FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)

TITLE OF THE INVENTION "ENTERIC COATED COMPOSITION OF TOPIRAMATE"
We, BA RESEARCH INDIA LIMITED, of BA Research House, Opposite "Pushparaj Towers", Nr. Judges Bungalows, Bodakdev, Ahmedabad-380-054, Gujarat, India.
The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF INVENTION
The present invention relates to a pharmaceutical imposition for oral administration and in particular to an enteric coated composition of Topiramate in the form of coated granules and/or pellets. BACKGROUND OF THE INVENTION
Topiramate is a sulfamate substituted monosaccharide sold under the trade name TOPAMAX(R) in the USA (Ortho-McNeil Pharmaceutical, Inc). It is approved for use as an antiepileptic agent, as an adjuvant therapy for patients with partial onset seizures or primary generalized tonic-clonic seizures, and for the prevention of migraine.
For the treatment of epilepsy, the recommended dose of Topamax(R) is 400 mg/day in one or more doses. For the treatment of epilepsy in adults; treatment is initiated with a dose of 25-50 mg/day, with the dose titrated in increments of 25-50 nig at weekly intervals to the recommended or effective dose. Topamax(R) is an immediate release formulation.
Adverse effects associated with the administration of Topamax(R) include, but are not limited to. somnolence, dizziness, ataxia, speech disorders and related speech problems, psychomotor slowing, abnormal vision, difficulty with memory paresthesia, diplopia, renal calculi (kidney stones), hepatic failure, pancreatitis, renal tubular acidosis, acute myopia and secondary angle closure glaucoma.
Topiramate is a white crystalline powder that is soluble in alkaline solutions containing sodium hydroxide or sodium phosphate, soluble in acetone, dimethylsulfoxide and ethanol. However, the solubility of topiramate in water at room temperature is only about 9.8 mg/ml.
Topiramate has been investigated for use as an anti-obesity agent, a blood pressure lowering agent, and a mood stabilizer, including use as an antimanic, antidepressant, and for the treatment of post-traumatic stress disorder, migraines (Rev Neurol. 2006 Aug 16-31;43(4):193-6), cluster headaches, and neuropathic pain. See. e.g.. U.S. Pat Nos. 6,191.1 17; 6,201,010; 5,753,693; 5,998,380; 6,319,903; 5,935,933; and 5,760,007. However, the time it takes for topiramate to reach peak plasma levels (i.e., about two hours) may be too slow for its effective use in the treatment of some conditions, such as neuropathic pain or migraine. We herein disclose a new enteric coated formulation of Tobiramate. EMBODIMENTS OF THE PRESENT INVENTION:
The present invention provides novel enteric compositions suitable for oral administration comprising: (a) a core comprising Topiramateor its pharmaceutically acceptable derivative thereof. The said core comprised of pharmaceutically inert nuclei and the Topiramateor its salts mixed and compressed together, (b) an intermediate layer, and (c)

an enteric layer; such that the said composition is substantially free of any alkaline reacting compounds.
Accordingly, it is an object of the present invention to provide a pharmaceutical composition and a process of manufacturing the same for the delayed release of antidepressant Topiramateor its pharmaceuticaiiy acceptable derivative thereof.
Another object of the present invention is an enteric released solid pharmaceutical composition adapted for oral administration.
Yet another In yet embodiment is provided an enteric Topiramatecomposition in a core formed by nuclei coated with an intermediate layer followed by an enteric layer. DETAILED DESCRIPTION
The present invention provides novel enteric compositions suitable for oral administration comprising: (a) a core comprising therapeutically effective amount of Topiramate or its salts, the said core comprised of pharmaceuticaiiy inert nuclei and the
Topiramate or its salts mixed and compressed together, (b) an intermediate layer, and (c) an enteric layer; such that the Topiramate used is substantially free of any alkaline reacting compound.
The term composition includes but not limited to solutions and/or suspensions, dispersions, concentrates, ready mix, powders, granules, tablets, micro-tablets, capsules, pellets, comprising Topiramate in a core constituted by nuclei and coated with intermediate layer/s followed by enteric layer.
The term "therapeutically effective amount" means an amount of the drug which is capable of eliciting a physiological response in a human patient.
The said medicament according to the present invention comprises a formulation substantially as herein described, and in particular a capsule or a tablet or micro-tablets or granules or pellets filled in capsule formulaton. typically an enteric or delayed release capsule formulation substantially as hereinafter further described.
Suitably a formulation according to the present invention provides a novel enteric dosage form, preferably capsules or micro-tablets in capsule form comprising core comprising pharmaceuticaiiy inert nuclei which is comprised of Topiramate or its pharmaceuticaiiy acceptable derivative thereof and optionally one or more suitable excipients and the said core coated with intermediate layer/s followed by enteric layer and the process for preparing the same.
In a preferred embodiment of the present invention, the pharmaceuticaiiy inert nuclei, as the name may suggest, is composed of a substance or a mixture of such substances that are pharmaceuticaiiy inert and preferably do not interfere with the biological action of the

Topiramate or its salts. Preferable examples of such substances include lactose, dextrose, saccharose, starch and other sugars. A wide variety of other substances can also be used in developing the inert nuclei.
The said core is comprised of pharmaceutically inert nuclei and Topiramate or its salts mixed and compressed together. The mixing here may be purely physical mixing, deposition, coating, adsorption, aggregation or adhesion and alike. Such a mixing of the said pharmaceutically inert nuclei and Topiramate may be achieved in several different ways, including those already documented in the prior art. According to one of the embodiment of the invention, such a mixing is achieved by granulation, and preferably through fluidized bed granulation. Such processes results in formation of granules comprising pharmaceutically inert nuclei and Topiramate , which are then compressed together.
In another embodiment of the invention, the said core may be prepared by contacting pharmaceutically inert nuclei with a medium containing Topiramate , drying the product and subjecting the product to compression. Yet another way of preparing the said core could be by coating of the pharmaceutically inert nuclei with Topiramate using one of the coating techniques generally known.
The present invention provides a process for the manufacture of a pharmaceutical product. The process comprises core comprised of Topiramate with pharmaceutically inert substance (nuclei) and the said core coated with intermediate layer/s followed by coating with enteric polymer/s. The said core is prepared by mixing of Topiramate with pharmaceutically inert nuclei and optionally mixed with other suitable pharmaceutical excipients. The said core is then coated with intermediate layer/s followed by enteric layer.
Hence, in a preferred embodiment of the present invention, the novel enteric
compositions of the present invention comprise at least one intermediate layer that separates
the core comprising Topiramate and the enteric layer. The intermediate layer is preferably
composed of a substance (or a mixture of such substances) that do not react or affect the
stability of the core comprising Topiramate. Typical examples of such substances that can be
used in the intermediate layer include organic or inorganic polymers, sugars and alike. In one
embodiment of the invention, the intermediate layer comprises at least one substance selected
from a group comprising of silicon dioxide, titanium dioxide, silica, talc, microcrystalline
cellule, sodium lauryi sulphate, sodium steryl fumarate, polyethylene glycol,
polyvinylpyrrolidinone, polyvinyl alcohol, hydroxypropylcellulose and
hydroxymethylcellulose. It is an advantageous feature of this invention that the intermediate layer may also contain other pharmaceutically acceptable excipient if desired. The


intermediate layer may be applied to the core using any known technique. These techniques include with any limitation for example powder coating, spraying, pan coating and alike.
In one embodiment of the invention, the enteric layer is comprised of a material that is stable In acidic medium of the stomach and thereby avoids the direct interaction between the acid medium and the contents of the composition. It is preferable that the enteric coat comprises at least one enteric polymer. Preferable examples of such enteric polymers without any limitation include, polyvinyl acetyl phthalate (PVAP) and derivatives thereof, vinyl copolymers, hydroxypropylmethyl cellulose (HPMC), methacrylate copolymers and acrylic acid polymers and derivatives thereof and alike. Several other commercially available enteric polymers can also be used as enteric coat if desired which include without any limitation Eudragit (Rohm Pharma), Aquateric (FMC Corporation), and alike. It is an advantageous feature of the invention that the enteric layer may also contain other pharmaceutical!}' acceptable excipient such as talc, pigments, colouring agents, flavouring agents, stabilizers, binders, lubricants and alike if desired. The enteric layer may be applied using known techniques including for example those described for intermediate layer.
The novel compositions according to the present invention may optionally contain other pharmaceutical^ acceptable excipient such as diluents, binders, plastifiers, fillers, surfactants, pigments, stabilizers, disintegrating agents, lubricants, wetting agents, colouring agents, flavouring agents and alike.
The novel compositions of the present invention can be provided in several forms that are suitable for oral administration. In one preferred embodiment, the composition according to the present invention is provided in a tablet form. In another preferred embodiment, such composition is in the form of micro-tablets in capsule e.g. a gelatine capsule.
The novel enteric compositions according to the present invention generally comprise a core representing about 5 to about 98% by weight based on the total weight of the composition, rest being accounted by an intermediate and the enteric layer.
The present invention further comprises a process of preparing a pharmaceutical product, or a pharmaceutical formulation, or a medicament substantially as hereinbefore described. Suitably such a process comprises providing at least one anti-ulcerant such as Topiramate in a core constituted by mixing Topiramate with a pharmaceutically inert nuclei optionally with other suitable pharmaceutical excipients and granulated optionally and the said core is further coated with one or more non-acid inert pharmaceutical excipients as "intermediate layer/s" followed by coating with at least one enteric polymer. The said process yields a novel enteric pharmaceutical formulation, typically in micro-tablets or tablets or granules/pellets in capsules (to be filled in capsules) form.


The present invention will now be further illustrated with reference to the following examples, which does not limit the scope of the invention in any way. Further different strengths of the formulation may be achieved by proportionately using a dose weight scale up or scale down formula. The concentration of the excipients may also be varied or modified to achieve the desired dissolution profile by a skilled artisan. EXAMPLES Example 1
An enteric-composition of Topiramate (25 mg tablet) according to present invention
was prepared as follows.
25 mg Topiramate tablet
Ingredient Amount (mg/tablet)
Core
Topiramate 25
HPMC 14
Lactose 205
Hydrogenated castor oil 2.6
Crospovidone 12
Water qs
Intermediate layer
Talc 6
Titanium dioxide 2.6
HPMC 1.2
Enteric layer
Methacrylic acid copolymer 22
Triethylcitrate 3.5
Talc 4.0
Water qs
Procedure:
Appropriate quantity of Hydroxypropylmethyl cellulose (HPMC) and Topiramate were dissolved in water and the contents w;ere homogenized. The homogenized suspension was then slowly sprayed onto a lactose nuclei in a fluidised bed granulator. After all the suspension was sprayed, the nuclei were dried and mixed with hydrogenated castor oil and crospovidone. The mixed contents are then made into granules. These were then coated with


an intermediate layer having composition as mentioned above. Typically, the intermediate layer was prepared by dissolving HPMC in water followed by addition of talc and titanium dioxide. The resulting contents after homogenisation were sprayed onto the granules above using a suitable coating device. Finally, these coated intermediate layer were coated with the enteric layer having composition as mentioned above. The enteric layer was prepared by mixing aqueous solutions of triethyl citrate, methacrylic acid copolymer (Eudragit) and talc and sprayed on the granules already coated with intermediate layer. These granules were either filled in gelatin capsules or compressed into tablets. Examples 2
An enteric-coated tablet comprising Topiramate (50 mg tablet) according to present
invention was prepared as follows.
Ingredient Amount (mg/tablet)
Core
Topiramate 50
HPMC 90
Lactose 525
Polyethylene glycol 6000 9.5
Polysorbate-80 2.3
Crospovidone 101
Water qs
Intermediate layer
Talc 21.5
Titanium dioxide 9.1
HPMC 35
Water qs
Enteric layer
CAP 54
Triethylcitrate 12.8
Talc 18.0
Water qs


Procedure: Similar as described in Example-1
In another set of examples, the compositions described in Examples 1 and 2 were compressed into conventional tablets and then coated with the respective intermediate and enteric layers Pharmacokinetic study:
In vivo dissolution differences between said between the aforesaid two preparations were demonstrated in a single dose, crossover, randomized comparative pharmacokinetic study performed in 27 healthy volunteers. // was found that
55 % subjects achieved Tmax earlier in test product compare to reference product ; 46 % of subjects have higher Cmax compare to ref product
Thus, it was found that among the test population, 35 % of subjects had earlier Tmax and higher Cmax in test product compare to reference product thereby demonstrating that the absorption rate of the present formulation has significantly improved over the test product.
While the invention has been described by way of examples and in terms of the preferred embodiments, it is to be understood that the invention is not limited to the disclosed embodiments. On the contrary, it is intended to cover various modifications as would be apparent to those skilled in the art. Therefore, the scope of the appended claims should be accorded the broadest interpretation so as to encompass all such modifications.


We claim
1. An oral pharmaceutical composition comprising: (a) a core comprising Topiramate, the said core comprised of pharmaceutical]}' inert nuclei and Topiramate mixed together, (b) an intermediate layer comprising one or more polymers and (c) an enteric layer comprising one or more enteric polymers; wherein the said composition is free of alkaline reacting compounds.
2. A pharmaceutical composition as claimed in claim 1, wherein the said core comprises of Topiramate and pharmaceutically inert nuclei are mixed together.
3. A pharmaceutical composition as claimed in claim 1 or 2, wherein the said pharmaceutically inert nuclei comprises at least one pharmaceutically acceptable excipient.
4. A pharmaceutical composition as claimed in claim any one of claims 1 to 3 wherein the said pharmaceutically inert nuclei is selected from a group comprising lactose, dextrose, saccharose, starch or their mixtures.
5. A pharmaceutical composition as claimed in claim 1, wherein the formulation is an oral solid dosage form.
6. A pharmaceutical composition as claimed in claim 5, wherein the formulation is tablet
7. The pharmaceutical formulation as claimed in claim 1, wherein the tablets comprises enteric released Topiramate with pharmaceutically inert nuclei mixed together and coated with intermediate layer followed by coating with enteric layer.
8. The pharmaceutical formulation as claimed in claim 1, wherein the formulation is manufactured comprising the steps of: (i) mixing pharmaceutically inert nuclei with Topiramate; (ii) optionally, granulating the product of step (i) to form a core comprising Topiramate (iii) coating the said core with an intermediate layer comprising at least one polymer followed by (iv) coating with one or more enteric polymers. And subsequently converting into tablets.
9. The pharmaceutical formulation as claimed in claim 1, wherein the core is manufactured by spraying a solution of Topiramate onto pharmaceutically inert nuclei, drying the resultant product and granulating the dried product to form the core comprising Topiramate.
10. The pharmaceutical formulation as claimed in claim 1, wherein at least one pharmaceutically acceptable lubricant is present additionally with the said pharmaceutically inert nuclei and Topiramate.
11. The pharmaceutical formulation as claimed in claim 10. wherein the said lubricant is selected from the group comprising light mineral oil, polyethylene glycol and derivatives

thereof, glyceryl behenate. hydrogenated vegetable oil, sodium steryl fumarate calcium silicate and the like.
12. The pharmaceutical formulation as claimed in claim 1, wherein the said intermediate layer comprises at least one material selected from a group comprising of silicon dioxide, titanium dioxide, talc, sugar and derivatives thereof, polyethylene glycol and derivatives thereof, polyvinylpyrrolidone, polyvinyl alcohol and derivatives thereof, hydroxypropylceliulose, hydroxymethylcellulose. sodium lauryl sulphate, microcrystalline cellulose, colloidal silica, sodium steryl fumarate, starch and derivatives thereof and the like.
13. The pharmaceutical formulation as claimed in claim 1, wherein the said intermediate layer contains silicon dioxide.
14. The pharmaceutical formulation as claimed in claim 1, wherein the said intermediate layer contains at least one organic or inorganic polymer or a mixture thereof
15. The pharmaceutical formulation as claimed in claim 1, wherein the said enteric layer contains at least one polymer.
16. The pharmaceutical formulation as claimed in any preceding claims, wherein the said enteric layer contains at least one polymer selected from a group comprising of cellulose acetate phthalate (CAP), polyvinyl acetyl phthalate (PVAP), vinyl copolymers, acrylic acid and copolymers and derivatives thereof.
17. A process for manufacture as claimed in enteric released tablet of Topiramate, the process comprises the steps of: (a) spraying a medium containing Topiramate onto the pharmaceutically inert nuclei in a fluidised bed processor followed by drying the resultant product and lubricating the same using suitable lubricant (b) granulating the product of step (a) to form a core containing Topiramate (c) coating the said core with an intermediate layer comprising at least one polymer (d) coating the resultant product of step (c) with an enteric layer and subsequently pressing into tablets.
18. A process as described in claim 17 wherein the individual ingredients are as described
hereinbefore including those disclosed in the specification.
Dated this the 4th day of April 2009
H. SUBRAMANIAM
Of Subramaniam Nataraj & Associates Attorneys for the Applicants