Field of the invention

The present invention relates to stable pharmaceutical compositions comprising tiagabine, and processes for their preparation.

Background of the invention

Tiagabine is a well-tolerated medication having antiepileptic activity. Chemically, tiagabine is (-)-(R)-l-[4,4-bis (3-methyl-2-thienyl)-3-butenyl] nipecotic acid hydrochloride, which is disclosed in U.S. 5,010,090. U.S. 5,354,760 and U.S. 5,958,951 disclose monohydrate and anhydrous forms of tiagabine hydrochloride, respectively. Presently, tiagabine is available as film coated tablets in 2 mg, 4 mg, 12 mg, or 16 mg strengths and marketed by Novo Nordisk under the trade name GABITRIL ^® .

GABITRIL ^® is indicated as adjunctive therapy in adults and children of 12 years and older, in the treatment of partial seizures. Partial seizures are characterized by the uncontrolled muscle activity, which begins with an electrical discharge limited to a specific area of one cerebral hemisphere. Tiagabine blocks gamma-amino butyric acid (GABA) uptake into presynaptic neurons, permitting more GABA to be available for receptor binding on the surfaces of post-synaptic cells, thus preventing the propagation of neural impulses that contribute to seizures by a GABA-ergic action Tiagabine is sparingly soluble in water and is hygroscopic. It has been found to be decomposed in the presence of, and in contact with, oxygen and water. One of the major causes of its chemical instability is oxidative degradation during storage. Further, it may also undergo decomposition on exposure to light and heat. Poor stability of tiagabine often poses problems associated with shelf life of its various dosage forms. To date various approaches have been undertaken to achieve sufficient stability of tiagabine hydrochloride in pharmaceutical compositions to the extent necessary to prepare dosage forms with reasonably acceptable shelf lives. For example, U.S. 5,866,590 discloses a stable pharmaceutical composition containing tiagabine hydrochloride monohydrate with at least one antioxidant selected from tocopherol and ascorbic acid, and their derivatives.

We have now developed an alternative approach to improve the resistance of tiagabine to chemical degradation in pharmaceutical compositions by using a specific combination of antioxidants. The shelf life of pharmaceutical compositions are thereby extended to reasonably acceptable periods. Summary of the Invention

In one general aspect there is provided a stable pharmaceutical composition comprising tiagabine, a combination of butylated hydroxy anisole (BHA), butylated hydroxy toluene (BHT), and ethylene diamine terra acetate (EDTA) as antioxidants, and one or more pharmaceutically acceptable excipients. Embodiments of the stable composition may include one or more of the following features or those described above. For example, the composition may include another stabilizing agent, propyl gallate. The pharmaceutically acceptable excipients may be selected from binders, diluents, fillers, glidants/ lubricants, disintegrants/ superdisintegrants, stabilizing agents, surfactants, coloring and flavoring agents. The composition may be in the form of a solid dosage form, for example, in the form of a tablet, a coated tablet, a capsule, a pill, granules or a powder.

In another general aspect there is provided a process for preparing a stable pharmaceutical composition of tiagabine. The process includes a step of blending with antioxidants. Embodiments of the process may include one or more of the following features.

For example, the process may further include blending tiagabine with one or more pharmaceutically acceptable excipients; granulating the blend to form a granulation; and processing into a solid dosage form.

The granulation step may be carried out by wet granulation or dry granulation. The wet granulation process may include blending tiagabine, antioxidants, diluents, binder, and a portion of superdisintegrant/disintegrant; granulating the blend with a granulating fluid or solution/dispersion; drying the granules; reducing the granules to a suitable size; lubricating and compressing the lubricated granules.

The dry granulation process may include blending tiagabine, antioxidants, diluents, binder, and a portion of superdisintegrant/disintegrant; compacting or slugging the blend;

breaking the slugs to make granules; reducing the granules to a suitable size; lubricating and compressing the lubricated granules.

The composition may further include one or more pharmaceutically acceptable excipients selected from filler, binder, disintegrant, surfactant, lubricant, coloring agent, and flavoring agent.

In another general aspect there is provided a medicament for the treatment of partial seizures, the medicament comprising tiagabine, a combination of butylated hydroxy anisole (BHA), butylated hydroxy toluene (BHT), and ethylene diamine tetra acetate (EDTA) as antioxidants, one or more pharmaceutically acceptable excipients and optionally another drug.

Embodiments of the medicament may include one or more of the following features or those described above. For example, the additional drug may include enzyme inducing anticonvulsants such as barbiturates, carbamazepine, and phenytoin; or nonenzyme inducing anticonvulsants such as gabapentin, lamotrigine, and valproate. The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims.

Detailed Description of the Invention

We have now discovered that use of a combination of butylated hydroxy anisole (BHA), butylated hydroxy toluene (BHT), and ethylene diamine tetra acetate (EDTA) as antioxidants surprisingly increases the stability of tiagabine in pharmaceutical compositions and can provide a reasonably long shelf life for dosage forms using these combinations.

Conventionally, BHA, BHT, and EDTA are individually known as antioxidants. However, when these antioxidants were used individually the desired stability was not obtained for tiagabine during storage. Further, use of various other antioxidants such as ascorbic acid, sodium metabisulphite and anhydrous citric acid has also not given satisfactory results. However, surprisingly a particular combination of BHA, BHT and EDTA showed an excellent stabilizing property for tiagabine. The combination of BHA, BHT and EDTA has synergistic action and is effective in reasonably low amounts. The

stability was further improved by including propyl gallate (PG) to this combination.

The above is evident from the comparative preformulation stability data obtained with various antioxidants by forced degradation (Table 1) at room temperature (RT) and at 50 ⁰ C for over a time period of 24 hours. The studies were carried out as follows: In an alcoholic solution of tiagabine hydrochloride (500 μg/ml) and in the presence of 1% hydrogen peroxide, antioxidants and their combinations were evaluated with respect to total related substances (RS) at 0 and 24 hour at room temperature (RT) and at 50 ⁰ C, against the control, i.e., the solution without any antioxidant. The concentrations of antioxidants selected were based on their respective HG limits. Antioxidants were used in the form of either water or isopropyl alcohol (IPA) solutions depending on their solubility.

Table 1. Evaluation of Antioxidants by Forced Degradation Study:

*NA = not applicable

The study clearly indicates the importance of the use of a combination of BHT, BHA and EDTA as antioxidants in stabilizing tiagabine pharmaceutical compositions. The term "stable pharmaceutical composition" as used herein refers to the chemical stability of tiagabine in dosage forms against degradation occurring during the shelf life due to hydrolysis and oxidation, wherein not more than 4.0% w/w total related substances and in particular not more than 2.0% w/w total related substances are formed on storage at 40 ± 2 ⁰ C and 75±5% relative humidity over a period of three months. The term "tiagabine" as used herein includes tiagabine in a free or pharmaceutically acceptable salt form such as an acid addition salt. Tiagabine or a pharmaceutically acceptable salt thereof may also be used in the form of a hydrate. In particular, the composition comprises the anhydrous tiagabine hydrochloride. Tiagabine may be present in an amount from about 1% to about 20% of the total composition by weight. In particular, it may be present in an amount from about 4% to about 10% based on the total weight of the pharmaceutical composition.

Antioxidants are substances that combat oxidation. They prevent degradation occurring from damaging oxidation reactions by interrupting free-radical chain reactions or by inactivating trace metal ions by chelation, hence hindering the process of oxidation. Thus antioxidants are also referred as "Free radical scavengers". BHA, BHT, and EDTA are synthetic antioxidants used widely in food and drug industry.

BHT and BHA are sterically hindered phenolic compounds. BHA is a mixture of the isomers 3-tert-butyl-4-hydroxyanisole and 2-tert-butyl-4-hydroxyanisole, also known as BOA, tert-butyl-4-hydroxyanisole, (l,l-dimethylethyl)-4-methoxyphenol, tert-butyl-4-

methoxyphenol, antioxyne B. BHT is a 2,6-bis (l,l-dimethylethyl)-4- methylphenol. They are extremely soluble in fat and insoluble in water. When used together, BHA and BHT assert a synergistic effect.

The term "EDTA" as used herein includes ethylenediamine terra acetic acid and derivatives and salts thereof. They form complexes or coordination compounds with trace metal ions present in free form or salts of fatty acids, thereby inactivating them. They have an additive effect when used synergistically with the BHT and BHA. In particular, disodium salt of EDTA has been used in the present invention.

Antioxidants are combined to take advantage of their differing properties, for providing synergistic effects, better control, accuracy and more convenience to handle. The total amount of antioxidants added to the pharmaceutical composition may vary from about 0.01 to about 2.0%, based on the total weight of the composition. BHA, BHT and EDTA may be present in a weight ratio of about 7 : 1 : 10 to about 15: 1: 5. In particular, these may be present in a weight ratio of about 10:1:7.5. Additionally, another antioxidant may also be included in the composition, for example propyl gallate (PG), which is a naturally derived antioxidant from gallic acid and is obtained by the hydrolysis of tannins from Tara pods. It is chemically known as N- propyl gallate or n-propyl ester of 3,4,5-trihydroxybenzoic. Propyl gallate has been used since 1948 as an antioxidant additive to stabilize cosmetics, food packaging materials, and medicinal preparations. It is available as fine, white to nearly white, odorless powder having a slightly bitter taste. It is slightly soluble in water and freely soluble in alcohol and in ether.

The term "pharmaceutically acceptable excipients" refers to ingredients of the composition, but excludes the active drug substance. Examples of other pharmaceutically acceptable excipients as used herein include binders, diluents, fillers, glidants/lubricants disintegrants/superdisintegrants, stabilizing agents, surfactants, colors, and the like.

Examples of binders include one or more of methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, and the like.

The fillers can be selected from one or more of calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, powdered cellulose, dextrates, dextrins, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, sucrose, sugar compressible, sugar confectioners, and the like. In particular, microcrystalline cellulose can be used.

Examples of diluents include one or more of cellulose powder, microcrystalline cellulose, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners, and the like. Examples of disintegrants/superdisintegrants include one or more of starches, clays, celluloses, alginates, gums, cross-linked polymers (such as cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethylcellulose), sodium starch glycolate, low-substituted hydroxypropyl cellulose, and soy polysaccharides, and the like. Superdisntegrants aid in quick disintegration of the pharmaceutical composition. Examples of lubricants and glidants include one or more of talc, magnesium stearate, calcium stearate, stearic acid, colloidal silicon dioxide, magnesium carbonate, magnesium oxide, calcium silicate, microcrystalline cellulose, starches, mineral oil, waxes, glyceryl behenate, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, sodium laurylsulfate, sodium stearyl fumarate, and hydrogenated vegetable oils, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and the like.

As the stabilizing agent, other antioxidants can also be used in addition, which includes natural or synthetic antioxidants, for example, vitamins and their derivatives (Vitamin A, Vitamin C ₅ Vitamin E); Sesamol; Gossypol; nordihydorguaiaretic acid (NDGA); herbal antioxidants containing flavanoids (curcumin, green tea, cabbage, broccoli, cauliflower, brussel sprouts, and kale; selenium; erythorbic acid, gum guaiac; 2,4,5-trihydroxybutyrophenone, 4-hydroxymethyl-2,6-di-tert-butylphenol, thiodipropionic acid, dilauryl thiodipropionate, tertiary-butylhydroquinon (TBQH), octyl gallate, dodecyl gallate and the like.

Examples of surfactants include both non-ionic and ionic (cationic, anionic and zwitterionic) surfactants suitable for use in sweetener compositions. These include polyethoxylated fatty acids and their derivatives, for example polyethylene glycol 400 distearate, polyethylene glycol - 20 dioleate, polyethylene glycol 4 -150 mono dilaurate, polyethylene glycol -20 glyceryl stearate; alcohol - oil transesterification products, for example polyethylene glycol - 6 corn oil; polyglycerized fatty acids, for example polyglyceryl - 6 pentaoleate; propylene glycol fatty acid esters, for example propylene glycol monocaprylate; mono and diglycerides for example glyceryl ricinoleate; sterol and sterol derivatives; sorbitan fatty acid esters and its derivatives, for example polyethylene glycol - 20 sorbitan monooleate, sorbitan monolaurate; polyethylene glycol alkyl ether or phenols, for example polyethylene glycol - 20 cetyl ether, polyethylene glycol - 10 - 100 nonyl phenol; sugar esters, for example sucrose monopalmitate; polyoxyethylene - polyoxypropylene block copolymers known as "poloxamer"; ionic surfactants, for example sodium caproate, sodium glycocholate, soy lecithin, sodium stearyl fumarate, propylene glycol alginate, octyl sulfosuccinate disodium, and palmitoyl carnitine.

The coloring agents of the present invention may be selected from any FDA approved colors for oral use.

The term "solid dosage form" as used herein includes conventional solid dosage forms such as tablets, capsules, pills, granules, powders, and the like. In particular, the solid dosage form may be a tablet.

In one of the embodiments, the pharmaceutical composition may be prepared by blending tiagabine, antioxidants, diluents, binder, and a portion of a superdisintegrant/ disintegrant; wet granulating the blend with a granulating fluid or solution/dispersion of inert excipient in the granulating fluid; and drying and reducing the granules to a suitable size. Other ingredients, such as lubricants, and additional disintegrants and filler, are added to the granules and mixed. This mixture is then compressed into a suitable size and shape using conventional tableting machines such as a rotary tablet press.

In another embodiment, the pharmaceutical composition may be prepared by blending tiagabine, antioxidants, diluents, binder, and a portion of a superdisintegrant/disintegrant; dry granulating the blend by roller compaction or slugging; reducing the granules to a suitable size; blending with other ingredients, such as

lubricants,and additional disintegrants and filler; and compressing into tablets.

In another embodiment, the pharmaceutical composition may be prepared by blending tiagabine, antioxidants, diluents, binder and superdisintegrant/disintegrant; and directly compressing into tablets. In another embodiment, the pharmaceutical composition may be prepared by blending tiagabine, antioxidants, diluents, and a portion of a superdisintegrant/disintegrant; forming a wet mass using a granulating fluid or solution/dispersion of inert excipient in the granulating fluid; passing the wet mass through an extruder equipped with a screen; spheronizing the extrudate in a spheronizer; drying and sizing the spheroids; blending with inert excipient; and compressing into tablet.

The granules or blends as prepared in any of the above embodiments may also be processed into capsules.

Examples of granulating fluid include aqueous, organic solvents or mixtures thereof, such as water, methanol, ethanol, isopropanol, dichloromethane, and acetone. The stable pharmaceutical compositions of tiagabine prepared in any of the above embodiments may optionally be coated with one or more functional and/or non-functional layers comprising film-forming polymers. The coating layers over the tablet may be applied as a solution/dispersion of coating ingredients using conventional techniques known in the art, such as spray coating in a conventional coating pan or fluidized bed processor, dip coating, and the like. Alternatively, coating can also be performed using hot melt technique where possible.

Examples of film-forming polymers include cellulose derivatives such as ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, partially hydrolyzed polyvinyl alcohol, cellulose acetate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate; waxes such as polyethylene glycol; methacrylic acid polymers such as Eudragit ® RL and RS; and the like. In particular, the coating may be a non-aqueous film coat and/or a moisture barrier coat. A non-aqueous film coat comprises hydroxypropyl methylcellulose (HPMC), titanium dioxide, polyethylene glycol, talc and a suitable approved color. An aqueous moisture

barrier coat comprises partially hydrolyzed polyvinyl alcohol, titanium dioxide, talc, soya lecithin, xanthan gum, and a suitable approved color. Alternatively, commercially available coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry® may also be used for coating. In order to further illustrate the present invention and the advantages thereof, the following specific examples are given with the understanding that these examples are intended only to be illustrations without serving as a limitation on the scope of the present invention.

Procedure:

Tiagabine tablets of examples 1 to 8 were prepared as per the composition listed in Table 2, using the following steps:

1. BHA, BHT, PG were dissolved in isopropanol to form a solution.

2. The solution obtained from step 1 was added to microcrystalline cellulose in a high shear mixer with continuous stirring followed by drying at 35 to 40 ⁰ C for removal of isopropanol. The dried mixture was finally sifted through sieve BSS# 44.

3. Tiagabine hydrochloride and disodium ethylene diamaine tetra acetate were sieved through sieve BS S# 60 and mixed together with the dried mixture of step 2 for about 15 minutes to form a uniform blend.

4. To the blend of step 3, hydroxypropylcellulose (HPC), colloidal silicon dioxide, one fifth of the total quantity of mannitol (for all Examples except 5 and 7) or lactose (for Examples 5 and 7) were added and mixed for about 15 - 20 minutes.

5. The remaining amounts of diluent (lactose or mannitol) and crospovidone (for Examples 1, 2 and 7) were mixed with the blend of step 4 and sifted through sieve BSS # 44.

6. The blend of step 5 was lubricated by addition of magnesium stearate and colloidal silicon dioxide and was directly compressed into tablets using suitable size punches to obtain compressed tablets.

7. The tablets obtained from Step 6 were coated with Opadry® to obtain the corresponding weight gains (Table 2), using spray coating techniques.

Product stability data was obtained for the above formulations by storage at 40 ⁰ C and 75% relative humidity for three months. Total related substances were determined using HPLC. This product stability data is presented in Table 3.

Table 3. Stability results generated at 4O ⁰ C and 75% relative humidity over a time period of three months

* Value after 2 Months

The above data indicates that a combination of butylated hydroxy anisole (BHA), butylated hydroxy toluene (BHT), and ethylene diamine tetra acetate (EDTA) as antioxidants effectively stabilizes tiagabine tablets under various formulation conditions. Li none of the examples was there found to be an increase in the percentage (w/w) of total related substances of more than 4%.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention. For example although the tablet dosage form has been prepared, other conventional solid dosage forms like capsule can also be prepared using the similar compositions. Similarly, though a direct compression method has been used in preparing tablets of Examples 1-8, other conventional methods can also be used such as wet granulation and melt granulation, followed by compression into suitable sized tablets.