WO2008015530A2

WO2008015530A2 - Stable solid oral formulation of pantoprazole

Info

Publication number: WO2008015530A2
Application number: PCT/IB2007/002176
Authority: WO
Inventors: Haranatha Babu Balanagu; Shailesh Suresh Bhamare; Kishor Dattatray Deo; Sumanth Reddy Vatti; Sivakumaran Meenakshisunderam
Original assignee: Aurobindo Pharma Limited
Priority date: 2006-08-03
Filing date: 2007-07-30
Publication date: 2008-02-07
Also published as: WO2008015530A3

Abstract

The present invention relates to a stable formulation comprising an acid-labile benzimidazole compound. More particularly, the present invention relates to a stable formulation comprising pantoprazole or its pharmaceutically acceptable salts. The present invention also relates to a process for the preparation of a stable formulation containing pantoprazole or its pharmaceutically acceptable salts.

Description

STABLE SOLID ORAL FORMULATION OF AN ACID LABILE DRUG

Field of the invention The present invention relates to stable formulations comprising an acid-labile benzimidazole compound. More particularly, the present invention relates to stable formulations comprising pantoprazole or its pharmaceutically acceptable salts.

The present invention also relates to a process for the preparation of stable formulations containing pantoprazole or its pharmaceutically acceptable salts. Background of the invention

Pantoprazole sodium is a substituted benzimidazole that inhibits gastric acid secretion and is chemically known as sodium 5-(difluoromethoxy)-2-[[3,4- dimethoxy-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole. Pantoprazole sodium is marketed under trade name PROTONIX® as a delayed release tablet and PROTONIX IV® as an injectable infusion in US.

Pantoprazole, being a benzimidazole proton pump inhibitor is very much susceptible to degradation/transformation in an acidic and neutral medium. So in order to avoid contact between the pantoprazole and the acidic gastric juice it is formulated as a capsule or tablet, which contains a core and a gastro-resistant coating that is entero-soluble. As most of the enteric coating polymer comprises acidic groups, benzimidazole compounds may rapidly decompose by direct or indirect contact with the acidic group of the coating polymer. To avoid the contact between the core and the enteric coating, a subcoating layer is established between the acidic drugs and enteric coating.

Further, it is necessary to add an inert substance to the composition, which provide an alkaline environment aimed at improving stability of the active substance during manufacturing and storage of the dosage form. Several prior art references describe compositions that are suitable for oral administration of acid-labile benzimidazole derivative. Some of the patents/ patent publications, which disclose compositions of acid labile benzimidazoles, are given below. U.S. Patent No. 4,853,230 discloses a pharmaceutical preparation comprising: (a) an alkaline reacting core comprising an acid-labile pharmaceutically active substance and an alkaline reacting compound different from said active substance (b) an inert subcoating which rapidly dissolves or disintegrates in water disposed on said core region and (c) an enteric coating layer surrounding said subcoating layer, wherein the subcoating layer isolates the alkaline reacting core from the enteric coating layer such that the stability of the preparation is enhanced.

U.S. Patent No. 5,035,899 discloses compositions which consists essentially of: a core containing an acid-unstable benzimidazole compound; a slightly water- soluble first coating layer coated on the core, comprising a slightly water-soluble, film- forming material selected from the group consisting of ethyl cellulose and polyvinyl acetate and fine particles of a slightly water-soluble substances and a second coating layer, coated on the first layer, of an enteric polymer film.

U.S. Patent No. 5,232,706 discloses compositions comprising: (a) a core containing omeprazole and an alkaline salt of omeprazole mixed with a first alkaline-reacting compound; (b) at least one intermediate layer formed by an excipient and a second alkaline-reacting compound and (c) an outer layer formed by an enteric coating.

U.S. Patent No. 5,997,903 discloses orally administrable medicament in pellet or tablet form which is resistant to gastric juice and in which each pellet or tablet consists of: a) a core comprising pantoprazole in admixture with binder, filler b) an inert water-soluble intermediate layer surrounding the core and c) an outer layer which is resistant to gastric juice wherein the binder is polyvinylpyrrolidone and/or hydroxypropylmethylcellulose and optionally, the filler is mannitol.

U.S. Patent No. 6,013,281 discloses in situ formation of separating layer as a water soluble salt layer between the alkaline reacting compound(s) and the enteric coating polymer.

U.S. Patent No. 6,068,856 discloses a delayed and controlled release oral composition comprising pantoprazole, an alkaline pellet or tablet core, at least one intermediate layer controlling release of active ingredient and an outer enteric layer.

U.S. Patent No. 6,207,198 discloses compositions that are exempt of alkaline-reacting compounds comprising: a core containing an acid-labile benzimidazole, and said active principle not being in the form of an alkaline salt; an intermediate layer and an enteric layer.

U.S. Patent No. 6,346,269 discloses oral formulations for acid-sensitive drugs, where the drug substance is mixed with an alkaline material such as trisodium phosphate and coated onto a core, such as a tablet, and an enteric coating.

U.S. Patent No. 6,479,075 discloses a method for producing a composition, comprising combining proton pump inhibitor compound and disintegrant to form a core; coating said core with at least one protector coat layer comprising from about

0.1% to about 10% aminoalkyl methacrylate copolymers and providing at least one enteric layer.

US 2004/0146558 discloses compositions comprising a core containing an active ingredient unstable to acid, an intermediate film enveloping the core, and an enteric film further enveloping the intermediate film, and the intermediate film comprises a matrix sparsely soluble in water and water-soluble fine particles dispersed therein. US 2005/042277 discloses compositions comprising a core containing the active ingredient and a disintegrant, a swellable coating surrounding the core, and an enteric coating surrounding the swellable coating.

WO 03/077829 discloses a process for preparation of a pharmaceutical composition comprises steps of manufacturing a) a core containing a pharmacologically effective acid labile compounds, and/or its alkaline salts, optionally with alkaline reacting substance, b) an inert subcoating layer which is a first coating layer, coated on the core, comprising film forming materials c) second coat, termed as a seal coat, comprising of a mixture of polymers over the subcoat, d) an enteric coating layer surrounding said seal coat layer.

WO 07/014928 discloses a composition comprising a core comprising pantoprazole having particle size in the range of 60-25 Oμm, an alkalizing substance, filler and a disintegrant, an optional water-soluble separating layer and finally coated by enteric coating layer. WO 07/029124 discloses a composition comprising a core of pantoprazole, an inert intermediate layer surrounding said core, wherein said intermediate layer insulates said core; and finally an outer layer.

Even though many patents disclose stable formulations of acid labile drugs, still there is need to develop dosage forms of acid labile drugs in which the drug will not be exposed to acidic media in the stomach and release the drug rapidly once the dosage form enters more alkaline environment.

The prior art patents disclose stable dosage forms for acid labile drugs containing core with or without alkaline reactive compound, an intermediate layer and an enteric coating. The inventors of the present invention during their efforts to develop stable and bioequivalent formulation found that the presence of subcoating comprising the dispersion of fine particles of slightly water soluble substance in ethylcellulose stabilizes the release of the drug from core. Objective of the invention

Accordingly, the main objective of the present invention is to provide a stable formulation containing pantoprazole or its pharmaceutically acceptable salts.

Yet another objective of the present invention is to provide a stable formulation of pantoprazole in such a way that it will comply with the reference product in terms of in vivo parameters like bioequivalence and in vitro parameters like dissolution, disintegration etc.

Yet another objective of the present invention is to provide process for the preparation of a stable formulation containing pantoprazole or its pharmaceutically acceptable salts.

Summary of the invention

Accordingly, the main embodiment of the present invention is to provide a stable formulation comprising: i. a core comprising pantoprazole or its pharmaceutically acceptable salts, at least one disintegrant, one water soluble diluent and an alkaline reacting compound, ii. an inert sub coating comprising a dispersion of fine particles of slightly water soluble substance over ethylcellulose and iii. an enteric coating over the sub coating. Detailed description of the invention

In an embodiment of the present invention, the core may be in the form of spheroid, pellets, tablets or mini tablets.

In one embodiment of the present invention, the core composition further comprises one or more excipients selected from lubricants, binder and surfactants. Suitable binders used in accordance with the present invention are selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone or starch and the like or a combination thereof. Suitable lubricants of the present invention include sodium stearyl fumarate, magnesium stearate, calcium stearate, hydrogenated vegetable oil, stearic acid, glyceryl behenate, talc and the like. The lubricant may be used in the range of 0.5- 5% of the total weight of the core. Suitable surfactants in accordance with the present invention are selected from sodium lauryl sulfate, polysorbates and the like or a combination thereof.

Suitable disintegrant used in accordance with the present invention are selected from low substituted hydroxypropylcelluloses, microcrystalline cellulose, sodium carboxymethyl cellulose, crosscarmellose sodium, crospovidone and the like. The disintegrant may be used in the range of 10-70 % of the total weight of the core.

Suitable water soluble diluents of the present invention include lactose, sucrose, dextrose, mannitol, sorbitol or a combination thereof. The diluent may be used in the range of 2-50% of the total weight of the core. Suitable alkaline reacting compounds of the present invention include calcium carbonate, magnesium carbonate, magnesium oxide, sodium carbonate, sodium bicarbonate and the like or a combination thereof.

The presence of alkaline reacting compound in the core is favorable since it prevents degradation of pantoprazole, which is unstable in acidic medium. In another embodiment, the pharmaceutically acceptable salts include its sodium, potassium and magnesium.

In yet another embodiment of the present invention, the amount of pantoprazole sodium used may be in the range of 20 to 70% of the total weight of the core. In another embodiment of the present invention, the sub coating composition comprises ethylcellulose, slightly water-soluble substance and a dispersing agent. In another embodiment of the present invention, the subcoating comprises a dispersion of fine particles of slightly water-soluble substance in ethyl cellulose. The presence of subcoating enhances the penetration of water through the pores, which enables the core to disintegrate rapidly thereby releasing the drug. Suitable slightly water soluble substances of the present invention include fine particles of colloidal silicon dioxide, magnesium oxide, calcium silicate, magnesium hydroxide, aluminium hydroxide, sucrose fatty acid esters, sodium carbonate and the like or a combination thereof. The content of the slightly water- soluble fine particles may be in the range of 30 to 70 % by weight of the sub coating dispersion. The presence of an insufficient amount of slightly water-soluble fine particles in the intermediate film often results in extension of disintegration time of the intermediate film, which delays release of pantoprazole.

Suitable dispersing agent of the present invention may be selected from polyethylene-propylene glycol copolymer, polyoxyethylene stearates, poly sorbates, propylene glycol, polyvinyl alcohol and the like and a mixture thereof.

In yet another embodiment of the present invention, the subcoated core is further coated with enteric coating composition comprising enteric coating polymer, plasticizer and anti-sticking agent.

Suitable enteric polymers used according to the present invention are selected from cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate butyrate and hydroxypropylmethylcellulose phthalate, methacrylic acid and ethyl acrylate copolymer such as eudragit or a combination thereof. In a preferred embodiment, the enteric coating has a thickness not less than 0.1% and preferably 1 to 50%, most preferably 2 to 25% by weight of the final dosage form. Suitable plasticizers used according to the present invention are selected from diethyl phthalate, dibutyl phthalate, cetyl alcohol, polyethylene glycol, triethyl citrate, triacetin and the like.

Suitable anti-sticking agents used according to the present invention are selected from talc, magnesium stearate and the like or a mixture, thereof.

The coating according to the present invention is applied by dissolving / dispersing the excipients in solvents such as isopropyl alcohol, water, acetone, ethanol, methylene dichloride and the like or a mixture thereof.

The present invention also provides a process for the preparation of a stable formulation comprising : i) a core comprising pantoprazole or its pharmaceutically acceptable salts, at least one disintegrant, one water soluble diluent and an alkaline reacting compound, ii) an inert sub coating comprising a dispersion of fine particles of slightly water soluble substance over ethylcellulose and iii) an enteric coating over the sub coating, which comprises the following steps:

1) blending pantoprazole, disintegrant, water soluble diluent, alkaline reacting compound and other excipients, 2) granulating the blend with binder solution,

3) drying the granules and then blending the dried granules with extra granular excipients,

4) lubricating the blended granules of step (3) and then compressing it to obtained tablets, 5) coating the tablets of step (4) with the coating suspension of ethylcellulose, slightly water soluble substance and dispersing agent in a solvent and finally 6) coating the sub coated tablets of step (5) with the enteric coating suspension. The following examples further exemplify the invention and are not intended to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry. Example 1

The processing steps involved in manufacturing enteric coated tablet dosage form of pantoprazole sodium are given below: i) pantoprazole sodium, mannitol, sodium carbonate and crospovidone were blended, ii) binder solution of polyvinylpyrrolidone in water was prepared, iii) granulated the blended material of step (i) with binder solution of step (ii) and dried the granulated mass at 40⁰C, iv) dried granules were blended with crospovidone, v) lubricated the blended granules of step (iv) with calcium stearate vi) compressed the lubricated blend of step (v) into tablets, vii) a suspension of ethylcellulose, colloidal silicon dioxide, iron oxide yellow and propylene glycol in ethanol was prepared, viii) tablets of step (vi) were coated with the coating suspension of step (vii), ix) a suspension of eudragit, triethylcitrate and talc in water was prepared and x) the coated tablets of step (viii) were coated with the coating suspension prepared in step (ix) to obtain delayed release tablets of pantoprazole.

The compositions given in examples 2, 3 and 4 were prepared using similar procedure described in example 1.

Example 2

Example 3

Example 4

The stable solid dosage forms of pantoprazole sodium prepared according to the present invention were tested for drug release in 0. IN HCl for 2hours followed by phosphate buffer having pH 6.8 using USP apparatus 2 with paddle speed at 75 rpm. The samples of the media were periodically withdrawn and spectrophotometrically analyzed for pantoprazole content. The dissolution profile is given in Table 1 below:

Table-l

Claims

We claim:

1. A stable formulation comprising: i. a core comprising pantoprazole or its pharmaceutically acceptable salts, at least one disintegrant, one water soluble diluent and an alkaline reacting compound, ii. an inert sub coating comprising a dispersion of fine particles of slightly water soluble substance over ethylcellulose and iii. an enteric coating over the sub coating.

2. A stable formulation as claimed in claim 1, wherein core composition further comprises one or more excipients selected from lubricants, binder and surfactants.

3. A stable formulation as claimed in claim 1, wherein the disintegrant is selected from low substituted hydroxypropyl cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, crosscarmellose sodium, crospovidone or a combination thereof.

4. A stable formulation as claimed in claim 1, wherein the water soluble diluent is selected from lactose, sucrose, dextrose, mannitol, sorbitol or a combination thereof.

5. A stable formulation as claimed in claim 1, wherein the alkaline reacting compound is selected from calcium carbonate, magnesium carbonate, magnesium oxide, sodium carbonate, sodium bicarbonate or a combination thereof.

6. A stable formulation as claimed in claim 2, wherein the binder is selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone starch or a combination thereof.

7. A stable formulation as claimed in claim 2, wherein the lubricant is selected from sodium stearyl fumarate, magnesium stearate, calcium stearate, hydrogenated vegetable oil, stearic acid, glyceryl behenate or talc.

8. A stable formulation as claimed in claim 1, wherein the slightly water soluble substance is selected from colloidal silicon dioxide, magnesium oxide, calcium silicate, magnesium hydroxide, aluminium hydroxide, sucrose fatty acid esters, sodium carbonate or a combination thereof.

9. A stable formulation as claimed in claim 1, wherein the dispersing agent is selected from polyethylene-propylene glycol copolymer, polyoxyethylene stearates, poly sorbates, propylene glycol or polyvinyl alcohol.

10. A stable formulation as claimed in claim 1, wherein the enteric coating composition comprises of enteric polymer, plastisizer and anti-sticking agent.

11. A stable formulation as claimed in claim 10, wherein the enteric polymer is selected from cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate butyrate, hydroxypropylmethylcellulose phthalate, methacrylic acid and ethyl acrylate copolymer or a combination thereof.

12. A stable formulation as claimed in claim 10, wherein the plasticizer is selected from diethyl phthalate, dibutyl phthalate, cetyl alcohol, polyethylene glycol, triethyl citrate or triacetin.

13. A stable formulation as claimed in claim 10, wherein the anti-sticking agent is selected from talc or magnesium stearate.

14. A process for the preparation of a stable formulation comprising: i) a core comprising pantoprazole or its pharmaceutically acceptable salts, at least one disintegrant, one water soluble diluent and an alkaline reacting compound, ii) an inert sub coating comprising a dispersion of fine particles of slightly water soluble substance over ethylcellulose and iii) an enteric coating over the sub coating, which comprises the following steps: 1) blending pantoprazole, disintegrant, water soluble diluent, alkaline reacting compound and other excipients,

2) granulating the blend with binder solution,

4) lubricating the blended granules of step (3) and then compressing it to obtain tablets,

5) coating the tablets of step (4) with the coating suspension of ethylcellulose, slightly water soluble substance and dispersing agent in a solvent and finally 6) coating the sub coated tablets of step (5) with the enteric coating suspension.