FIELD OF INVENTION

The invention relates to individually enteric-coated multiple-unit pharmaceutical composition comprising benzimidazole compounds, wherein the amount of plasticizer in the enteric coating layer is above 50% by weight with respect to the dry weight of enteric polymer.

BACKGROUND OF THE INVENTION

Benzimidazole compounds such as omeprazole, lansoprazole, pantoprazole, rabeprazole or single enantiomers thereof are strong inhibitors of proton pump and thus are widely used as therapeutic agents for stomach ulcer, duodenal ulcer, gastro esophageal reflux disorders etc. by inhibiting gastric acid secretion.

Omeprazole is disclosed in European Patent No. 0005129, chemically known as 5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfmyl]-lH-benzimidazole, certain salts of omeprazole including alkaline salts of omeprazole are described in European Patent Application No. 0124495 and in PCT Application No. WO 95/01977, U.S. Patent No. 5,877,192 describes the use of the (-)-enantiomer of omeprazole (esomeprazole), or a pharmaceutically acceptable salt thereof, novel salts of the single enantiomers of omeprazole are also described in PCT Application No. WO 94/27988. U.S. Patent No. 4,628,098 describes generic lansoprazole compound. Lansoprazole chemically is (2-[[[3-methyl-4-(2, 2, 2-trifluoro-ethoxy)-2-pyridinyl] methyl] sulfinyl]-lH-benzimidazole). Pantoprazole is disclosed in U.S. Patent No. 4,758,579 while U.S. Patent No. 5,045,552 covers rabeprazole. PCT Application No. WO 00/10995 describes the dihydrate of magnesium salt of racemic pantoprazole. The single isomers of corresponding benzimidazole compounds are reported to be more useful in therapy compared to the racemic benzimidazole compounds.

Benzimidazole compounds are useful for inhibiting gastric acid secretion in mammals including humans by controlling gastric acid secretion at the final step of the acid secretory pathway and thus reduce basal and stimulated gastric acid secretion irrespective of stimulus. In a more general sense, benzimidazole compounds are used for prevention and treatment of gastric-acid related diseases in mammals and man, including reflux oesophagitis, gastritis, duodenitis, gastric ulcer, duodenal ulcer and Zollinger-Ellison syndrome. Further, it may be used for treatment of other gastrointestinal disorders where gastric acid inhibitory effect is desirable e. g. in patients on NSAID therapy, in patients with Non Ulcer Dyspepsia, and in patients with symptomatic gastro-esophageal reflux disease (GERD).

Omeprazole is also used in patients who are in intensive care situations, with acute upper gastrointestinal bleeding, pre-and post-operatively to prevent aspiration of gastric acid and to prevent and treat stress ulceration. Further, it may be useful in treatment of psoriasis as well as in treatment of Helicobacter infections and diseases related to these, where therapeutic control of gastric acid secretion is fundamental in the treatment.

Because of the instability of benzimidazole compounds under neutral and acidic environment, moisture, heat, organic solvents and to some degree by light, numerous approaches have been tried to form a stable pharmaceutical formulation comprising a benzimidazole compound.

Most oral benzimidazole preparations/ compositions need enteric-coating, to prevent rapid degradation of the drug in the acidic conditions of the stomach. The half-life of degradation of omeprazole in aqueous solution at pH-values less than 3 is shorter than ten minutes. The degradation of omeprazole is catalyzed by acidic compounds and is stable in admixture with alkaline compounds.

In respect to the stability properties of benzimidazole compounds, it is obvious that benzimidazole compounds in an oral solid dosage form must be protected from contact with acidic gastric juices, and the active substance must be transferred in intact form to that part of the gastrointestinal tract where pH is near neutral and where rapid absorption of benzimidazole compounds can occur. This is most commonly achieved by formulating enteric-coated compositions i.e. enteric-coated granules within capsules, enteric-coated granules or cores compressed into tablets etc., and single unit immediate release matrix tablets coated with enteric coating.

Prior art discloses many different types of multiple-unit dosage forms. U.S. Patent Nos. 4,786,505 and 4,853,230 teach compositions of benzimidazole compounds having an alkaline core, separating layer and enteric coating optionally containing plasticizer usually in the range of 1-20% by weight of the enteric coating polymer.

U.S. Patent Application No. 2006/0018964 discloses a multiparticulate tablet comprising a pharmaceutically active substance in the form of enteric-coated particles,and a mixture of tableting excipients. The enteric coating composition may also comprise a plasticizer. The plasticizer is usually used in a total proportion of at most 40%, preferably between 10% and 30%, expressed by weight with respect to the dry weight of polymer.

European Patent No. 0723437 teaches an oral pharmaceutical multiple-unit tabletted dosage form comprising acid labile proton pump inhibitor or one of its single enantiomers, the core material being covered with one or more layer(s) of which at least one is an enteric coating layer, characterized in that the enteric coating layer has a thickness of at least 10^ and said layer comprises a plasticizer in an amount of 15 - 50 % by weight of the enteric coating layer polymer.

European Patent Application No. 0723777 teaches tablets containing enteric granules prepared by tabletting a mixture of enteric granules with at least one member selected from the group consisting of synthetic hydrotalcite, dried aluminium hydroxide gel, a coprecipitate of aluminium hydroxide with sodium hydrogen carbonate, aluminium magnesium hydroxide, synthetic aluminium silicate and dihydroxyaluminium amino acetate. The enteric-coated granules include a plasticizer, preferably added during formulation of the coating to be coated on the granules, at 15-40% w/w, and preferably 30- 40 % w/w with respect to the total amount of the enteric coating.

PCT Application No. WO 02/19991 teaches a multiparticulate dosage form, produced from particles compressed with conventional binding agents. Said particles contain a pharmaceutical active ingredient and are covered with a gastric juice resistant coating consisting of a methacrylate copolymer and more than 15 and up to 50 wt % of the plasticizer propylene glycol in relation to the methacrylate copolymer.

PCT Application No. WO 2008/006534 discloses multiple-unit tablets comprising multiple-units compacted together with at least two tablet filler-binders and optionally other pharmaceutically acceptable excipients, wherein at least one of said tablet filler-binder is a tablet filler-binder having mean particle size-to-mean multiple-unit size ratio from 10% to 40%, and at least one of said tablet filler-binder is a tablet filler-binder having mean particle size-to-mean multiple-unit size ratio from 1 % to 10%.

However, there is still a need for development of new and improved enteric-coated multiple-unit pharmaceutical composition with good mechanical and chemical stability. When preparing multiple-unit tablets, the application of compression forces to the tablet mixture comprising enteric-coated particles present a problem with respect to the strength of the coating and specifically the requirement to maintain gastro-resistance and integrity of the tablet and of the enteric-coated units after tabletting.

We have surprisingly found that enteric-coated multiple-unit tablets of benzimidazole compounds having desired mechanical properties and good acid resistance can be prepared by using high amount of plasticizer in the enteric coating layer, i.e. above 50%, preferably between 55% and 75%, by weight with respect to the dry weight of enteric polymer.

SUMMARY AND OBJECTIVES OF THE INVENTION

The invention relates to stable enteric-coated multiple-unit pharmaceutical composition comprising a benzimidazole compound selected from omeprazole or esomeprazole or their pharmaceutically acceptable salts.

Particularly, the invention relates to a stable multiple-unit pharmaceutical composition comprising:

a) individually enteric-coated cores comprising:

i) a benzimidazole compound selected from omeprazole or esomeprazole or their pharmaceutically acceptable salts,

ii) at least one separating layer containing a sugar alcohol,

ii) at least one enteric coating layer,

b) a mixture of two or more tablet diluents of similar particle size,wherein said enteric coating layer comprises a mixture of at least one water-soluble plasticizer and at least one water-insoluble plasticizer, having a weight ratio from about 1:0.2 to about 1:1, relative to each other.

The invention also provides a process for preparing stable multiple-unit pharmaceutical composition, wherein said process comprises the steps of: a) preparing individually enteric-coated cores comprising:

i) a benzimidazole compound selected from omeprazole or esomeprazole or their pharmaceutically acceptable salts,

ii) at least one separating layer containing a sugar alcohol,

ii) at least one enteric coating layer,

b) blending cores of step (a) with
iii) at least two extra-granular tablet diluents of similar particle size; and iv) optionally other pharmaceutically acceptable excipients; and

c) compressing said blend of step (c) to form multiple-unit tablet;

wherein said enteric coating layer comprises a mixture of at least one water-soluble plasticizer and at least one water-insoluble plasticizer, having weight ratio from about 1:0.2 to about 1:1, relative to each other.

In an embodiment of the invention, there is provided a stable multiple-unit pharmaceutical composition comprising:

a) individually enteric-coated cores comprising:

i) a benzimidazole compound selected from omeprazole or esomeprazole or their pharmaceutically acceptable salts,

ii) at least one separating layer containing a sugar alcohol,

ii) at least one enteric coating layer,

b) a mixture of two or more tablet diluents of similar particle size,

wherein said enteric coating layer comprises a mixture of at least one water-soluble plasticizer and at least one water-insoluble plasticizer, having a weight ratio from about 1:0.2 to about 1:1, relative to each other.
In another embodiment of the invention, there is provided a process for preparing stable multiple-unit pharmaceutical composition, wherein said process comprises the steps of:

a) preparing individually enteric-coated cores comprising:

i) a benzimidazole compound selected from omeprazole or esomeprazole or their pharmaceutically acceptable salts,

ii) at least one separating layer containing a sugar alcohol,

ii) at least one enteric coating layer,

b) blending cores of step (a) with
iii) at least two extra-granular tablet diluents of similar particle size; and

iv) optionally other pharmaceutically acceptable excipients; and

c) compressing said blend of step (c) to form multiple-unit tablet;

wherein said enteric coating layer comprises a mixture of at least one water-soluble plasticizer and at least one water-insoluble plasticizer, having weight ratio from about 1:0.2 to about 1:1, relative to each other.

In a preferred embodiment of the invention, there is provided a stable multiple-unit pharmaceutical composition comprising:

a) individually enteric-coated cores comprising:

i) esomeprazole magnesium,

ii) a separating layer consisting of mannitol,

ii) at least one enteric coating layer,

b) a mixture of mannitol and microcrystalline cellulose of similar particle size,

wherein said enteric coating layer contains a mixture of triethyl citrate and glyceryl monostearate, having a weight ratio of about 0.85:0.15.

DETAILED DESCRD7TION INCLUDING PREFERRED EMBODIMENTS OF THE INVENTION

The invention relates to a multiple-unit pharmaceutical composition comprising enteric-coated pellets wherein the plasticizer present in enteric polymer(s) layer comprises a mixture of at least one water-soluble plasticizer and at least one water-insoluble plasticizer. The total amount of enteric polymer(s) in the enteric layer is least 30% by weight of the enteric-coated pellets and the amount of plasticizer is above 50% by dry weight of enteric polymer, resulting in no appreciable change in release profile of active ingredient on compression of enteric-coated pellets into tablets. Additionally according to invention the composition comprises at least two extra-granular tablet diluents used in the compression step, wherein the extra-granular tablet diluents have same particle size. The multiple-unit tablets prepared according to the invention involves use of only aqueous based solvents at each and every step wherever use of solvents is necessary.

The acid labile compounds that can be incorporated in the multiple-unit tablets of the invention belongs to the therapeutic category of proton pump inhibitors structurally defined as benzimidazole compounds or benzimidazole derivatives. The term 'benzimidazole derivatives or benzimidazole compounds' as used herein refers to any of the compounds belonging to the category of benzimidazole used for gastrointestinal disorders and may include omeprazole, lansoprazole, rabeprazole, pantoprazole, leminoprazole and pariprazole used in their neutral form or in the form of an alkaline salt, single enantiomer or their pharmaceutically accepted salts, solvates or mixtures thereof. Preferably, the benzimidazole compound is omeprazole in the form of a pharmaceutically acceptable alkaline salt, preferably omeprazole magnesium or esomeprazole magnesium.

The multiple-unit pharmaceutical composition of the invention comprises at least one benzimidazole derivative or an alkaline salt or one of its single enantiomer or alkaline salt thereof. Enteric coating layered 'units' containing benzimidazole derivative are mixed with at least two extra-granular tablet diluents having same particle size and compressed into multiple-unit tabletted dosage forms.

In an embodiment of the invention, there is provided an enteric-coated multiple-unit pharmaceutical composition comprising a benzimidazole compound selected from omeprazole or esomeprazole or their pharmaceutically acceptable salts, wherein the multiple-units are compressed with at least two tablet diluents of similar particle size to form tablet.

In another embodiment of the invention, there is provided an enteric-coated multiple-unit pharmaceutical composition comprising a benzimidazole compound selected from omeprazole or esomeprazole or their pharmaceutically acceptable salts, wherein the enteric coating contains a mixture of at least one water-soluble plasticizer and at least one water-insoluble plasticizer, having a weight ratio from about 1:0.2 to about 1:1, relative to each other.

In another embodiment of the invention, there is provided an enteric-coated multiple-unit pharmaceutical composition comprising a benzimidazole compound selected from omeprazole or esomeprazole or their pharmaceutically acceptable salts, wherein the total amount of plasticizer in the enteric coating layer is in the range of about 55% to about 75% by weight with respect to the dry weight of enteric polymer.

In another embodiment of the invention, there is provided an enteric-coated multiple-unit tablets, said tablet comprises at least one benzimidazole compound selected from omeprazole or esomeprazole or their pharmaceutically acceptable salts, wherein the process involves use of only aqueous based solvents at each and every processing step.

In another embodiment of the invention, there is provided a process for the preparation of an enteric-coated multiple-unit pharmaceutical composition comprising the steps of:

a) dispersing benzimidazole compound and at least one binder in an aqueous medium to obtain a dispersion;

b) spraying the dispersion onto a pharmaceutically acceptable inert carrier;

c) coating the cores of step b) with a separating layer;

d) applying an enteric coat over said cores of step d);

e) blending the cores of step d with at least two extra-granular tablet diluents and optionally other pharmaceutically acceptable excipients; and

f) compressing the blend of step e) into tablets;

wherein the enteric coating contains a mixture of at least one water-soluble plasticizer and at least one water-insoluble plasticizer, having a weight ratio from about 1:0.2 to about 1:1, relative to each other.

In another embodiment of the invention, there is provided a process for the composition of an enteric-coated multiple-unit pharmaceutical composition comprising the steps of:

a) blending benzimidazole compound with at least one pharmaceutically acceptable additive;

b) granulating the blend of step a) with a solution of binder to form granules;

c) coating the granules of step b) with a separating layer containing sugar alcohol;

d) applying an enteric coat over said granules;

e) blending the granules of step d) with at least two extra-granular tablet diluents and optionally other pharmaceutically acceptable excipients; and

f) compressing the blend of step e) into multiple-unit tablets;

wherein the enteric coating contains a mixture of at least one water-soluble plasticizer and at least one water-insoluble plasticizer, having a weight ratio from about 1:0.2 to about 1:1, relative to each other.

In a preferred embodiment of the invention, there is provided a stable multiple-unit pharmaceutical composition comprising:

a) individually enteric-coated cores comprising:

i) esomeprazole magnesium,

ii) a separating layer consisting of mannitol,

ii) at least one enteric coating layer, b) a mixture of mannitol and microcrystalline cellulose of similar particle size, wherein said enteric coating layer contains a mixture of triethyl citrate and glyceryl monostearate, having a weight ratio of about 0.85:0.15, relative to each other.

Multiparticulate composition of the invention is considered stable if it retains 90% to 110% of its potency during shelf life storage. The composition according to the invention is also stable during its passage through the stomach and remains in a microenvironment that is not acidic or lower than pH 7.0, at the same time when the composition exits from the stomach and reaches the proximal part of the intestine, the drug dissolves rapidly.

The compaction process (compression) for formulating the multiple-unit tabletted dosage form must not significantly affect the acid resistance of the enteric coating layered pellets. In other words the mechanical properties, such as the flexibility and hardness as well as the thickness, of the enteric coating layer(s) must meet that the requirements of enteric-coated dosage form in the United States Pharmacopeia and that the amount of drug release in acid resistance test should not increase more than 10% during the compression of pellets into tablets.

Enteric protection from delayed release film coating systems has been shown to be influenced by the hydrophilic and lipophilic properties of the plasticizer, level of plasticizer, and amount of polymer applied to the substrate. Normally, the ductility of enteric coatings can be improved by the addition of plasticizers, but this is often accompanied by a reduction in the tensile strength of the polymer. As the degree of plasticization of the polymer increases, the elongation at break of the film also increases i.e. the film coating becomes more elastic and is better able to deform during compression, thereby improving the acid resistance of the coated pellets compressed into tablets. This also facilitates the use of a wide range of compression forces during the compression cycle, without significantly affecting the release behavior of the compressed pellets. This makes the process robust and manufacture friendly. Besides a tablet having sufficient hardness is also essential if the compressed tablets are meant for film coating.

There are hydrophilic plasticizer i.e. water-soluble plasticizer and hydrophobic plasticizer i.e. water-insoluble plasticizer.

Increasing water-soluble plasticizer

concentration leads to processing problems associated with tackiness of the casted films leading to generation of agglomerates in the process. Proper optimization of the processing conditions is required with special emphasis on temperature, RH, air flow and spray rate.

Increased concentration of plasticizers in the coating is also associated with alteration in the release pattern of the pellets. The release rate increases if the plasticizer is water-soluble and the reverse if the plasticizer is water insoluble. To achieve a desired release profile from the pellets proper selection of the type and concentration of the plasticizers is required. It has surprisingly been found that it is beneficial to use more than one plasticizer (one or more water-soluble plasticizer together in admixture with one or more water-insoluble plasticizers) each with optimum concentration.

Water-soluble plasticizer that can be employed according to the invention includes triethyl citrate, triacetin, propylene glycol, polyethylene glycol, polysorbate 80, while water-insoluble plasticizer that can be employed includes dibutylsebacate, diethyl phthalate, dibutylphthalate, fractionated coconut oil, oleic acid, cetyl alcohol, glyceryl monostearate, acetyl tributyl citrate, acetyl triethylcitrate, and tributyl citrate.

Acid resistance;

It is defined as the amount of active substance released from enteric-coated tablets or pellets after being exposed to simulated gastric fluid, or to 0.1 N HC1. The first step of the test is accomplished in the following way: tablets or pellets are exposed to . simulated gastric fluid at a temperature of 37 °C, the tablets disintegrate and release the enteric coating layered pellets into the medium. After two hours the enteric coating layered pellets are removed and analyzed for drug content. The amount of active substance released makes it possible to directly assess the integrity of the enteric-coated particle itself. The result is expressed as percentage by weight with respect to the total starting amount of the active substance.

Then, in a second step, this same enteric-coated dosage tablets are placed for 30 minutes in a medium with a pH, which is increased up to a value of 6.8 by addition of an alkaline buffer solution to the medium from the first step. The amount of active substance released into the medium at pH 6.8 after 30 minutes is subsequently measured, confirming that the active substance is indeed immediately released in the second medium.

Core:

The core material for the enteric coating layered 'units' can be constituted according to different principles. With the xpression "units" is meant small beads, particles, granules or pellets. Inert seeds layered with benzimidazole derivative used in their neutral form or in the form of an alkaline salt, single enantiomer or their pharmaceutically accepted salts, can be used as the core material for further processing.

The seeds, which are to be layered with the benzimidazole derivative, can be water-insoluble seeds comprising different oxides, celluloses, organic polymers and other materials, alone or in mixtures or water-soluble seeds comprising different inorganic salts, sugars, non-pareils and other materials, alone or in mixtures.
The size of the seeds according to the invention may vary between approximately 600 microns to 1000 microns. The seeds layered with benzimidazole derivative are produced either by powder or solution/ suspension layering using for instance granulating or spray coating/ layering equipment.

Before the seeds are layered with benzimidazole derivative, the benzimidazole derivative may optionally be mixed with at least one binder and optionally with other pharmaceutically acceptable excipients. The binders that can be used according to the invention includes but are not limited to celluloses such as hydroxypropyl methylcellulose, hydroxypropyl cellulose and carboxymethyl-cellulose sodium, polyvinyl pyrrolidone, sugars, starches and other pharmaceutically acceptable substances with cohesive properties.

Alternatively, core material can be prepared by mixing benzimidazole derivative and one or more pharmaceutically acceptable additive. Said core materials may be produced by extrusion/ spheronization, balling or compression utilizing different process equipments. The size of the formulated core materials is approximately in between 800 microns and 1400 microns.

Separating Layer;

The cores comprising benzimidazole derivative are over coated with at least one separating layer essentially comprising one or more non-polymeric material and optionally contains other pharmaceutically acceptable additives. The non-polymeric material is either dispersed or dissolved in a solvent optionally with other pharmaceutically acceptable additives and the resulting solution or dispersion is sprayed on the core to form the separating layer over the core. Coated cores are dried to moisture content of less than 5%, preferably less than 3% and more preferably less than 2% by weight of separating layer coated cores. Total solid content in sub-coating dispersion is in the range of 15 to about 30%w/w.

Non-polymeric material for the separating layer according to the invention includes sugar alcohols selected from mannitol, xylitol, sucrose, sorbitol, maltitol, lactitol and mixtures thereof; preferred sugar alcohol being mannitol.

The cores may optionally be coated with second separating layer over the first separating layer comprising sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methyl-cellulose, ethyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose sodium and others, used alone or in mixtures. Additives such as plasticizers, colorants, pigments, fillers, anti-tacking and antistatic agents, such as for instance magnesium stearate, titanium dioxide, talc and other additives may also be included into the separating layer(s).

The separating layer(s) can be applied by coating or layering procedures in suitable equipments such as coating pan, coating granulator or in fluidized bed apparatus using water and/or organic solvents for the coating process. As an alternative the separating layer(s) can be applied to the core material by using powder coating technique.

Enteric layer:

Enteric coating layer comprising enteric polymer and plasticizers is applied on to the sub-coated cores by conventional coating techniques such as, for instance, pan coating or fluidized bed coating using solutions of enteric polymers in water. Enteric polymers that can be used, include cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethylethyl cellulose, water-soluble or water dispersible acrylic resins i.e., poly(meth)acrylates are copolymers derived from esters of acrylic and methacrylic acid, such as, for instance, compounds known under the trade name Eudragit™ L30-D55, Eudragit™ L100-55, Eudragit™ LI 00, Eudragit™ NE 30-D55, Eudragit™ RLPO, Eudragit™ RSPO.

Water-soluble plasticizer that can be employed includes triethyl citrate, triacetin, propylene glycol, polyethylene glycol and polysorbate 80 or mixtures thereof.

Water-insoluble plasticizer that can be employed includes dibutylsebacate, diethyl phthalate, dibutylphthalate, fractionated coconut oil, oleic acid, glyceryl monostearate, acetyl tributylcitrate, acetyl triethylcitrate and tributyl citrate or mixtures thereof.

Enteric coating/ layer optionally comprises of anti-adherents, pigments, colorants, surfactants and anti-foaming agents such as silicone oil.

Anti-adherent in the enteric layers is selected from talc, colloidal silicon dioxide, glyceryl monostearate, stearic acid, kaolin, magnesium stearate, calcium stearate, sodium stearyl fumarate, glyceryl behenate, starch and mixtures thereof. These are present up to 30%, preferably 1% to 20%, more preferably 5% to 15% and most preferably about 10% by weight of the enteric-coated pellets.

Pigments and colors are selected from pharmaceutically acceptable pigments and colors such as titanium oxide, iron oxide red and lake of sunset yellow.

Surfactant is selected from sodium lauryl sulfate and polysorbates such as polysorbate 80 and mixtures thereof.

Compression into Tablets:

Enteric-coated pellets prepared above are compressed into swallowable tablets or orally dispersible tablets. The size of enteric-coated pellets for compression should be less than 1400 microns, preferably about 600 to 1200 microns.

The composition may further omprise 'pharmaceutically acceptable additives or excipients' known in the art. The term pharmaceutically acceptable additive' includes pharmaceutically acceptable excipient' within its ambit and the singular term includes plural as well.The pharmaceutically acceptable excipients may be one or more of diluents, binders, disintegrants, surfactants, lubricants/ glidants and coloring agents.

The term "diluent" as used herein is intended to mean inert substances used as carriers to create the desired bulk, flow properties, and compression characteristics in the preparation of tablets of the invention. The diluents according to the invention can be added intra-granularly or extra-granularly. The multiple cores/ units comprising a benzimidazole derivative may optionally comprise an intra-granular diluent whereas the extra-granular diluent is mixed with the final individually enteric-coated cores/ units to form multiple-unit tablets. Diluents that can be used include mannitol, lactose, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, starch, pregelatinized starch, sorbitol or mixtures thereof.

According to the invention, two or more extra-granular diluents are employed to minimize the problem of particle segregation and consequently avoid problems in tablet manufacturing. There is no need to use diluents having differing particle size i.e. one diluent having larger particle size and one diluent having smaller particle size, as suggested in the prior arts. It has been found that use of diluents possessing "similar particle size" does not hinder the process of compressing multiple-units together and the problem of particle segregation reported in the literature can be avoided. Particle segregation in the tabletting mixture results in tabletting problems, such as weight variation and poor content uniformity. The term "similar particle size" means average particle size of extra-granular diluents is same or equal and wherein the volume weighted median diameter (d50) of the particles of the diluents used is less than 300um, preferably from about l00um to about 250um.

Suitable binders include one or more of cellulose derivatives, such as hydroxypropyl cellulose, hydroxy ethyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose, methylcellulose; gums, such as xanthan gum, gum acacia, tragacanth; water-soluble vinylpyrrolidone polymers, such as polyvinylpyrrolidone, copolymer of vinylpyrrolidone and vinyl acetate; sugars, such as sorbitol, mannitol and mixtures thereof.

Suitable disintegrant include one or more of; cross-linked polyvinylpyrrolidones, modified starches, particularly sodium starch glycolate, modified celluloses and L-HPC (low substituted hydroxypropyl cellulose), croscarmellose sodium (commercialized under the trade name Ac-Di-Sol™) and sodium starch glycolate (commercialized under the trade names Primojel™ and Explotab™). Kollidon™ CL and Polyplasdone™ XL are commercial crospovidone products.

The term "lubricant" as used herein is intended to mean substances used in tablet formulations to reduce friction during tablet compression. Suitable lubricants according to the invention can be selected from calcium stearate, magnesium stearate, sodium lauryl sulfate, talc, mineral oil, stearic acid, zinc stearate, colloidal silicon dioxide, glyceryl behenate, polyethylene glycol, sodium stearyl fumarate, hydrogenated cottonseed oil, sodium benzoate, leucine or combinations thereof and other such materials known to those of ordinary person skilled in the art.

Glidant can be selected from a group consisting of: silicon dioxide, colloidal silicon dioxide, fumed silicon dioxide, sodium aluminosilicate, calcium silicate, powdered cellulose, microcrystalline cellulose, corn starch, sodium benzoate, calcium carbonate, magnesium carbonate, asbestos free talc, metallic stearates, calcium stearate, magnesium stearate, zinc stearate, Stear-o-wet™ C, magnesium lauryl sulfate, or magnesium oxide, where colloidal silicon dioxide is the preferred glidant.

Examples of suitable solvent employed in the preparation of present composition include aqueous, alcoholic and hydro-alcoholic solvents and is preferably selected from water, isopropyl alcohol, methanol, ethanol and mixture thereof. The solvent of choice for the preparation of the cores is water.

Brief manufacturing process:

A) Drug layering:

a. Dissolve hydroxy propyl cellulose- LF in purified water under stirring.

b. Disperse esomeprazole magnesium and crospovidone in the solution of step a.

c. Sift sugar spheres through suitable mesh or screen and load them in the bowl of wurster
coater.

d. Spray the dispersion of step no. b onto the sugar spheres till there is complete drug loading on the sugar spheres.

B) Sub coating:

e. Dissolve mannitol in purified water with stirring.

f. Spray the solution of step no. e onto the drug loaded pellets of step no d till a desirable weightgain is achieved.

C) Enteric coating:

g. Dissolve glyceryl monostearate and polysorbate 80 in hot purified water with high speed stirring. Cool the solution to room temperature. With continuous stirring, add triethyl citrate.

h. Disperse talc and titanium dioxide in colloidal mill with purified water.

i. Take methacrylic acid - ethyl acrylate co-polymer (1:1) dispersion 30%, add the solution of step no g and h with stirring continued slowly for suitable period of time.

j. Spray the dispersion of step no. i onto the sub coated pellets of step no f till a desirable weight gain is achieved.

D) Blending:

k. Blend the enteric-coated pellets with sifted Silicified microcrystalline cellulose and polyethylene glycol 6000 for sufficient period of time.

1. Lubricate the blend of step k with sodium stearyl fumarate for sufficient period of time.

£) Compression:

m. Compress the lubricated blend into tablets using rotary compression machine. F) Film Coating:

n. Disperse Opadry™ in purified water with stirring.

o. Spray the dispersion of step no. n onto the compressed coated tablets of step no m till a desirable weight gain is achieved.

Table II: Comparative data for Examples 1 to 9:

Ex. % % % Process Acid Hardness Acid
No. TEC GMS Tween™ Challenge release of Resistance of
80 Compressed compressed
Tablets (Kp) Tablets (%)
1 15 - none 5,0 12J) 8.5
1 15 - none 5X) 15X) 11.0
1 15 - none 5J) lO 15.2
2 30 - -- high% 12.7 13 13.5 rejections
3 50 -- - Extremely 16.9 15 12.5
high %
rejections
4 30 - none 12.6 14 12.0
5 30 - none 12.2 13 11.5
6 30 - none 12.1 12 11.0
7 30 5 0.5 none 10.6 12.0 15.0
8 30 15 1.5 none 9.2 12.0 12.7
9 30 25 2.5 none 0.5 12.0 1.3
9 30 25 2.5 none 0.5 12.0 1.6
9 | 30 1 25 I 2.5 1 none [ 0.5 [ 18.0 | 1.8

Observations and Conclusions:

In case of example 1, where the enteric coating only contains a water-soluble plasticizer at a concentration of around 15%, the processing of the pellets did not provide any particular challenges related with the manufacturing process. The acid resistance of the intact enteric-coated pellets in 0.1N HC1 for 2 hrs was also satisfactory. But when these pellets were compressed into tablets along with other tabletting excipients the acid resistance behavior of the compressed tablets was not satisfactory. As the compression pressure was increased for increasing the hardness the tablets failed to pass the acid resistance test. In example 2, where the water-soluble plasticizer concentration was increased to around 30%, the manufacturing process was troublesome with large amounts of agglomerates being formed during the process. The acid resistance of the core pellets was also not satisfactory. In example 3, the water-soluble plasticizer concentration was increased to 50% by dry weight of enteric coating polymer; the process was associated with high amounts of rejection. Agglomerates of pellets were observed during the process. Further the enteric-coated pellets failed to pass the acid resistance test. Hence the enteric coating composition was further modified so as to get an enteric coating which provides satisfactory results.

As a modification to the processing challenge observed with 30% of water-soluble plasticizer in example 2, 10% talc was incorporated in the formulation (as in example 4). This modification helped to solve the processing challenges and the extent of agglomerates formed in the process was reduced to negligible. But the acid resistance of the enteric-coated pellets was not achieved to the desired extent. Hence attempts were made to improve the acid resistance of the pellets by increasing the percentage coating build-up to 70.00% and 90.00% upon the weight of sub-coated pellets (as shown in example 5 and example 6 respectively). But none of these approaches improved the acid resistance of the enteric-coated pellets. This challenge to achieve the desired acid resistance of the uncompressed pellets were assumed to be due to the channeling effects of the water-soluble plasticizer triethyl citrate which caused the penetration of the aqueous media across the enteric coat and effect the acid resistance of the pellets. Hence the enteric coating composition was further modified so as to get an enteric coating which provides satisfactory results.

To counteract the channeling effects of the water-soluble plasticizer triethyl citrate, a water-insoluble plasticizer glyceryl mono-stearate (GMS) was incorporated in the coating composition along with another water-soluble plasticizer cum surfactant in different proportions as shown in examples 7, 8 and 9.

Satisfactory acid resistance values of the enteric-coated pellets were not achieved by use of glyceryl mono-stearate at a concentration of 5% and 15%. But at a concentration of above 20%, pellets with adequate acid resistance were obtained. Moreover these pellets showed excellent compression behavior, the acid resistance of the compressed tablets hardly changed with respect to that of the uncompressed pellets and also these pellets showed sufficient compressibility while maintaining their integrity upon a wide range of tablet hardness thus facilitating a robust formulation. The amount of water-soluble plasticizer can vary from about 50% to about 80%) by weight of total amount of plasticizer in the enteric polymer layer and the amount of water-insoluble plasticizer can vary from about 20%> to about 50% by weight of total amount of plasticizer in the enteric polymer layer. The weight ratio of water-soluble plasticizer to water-insoluble plasticizer is about 1:0.2 to about 1:1.

Increased concentration of plasticizers in the coating is also associated with alteration in the release pattern of the pellets itself, the release being faster if the plasticizer is water-soluble and the reverse if the plasticizer is water insoluble. To achieve a desired release profile from the pellets proper selection of the type and concentration of the plasticizers is required. In this regard it is beneficial to use more than one plasticizer (one or more water-soluble plasticizers together with one or more water-insoluble plasticizers) each with optimum concentration.

Effect of pellet size on drug release and acid resistance:

Acid release of the enteric-coated pellets also depends upon final size of the coated pellets. An acid release of 3% (after 2hrs in 0.1N HC1) is achieved for enteric-coated pellets having mean size around 1200 microns (#14mesh) at around 55.00% of enteric coating build-up upon sub-coated pellets. Whereas to achieve the same for smaller sized pellets of around 600 microns (# 30mesh) it requires more than 150% enteric coating build-up upon sub-coated pellets. Hence to provide such a large build-up of enteric coat, the process becomes time consuming and uneconomical. Also with such a huge build-up the proportion of pellets in the MUPS tablet becomes more and an increase in tablet dimensions becomes necessary. But increase in tablet dimension beyond the range will render the tablet less patient compliant. Hence the final pellet size should be around 800 to 1400 microns. The effect of pellet size on percent coating build-up is described in below table - III.

Table III:

Formulation Acid release % Coating build-up
after 2 hrs
Enteric-coated pellet size of 600 3% > 150% w/w based on wt of sub-
microns coated pellets
Enteric-coated pellet size of 800 3% > 100% w/w based on wt of sub-
microns coated pellets
Enteric-coated pellet size of more than 3% 55% w/w based on the wt of sub-
1200 microns coated pellets

Effect of non-polymeric sub-coatings on stability of the product:

The use of sub-coat is to preventing direct contact of benzimidazole and the enteric coating polymer. It has been surprisingly found that use of non-polymeric materials results in better stability as compared to formulation where only polymeric separating layer is used. For comparison purpose two compositions were formulated one comprises on a non-polymeric sub-coat comprising of mannitol and the second sub-coat comprises povidone. The effect of these two different sub-coats on the stability of the composition is described in below table - IV.

Table IV:

S. Ingredients Example 10 Example 11
No.
1 Esomeprazole 40.00 40.00
2 Sugar spheres 100.00 100.00
3 Crospovidone 40.00 40.00
4 Hydroxy propyl cellulose-LF 20.00 20.00
5 Purified water qs qs
B) Sub-Coating __
6 I Mannitol I 30.00 I
7 Purified Water gs —
8 Povidone -- 10.950
9 Talc -- 39.840
10 Macrogol6000 -- 1.100
11 Silica, Colloidal anhydrous -- 0.550
12 I Purified water -- qs
C) Enteric Coating
13 I Methacrylic acid-ethyl I 962 I 95.15
acrylate co polymer (1:1) Dispersion 30 %
14 Triethyl citrate 28.9 28.7
16 Glycerol monostearate 14.4 23.9
17 Polysorbate 80. 14 2.4
18 Talc 9.6 9.6
19 Purified water qs qs
D) Blending and Compression
20 I Silicified Microcrystalline Cellulose I 500.00 I 500.00
21 Crospovidone 80.00 80.00
22 Macrogol 6000 100.00 100.00 '
23 Sodium Stearyl Fumarate 10.00 10.00
24 ~Qpadry'M 20.00 20.00
25 Purified water qs qs

As shown in the examples above the formulation example 10 has a mannitol sub-coat, whereas the formulation of example 11, sub-coat only contains povidone and is devoid of mannitol. It is clear from 30 days accelerated stability data that the total impurity has increased in the formulation which is devoid of mannitol, as compared to formulation comprising mannitol in the sub-coat. So incorporation of mannitol in the sub-coating directly over the drug layer in the formulation results in stabilization of the formulation and lesser amounts of impurities are generated.

Table V: Related substances data after 30 days storage at accelerated storage condition

Related substances Example 10 Example 11
Desmethoxy impurity 0.05% 0.10%
2-Mercapto-5-methoxy 0.05% 0.15%
Benzimidazole
N-oxide impurity 0.05% 0.10%
Sulphone impurity 0.02% 0.12%
Sulphide impurity 0.04% 0.09%
Single unknown impurity 0.04% 0.45%
Total impurity | 0.20% | 1.01%
Example 12:
Ingredients Qty/unit (mg)
Core Pellets
Omeprazole I 40.000
Mannitol 236.000
Microcrystalline cellulose 6.000
Lactose anhydrous 16.000
Sodium carbonate anhydrous 1.200
Sodium lauryl sulphate 1.000
Hydroxypropyl cellulose LF 9.000
Water qs
Sub coating
Mannitol I 38.959
Water 3s
Enteric coating
Eudragit L30 D55 1 74.62
Triethyl citrate 22.38
Glyceryl mono stearate 18.65
Tween 80 1.86
Talc 7.46
Water qs

Blending and Compression

Silicified Microcrystalline Cellulose 200.00
Lactose 200.00
Crospovidone 80.00
Macrogol 6000 100.00
Sodium Stearyl Fumarate 10.00

Brief Manufacturing Process: Core pellets

a. Dissolve hydroxypropyl cellulose LF in water.

b. Sift omeprazole and disperse in dispersion of step a.

c. Dissolve sodium carbonate anhydrous in purified water and add to step b dispersion.

d. Mixing mannitol, microcrystalline cellulose, lactose anhydrous, sodium carbonate anhydrous, and sodium lauryl sulfate.

e. Granulate the step d materials by using the binding solution of step c to get the desired wet mass.

f. Prepare the extrudates of wet mass using 1.20 mm screen in extruder.

g. Spheronize the extrudates using 3.00 mm chequered plate in spheronizer.

h. Dry the pellets in dryer.

i. Sift the dried pellets through suitable sieve. Separating Layer:

j. Disperse mannitol in purified water.

k. Spray the step k dispersion onto the pellets, till desired weight gain is achieved.

Enteric coating:

1. Dissolve glyceryl mono stearate and polysorbate 80 in hot purified water with high speed stirring. Cool the solution to room temperature. With continuous stirring, add Triethyl citrate.

m. Disperse talc and titanium dioxide in colloidal mill with purified water.

n. Take methacrylic acid-ethyl acrylate copolymer (1:1) dispersion 30 %. Add the solution of step no 1 and m, stirring continued slowly for suitable period of time.

o. Spray the dispersion of step no. n onto the sub-coated pellets of step no k till a desirable weight gain is achieved.

D) Blending:

p. Blend the cellulose coated pellets with sifted Silicified microcrystalline cellulose and polyethylene glycol 6000 for sufficient period of time.

q. Lubricate the blend of step k with sodium stearyl fumarate for sufficient period of time.

E) Compression:

r. Compress the lubricated blend into tablets using rotary compression machine.

Example 13:

Ingredient Qry/unit
Core
Lansoprazole 30 mg
Sugar Spheres 150 mg
Magnesium carbonate, heavy 20 mg
Sucrose 20 mg
Corn Starch 20 mg
Low substituted, Hydroxypropyl Cellulose 20 mg
Hydroxypropyl Cellulose 4 mg
Purified Water | QS
Sub coating
Mannitol 30 mg
Water qs
Enteric coating

Methacrylic acid Copolymer Dispersion 35 mg
Talc 10 mg
Triethylcitrate 10 mg
Cetyl alcohol 10 mg
Titanium Dioxide 2 mg
Polysorbate 80 0.1 mg
Colloidal Silicon Dioxide 0.2 mg
Blending
Silicified microcrystalline cellulose 300 mg
(SMCC 90)
Silicified microcrystalline cellulose (HP 90) 200 mg
Crospovidone 50 mg
Polyethylene glycol 20 mg
Sodium Stearyl fumarate 10 mg

Brief Manufacturing Process:

A) Binder Solution

a. Dissolve hydroxypropyl cellulose in purified water under stirring till a clear solution is obtained.

B) Sifting

b. Sift low-substituted hydroxypropyl cellulose, corn starch and sucrose together through a suitable sieve or screen.

c. Sift lansoprazole, magnesium carbonate, low-substituted hydroxypropyl cellulose, corn starch and sucrose together through a suitable sieve or screen.

C) Blending

d. Blend the ingredients of step no. b in a blender for suitable period of time (Blend 2).

e. Blend the ingredients of step no. c in a blender for suitable period of time (Blend 1).

D) Solid Powder Layering

e. Load sugar spheres onto the plate of solid drug layering machine revolving at a suitable rpm. Start spraying binder solution at suitable atomization. When sugar spheres are sufficiently wet spray/ add drug layering blend (Blend 1). As soon as the spray of Blend 1 is over, start the spray sub-coat blend (Blend 2). When the spray of Blend 2 is over, continue the spray of binder solution for a suitable period of time. Unload the sub-coated wet pellets in a suitable container.

E) Drying

f Dry the wet pellets of step no. e in vacuum tray dryer at a suitable temperature and pressure till the desired loss on drying is achieved.

F) Sifting

g. Sift the dried pellets of step no. f through a pair of suitable sieves.

G) Enteric Coating

h. Dissolve triethylcitrate, glyceryl monostearate and polysorbate 80 in hot purified water under stirring till a clear dispersion is obtained. To this solution add talc and titanium dioxide and homogenize/ mix for suitable period of time.

i. Take methacrylic acid copolymer dispersion and add to it the dispersion of step no. h and homogenize/ mix for suitable period of time.

j. Spray the dispersion of step no. i onto the sifted pellets of step no g till a desirable weight gain is achieved.

H) Blending and Compression

k. Blend the lubricated pellets with silicified microcrystalline cellulose, polyethylene glycol, crospovidone and sodium stearyl fumarate.

1. Compress the lubricated blend into tablets using suitable punch.

WE CLAIM:

1. A stable multiple-unit pharmaceutical composition comprising:

a) individually enteric-coated cores comprising:

i) a benzimidazole compound selected from omeprazole or esomeprazole or their pharmaceutically acceptable salts,

ii) at least one separating layer containing a sugar alcohol,

ii) at least one enteric coating layer,

b) a mixture of two or more tablet diluents of similar particle size,wherein said enteric coating layer comprises a mixture of at least one water-soluble plasticizer and at least one water-insoluble plasticizer, having a weight ratio from about 1:0.2 to about 1:1, relative to each other.

2. The pharmaceutical composition according to claim 1, wherein said mixture of water-soluble plasticizer and water-insoluble plasticizer is present in an amount from about 55% to about 75%, by weight with respect to the dry weight of enteric polymer.

3. The pharmaceutical composition according to claim 1, wherein said water-soluble plasticizer is selected from triethyl citrate, triacetin, propylene glycol, polyethylene glycol, polysorbate 80 or mixtures thereof.

4. The pharmaceutical composition according to claim 1, wherein said water-insoluble plasticizer is selected from dibutylsebacate, diethyl phthalate, dibutylphthalate, fractionated
coconut oil, oleic acid, cetyl alcohol, glyceryl monostearate, acetyl tributylcitrate, acetyl triethylcitrate, tributyl citrate or mixtures thereof.

5. The pharmaceutical composition according to claim 1, wherein said sugar alcohol is selected from mannitol, xylitol, sorbitol, maltitol, lactitol or mixtures thereof

6. The pharmaceutical composition according to claim 1, wherein said tablet diluent is selected from mannitol, lactose, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, starch, pregelatinized starch, sorbitol or mixtures thereof.

7. The pharmaceutical composition according to claim 1, wherein said tablet diluent has a volume weighted median diameter (d50) from about 100 µm to about 250 µm.

8. The pharmaceutical composition according to claim 1, said benzimidazole compound is amorphous esomeprazole magnesium.

9. A process for preparing stable multiple-unit pharmaceutical composition, wherein said process comprises the steps of:

a) preparing individually enteric-coated cores comprising:

i) a benzimidazole compound selected from omeprazole and esomeprazole or their pharmaceutically acceptable salts,

ii) at least one separating layer containing a sugar alcohol,

ii) at least one enteric coating layer,

b) blending cores of step (a) with
iii) at least two extra-granular tablet diluents of similar mean particle size; and

iv) optionally other pharmaceutically acceptable excipients; and

c) compressing said blend of step (c) to form multiple-unit tablet;

wherein said enteric coating layer comprises a mixture of at least one water-soluble plasticizer and at least one water-insoluble plasticizer, having weight ratio from about 1:0.2 to about 1:1, relative to each other.

10. A stable multiple-unit pharmaceutical composition comprising:

a) individually enteric-coated cores comprising:

i) esomeprazole magnesium,

ii) a separating layer consisting of mannitol,

ii) at least one enteric coating layer,

b) a mixture of mannitol and microcrystalline cellulose of similar particle size, wherein said enteric coating layer contains a mixture of triethyl citrate and glyceryl monostearate, having a weight ratio of 0.85:0.15.