WO2011144975A1

WO2011144975A1 - Multi-unit compositions

Info

Publication number: WO2011144975A1
Application number: PCT/IB2011/000806
Authority: WO
Inventors: Pratik Kumar; Gour Mukherji; Pulak Kumar Metia
Original assignee: Jubilant Life Sciences Ltd
Current assignee: Jubilant Pharmova Ltd
Priority date: 2010-05-15
Filing date: 2011-04-12
Publication date: 2011-11-24
Anticipated expiration: 2012-11-15
Also published as: CN102762198A

Abstract

Disclosed herein a compressed tablet composition comprising (a) coated multiple units, containing at least one active pharmaceutical ingredient, (b) at least one compressibility enhancing agent comprising neutral spheres, (c) at least one cohesiveness imparting agent comprising binder(s). Such a composition provides solution to chipping, cracking and leaking problems associated with compression of coated multiple units (pellets or beads).

Description

Multi-Unit Compositions

Field of invention

The present invention relates to a multiple unit compressed tablet composition.

Background of the Invention

Multiple unit dosage forms are multiparticulate drug delivery systems consisting of a plurality of pellets, granules, spherules, microspheres, minitab!ets or other drug containing agglomerations of particles that can be loaded into either a capsule or compressed into tablets. Multiple unit dosage forms offer numerous significant advantages over traditional single unit dosage forms. These include decreased variability of gastric emptying, lessened dependency on the nutrition state, reduced risk of high local drug concentration within the gastro-intestinal tract, lower intra- and inter- individual variability, controlled onset time of drug release and delivery of acid sensitive active ingredient to the lower end of intestines and extended release of highly water soluble active ingredients.

However, multiple unit compositions also pose many disadvantages. Their manufacturing is very complicated, especially manufacturing of multiple-unit tablet compositions offer significant formulation challenges.

Coating of formulated substrates is well known in the pharmaceutical art. Coating performs numerous functions. It modifies the release of the drug from dosage form, i.e. extended or delayed release of the active pharmaceutical ingredient (API), taste-masking of the API, and protection from detrimental effects of environmental conditions and co- processed excipients. The very purpose of the coating is defeated when it is damaged during processing of coated multiple units into tablets while subjecting it to compression pressure required for the conversion. This phenomenon is very pronounced when the coated substrate is of relatively higher size range. Besides, there are other onerous challenges in formulating the coated substrates into compressed tablets. It has been noticed that compression of coated multiple units or pellets may result in cracks and chipping in the compressed mass (tablets) which could be due to lack of cohesiveness in the compression mixture and entrapment of air in the compacted conglomerate. These surface fissures not only result in dismal aesthetics but also leads to high rejection rates and hence unacceptably low yield of finished product. Inelegant appearance of the product also leads to poor patient acceptability. Furthermore, TGA and other international medicine and health regulatory authorities, e.g. USFDA and MHRA, impose exacting registration requirements for these products.

References in prior arts describe pharmaceutical compositions dealing with the problem of mechanical damage of the coatings resulting from compression force leading to loss of functionality of coating and content uniformity.

Multiple unit tableted dosage forms (MUPS) comprising proton pump inhibitors or their alkaline salts are described in EP0723437. MUPS are produced by combining enteric coated beads and tablet excipients in the ratio of 60 to 40 and subsequently, subjecting the blend to compression. Compositions disclosed in this reference employ a high concentration of plasticizer in the coating layer and overcoating layer of polymers to resist the mechanical damage to the coating.

EP0548356 supposedly teaches an orally disintegrating MUPS, comprising microcrystals and microgranules of active pharmaceutical ingredients having a taste-masking coating. Said composition further comprises disintegrating and swelling or soluble agents.

US7314640, assigned to Andrx, discloses MUPS comprising extended release coated granules of metoprolol succinate, superdisintegrants, cushioning agent, filler and lubricant.

EP 1837016 discloses pharmaceutical multiple unit compositions that comprise coated active ingredient units and protected granules comprising microcrystalline cellulose and polyethylene glycol. Said compositions show improved resistance against mechanical damage.

WO2010/018593 discloses gastric acid resistant benzimidazole multiple unit tablet compositions comprising enteric-coated pellets containing benzimidazole compounds and cushioning agents in the form of polyethylene glycol. WO2008/014175 discloses wet granulation of the coated particles of active pharmaceutical ingredients using binder and silicified microcrystalline cellulose and subsequent compression after addition of disintegrant and lubricant. Such composition affords better content uniformity.

Objective of the Invention

The main objective of the present invention is to provide a multiple unit compressed tablet composition, which has a smooth surface and is free of cracking, chipping, capping, and pinholes problems.

Another objective of the composition of the present invention is to improve the yield of compressed tablet comprising coated multiple units. Another objective of the composition of the invention is to prevent or minimize the damage to coating of multiple units following compression.

Summary of the Invention

The present invention relates to a compressed tablet composition of functionally coated multiple units comprising at least one active pharmaceutical ingredient and at least one functional coating. The composition of the present invention provides a solution to the chipping, cracking and leaking problems associated with compression of coated multi units (pellets or beads). Moreover, the tablet composition of the present invention is elegant in appearance, which aids to patient's acceptability of dosage form.

In one aspect, there is provided a compressed tablet composition comprising (a) coated multiple units comprising at least one pharmaceutically active ingredient and at least one functional coating, (b) at least one compressibility enhancing agent comprising neutral spheres, (c) at least one cohesiveness imparting agent comprising binder(s), and (d) optionally, other compression excipients.

Preferably, the compressibility enhancing agent(s) comprising neutral spheres, the cohesiveness imparting agent(s) including binder(s) and the optional other compression excipients are incorporated extragranularly. The multiple units of the present composition are selected from granules, pellets, beads, seeds and particles. The preferred multiple units are pellets or beads. The active ingredients are either incorporated in the granules or layered on the beads or pellets with or without the use of binders.

The multiple units of the composition also comprise at least one functional coating. For the composition of the present invention, functional coatings are selected from sustained or extended release coating designed to extend the release of the drug from the core, delayed release coating, taste-masking coating, coating to impart stability to the underlying or overlaying active pharmaceutical ingredient, or coating to modify the texture of the multiple units to ease further processing. The stability protection can be from environmental constituents or other excipients of the composition. Multiple units of present composition can also have combinations of the above-mentioned coatings. The coated multiple units constitute from 20% to 60 %, preferably from 30% to 50% by weight of the total tablet weight. For the purpose of this invention, concentration (expressed as percentage) of all components are based on the total tablet weight.

The ratio of compressibility enhancing agents and cohesiveness imparting agents may be beneficial for the composition of the present invention. Preferably, the ratio of compressibility enhancing agents and cohesiveness imparting agents is from 8:1 to 2:1, more preferably, the ratio is from 6:1 to 4:1.

The compressibility enhancing agents comprise neutral spheres. Neutral spheres used in the tablet composition of present invention may be selected from microcrystalline cellulose spheres (Celphere®), sugar spheres (Non-pareil Seeds) and cornstarch spheres, or any combinations thereof. Neutral spheres made up of silicon dioxide, dicalcium phosphate, calcium stearate, magnesium stearate, glass, polypropylene, polyethylene, ethylcellulose, hydroxy ethylcellulose and the like are also contemplated for the composition of the present invention.

The neutral spheres constitute from 2% to 40%, preferably 5% to 30%, more preferably from 5% to 20 % by weight of total tablet weight. The cohesiveness imparting agents, which are vital ingredients in the compressed tablet composition of the present invention, comprise binders. These are selected from the category of (1) natural polymers, e.g. starch, pregelatinized starch, gelatin, acacia gum, alginic acid, sodium alginate, xanthan gum, locust bean gum, karaya gum, tragacanth, Anacardium occidentale gum, kharaya gum, veegum and detarium gum ; (2) sugars, e.g. sucrose, glucose (dextrose), sorbitol, mannitol and maltrodextrins; (3) synthetic polymers, e.g. polyvinylpyrrolidone (povidone), cross-linked polyvinylpyrrolidone, vinylpyrrolidone vinyl acetate copolymer (Kollidon® VA 64), hydroxypropyl methylcellulose (hypromellose), hydroxypropyl cellulose, methyl cellulose, sodium carboxy methyl cellulose, polyethylene glycol, ethyl cellulose, polyvinyl alcohol, microcrystalline cellulose and polymethacrylates (Eudragit) e.g. Eudragit NE30 D, Eudragit RS 30D, Eudragit EPO, Eudragit LI 00, or any combinations thereof. The preferred binder is povidone available under the brand name Kollidon® from BASF Corporation. Kollidon has the versatility of being used as a dry or a wet binder. Preferably, binders constitute from 0.5 % to 15 %, more preferably from 2 % to 10 % by weight of the total tablet weight.

Preferably, the ratio of neutral spheres to binder(s) is from 2:1 to 8:1, more preferably from 4:1 to 6:1.

An active pharmaceutical ingredient contemplated for the present invention is any active ingredient which produces desired therapeutic response in human or animal body when administered in the recommended manner. The categories of active pharmaceutical ingredients are (a) proton pump inhibitors, e.g., esomeprazole, omeprazole, lansoprazole, pantoprazole, rabeprazole and the like; (b) beta blockers, e.g., atenolol, bisoprolol, esmolol, propranolol and metoprolol and the like; (c) antidepressants, e.g. duloxetine, venlafaxine, tolterodine, olanzapine and the like; (d) antiallergic agents, e.g. cetirizine, loratadine, desloratadine, fexofenadine and montelukast and the like; (e) non-steroidal anti-inflammatory drugs, e.g. indomethacin, diclofenac sodium or potassium and the like; (f) antipyretics and analgesics, e.g. paracetamol, aspirin, mefenamic acid, tramadol and the like; (g) antimigraine agents, e.g. sumatriptan, rizatriptan, clonazepam, zolmitriptan, frovatriptan, naratriptan, eletriptan, almotriptan and the like; (h) anti- epileptic drugs, e.g. carbamazepine, lamotrigine, levetiracetam and the like; (i) anti- emetics, e.g. domperidone, metoclopramide and ondansetron and the like. Other pharmaceutical active ingredient categories may include, without limitation, antacids, antibiotics, antimicrobials, antispasmodics, anti-anxiety agents, cholesterol lowering agents, hormones, enzymes, antitussives, antidiarrheals, antivirals, laxatives, anorexics, antihistamines, antiasthmatics, mucoregulators, antidiuretics, antiflatuents, antiepileptic agents, biologicals, antispasmodics, sedatives, antipsychotics (risperidone, quetiapine and the like), antihyperactives, antihypertensive, tranquilizers, decongestants, and combinations thereof. Any combination of above mentioned active pharmaceutical ingredients can also be used for the composition of the present invention.

Various other tabletting excipients include fillers, cushioning agents, disintegrants, flavoring agents, sweeteners, colorants, anti-adherents, glidants, lubricants and the like. Although a preferred method of manufacturing the composition of the present invention is direct compression, other conventional methods of manufacturing, such as wet granulation or dry granulation followed by compression, are also within the scope of the present invention. Detailed Description of the Invention

Definitions

Coated multiple units: As used herein, the term 'coated multiple units' refers to multiple inert cores which are coated with, not necessarily in that order, seal coating, drug layering, sub-coating and/or functional coating. Constituents of coated multiple units constitute the intragranular constituents. For the purpose of present invention, coated multiple units are also termed as pellets or beads Multiple unit tablets. As used herein, the term 'multiple unit tablet' refers to a tablet formed by compression or tableting of coated multiple units along with neutral spheres, binders and other tabletting excipients like fillers, disintegrants, cushioning agents, lubricants, and anti-adherents.

Extragranular constituents: As used herein, the neutral spheres, binders and other tabletting excipients like fillers, disintegrants, cushioning agents, lubricants, and anti- adherents are extragranular constituents. Extragranular constituents facilitate the tabletting or compression of coated multiple units into tablets.

Yield. As used herein, the term 'yield' is the percentage number calculated by dividing the number of actual accredited tablets by theoretical number of tablets in a

predetermined batch size.

Capping: As used herein, the term 'capping' refers to, when the upper or lower segment of the tablet separates horizontally, either partially or completely from the main body of a tablet and comes off as a cap during ejection from the tablet press, or during subsequent handling.

Cracking: As used herein, the term 'cracking' refers to small, fine cracks observed on the upper and lower central surface of tablets, and/or on the sidewall of the tablet

Leaking: As used herein, the term 'leaking' refers to the observation of coated multiple- units coming out of compressed tablet.

Coated multiple units

Coated multiple units of the present invention are preferably prepared by drug layering on inert cores. Inert cores of the present invention can be water-soluble, water-swellable and water-insoluble. Non-pareil seeds (NPS) or sugar spheres exemplifies inert core of water-soluble type. NPS are white, spherical particles of 62-92% sucrose and rest starch. NPS are commercially available from JRS Pharma, USA in various sieve sizes. Suitable examples of water swellable cores are microcrystalline cellulose spheres, commercially available from FMC Corporation under the trade name CELPHERE^®. Exemplary water- insoluble inert cores are glass beads and coarse grade silicon beads. The inert core must be of sufficient density and strength to withstand stress and strain of coating process. Preferably, inert core for the tablet of the present invention is CELPHERE^®. Preferably, size of inert cores are selected from the following sieve sizes: 40-60 mesh sieve (250-425 μιη), 40-50 mesh size (420-300μπι), 35-40 mesh sieve (425-500μπι), 30-35-mesh sieve (500-600μπι), 25-30 mesh sieve (600-710 μπι), 20-25 mesh sieve (710-850μπι), 18-20 mesh sieve (850-1000μπι), 16-18 mesh sieve (1000-1180 μπι), 14-16 mesh sieve (1000- 1400 μπι).

In a more preferred embodiment the inert cores have a diameter ranging from about 250 to 600 μπι, preferably from 300 to 500μηι and most preferable 300 to 420μπι. Alternatively, combination of above-mentioned sieve sizes can be employed. Preferably, inert core constitute from about 5% to about 30% by weight of the coated multiple-units, more preferably, from about 10 % to about 25% by weight of coated multiple units.

The inert core is coated with aqueous or non-aqueous dispersion/suspension/solution essentially comprising of active pharmaceutical ingredient, and optional binder, and optionally other pharmaceutically acceptable excipients such as, filler, stabilizers, surfactant, anti-tacking agents, and the like.

An active pharmaceutical ingredient contemplated for the present invention is any ingredient which produces a desired therapeutic response in human or animal body when administered in the recommended manner. The categories of active pharmaceutical ingredients are (a) proton pump inhibitors, e.g., esomeprazole, omeprazole, lansoprazole, pantoprazole, rabeprazole and the like; (b) beta blockers, e.g., atenolol, bisoprolol, esmolol, propranolol and metoprolol and the like; (c) antidepressants, e.g. duloxetine, venlafaxine, tolterodine, olanzapine and the like; (d) antiallergic agents, e.g. cetirizine, loratadine, desloratadine, fexofenadine and montelukast and the like; (e) non-steroidal anti-inflammatory drugs, e.g. indomethacin, diclofenac sodium or potassium and the like; (f) antipyretics and analgesics, e.g. paracetamol, aspirin, mefenamic acid, tramadol and the like; (g) antimigraine agents, e.g. sumatriptan, rizatriptan, clonazepam, zolmitriptan, frovatriptan, naratriptan, eletriptan, almotriptan and the like; (h) antiepileptic drug, e.g. carbamazepine, lamotrigine, levetiracetam and the like; Other pharmaceutical active ingredient categories may include, without limitation, antacids, antibiotics, antimicrobials, anti-emetics, antispasmodics, antianxiety agents, cholesterol lowering agents, hormones, enzymes, antitussives, antidiarrheals, antivirals, laxatives, anorexics, antihistamines, antiasthmatics, mucoregulators, antidiuretics, antiflatuents, antiepileptic agents, antimigraine agents, biologicals, antispasmodics, sedatives, antipsychotics (risperidone, quetiapine and the like), antihyperactives, antihypertensive, tranquilizers, decongestants, and combinations thereof. Any combination of above mentioned active pharmaceutical ingredients can also be used for the composition of the present invention. Preferably, the active pharmaceutical ingredient (s) constitute from about 5% to about 60 % by weight of coated multiple units.

In one embodiment, the most preferred active pharmaceutical agents are esomeprazole, lansoprazole, omeprazole, olanzapine and metoprolol.

Suitable examples of preferred intragranular binders are polyvinyl pyrrolidone, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyacrylate, and ethyicellulose. In the most preferred embodiment of the present invention, the binder is hydroxypropyl cellulose (HPC). HPC, for binder use, is commercially available from Aqualon, USA under the brand name lucel^® EF and EXF. Binders) constitute up to 15%, preferably from upto 5% by weight of the coated multiple units.

Suitable anti-tacking agents include, but are not limited to, talc, silicon dioxide and magnesium stearate. Anti-tacking agent constitutes preferably upto 1% by weight of the coated multiple units.

The drug layer is applied to the inert core by any conventional techniques known in the art, such as, pan coating, roto-granulation or fluidized bed coating. During such coating operations the drug is dispersed or dissolved or suspended in an organic or aqueous solvent, which can also contain above-mentioned excipients. The solvent system used for processing the drug layer can be aqueous or non aqueous. Appropriate non-aqueous solvents can be alcoholic, such as methanol, ethanol, isopropyl alcohol (IPA); hydro- alcoholic, such as water-IPA; organic solvents, such as acetone, methylene chloride or any combination of those mentioned above. In a preferred embodiment, as aqueous solvent, purified water is employed and drug layering is carried out in fluid bed processor fitted with a Wurster apparatus.

Drug layering constitutes from 5% to 50% by weight of coated multiple units. A separating coat can be applied between the API-containing layer and functional coating layer or between API containing layer and the inert core. Separating coat comprises water-soluble and/or water insoluble polymers, anti-tacking agents and, optionally, alkaline or acidic agents and filler. Water-soluble polymer is exemplified by hydroxy propyl cellulose or hydroxy propyl methylcellulose, and polyethylene glycols

(macrogol e.g. PEG- 6000), while preferred water insoluble polymer is ethyl cellulose. Fillers are exemplified by sucrose, lactose, mannitol, xylitol and sorbitol. Anti-tacking agents may be talc, colloidal silicon dioxide or glyceryl monostearate. Various alkaline agents contemplated are sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide and magnesium oxide. Examples of organic acids are citric acid, fumaric acid and tartaric acid. The separating coating can be applied by a fluid bed processor.

The coated multiple units of the composition also comprise at least one functional coating. For the composition of the present invention functional coatings are selected from sustained or extended release coatings designed to extend the release of the drug from the core; delayed release coatings, taste-masking coating, coating to impart stability to the underlying or overlaying active pharmaceutical ingredient, and coating to modify the texture of the multiple units to ease further processing. The stability protection can be from environmental constituents or other excipients of the composition. Coated multiple units of the present composition can also have combinations of the above-mentioned coatings.

The coating of the multiple units mainly comprises of polymers, plasticizers, anti-static agents, opacifying agents, anti-tacking agents, stabilizers, surfactants, colorants, pigments, anti-foaming agents and, optionally, alkaline or acidic agents or pH modifiers.

The type of polymer used for coating depends on the function of the desired coating. For example, for enteric coating or gastro-resistant coating, the polymers are selected from hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate succinate, cellulose acetate phthalate, hydroxypropylmethyl cellulose acetate succinate, cellulose acetate trimellitate; starch acetate phthalate, polyvinyl acetate phthalate, co-polymers of acrylic acid and/or methacrylic acid with a monomer selected from the following: methyl methacrylate, ethyl methacrylate, ethyl acrylate, butyl methacrylate, hexyl methacrylate, decyl methacrylate, lauryl methacrylate, phenyl methacrylate, methyl acrylate, isopropyl acrylate, isobutyl acrylate, or octadecyl acrylate, e.g., EUDRAGIT™-L, such as L100-55, L30D55, L100, S100, L12.5, available from Rohm Pharma Polymers, Germany. Combination of above mentioned polymers can be used.

For sustained or extended or controlled release coating, polymers are selected from cellulose ethers, such as, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, polyethylene oxide (PEO), available under brand name Polyox; polyvinylpyrrolidone (PVP) and vinyl pyrrolidone/ vinyl acetate copolymers

(copolyvidones), methacrylic ester copolymers as described above and available under the brand name EUDRAGIT™ such as Eudragit RL 100, Eudragit RS 100, Eudragit RL 30 D/RS 30 D, Eudragit NE 30D. Combination of above-mentioned polymers can also be used.

For taste-masking coating, polymer combinations described in EP997143 Bl and US7695735 are contemplated. However, the preferred taste-masking polymers are combination of ethyl cellulose and hydroxy propyl methylcellulose; or poly (butyl methacrylate, (2-dimethylaminoethyl) methacrylate, and methyl methacrylate in a ratio of 1 : 2:1, commercially available under the brand name EUDRAGIT™ (Eudragit - E, Eudragit E-100, E-12.5). These polymers do not dissolve but swell in saliva, and dissolve only in the acidic environment of the stomach.

^•For stabilization affording coating, polymers or substances are selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, sodium carboxy methylcellulose, methylcellulose, polyvinylpyrrolidone (PVP) and vinyl pyrrolidone/ vinyl acetate copolymers (copolyvidones), mannitol, polyethylene glycols (Macrogol), sorbitol, sucrose, ethyl cellulose and polymethacrylates. These coatings may additionally contain alkaline agents, such as, magnesium oxide, magnesium hydroxide, sodium hydroxide, sodium carbonate and bicarbonate. Similarly, coating can also contain organic acids like citric and tartaric acids. The coating is preferably present in an amount of from about 10 % to about 90 % by weight, based on the total weight of coated multiple units. More preferably, the coating is present in an amount of from about 25 % to about 70 % by weight, based on the total weight of the coated multiple-units. The coating is preferably applied to multiple units by conventional coating techniques, such as fluidized bed employing polymer solutions in water or in suitable organic solvents or using latex suspensions of these polymers.

A combination of different functional coatings can be applied to the multiple units.

The coating compositions apart from polymers also contain plasticizers which are selected from citric acid esters (acetyl-triethyl citrate, acetyl tributyl-, tributyl-, triethyl- citrate); glycerol and glycerol esters (glycerol diacetate, -triacetate, acetylated monoglycerides, castor oil); phthalic acid esters (dibutyl-, diamyl-, diethyl-, dimethyl-, dipropyl-phthalate, di-(2-methoxy- or 2-ethoxyethyl)-phthalate); ethylphthalyl glycolate, butylphthalylethyl glycolate and butylglycolate; alcohols (propylene glycol, polyethylene glycol of various chain lengths); adipates (diethyladipate, di-(2-methoxy- or 2- ethoxyethyl)-adipate; benzophenone; diethyl- and diburylsebacate, dibutylsuccinate, dibutyltartrate; diethylene glycol dipropionate; ethyleneglycol diacetate, -dibutyrate, - dipropionate; tributyl phosphate, tributyrin; polyethylene glycol sorbitan monooleate (polysorbates, such as polysorbate 80); sorbitan monooleate. A combination of plasticizers may also be used.

The amount of plasticizer, in general, is optimized for each coating polymer and generally represents from about 1 % to about 50 %, preferably 2 to 20 %, by weight, based on the total weight of the coating polymer.

Anti-static agents used in coating are selected from colloidal silica, talc and magnesium stearate. Antistatic agents are used in concentration upto 7 %, preferably upto 5 % by weight, based on the weight of the coating polymer.

Surfactants for use in coating can be sodium lauryl sulphate, polysorbate 80 and polysorbate 20. The preferred range of the surfactant is up to 5 % by weight based on the weight of the coating polymer. Preferably, the coating of multiple units is carried out in fluid bed processor fitted with Wurster apparatus. However, other coating techniques can be used for the coating of the multiple units

Coated multiple units, for the composition of the present invention, are prepared by extrusion spheronizer, rapid mixer granulators or fluid bed processor. However preferred method of multiple-units is drug layering and coating with fluid bed processor using Wurster apparatus.

Coated multiple units constitute from 20 % to 60% by weight, based on the total tablet weight. Preferably, coated multiple units constitute from 30 % to 50% by weight, based on the total weight of the tablet.

Compression of coated multiple units

The compressed tablet composition of the present invention comprises (a) coated multiple units comprising at least one pharmaceutically active ingredient and at least one functional coating, (b) at least one compressibility enhancing agent comprising neutral spheres, (c) at least one cohesiveness imparting agent comprising binder(s), and (d) optionally, other compression excipients.

Extragranular components

Neutral spheres

The compressibility enhancing agents comprise neutral spheres. Neutral spheres used in the tablet composition of present invention may be selected from, microcrystalline cellulose (MCC) spheres (Celphere®), sugar spheres (Non-pareil Seeds) and cornstarch spheres, or any combinations thereof. Neutral spheres made up of silicon dioxide, dicalcium phosphate, calcium stearate, magnesium stearate, glass, polypropylene, polyethylene, polystyrene, ethylcellulose, hydroxy ethylcellulose and the like are also contemplated for the composition of the present invention. Alternatively, neutral spheres can be prepared by granulating sugar or sugar alcohols or their chemically modified derivatives e.g. lactose, maltitol, sucrose, starch, microcrystalline cellulose, mannitol and the like with suitable granulating agents like hydroxypropyl methyl cellulose, hydroxy propylcellulose, methyl cellulose, poly vinyl alcohol, polyvinylpyrrolidone, acacia gum, water and the like and obtaining granules of suitable shape and size. The features of preferred neutral spheres for the tablet composition of present invention are described in table below:

More preferred choice of neutral spheres for the composition of the present invention is sugar spheres. Neutral spheres constitute from 2.0 to 40%, preferably from 5 % to 30% by weight of the total tablet weight. Still more preferably, from 5% to 20% by weight, based on the total tablet weight. Extra-granular neutral spheres of compression blend are critical for the composition of the present invention. Preferred particle size for the neutral spheres is from 280 μιη to 450 μιη; and spherical in shape.

Cohesiveness imparting agents

Cohesiveness imparting agents which are the vital ingredients in the compressed tablet composition of the present invention comprises binders. These are selected from the category of, (1) natural polymers, e.g. starch, pregelatinized starch, gelatin, acacia alginic acid, sodium alginate, xanthan gum, locust bean gum, karaya gum, tragacanth, Anacardium occidentale gum, khaya gum, veegum and detarium gum ; (2) sugars, e.g. sucrose, glucose (dextrose), sorbitol, mannitol, chitosan and maltrodextrins; (3) synthetic polymers, e.g. polyvinylpyrrolidone (Povidone), cross-linked polyvinylpyrrolidone, vinylpyrrolidone vinylacetate copolymer (Kollidon® VA 64), hydroxypropyl methylcellulose (hypromellose), hydroxypropyl cellulose, methyl cellulose, sodium carboxy methyl cellulose, polyethylene glycol, ethyl cellulose, polyvinyl alcohol, microcrystalline cellulose and polymethacrylates (Eudragit) e.g. Eudragit NE30 D, Eudragit RS 30D, Eudragit EPO, Eudragit LI 00 or any combinations thereof. The preferred binder is povidone available under the brand name Kollidon® from BASF Corporation. Kollidon has the versatility of being used as a dry or a wet binder. Preferably, binders constitute from 0.5 % to 15 %, more preferably, from 2.0 % to 10 % by weight, based on the total tablet weight.

The combination of neutral spheres and binders may be beneficial for the composition of the present invention. The ratio of the neutral sphere to binder also seems to play a role for the composition of the invention. Preferably, the ratio of neutral sphere to binder is 2:

1 to 8:1, more preferably the ratio is 4:1 to 6:1.

Successful tabletting (compression) of coated multiple units is facilitated by the interplay of nature and amount of other tabletting excipients.

The various other tabletting excipients include fillers, surfactants, cushioning agents, disintegrants, flavoring agents, sweeteners, coloring agents, anti-adherents, glidants, lubricants and the like. Fillers are selected from microcrystalline cellulose, cellulose, mannitol, sorbitol, sucrose, dicalcium phosphate, lactose, DCL, starch, modified starch, pregelatinized starch or any combination thereof or any co-processed combinations thereof. Fillers can also be modified to impart features of direct compressibility together with good flow properties. The directly compressible fillers are available under the brand name Avicel PHI 02, Pearlitol DC 300 and the like.

Fillers constitute from 30% to 60 %, preferably from 40% to 50% by weight, based on the total tablet weight.

Cushioning agents for the composition of the present invention are precipitated silica, microcrystalline cellulose, polyethylene glycol (Macrogol), and granules of mannitol. Cushioning agents constitute from 0.5% to 5% by weight of the total tablet weight. Disintegrants used in the composition of the invention are modified starch (like, pregelatinized starch), microcrystalline cellulose, cross-carmellose sodium and sodium starch glycolate, crospovidone (cross linked polyvinyl pyrrolidone, available under the brand name Polyplasdone^® XL, XL 10), low substituted hydroxy propyl cellulose (L- HPC). Disintegrants constitute from 0.5% to 10% by weight, based on the total tablet weight.

Flavoring or sweetening agents constitute less than 1% by weight based on the total tablet weight.

Coloring agents, e.g. ferric oxide, constitutes less than 1% by weight based on the total tablet weight.

Unlimited examples of lubricants include calcium stearate, magnesium stearate and sodium stearyl fumarate or combination thereof. Lubricants constitute upto 5% by weight, based on the total tablet weight.

Suitable examples of antiadherents include colloidal silica, talc and magnesium stearate. Anti-adherents constitute up to 5% by weight, based on the total tablet weight.

Suitable examples of glidants include colloidal silicon dioxide, starch and talc or combination thereof. Glidants constitute up to 5% by weight, based on the total weight of the tablet. There seems to be a synergistic effect of the neutral spheres and binder(s). Combination of the neutral spheres with binder resulted in the tablets free from cracks, chipping and capping leading to significantly improved yield of compressed tablets.

Optionally, the compressed tablet the present invention can be film coated to improve its elegance. Film coating materials and its use is well known to the skilled artisan.

Tablet composition of the present invention can be prepared by dry or wet granulation and subsequently compressed in a suitable tabletting machine using appropriate tooling. The preferred method for manufacturing present composition is direct compression. Direct compression is a convenient, versatile, and cost-effective process. The process involves blending the coated multiple units with neutral spheres, binders) and other compression excipients and subsequently, compressing the blend in a tabletting machine.

In one of the preferred embodiments, the process for the preparation of tablet composition of present invention comprises the steps of:

(a) coating an inert core with the active ingredient(s), (b) coating the active ingredient coated core with one or more separating layers, (c) coating the separating layer coated core with the functional coating and drying said cores,

(d) blending the functional coated core with neutral spheres, binders, and optionally fillers, (e) optionally, mixing separately the cushioning agent with disintegrant, lubricant and antiadherent, (f) optionally blending the product of step (d) and step (e); and (g) finally, compressing the blend obtained in step (d) or (f) on a tablet compression machine.

In another embodiment process for preparation of tablet composition of present invention comprises the steps of:

(a) coating of the seal coating layer on inert cores, and subsequently coating seal coated cores with the active ingredient(s), (b) coating the active ingredient coated core with one or more separating coating layers, (c) coating the separating layer coated cores with the functional coating and drying said cores, (d) blending the functional coated cores with neutral spheres, binders and, optionally, fillers,

(e) optionally mixing separately the cushioning agent with disintegrant and antiadherent, (f) blending the products of step (d) and step (e); (g) finally, compressing the blend obtained in step (f on a tablet compression machine.

The tablet composition of the invention is free of all tabletting and coating defects, and contributes greatly to high yield and enhanced aesthetic appeal, as is evidenced by the following examples. These examples are for illustrative purposes only and should not be construed as limiting the scope of the invention.

Example 1.

Composition of Gastro-resistant coated multiple units of Esomeprazole magnesium Table 1

Gastro-resistant coated pellets (Γ) 155.64 311.28

Hypromellose phthalate 42.45 84.89

Polyethylene glycol (Macrogol 400) 4.25 8.49

Purified water q.s. q.s.

Acetone q.s. q.s.

Total 202.32 404.73

weight

Manufacturing Process:

1. The weight of all the ingredients was checked for correctness.

2. Hydroxy propylcellulose was dispersed in purified water.

3. Crospovidone was added to dispersion of step 2.

4. Esomeprazole magnesium amorphous was added to suspension of step 3 under stirring.

5. Specified quantity of inert core was loaded into the fluid bed processor and same was coated with suspension of step 4.

6. Drug layered cores (pellets) were dried and sifted through suitable size mesh.

7. Confectioner's sugar was dispersed in sufficient quantity of purified water

8. Magnesium oxide and talc were added to the dispersion of step 7 under stirring.

9. Drug layered cores (pellets) were loaded in fluid bed processor and coated with sub-coating I suspension of step 8.

10. Sub-coated cores (pellets) were dried and passed through suitable size mesh.

1 1. Polyethylene glycol (Macrogol 6000) was dispersed in sufficient quantity of purified water under stirring.

12. Sub-coated cores (pellets) of step 10 were loaded in fluid bed processor and coated with sub-coating Π suspension of step 11.

13. Sub-coated cores (pellets) of step 12 were dried and passed through suitable size mesh.

14. Polysorbate 80 and glycerol monostearate were dispersed in sufficient quantity of purified water.

15. Polyethylene glycol (Macrogol 400) was dissolved in the sufficient quantity of purified water and the resulting solution was added to solution of step 14 under stirring. 16. Methacrylic acid copolymer (Eudragit L 30 D) was sifted through #100 mesh and dispersion of step 15 was added to Eudragit L 30 dispersion.

17. Sub-coated pellets of step 13 were loaded in fluid bed processor and coated with dispersion of step 16.

18. Gastro-resistant (enteric) coated pellets obtained were dried and passed through appropriate mesh size.

19. Polyethylene glycol (macrogol 400) was dispersed in mixture of purified water and acetone under stirring.

20. Hypromellose phthalate (55) was added to the above dispersion of step 19 under stirring.

21. Gastro-resistant (enteric) coated pellets of step 18 were loaded in fluid bed processor and coated with dispersion of step 20.

22. Gastro-resistant (enteric) coated pellets of step 21 were dried and passed through appropriate mesh size.

Example 2 - Gastro-resistant coated multiple units of Lansoprazole

TABLE 2

Components Quantity in mg

Drug layering

Inert core 60.0

Lansoprazole 30.0

Magnesium Carbonate 22.50

Icing sugar with starch 25.00

Low substituted hydroxy propyl 10.00

cellulose (L-HPC)

Corn starch 10.00

Crospovidone 5.00

Red -iron oxide 0.06

Hydroxy propylcellulose 4.00

Purified water qs

Seal coating Drug layered pellets 166.56

Icing sugar with starch 13.10

L-HPC 9.88

Corn starch 8.69

Hydroxypropyl cellulose 1.60

Purified water qs

Gastro-resistant coating -I

Seal coated pellets 199.83

Methacrylic acid Copolymer 45.00

(Eudragit L-30 D55)

Glyceryl monostearate 2.25

Polysorbate 80 0.90

Polyethylene glycol 6000 6.75

Purified water qs

Gastro-resistant coating -II

Gastro -resistant coated pellets 254.73

Hydroxypropyl methylcellulose 23.15

phthalate - 55 (HPMCP-55)

Polyethylene glycol 400 2.32

Acetone qs

Water qs

Total weight 280.20

Manufacturing Process:

1. The weight of all the ingredients was checked for correctness.

2. Hydroxypropyl cellulose and ferric oxide were dispersed in purified water.

3. Magnesium carbonate, icing sugar with starch, low substituted hydroxy propyl cellulose, corn starch and crospovidone were added to dispersion of step 2.

4. Lansoprazole was added to the above solution under constant stirring.

5. Celphere were loaded in the fluid bed processor and coated with dispersion of step 4

6. drug layered pellets were dried and passed through appropriate mesh size.

7. Hydroxypropyl cellulose and ferric oxide were dispersed in purified water.

8 Icing sugar with starch, low substituted hydroxy propyl cellulose, and corn starch were added to dispersion of step 7.

9. Drug layered pellets were loaded in fluid bed processor and coated with dispersion of step 8.

10. Seal coated pellets were dried and passed through appropriate size mesh.

11. Polysorbate 80 was dispersed in purified water and then polyethylene glycol and glyceryl monostearate were dispersed in the said dispersion.

12. Required amount of methacrylic acid copolymer (Eudragit L-30 D55) was filtered out

through #100 mesh.

13. Content of step 11 was added to content of step 12.

14. seal-coated pellets were loaded in the fluid bed processor and same were coated with dispersion of step 13 and enteric coated pellets were dried.

15. Polyethylene glycol 400 was dissolved in mixture of purified water and acetone.

16. HPMCP-55 was added to the dispersion of step 15 under constant stirring.

17. Enteric coated pellets of step 14 were loaded in the fluid bed processor and coated with dispersion of step 16.

18. The enteric coated pellets of step 17 were dried and passed through appropriate mesh.

Example 3— Extended release coated multiple units of Metoprolol succinate

Table 3

Ethyl cellulose 32.11

Hydroxypropyl methylcellulose 8.02

Talc 4.01

Magnesium stearate 4.01

Dichloromethane qs

Isopropyl Alcohol qs

Over-coating

Polyethylene glycol 77.68

Dichloromethane qs

Isopropyl Alcohol qs

Total weight 400.03

Manufacturing process:

(1) Ethyl cellulose was dissolved in mixture of isopropyl alcohol and dichloromethane under stirring.

(2) Magnesium stearate and talc were added to the dispersion of step 1.

(3) Inert cores were loaded into the fluid bed processor and coated with seal coating dispersion of step 2.

(4) Seal-coated inert cores of step 3 were dried and passed through 30 mesh sieve.

(5) Metoprolol succinate was dissolved in purified water under stirring

(6) Seal coated inert cores were loaded in fluid bed processor and coated with dispersion of step 5.

(7) Drug coated inert cores (pellets) were dried and passed through 20 mesh sieve.

(8) Ethyl cellulose and hypromellose were dispersed in mixture of isopropyl alcohol and dichloromethane under stirring.

(9) Talc and magnesium stearate were added to the dispersion of step 8.

(10) Drug coated cores (pellets) of step 7 were loaded in the fluid bed processor and coated with dispersion of step 9.

(11) Extended release coated cores (pellets) of step 10 were dried and passed through 20 mesh sieve.

(12) Polyethylene glycol 6000 was dissolved in mixture of isopropyl alcohol and dichloromethane.

(13) Pellets of step (11) were loaded in fluid bed processor and coated with solution of Step 12.

(14) Pellets of step 13 were dried and passed through suitable size mesh.

Example 4

Compositions of compressed multiple unit tablet (MUPS) Table 4

+ means presence of mentioned problems

- means absence of mentioned problems From above data, it is abundantly clear that the composition of invention improves the yield significantly.

Manufacturing Process (Processing-) of MUPS (Example 4.1 and 4.2)

1 Ferric oxide and microcrystalline Cellulose were mixed and sifted through # 36 mesh size.

2 Gastro-resistant pellets of step 22 of (Example 1) were passed through #16 mesh.

3 Material of step 1, step 2 above and neutral spheres (NPS) were blended

together for 10 minutes.

4 Polyethylene glycol (Macrogol 6000), crospovidone (Polyplasdone XL), polyvinylpyrrolidone (Povidone K-90), pregelatinized starch and colloidal silica were sifted through #36 mesh.

5 Material from step 3 was blended with material from step 4 for 10 minutes.

6 Lubricated material obtained from step 5 was compressed in tablet compression machine using suitable tooling.

Manufacturing process (Example 4.3)

Process is same as mentioned for Example 4.1 and 4.2 above with following changes.

Pregelatinized starch is replaced by talc and povidone is replaced by hydroxy propylcellulose in step 4.

Manufacturing Process (Reference Example 1)

Process is same as for Ex. 4.1, except for the fact that neutral spheres (NPS) were not used in step 3; said qty was compensated with proportionate qty of microcrystalline cellulose.

Manufacturing Process (Reference Example 2)

Process is same as for Ex. 4.1, except for the fact that povidone was not used in step 4. Weight of the tablet was adjusted with other ingredients.

Manufacturing process (Reference Example 3)

Process is same as for Ex. 4.1, except for the fact that neutral spheres (NPS) and povidone was not used in step 3 and step 4 respectively. Final weight of the tablet was adjusted with other ingredients like polyethylene glycol and microcrystalline cellulose. Example 5

Lansoprazole gastro-resistant orally disintegrating tablet Example 6

Metoprolol succinate extended release tablet

Composition of example 5 and example 6 is represented in Table 5

TABLE 5

+ means presence of mentioned problems

- means absence of mentioned problems Manufacturing Process for Lansoprazole delayed release tablet:

1 Mannitol and microcrystalline cellulose were mixed and sifted through # 36 size.

2 Gastro-resistant pellets of step 18 of example 2 were passed through # 20 mesh.

3 Content from step 1 , step 2 and neutral spheres (celphere^®) were blended

together.

4 Polyethylene glycol (Macrogol 6000), polyvinylpyrrolidone (Povidone K-90), pregelatinized starch and colloidal silica were sifted through #36 mesh.

5 Material from step 3 was blended with material from step 4 for 10 minutes.

6 Lubricated material obtained from step 5 was compressed on tablet compression machine using appropriate tooling.

Manufacturing Process for Metoprolol extended release tablet:

1 Crospovidone and microcrystalline cellulose were mixed and sifted through # 36 mesh.

3 Metoprolol extended release pellets of step 14 of example 3 were passed through suitable # mesh.

3 Content from step 1, step 2 and neutral spheres (celphere^®) were blended together.

5 Material from step 3 was blended with material from step 4 for sufficient time.

6 Lubricated material obtained from step 5 was compressed on tablet compression machine using suitable tooling.

Claims

A compressed tablet composition comprising (a) coated multiple units comprising at least one pharmaceutically active ingredient and at least one functional coating, (b) at least one compressibility enhancing agent comprising neutral spheres, (c) at least one cohesiveness imparting agent comprising binder(s), and (d) optionally, other compression excipients.

The compressed tablet composition of claim 1, wherein the pharmaceutically active ingredient is selected from esomeprazole, omeprazole, lansoprazole, olanzapine and metoprolol.

The compressed tablet composition of claim 1 or 2, wherein the functional coating is selected from the group consisting of gastro-resistant coating, extended release coating, taste-masking coating, stability imparting coating and seal coating, or a combination thereof.

The compressed tablet composition of any of claims 1 to 3, wherein the neutral spheres are selected from the group consisting of sugar spheres, microcrystalline cellulose spheres, silicon dioxide spheres, glass spheres, polypropylene spheres and cornstarch spheres, or a combination thereof.

The compressed tablet composition of claim 4, wherein the neutral sphere is a sugar sphere.

6. The compressed tablet composition of any of claims 1 to 5, wherein the binder is selected from the group consisting of polyvinylpyrrolidone, vinylpyrrolidone vinylacetate copolymer, hydroxypropyl methylcellulose, and hydroxypropyl cellulose, or a combination thereof.

7. The compressed tablet composition of claim 6, wherein the binder is polyvinylpyrrolidone.

8. The compressed tablet composition of any of claims 1 to 7, wherein the coated multiple units constitute from 20 % to 60% by weight of the total tablet weight.

9. The compressed tablet composition of any of claims 1 to 8, wherein the neutral spheres constitute from 2% to 40% by weight of the total tablet weight.

10. The compressed tablet composition of any of claims 1 to 9, wherein the binder(s) constitute from 0.5% to 15 % by weight of the total tablet weight.

11. The compressed tablet composition of any of claims 1 to 10, wherein the other compression excipients are selected from fillers, disintegrants, cushioning agents, glidants, antiadherents, and lubricants.

12. The compressed tablet composition of any of claims 1 to 11, wherein the ratio of compressibility enhancing agents to cohesiveness imparting agents is from 2:1 to 8:1.

13. A process of manufacturing a compressed tablet composition of any preceding claims comprising the steps of:

(a) coating an inert core with the active ingredient(s), (b) coating the active ingredient coated core with one or more separating layers, (c) coating the separating layer coated core with the functional coating and drying said cores, (d) blending the functional coated core with neutral spheres, binders, and optionally fillers, (e) optionally, mixing separately the cushioning agent with disintegrant, lubricant and antiadherent, (f) optionally blending the product of step (d) and step (e); and (g) finally, compressing the blend obtained in step (d) or (f) on a tablet compression machine.

14. A process of manufacturing a compressed tablet composition of any of claims 3 to 12 comprising the steps of: (a) coating of the seal coating layer on inert cores, and subsequently coating seal coated cores with the active ingredient(s), (b) coating the active ingredient coated core with one or more separating coating layers, (c) coating the separating layer coated cores with the functional coating and drying said cores, (d) blending the functional coated cores with neutral spheres, binders and, optionally, fillers,

(e) optionally mixing separately the cushioning agent with disintegrant and antiadherent, (f) blending the products of step (d) and step (e); (g) finally, compressing the blend obtained in step (f) on a tablet compression machine.