AU729038B2

AU729038B2 - Benzimidazole pharmaceutical composition and process of preparation

Info

Publication number: AU729038B2
Application number: AU75390/98A
Authority: AU
Inventors: Yusuf Khwaja Hamied; Geena Malhotra; Vinay G. Nayak
Original assignee: Cipla Ltd
Current assignee: Cipla Ltd
Priority date: 1997-05-23
Filing date: 1998-05-21
Publication date: 2001-01-25
Anticipated expiration: 2018-05-21
Also published as: GB2343117A; WO1998052564A1; GB9927132D0; EP0983067A1; GB9710800D0; GB2343117B; CA2290824A1; ZA984266B; AU7539098A

Description

WO 98/52564 PCT/GB98/01465 -1- BENZIMIDAZOLE PHARMACEUTICAL COMPOSITION AND PROCESS OF PREPARATION The present invention relates to a pharmaceutical composition and to a process of preparation thereof, and more particularly to a pharmaceutical composition containing a benzimidazole.

Benzimidazole derivatives, such as omeprazole, lansoprazole and timoprazole, etc., are known potent proton pump inhibitors with powerful inhibitory action against the secretion of gastric acid (Lancet, Nov. 27, 1982, pages 1223 1224). They are used in the treatment of Zollinger-Ellison syndrome and stress related oesophagitis ulceration. The derivatives are well known and are described, for example, in EP-A-0005129.

It has been found that these benzimidazole derivatives, and in particular omeprazole, are susceptible to degradation in acid and neutral media and it is known to protect oral dosage forms by provision of an enteric coating. In this way, the active material is protected from acidic gastric juices until it reaches the site of desired release, e.g. the small intestine. Because certain enteric coatings can themselves be, or contain, acidic materials it is also often required to protect the benzimidazole from the acidity of the enteric coatings. For example, it is known to formulate the benzimidazole with an alkaline material before applying the enteric coating; it is also known to provide an intermediate coating between the benzimidazole and the enteric coating, generally the intermediate coating is selected so as to be substantially water soluble.

WO 98/52564 PCT/GB98/01465 -2- EP-A-0247983 describes an oral pharmaceutical preparation of omeprazole which is composed of a core material in the form of small beads or tablets containing omeprazole together with an alkaline reacting compound, the core material having one or more inert reacting subcoating layers thereon. The alkaline reacting compounds can be chosen among but are not restricted to substances such as the sodium, potassium, calcium, magnesium and aluminium salts of phosphoric acid, carbonic acid, citric acid or other suitable weak inorganic or organic acids; substances normally used in antacid preparations such as aluminium, calcium and magnesium hydroxides; magnesium oxide or composite substances, such as A1 2 0 3 .6MgO.CO 2 .12H 2 0, (Mg, 6

A

2

(OH),

6

CO

3 .4H 2 0), MgO.A1 2 0 3 .2SiO 2 .nH20 or similar compounds; organic pH-buffering substances such as trihydroxymethylaminomethane or other similar, pharmaceutically acceptable pH-buffering substances. The specification further states that if an alkaline reacting salt of omeprazole such as the sodium, potassium, magnesium, calcium or ammonium salt of omeprazole (which are described in EP-A-0124495) is used, this can be in place of or in addition to the alkaline reacting compound.

TW289733 describes a process of preparing pellets containing omeprazole. The process comprises spraying a solution comprising omeprazole, excipient, ethanol, water, ammonia and binder on an inert core; granulating; spraying an intermediate coating solution comprising excipient, ethanol, water, ammonia and binder on the granules; and providing a final outer coating.

US4786505 describes pharmaceutical preparations containing omeprazole in an alkali environment as the core material, one or more inert subcoating layers which are water soluble and an outer enteric coating.

There is however provided by the present invention pharmaceutical compositions, and processes of preparing the same, wherein an active ingredient comprising a benzimidazole can be protected from surrounding acidic media, and the compositions offer further advantages over the prior art by exhibiting extended shelf life.

WO 98/52564 PCT/GB98/01465 -3- According to the present invention, there is provided a pharmaceutical composition which is a solid pellet comprising an inert core, a benzimidazole in or on the core, a moisture resistant coating around the core, the moisture resistant coating comprising at least one hydrophobic material, and an enteric coating around the moisture resistant coating.

There is further provided by the present invention a process of preparing a composition substantially as described above, which process comprises providing an inert core having a benzimidazole therein or thereon, applying a moisture resistant coating around the core, the moisture resistant coating comprising at least one hydrophobic material, and applying an enteric coating around the moisture resistant coating.

Preferably, the benzimidazole in or on the core is present in an alkaline environment, and more particularly the benzimidazole is present as an intimate mixture with at least one alkali. Suitably, the alkali is ammonia or a solution of ammonia or ammonium carbonate. A process according to the present invention therefore preferably further comprises formulating the benzimidazole in an alkaline environment substantially as herein described.

It is generally preferred that an alkali employed in the present invention comprises an aqueous solution of ammonia ammonium hydroxide) or ammonium carbonate, although it is of course also possible to use liquid ammonia or ammonia gas. In such cases, the benzimidazole may be formulated under an ammonia atmosphere, for example, and the gas may be absorbed, such as by dissolution in any aqueous material present.

In accordance with the invention, the pH of the benzimidazolecontaining part of any formulation is preferably from above 7 to 10, and is more preferably in the range 8 to 9. Advantageously, an ammonia solution is used, the solution preferably containing from 20 to 40wt% ammonia, more preferably about wt% ammonia.

WO 98/52564 PCT/GB98/01465 -4- The invention is applicable to pharmaceutically active benzimidazole derivatives. Particularly useful such derivatives are the alkali metal salts of the benzimidazole. Examples of specific useful derivatives are omeprazole, lansoprazole, timoprazole, pariprazole and pantoprazole, in particular omeprazole.

The purpose of the moisture resistant coating employed in the present invention is to resist moisture absorption by the pharmaceutical composition, thereby extending shelf life. Suitably, the hydrophobic material of the coating is present in sufficient amount to ensure that the coating substantially repels water therefrom. The hydrophobic material can be solid or liquid, and is desirably selected from the group consisting of a polyalkylsiloxane, castor oil, mineral oil, isopropyl myristate, stearic acid, cetyl alcohol or the like. Preferably, the hydrophobic material comprises a polyalkylsiloxane, and it is particularly preferred that the hydrophobic material comprises polydimethylsiloxane.

The moisture resistant coating may further comprise at least one binding agent. The binding agent may be hydrophobic or hydrophilic. In the latter case, the binding agent is incorporated in the moisture resistant coating in an amount which ensures that the water repellent properties of the latter (as provided by the hydrophobic material substantially as described above), are substantially unaffected by the hydrophilic nature of the binding agent. The binding agent is preferably selected from the group consisting of a sugar, polyvinyl-pyrrolidone, shellac and gums, such as xanthan gum, or the like. It is especially preferred that the binding agent comprises a sugar, such as sucrose or the like.

Advantageously, a binding agent is employed in the moisture resistant coating when the hydrophobic material is a liquid. A preferred moisture resistant coating comprises an emulsion of a polyalkylsiloxane (especially polydimethylsiloxane) or an admixture thereof, with the binding agent.

WO 98/52564 PCT/GB98/01465 The moisture resistant coating may contain one or more other conventional additives that typically aid in the process of adhesion onto the inert core.

The moisture resistant coating may also be useful in benzimidazole pharmaceutical compositions that do not have an alkaline binder. The moisture resistant coating can be typically applied by spraying, using conventional equipment. In addition to the moisture resistant coating applied directly to the inert core substantially as hereinbefore described, a further moisture resistant coating can be provided over the enteric coating.

A wide variety of conventional enteric coatings may be employed in the present invention, including for example: cellulose acetate phthalate; hydroxypropyl methyl cellulose phthalate (HPMCP); hydroxypropyl cellulose acetyl succinate; polyvinyl acetate phthalate; copolymerised methacrylic acid/methacrylic acid methyl esters, such as Eudragit L 12-5, Eudragit L 100 55 or Eudragit S 100; and mixtures thereof. The enteric coating may contain conventional plasticisers, pigments and/or dispersants, including for example polyethylene glycols, triacetin, triethyl citrate, and Citroflex, dibutyl sebacate.

The enteric coating can be applied in any suitable manner, for example in the form of an aqueous dispersion in water, or other dispersing medium, or in the form of a solution. It is preferred that a dispersion or solution of the enteric coating is treated with an alkali in order to neutralise at least part of any free acid content. The alkali may be, for example, a carbonate or hydroxide of sodium, potassium, magnesium or calcium.

According to a first embodiment of the present invention, the benzimidazole is present in the inert core. Suitably, the inert core of the pharmaceutical composition comprises a plurality of compressed granules of the benzimidazole. This embodiment is particularly useful when it is desired toprovide the pharmaceutical composition in tablet form, and there is further provided by the present invention a tablet which comprises a pharmaceutical WO 98/52564 PCT/GB98/01465 -6composition substantially as herein described, wherein the inert core is formed from a plurality of granules comprising the benzimidazole, which granules are compressed together to form the core.

According to the first embodiment of the present invention, the moisture resistant coating is applied around the inert core, then the enteric coating is suitably provided around the moisture resistant coating on the inert core.

According to a second embodiment of the present invention, the benzimidazole is present on the inert core. The second embodiment of the present invention is particularly applicable for the inclusion of a plurality of pellets substantially as herein before described in a capsule. The inert cores of the pellets may typically be non-pareils, and suitably provided in the form of sugar beads or sugar/starch beads. According to the second embodiment of the present invention there is therefore provided a capsule which comprises a capsule shell containing a plurality of pellets substantially as herein before described.

According to the second embodiment of the present invention, the moisture resistant coating is applied around the inert core of each of the pellets to be provided in a capsule, and the enteric coating is suitably provided around the moisture resistant coating on each of the inert cores.

Pharmaceutical compositions according to the present invention may comprise one or more additives. Examples of particularly useful additives include a solubiliser to aid solubilisation of the pharmaceutically active ingredient, and a lubricant to aid flow of the active ingredient during manufacture. The solubiliser may be, for example, a sugar, which is preferably in pulverised form. An example of a suitable sugar is sucrose. The lubricant may be, for example, starch and/or talcum. It will be appreciated that the pharmaceutical compositions of the invention may contain any one or more other additives conventionally used in the formulation of pharmaceutical compositions.

The pharmaceutical compositions of the invention may be used to treat conditions in the same manner as the prior known benzimidazole WO 98/52564 PCT/GB98/01465 -7compositions. The pharmaceutical compositions may be formulated for oral, topical, parenteral or rectal administration. Oral administration is preferred.

The pharmaceutical compositions may take the form of, for example, a tablet or peltab comprising a plurality of granules comprising a benzimidazole, together with conventional excipients, such as disintegrants and binders, compressed into a tablet) or a capsule containing a plurality of individual pellets comprising a benzimidazole disposed within the capsule shell).

Furthermore, the pharmaceutical composition may include conventional excipients.

Tablets to be employed in compositions of the invention can be made, for example, by using equipment known as a marumerizer (which is also called a spheronizer). In such cases, core ingredients, including the benzimidazole, can be extruded into the marumerizer, and converted into substantially spherical granules by a high speed rotating disk. Subsequently, the granules may be compressed by conventional means in order to form a solid core, and subsequently coated with a moisture resistant coating and an enteric coating as herein before described.

When, alternatively, the pellets comprise benzimidazole loaded onto a plurality of inert cores suitable for inclusion in a capsule, the benzimidazole can be supplied as a spray, for example. The benzimidazole may be mixed with one or more additives before being loaded on the inert cores. As described above, the additives may include, for example, a solubiliser and/or a lubricant. The inert cores can be loaded with the benzimidazole (together with any additives), and sprayed with a binder, in a centrifugal coating apparatus.

The following Intermediate Examples and Examples illustrate the invention. In each case, the active drug was omeprazole unless indicated otherwise. Whilst sucrose (sugar) is the illustrated binding agent, other binding agents such as polyvinylpyrrolidone, shellac or xanthan gum, may be used instead.

Intermediate Example 1 WO 98/52564 PCT/GB98/01465 -8- A plurality of particles containing the active drug were prepared from the following materials: Non-pareil seeds 95.00 mg Active drug 20.00 mg Sucrose 32.00 mg Corn starch 32.00 mg Talcum 10.00 mg HPMC 1.00 mg 90.00 mg Water: as required.

Particles were also made of the above materials with the addition of by weight ammonia solution in an amount to provide a pH of 8.0-9.0.

Initially, the active drug, the sucrose, the corn starch and the talcum were blended thoroughly to yield a dusting powder. The non-pareil seeds were loaded into a centrigual coater and then coated with the dusting powder while spraying the HPMC (hydroxypropyl methyl cellulose) solution, with the ammonia solution when used. This resulted in the production of a plurality of discrete particles containing the active ingredient. The particles so obtained were dried using conventional tray dryers/fluid bed dryers to an outlet temp. of 45 C.

Intermediate Example 2 A plurality of particles containing the active drug were prepared as follows: Non-pareil seeds 95.00 mg WO 98/52564 PCT/GB98/01465 -9- Active drug 20.00 mg Sucrose 32.00 mg Corn starch 32.00 mg Talcum 10.00 mg HPMC 1.00 mg 190.00 mg Water: as required.

Particles were also made of the above materials with the addition of 3.00 mg ammonium carbonate.

Initially, the active drug, the sucrose, the corn starch, the ammonium carbonate (when present) and the talcum were blended thoroughly to yield a dusting powder. The non-pareil seeds were loaded into the centrifugal coater and then coated with the dusting powder while spraying the HPMC (hydroxypropyl methyl cellulose) solution. This resulted in the production of a plurality of discrete particles containing the active ingredient. The particles so obtained were dried using conventional tray dryers/fluid bed dryers to an outlet temp. of 45 C.

Intermediate Example 3 A plurality of particles containing the active drug were prepared from the following materials: Non-pareil seeds 108.00 mg Active drug 20.00 mg Sucrose 35.90 mg Corn starch 21.10 mg Talcum 2.00 mg WO 98/52564 PCT/GB98/01465 HPC-L Klucel 1.00 mg 186.00 mg Water: as required.

Particles were also made of the above materials but with the addition of 3.00 mg ammonium carbonate.

Initially, the active drug, the sucrose, the corn starch, the ammonium carbonate (when present) and the talcum were blended thoroughly to yield a dusting powder. The non-pareil seeds were loaded into the centrifugal coater and then coated with the dusting powder while spraying the HPC-L Klucel (hydroxypropyl cellulose) solution. This resulted in the production of a plurality of discrete particles containing the active ingredient. The particles so obtained were dried using conventional tray dryers/fluid bed dryers to an outlet temp. of 0

C.

Intermediate Example 4 A plurality of tablet cores containing an active drug were prepared from the following materials: Sucrose 80.00 mg Corn Starch 86.00 mg Active drug 20.00 mg Talcum 1.00 mg Magnesium stearate 1.00 mg Gelatine 2.00 mg 190.00 mg WO 98/52564 PCT/GB98/01465 11 Water: as required- Particles were also made of the above materials but with the addition of 30% by weight solution of ammonia to give a pH of 8.0-9.0.

Initially the active drug was blended with the sucrose and the corn starch in a suitable mixer. The blend containing the active drug was then granulated with a solution of the gelatine binder (with the ammonia when present).

The granules were dried using conventional means, then lubricated with the talcum and magnesium stearate. Finally, the granules were compressed into a suitable shape for a tablet core using conventional compression equipment.

Intermediate Example Employing the same procedure of Intermediate Example 4, tablet cores were also made of the following composition: Sucrose Dicalcium phosphate Corn starch Active drug Talcum Magnesium stearate Gelatine 45.00 mg 75.00 mg 45.00 mg 20.00 mg 1.00 mg 2.00 mg 2.00 mg 190.00 mg Water: as required WO 98/52564 PCT/GB98/01465 12- Particles were also made of the above materials but with the addition of 30% by weight solution of ammonia to a pH of 8.0-9.0.

Intermediate Example 6 A plurality of tablet cores containing an active drug were prepared from the following materials: Sucrose 80.00 mg Corn Starch 86.00 mg Active drug 20.00 mg Talcum 1.00 mg Magnesium stearate 1.00 mg Gelatine 2.00 mg 190.00 mg Water: as required Particles were also made of the above materials but also including 3.00 mg ammonium carbonate.

Initially the active drug was blended with the sucrose, corn starch and the ammonium carbonate (when present) in a suitable mixer. The blend containing the active drug was then granulated with a solution of the gelatine binder. The granules were dried using conventional means, then lubricated with the talcum and magnesium stearate. Finally, the granules were compressed into a suitable shape for a tablet core using conventional compression equipment.

Intermediate Example 7 WO 98/52564 PCT/GB98/01465 -13- A plurality of tablet cores containing an active drug were prepared from the following materials: Active drug Mannitol Polyvinylpyrrolidone K30 Crospovidone Magnesium stearate Talcum Polyethylene Glycol 6000 20.00 mg 115.50 mg 4.00 mg 7.00 mg 3.00 mg 1.50 mg 2.00 mg 153.00 mg Water: as required Particles were also made of the above materials but also including 2.00 mg ammonium carbonate.

The active drug was blended with the mannitol, and then granulated with a solution of PVP-K30 containing ammonium carbonate (when present). The granules were dried using conventional means, then lubricated with the talcum, magnesium stearate, PEG 6000 and Crospovidone. Finally, the granules were compressed into a suitable shape for a tablet core using conventional compression equipment.

Intermediate Example 8 WO 98/52564 PCT/GB98/01465 14- A plurality of tablet cores containing an active drug were prepared from the following materials: Active drug Mannitol Polyvinylpyrrolidone K30 Crospovidone Magnesium stearate Talcum Polyethylene Glycol 6000 20.00 mg 115.50 mg 4.00 mg 7.00 mg 3.00 mg 1.50 mg 2.00 mg 153.00 mg Water: as required Particles were also made of the above materials but including by weight ammonia solution to a pH of 8.0-9.0.

The active drug was blended with the mannitol. It was then granulated with the ammonia solution (when present). The granules were dried using conventional means, then lubricated with the talcum, magnesium stearate, PEG 6000 and Crospovidone. Finally, the granules were compressed into a suitable shape for a tablet core using conventional compression equipment.

Intermediate Example 9 190.00 mg of the particles of the composition formed in Intermediate Example 1 were treated with 3.00 mg of polydimethylsiloxane, and as much water as necessary. The coating was carried out using a conventional coating pan.

WO 98/52564 PCT/GB98/01465 Instead, it could have been carried out using a fluidised bed coater. This produced a moisture resistant coating around the particles of the composition of Intermediate Example 1.

Intermediate Example 190.00 mg of the particles of the composition formed in Intermediate Example 1 were also treated with 20.00 mg of an emulsion of 4.27 mg of polydimethylsiloxane, and 15.73 mg sucrose along with other conventional coating additives. The coating was carried out using a conventional coating pan. Instead, it could have been carried out using a fluidised bed coater. This produced a moisture resistant coating around the particles of the composition of Intermediate Example 1.

Intermediate Example 11 193.00 mg of the particles of the composition formed in Intermediate Example 2 were also treated with 20.00 mg of an emulsion of 4.27 mg of polydimethylsiloxane, and 15.73 mg sucrose along with other conventional coating additives. The coating was carried out using a conventional coating pan. Instead, it could have been carried out using a fluidised bed coater. This produced a moisture resistant coating around the particles of the composition of Intermediate Example 2.

Intermediate Example 12 189.00 mg of the particles of the composition formed in Intermediate Example 3 were treated with 3.00 mg of polydimethylsiloxane, and as much water as necessary. The coating was carried out using a conventional coating pan.

WO 98/52564 PCT/GB98/01465 -16- Instead, it could have been carried out using a fluidised bed coater. This produced a moisture resistant coating around the particles of the composition of Intermediate Example 3.

Intermediate Example 13 189.00 mg of the particles of the composition formed in Intermediate Example 3 were also treated with 20.00 mg of an emulsion of 4.27 mg of polydimethylsiloxane, and 15.73 mg sucrose along with other conventional coating additives. The coating was carried out using a conventional coating pan. Instead, it could have been carried out using a fluidised bed coater. This produced a moisture resistant coating around the particles of the composition of Intermediate Example 3.

Intermediate Example 14 Intermediate Example 9 was repeated, using an amount of 30% by wt. ammonia solution, in addition to the polydimethylsiloxane. This produced a moisture resistant coating around the particles of the composition of Intermediate Example 1.

Intermediate Example The 190.00 mg particles formed in Intermediate Example 4 were coated with 3.00 mg polydimethylsiloxane to produce a moisture resistant coating around each particle.

Intermediate Example 16 WO 98/52564 PCT/GB98/01465 17- The 190.00 mg particles formed in Intermediate Example 5 were coated with 3.00 mg polydimethylsiloxane to produce a moisture resistant coating around each particle.

Intermediate Example 17 The 190.00 mg particles formed in Intermediate Example 4 were also treated with 20.00 mg of an emulsion of 4.27 mg of polydimethylsiloxane, and 15.73 mg sucrose along with other conventional coating additives to produce a moisture resistant coating around each particle.

Intermediate Example 18 The 190.00 mg particles formed in Intermediate Example 5 were also treated with 20.00 mg of an emulsion of 4.27 mg of polydimethylsiloxane, and 15.73 mg sucrose along with other conventional coating additives to produce a moisture resistant coating around each particle.

Intermediate Example 19 The 193.00 mg particles formed in Intermediate Example 6 were coated with 3.00 mg polydimethylsiloxane to produce a moisture resistant coating around each particle.

Intermediate Example The 193.00 mg particles formed in Intermediate Example 6 were also treated with 20.00 mg of an emulsion of 4.27 mg of polydimethylsiloxane, and WO 98/52564 PCT/GB98/01465 18- 15.73 mg sucrose along with other conventional coating additives to produce a moisture resistant coating around each particle.

Intermediate Example 21 The 190.00 mg particles formed in Intermediate Example 4 were coated with polydimethylsiloxane, and an amount of 30% by wt. ammonia solution, to produce a moisture resistant coating around each particle.

Intermediate Example 22 The 190.00 mg particles formed in Intermediate Example were coated with polydimethylsiloxane, and an amount of 30% by wt. ammonia solution, to produce a moisture resistant coating around each particle.

Intermediate Example 23 A plurality of particles containing the active drug were prepared from the following materials: Non-pareil seeds Active drug

HPMC

Polyvinylpyrrolidone Talcum Water 108.00 mg 20.00 mg 10.00 mg 4.00 mg 2.50 mg As required 144.50 mg Total WO 98/52564 PCT/GB98/01465 -19- Initially, the polyvinylpyrrolidone and HPMC were dissolved in water, to obtain a clear solution. To this solution were added the active drug and talcum, in that order, and dispersed well. This drug suspension was sprayed onto the non-pareil seeds using a fluidised bed coater to obtain drug-loaded cores.

These cores were then given a moisture resistant coating in the same way as described in Intermediate Example 9 or 10. Also, an addition of 30% by weight ammonia solution can be used as in Intermediate Example 14.

Intermediate Example 24 A plurality of particles containing the active drug were made from the following materials: Non-pareil seeds 95.00 mg Active drug 20.00 mg Sucrose 30.00 mg Corn Starch 30.00 mg Talcum 10.00 mg Polyvinylpyrrolidone 4.00 mg HPMC 100 mg Water As required Total 190.00 mg Particles were also made of the above materials with the addition of by weight solution of ammonia to pH 8.0-9.0.

The procedure used was as in Intermediate Example 1, the PVP being included in the dusting powder.

WO 98/52564 PCT/GB98/01465 Intermediate Example A plurality of particles containing the active drug were prepared from the following materials: Non-pareil seeds 108.00 mg Active drug 20.00 mg Sucrose 35.90 mg Corn Starch 21.10 mg Talcum 2.00 mg Polyvinylpyrrolidone 4.00 mg HPC-L Klucei 1.00 mg Water As required Total 192.00 mg Particles were also made of the above materials with the addition of by weight solution of ammonia to pH 8.0-9.0.

Intermediate Example 26 The compositions obtained in Intermediate Examples 1 8 and 23, 24, 25 were treated with 11.00 mg of a mixture comprising of 2.85 mg of an emulsion of polydimethylsiloxane with 9.00 mg of a binding agent as described earlier (Sucrose/Polyvinylpyrrolidone/Shellac/Xanthan Gum), along with 1 mg of talc. The coating was carried out using a fluidised bed coater. Alternately, it could have been carried out using a conventional coating pan. This produced a moisture resistant coating around each composition of the respective examples.

WO 98/52564 PCT/GB98/01465 -21- Example 1 In this Example, the particles formed in Intermediate Examples 9 to 14 were provided with an enteric coating to yield compositions according to the present invention. Some were coated with cellulose acetate phthalate, some with HPMCP and some with Eudragit L 100 55. In each case, 500.00 g of the particles were each coated with 55.00 g of the respective enteric coating polymer. The enteric coating polymer was deposited using a conventional coating process.

Example 2 In this Example, the particles formed in Intermediate Examples 15 to 22 were each coated with an enteric coating polymer to yield tablet compositions according to the present invention. Some were coated with cellulose acetate phthalate, some with HPMCP and some with Euragdit L 100 55. In each case, the enteric coating polymer was deposited using a conventional process for coating.

Example 3 500.00 g of the enteric coated particles from Example 1 were coated with 3.00 mg per unit dosage form of a moisture resistant coating of polydimethylsiloxane. The moisture resistant coating was sprayed onto the particles.

Example 4 500.00 g of the enteric coated particles from Example I were coated with 20.00 mg of an emulsion containing 4.27 mg of polydimethylsiloxane, and 15.73 mg sucrose per unit dosage form to give a moisture resistant coating. The moisture resistant coating was sprayed onto the particles.

WO 98/52564 PCT/GB98/01465 -22- Example 500.00 g of the enteric coated tablets from Example 2 were each coated with 3.00 mg per unit dosage form of a moisture resistant coating of polydimethylsiloxane. The moisture resistant coating was sprayed onto the tablets.

Example 6 500.00 g of the enteric coated tablets from Example 2 were each coated with 20.00 mg of an emulsion containing 4.27 mg of polydimethylsiloxane, and 15.73 mg sucrose per unit dosage form to give a moisture resistant coating.

The moisture resistant coating was sprayed onto the tablets.

Example 7 The enteric coated particles of Examples 1 and 2 were respectively employed in the following formulae: Particles Microcrystalline Cellulose Starch Talcum Particles Microcrystalline Cellulose Starch Talcum 193.00 mg 20.00 mg 50.00 mg 1.00 mg 189.00 mg 20.00 mg 50.00 mg 1.00 mg I 1 -23- The particles were intimately mixed with the other ingredients in a suitable mixer.

The resultant blend was made into peltabs which were subsequently respectively provided with a moisture resistant and an enteric coating as follows.

Moisture Resistant Coatings 3.00 mg polydimethylsiloxane (optionally with 30% ammonia solution) to produce a moisture resistant coating around each particle; or 20.00 mg of an emulsion of 4.27 mg of polydimethylsiloxane, and 15.73 mg sucrose, along with other conventional coating additives to produce a S moisture resistant coating around each particle.

SEnteric Coatings 0 Enteric coatings included cellulose acetate phthalate, HPMCP and Euragdit L 100 It will appreciated that modifications may be made to the invention S. described above.

Where the terms "comprise", "comprises", "comprised" or "comprising" are used in this specification, they are to be interpreted as specifying the presence of the stated features, integers, steps or components referred to, but not to preclude the presence or addition of one or more other feature, integer, step, component or group thereof.

Claims

1. A pharmaceutical composition which is a solid pellet comprising an inert core, a benzimidazole in or on the core, a moisture resistant coating around the core, the moisture resistant coating comprising at least one hydrophobic material selected from a polyalkylsiloxane, castor oil, mineral oil, isopropyl myristate and cetyl alcohol, and an enteric coating around the moisture resistant coating.

2. A composition according to claim 1, wherein the benzimidazole S. is omeprazole, lansoprazole, timoprazole, pariprazole or pantoprazole.

S3. A composition according to claim 1 or 2, wherein the polyalkylsiloxane is polydimethylsiloxane.

4. A composition according to any of claims 1 to 3, wherein the moisture resistant coating further comprises at least one binding agent.

5. A composition according to claim 4, wherein the binding agent is selected from a sugar, polyvinyl-pyrolidone, shellac and xanthan gum.

6. A composition according to any of claims 1 to 5, wherein the benzimidazole in or on the core is in an alkaline environment.

7. A composition according to claim 6, wherein the benzimidazole is present as an intimate mixture with at least one alkali selected from ammonia, ammonium hydroxide or ammonium carbonate.

8. A pharmaceutical composition according to any of claims 1 to 7, wherein the pellet is in the form of a tablet, wherein the inert core is formed from a plurality of granules comprising the benzimidazole, which granules are compressed together to form the core.

9. A capsule which comprises a capsule shell containing a plurality of pellets as provided by a pharmaceutical composition according to any one of claims 1 to 7.

10. A process for preparing a composition according to any of claims 1 to 7, which process comprises providing an inert core having a S benzimidazole in or on the core, applying a moisture resistant coating around the core, the moisture resistant coating comprising at least one hydrophobic material, and applying an enteric coating around the moisture resistant coating. *o

11. A process for preparing a tablet according to claim 8, which process comprises compressing together a plurality of the granules to form the core, applying the moisture resistant coating to the core and applying the enteric coating to the moisture resistant coating.

12. A process of preparing a capsule according to claim 9, which process comprises providing the benzimidazole on the inert core, applying the moisture resistant coating thereto, applying the enteric coating to the moisture resistant coating, so as to provide a plurality of pellets as provided by pharmaceutical composition according to any of claims 1 to 7, and enclosing the pellets in a capsule shell. -26-

13. A pharmaceutical composition according to any one of claims 1 to 8 substantially as hereinbefore described with reference to any one of the accompanying Examples.

14. A process according to any one of claims 10 to 12 substantially as hereinbefore described with reference to any one of the accompanying Examples. Use of the process according to any one of claims 10 to 12 substantially as hereinbefore described with reference to any one of the accompanying Examples. S. 1 DATED this 9 th day of November, 2000 S CIPLA LIMITED By their Patent Attorneys: CALLINAN LAWRIE 09/11/00,al 11006.clm,26