Technical field of invention
The technical field of the present invention relates to a stabilized tiagabine composition comprising a stabilizing amount of a combination of antioxidants; and process of preparing solid dosage forms thereof.
Background of the invention
Tiagabine is a well-tolerated medication, having antiepileptic activity. Chemically tiagabine is (-)-(R)-1-[4,4-bis (3-methyl-2-thienyl)-3- butenyl] nipecotic acid hydrochloride, which is being disclosed in US Pat. No. 5,010,090. Further, US Pat. Nos. 5,354,760 and 5,958,951 disclose monohydrate and anhydrous forms of tiagabine hydrochloride, respectively. It is being commercially marketed by Novo Nordisk under the trade name "GABITRIL®". It is available as film coated tablets in strengths of 2 mg, 4 mg, 12 mg, 16 mg, and 20 mg. 20 mg tablets have now been discontinued.
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 begin 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 prevents 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 in fact been found that it gets decomposed in the presence of, and in contact with oxygen and water. One of the major cause of its chemical instability is oxidative degradation during storage. Further, it may also undergo decomposition on exposure to light and heat. Low stability of tiagabine often poses problems associated with shelf life of its various dosage forms.
Till date various approaches have been undertaken worldwide, to achieve sufficient stability of tiagabine hydrochloride neccesary to prepare dosage forms of reasonably acceptable shelf lives. For example, US 5,866,590 discloses a new 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, using a particular combination of antioxidants. The shelf lives of pharmaceutical compositions are thereby extended to reasonably acceptable periods.
Summary of the Invention
In one of the aspect it provides, a stable pharmaceutical composition of tiagabine comprising:
(a) tiagabine;
(b) Butylated Hydroxy Anisole (BHA), Butylated Hydroxy Toluene (BHT), and Ethylene diamine tetracetate (EDTA) as antioxidants; and
(c) one or more pharmaceuticaiy acceptable excipient.
In another aspect it provides, a stable pharmaceutical composition of tiagabine comprising:
(a) tiagabine;
(b) BHA, BHT, and EDTA as antioxidants in a weight ratio of from about 7:1:10 to about 15:1:5; and
(c) one or more pharmaceutically acceptable excipient.
In another aspect it provides, a stable pharmaceutical composition of tiagabine comprising:
(a) tiagabine;
(b) BHA, BHT, and EDTA as antioxidants in a weight ratio is 10: 1: 7.5; and
(c) one or more pharmaceutically acceptable excipient.
In another aspect it provides, a stable pharmaceutical composition of tiagabine comprising:
(a) tiagabine;
(b) BHA), BHT, EDTA and PG as antioxidants; and
(c) one or more pharmaceutically acceptable excipient.
In another aspect there is provided, a process for the preparation of a stable pharmaceutical composition of tiagabine comprising the steps of:
(a) blending tiagabine, antioxidants and one or more pharmaceutical^ inert excipients;
(b) optionally granulating the blend; and
(c) processing into a solid dosage form,
wherein the antioxidants is a mixture of BHA, BHT, and EDTA.
In another general aspect there is provided, a method of treating partial seizures in mammals in need of treatment, by administering a stable pharmaceutical composition of tiagabine comprising:
(a) tiagabine;
(b) BHA, BHT, and EDTA as antioxidants; and
(c) one or more pharmaceutically acceptable excipients.
In one another aspect there is provided, a stable pharmaceutical composition of tiagabine comprising:
(a) tiagabine;
(b) additional drug;
(c) BHA, BHT, and EDTA as antioxidants; and
(d) one or more pharmaceutically acceptable excipients.
The additional drug may include enzyme inducing anticonvulsants such as barbiturates, carbamazepine, phenytoin, etc.; or non- enzyme inducing anticonvulsants such as gabapentin, lamotrigine, valproate, etc.
The details of one or more embodiments are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description and claims.
Detailed Description of the Invention
The present invention is not limited to particular process steps and materials disclosed herein, but is extended to equivalents thereof as would be recognized by those ordinarily skilled in the relevant arts. It should also be understood that terminology employed herein is used for the purpose of describing particular embodiments only and is not intended to be limiting.
As used herin, the term "BHA" refers to butylated hydroxyanisole. The term "BHT" refers to butylated hydroxytoluene. The term "EDTA" refers to ethylenediamine tetra acetic acid. The term "PG" refers to propyl gallate. The term "HPMC" refers to hydroxyl propyl methylcellulose. The term "HPC" refers to hydroxy propyl cellulose. The term "IPA" refers to isopropyl alcohol.
In the present invention, we have discovered that use of a combination of BHA, BHT and EDTA surprisingly increases the stability of tiagabine in pharmaceutical compositions and provides reasonably long shelf lives.
Conventionally, BHA, BHT and EDTA are used as antioxidants. 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 have also not given satisfactory results. However, to our surprise the 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 prefomulation stability data obtained with various antioxidants by forced degradation (Table 1) at room temperature (RT) and at 50°C for over a time period of 24 hours. The studies were carried out as follows:
In the alcoholic solution of Tiagabine hydrochloride with concentration 500 ng/ml and in presence of 1% Hydrogen peroxide, following antioxidants and their combinations were evaluated with respect to total related substances (RS) at 0 and 24 hour at room temperature (RT) & at 50°C .against the control i.e. without any antioxidant. The concentrations of antioxidants selected were based on their respective IIG limit. Antioxidants were used as either water or IPA solution depending on their solubility.
Table 1: Evaluation of Antioxidants by Forced Degradation Study:

(Table Removed)
The study clearly indicates the importance of the use of a combination of BHT, BHA and EDTA as antioxidants in stabilizing tiagabine pharmaceutical compositions.
Present invention is further evident from the stability results of the pharmaceutical compositions prepared as per the Examples l-VIII (Table 2), generated at 40°C and 75% relative humidity over a time period of three months, (Table 3).
The term "stable pharmaceutical composition" as used herein refers to chemical stability of tiagabine 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°C and 75±5% relative humidity over a period of 3 months.
The term 'tiagabine' as used herein includes free tiagabine base and its pharmaceutically acceptable acid addition salts, hydrates or mixtures thereof. In particular, anhydrous tiagabine hydrochloride is used. Tiagabine constitutes from about 1% to about 20% of the total composition by weight. In particular, it may constitute from about 4% to about 10% based on the weight of the total composition.
Antioxidants are the 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, EDTA are synthetic antioxidants, used widely in food and drug industry.
Butylated hydroxy toluene and Butylated hydroxy anisole are 'sterically hindered phenolic antioxidants'. 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, (1,1-dimethylethyl)-4-methoxyphenol, tert-butyl-4-methoxyphenol, antioxyne B. BHT is a 2,6-bis (1,1-dimethylethyl)-4- methylphenol. Both BHT and BHA are synthetic antioxidants and are widely used as food additives. 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 tetra acetic acid and derivatives and salts thereof. They forms a complex or coordination compounds with trace metal ions present in free form or salts of fatty acids, thereby inactivating them. They have add-on
effect when used synergistically with the BHT and BHA. Particularly, disodium salt of EDTA has been used in the present invention.
Antioxidants are usually 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. In the present invention, BHA: BHT: EDTA may be present in a ratio from about 7: 1: 10 to about 15: 1: 5 and particularly 10:1:7.5.
In addition to above another antioxidant may also be included such as propyl gallate (PG), which is a naturally derived antioxidant from natural gallic acid, 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" as used herein includes all physiologically inert excipients used in the art for preparation of pharmaceutical compositions. Examples include binders, diluents, fillers, glidants/ lubricants disintegrants/ superdisintegrants, stabilizing agents, surfactants, colors, and the like.
Examples of 'Binders' include methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, and the like.
Examples of 'Fillers' include 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, and sugar confectioners. In particular, microcrystalline cellulose may be used.
Examples of 'Diluents' include cellulose powdered, microcrystalline cellulose, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners and mixtures thereof.
Examples 'Disintegrants/ Superdisintegrants' include 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. Superdisntegrants aids in quick disintegration of the pharmaceutical composition.
Examples of 'Lubricants' or 'Glidants' include 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 Stabilizing agents' other antioxidants can also be used in addition, which includes natural or synthetic antioxidants, for example Vitamins and their derivatives (Vitamin A, Vitamin C, Vitamin E); Sesamol; Gossypol; nordihydorguaiaretic acid (NDGA); herbal antioxidants containing flavanoids (curcumin, green tea, cabbage, broccoli, cauliflower, brussels 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, including pharmaceutically acceptable salts and esters of these compounds.
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 its 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 include 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 is tablet.
In one of the embodiments, the pharmaceutical composition may be prepared by a process comprising the steps of 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; followed by 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 tabletting machines such as a rotary tablet press.
In another embodiment, the pharmaceutical composition may be prepared by a process comprising the steps of 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 directly compressing into tablet.
In another embodiment, the pharmaceutical composition may be prepared by a process comprising the steps of blending tiagabine, antioxidants, diluents, binder and
superdisintegrant/ disintegrant; and directly compressing into tablet.
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 directly 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 includes aqueous, organic solvents or mixtures thereof, such as water, methanol, ethanol, IPA, dichloromethane or acetone etc.
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, by techniques well known in the art such as spray coating in a conventional coating pan or fluidized bed processor; or dip coating. Alternatively, coating can also be performed using hot melt technique whenever 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, coating may be a Non-aqueous film coat and/ or a moisture barrier coat. Nonaqueous film coat comprises hydroxy propyl methylcellulose (HPMC), titanium dioxide, polyethylene glycol, talc and a suitable approved color. Aqueous moisture barrier coat comprises partially hydrolysed 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.
Table 2:The stable pharmaceutical compositions of tiagabine, Example l-VIII:
(Table Removed)
Procedure:
Tiagabine tablets of examples I to VIII were prepared as per the composition listed in Table 2, using the following steps:
1. Butylated hydroxy anisole (BHA), Butylated hydroxy toluene (BHT), Propyl gallate (PG) were dissolved in Isopropyl alcohol (IPA) 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°C for removal of IPA. The dried mixture was finally sifted through sieve BSS#44.
3. Tiagabine hydrochloride and Disodium EDTA were sieved through sieve BSS# 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, hydroxy propyl cellulose (HPC), colloidal silicon dioxide, one fifth of the total quantity of mannitol (for all Examples except V and VII) or lactose (for Example V and VII) were added and mixed for about 15- 20 minutes.
5. The remaining amount of diluent (lactose or mannitol) and crospovidone (for example I, II and VII) was 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 as obtained from Step 6, were coated with Opadry® to obtain the
corresponding weight gains (Table 2), using spray coating techniques.
The tablets prepared above were subjected to stability studies at 40°C and 75% relative humidity for 3 months. The results of the studies are incorporated herein for reference as Table 3.
Table-3: Stability results generated at 40°C and 75% relative humidity over a time period of three months:

(Table Removed)
* Value after 2 Months
As evident from the above studies, the tablets thus prepared by the process of the present invention had improved shelf stability. BHA, BHT, EDTA when used in combination work together synergistically far more effectively than a single antioxidant.
Particular formulations have been described above, it will be apparent that various modifications and combinations of the formulations detailed in the text can be made without departing from the spirit and scope of the 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 Example l-VIII, other conventional methods can also be used such as wet granulation and melt granulation, followed by compression into suitable sized tablets.

WE CLAIM:
1. A stable pharmaceutical composition of tiagabine comprising:
(a) tiagabine;
(b) Butylated Hydroxy Anisole (BHA), Butylated Hydroxy Toluene (BHT), and Ethylene diamine tetra acetate (EDTA) as antioxidants; and
(c) one or more pharmaceutically acceptable excipient.

2. The pharmaceutical composition according to claim 1, wherein the ratio of BHA, BHT, and EDTA may vary from about 7:1:10 to about 15:1:5.
3. The pharmaceutical composition according to claim 2, wherein the ratio of BHA, BHT, and EDTAis 10:1:7.5.
4. The pharmaceutical composition according to claim 1, wherein the composition may
further comprises propyl gallate (PG).
5. The pharmaceutical composition according to claim 1, wherein tiagabine is selected from amongst free tiagabine base, and its pharmaceutically acceptable acid addition salts, hydrates or mixtures.
6. The pharmaceutical composition according to claim 5, wherein the pharmaceutically acceptable acid addition salt of tiagabine is tiagabine hydrochloride.
7. The pharmaceutical composition according to claim 1, wherein pharmaceutically acceptable excipients are selected from amongst binders, diluents, fillers, glidants/ lubricants, disintegrants/ superdisintegrants, stabilizing agents, surfactants, and colors.
8. The pharmaceutical composition according to claim 1, wherein the composition further comprises additional drug.
9. The pharmaceutical composition according to claim 8, wherein the additional drug is
enzyme inducing anticonvulsant' such as barbiturates, carbamazepine, phenytoin or is
non- enzyme inducing anticonvulsants such as gabapentin, lamotrigine, valproate etc.
10. The pharmaceutical composition according to claim 1, wherein the composition may be coated with one or more functional and/or non-functional layers comprising film-forming polymers.
11. The pharmaceutical composition according to claim 10, wherein the coating may be a non-aqueous film coat and/ or a moisture barrier coat.
12. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is a solid dosage form is selected from amongst tablet, capsule, pill, granule and powder.
13. A process for preparing a stable pharmaceutical composition of tiagabine comprising the steps of:

(a) blending tiagabine, antioxidants and one or more pharmaceutically inert excipients;
(b) optionally granulating the blend; and
(c) processing into a solid dosage form,
wherein the antioxidants is a mixtures of Butylated Hydroxy Anisole (BHA), Butylated Hydroxy Toluene (BHT), and Ethylene diamine tetractate (EDTA).
14. The process according to claim 13, wherein the blend of step (a) is granulated.
15. The process according to claim 14, wherein the blend is granulated using a wet granulation process.
16. The process according to claim 14, wherein the blend is granulated using a dry
granulation process.
17. The process according to claim 13, wherein the solid dosage form is selected from amongst tablet, capsule, pill, granule and powder.
18. A method of treating partial seizures in mammals in need of such treatment, comprising administering to said mammal a stable pharmaceutical composition of tiagabine according to claim 1.
19. A stable pharmaceutical composition of tiagabine and a process of its preparation as described and illustrated in the examples herein.