FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATIONS (SECTION 10)
"STABLE PHARMACEUTICAL COMPOSITIONS OF TIAGABINE HCI"
UNICHEM LABORATORIES LIMITED, A COMPANY REGISTERED UNDER
THE INDIAN COMPANIES ACT, 1956, HAVING ITS REGISTERED OFFICE
LOCATED AT UNICHEM BHAVAN, PRABHAT ESTATE, OFF S. V. ROAD,
JOGESHWARI (WEST), MUMBAI - 400 102,
MAHARASTRA, INDIA.
The following specification particularly describes the invention and the manner in which it is to be performed.

'STABLE PHARMACEUTICAL COMPOSITIONS OF TIAGABINE HC1"
FIELD OF INVENTION
The present invention relates to the preparation of stable and dose proportional immediate release solid oral pharmaceutical composition comprising tiagabine or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof. In particular, the present invention is related to pharmaceutical technology, which discloses the improved methods of manufacturing of pharmaceutica1 composition for tiagabine HC1 film coated tablets.
BACKGROUND OF THE INVENTION
Tiagabine is an antiepileptic drug. The mechanism by which tiagabine exerts its antiseizure effect is unknown, although it is believed to be related to its ability of enhancing the activity of gamma amino butyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Tiagabine is rapidly and completely absorbed following oral administration. Its chemical name is (-)-(R)-l-{4,4-bis(3-methyl-2-thienyl)-3-butenyl]nipecotic acid hydrochloride. It has a molecular formula of C20H25NO2S2. HCI with a molecular weight of 412.0.1. Film coated tablets of tiagabine HCI have been developed in various strengths like 2 mg, 4 mg, 5mg, 6mg, 8mg, l0mg, 12 mg, 15mg & 16 mg for the treatment of partial seizures.
Tiagabine HCI film coated tablets are currently marketed by Cephalon under the brand name of GABITRIL in seven different strengths i.e., 2mg, 4mg, 6mg, Smg, lOmg 12mg and 16mg in the USA and three different strengths i.e., Smg, lOmg and 15mg in Europe.
U.S. Patent. No. 5,010,090 (Frederik C. Gronvald et al, 1991) discloses a class of novel compounds that exhibit GABA uptake inhibitory properties and hence these compounds are useful in the treatment of epilepsy and other diseases related to GABA uptake. It also discloses that this, class of compounds may be formulated in the form of tablets and capsules for oral administration.
WO 2006/067605 Al (Bhiwgade, Ravishekhar et al., 2006) discloses stable pharmaceutical compositions comprising tiagabine HCI, an enzyme inducing anti-

convulsant by using either wet granulation or dry granulation techniques. This composition utilizes surfactant and more than one antioxidant etc. making the formulation more complex. Granulating tiagabine and excipients together exposes the drug to granulating fluid and heat, this may result in the degradation of the tiagabine since it is prone to hydrolytic degradation. More over, one of the disclosed methods of preparation of drug granulates by slugging is a disadvantageous process i.e., water content of resulting drug granulates may be relatively higher (due to higher water content of excipients used in the formulation) when compared to drug granulates prepared by wet granulation method or addition of drug substance to placebo granules. In addition, the method of preparation of drug granulates by slugging process involves special equipment like roller compactor.
This possibility can be ruled out by employing placebo granules strategy wherein placebo granules are prepared by using selected pharmaceutically acceptable excipients, co-sifting of the active substance along with placebo granules and other pharmaceutically acceptable excipients and then compression into tablets.
US patent number 5,866,590 (Jorgen Ryhl Svensson et al, 1999) discloses the pharmaceutical composition of tiagabine which utilizes one or more of antioxidants. This composition is manufactured by melt granulation technique under special conditions like low water vapor pressure and low oxygen pressure, which increases the cost of manufacturing and hence increases the cost of drug product.
Even though many technologies with different compositions are known for the manufacturing of tiagabine oral dosage forms, they suffer from problems like higher manufacturing costs and increased process times. In addition, tiagabine degrades in the presence of moisture, oxygen and light. Hence, there is a necessity for the development of simple, stable and cost effective pharmaceutical composition and manufacturing process for tiagabine, which can eliminate all these disadvantages.
OBJECT OF THE INVENTION
An object of the present invention is to provide a stable pharmaceutical composition comprising Tiagabine or its pharmaceutically acceptable salt or solvate or enantiomers or mixtures thereof.

Another object of the invention is to provide dose proportional immediate release solid oral pharmaceutical composition of tiagabine and simple, cost effective manufacturing process for its preparation thereof using tiagabine or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof.
SUMMARY OF THE INVENTION
The present invention relates to stable, dose proportional, solid oral immediate release solid pharmaceutical composition comprising tiagabine or its pharmaceutically acceptable salt, solvate or enantiomers or mixtures thereof with cost effective method of manufacturing of solid dosage forms of tiagabine or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof.
The present invention relates to stable immediate release pharmaceutical compositions comprising tiagabine or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures and pharmaceutical excipients thereof prepared by i) co-sifting the active substance along with placebo granules; or ii) direct compression of active substance along with pharmaceutically acceptable excipients; or iii) melt granulation of active substance along with pharmaceutically acceptable excipients.
The processes used for the preparation of pharmaceutical composition is as given below.
A. Addition of drug substance to placebo granules
1. Preparation of the placebo granules.
a. Sifting of the inactive ingredients.
b. Mixing of the inactive ingredients and granulation.
c. Drying of the prepared granules.
2. Adsorption of the active pharmaceutical ingredient onto the placebo granules by co-sifting and mixing.
3. Lubrication of the blend of step 2.
4. Compression of the lubricated blend of step 3 into tablets.
5. Film coating the compressed tablets of step 4.
6. Direct filling of the lubricated blend of step 3 into capsules or sachets.
B. Preparation of drug granules by melt granulation method

1. Sifting of the active ingredient.
2. Sifting of anti-oxidant and diluents.
3. Mixing of active ingredient with step-2 dry mix.
4. Sifting and melting of hydration inhibitor and optionally other excipients having low melting point.
5. Solubilization or uniform distribution of step-3 dry mix in step-4 molten excipient mix.
6. Drying and milling of step-5 mix.
7. Sifting extra-granular excipients and then mixing with step-6 milled granules.
8. Compression of the lubricated blend of step 7 into tablets.
9. Film coating of the compressed tablets of step 8.
10. Direct filling of the lubricated blend of step 8 into capsules or sachets.
C. Direct compression method
1. Sifting of the active ingredient
2. Sifting of anti-oxidants and mixing with step-1 active ingredient by geometric dilution technique.
3. Sifting of hydration inhibitors and mixing with step-2 dry mix by geometric dilution technique.
4. Sifting of other excipients and mixing with step-3 dry mix by geometric dilution technique.
5. Lubrication of the blend of step 4.
6. Compression of the lubricated blend of step 5 into tablets.
7. Film coating the compressed tablets of step 6.
8. Direct filling of the lubricated blend of step 5 into capsules or sachets.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1: Comparative dissolution profile of Example 3 and Gabitril in purified water. Figure 2: Comparative dissolution profile of Example 4 and Gabitril in purified water.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a stable, dose proportional, solid oral pharmaceutical composition, simple and cost effective process for the preparation of stable solid oral

pharmaceutical composition comprising, tiagabine or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof.
In particular, the present invention has an immediate release solid oral pharmaceutical composition comprising, tiagabine or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof, more preferably, the tiagabine is tiagabine HC1 and one or more of pharmaceutically acceptable excipients.
According to the present invention, present composition may be manufactured by addition of active substance present in the solid form to placebo granules or direct compression or melt granulation of active substance along with suitable pharmaceutically acceptable excipients.
According to the present invention, pharmaceutical compositions manufactured by addition of active substance to placebo granules, wherein active substance is tiagabine or preferably tiagabine HC1. These pharmaceutical compositions also comprise at least one or more of pharmaceutically acceptable excipients along with placebo granules.

In accordance with the present invention, manufacturing methods used are preparation of placebo granules by wet granulation or melt granulation.
Method of manufacturing by wet granulation includes, preparation of the acidified placebo granules, addition of tiagabine or preferably tiagabine HC1. and other pharmaceutically acceptable excipients extra-granularly, lubrication and then compression.
According to the present invention, pharmaceutical compositions manufactured by melt granulation preferably comprise, tiagabine, anti-oxidants, diluents and hydration inhibitors mixture. More preferably, the tiagabine is tiagabine HC1. These pharmaceutical compositions also comprise at least one or more of pharmaceutically acceptable excipients along with excipients used in granules prepared by melt granulation.
Method of manufacturing by melt granulation includes mixing of tiagabine HC1 with suitable pharmaceutically acceptable excipient, drying, milling and then mixing with extra granular excipients, lubrication and compression.

Method of manufacturing by direct compression includes mixing of tiagabine or preferably tiagabine HC1 with pharmaceutically acceptable excipients in geometric dilution technique, lubrication and compression.
Mixing by geometric dilution technique helps in ensuring more uniform distribution of active pharmaceutical ingredient throughout the blend, which in turn ensures the uniformity of drug among the final dosage forms.
In accordance with the present invention, pharmaceutical compositions comprise tiagabine or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures and at least one or more of pharmaceutically acceptable excipients. In particular, the pharmaceutical compositions comprise tiagabine or preferably tiagabine HC1 and one or more of diluent(s), hydration inhibitors, antioxidants, disintegrants, binders, lubricants and coating agents.
Diluents used in the present invention are at least one or more of the microcrystalline cellulose, anhydrous lactose, directly compressible lactose, starch 1500. calcium phosphate (dibasic/tribasic), calcium sulphate, calcium sulphate dihydrate, fructose, sucrose, sorbitol, xylitol, dextrose, compressible sugar, dextrates, dextrin, starch, powdered cellulose, cellulose acetate, polymethacrylates, sodium alginate and tragacanth. Binders used in the present invention may be at least one or more of polyvinyl pyrrolidone, co-povidone, acacia gum, guar gum, xanthan gum, karaya gum, gellan gum, hupu gum, carob bum, caramania gum, gelatin, glucose, sugar, dextrin, sorbitol, maltose, pregelatinised starch, carboxymethyl cellulose sodium, methyl cellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose, hyroxyethyl cellulose, cellulose acetate, agar, alginic acid, sodium alginate, carbomers, carrageenan, ceratonia, chitosan, poloxamer, polyethylene oxide, magnesium aluminum silicate.
Preferred diluents used in the present invention include one or more of the microcrystalline cellulose, anhydrous lactose, directly compressible lactose, starch 1500, calcium phosphate (dibasic/tribasic), sorbitol, xylitol, dextrose, compressible sugar, dextrates, dextrin, starch, powdered cellulose, cellulose acetate, polymethacrylates, sodium alginate and tragacanth.

More preferred diluents used in the present invention include one or more of the microcrystafiine cellulose, anhydrous lactose, directly compressible lactose, starch 1500, calcium phosphate (dibasic/tribasic), compressible sugar, dextrates, dextrin, starch and powdered cellulose.
Binders used in the present invention may be at least one or more of polyvinyl pyrrolidone, co-povidone, acacia gum, guar gum, xanthan gum, karaya gum, gellan gum, hupu gum, carob gum, caramania gum, gelatin, glucose, sugar, dextrin, sorbitol, maltose, pregelatinised starch, carboxymethyl cellulose sodium, methyl cellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose, hyroxyethyl cellulose, cellulose acetate, agar, alginic acid, sodium alginate, carbomers, carrageenan, ceratonia, chitosan, poloxamer, polyethylene oxide, magnesium aluminum silicate.
Preferred binders used in the present invention include one or more of polyvinyl pyrrolidone, co-povidone, acacia gum, guar gum, xanthan gum, karaya gum, gellan gum, hupu gum, carob gum, caramania gum, dextrin, sorbitol, maltose, pregelatinised starch, carboxymethyl cellulose sodium, methyl cellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose, hyroxyethyl cellulose, alginic acid, sodium alginate, carbomers, carrageenan, ceratonia, chitosan, poloxamer, polyethylene oxide, magnesium aluminum silicate.
More Preferred binders used in the present invention include one or more of polyvinyl pyrrolidone, co-povidone, pregelatinised starch, low substituted hydroxypropyl cellulose, carbomers and polyethylene oxide.
Hydration inhibitors used in the present invention are at least one or more of stearic acid, colloidal silicone dioxide, glyceryl monostearate, glyceryl behenate, gelyceryl monooleate, glyceryl palmitostearate, microcrystalline wax, stearyl alcolhol, cetyl alcohol, cetostearyl alcohol, hydrogeneated vegetable oil, hydrogenated caster oil, tristearin, waxes, polyvinyl acetates, polyethylenes, polypropylenes, polyamides, ethylene glycol polyterephthalate, polyvinyl cholorides, polyformaldehyde chlorides, polycarbonates, ethylene copolymers, polyurethanes, polyacetonitriles, shellac and rosin.
Preferred hydration inhibitors used in the present invention are at least one or more of stearic acid, colloidal silicone dioxide, glyceryl monostearate, glyceryl behenate,

gelyceryl monooleate, glyceryl palmitostearate, hydrogenated vegetable oil, hydrogenated caster oil, polyvinyl acetates, polyethylenes, polypropylenes, polyamides, ethylene glycol polyterephthalate, polyvinyl cholorides, polyformaldehyde chlorides, polycarbonates, ethylene copolymers, polyurethanes, polyacetonitriles, shellac and rosin.
More preferred hydration inhibitors used in the present invention are at least one or more of stearic acid, colloidal silicone dioxide, glyceryl monostearate, glyceryl behenate, gelyceryl monooleate, glyceryl palmitostearate, hydrogenated vegetable oil, hydrogenated caster oil and polyvinyl acetates.
Anti-oxidants used in the present invention are at least one or more of salts of citric acid, L-ascorbic acid, ascorbyl palmitate, citric acid, tocopherols such as a- or p- or y-tocopherol, tocopherol esters, propyl gallate, octyl gallate, dodecyl gallate, butylated hydroxyl anisole, butylated hydroxyl toluene.
Preferred anti-oxidants used in the present invention are at least one or more of salts of L-ascorbic acid, ascorbyl palmitate, citric acid, tocopherols such as a- or p- or y-tocopherol, tocopherol esters, dodecyl gallate, butylated hydroxyl anisole, butylated hydroxyl toluene.
More preferred anti-oxidants used in the present invention are at least one or more of salts of L-ascorbic acid, citric acid, tocopherols such as a- or p- or y-tocopherol, tocopherol esters, butylated hydroxyl anisole, butylated hydroxyl toluene.
Disintegrants used in the present invention are at least one or more of the croscarmellose sodium, crospovidone, sodium starch glycollate, starch, pregelatinized starch, microcrystalline cellulose, emcosoy (Soya polysaccharide) and potassium polacrilin.
Preferred disintegrants used in the present invention are at least one or more of the croscarmellose sodium, crospovidone, sodium starch glycollate, starch, pregelatinized starch, microcrystalline cellulose.
More preferred disintegrants used in the present invention are at least one or more of the croscarmellose sodium, crospovidone, sodium starch glycollate, pregelatinized starch, microcrystalline cellulose.
Lubricants used in the present invention are one or more of magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumerate, hydrogenated vegetable oils, magnesium

lauryl sulfate, wax, polyethylene glycol, glyceryl behenate, glyceryl palmitostearate, palmitic acid, poloxamer, sodium benzoate and sodium lauryl sulfate.
Preferred lubricants used in the present invention are one or more of magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumerate, hydrogenated vegetable oils, glyceryl behenate, glyceryl palmitostearate, palmitic acid, poloxamer, sodium benzoate and sodium lauryl sulfate.
More preferred lubricants used in the present invention are one or more of magnesium stearate, stearic acid, sodium stearyl fumerate, hydrogenated vegetable oils, glyceryl behenate and glyceryl palmitostearate.
According to the present invention, the pharmaceutical composition contains from about 1 to 20% of the active ingredient, from about 1 to 95% of diluents, from about 1 to 20% of binders, from about 1 to 20% of antioxidants, from about 1 to 25% of hydration inhibitors, from about 1 to 20% of d isintegrants, and from about 0.1 to 5% of lubricants.
The immediate release formulation contains 1 to 20% of the active pharmaceutical ingredient. Preferably, the formulation contains 1 to 10 % of the active pharmaceutical ingredient. More preferably, formulation contains 1 to 5 % of the active pharmaceutical ingredient.
The composition of the present invention contains active ingredient in the range of about 0.5 mg to about 100 mg. Preferably, the formulation contains from about 1 mg to about 60 mg of active ingredient. More preferred range of active ingredient in the formulation is about 2 mg to about 20 mg. The term 'active ingredient' refers tiagabine or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof.
In accordance with the present invention, pharmaceutical composition of tiagabine is in the form of solid dosage form i.e., either a tablet or capsule or sachet of granules.
In accordance with the present invention, the tiagabine composition may be in the form of a film-coated tablet comprising the tiagabine and one or more of pharmaceutically acceptable excipients along with one or more of coating agents.

The coating layers over the tablet may be applied as dispersion/solution of coating ingredients using any technique known as spray coating, dip coating and conventional pan coating.
In accordance with the present invention, coating composition comprises one or more of film forming agent, opacifiers, plasticizers surfactants and coloring agents etc.
Film forming agents used in the film coating of present invention may be one or more of cellulose derivatives such as hydroxypropylmethyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose acetate succinate; polyethylene glycol, polyvinyl alcohol, povidone, chitosan, maltodextrin, isomalt, ammonium alginate, gelatin, carrageen, ethyl lactate, acrylate polymers like dimethyl aminoethyl methylmethacrylate and other neutral methacrylic acid esters, polymethacrylates, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, and mixture thereof.
Preferred film forming agents used in the film coating of present invention may be one or more of cellulose derivatives such as hydroxypropylmethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose; polyethylene glycol, polyvinyl alcohol, povidone, acrylate polymers like dimethyl aminoethyl methylmethacrylate and other neutral methacrylic acid esters, polymethacrylates, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, and mixture thereof.
More preferred film forming agents used in the film coating of present invention may be one or more of cellulose derivatives such as hydroxypropylmethyl cellulose; polyethylene glycol, polyvinyl alcohol, and mixture thereof.
Opacifiers used in the present invention may be one or more of titanium dioxide, ethylene glycol palmitostearate, acetates such as zinc acetate, silicates such as talc and aluminium silicate, carbonates such as magnesium carbonate, calcium carbonate etc., stearates such as aluminium stearate and zinc stearate etc., sulfates such as calcium sulfate, oxides such as magnesium oxide and hydroxides such as aluminiuim hydroxides.
Preferred opacifiers used in the present invention may be one or more of titanium dioxide, silicates such as talc and aluminium silicate, carbonates such as magnesium carbonate,

calcium carbonate etc., stearates such as aluminium stearate and zinc stearate etc., oxides such as magnesium oxide and hydroxides such as aluminiuim hydroxides.
More preferred opacifiers used in the present invention may be one or more of titanium dioxide, silicates such as talc and aluminium silicate.
Plasticizers used in the present invention may be one or more of polyethylene glycols, propylene glycol, glycerine, caster oil, acetyltriethyl citrate, benzyl benzoate, chlorbutanol, dextrin, acetyltributyl citrate, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, glyceryl monooleate, glyceryl monostearate, 2-pyrrolidone, sorbitol, stearic acid, palmitic acid, triacetin, tributyl citrate, triethyl citrate, triethanolamine, lecithin, surfactants like polysorbates, sorbitan esters and organic acid esters and mixtures thereof.
Preferred plasticizers used in the present invention may be one or more of polyethylene glycols, propylene glycol, glycerine, glyceryl monooleate, glyceryl monostearate, 2-pyrrolidone, sorbitol, stearic acid, palmitic acid, triacetin, tributyl-citrate, triethyl citrate, triethanolamine, lecithin, surfactants like polysorbates, sorbitan esters and organic acid esters and mixtures thereof.
More preferred plasticizers used in the present invention may be one or more of polyethylene glycols, propylene glycol, glycerine, glyceryl monooleate, glyceryl monostearate, stearic acid, surfactants like polysorbates, sorbitan esters and organic acid esters and mixtures thereof. Suitable coloring agents include one or more colors approved by FDA.
Suitable solvents used in the manufacturing of pharmaceutical composition include one or more of water, ethyl acetate, acetone, isopropyl alcohol, n-propanol, ethanol and mixtures thereof.
The stable immediate release pharmaceutical compositions is prepared by addition of active substance with placebo granules, comprises the steps-
i. Preparation of the placebo granules.
a) Sifting of the inactive ingredients.
b) Mixing of the inactive ingredients and granulation.
c) Drying of the prepared granules.

ii. Adsorption of the active pharmaceutical ingredient onto the placebo granules
by co-sifting and mixing.
iii. Lubrication of the blend of step- ii.
iv. Compression of the lubricated blend of step- iii into tablets.
v. Film coating the compressed tablets of step- iv.
vi. Direct filling of the lubricated blend of step-iii into capsules or sachets.
Also, the stable immediate release pharmaceutical compositions is prepared by melt granulation method, comprises the steps-
i. Sifting of the active ingredient. ii. Sifting of anti-oxidant and diluents. iii. Mixing of active ingredient with step-ii dry mix. iv. Sifting and melting of hydration inhibitor and optionally other excipients having low melting point. v. Solubilization or uniform distribution of step-iii dry mix in step-iv molten excipient mix. vi. Drying and milling of step-v mix. vii. Sifting extra-granular excipinets and then mixing with step-vi milled granules. viii. Compression of the lubricated blend of step viii into tablets. ix. Film coating of the compressed tablets of step viii. x. Direct filling of the lubricated blend of step viii into capsules or sachets
Further, the stable immediate release pharmaceutical compositions is also prepared by direct compression method comprises steps of-
i. Sifting of the active ingredient ii. Sifting of anti-oxidants and mixing with step-i active ingredient by geometric dilution technique. iii. Sifting of hydration inhibitors and mixing with step-ii dry mix by geometric dilution technique. iv. Sifting of other excipients and mixing with step-iii dry mix by geometric dilution technique. v. Lubrication of the blend of step-iv. vi. Compression of the lubricated blend of step-v into tablets or Direct filling of the lubricated blend of step-v into capsules or sachets.

vii. Film coating the compressed tablets of step-vi.
The composition of the present invention may be administered to the mammals. Preferably the mammal is a human, and the composition is administered as pharmaceutical composition. Preferably, the pharmaceutical composition of present invention containing tiagabine or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures thereof, may be used in the treatment of partial seizures in adult and children's of 12 years and older as per the approved indications for GABITRIL prescribing information. The amount of the tiagabine in pharmaceutical composition of present invention is preferably an amount that provides a therapeutically effective amount of tiagabine.
Although the invention has been described with reference to specific embodiments, this description is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the invention, will become apparent to person skilled in the art upon reference to the description of the invention. It is therefore contemplated that such modifications can be made without departing from the spirit or scope of the present invention as defined.
Examples
The following examples are presented for illustration only, and are not intended to limit the scope of the invention or appended claims
Example 1
Table 1: Formulation of example - 1

s.
No. Ingredients Quantity per tablet (in mg)

I n III IV
I. Tiagabine HCI 2.000 4.000 12.000 16.000
2. Microcrystalline cellulose 25.000 50.000 150.000 200.000
3. Anhydrous lactose 12.900 25.800 77.400 103.200
4. Low-substituted hydroxypropyl cellulose 1.125 2.250 6.750 9.000
5. Pregelatinized starch 1.875 3.750 11.250 15.000
6. Citric acid (anhydrous) 80 mesh powder 1.375 2.750 8.250 11.000
7. Crospovidone 1.375 2.750 8.250 11.000
8. Magnesium stearate 0.350 0.700 2.100 2.800
Total weight (mg) 46.000 92.000 276.000 368.000
9. Hydroxypropyl methyl cellulose (6 cps) 0.625 1.250 3.750 5.000
10. Titanium dioxide 0.3125 0.625 1.875 2.500

11. Polyethylene glycol-400 0.0625 0.125 0.375 0.500
12. Purified water q.s. q.s. q.s. q.s.
Total weight (mg) 47.000 94.000 282.000 376.000
MANUFACTURING PROCESS:
1. Sifted tiagabine HC1, anhydrous lactose, pregelatinized starch, low-substituted hydroxypropyl cellulose and citric acid through ASTM # 40 mesh and mixed for l0min.
2. Sifted microcrystalline cellulose through ASTM # 40 mesh and added to the blend of step 1 and mixed for 5 min.
3. Sifted crospovidone through ASTM # 40 mesh, added to blend of step 2 and mixed for 3 min.
4. Sifted magnesium stearate through ASTM # 60 mesh, added to blend of step 3 and mixed for 3 min.
5. Compressed the lubricated blend of step 4 into tablets or fill into capsules or sachets.
6. Prepared the coating solution/dispersion.
7. Coated the compressed tablets.
Example 2
Table 2: Formulation of example - 2

S. No. Ingredients Quantity per tablet (in mg)

I II III IV
1. Tiagabine HC1 2.000 4.000 12.000 16.000
2. Microcrystalline cellulose 25.000 50.000 150.000 200.000
3. Anhydrous lactose 12.900 25.800 77.400 103.200
4. Low-substituted hydroxypropyl cellulose 1.125 2.250 6.750 9.000
5. Pregelatinized starch 1.875 3.750 11.250 15.000
6. Citric acid (anhydrous) 80 mesh powder 1.375 2.750 8.250 11.000
7. Crospovidone 1.375 2.750 8.250 11.000
8. Magnesium stearate 0.350 0.700 2.100 2.800
9. Purified Water q.s. q.s. q.s. q.s.
Total weight (mg) 46.000 92.000 276.000 368.000
9. Hydroxypropylmethyl cellulose (6 cps) 0.625 1.250 3.750 5.000
10. Titanium dioxide 0.3125 0.625 1.875 2.500
11. Polyethylene glycol-400 0.0625 0.125 0.375 0.500
12. Purified water q.s. q.s. q.s. q.s.
Total weight (mg) 47.000 94.000 282.000 376.000
MANUFACTURING PROCESS:

1. Sifted anhydrous lactose, microcrystalline cellulose, pregelatinized starch, and low-substituted hydroxy propyl cellulose through ASTM # 40 mesh and mixed for l0min.
2. Prepared citric acid solution using purified water.
3. Granulated the above dry mix of step 1 with aqueous citric acid solution.
4. Dried the granules of step 3 till the LOD reached in the range of 1.5-3% w/w.
5. Sifted the dried granules of step 4 through ASTM # 30 mesh.
6. Sifted tiagabine HC1 and crospovidone through ASTM # 40 mesh and added to granules of Step 5 & mixed for 5min.
7. Sifted magnesium stearate through ASTM # 60 mesh, added to granules of Step 6 and mixed for 3 min.
8. Compressed the lubricated blend of step 7 into tablets or fill into capsules or sachets.
9. Prepared the coating solution/dispersion.
10. Coated the compressed tablets.
Example 3
Table 3: Formulation of example - 3

s.
No. Ingredients Quantity per tablet (in mg)

I II III IV
1. Tiagabine HC1 2.000 4.000 12.000 16.000
2. Microcrystalline cellulose 26.375 52.750 158.250 211.000
3, Anhydrous lactose 12.900 25.800 77.400 103.200
4. Low-substituted hydroxypropyl cellulose 1.125 2.250 6.750 9.000
5. Pregelatinized starch 1.875 3.750 11.250 15.000
6. Citric acid (anhydrous) 80 mesh powder 1.375 2.750 8.250 11.000
7. Sodium Stearyl fumarate 0.350 0.700 2.100 2.800
8. Purified water q.s. q.s. q.s. q.s.
Total weight (mg) 46.000 92.000 276.000 368.000
9. Hydroxypropylmethyl cellulose (6 cps) 0.625 1.250 3.750 5.000
10. Titanium dioxide 0.3125 0.625 1.875 2.500
11. Polyethylene glycol-400 0.0625 0.125 0.375 0.500
12. Purified water q.s. q.s. q.s. q.s.
Total weight (mg) 47.000 94.000 282.000 376.000
MANUFACTURING PROCESS:
1. Sifted anhydrous lactose, microcrystalline cellulose and pregelatinized starch through ASTM # 40 mesh and mixed for l0min.
2. Prepared citric acid solution using purified water.
3. Granulated the above dry mix of step 1 with aqueous citric acid solution.
4. Dried the granules of step 3 till the LOD reached in the range of 1.5-3% w/w.

5. Sifted the dried granules of step 4 through ASTM # 30 mesh.
6. Sifted Tiagabine HCI and low-substituted hydroxypropyl cellulose through ASTM # 40 mesh and added to granules of Step 5 & mixed for l0min.
7. Sifted sodium Stearyl Fumarate through ASTM # 60 mesh, added to granules of Step 6 and mixed for 3 min.
8. Compressed the lubricated blend of step 7 into tablets or fill into capsules or sachets.
9. Prepared the coating solution/dispersion.
10. Coated the compressed tablets.
Dissolution studies of tablets of Example-3 and Gabitril were carried out in USP Type-II apparatus using 900 ml of purified water as dissolution medium maintained 37±0.5° C with the paddle speed of 50 rpm, and the comparative dissolution profiles are given in Table 4 and Fig. 1
Table 4: Comparative dissolution profiles of the tablets of Example 3 and Gabitril in water.

Time (minutes) Percent tiagabine HCI released

Gabitril Tablets Example-3
0 0 0
5 25.0 75.6
10 84.1 85.1
15 94.7 87.5
20 96.2 88.4
30 96.9 89.6
Tablets of Example-3 were evaluated for assay and related substances. Results of these studies are shown in Table 5.
Table 5: Evaluation of the formulation of Example-3

S.N. Parameters Result
1. Assay (%) 102.3
2. Related substances (%)

(R)-1-Bis(3-methyl-thieny)-3,4-dihydroxybutyl]-3-piperidinecarboxylic acid BRT

(R)-l-[4,4-Bis(3-methyl-2-thienyl)-3-oxybutyl]-3-piperidinecarboxylicacid 0.21

(R)-l-[4-(3-Methyl-2-thienyl)-4-(2-thienyl)-3-butenyl]-3-piperidinecarboxylicacid BDL

(R)-Methyl l-[[4-(x-methyl-2-thienyl)-4-0-methyl-2-thienyl)]-3-butenyl]-3-piperidinecarboxylic acid* BDL

(R)-Methyl l-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylate BRT

Tiagabine related compound A BDL

4,4-Bis(3-methyl-2-thienyl)-3-buten-l-ol BDL

Bis(3-methyl-2-thienyl)methanone BDL

4,4-Bis(3-methyl-2-thienyl)-3-buten-l-ol, methanesulfonate BDL

2,2-Bis(3-methyl-2-thienyl)tetrahydrofuran BDL

Unknown impurities (%) 0.05

Total impurities (%) 0.26
BQL : Below quantification limit; BRT: Below reporting threshold
Stability studies were also conducted for the tablets of Example 3 after packing in HDPE bottle for 3 months at accelerated conditions (40°C/75% RH) to evaluate the changes in related substances as well as changes in the dissolution profile in USP Type-II apparatus run at the paddle speed of 50 rpm by using 900 ml of purified water maintained at 37±0.5°C. The results of these studies are shown in Table 6 to 7.
Table 6: Accelerated stability study results of tablets of Example-3

S. No. Parameters Accelerated conditions (40°C/75% RH)

3 month
1. Assay (%) 98.2
Related substances (%)

(R)-l-[4,4-Bis(3-methyl-2-thienyl)-3,4-dihydroxybutyl]-3-piperidinecarboxylic acid 0.14

(R)-l-[4,4-Bis(3-methyl-2-thienyl)-3-oxybutyl]-3-piperidinecarboxylic acid 0.30

(R)-l.[4.(3-Methyl-2-thienyl)-4-(2-thienyl)-3-butenyl]-3-piperidinecarboxylic acid BDL

(R)-MethyI 1 -[[4-(x-methyl-2-thienyl)-4-(y-methyl-2-thienyl)]-3-butenyl]-3-piperidinecarboxylic acid- BDL
(R)-Methyl l-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylate BRT
Tiagabine related compound A BDL
4,4-Bis(3-methyl-2-thienyl)-3-buten-l-ol 0.06
Bis(3-methyl-2-thienyl)methanone BDL
4,4-Bis(3-methyl-2-thienyl)-3-buten-l-ol, methanesulfonate BDL
2,2-Bis(3-methyl-2-thienyl)tetrahydrofuran BDL
Unknown impurities (%) 0.09
Total impurities (%) 0.59
BDL: Below detection limit; BRT: Below reporting threshold
Table 7: Dissolution profile of tablets of Example-3 stored at accelerated storage condition (40°C/75%RH).

Time Percent tiagabine HCI released |

3 Month sample (40°C/75%RH)
0 0
5 60.2
10 81.5
15 84.4
20 86.5
30 88.1
Example-4
Table 8: Formulation of example - 4

S.
No. Ingredients Quantity per tablet (in mg)

I II III IV
1. Tiagabine HC1 2.000 4.000 12.000 16.000
2. Microcrystalline cellulose 18.750 37.500 112.500 150.000
3. Crospovidone XL-10 1.750 3.500 10.500 14.000
4. Anhydrous lactose 18.750 37.500 112.500 150.000
5. Low-substituted hydroxypropyl cellulose 1.125 2.250 6.750 9.000
6. Pregelatinized starch 1.875 3.750 11.250 15.000
7. Citric acid (anhydrous) 80 mesh powder 1.375 2.750 8.250 11.000
8. Stearic acid 0.375 0.750 2.250 3.000
9. Purified water q.s. q.s. q.s. q.s.
Total weight (mg) 46.000 92.000 276.000 368.000
10. Hydroxypropylmethyl cellulose (6 cps) 0.625 1.250 3.750 5.000
11. Titanium dioxide 0.3125 0.625 1.875 2.500
12. Polyethylene glycol-400 0.0625 0.125 0.375 0.500
13. Purified water q.s. q.s. q.s. q.s.
Total weight (mg) 47.000 94.000 282.000 376.000
MANUFACTURING PROCESS:
1. Sifted anhydrous lactose, microcrystalline cellulose and crospovidone XL-10 through ASTM # 40 mesh and mixed for l0min.
2. Prepared citric acid solution using purified water.
3. Granulated the above dry mix of step 1 with aqueous citric acid solution.
4. Dried the granules of step 3 till the LOD reached in the range of 1.5-3% w/w.
5. Sifted the dried granules of step 4 through ASTM # 30 mesh.
6. Sifted Tiagabine HC1, pregelatinized starch and low-substituted hydroxypropyl cellulose through ASTM # 40 mesh and added to granules of Step 5 & mixed for l0min.
7. Sifted Stearic acid through ASTM # 60 mesh, added to granules of Step 6 and mixed for 3 mins.
8. Compressed the lubricated blend of step 7 into tablets or fill into capsules or sachets.
9. Prepared the coating solution/dispersion.

10. Coated the compressed tablets.
Dissolution studies of tablets of Example-4 and Gabitril were carried out in USP Type-II apparatus using 900 ml of purified water as dissolution medium maintained 37±0.5° C with the paddle speed of 50 rpm, and the comparative dissolution profiles are given in Table 9 and Fig. 2.
Table 9: Comparative dissolution profiles of the tablets of Example-4 and Gabitril in water.

Time (minutes) Percent tiagabine HC1 released

Gabitril Tablets Example 4
0 0 0
5 16.7 30.5
10 81.8 92.9
15 98.3 99.5
20 100.9 100.4
30 101.5 100.8
Tablets of Example-4 were evaluated for assay and related substances. Results of these studies are shown in Table: 10.
Table 10: Evaluation of the formulation of Example-4

S.N. Parameters Result
1. Assay (%) 102.1
2. Related substances (%)

(R)-l-[4,4-Bis(3-methyl-2-thienyI)-3,4-dihydroxybutyl]-3-piperidinecarboxylic acid 0.09

(R)-l-[4,4-Bis(3-methyl-2-thienyl)-3-oxybutyl]-3-piperidinecarboxylic acid 0.08

(R)-l-[4-(3-Methyl-2-thienyl)-4-(2-thieny:)-3-butenyl]-3-piperidinecarboxylic acid BDL

(R)-Methyl l-[[4-(x-methvl-2-thienyl)-4-(y-methyl-2-thienyl)]-3-butenyl]-3-piperidinecarboxylic acid- BDL

(R)-Methyl l-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylate BRT

Tiagabine related compound A BRT

4,4-Bis(3-methyl-2-thienyI)-3-buten-l-ol BRT

Bis(3-methyl-2-thienyl)methanone BDL

4,4-Bis(3-methyl-2-thienyl)-3-buten-l-ol, methane sulfonate BDL

2,2-Bis(3-methyl-2-thienyl)tetrahydrofuran BDL

Unknown impurities (%) BRT

Total impurities (%) 0.17
BDL : Below detection limit; BRT: Below reporting threshold
Stability studies were also conducted for the tablets of Example-4 after packing in HDPE bottle for 3 months at accelerated conditions (40°C/75% RH) to evaluate the changes in

related substances as well as changes in the dissolution profile in USP Type-II apparatus run at the paddle speed of 50 rpm by using 900 ml of purified water maintained at 37±0.5°C. The results of these studies are shown in Table 11 to 12.
Table 11: Accelerated stability study results of tablets of Example-4

S.No. Parameters Accelerated conditions (40°C/75% RH)

3 month
1. Assay (%) 95.7
Related substances (%)

(R)-1-[4,4-Bis(3-methyl-2-thienyl)-3,4-dihydroxybutyl]-3-piperidinecarboxylic acid 0.10

(R)-1-[4,4-Bis(3-methyl-2-thienyl)-3-oxybutyl]-3-piperidinecarboxylic acid 0.28

(R)-l.[4.(3-Methyl-2-thieny!)-4-(2-thienyI)-3-butenyl]-3-piperidinecarboxylic acid 0.05

(R)-Methyl-[[4-(x-methyl-2-thienyl)-4-(y-methyl-2-thienyl)]-3-butenyl]-3-piperidinecarboxyIicacid- BDL

(R)-Methyl l-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylate BDL

Tiagabine related compound A BDL

4,4-Bis(3-methyl-2-thienyl)-3-buten-l-ol 0.10

Bis(3-methyl-2-thienyl)methanone BDL

4,4-Bis(3-methyl-2-thienyl)-3-buten-l-ol, methanesulfonate BDL

2,2-Bis(3-methyl-2-thienyl)tetrahydrofuran BDL

Unknown impurities (%) 0.06;0.06;0.09;0.07

Total impurities (%) 0.81
BDL : Below detection limit; BRT: Below reporting threshold
Table 12: Dissolution profile of tablets of Example-4 stored at accelerated storage condition (40°C/75%RH).

Time
(minutes) Percent tiagabine HCI released

3 Month sample (40°C/75%RH)
0 0
5 18.2
10 52.4
15 87.3
20 94.9
30 95.1

Example 5
Table 13: Formulation of example - 5

s.
No. Ingredients Quantity per tablet (in mg)

I II in IV
1. Tiagabine HC1 2.000 4.000 12.000 16.000
2. Microcrystalline cellulose 12.500 25.000 75.000 100.000
3. Anhydrous lactose 13.000 26.000 78.000 104.000
4. Ascorbic acid 1.125 2.250 6.750 9.000
5. Pregelatinized starch 1.875 3.750 11.250 15.000
6. glyceryl dibehenate 12.500 25:000 75.000 100.000
7. stearic acid 1.275 2.550 7.650 10.200
8. Crospovidone 1.375 2.750 8.250 11.000
9. Magnesium stearate
Total weight (mg) 46.000 92.000 276.000 368.000
10. Hydroxypropylmethyl cellulose (6 cps) 0.625 1.250 3.750 5.000
11. Titanium dioxide 0.3125 0.625 1.875 2.500
12. Polyethylene glycol-400 0.0625 0.125 0.375 0.500
13. Purified water q.s. q.s. q.s. q.s.
Total weight (mg) 47.000 94.000 282.000 376.000
MANUFACTURING PROCESS:
■ 1. Sifting of the tiagabine HC1.
2. Sifting of ascorbic acid and lactose anhydrous.
3. Mixing of active ingredient with step-2 dry mix.
4. Sifting and melting of glyceryl dibehenate and stearic acid, colloidal silicon dioxide.
5. Solubilization or uniform distribution of step-3 dry mix in step-4 molten excipient mix.
6. Drying and milling of step-5 mix.
7. Sifting microcrystalline cellulose, pregelatinized starch, and then mixing with step-6 milled granules.
8. Sifting crospovidone and mixing with step-7 blend.
9. Sifting of magnesium stearate and mixing with step-8 blend
10. Compression of the lubricated blend of step 9 into tablets.
11. Preparation coating dispersion and film coating of the compressed tablets of step 10.
12. Direct filling of the lubricated blend of step 9 into capsules or sachets.

Claims:
1. Stable immediate release pharmaceutical compositions comprising tiagabine or its pharmaceutically acceptable salt, solvate, enantiomers or mixtures and pharmaceutical excipients thereof prepared by i) co-sifting the active substance along with placebo granules; or ii) direct compression of active substance along with pharmaceutically acceptable excipients; or iii) melt granulation of active substance along with pharmaceutically acceptable excipients.
2. Stable immediate release pharmaceutical composition of claim 1, wherein pharmaceutically acceptable excipients comprises of diluents, binders, d is integrants, hydration inhibitors, anti-oxidants, lubricants and coating agents.
3. Stable immediate release pharmaceutical composition of claim 2, wherein the diluents comprises at least one or more of microcrystalline cellulose, anhydrous lactose, directly compressible lactose, starch 1500, calcium phosphate (dibasic/tribasic), compressible sugar, dextrates, dextrin, starch and powdered cellulose; binders comprises at least one or more of polyvinyl pyrrolidone, co-povidone, pregelatinised starch, low substituted hydroxypropyl cellulose, carbomers and polyethylene oxide; disintegrants comprises at least one or more of croscarmellose sodium, crospovidone, sodium starch glycollate, pregelatinized starch, microcrystalline cellulose; antioxidants comprises at least one or more salts of L-ascorbic acid, citric acid, tocopherols such as a- or p- or y-tocopherol, tocopherol esters, butylated hydroxyl anisole, butylated hydroxyl toluene; hydration inhibitors comprises at least one or more of stearic acid, colloidal silicone dioxide, glyceryl monostearate, glyceryl behenate, gelyceryl monooleate, glyceryl palmitostearate, hydrogenated vegetable oil, hydrogenated caster oil and polyvinyl acetates; lubricants comprises at least one or more of magnesium stearate, stearic acid, sodium stearyl fumerate, hydrogenated vegetable oils, glyceryl behenate and glyceryl palmitostearate.
4. Stable immediate release pharmaceutical composition of claim 1, wherein the solid pharmaceutical composition comprises by weight between about 1 to 20% the active ingredient, from about 1 to 95% of diluents, from about 1 to 20% of binders, from about 1 to 20% of antioxidants, from about 1 to 25% of hydration inhibitors, from about 1 to 20% of disintegrants, and from about 0.1 to 5% of lubricants.

5. Stable immediate release pharmaceutical composition of claim 1, wherein tiagabine HC1 is present in an amount of about 0.5 mg to about 100 mg, preferably from about 1 mg to about 60 mg, and more preferably from about 2 mg to 20 mg.
6. Stable immediate release pharmaceutical composition of claim 1, wherein the dosage forms comprises tablets, capsules, granules suitable for oral administration.
7. Stable immediate release pharmaceutical composition of claim 6, wherein tablets are film coated immediate release tablets.
8. Stable immediate release pharmaceutical compositions of claim 7, wherein coating excipients comprises one or more of film forming agents, opacifying agents, plasticizers surfactants and colorants.
9. Stable immediate release pharmaceutical compositions of claim 8, where in film forming agents may be one or more of cellulose derivatives like hydroxypropylmethyl cellulose; polyethylene glycol, polyvinyl alcohol, and mixture thereof; opacifiers may be one or more of titanium dioxide, silicates such as talc and aluminium silicate; plasticizers may be one or more of polyethylene glycols, propylene glycol, glycerine, glyceryl monooleate, glyceryl monostearate, stearic acid; surfactants like polysorbates, sorbitan esters and organic acid esters and mixtures thereof ; and coloring agents include one or more colors approved by FDA.
10. Stable immediate release pharmaceutical compositions of claim 1, wherein suitable solvents used in the manufacturing of pharmaceutical compositions of claim 1, comprises one or more of water, ethyl acetate, acetone, isopropyl alcohol, n-propanol, ethanol and mixtures thereof.
11. Stable immediate release pharmaceutical compositions of claim 1 prepared by addition of active substance with placebo granules, comprises the steps-
vii. Preparation of the placebo granules.
d) Sifting of the inactive ingredients.
e) Mixing of the inactive ingredients and granulation.
f) Drying of the prepared granules.
viii. Adsorption of the active pharmaceutical ingredient onto the placebo granules by co-sifting and mixing.

ix. Lubrication of the blend of step- ii.
x. Compression of the lubricated blend of step- iii into tablets.
xi. Film coating the compressed tablets of step- iv.
xii. Direct filling of the lubricated blend of step-iii into capsules or sachets.
12. Stable immediate release pharmaceutical compositions of claim 1 prepared by melt
granulation method, comprises the steps-
xi. Sifting of the active ingredient. xii. Sifting of anti-oxidant and diluents. xiii. Mixing of active ingredient with step-ii dry mix. xiv. Sifting and melting of hydration inhibitor and optionally other excipients having low melting point. xv. Solubilization or uniform distribution of step-iii dry mix in step-iv molten excipient mix. xvi. Drying and milling of step-v mix. xvii. Sifting extra-granular excipinets and then mixing with step-vi milled granules. xviii. Compression of the lubricated blend of step viii into tablets. xix. Film coating of the compressed tablets of step viii. xx. Direct filling of the lubricated blend of step viii into capsules or sachets
13. Stable immediate release pharmaceutical compositions of claim 1 prepared by direct
compression method comprises steps of-
viii. Sifting of the active ingredient ix. Sifting of anti-oxidants and mixing with step-ii active ingredient by geometricdilution technique. x. Sifting of hydration inhibitors and mixing with step-ii dry mix by geometric dilution technique. xi. Sifting of other excipients and mixing with step-iii dry mix by geometric dilution technique. xii. Lubrication of the blend of step-iv. xiii. Compression of the lubricated blend of step-v into tablets. xiv. Film coating the compressed tablets of step-vi. xv. Direct filling of the lubricated blend of step-v into capsules or sachets.

14. Stable immediate release pharmaceutical compositions of claim 1, wherein the dosage form is used in the treatment of partial seizures.
15. The stable pharmaceutical composition substantially as herein described and illustrated with reference to the accompanying examples