FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"A NOVEL CONTROLLED RELEASE GASTRORETENTIVE DOSAGE
FORM OF PREGABALIN"
2. APPLICANT (S):
(a) NAME: FDC Limited
(b)NATIONALITY: Indian company incorporated under the Companies Act 1956
(c) ADDRESS: 142-48, S.V. Road, Jogeshwari (West), Mumbai - 400 102, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to a novel controlled release gastroretentive dosage form of pregabalin optionally with methytcobalamin in a floating swellable matrix system comprising hydrophilic swellable polymers, in situ gelling polymers, superdisintegrent(s) and other pharmaceutically acceptable excipients.
BACKGROUND OF THE INVENTION
Pregabalin, a gamma-aminobutyric acid (GABA) analogue, used in the treatment of diabetic peripheral neuropathy, postherpetic neuralgia, adult refractory partial-onset seizures, as well as anxiety disorders, specifically social phobia and generalized anxiety disorder.
Pregabalin, chemically known as (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid, binds to the alpha-2-delta (a-5) subunit of a calcium channel and is related to the endogenous inhibitory neurotransmitter [γ] amino butyric acid (GABA), which is involved in the regulation of brain neuronal activity.
Pregabalin is well absorbed after oral administration, is eliminated largely by renal excretion, and has an elimination half-life of about 5-6 hours.
The absorption mechanism of Pregabalin is through active carrier mediated transport system and most of the drug is absorbed in proximal part of gastrointestinal tract (GIT) before hepatic flexure. Moreover, Pregabalin has good solubility and permeability in Gastro Intestinal Tract (GIT) and hence is classified as a Class I drug in Biopharmaceutica! Classification System (BCS). Conventional immediate release dosage forms release the drug immediately and hence there is no reported potential bioavailability issue with Pregabalin.
Methylcobalamin is a derivative of Vitamin B12 that mediates methyl group transfer in the metabolic generation of methionine from homocysteine. Similar to vitamin B12 methylcobalamin is based on a corrin ring and has the formula C 63 H 91 CoN 13 O 14 P.

Methylcobalamin, administered orally, is effective in the treatment of peripheral neuropathy, diabetic neuropathy as it promotes protein synthesis for maintaining healthy nerves cells and myelin. It also helps to moderate levels of glutamate in the brain, encouraging healthy brain cell activity, as well as memory, mood, and cognitive function. It also helps to improve oxidative stress in children with autism, and to help improve DNA methylation and nerve regeneration. In general, vitamin B12 works with folate to promote DNA and red blood cell health. Additionally, vitamin B12 is a vital component of the methionine synthase pathway, which supports healthy homocysteine metabolism and S-adenosylmethionine production.
Gastroretentive drug delivery is an approach to prolong gastric residence time, thereby targeting site-specific drug release in the upper gastrointestinal tract for local or systemic therapies. Gastroretentive dosage forms can remain in the gastric region for long period of time and hence significantly prolong the gastric retention time (GRT) of drugs. Prolonged gastric retention improves bioavailability, reduces drug waste, and improves the solubility of drugs that are less soluble in a high pH environment. It has applications also for local drug delivery to the stomach and proximal small intestines. Gastro retention helps to provide better availability of new products with new therapeutic possibilities and substantial benefits to the patients.
There are several references in literature that describe the technologies associated with gastroretentive drug delivery system and their therapeutic applications in last two decades. Several gastroretentive drug delivery systems are being designed and developed, including high density (sinking) systems that are retained in the bottom of the stomach, low density (floating) systems that causes buoyancy in gastric fluid, mucoadhesive systems that cause bioadhesion to stomach mucosa, unfoldable, expandable, or swellable systems which limits emptying of the dosage forms through the pyloric sphincter.
Oral medications are generally administered as immediate release dosage forms. The major disadvantage of such immediate release preparations is the high frequency of drug administration and fluctuations in drug plasma levels and hence associated with poor

patient compliance and Adverse Drug Reactions (ADRs). Controlled release gastroretentive dosage forms have been developed to deliver the drug in upper part of GIT, where the drug gets maximum absorption. Retaining the drug/dosage form for prolonged period of time in the absorption window offers the maximum extent of drug absorption and hence it might be used to enhance the bioavailability. Gastro retention along with controlled release dosage form reduces the fluctuation in plasma drug concentration and also maintains the drug concentration in therapeutic window for prolonged period of time. Moreover, controlled release dosage forms offer better patient compliance by reducing the dosing frequency of short and intermediate half life drugs.
There has been an increased interest in novel dosage forms which possess not only a mechanism for the controlled release of a drug but also a controlled gastrointestinal transit time. Dosage forms with a prolonged gastrointestinal transit time i.e. Gastroretentive dosage forms bring about a new and important therapeutic option. The controlled gastric retention of solid dosage forms may be achieved by the mechanisms of muco-adhesion, floatation, sedimentation, expansion or by the simultaneous administration of pharmacological agents which delay gastric emptying.
Indian Patent Application 2096/DEL/2006 describes an extended release tablet for oral administration of pregabalin comprising at least one rate-controlling polymer and optionally other pharmaceutical excipients, and process for the preparation thereof. However, the application doesn't describe the gastroretentive dosage form.
US Patent Application 2007184104 describes method of treating a pain state by administering a gastric retentive dosage form containing GABA analog such as pregabalin, which is once or twice a day administration. The said invention describes the pH independent matrix system for controlled delivery of GABA analogs. Pregabalin is highly water soluble and has a high dose, has better drug dissolution in stomach and hence may weaken the hydrophilic matrix that may potentiate the dose dumping.
WO 2006078811 relates to pharmaceutical formulations and to new medical uses of gabapentin and pregabalin. The formulations comprise up to three components including an immediate release component, a sustained release component and a delayed release

component. The application describes the combination of immediate release and sustained release dosage form, and immediate release and delayed release dosage form in a bilayered or multilayered tablet dosage forms. Such dosage forms have many manufacturing and biopharmaceutical issues. The application does not teach gastroretentive drug delivery.
US Patent Application 2007269511 describes solid pharmaceutical composition containing Pregabalin and excipients comprising matrix forming agent and a swelling agent. The application is based on swellable matrix system using polyvinyl acetate and polyvinylpyrrolidone, which requires lag time for swelling and retention of the dosage form in the GIT, The application does not teach floating hydrophilic swellable with in situ gelling matrix system.
IN Patent Application 1593/KOL/2007 describes controlled release pharmaceutical composition of pregabalin or salts thereof as active ingredient, a hydrophobic release controlling agents and optionally other pharmaceutically acceptable excipients thereof.
WO2010143052 describes a gastroretentive floating bilayer tablet of pregabalin with ethylcellulose and hydrogenated castor oil as water insoluble component or gastroretentive floating bilayer tablet of pregabalin with ethylcellulose as water insoluble component and polyethylene glycol as water soluble component.
Pregabalin is generally administered twice or thrice daily because of its intermediate half life of 5-6 hr. The dosing frequency of chronic therapy of Pregabalin is one of the rate limiting factors to achieve the better therapeutic efficacy. Most of the prior art mentions controlled release composition of pregabalin. In case of controlled release dosage form, drug releases throughout the GIT most often beyond the hepatic flexure and results into less absorption in stomach. Hence, there is a need to develop a novel controlled release dosage form that retains the drug in stomach for prolonged period of time. Gastroretentive controlled release dosage form of Pregabalin may provide the prolonged plasma drug concentration in therapeutic window along with maximum extent of absorption.

Accordingly, the present invention provides a solid oral pharmaceutical composition comprising controlled release gastroretentive dosage form of Pregabalin optionally with other therapeutic agents such as methylcobalamin. The controlled release drug delivery system releases pregabalin at a predetermined rate and also eliminates the undesired peak plasma concentration and hence reduces or eliminates unwanted side effects. Moreover, the proposed dosage form offers better patient compliance by reducing the dosing frequency. The present invention describes the gastroretentive dosage form of pregabalin with or without methylcobalamin in a floating swellable matrix system comprising hydrophilic swellable polymers, in situ gelling polymers, superdisintegrent(s) and other pharmaceutically acceptable excipients.
OBJECT OF THE INVENTION
The primary objective of the present invention is to design a novel controlled release gastroretentive drug delivery system for administration of pregabalin with or without methylcobalamin, which releases drug at a predetermined rate and eliminating the undesired peak plasma drug concentration.
Another objective of the present invention is to provide gastroretentive drug delivery system with reduced side effects and better safety and clinical efficacy by preventing fluctuation in plasma drug.
Yet another objective of the present invention is to improve the patient compliance by reducing the dosing frequency of the dosage form.
SUMMARY OF THE INVENTION:
The present invention discloses a novel controlled release gastroretentive delivery of pregabalin optionally with methylcobalamin in a floating swellable matrix system comprising hydrophilic swellable polymers, in situ gelling polymers, superdisintergrant(s) and other pharmaceutically acceptable excipients, wherein hydrophilic polymers are used as rate controlling polymers and in situ gelling polymers are used as pH dependent agents. Further, the proposed controlled release

gastroretentive dosage form offers better safety and clinical efficacy by maintaining the plasma drug concentration within the therapeutic window which enhances the bioavailability of dosage forms.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a novel controlled release gastroretentive dosage form of pregabalin optionally with methylcobalamin in a floating swellable matrix system comprising hydrophilic swellable polymers, in situ gelling polymers, superdisintergrant(s) and other pharmaceutically acceptable excipients.
The amount of pregabalin in the compositions of the invention varies in an amount of 10% to 80% by weight of total formulation and methylcobalamin in the compositions of the invention varies in an amount of 0.05% to 2% by weight of total formulation.
The oral delivery of pregabalin for systemic effect has been considered as a challenging task for formulation scientist. Optimization of biopharmaceutical properties and hence improve the bioavailability by proper formulation designing is the prerequisite for delivery of pregabalin.
Accordingly, in a preferred embodiment, the present invention comprises pregabalin in an amount of 10% to 80%; hydrophilic swellable polymer(s) in an amount of 0.5% to 40% ; In situ gelling agents in an amount of 0.5% to 25% by weight of total formulation in association with one or more of pharmaceutical diluents, binders, lubricants, disintegrants, gas generating agents, Ionic gelling agents etc.
Accordingly, in another preferred embodiment, the present invention comprises pregabalin in an amount of 10% to 80%; methylcobalamin in an amount of 0.05% to 2%; hydrophilic swellable polymer(s) in an amount of 0.5% to 40% ; In situ gelling agents in an amount of 0.5% to 25% by weight of total formulation in association with one or more of pharmaceutical diluents, binders, lubricants, disintegrants, gas generating agents, Ionic gelling agents etc.

The present invention describes the role of superdisintegrants, which absorb high quantity of gastric fluids and hence offer aqueous environment for matrix system. Gastric fluid is absorbed by superdisintegrants that lead to faster gellation of hydrophillic polymer and form a viscous gel layer. The formed gel layer maintains the integrity of the tablet dosage form and acts as a barrier for drug release.
Moreover, use of superdisintegrants in tablet dosage form increases the floating time and reduces the floating lag time by offering low density and high matrix integrity. Hence superdisintegrants along with hydrophilic polymer and in situ gelling agent offers ideal gastroretention drug delivery system that would provide better drug release in stomach. Superdisintegrants used in the present invention include but not restricted to crospovidone, croscarmellose sodium and sodium starch glycollate in the range of 0.5% to 10% by weight of total formulation.
Release retarding hydrophilic gelling polymer(s) is a network of well established polymeric chains that not only retards in vitro drug release and provide time independent release kinetics but can also work effectively in vivo and establish constant drug plasma levels. Hydrophillic polymers are highly absorbent and derived from natural or synthetic polymers. Hydrophillic polymers also possess a degree of flexibility very similar to natural tissue, due to their significant water content. These polymers are used in the present invention not only to provide the stable matrix system but also to act as a barrier for drug release.
Hydrophillic polymer(s) used in the present invention is selected from the group consisting of but not limited to hydroxypropylmethylcellulose, hydroxypropyl cellulose, xanthan gum, karaya gum, locust bean gum, guar gum, karaya gum, agar, pectin, carrageenan, methylcellulose, hydroxyethylcellulose, sodium carboxymethylcellufose in the range of 0.5% to 40% by weight of total formulation.
pH dependent in situ gelling agents in the formulation offer not only rigidity to matrix, which prevents dose dumping but also provide controlled mode of drug release in addition to hydrophilic gelling polymer. In general in situ gellation takes place by one or more combinations of mechanism such as thermal gellation, ionic gellation, pH induced

gellation. The present invention involves the in situ gelling agent selected from the categories of pH induced gellation and ionic gellation or both,
In situ gelling agents are selected from the group consisting of but not limited to gellan gum, sodium alginate, locust bean gum and other natural gums, cellulose esters, modified cellulose esters, acrylate, methacrylates copolymers and co-block polymers of acrylates and acrylic acid derivatives preferably gellan gum and sodium alginate in the range of 0.5% to 25% by weight of total formulation.
Ionic gelling agents are used to induce the gellation by exchange of ions preferably cations with in situ gelling polymer. Ionic gelling agents are selected from group consisting of but not limited to calcium chloride, calcium sulfate, calcium carbonate, calcium stearate, magnesium chloride, magnesium sulfate, magnesium carbonate, magnesium stearate, zinc chloride, zinc carbonate preferably calcium carbonate, calcium chloride and calcium stearate in the range of 0% to 5% by weight of total formulation.
The compositions of the present invention further comprise excipients such as gas generating agent(s), diluents, lubricants and glidants.
The gas generating agent used in the formulations is selected from group comprising carbonates and bicarbonates more preferably sodium carbonate, sodium bicarbonate, magnesium carbonate, calcium carbonate, aluminium carbonate and zinc carbonate.
Diluent is at least one component selected from a group consisting of but not limited to monosaccharide, a disaccharide, a polyols, and mixtures thereof; sugars including lactose, sucrose, glucose, lactulose and dextrose and polyols including mannitol, xylitol, erythritol, dulcitol, ribitol, lactitol and sorbitol, polysaccharides such as microcrystalline cellulose in the range of 0.5-80% by weight of the total composition.
Lubricant is at least one component selected from a group consisting of magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearte, stearic acid, talc, zinc stearate, hydrogenated vegetable oil, glyceryl behenate, and colloidal silicon dioxide in the range of 0.5 to 2% of total weight of the composition.

Glidant is at least one component selected from group consisting of but not limited to colloidal silicon dioxide, talc and synthetic aluminum silicate, in the range of 0.5 to 2% of total weight of the composition.
The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.
Example: Example 1:
Pregabalin, Methylcobaiamin, Sodium Alginate, Xanthan Gum, lactose,
Microcrystalline Cellulose, Crospovidone are weighed and sifted through 40 mesh
sieve.
The above blend is granulated with IPA: Water (50:50), dried the granules and sifted
through 30 mesh sieve.
These granules are blended with Sodium Bicarbonate, lubricated with Calcium Stearate
and Colloidal Silicon Dioxide and compressed the granules with caplet shape punch
15.0mm X 7.5mm.

Sr.
No Ingredient rag/ tablet
1 Pregabalin 300
2 Methylcobaiamin 1.5
3 Sodium alginate 100
4 Xanthan gum 100
5 Lactose 50
6 Microcrystalline Cellulose 50
7 Sodium bicarbonate 40
8 Crospovidone 40
9 Calcium stearate 6
10 Colloidal silicon dioxide 6

Example 2:
Pregabalin, Methylcobalamin, Gellan Gum, Xanthan Gum, Lactose, Microcrystalline
Cellulose, Crospovidone are weighed and sifted through 40 mesh sieve.
The above blend is granulated with IPA: Water (50:50), dried the granules and sifted
through 30 mesh sieve.
These granules are blended with Sodium Bicarbonate. Lubricate with Calcium Sulphate
and Colloidal Silicon Dioxide and compressed the granules with caplet shape punch
13.0mm X 6.0mm.

Sr.
No Ingredient mg/
tablet
1 Pregabalin 150

2 Methylcobalamin 0.75

3 Gellan gum 55

4 Xanthan gum 50

5 Lactose 40

6 Microcrystalline Cellulose 35

7 Sodium bicarbonate 25

8 Crospovidone 20

9 Calcium sulphate 5

10 Colloidal silicon dioxide 5

Stability Dal a:
Stage Assay Dissol ution (0. 06N HC1)

% 30 min 1hr 2hr 4hr 8hr 12hr

Initial 98.5 10 16 30 52 73 89
50°C/ 75%RH 1M 96.3 11 17 30 51 76 87
40°C/ 75%RH 1M 98.2 11 19 29 48 75 88

2M 98.6 12 17 30 53 77 90

3M 97.9 10 18 26 49 79 88

6M 97.2 12 16 28 48 77 86
30°C/65%RH 3M 99.2 10 18 29 47 80 89

6M 98.7 12 16 30 50 78 87
25oC60%RH 3M 99.1 10 17 27 48 74 90
6M 98.6 11 17 29 52 76 86

Example 3:
Pregabalin, Methylcobalamin, Sodium Alginate, Locust Bean Gum, Mannitol,
Microcrystalline Cellulose, Sodium Bicarbonate, Crospovidone are weighed and sifted
through 40 mesh sieve.
Granulated the above blend with 1PA: Water (50:50), dried the granules and sifted
through 30 mesh sieve.
The above granules are lubricated with Calcium Chloride and Colloidal Silicon Dioxide
and
compressed the granules with caplet shape punch 15.0mm X 7.5mm.

Sr.
No Ingredient mg/ tablet
1 Pregabalin 300

2 Methylcobalamin 1.5

3 Sodium alginate 90

4 Locust bean gum 85

5 Mannitol 40

6 Microcrystalline Cellulose 50

7 Sodium bicarbonate 30

8 Crospovidone 40

9 Calcium chloride 6

10 Colloidal silicon dioxide 6

Stability and dissolution Data:
Stage Assay Dissolution (0 .06N HCI)

% 30 min lhr 2hr 4hr 8hr 12hr

Initial 99.3 14 22 32 48 68 89
50°C/75%RH 1M 97.6 12 20 30 45 73 89
40°C/75%RH 1M 99.1 13 19 28 46 69 86

2M 98.8 11 17 29 46 68 85

3M 98.2 11 19 31 48 70 88

6M 97.3 13 20 27 46 71 87
30°C/65%RH 3M 98.8 12 20 28 44 67 89

6M 98.6 13 16 30 46 69 84
25oC60%RH 3M 99.2 13 20 30 46 70 85
6M 98.3 12 17 28 45 69 87

Example 4:
Pregabalin, Methylcobalamin, Sodium Alginate, Karaya Gum, Lactose, Microcrystalline
Cellulose, Sodium Bicarbonate, Crospovidone are weighed and sifted through 40 mesh
sieve.
The above blend is granulated with IPA: Water (50:50), dried the granules and sifted
through 30 mesh sieve.
Lubricated the above granules with Calcium Stearate and Colloidal Silicon Dioxide and
compressed the granules with caplet shape punch 13.0mm X 6.5mm.

Sr. No Ingredient mg/ tablet
1 Pregabalin 150
2 Methylcobalamin 1.5
3 Sodium alginate 90
4 Karaya gum 100
5 Lactose 50
6 Microcrystalline Cellulose 50
7 Sodium bicarbonate 40
8 Crospovidone 40
9 Calcium stearate 6
10 Colloidal silicon dioxide 6
Example 5:
Pregabalin, Methylcobalamin, Gellan Gum, Hypromellose K 15 M, Dicalcium
Phosphate, Microcrystalline Cellulose, Sodium Bicarbonate, Sodium Starch Glycollate
are weighed and sifted through 40 mesh sieve.
Granulated the above blend with IPA: Water (50:50), dried the granules and sifted
through 30 mesh sieve.
Lubricated the above granules with Zinc Carbonate and Colloidal Silicon Dioxide and
compressed the granules with caplet shape punch 15.0mm X 7.5mm.

Sr.
No Ingredient rag/ tablet
1 Pregabalin 300
2 Methylcobalamin 1.5
3 Gellan Gum 100
4 Hypromellose K 15 M 100
5 Dicalcium phosphate 50
6 Microcrystalline Cellulose 50
7 Sodium bicarbonate 40
8 Sodium starch glycollate 40
9 Zinc carbonate 6
10 Colloidal silicon dioxide 6
Example 6:
Pregabalin, Methylcobalamin, Sodium alginate, Gaur Gum, Lactose, Microcrystalline
Cellulose, Sodium Bicarbonate, Croscarmellose Sodium are weighed and sifted through
40 mesh sieve.
Granulated the above blend with 1PA: Water (50:50), dried the granules and sifted
through 30 mesh sieve.
Lubricated the above granules with Calcium Carbonate and Colloidal Silicon Dioxide
and
compressed the granules with caplet shape punch 15.0mm X 7.5mm.

Sr. No Ingredient mg/ tablet
1 Pregabalin 300
2 Methylcobalamin 1.5
3 Sodium alginate 100
4 Gaur Gum 100
5 Lactose 50
6 Microcrystalline Cellulose 50
7 Sodium bicarbonate 40
8 Croscarmellose sodium 40

9 Calcium carbonate 6
10 Colloidal silicon dioxide 6

Stability and dissolution Data:
Stage Assay Dissolution (0.06N HC1)

% 30min 1hr 2hr 4hr 8hr 12hr

Initial 98,6 14 21 29 47 72 89
50°C/75%RH 1M 97.9 14 20 28 48 73 85
40°C/75%RH 1M 99.1 12 19 30 47 68 89

2M 98.8 13 18 28 48 70 87

3M 98.2 13 21 29 45 69 88

6M 97.7 14 17 27 46 67 85
30°C/65%RH 3M 98.3 15 19 29 46 69 88

6M 98.5 13 19 30 44 69 82
25°C/60%RH 3M 99.1 14 19 31 48 70 87

6M 98.6 11 17 27 49 69 85
Example 7:
Pregabalin, Sodium alginate, Xanthan Gum, Lactose, Microcrystalline Cellulose, Sodium bicarbonate, Crospovidone are weighed and sifted through 40 mesh sieve. Granulated the above blend with IPA: Water (50:50), dried the granules and sifted through 30 mesh sieve.
Lubricate the above granules with Calcium Stearate and Colloidal Silicon Dioxide and compressed the granules with caplet shape punch 13.0mm X 6.5mm.

Sr.
No Ingredient mg/ tablet
1 Pregabalin 75
2 Sodium alginate 60
3 Xanthan gum 55
4 Lactose 35
5 Microcrystalline Cellulose 25
6 Sodium bicarbonate 15
7 Crospovidone 15
8 Calcium stearate 4
9 Colloidal silicon dioxide 4

Example 8
Pregabalin, Methylcobalamin, Sodium Alginate, Xanthan Gum, lactose,
Microcrystalline Cellulose, Crospovidone are weighed and sifted through 40 mesh
sieve.
The above blend is granulated with IPA: Water (60:40), dried the granules and sifted
through 30 mesh sieve.
These granules are blended with Sodium Bicarbonate, lubricated with Calcium Stearate
and Colloidal Silicon Dioxide and compressed the granules with caplet shape punch
15.0mm X 7.5mm.

Sr.
No. Ingredient mg/tablet
1 Pregabalin 150.8

2 Methylcobalamin 0.75

3 Sodium alginate 60

4 Xanthan gum 94

5 Lactose 49.2

6 Microcrystalline cellulose 36

7 Sodium bicarbonate 40

8 Crospovidone 20

9 Calcium stearate 5

10 Colloidal silicon dioxide 5

Stability and d issolution Data:

Stage Assay Dissol ution (0.0 6NHCI)

% 30 min 1hr 2hr 4hr 8hr 12hr

Initial 98.7 11 18 29 49 16 90
50°C/ 75%RH 1M 97.4 10 19 30 50 78 87
40°C/ 75%RH 1M 101.2 10 16 27 47 77 89

2M 99.2 11 18 31 55 83 93

3M 98.6 10 16 27 46 77 89

6M 97.3 10 18 29 50 80 90
30°C/65%RH 3M 99.1 10 17 28 47 77 90

6M 98.3 10 16 28 48 79 89
25°C/60%RH 3M 99.5 12 18 29 47 76 89

6M 99.0 10 17 28 48 78 91
Example 9:
Pregabalin, Methylcobalamin, Sodium Alginate, Xanthan Gum, lactose,
Microcrystalline Cellulose, Crospovidone are weighed and sifted through 40 mesh
sieve.
The above blend is granulated with IPA: Water (60:40), dried the granules and sifted
through 30 mesh sieve.
These granules are blended with Sodium Bicarbonate, lubricated with Calcium Stearate
and Colloidal Silicon Dioxide and compressed the granules with caplet shape punch
15.0mm X 7.5mm.

Sr.
No. Ingredient mg/tablet
1 Pregabalin 300
2 Methylcobalamin 1.5
3 Sodium alginate 70
4 Xanthan gum 100
5 Lactose 50
6 Microcrystalline cellulose 36
7 Sodium bicarbonate 40
8 Crospovidone 24
9 Calcium stearate 6
10 Colloidal silicon dioxide 7.5
Stability an d dissolution Data:
Stage Assay Dissolution (0.06N HCI)

% 30min 1hr 2hr 4hr 8hr 12hr

Initial 99.5 13 20 30 45 69 86
50°C/75%RH 1M 99.3 13 19 29 46
45 74 89
40°C/75%RH 1M 100.6 12 17 29
70 85

2M 99.4 11 18 28 45 69 85

3M 98.9 12 20 30 47 72 86

6M 97.1 12 19 29 44 70 85
30°C/65%RH 3M 98.4 12 20 30 46 69 84

6M 97.8 12 19 29 45 68 82
25oC60%RH 3M 99.0 12 18 29 45 71 84
6M 97.5 11 17 27 42 66 82

We claim:
1. A controlled release gastroretentive dosage form of pregabalin comprising pregabalin and optionally methylcobalamin, in a floating swellable matrix system comprising hydrophilic swellable polymers, in-situ gelling agents, superdisintergrant(s) and other pharmaceutically acceptable excipients.
2. The controlled release gastroretentive dosage form of pregabalin according to claim 1, comprising pregabalin in an amount of 10% to 80%, hydrophilic swellable polymer(s) in an amount of 0.5% to 40%, in situ gelling agents in an amount of 0.5% to 25%, superdisintegrant(s) in the an amount of 0.5% to 10%, by weight of total formulation, and other pharmaceutically acceptable excipients.
3. The controlled release gastroretentive dosage form of pregabalin according to claim 1, comprising pregabalin in an amount of 10% to 80%, methylcobalamin in an amount of 0.05% to 2%, hydrophilic swellable polymer(s) in an amount of 0.5% to 40%, in situ gelling agents in an amount of 0.5% to 25%, superdisintegrant(s) in the an amount of 0.5% to 10%, by weight of total formulation, and other pharmaceutically acceptable excipients.
4. The controlled release gastroretentive dosage form of pregabalin according to claim 1, wherein the hydrophilic swellable polymers are selected from a group consisting of hydroxypropylmethylcellulose, hydroxypropyl cellulose, xanthan gum, karaya gum, locust bean gum, guar gum, karaya gum, agar, pectin, carrageenan, methylcellulose, hydroxyethylcellulose and sodium carboxymethylcelllulose.
5. The controlled release gastroretentive dosage form of pregabalin according to claim 1, wherein the in situ gelling agents comprise in situ gelling polymers with or without ionic gelling agents.
6. The controlled release gastroretentive dosage form of pregabalin according to claim 5, wherein the in situ gelling polymers are selected from a group consisting

of natural gums comprising gellan gum and sodium alginate, locust bean gum; cellulose esters, modified cellulose esters; acrylate, methacrylate copolymers and co-block polymers of acrylates and acrylic acid derivatives; preferably gellan gum and sodium alginate.
7. The controlled release gastroretentive dosage form of pregabalin according to claim 5, wherein the ionic gelling agents are selected from a group consisting of calcium chloride, calcium sulfate, calcium carbonate, calcium stearate, magnesium chloride, magnesium sulfate, magnesium carbonate, magnesium stearate, zinc chloride and zinc carbonate, preferably calcium carbonate, calcium chloride and calcium stearate.
8. The controlled release gastroretentive dosage form of pregabalin according to claim 1, wherein the superdisintegrant(s) are selected from a group consisting of crospovidone, croscarmellose sodium and sodium starch glycol ate.
9. The controlled release gastroretentive dosage form of pregabalin according to claim 1, wherein said other pharmaceutically acceptable excipients are selected from a group consisting of gas generating agent(s), diluents, binders, lubricants and glidants.
10. The controlled release gastroretentive dosage form of pregabalin according to claim 9, wherein the gas generating agent(s) are selected from carbonates or bicarbonates, comprising sodium carbonate, sodium bicarbonate, magnesium carbonate, calcium carbonate, aluminum carbonate and zinc carbonate.