and xylitol) and combinations thereof and the like. Oils include peanut oil, soy bean oil, corn oil, sesame oil, cottonseed oil, acetylated glycerides, ethyl oleate, mineral oil, mono or di- fatty acid esters of polyethylene glycols, glyceryl mono-oleate, and combinations thereof.

The average particle size of pregabalin is less than about 300 µm, particularly in the range of about 5 µm to about 300 µm. The particle size can be measured by suitable techniques such as laser light scattering (e.g. Malvern Light Scattering), coulter counter, microscopy, fraunhofer diffraction, and any other technique known in the art.
The gastro-retentive multiparticulate compositions can include an immediate release component to provide immediate release of pregabalin.
The gastro-retentive multiparticulate compositions of the present invention can be prepared by any method known in the art e.g., dry granulation, wet granulation, extrusion- spheronization, pelletization, fluidized bed coating, hot melt extrusion, spray coating, fluidized bed granulation/pelletization and spray drying. Pregabalin can also be directly coated with a release-controlling agent to form microparticles or microcapsules. Microspheres of pregabalin can be prepared by any method known in the art e.g., ionic gelation, emulsification and solvent evaporation.
Suitable solvents include aqueous, organic solvents and combinations of aqueous and organic solvents. Suitable solvents include, but are not limited to water, alcohols such as methanol, ethanol, isopropanol, butanol, dichlomethane, chloroform, dimethyl sulfoxide, dimethyl acetamide, ether, diethyl ether esters such as ethyl acetate, ketones such as acetone, and combinations thereof.
Extrusion-spheronization process can be used to prepare spherical particles/cores of pregabalin in the form of beads or granules. It includes the following process steps: (i) dry mixing of pregabalin and one or more pharmaceutically acceptable excipients; (ii) wet massing of step (i) using binder solution to form granules; (iii) extrusion of wet granules of step (ii) to form uniformly rod-shaped particles; (iv) spheronization of uniformly rod-shaped particles of step (iii) to produce spherical particles; and (v) screening to achieve the particles with narrow distribution of size. The release-controlling agent can be included in the particles such as during dry mixing or granulation, or can be layered over the particles to form the cores. The cores are optionally mixed with one or more pharmaceutically acceptable excipients.
The gastro-retentive multiparticulate pharmaceutical composition can be administered directly into the patient's mouth or sprinkled onto food or dispersed into a liquid medium such as water to form a suspension and then administered. The gastro-retentive multiparticulate pharmaceutical composition upon reconstitution with a suitable pharmaceutically acceptable carrier is expected to provide desirable viscosity, pH, pourability, re-dispersibility and dissolution. The gastro-retentive multiparticulate pharmaceutical composition can also be in the form of ready to use suspension which can be directly administered to a patient.
The gastro-retentive multiparticulate compositions of the present invention can be dispensed in a suitable pack e.g., sachet or bottle. The sachet may be formed of any suitable material, including plastic, metal foil, paper or a combination thereof. Sachet can be three layered with sandwiched polyethylene terephthalate (PET)/aluminium/polyethylene layers or four layered or more with addition of more layers of PET/aluminium/polyethylene. The sachet may be provided with any suitable means for opening thereof, including a perforated region or a nick in the edge of the sachet for ease of tearing.
Floatation Test and Total Floating Time:
Floatation test is the time to be measured when all pellets are floating. It is measured by immersing pregabalin gastro-retentive multiparticulate pharmaceutical composition in an acetate buffer solution (pH 4.0) under shaking at a rate of 80 times per minute. This process is repeated thrice. Total floating time is the total duration of time during which composition remains buoyant.

The gastro-retentive multiparticulate pharmaceutical compositions are expected to have desired technical attributes such as floatation time, total floating time, assay and dissolution.
EXAMPLES
The following examples are intended to further illustrate certain preferred embodiments of the invention and are not limiting in nature.

Pregabalin multiparticulate compositions can be prepared by using quantitative formula as given in Examples 1, 2 and 3.

Example 1
Ingredients % (w/w)
Core
Pregabalin 0.1-95 0.1-95
Microcrystalline sphere 5-60 -
Sugar sphere - 5-60
Hydroxypropyl methylcellulose 0.1-10 0.1-10
Isopropyl alcohol/Water q.s q.s
Gas Generating layer
Sodium bicarbonate 0.01-5 0.01-5
Hydroxypropyl methylcellulose 0.1-10 0.1-10
Tartaric acid/ citric acid 0-5 0-5
Ethanol (anhydrous) q.s q.s
Release controlling layer
Hydroxypropyl methylcellulose acetate succinate/ vinyl acetate, shellac, hydroxypropyl methylcellulose phthalate 0.5-50 0.5-70
Polyethylene glycol/ acetyl monoglyceride 0.01-2 0.01-2
Ethanol (anhydrous) q.s q.s

Procedure:
1. Pregabalin and hydroxypropyl methylcellulose was dissolved in water and isopropyl mixture.
2. Microcrystalline spheres/ sugar spheres were coated with the solution of step 1.
3. Pregabalin pellets were coated with a gas generating layer of sodium bicarbonate, hydroxypropyl methylcellulose and tartaric acid/ citric acid.
4. Pregabalin core was optionally coated with seal coat of hypromellose, talc, titanium dioxide, Polysorbate 80 and water.
5. The gas generating layer of step 3 was coated with a release coating layer of hydroxypropyl methylcellulose acetate succinate or vinyl acetate, shellac, hydroxypropyl methylcellulose phthalate and polyethylene glycol/ acetyl monoglyceride to form gastro-retentive pellets.
6. The gastro-retentive pellets of step 4 were optionally mixed with dextrose and packed in a sachet.

The gastro-retentive pellets can be administered orally directly into patient’s mouth or sprinkled onto soft food such as applesauce or yoghurt, or dispersed into a liquid medium.

Example 2
Ingredients % (w/w)
Core
Pregabalin 0.1-95
Calcium phosphate 5-60
Hydroxypropyl methylcellulose 1-40
Isopropyl alcohol /Water q.s
Gas Generating layer
Sodium bicarbonate 0.01-5
Hydroxypropyl methylcellulose 0.1-10
Tartaric acid/ citric acid 0-5
Ethanol (anhydrous) q.s
Release controlling layer
Hydroxypropyl methylcellulose acetate succinate 0.5-60
Polyethylene glycol 0.01-10
Ethanol (anhydrous) q.s

Procedure:
1. Mixture of pregabalin, calcium phosphate was granulated with a dispersion of hydroxypropyl methylcellulose in water and isopropyl mixture to form pellets
2. The pellets of step 1 were coated with a gas generating layer of sodium bicarbonate, hydroxypropyl methylcellulose and tartaric acid/ citric acid.
3. The gas generating layer of step 3 was coated with a release coating layer consisting of hydroxypropyl methylcellulose acetate succinate and polyethylene glycol to form gastro-retentive pellets.
4. The gastro-retentive pellets of step 3 were optionally mixed with dextrose and packed in a sachet.
Example 3
Ingredients % (w/w)
Core
Pregabalin 0.1-95
Microcrystalline sphere 5-60
Hydroxypropyl methylcellulose 0.1-10
Isopropyl alcohol/Water q.s
Gas Generating layer
(a) Bicarbonate layer
Sodium bicarbonate 0.01-5
Talc 0.1-4
Light silicic anhydride 0-2
Hydroxypropyl cellulose 0.1-10
Ethanol (anhydrous) q.s
(a) Tartaric acid layer
Tartaric acid 0.01-5
Talc 0.1-4
Light silicic anhydride 0-2
Calcium stearate 0-1
Ethanol (anhydrous) q.s
Release controlling layer
Vinyl acetate 0.1-30
Shellac 0.5-40
Hydroxypropyl methylcellulose phthalate 0.1-10
Talc 0.1-5
Acetyl monoglyceride 0.02-1
Ethanol (anhydrous) q.s

Procedure:
1. Pregabalin and hydroxypropyl methylcellulose was dissolved in water and isopropyl mixture
2. Microcrystalline spheres were coated with the solution of step 1.
3. Pregabalin pellets were coated with a gas generating layer which has two components (a) bicarbonate layer prepared by coating pellets of step 2 with a dispersion of sodium bicarbonate, talc, light silicic anhydride, hydroxypropyl cellulose in ethanol (b) tartaric acid layer over bicarbonate layer prepared by coating bicarbonate layer with a dispersion of tartaric acid, talc, light silicic anhydride, calcium stearate in ethanol.
4. The gas generating layer of step 3 was coated with a release coating layer consisting of vinyl acetate, shellac, hydroxypropyl methylcellulose phthalate, talc and acetyl monoglyceride to form gastro-retentive pellets.
5. The gastro-retentive pellets of step 3 were optionally mixed with dextrose and packed in a sachet.

The proposed test compositions as per present invention are expected to have desired technical attributes with technical and regulatory requirement.

WE CLAIM:
1. A gastro-retentive multiparticulate pharmaceutical composition of pregabalin comprising:
(a) an inert core coated with pregabalin;
(b) optionally a seal coat over the pregabalin core;
(c) a gas generating layer coated over the pregabalin core or seal coated pregabalin core; and
(d) a release controlling layer coated on the gas generating layer comprising a release controlling agent.

2. A gastro-retentive multiparticulate pharmaceutical composition of pregabalin comprising:
(a) an inert core;
(b) optionally a seal coat over the inert core;
(c) pregabalin layer over the inert core or seal coated inert core;
(d) optionally a seal coat over the pregabalin layer;
(e) a gas generating layer coated over the pregabalin layer or seal coated pregabalin layer; and
(f) a release controlling layer coated on the gas generating layer comprising a release controlling agent.

3. A gastro-retentive multiparticulate pharmaceutical composition of pregabalin comprising:
(a) a core comprising pregabalin and one or more pharmaceutically acceptable excipients;
(b) a gas generating layer over the pregabalin core; and
(c) a release controlling layer coated on the gas generating layer comprising a release controlling agent.

4. A gastro-retentive multiparticulate pharmaceutical composition of pregabalin comprising:
(a) an inert core coated with pregabalin;
(b) a gas generating layer coated over the pregabalin core;
(c) a release controlling layer coated on the gas generating layer comprising a release controlling agent; and
(d) a pharmaceutically acceptable carrier.

5. The gastro-retentive multiparticulate pharmaceutical composition of claims 1-4, wherein the composition is in the form of pellets, granules, beads, spheroids or powder for oral suspension.

6. The gastro-retentive multiparticulate pharmaceutical composition of claims 1-2, wherein the seal coat is selected from hydroalkylcellulose derivatives such as methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxymethylethyl cellulose, hydroxypropyl methylcellulose, starch derivatives, polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone.

7. The gastro-retentive multiparticulate pharmaceutical composition of claims 1-4, wherein the gas-generating layer comprises a carbonate or a bicarbonate.

8. The gastro-retentive multiparticulate pharmaceutical composition of claims 1-4, wherein the gas generating layer further comprises an organic acid.

9. The gastro-retentive multiparticulate pharmaceutical composition of claims 1-4, wherein the release controlling layer comprises agents selected from hydroxypropyl methylcellulose acetate succinate, vinyl acetate, shellac, hydroxypropyl methylcellulose phthalate, polyethylene glycol, hydroxypropyl cellulose (HPC), hydroxyethyl cellulose, polyvinyl, polyvinyl alcohol; polyvinylpyrrolidone; gums e.g. carrageenan, xanthan gum, guar gum.
10. A process for the preparation of multiparticulate pharmaceutical composition of pregabalin comprising:
(i) preparing a core comprising pregabalin;
(ii) optionally coating a seal coat over the pregabalin core;
(iii) coating the pregabalin core or seal coated pregabalin core with a gas generating layer;
(iv) optionally coating a seal coat over the gas generating layer; and
(v) coating the gas generating layer of step (iii) or seal coated core of step (iv) with a release controlling layer.