Title of Invention

MULTIPLE UNIT COMPOSITIONS

Abstract

The present invention provides a multiple unit compositions comprising of enteric coated pellets and at least one tablet excipient, wherein each pellet comprises: i) a core comprising active ingredient(s); ii) optionally a separating layer coated on the core; iii) at least two enteric layers comprising of enteric polymers and plasticizer either coated on the core or on the separating layer to obtain enteric coated pellets, such that the last enteric layer is formed from a solution comprising of enteric polymer and plasticizer in organic solvent(s), resulting in no appreciable change in release profile of active ingredient on compression of enteric coated pellets into tablets.

Full Text

FORM-2 THE PATENTS ACT, 1970 (39 OF 1970) & The Patent Rules, 2003 PROVISIONAL SPECIFICATION (See Section 10 and Rule 13) "MULTIPLE UNIT COMPOSITIONS" Themis Laboratories Pvt. Ltd. having its administrative office at Unit No. S - 4 , Khira Industrial Estate, B.M Bhargava Road, Santacruz West, Mumbai 400054, Maharashtra, India an Indian Company The following specification describes the invention. Field of the Invention: The invention relates to unit dosage form comprising enteric coated multiple unit particles comprising active ingredient and process for their preparation. Background of the Invention: Multiple unit particulate system has distinct advantages over single unit system. 1) Multiple unit particles get distributed throughout the Gl tract thereby avoiding localized accumulation and local irritation,2) Minimized inter and intra subject variation 3) Incorporation of 2 or more drugs in a single dosage form, 4) Allows preparation of multi-dose formulation without any change in process or formulation, 5) Particles having different release profile can be delivered together. It is not uncommon to protect various active ingredients from gastric acidity for reasons such as instability of drug molecule in acidic contents, gastric irritation. Some drugs have limited absorption window, present beyond stomach and need to be released at appropriate site of absorption. Drugs belonging to classes such as proton pump inhibitors, SSRIs or mixtures thereof are to be protected from acidic gastric contents and or released enterically. Active ingredients of preference are selected from Omeprazole, Pantoprazole, Lansoprazole, Esomeprazole, Rabeprazole, substituted phenylmethylsulfinyl-1H-benzimidazoles, cycloheptapyridin-9-ylsulfinyl-1H-benzimidazoles or pyridin-2-ylmethylsulfinylthienoimidazoles as disclosed in DE-A-35 31 487, EP-A-0 434 999 or EP-A-0 234 485, 2-[2-(N-isobutyl-N-methylamino)benzylsulfinyl]benzimidazole (leminoprazole), 2-(4-methoxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ylsulfinyl)-1H-benzimidazole (nepaprazole), citalopram, clomipramine, fluoxetine, fluvoxamine, paroxetine, sertraline, trazodone, venlafaxine, duloxetine, Atomoxetine and zimeldine or their pharmaceutical^ acceptable salts or their enantiomers or pharmaceutically acceptable salts of their enantiomers. Enteric coated multiple unit particulate systems are generally prepared by coating the particles containing drug with a polymeric film that modifies the release of drug. When these enteric coated multiple unit particles are compressed into tablet, polymeric film is damaged, exposing drug molecule to gastric acid contents. This results in destruction of acid labile drug molecule and/or renders the drug unavailable at absorption site which is undesirable feature. Various prior arts have identified and tried to resolve this issue. PCT publication WO03/103637 teaches modified release multiple unit drug delivery system and methods for preparation of such systems. Each unit comprises atleast one core coated with first coating layer that includes one or more active pharmaceutical ingredient and one 1 or more rate controlling polymer and an outer layer comprising a material that is one or both of elastic and compressible waxy material such as PEG. Waxy outer layer protects the release control polymer layer from cracking during compression, EP 1072257 teaches a sustained release polymer incorporated, multiple-unit sustained release tablet consisting of a granular part and a powdery part. The granular part comprises a matrix of water insoluble polymer and an active ingredient. These matrix granules were further coated with water insoluble release controlling polymer. This coated matrix granules are blended with powdery part in the ratio of 1:0.5 or more, which otherwise would fail to disintegrate into sub units. United States Patent 6,328,994 teaches orally disintegrable tablets which comprise fine granules having an average particle diameter of 400 microns or less and an additive. These granules comprise a composition having lansoprazole coated with an enteric coating layer comprising an enteric coating agent and sustained release agent. WO 97/25029 teaches a preparation of disintegratable tablets comprising three types of pellets viz. the mixture of active pellets, deformable pellets and disintegratable pellets. The drug pellets are coated with a controlled release binder, soft pellets contain an ester of fatty acid and the disintegratable pellets preferably comprise a water insoluble inorganic powder. The soft pellets deforms during the tabletting procedure that minimizes damage to drug pellets by minimizing disruption of the coating and the disintegratable pellets ensures retention of release characteristic from the drug pellets. US6923984 teaches use of biologically inactive cushioning beads of a size of about 0.5 to 2 mm for protecting brittle coating over beads containing biologically active material, during compression. Said biologically inactive cushioning beads comprise at least one compressible cushioning component consisting essentially of a microcrystalline hydrocarbon wax or a natural wax, the said wax being at least 30% by weight of the biologically inactive cushioning beads, and optionally up to 70% by weight of another biologically inactive compressible cushioning component or pharmaceutically acceptable excipient. US4713248 teaches an oral pharmaceutical controlled release multiple-unit formulation, comprising individual units constituted of an active substance coated with a substantially water-insoluble, but water-diffusible controlled release coating. The coating comprises a homogeneous mixture of a water-dispersible film-forming agent and a polymeric substance. Polymeric substance functions as a reinforcing agent by imparting greater hardness as well as plastic deformability to the layer. Plastic deformability results in no significant changes in 2 the release characteristics of compressed coated units relative to non-compressed coated units. US5753265 and EP0723437 teaches an oral pharmaceutical composition in the form of a multiple unit tablet comprising: a tablet excipient and a multiple of a core unit comprising an acid-labile H.sup.+ K.sup.+ -ATPase inhibitor compound. The core unit is covered with at least one enteric coating layer having mechanical properties so as not to significantly affect the acid resistance of the enteric coating layered unit by compression during tableting. All examples described in this specification require plasticizer not less than 20%w/w of enteric polymer used. EP0723436 and US5817338 teach a pharmaceutical multiple unit tablet composition comprising: at least one tablet excipient; and a multiple of a pellet or granule ranging between 0.1 mm and 2 mm in size comprising omeprazole. The pellet or granule is covered with at least one enteric coating layer comprising a plasticizing compound in the amount of more than about 20% to less than about 50% by weight of the enteric coating layer polymer so as to minimize the reduction of acid resistance of the enteric coating layered units upon compression into the tablet form. Prior art teachings for protecting desired layer from cracking during compression involve: 1) Use of elastic and compressible outer layer comprising waxy material such as PEG, to protect inner rate controlling polymer layer, 2) Use of powdery part to protect granular part comprising drug at least in the ratio of 0.5:1, 3) Use of sustained release agent in combination with enteric coating agent, 4) Use of deformable pellets or biologically inactive cushioning beads , 5) Use of plasticizer at least 15%w/w of enteric polymer in enteric layer to have mechanical properties so as not to significantly affect the acid resistance of the enteric coating layered unit by compression during tableting. Prior art has failed to provide a tablet composition comprising enteric coated multiple units comprising active ingredient and at least two enteric coatings comprising of plasticizer upto 15% w/w of enteric polymer, preferably upto 10w/w of enteric polymer, exhibiting release profile of active ingredient that is independent of compression. There is a long standing need to have alternative for preserving active ingredients as listed above that are acid labile or cause undesirable side effects when released in stomach or for preparing patient compliant dosage form. 3 OBJECTS OF THE INVENTION The main object of the invention is to provide compressible enteric coated multiple unit particles comprising active ingredient and at least two enteric coats wherein plasticizer in enteric coats is upto 15% w/w of enteric polymer such that particles do not exhibit significant change in release profile of active ingredient after compression and process for their preparation. Another object of the invention is to provide compressible enteric coated multiple unit particles comprising active ingredient and at least two enteric coats wherein plasticizer in enteric coats is upto 10% w/w of enteric polymer such that particles do not exhibit significant change in release profile of active ingredient after compression and process for their preparation. Yet another object of the invention is to provide compressible enteric coated multiple unit particles comprising active ingredient and at least two enteric coats wherein plasticizer in enteric coats is upto 15% w/w preferably upto 10% w/w of enteric polymer such that the active ingredient is prevented from degradation and dissolution in acidic media and exhibits desired release profile in near neutral or alkaline media and process for their preparation. Yet another object of the invention is to provide a stable composition comprising compressible enteric coated multiple unit particles comprising active ingredient and at least two enteric coats wherein plasticizer in enteric coats is upto 15% w/w preferably upto 10% w/w of enteric polymer and process for their preparation. Yet another object of the invention is to provide orally dispersible tablets comprising enteric coated multiple unit particles comprising active ingredient and at least two enteric coats wherein plasticizer in enteric coats is upto 15% w/w preferably upto 10% w/w of enteric polymer and process for their preparation. SUMMARY OF INVENTION The invention relates to stable composition comprising compressible enteric coated multiple unit particles comprising at least two enteric coats wherein plasticizer in enteric coats is upto 15% w/w preferably upto 10% w/w of enteric polymer such that these particles comprise active ingredient and do not exhibit significant change in release profile of active ingredient after compression. The desired in vitro release profile being not more than 10% of active ingredient is released in acidic pH and not less than 70% of active ingredient is released in near neutral or alkaline media. The invention involves preparation of compressible enteric coated multiple unit particles. These are prepared by 4 a) simultaneous or alternate layering of binder and powder mixture comprising drug over neutral cores, followed by drying to obtain drug cores, or granulating a mixture comprising drug and suitable pharmaceutical ingredients followed by extrusion and spheronization to obtain drug cores b) seal coating of drug cores by nonfunctional polymer to obtain seal coated cores, c) Applying first enteric coating polymer coat on seal coated cores to obtain first enteric coated cores, d) Applying second enteric coating polymer coat on first enteric coated cores to obtain compressible enteric coated multiple unit particles. Application of these enteric coating polymers is done from solution or dispersion in aqueous and non-aqueous solvents. Composition of first enteric coat and second enteric coat is different. Enteric polymer used in first and subsequent coats may be same or different. The enteric coated multiple unit particles so prepared are then compounded into desired pharmaceutical dosage form like orally dispersible tablet or swallowable tablet. DETAILED DESCRIPTION OF INVENTION The present invention provides compressible enteric coated multiple unit particles coated with at least two enteric coats wherein plasticizer used in enteric coat is upto 15% w/w preferably upto 10% w/w of enteric polymer comprising active ingredient, a modified release pharmaceutical composition thereof and process for their preparation such that there is no significant change in the release profile of active ingredient before and after compression. When seal coated cores are coated with single layer of enteric polymer from aqueous dispersion comprising plasticizer upto 15%w/w of enteric polymer, preferably 10%w/w of enteric polymer, the enteric coated cores fail in arresting release of active ingredient in acidic media. Use of higher quantities of enteric polymers keeping plasticizer upto 15%w/w of enteric polymer, preferably 10%w/w of enteric polymer, in aqueous dispersion for protecting active ingredient from gastric contents often results in undesirable release profile in intestinal milieu, or exceeding the quantities beyond GRAS (generally regarded as safe) levels, increased processing times. When seal coated cores are coated with single layer enteric polymer in non-aqueous solvents comprising plasticizer upto 15%w/w of enteric polymer, preferably 10%w/w of enteric polymer, cores arrest the release of active ingredient in acidic media but they do not exhibit desirable release profile of active ingredient in near neutral or alkaline media. When these enteric coated cores are compressed they fail to provide desired release profile of active ingredient in near neutral or alkaline media. 5 It is surprisingly found that when such aqueous enteric coat and the non-aqueous enteric coat which is individually incapable of preserving the active ingredient in acidic media to allow its desired release in near neutral or alkaline media, when combined, preserve the active ingredient in acidic media and allow its desired release profile in near neutral or alkaline media. The plasticizer used in enteric coat is upto 15% w/w preferably upto 10% w/w of enteric polymer. It is also surprisingly found that there is no significant change in the release profile of active ingredient from enteric coated multiple unit particles and tablet prepared thereof. The desired in vitro release profile being not more than 10% of active ingredient is released in acidic pH and not less than 70% of active ingredient is released in near neutral or alkaline media and the compositions disclosed by this invention exhibit release profile that is independent of compression. Coating equipments like coating pan, fluid bed processors, extrusion and spheronizer, centrifugal coater, tangential coater can be used. Enteric coated multiple unit particles of the present invention are prepared as described below: Step 1) Preparation of drug core Step 2) Application of seal coat(s) Step 3) Application of enteric coats STEP 1) Preparation of drug core: The process involves deposition of layer containing active ingredient optionally with other Pharmaceutical acceptable ingredients on inert seeds such as sugar sphere or non pareil seeds. Such deposition of active ingredient can be simultaneous with binder which may be an aqueous or non-aqueous solution or dispersion. The active substance may be mixed with other components like surfactants, binders, disintegrating agents, fillers, alkaline additives or other pharmaceutically acceptable ingredients, alone or in mixtures, before layering the seeds. In one of the embodiments the binder solution or dispersion contains the active ingredient in it, which is deposited on non pareil seeds. In this case suspension of active ingredient, binder and antitack agent in suitable aqueous or nonaqueous solvent where active ingredient is in dissolved state can be coated as a single layer on sugar sphere to obtain drug cores. In another embodiment, deposition of active ingredient layer is alternating with that of binder. The pulverized active ingredient is optionally mixed with an inert excipient to obtain 6 an admixture, which is deposited on inert seeds in a coating pan using suitable aqueous or nonaqueous binder solution to obtain drug core. The process is continued till entire admixture containing active ingredient is used for deposition. In yet another embodiment the active ingredient is mixed optionally with other pharmaceutically acceptable ingredients, extruded and spheronized into pellets. Process and the compositions disclosed enable incorporation of more than one active ingredient which may or may not be belonging to the same class of drugs. Preferably the active ingredients belong to classes of proton pump inhibitors, SSRI's. These modified release compositions comprise active ingredient up to about 50%w/w of the pellet composition. The drug cores prepared above are suitably dried in equipments such as coating pan, tray drier or fluid bed drier or their likes to moisture content of less than 5%w/w preferably less than 3%w/w and more preferably less than 2%w/w. Inert seeds such as sugar sphere comprising of sugar and starch is preferably used. Alternatively inert seeds comprising of microcrystalline cellulose or any other suitable inert material may also be used. The size of the seeds is not essential for the present invention and it may be in the range of about 300 to 1680 microns preferably about 500 to 1200 microns. The seeds, used for layering the active substance, can be water insoluble seeds comprising organic polymers, celluloses, different oxides and other materials, alone or in mixtures or water soluble seeds comprising sugars, different inorganic salts, non-pareils and other materials, alone or in mixtures. Alternatively one can build on drug crystal as seed. The pharmaceutically acceptable excipient comprise of one or more of filler, binder, disintegrant, lubricant, polymer, colorant, coating agent, preservatives and stabilizer, surfactant, anti-adherent, alkalizing agent, acidulant, pH modifiers, plasticizers, gums, glidant, buffers and their mixtures thereof. Alkalizing agents, pH modifiers and buffers are selected from but not limited to acetic, boric, carbonic, phosphoric, malic, maleic, citric, bicarbonic, tartaric, succinic, benzoic, lactic, glyceric, glutamic, lauric, adipic, gluconic, fumaric, monocarboxylic, hydroxycarboxylic, polycarboxylic acids, glutaric acids, essential and non- essential amino acids and their pharmaceutically acceptable salts preferably sodium, potassium, calcium, magnesium and ammonium salt, alkali or alkali earth metal chlorides, sulfates, phosphates, oxides, bicarbonates, citrates, borates, acetates and succinates, sodium or potassium hydrogen phosphate, sodium or potassium dihydrogen phosphate, sodium hydroxide, potassium hydroxides, tris buffer, organic acid buffer, alkali hydroxide, ammonia, and their mixtures. 7 The binders are pharmaceutical^ acceptable substances with cohesive properties when used in appropriate form known to the persons skilled in the art. Binder is selected from the group consisting of cellulose derivatives such as hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose, carboxymethylcellulose sodium, sugar, acacia, hydroxethylcellulose; polyvinylpyrrolidone, polymethacrylates, carbomer, gums like xanthan gum, guar gum, starches, tragacanth, gelatin, carragenan, locust bean gum, karaya gum, agar, chitosan, alginic acid and its pharmaceutical acceptable salts such as sodium, potassium and calcium salt, alone or in mixtures. Binder may be used alone or in combination and is preferably polyvinylpyrollidone used in the concentration upto about 0.1% to 80% w/w of composition. Although the solvent of preferred choice for processing active ingredient(s) is water, other solvents such as alcohol, hydroalcoholic mixture, organic solvent or their mixtures can also be used. STEP 2) Application of seal coat: The drug cores are optionally coated with a layer of non-functional polymer and antitack agent to obtain seal coated cores. In another embodiment of the invention, non-functional polymer and antitack agent is deposited from aqueous media as a single layer on drug cores. Alternatively, non-functional polymer in water can be deposited with antitack agent as an alternate layer on drug cores to obtain hardened drug cores. The hardened drug cores are suitably dried in equipments such as coating pan, tray drier and fluid bed drier or their likes to arrive a moisture content of less than 5%w/w preferably less than 3%w/w and more preferably less than 2%w/w. Non-functional polymer is selected from the group consisting of cellulose derivatives like hydroxypropylmethylcellulose, sugar, hydroxethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone and polymethacrylates is used in the concentration of upto about 20%w/w of composition. Antitack agent used in the present invention is selected from talc, colloidal silicon dioxide, magnesium stearate, glyceryl behenate, glyceryl monostearate and their mixtures the preferable choice being talc with or without colloidal silicon dioxide and are used in the concentration range of about 0.1 - 80% w/w of composition. Inert fillers are selected from starch, lactose, microcrystalline cellulose, low viscosity grade hydroxypropylcellulose, mannitol, pulverized sugar, sorbitol and their likes. Inert excipient 8 may be used alone or in combination and is preferably starch and is used in concentration range of about 0.1 - 80% w/w of composition. Seal coat(s) are applied to the core material by using powder coating technique. Suitable materials for seal coating are pharmaceutical^ acceptable compounds such as, for instance, sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methyl-cellulose, ethylcellulose, hydroxypropyl methylcellulose, carboxymethylcellulose sodium and others, used alone or in mixtures. Additives such as plasticizers, Alkalizing agents, 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 seal coat(s). STEP 3) Application of enteric coat: Drug core or Seal coated drug core so obtained is then coated with at least two enteric coats of which at least one is aqueous enteric coat and at least one is non-aqueous enteric coat. Aqueous enteric coating is done with an enteric polymer in the form of aqueous suspension. Combination of enteric polymers in the range of 1 - 100% w/w of drug core or Seal coated core, in aqueous suspension form to lay an aqueous coat is effective. For nonaqueous enteric coating, a solution of enteric polymer in non-aqueous solvent is used. Combination of enteric polymers in the range of 1 - 100% w/w of drug core or Seal coated core, in non-aqueous solution form to lay a non-aqueous coat is equally effective. Plasticizer and optionally antitack agent is incorporated to obtain required enteric composition. Quantity of plasticizer present in the enteric coating layer is upto 15% w/w preferably upto 10% w/w of enteric polymer used. Antitack agent is selected from talc, glyceryl monostearate, glyceryl behenate, stearic acid and its salts such as Calcium stearate, Magnesium stearate, colloidal silicon dioxide, kaolin, titanium dioxide, alumina, starch, polacrilin potassium, microcrystalline cellulose. Quantity of enteric polymer used in the invention if incorporated into any single layer either fails to preserve the drug molecule in acidic environment or does not allow desired release profile of active in near neutral or alkaline media or both. The release profile before and after compression is substantially different. However it is surprisingly found that when same or lesser quantity of enteric polymer is loaded on seal coated core in at least two enteric coats at least one of which is aqueous and at least one is non-aqueous, such combination is able to preserve the drug molecule in acidic surroundings and yet allows desired release profile in near neutral or alkaline media. In other words two incapable coats when present in combination, preserve the drug 9 molecule in acidic surroundings and yet ensure desired release profile in near neutral or alkaline media. Enteric polymer in the present invention is in the form of aqueous dispersion or nonaqueous solution. Enteric polymer is selected from the group of methacrylic acid copolymer (polymethacrylates) (Eudragit RTM)s uch as Eudragit L30 D55, Eudragit L100 55, Eudragit FS30D, Eudragit S30D, Eudragit S100 Cellulose derivatives like HPMCP different grades, HPMCAS, Cellulose acetate phthalate, Cellulose acetate trimelliate, Cellulose propionate phthalate, Cellulose acetate maleate, HPMC Hexahydrophthalate. Other enteric polymers include Polyvinyl alcohol phthalate, Polyvinyl acetate phthalate and compatible mixtures thereof. Plasticizers is selected from substances that have one or more hydrophilic groups such as hydroxyl, ester or amino groups for example citric acid alkyl esters, phthalic acid esters, sebacic acid esters, sucrose esters, sorbitan esters, castor oil and its derivatives, dibutylsebacate and polyethylene glycols. Preferred plasticizers are dibutylsebacate, triethyIcitrate and acetyltriethyl citrate. Expression "multiple unit particles" means small beads, cores, particles, granules or pellets. The terms are used interchangeably. Terms "non-aqueous" and "organic" solvents mean same thing. Suitable surfactants found in the groups of pharmaceutically acceptable non-ionic or ionic surfactants such as for instance sodium lauryl sulfate are used. The above process can be carried out in equipment such as fluid bed bottom spray processor, coating pan and their likes. The process described can be carried out using single equipment either fluid bed bottom spray processor or coating pan or involves use of both equipments. The process of the invention described herein is the viable continuous process for the preparation of modified release composition comprising of active ingredient(s) such that not more than 10% of the active is released in about two hours in acidic media in vitro yet exhibiting desired release profile in near neutral or alkaline media such that not less than 70%w/w of active is released in 7 hours. The invention is now described with non - limiting examples for the preparation of modified release multiple unit particles comprising Rabeprazole /salt. Illustration 1: Rabeprazole Sodium drug cores: Preparation of drug core 10 Ingredients MG/UNIT QTY/BATCH in GM Rabeprazole Sodium (Nifty Labs) 20 400 MCC pellets NPS (#40/#60) 30 600 HPMCE15 2 40 Sodium Hydroxide 2 40 Sodium Starch Glycolate 0.4 8 Talc 2 40 Methanol 42.24 844.80 Water 63.36 1267.2 TOTAL 56.4 1128 1) HPMC E15 and Sodium Starch Glycolate were weighed and dispersed in Methanol under stirring, to which was added water to get clear solution. 2) Aqueous solution of Sodium Hydroxide was added to solution of step 1). 3) Weighed Rabeprazole Sodium, Talc was added to solution of step 2) and filtered through muslin. 4) Solution from step 3 was spread on MCC pellets in fluid bed processor. These cores could not protect the active ingredient in acidic surroundings and could not exhibit desired release profile. Illustration 2: Rabeprazole Sodium seal coated cores: Ingredients MG/UNIT QTY/BATCH in GM Rabeprazole Sodium drug cores from 56.4 1000 Illustration 1 HPMCE15 3.95 70 Ethyl Cellulose 1.69 30 Methylene Chloride 64.30 1140 Methanol 42.86 760 TOTAL 62.04 1100 1) Weighed quantity of HPMC E15 and Ethyl Cellulose was dispersed in Methylene Chloride and Methanol mixture under stirring to get clear solution. 2) Rabeprazole Sodium drug cores are coated with solution from step 1) in Fluid Bed Processor. 11 These cores could not protect the active ingredient in acidic surroundings and could not exhibit desired release profile. Illustration 3 Rabeprazole Sodium cores with aqueous enteric coat Ingredients MG/UNIT QTY/BATCH in GM Rabeprazole Sodium seal 62.04 250 coated cores from Illustration 2 Eudragit L30 D55 155.10 625 Dibutylsebacate 6.20 25 Glycerylmonostearate 9.31 37.5 Tween 80 1.55 5 Talc 2.33 7.5 Ferric Oxide Red USP 1.16 3.75 Water 159.75 662.5 TOTAL 128.21 516.25 1) Weighed quantity of Dibutylsebacate, Glycerylmonostearate, Tween 80 was mixed and heated at 70°C to form a solution. 2) Water quantity 4 times the weight of mixture in step 1 was heated to 70°C and added to solution of step 1, with continuous stirring using hand homogenizer for 3 minutes. 3) Emulsion formed in step 2 was allowed to cool to room temperature and filtered through muslin. 4) Weighed quantity of Eudragit L30 D55 was added to solution of step 3) under slow stirring carried out by hand homogenizer for two minutes. 5) Talc and Ferric Oxide Red USP was dispersed in water to get 10%w/w suspension and the suspension was added to solution of step 4 under stirring and resulting mixture was filtered through muslin. 6) Solution of step 5 was weighed and weight was adjusted using water to make 20%w/w solid content of total enteric coating solution. These cores could not protect the active ingredient in acidic surroundings and could exhibit desired release profile. Illustration 4 Rabeprazole Sodium cores with non-aqueous enteric coat 12 Ingredients MG/UNIT QTY/BATCH in GM Rabeprazole Sodium cores with aqueous 129.12 450 enteric coat HPMC Phthalate P 55 32.28 112.5 Dibutylsebacate 3.23 11.25 Methylene Chloride 337.33 1175.63 Methanol 337.33 1175.63 TOTAL 164.63 573.75 1) HPMC Phthalate P 55 was dissolved in mixture of Methylene Chloride and Methanol. 2) Dibutylsebacate was dissolved in above solution under stirring to get a clear solution. 3) Rabeprazole Sodium cores with aqueous enteric coat were coated with solution from step 2) in Fluid Bed Processor. These cores could preserve the active ingredient in acidic surroundings and could not exhibit desired release profile. Illustration 5Compression into tablet Ingredients MG/UNIT QTY/BATCH in GM Rabeprazole Enteric coated cores from 164.63 246.95 Illustration 4 Mannitol 461.62 692.43 Crospovidone 75.00 112.5 Magnesium. Stearate 11.25 16.88 Aerosil 15.00 22.5 Aspartame 15.00 22.5 Strawberry flavor 7.5 11.25 TOTAL 750 1125 1) Weighed quantities of Mannitol, Crospovidone, Aspartame and Strawberry Flavor through #40 sieve. 2) Add Rabeprazole enteric coated cores and blend in hexagonal blender for 15 minutes. 3) Sift Magnesium stearate and aerosil through 40 mesh and add to blend obtained in step 2). Blend for 15 minutes. 4) Compress the blend obtained in step 3) with 13mm punch and die set. 13 5) The tablets disperse in 33 seconds in 100 ml water, open in mouth in 5 seconds and melt in mouth in 45 seconds. 6) % of Rabeprazole released in 2 hours in acidic media is 7) % of Rabeprazole released in near neutral or alkaline media in hours is Illustration 6 Comparison of release profile from (pellets only aqueous enteric coated, only non-aqueous enteric coated and with both coats) pellets and compressed tablets. Only aqueousenteric coat likeIllustration 3 Only non-aqueousenteric coat(Illustration 4 -Aqueous coat) Multiple coat Pellets Tablets Pellets Tablets Pellets Tablets Weight in mg 177.69 800 149.14 Not Done 164.63 750 Quantity of polymer used in mgs 78.79 78.79 78.79 78.79 46.53 + 32.28 46.53 + 32.28 Acid degradation in twohrsinO.1 N HCI % 7.64 42.67% 26.11 Not Done 1.44 3.63 Drug release in Phosphate buffer pH 7.4at30min. 92% Not Done Not Done Not Done 92% 96% Hardness In Kps - 5.0 Kp - - - 5.0 Kp Above table shows: 1) Tablets undergo excessive degradation in acid when pellets are coated with only aqueous coat. 2) Pellets undergo excessive acid degradation when coated with only non-aqueous enteric coat. 3) Release profile of pellets and tablets compressed therefrom is similar when pellets are coated with aqueous enteric and non-aqueous enteric coats. Dated this 20,n day of April 2006 (Maya J. Shah) Applicant - For Themis Laboratories Private Limited 14

Documents:

627-MUM-2006-ABSTRACT(13-4-2007).pdf

627-mum-2006-abstract(complete)-(13-4-2007).pdf

627-mum-2006-abstract(granted)-(22-2-2010).pdf

627-mum-2006-cancelled pages(8-9-2009).pdf

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627-MUM-2006-CORRESPONDENCE 2(11-12-2008).pdf

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627-MUM-2006-CORRESPONDENCE(11-12-2008).pdf

627-MUM-2006-CORRESPONDENCE(22-5-2009).pdf

627-MUM-2006-CORRESPONDENCE(26-5-2009).pdf

627-MUM-2006-CORRESPONDENCE(8-9-2009).pdf

627-mum-2006-correspondence(ipo)-(26-3-2010).pdf

627-mum-2006-correspondence-po.pdf

627-mum-2006-correspondence-received.pdf

627-mum-2006-description (provisional).pdf

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627-MUM-2006-DESCRIPTION(COMPLETE)-(22-5-2009).pdf

627-mum-2006-description(granted)-(22-2-2010).pdf

627-MUM-2006-FORM 1(13-4-2007).pdf

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627-MUM-2006-FORM 2(TITLE PAGE)-(22-5-2009).pdf

627-mum-2006-form 2(title page)-(complete)-(13-4-2007).pdf

627-mum-2006-form 2(title page)-(granted)-(22-2-2010).pdf

627-MUM-2006-FORM 3(11-12-2008).pdf

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