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 PANTOPRAZOLE"
We, BA RESEARCH INDIA LIMITED, of BA Research House, Opposite "Pushparaj Towers", Nr. Judges Bungalows, Bodakdev, Ahmedabad - 380054, Gujarat, India;
The following specification particularly describes the nature of the invention and the manner in which it is to be performed.

BA_formul_006_compl
FIELD OF INVENTION
The present invention relates to a pharmaceutical composition for oral administration and in particular to an enteric coated composition of Pantoprazole in the form of coated granules and/or pellets.
BACKGROUND OF THE INVENTION
Pantoprazole (5-(difluorornethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]
sulfamyl-lH-benzimidazole) is a benzimidazole compound that inhibits gastric acid secretion. Pantoprazole sodium sesquihydrate has been approved by the FDA for parenteral administration under the name Protonix 1V(R) and for oral administration under the name Protonix(R), for short-term treatment of erosive esophagitis associated with gastroesophageal reflux disease (GERD), for maintenance of healing of erosive esophagitis and for the treatment of pathological hypersecretory conditions, including, for example, Zollinger-Ellison syndrome.
The pharmaceutically active ingredient Pantoprazole is disclosed U.S. Patent No. 4,758,579 (equivalent to EP 0 166 287), which characterizes Pantoprazole only by its melting point.
Protonix is marketed in the form of a delayed release tablet, which is resistant to gastric juice, and consists of: (i) a core, (ii) an outer layer resistant to gastric juice layer and (iii) an inert intermediate layer between the core and outer layer, which are not compatible with one another, in order to protect the active ingredient from the outer layer. U.S Patent No. 5,997,903 (equivalent to EP 589 981 B) discloses an orally administrable medicament in pellet or tablet form that is resistant to gastric juice which consists of(i) a core of active compound (or its physiologically-tolerated salt) admixed with binder, a filler and, optionally, another tablet auxiliary or basic physiologically-tolerated inorganic compound, (ii) an inert water-soluble intermediate layer surrounding the core and (iii) an outer layer which is resistant to gastric juice. The active compound is Pantoprazole, the binder is polyvinylpyrrolidone and/or hydroxypropyirnethylcellulose and, optionally, the filler is mannitol.
Thus, according to U.S Patent No. 5,997,903, oral pharmaceutical compositions of pantoprazole are described that do not create problems of stability of the active ingredient by using a selected binder and filler in the core. The binder materials described


BAformul _006_compl
therein are polyvinyl pyrrolidone and/or hydroxypropylmethyl cellulose and are combined with mannitol as the inert filler to minimize instability of the active ingredient. According to U.S Patent No. 5,997,903, therefore, mannitol cannot be used as the sole or only filler for Pantoprazole tablets absent the inclusion of a suitable binder capable of imparting an adequate hardness to the core.
Furthermore, commercially-marketed Protonix tablets contain sodium carbonate in the core as a basic physiologically-tolerated inorganic compound. The use of a carbonate salt can cause handling difficulties during processing because part of the carbonate salt can be hydrolyzed by water or moisture to produce effervescence. Additionally, uniform distribution of the carbonate salt in the tablets is not consistently assured.
We herein describe an enteric coated formulation of Pantoprazole which uses readily available material, cheap and commercially viable.
EMBODIMENTS OF THE PRESENT INVENTION:
The present invention provides novel enteric compositions suitable for oral administration comprising: (a) a core comprising Pantoprazole or its pharmaceutically acceptable derivative thereof. The said core comprised of pharmaceutically inert nuclei and the Pantoprazole or 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 Pantoprazole or its pharmaceutically acceptable derivative thereof.
Another object of the present invention is an enteric released solid pharmaceutical composition adapted for oral administration.
In yet embodiment is provided an enteric Pantoprazole composition 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 Pantoprazole or its salts, the said core comprised of pharmaceutically inert nuclei and the


BA_formul_006_compl
Pantoprazole or its salts mixed and compressed together, (b) an intermediate layer, and (c) an enteric layer; such that the Pantoprazole 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 Pantoprazole 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 pharmaceutically inert nuclei which is comprised of Pantoprazole or its pharmaceutically 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 pharmaceutically inert nuclei, as the name may suggest, is composed of a substance or a mixture of such substances that are pharmaceutically inert and preferably do not interfere with the biological action of the Pantoprazole 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 Pantoprazole 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 Pantoprazole 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


BA_formul_006_compl
through fluidized bed granulation. Such processes results in formation of granules comprising pharmaceutical^ inert nuclei and Pantoprazole, 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 Pantoprazole, 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 Pantoprazole 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 Pantoprazole 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 Pantoprazole 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 Pantoprazole 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 Pantoprazole. 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 lauryl 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.


BA_formul_006_compl
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 ly 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 pharmaceutically 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 Pantoprazole in a core constituted by mixing Pantoprazole with a pharmaceutically inert nuclei optionally with other suitable pharmaceutical excipients and granulated optionally


BA formul_006_compl
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 Pantoprazole (equivalent to 20 mg tablet) according to
present invention was prepared as follows.
20 mg Pantoprazole tablet
Ingredient Amount (mg/tablet)
Core
Pantoprazole (EQ base) 22.55
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


BA_formul_006_compl
Procedure:
Appropriate quantity of Hydroxypropylmethyl cellulose (HPMC) and Pantoprazole sodium were dissolved in water and the contents were 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 Pantoprazole (equivalent to 40 mg tablet) according to present invention was prepared as follows.

Ingredient Amount (mg/tablet)
Core
45.1

Pantoprazole (EQ base)
HPMCLactosePolyethylene glycol 6000Polysorbate-80CrospovidoneWater 905259.52.3101qs
Intermediate layer Talc 21.5
Titanium dioxide 9.1
HPMC 35
Water qs


BA_formul_006_compl
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 & 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. It was found that
- 54 % subjects achieved Tmax earlier in test product compare to reference product; 50 % of subjects have higher Cmax compare to ref product
Thus, it was found that among the test population, 31 % 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.


BA formul 006 compl
We claim
1. An oral pharmaceutical composition comprising: (a) a core comprising Pantoprazole or its salts and the said core comprised of pharmaceutically inert nuclei and Pantoprazole or its salts 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 Pantoprazole or its salts 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 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 any preceding claim 1, wherein the formulation is an oral solid dosage form
6. A pharmaceutical composition as claimed in claim 5, wherein the formulation is in the form of a tablet
7. The pharmaceutical composition as claimed in claim 5, wherein the tablets comprises enteric released Pantoprazole or its salts with pharmaceutically inert nuclei mixed together and coated with intermediate layer followed by coating with enteric layer.
8. The pharmaceutical composition as claimed in any preceding claim, wherein at least one pharmaceutically acceptable lubricant is present additionally with the said pharmaceutically inert nuclei and Pantoprazole or its salts.
9. The pharmaceutical composition as claimed in claim 10, wherein the said lubricant is selected from the group comprising light mineral oil, polyethylene glycol and


BA_formul_006_compl
derivatives thereof, glyceryl behenate, hydrogenated vegetable oil, sodium steryl fumarate calcium silicate and the like.
10. The pharmaceutical composition as claimed in any preceding claim 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, hydroxypropylcellulose, hydroxymethylcellulose, sodium lauryl sulphate, microcrystalline cellulose, colloidal silica, sodium steryl fumarate, starch and derivatives thereof and the like.
11. The pharmaceutical composition as claimed in claim 1, wherein the said intermediate layer contains at least one organic or inorganic polymer or a mixture thereof
12. The pharmaceutical composition as claimed claim 1, wherein the said enteric layer contains at least one polymer.
13. The pharmaceutical composition as claimed 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.
14. A process for the manufacture of pharmaceutical composition as claimed in any preceding claim which comprises the steps of: (i) mixing pharmaceutically inert nuclei with Pantoprazole or its salts; (ii) optionally, granulating the product of step (i) to form a core comprising Pantoprazole (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.
15. The process as claimed in claim 14 wherein the core is manufactured by spraying a solution of Pantoprazole or its salts onto pharmaceutically inert nuclei, drying the resultant product and granulating the dried product to form the core comprising Pantoprazole.


BA_formul_006_compl
16. A process for manufacture of enteric released tablet of Pantoprazole or its salts the
process comprises the steps of: (a) spraying a medium containing Pantoprazole or its
salts 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 Pantoprazole or its salts
(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.

17. An oral pharmaceutical composition substantially as described herein with reference to the forgoing examples.
18. A process for the preparation of oral pharmaceutical composition substantially as described herein with reference to the forgoing examples.




BA_formul_006_compl
ABSTRACT
ENTERIC COATED COMPOSITION OF PANTOPRAZOLE
The present invention relates to a pharmaceutical composition for oral administration and in particular to an enteric coated composition of Pantoprazole in the form of coated tablets.