WO2022074681A1

WO2022074681A1 - Pharmaceutical compositions with enhanced blend uniformity and content uniformity

Info

Publication number: WO2022074681A1
Application number: PCT/IN2021/050970
Authority: WO
Inventors: Jaya Mohit Abraham; Vikram Jeet Singh; Gurpreet Singh Minhas; Harpreet Singh Minhas
Original assignee: Harman Finochem Limited
Priority date: 2020-10-08
Filing date: 2021-10-08
Publication date: 2022-04-14

Abstract

The present invention, in general, discloses pharmaceutical composition of oral multiunit pellets comprising one or more pharmaceutical active ingredients or pharmaceutically acceptable salt, solvates or polymorphs thereof, specifically, present invention discloses pharmaceutical composition of multiunit pellet system (MUPS) tablets, there method of preparation and administration, providing immediate release, delayed release, sustained release or extended release profile of the active ingredients.

Description

“PHARMACEUTICAL COMPOSITIONS WITH ENHANCED BLEND

UNIFORMITY AND CONTENT UNIFORMITY”

Field of Invention

The present invention, in general, relates to pharmaceutical composition of oral multi-unit pellets systems (MUPS) comprising one or more pharmaceutical active ingredient or pharmaceutically acceptable salt, solvates or polymorphs thereof, specifically present invention relates to pharmaceutical composition of MUPS tablets, there method of preparation and administration, providing immediate release, delayed release, sustained release and extended release profile of the pharmaceutical active ingredient or pharmaceutically acceptable salt, solvates or polymorphs thereof.

Background of the Invention

Multi -unit pellet systems (MUPS) are viewed superior in terms of intra- and inter-individual variability of in vivo drug absorption (Lehmann K. Petereit HU, Dreher D 1993, Pharm Ind 55:940-947) in combination with oral modified release products. These pellets can be filled into hard capsules or be compressed together with suitable diluents, binders and other suitable pharmaceutical excipients into tablets. In MUPS system, each bead is a discrete depot unit. Each bead may be coated with a polymeric membrane, which can control the rate of drug release, masks the taste of the active ingredient, or improve the stability of the active ingredients contained in or on the pellets. The pellets when compressed into the tablet, disintegrates rapidly in contact with fluid whereby the beads are dispersed over a large surface in the gastrointestinal tract. The pediatric and geriatric population, who cannot swallow tablet or capsule as such, are more beneficial from dosage form like MUPS, e.g. Prevacid SoluTab such medication can be taken without any fluid such as water, especially during traveling since the formulation is designed as the orally disintegrating preparation that contains flavors and sweeteners which stimulate salivation and swallowing. MUPS tablets can be designed into a divisible dosage form, without compromising the drug release characteristics of coated particles contained therein. The MUPS have a lesser tendency of adhering to esophagus during swallowing {(Nrupa G. Patel et al: J. Pharm. Sci. Innov. 2017; 6(3)}.

Despite numerous advantages of the MUPS tablet composition, MUPS tablet Technologies have not been used extensively in the approved products in globally. Processing of pellets into tablets is frequently encountered with numerous challenges in meeting the quality target product profile, which leads to major loss of production of drug product batch recalls and poses risk to patient population at large.

One of the main problems in processing the MUPS pellets into tablet is the damage of the of the release controlling polymer coatings and/or generation of non-disintegrating pellet agglomerates which are formed during tableting and caused by sticky coating polymers or sintering pellets at higher pellets loads (Lopez-Rodriguez FJ, Torrado JJ, Escamilla C, Cadomiga R, Augsburger LL, Torrado S 1993, Drug Dev Ind Pharm 19: 1369-1377).

Another profound problem encounterd with processing of pellets into MUPS tablet, is lack of the blend uniformity and content uniformity. Rey described high variances in tablet weight for pellet-containing tablets made from pellets (60 % w/w, 850 - 1700 μ η) and fine grade Avicel PH 101, which was attributed to the poor flow properties of the mixture (Rey H 2003).

EP0277127 Bl, assigned to Aktiebolaget Hassle disclosed in example 9, a MUPS tablet wherein Silicon dioxide inert beads were drug layered with metoprolol succinate, drug layered beads were coated with extended release polymer coating comprising Ethyl cellulose and Hydroxypropyl methylcellulose. Polymer coated beads were subsequently mixed with equal quantities of tablet additives and compressed into tablet.

WO9601623, assigned to Astra AB, an oral pharmaceutical multiple unit tableted dosage form, wherein tablet comprises enteric-coated drug layered inert core. Enteric coated pellets, which were optionally further coated with PEG and compressed into tablets after addition of tableting excipients.

W02012017074, assigned to Valpharma, discloses MUPS tablet composition of Esomeprazole wherein enteric polymer coated micro granules were compressed into tablets at suboptimal compression force.

WO2013092497, assigned to Boehringer, discloses MUPS tablet of Dabigatran etexilate wherein tartaric acid starting inert core was drug layered and subsequently coated with immediate release coating. Coated pellets were subsequently compressed into tablets after blending with tableting excipients.

According to Innovations in Pharmaceutical Technology Issue 49, page 31- 33, pellets in a MUPS formulation have a mass percentage of 20-70% and range in size from 300pm to 2,000pm, whereas the excipients are usually smaller than 200pm. As a result, MUPS formulations can behave very differently in terms of flowability, compressibility and the risk of segregation, depending on the concentration and size of the pellets. The particle size of the powder phase excipients is typically between 50pm and 200pm, whereas the bulk density of the pellet phase is generally greater than 0.7g/cm3, and the density of the excipient mixture is 0.4-0.6g/cm3. These significant differences in average particle size and density make a MUPS mixture extremely sensitive to segregation.

If segregation occurs during transfer, tablets would be produced with an out of specification of drug product which leads to rejection of the product. The uniformity of the produced batch would subsequently fail quality assurance checks, and the batch need to be rejected leading to loss of yield and efficiency of the production process.

Due to enhanced requisites of bioavailability and safety of the drug products, compendial authorities such as the United States Pharmacopoeia (USP) have implemented a multi-stage content uniformity test, which includes:

1) assaying ten tablets to ensure that the relative standard deviation (RSD) of active content is less than or equal to 6.0% and no value is outside 85-115%; and

2) assaying twenty more tablets to ensure that the RSD for all thirty tablets is less than or equal to 7.8%, no more than one value is outside 85-115% and no value is outside 75-125% of stated drug content.

USFDA has also imposed stringent regulations (like PAT tools) to monitor the content uniformity of the drug product made with MUPS tablet technology to ensure the quality, efficacy and safety of the drug product.

The solution to the problem of lack of blend uniformity and content uniformity can be addressed by use of high cost intensive equipment which is not commercially viable.

Inventors of the present invention has found the cost effective, efficient, practically feasible and industrially scalable solution to the above mentioned problem of segregation which result in low of blend uniform and content uniformity related to production of MUPS tablet.

Inventors of the present invention provide pharmaceutical composition of the MUPS tablet wherein the composition of the invention has substantially improved blend uniformity and content uniformity. Inventors of the present invention provide a pharmaceutical composition of the MUPS tablet wherein the controlled release coating over the pellets remain unaffected by the compression force applied during tableting.

Objects of the invention

Primary object of present invention is to provide a Pharmaceutical composition of the MUPS tablets comprising multiunit pellets, one or more pharmaceutical active ingredients and tableting excipients, wherein multiunit pellets are granulated with pharmaceutically acceptable excipients comprising one or more diluent, binder, disintegrant, and wherein the ratio of intragranular component to extragranular component is from 80: 20 to 95: 05.

Primary object of present invention is to provide a Pharmaceutical composition of the MUPS tablets comprising multiunit pellets, one or more pharmaceutical active ingredients and tableting excipients, wherein multiunit pellets are granulated with pharmaceutically acceptable excipients comprising one or more diluent, binder, disintegrant, and wherein the ratio of intragranular component to extragranular component is from 70: 30 to 97: 03.

The object of the present invention is to provide a pharmaceutical composition of the MUPS (Multi-unit pellet system) tablet comprising one or more pharmaceutical active ingredient and wherein pharmaceutical composition has acceptance value of less than 10 as per USP <905> uniformity of dosage unit.

The another object of the present invention is to provide a pharmaceutical composition of the MUPS tablet comprising one or more pharmaceutical active ingredient and tableting excipients wherein the content uniformity of the pharmaceutical composition is between 95 to 105%, and acceptance value of less than 15 as per USP <905> uniformity of dosage unit.

The another object of the present invention is to provide a process for preparation of pharmaceutical composition of the Multi-unit pellets system tablet comprising one or more pharmaceutical active ingredient and combination of tableting excipients wherein the blend uniformity of the pharmaceutical composition is between 95 to 105%.

Another object of the present invention is to provide a pharmaceutical composition of MUPS tablet comprising one or more pharmaceutical active ingredients and combination of tableting excipients wherein drug release from MUPS tablets is not altered compared to the drug release from multiple units pellets prior to tableting.

Summary of the invention

Present invention relates to pharmaceutical composition of the MUPS tablets comprising multi-unit pellets, one or more pharmaceutical active ingredients and tableting excipients, wherein multi-unit pellets are granulated with tableting excipients comprising one or more diluent, binder, disintegrant, wherein the ratio of intragranular component to extragranular component is from 80: 20 to 95: 05.

Present invention relates to pharmaceutical composition of the MUPS tablets comprising multi-unit pellets, one or more pharmaceutical active ingredients and tableting excipients, wherein multi-unit pellets are granulated with tableting excipients comprising one or more diluent, binder, disintegrant, wherein the ratio of intragranular component to extragranular component is from 70: 30 to 97: 03. The present invention relates to a pharmaceutical composition of the MUPS (Multi-unit pellet system) tablet comprising one or more pharmaceutical active ingredient and wherein pharmaceutical composition has acceptance value of less than 10 as per USP <905> uniformity of dosage unit.

The present invention relates to a pharmaceutical composition of the MUPS tablet comprising one or more pharmaceutical active ingredient and tableting excipients wherein the content uniformity of the pharmaceutical composition is between 95 to 105%, and acceptance value of less than 15 as per USP <905> uniformity of dosage unit.

Present invention relates to a pharmaceutical composition of the MUPS tablet, wherein composition has content uniformity between 95% and 105 %.

Present invention relates to a pharmaceutical composition of the MUPS tablet, wherein composition has acceptance value of less than 15 as per USP <905> uniformity of dosage unit.

Present invention relates to a pharmaceutical composition of the MUPS tablets wherein composition has the blend uniformity between 90% and 110% and the relative standard deviation (RSD) of the blend uniformity is less than 5%.

Present invention relates to a pharmaceutical composition of the MUPS tablet, wherein composition has content uniformity between 95% and 105 % and relative standard deviation (RSD) less than 5%.

The present invention addresses the grievous problem of blend uniformity and content uniformity associated with manufacturing of MUPS tablet compositions. The present invention provides a simple, cost-effective, efficient and industrially scalable solution for the grievous problem of blend uniformity and content uniformity associated with manufacturing of MUPS tablet compositions.

The present invention also provides a simple, cost-effective, solution for the grievous problem of cracking of multi-unit pellet during compression of multi-unit pellets into MUPS tablet.

The pharmaceutical composition of the present invention is for oral administration and can be used for the preparation of pharmaceutical compositions of the multi -unit pellets system tablet for the treatment of wide array of human diseases and disorders depending upon the pharmaceutical active ingredient (s) incorporated in the pharmaceutical compositions. For example, controlled release MUPS tablet of Metoprolol Succinate in the dose range of about 25 mg to about 200 mg can be used in the treatment of hypertension either alone or in combination with other antihypertensive agents.

The process of manufacturing the pharmaceutical composition of present invention comprises the steps of: a. preparation of the multiunit pellets comprising one of or pharmaceutical active ingredient; b. granulation of the multiunit pellets with one or more diluent, binder, disintegrant using suitable solvent; c. mixing the granulated multiunit pellets with one or more lubricant, diluent, binder, disintegrant, lubricant and glidant; d. compressing the blend of step (c) to form a tablet e. optionally film coating the tablet of step (d). Detailed description of the invention

Present invention provides a pharmaceutical composition of the MUPS tablets comprising multi-unit pellets, one or more pharmaceutical active ingredients and tableting excipients, wherein multi-unit pellets are granulated with tableting excipients comprising one or more diluent, binder, disintegrant, wherein the ratio of intragranular component to extragranular component is from 80: 20 to 95: 05.

Present invention provides a pharmaceutical composition of the MUPS tablets comprising multi-unit pellets, one or more pharmaceutical active ingredients and tableting excipients, wherein multi-unit pellets are granulated with tableting excipients comprising one or more diluent, binder, disintegrant, wherein the ratio of intragranular component to extragranular component is from 70: 30 to 95: 05.

The present invention provides a pharmaceutical composition of the MUPS tablet comprising one or more pharmaceutical active ingredient and tableting excipients wherein the content uniformity of the pharmaceutical composition is between 95 to 105%, and acceptance value of less than 15 as per USP <905> uniformity of dosage unit.

The present invention relates to a pharmaceutical composition of the MUPS (Multi-unit pellet system) tablet comprising one or more pharmaceutical active ingredient and wherein pharmaceutical composition has acceptance value of less than 10 as per USP <905> uniformity of dosage unit.

Present invention provides a pharmaceutical composition of the MUPS tablet, wherein composition has content uniformity between 95% and 105 % and relative standard deviation (RSD) less than 5%. The process of manufacturing the pharmaceutical composition of present invention comprises the steps of: a. preparation of the multiunit pellets comprising one of or pharmaceutical active ingredient; b. granulation of the multiunit pellets with one or more diluent, binder, disintegrant using suitable solvent; c. mixing the granulated multiunit pellets with one or more lubricant, diluent, binder, disintegrant, lubricant and glidant; d. compressing the blend of step (c) to form a tablet e. optionally film coating the tablet of step (d).

Unless otherwise indicated, the terms in this specification intended to have their simple and ordinary meaning in the pharmaceutical and chemical art.

Multiple or Multi-unit pellets as used herein is “Multi-unit pellet” comprises 1) an inert or active core 2) Active ingredient layering 3) optional seal coating and 4) functional coating, wherein core can be prepared by numerous technique as described herein.

Multiple-Unit Pellet System (MUPS) which is a multiparticulate drug delivery system for immediate or modified drug release which include delayed release, sustained release and extended release of the active ingredient. These Multiple Units pellets are compressed to form tablet known as MUPS tablet. When multi-unit pellets are coated with sustained, extended, or prolonged release polymers or materials, theses pellets are interchangeably known as sustained, extended, or prolonged release pellets. Similarly, when multi-unit pellets are coated with enteric polymer or material they are meant to delay the release of the drug from the dosage form especially in the intestinal region of the body. Immediate release multi-unit pellets can be barrier coated or taste-masked coated to impart stability and taste making properties respectively to the drug or dosage form.

For the purpose of this invention, the term “multi-unit pellets” include taste-masked, barrier, delayed release, sustained release, and extended release coated pellets. Typically, multi-unit pellet of the invention comprises a core or inert core; one or more seal coat over core; one or more drug in or over core; immediate release (Barrier or taste masked coating) or modified release (Enteric, sustained, extended or prolonged release) polymeric coating. These coating as described above are also known as functional coating. Functional coated multi-unit pellet can be over coated with cushion coating to enhance the resistance to mechanical stress of compression. Multi-unit pellets of the invention encompass all types of the multi-unit pellets as defined above.

The term " In tr agranular" component refers to being or occurring within granules of the pharmaceutical composition i.e. granules comprising multi- unit pellets, pharmaceutically acceptable active ingredients, and tableting excipients selected from the group comprising of a binder, a disintegrant, a diluent, a glidant and/or a solvent. All these elements fall under an intragranular component of the pharmaceutical composition. The term "Extra granular" component refers to the addition of pharmaceutically acceptable excipients to a material following granulation to facilitate the compression into tablet i.e. said extra- granular component comprises a second tableting excipient, wherein said second tableting excipient is selected from the group consisting of a disintegrant, a diluent, binder, a lubricant, a glidant, Anti-adherent and/or a like thereof.

The term “Active ingredient” or “active or pharmaceutical active ingredient” or “drug substance” or “drug” has been used interchangeably herein means a pharmaceutical active ingredient or drug substance, including any salt or ester of the active ingredient or drug substance that shows a physiological effect when it is absorbed in sufficient amount by the body of an organism. Active ingredient or drug substance must be present in the drug product when administered by the organism. Active ingredients contemplated for the invention are Metoprolol succinate, Bisoprolol, aspirin, dipyridamole, Diclofenac Sodium, Diltiazem, Galantamine, Nebivolol, Sacubitril, Valsartan, Odevixibat, Indomethacin, Ketoprofen , Levomilnacipran, Etrasimod, Ozanimod, Maralixibat, Methylphenidate, Cenobamate, Linaclotide, Omecamtiv Mecarbil, Memantine Omeprazole, Esomeprazole magnesium, Aprepitant, Dutasteride, Donepezil, Fenofibrate, Ebastine, Mebeverine, Methylphenidate, Theophylline, Venlafaxine, Lansoprazole; Orlistat, ferrous fumarate, folic acid, Pantoprazole; Rabeprazole, Dexlansoprazole, Dabigatran, dimethyl fumarate, Pancreatin, Dabigatran etexilate, Propranolol , Duloxetine, Ranolazine, Pseudoephedrine, Tamsulosin, Loratadine, Desloratidine, Vitamin B12, Ascorbic acid Famotidine, Zinc sulphate, methylcobalamine Naproxen, Ibuprofen, Divalproex sodium, Doxycycline, Sofosbuvir, Ledipasvir, Viloxazine, Viloxazine HC1 or pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof. Any combination of the active ingredients as recited above are also contemplated for the present invention.

“Pharmaceutically acceptable excipients or Tableting excipients” as used herein interchangeably means inert additives known and mentioned in various pharmacopoeias and in various additions of the Hand Books of Pharmaceutical excipients, which are generally added to the Active ingredients or to pellets or micro-granules, granules containing them, to facilitate their granulation and subsequent compression into tablets; in particular , for preparation of the tablets of the Multi-unit pellet system, for example lactose, mannitol , Dicalcium phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, povidone, hydroxypropyl methylcellulose, pre-gelatinized starch, maize starch, hydroxypropyl cellulose , carboxymethyl starch, Croscarmellose, Crospovidone, magnesium stearate, sodium stearyl fumarate, magnesium fumarate, silicon dioxide, colloidal silica, talc, polyethylene glycol and the like.

“Content Uniformity” means the homogeneity of the active ingredient content among dosage units after formulation. Content uniformity and acceptance value test can be performed according to US Pharmacopoeia chapter <905>Uniformity of dosage units. The term “Uniformity of dosage unit” is defined as the degree of the uniformity in the amount of the drug substance among dosage units. According to US Pharmacopoeia criteria, the requirements for dosage uniformity is met if the acceptance value of the first 10 dosage unit is less than or equal to 15%.

“Blend Uniformity” means the homogeneity of the active ingredient with other componenets of the drug product. Blend uniformity and acceptance value test can be performed in accordance with USFDA Guidance to the industry, Powder Blends and Finished Dosage Units — Stratified In-Process Dosage Unit Sampling and Assessment, Published in Oct 2003.

In the first embodiment, invention provides a pharmaceutical composition of the MUPS tablets comprising multi-unit pellets, one or more pharmaceutical active ingredients and tableting excipients, wherein multi- unit pellets are granulated with tableting excipients comprising one or more diluent, binder, disintegrant, wherein the ratio of intragranular component to extragranular component is from 80: 20 to 95: 05.

In another embodiment, present invention provides a pharmaceutical composition of the MUPS tablets comprising multi-unit pellets, one or more pharmaceutical active ingredients and tableting excipients, wherein multi- unit pellets are granulated with tableting excipients comprising one or more diluent, binder, disintegrant, wherein the ratio of intragranular component to extragranular component is from 70: 30 to 97: 03.

In the first embodiment, invention provides a pharmaceutical composition of the MUPS tablets comprising multi-unit pellets, one or more pharmaceutical active ingredients and tableting excipients, wherein multi- unit pellets are granulated with tableting excipients comprising one or more diluent, binder, disintegrant, wherein the ratio of intragranular component to extragranular component is from 80: 20 to 95: 05 and wherein blend uniformity of the pharmaceutical composition is between 95 to 105%, preferably 98 to 102%.

In the first embodiment, invention provides a pharmaceutical composition of the MUPS tablets comprising multi-unit pellets, one or more pharmaceutical active ingredients and tableting excipients, wherein multi- unit pellets are granulated with tableting excipients comprising one or more diluent, binder, disintegrant, wherein the ratio of intragranular component to extragranular component is from 80: 20 to 95: 05 and wherein content uniformity of the pharmaceutical composition is between 95 to 105%.

In the another embodiment, invention provides a pharmaceutical composition of the MUPS tablets comprising multi-unit pellets, one or more pharmaceutical active ingredients and tableting excipients, wherein multi- unit pellets are granulated with tableting excipients comprising one or more diluent, binder, disintegrant, wherein the ratio of intragranular component to extragranular component is from 80: 20 to 95: 05 and wherein acceptance value of the pharmaceutical composition is less than 15 as per USP <905> uniformity of dosage unit. Content uniformity and acceptance value test can be performed according to revised US Pharmacopoeia Chapter <905>uniformity of dosage units as described herein.

According to the present invention, the multiple unit pellets contained in the MUPS tablets can be derived from the group consisting of pellets, granules, crystals, spherules, micro spheres, mini tablets and other agglomerations containing one or more pharmaceutically active ingredient. The multiple units' size may be 100-2000 pm, preferably 200-1200 pm, more preferably 500-1000 pm, most preferably about 750 pm.

In the pharmaceutical composition of the invention, multi-unit pellets constitute 40 % to 80 % of the total weight of the pharmaceutical composition.

In the pharmaceutical composition of the invention, multi-unit pellets constitute preferably 50 % to 75 % by weight of the total weight of the pharmaceutical composition.

In the pharmaceutical composition of the invention, multi-unit pellets constitute most preferably 40 % to 65 % of the total weight of the composition.

The multi-unit pellets of the present invention can be enteric-coated pellets for the delayed release of the active ingredient.

The multi-unit pellets of the present invention can be sustained or extended release coated pellets for prolong release of the active ingredient from the Multi-unit pellet system (MUPS) tablet. The multi-unit pellets of the present invention can be immediate release coated pellets for stabilization of the active ingredient or for taste masking of unpleasant tasting active ingredients by providing a barrier coating.

Intragranular Components

The intragranular component of the composition of the present invention present comprises Multi-unit pellet” which comprises 1) an inert or active core 2) Active ingredient layering 3) optional seal coating and 4) functional coating; and tableting excipient used for granulating the multi- unit pellets

Core

According to the present invention, the inert core 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®. Suitable Examples of water-insoluble inert cores are glass beads and coarse grade silicon dioxide beads.

Any inert excipient like Lactose, spray dried lactose, povidone, hydroxypropyl methyl cellulose, hydroxy propyl cellulose, microcrystalline cellulose, mannitol, calcium phosphate dihydrate, dicalcium phosphate, magnesium carbonate, magnesium oxide, calcium sulfate dehydrate, calcium carbonate , dibasic calcium phosphate monohydrate and tribasic calcium phosphate granulated with a suitable granulating agent and medium into suitable size granules can also form inert core of the present invention. Said granulation can be carried out by convention process and equipment such fluid bed granulation, extrusion Spheronization or Rapid Mixer Granulator (RMG).

The inert core must be of sufficient density and strength to withstand strain of drug layering or coating process.

Preferably, the inert core unit is made up of microcrystalline cellulose or inert non-pareil sugar spheres Preferably according to the invention, size of NPS or Celphere is selected from the following sieve sizes: 40-60 mesh sieve (250-425 pm), 40-50 mesh size (420-300pm), 35-40 mesh sieve (425- 500pm), 30-35-mesh sieve (500-600pm), 25-30 mesh sieve (600-710 pm), 20-25 mesh sieve (710-850pm), 18-20 mesh sieve (850- 1000pm), 16- 18 mesh sieve (1000-1180 pm), 14-16 mesh sieve (1000-1400 pm).

In a more preferred embodiment, the starting inert cores have a diameter ranging from about 250 to 600 pm, preferably from 300 to 500pm and most preferably 300 to 420pm. Alternatively, combination of the above- mentioned sieve sizes can be employed. Preferably, inert core constitutes from about 5% to about 40% by weight of the total multi-unit pellets, preferably from 10% to 30%, still more preferably, from 15% to 25% by weight of total multi-unit pellets.

The type and size of inert core is appropriately selected based upon the physical properties (particle size, density, solubility and the like) of drug substance and amount of the drug substance (dose) to be loaded on the inert core or seal coated core as known to the person skilled in the art.

Seal coating

The inert core of the invention is optionally coated with the seal coating material. The seal coating material can be a water-soluble, water swellable or water insoluble polymer with or without other pharmaceutical excipients like binder, stabilizer, plasticizer, anti -adherents, surfactants, solvent and the like. The water-soluble seal-coating polymers constitute povidone, zein, hydroxy propyl cellulose and hydroxy propyl methylcellulose and the like. Water insoluble seal coating material constitute ethyl cellulose, acrylic polymer or methacrylic acid co-polymer and the like. Seal coating layer constitute from 0.5% to 3.0 % by weight of the total multi-unit pellets. Polymer material in seal coating constitute from 50 % to 90% by weight of the seal coating layer. Seal coating on inert core can be carried by in conventional equipment such as pan coating, fluid bed coater, and Solvent systems used for seal coating are preferably aqueous or hydro-alcoholic.

Active substance layers

The inert or seal coated core of the invention are layered with one or more active substance or active ingredients. Active ingredients contemplated for the invention are Metoprolol succinate, Bisoprolol, aspirin, dipyridamole, Diclofenac Sodium, Diltiazem, Galantamine, Nebivolol, Sacubitril, Valsartan, Odevixibat, Indomethacin, Ketoprofen , Levomilnacipran, Etrasimod, Ozanimod, Maralixibat, Methylphenidate, Cenobamate, Linaclotide, Omecamtiv Mecarbil, Memantine Omeprazole, Esomeprazole magnesium, Aprepitant, Dutasteride, Donepezil, Fenofibrate, Ebastine, Mebeverine, Methylphenidate, Theophylline, Venlafaxine, Lansoprazole; Orlistat, ferrous fumarate, folic acid, Pantoprazole; Rabeprazole, Dexlansoprazole, Dabigatran, dimethyl fumarate, Pancreatin, Dabigatran etexilate, Propranolol , Duloxetine, Ranolazine, Pseudoephedrine, Tamsulosin, Loratadine, Desloratidine, Vitamin B12, Ascorbic acid Famotidine, Zinc sulphate, methylcobalamine Naproxen, Ibuprofen, Divalproex sodium, Doxycycline, Sofosbuvir, Ledipasvir, Viloxazine, Viloxazine HC1 or pharmaceutically acceptable salts, polymorphs, solvates, hydrates or esters thereof. Any combination of the active ingredients as recited above are also contemplated for the present invention. The active substance can be either crystalline or amorphous form or combination thereof. The amount of active substance loaded on the inert or seal coated cores depend upon the per unit (tablet or capsule) dose of the active ingredient to be administered to patient. According to present invention, active substances constitute from about 10% to about 50% by weight of total weight multi-unit pellets.

Active substance layering can be performed one or more times that can be on or prior to the functional polymeric coating and said functional polymeric coating can be sustained, extended or enteric, or taste-masked or barrier polymeric coating.

Apart from active substance, active substance layer can also comprise other pharmaceutical excipients such as binders, anti-adherants, anti-tacking agents, surfactants, stabilizers and suitable solvents for dispersing/suspending/ dissolving the active ingredients and other pharmaceutical excipients. Preferably, solvent system for the present invention is aqueous or hydro alcoholic as to be environment friendly.

According to the present invention, the binders employed include, but not limited to, starch, polyvinyl pyrrolidone (Povidone K-30), hydroxyethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyacrylate, ethyl cellulose, glucose, sucrose, sorbitol, mannitol, dextrose, sodium carboxymethyl cellulose, low substituted hydroxypropyl cellulose, polyvinyl alcohol, polymethacrylates (Eudragit®NE 30 D and Eudragif® RS 30 D) and, maltodextrins and chitosan derivatives. In accordance with the present invention, preferably the binder is hydroxypropyl cellulose (HPC) or Hydroxypropyl methylcellulose. HPC, for binder use, is commercially available from Aquaion, USA under the brand name Klucel® EF and EXF. Similarly, hydroxypropyl methylcellulose is commercially available from DuPont under brand name METHOCEL E3 LV, E5LV, and E15LV. Binder constitute from about 0.5% to about 15%, preferably from about 1 to about 10% by weight of the total weight of the multi -unit pellets.

Suitable anti-tacking agents according to the invention include but are not limited to talc, silicon dioxide and magnesium stearate. Anti-tacking agents constitute preferably from about 0% to about 1% by weight of the total weight of the multi-unit pellets.

Suitable examples of surfactants include, but not limited to, polysorbate series such as, 80, 60, 40, 20; sorbitan monooleate, sodium lauryl sulphate, benzalkonium chloride, cetylpyridinium chloride. Surfactants promote the dispersion of the drug and low aqueous-solubility excipients in aqueous medium. Surfactant constitute preferably from about 0% to about 1% by weight of total weight of the multi-unit pellets.

Stabilizers used in the drug layer promote the stabilization of the unstable active ingredient against degradation. Suitable examples of stabilizers are anti-oxidants, basifying agents, acidifying agents or buffering agents as known to the person skilled in the art.

According to present invention, active substance layering constitutes from about 20% to about 80% by weight of total weight of the multi-unit pellets. The active substance layer is applied to the inert or seal coated core by any conventional techniques known in the art, such as, pan coating, roto- granulation or fluidized bed coating equipment. During such active substance layering operations the active substance dispersed, 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-IP A; organic solvents, such as, acetone, methylene chloride or any combination of those mentioned above. In a preferred embodiment according to the invention, aqueous solvent, purified water is used and drug layering is performed in either equipment or fluid bed processor fitted with Wurster apparatus equipment.

In one embodiment, active substance layer can optionally be coated with intermediate coating of inert excipient like povidone, polyvinyl alcohol, hydroxy propyl cellulose or hydroxy propyl methylcellulose. Person skilled in the art knows such inert layer coating process.

Polymeric Coating

Polymeric coating over the active substance layer or seal coated layer may be either be one or more sustained or extended release coating, one or more enteric coating, barrier coating for stabilization of active substance and taste-masking of the unpleasant tasting active substance depending upon the type of the polymer used in the polymeric layer. In one embodiment of the present invention, any combination of the above-mentioned polymer coating can be used for example extended release coating followed by enteric coating followed by taste-masking coating though not necessarily in the same order.

Sustained or Extended or prolonged polymer coating

Polymers for sustained or extended release coating include but are not limited to, one or more of cellulosic polymers/copolymers or its derivatives including ethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, povidone, carboxymethylcellulose, sodium carboxymethylcellulose; polyethylene oxides, chitosan, gums, starch derivatives, polyurethanes, polysaccharides, polyalcohols, cellulose derivatives as ethyl cellulose, ethyl cellulose aqueous dispersion, cellulose acetate, poly (alkyl) methacrylate, copolymers of acrylic or methacrylic acid esters, Eudragit like EudragitNE 30 D, 40 D, Eudragit RS and Eudragit RL, EUDRAGIT E , polymethacrylates containing quaternary ammonium group, high molecular weight polyvinyl alcohols, polyvinyl acetate dispersion (e.g.: Kollidon), waxes, hydrogenated vegetable oil, fatty acids; long chain fatty alcohols, or mixtures thereof , and other polymeric or non- polymeric materials known to one of ordinary skill in the art.

Sustained, extended, or prolonged release coating of the present invention may also contain suitable plasticizers and suitable anti-tacking agents. The suitable examples of plasticizer are but not limited to dibutyl sebacate and polyethylene glycols such as PEG 400, PEG 6000 and the like.

Suitable examples of anti-tacking agents are but not limited to Talc, silicon dioxide and magnesium stearate and the like.

Preferably, sustained or extended release polymer for the present invention is the combination of ethyl cellulose and hydroxy propyl cellulose. Ethyl cellulose is a water-insoluble, water-permeable film-forming polymer and is commercially available from Dow

Chemical under the trade name Ethocel® having viscosity of 45 CPS. Ethyl cellulose is also commercially available as Surerelase® from Colorcon Company. Surelease is aqueous coating system containing aqueous dispersion of the ethyl cellulose. Hydroxy propyl cellulose is commercially available under brand name KLUCEL LF from ASHLAND Company. KLUCEL LF is nonionic water-soluble cellulose ether with viscosity (25°C) of 75-150, and a concentration of 5% wt. (5 to 20% of the coating dry weight). The relative proportions of the ingredients, notably the ratio of ethyl cellulose and hydroxy propyl cellulose can be varied depending on the release profile to be obtained for example a more extended release is generally obtained with a higher amount of water-insoluble, water- permeable film forming polymer i.e ethyl cellulose. The amount of ethyl cellulose in extended release coating may vary from about 20% to about 85% of the coating dry weight. The amount of hydroxy propyl cellulose in the coating may vary from about 10% and about 35% of the coating dry weight. The amount of plasticizer may van,' from about 0% to about 20% of the coating dry weight. The amount of anti-tacking agent may vary from about 5% to about 25% of the coating dry weight.

The multi-units of the present invention can be coated with one or more sustained/extended release/prolonged coatings such coatings can be disposed beneath the active substance or drug layer or over the Active substance or drug layer

The solvent system used for sustained/ extended release /prolonged release coating is either aqueous or non-aqueous or hydro-alcoholic in nature.

Ethyl cellulose and hydroxypropyl cellulose are dissolved in a solvent system comprising isopropyl alcohol and methylene chloride. Talc is added under stirring and stirring is continued to form a homogeneous dispersion. The resulting dispersion is sprayed onto the drug-coated core to desired weight gain and subsequently dried to have extended release-coated pellet. The said coating process can be carried out using equipment or a coating pan or a fluidized bed apparatus.

The extended release coating constitutes from about 5 % to about 50% by weight of the total weight of multi-unit pellets.

Enteric Polymer coating

In one embodiment, multi-unit pellets of the present invention may comprise one or more enteric coated layers, of same or different enteric polymers. In the present invention, enteric coating is disposed on drug- layered cores or sustained release coated pellets. The enteric layer essentially consists of enteric polymers. Besides, enteric layer may also contain plasticizers, opacifying agents, anti-tacking agents, stabilizers, antifoaming agents, surfactants, antistatic agent, colorants, and pigments to enhance the processability, functionality and elegance of the said layers.

The polymers useful in the enteric layers include, but not limited to, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), shellac, polyvinyl acetate phthalate, acrylic acid polymers & copolymers, and methacrylic acid polymers & co- polymers or any combinations thereof. Preferably, according to the present invention, the enteric polymers are methacrylic acid copolymers, HPMCP, or combination thereof. Methacrylic acid copolymer is commercially available under the brand name Eudragif® L30 D55 from Rohm Pharma. Similarly, HPMCP is commercially available from ShinEtsu Company.

The enteric polymers constitute from about 25 % to about 90% by weight of enteric coating layer on dry weight basis. The plasticizers, which impart flexibility to the enteric layer constitute from about 1% to about 15%, preferably from about 3% to about 9% by weight of enteric coating layer, all percentages based on weight-by-weight basis. Exemplary, plasticizers are triacetin, citric acid esters, phthalic acid esters, dibutyl sebacate, polyethylene glycol and cetyl alcohol.

Various anti-tacking and antistatic agents according to the invention include, but are not limited to talc, silicon dioxide, metallic salts of stearic acid and glyceryl monostearate. Optimum concentration of these agents in the enteric layer is well known to the skilled artisan. Optionally, the enteric layer may also include 0.1% to about 2% of surfactant. Optionally, the enteric coating layer may comprise pore-forming agents.

The enteric coating layer constitute from about 5 % to about 30% by weight of the total weight of multi-unit pellets.

The enteric layers are deposited on the drug-layered cores or sustained release pellets in suitable equipment like, Coating Pan, and fluid bed processor using aqueous or non-aqueous solvents. The solvent system employed for processing of enteric layer and is preferably aqueous, but it can be a combination of aqueous and organic solvent. The enteric layer is essential to prevent degradation of the acid-susceptible drug during its transit from the acidic environment of stomach.

According to the invention, enteric coatings are performed preferably using fluid bed processor with process variable well known to skilled artisan.

Taste -Masking Coating

Taste- Making coating of the present invention is performed to eliminate the unpleasant taste of the drug substance and enhance the patient compliance. Tongue provides the sensory perception to the taste of various ingredients. In general, pH of the mouth including tongue is about 7. Unpleasant taste of a drug substance, drug particle, or an agglomeration of drug particles can be masked with a coating composition that is insoluble in the mouth. The coating must be formulated to rapidly break down in the stomach to release the pharmaceutically active ingredient into the body. The coating should be such that it immediately dissolves in the acidic environment of the stomach to release the active ingredient instantaneously. Polymers used in taste masking coating of the present invention include but are not limited to dimethylaminoethyl methacrylate and neutral methacrylic acid ester; and cellulose ester polymer or combination thereof.

The taste masking coating layer constitute from about 5% to about 25 % by weight of the total weight of the multi-unit pellets.

Taste masking coating composition of the present invention may be applied onto one or more drug layered or loaded cores or particles of the active ingredient by using a fluidized bed coating operation. The coated pellets granules or particles are then processed into a multi-unit pellet tablet dosage form.

Cushion (protective) Coating

Multi- unit Pellets covered sustained release/ enteric/barrier coating /Taste- mask coating layer(s) may further be covered with one or more cushion coating layer (s). The cushion coating can be applied to the functionally coating layered pellets by coating or layering procedures in suitable equipment such as coating pan, coating granulator or in a fluidized bed apparatus using water and/or organic solvents for the coating or layering process. The material for cushion coating layers are chosen among pharmaceutically acceptable excipients such as, but not limited to, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methylcellulose, Ethylcellulose, hydroxypropyl methyl cellulose, carboxy methylcellulose sodium and others, used alone or in mixtures. The preferred cushion coating materials are hydroxy propyl cellulose or polyethylene glycol or combination thereof. Pharmaceutical additives such as plasticizers, colorants, pigments, anti- tacking and anti-static agents, such as magnesium stearate, titanium dioxide, talc and other additives may also be included into the cushion coating layer(s). Said cushion coating layer may further prevent potential agglomeration of functionally coated pellets and further protect the functionally coated pellets towards cracking during the compaction process and enhance the tableting process. The maximum thickness of the applied cushion coating layer(s) is normally only limited by processing conditions. Cushion coating polymer constitute from about 80 % to about 98% by weight of dry coating weight of cushion coating composition.

Cushion coating layer constitute from about 5% to about 30% by weight of the total weight of the multi-unit pellets

Cushion coating can be conveniently performed in Fluidized bed coater, pan coater.

Granulation of multiple unit pellets

Multi-unit pellets comprising one or more pharmaceutical active ingredients, as described above, are granulated with tableting excipients comprising diluent(s), binder(s), disintegrant(s), glidant and optionally surfactant(s) and cushioning agents using a solvent or mixture of solvents in suitable equipment like or Fluidized Bed Granulator to obtain suitable size granules.

The granulated composition of the invention comprises multi-unit pellets with one or more active substances, one or more diluent(s) one or more binder(s), one or more disintegrant(s), optionally one or more surfactant(s), glidant, cushioning agents and solvent. Optionally, the granulated composition may also comprise suitable stabilizers like anti-oxidants.

Appropriate size granules are mixed with lubricant, anti-adherents, disintegrant in a suitable blender, and compressed into tablets. The tablet produced by said process exhibit substantially superior content uniformity. Multi -unit pellets constitute from about 40% to about 80% by weight of total weight of the granulated composition.

Diluents constitutes from about 15% to 50% by weight of the total weight of the granulated composition. Suitable examples of diluents include but are not limited to microcrystalline cellulose, silicified microcrystalline cellulose (Co-processed excipient using [2%] silicon dioxide and [98%] microcrystalline cellulose), Lactose anhydrous or monohydrate, mannitol, dextrose, sorbitol, pre-gelatinized starch, and di or tri basic calcium phosphate. The preferred diluent is silicified microcrystalline cellulose. It is commercially available under the Brand Name PROSOL V^® SMCC from JRS pharma.

Binders constitute from about 1% to 10% by weight of total weight of the granulated composition. Suitable examples of binders include but are not limited to dextrin, maltodextrins, methylcellulose, ethyl cellulose, hydroxymethylcellulose, hydroxy ethyl cellulose, hydroxy propyl cellulose, hydroxy propyl methylcellulose, polyvinyl alcohol, polyvinyl pyrrolidone (povidone k30), and sodium carboxy methylcellulose. The preferred binder is Povidone K30 or Povidone K90. Povidone K30 and K90 are commercially available under the Brand Name Plasdone K30 and K90 respectively from Ashland Company.

Disintegrant constitute from about 3% to 20% by weight of the total weight of the granulated composition. Suitable examples of disintegrant include, but are not limited to, starch, carboxy methylcellulose sodium, which commercially available under the brand name Ac-Di-Sol®, cross-linked polyvinylpyrrolidone (Crospovidone), sodium starch glycolate, which is commercially available under the brand name Explotab®. For the present invention, Crospovidone is the preferred disintegrant. Crospovidone is commercially available under the brand name Polyplasdone® XL from Ashland Company. Crospovidone is also commercially available under brand name Kollidon® XL Kollidon ® CL-SF from BASF Company. It will be appreciated by the skilled in the art that disintegrant can also be used extra-granularly along with lubricants and anti-adherants just before tableting to facilitate the disintegration of the tablet.

Surfactant constitute from about 0 % to about 10% by weight of the total weight of the granulated composition. Suitable examples of surfactants include but are not limited to, sodium lauryl sulphate, polysorbate 80 or 20, benzalkonium chloride and propylene glycol. The preferred disintegrant for the present invention is polyethylene glycol. It is commercially available under the brand name Macrogol.

Cushioning agent constitute from about 0% to about 10% by weight of the total weight of the granulated composition. Preferable example of cushioning agent is polyethylene glycol, which is commercially available under the brand name Macrogol.

The granulation of the multi-unit pellets can be carried out in or Fluid bed processor fitted with appropriate apparatus.

Granulation of the multi-unit pellets with other excipients can be performed with aqueous, non-aqueous or hydro-alcoholic solvent system. Preferably, granulating medium is aqueous based i.e water.

For the composition of the present invention the intragranular components comprises multiple unit pellets, tableting excipients like diluents, binders, disintegrant, cushioning agents, glidant, solvents and the like. For the composition of the present invention, ratio of the intragranular component to extragranular component is 70: 30 to 97:3, preferably 80:20 to 95:5. Granulated composition constitutes 70% to 97 % by weight of the total weight of the MUPS tablet composition.

Extragranular components

Extragranular tableting excipient used, in the present invention are, lubricant, glidant or anti -adherents and binders, diluents, surfactants, disintegrant and active ingredients and the like. Granulated Multi-unit pellets as obtained above are mixed well with diluents, lubricants, binders, disintegrant, glidant anti-adherants, disintegrant in a suitable blender, and compressed into tablet using suitable tooling. Extragranular components comprise 5% to 35 % by weight of the MUPS tablet composition. Extragranular components are used in such a manner so that ratio of intragranular component to Extragranular component in the composition is 70: 30 to 97 to 3. Extragranular components are used in such a manner so that ratio of intragranular component to Extragranular component in the composition is 80: 20 to 95 to 5.

Appropriate size granules are mixed with diluent, binders, lubricant, anti- adherants, glidant cushioning agents, disintegrant in a suitable blender, and compressed into tablets. The tablet produced by said process exhibit substantially superior content uniformity.

Lubricant is used in concentration of 0.1% to 2% by weight of the total weight of the MUPS Tablet composition. Glidant is used in concentration of 0.1% to 2% by weight of the MUPS tablet composition. Sodium stearyl fumarate is the choice of the Lubricant for the composition of the invention. Silicon dioxide is the preferred glidant and talc is the preferred anti- adherent. Extra granularly, disintegrant is used in concentration of 2% to about 10% by weight of the total weight of the composition. Croscarmellose sodium and crospovidone are the preferred choice of extragranular disintegrant.

Extragranular cushioning agent is used in concentration of 0.5 % to 10% by weight of the total weight of the MUPS Tablet composition.

The multi -unit tablet can optionally be film coated to impart aesthetic appeal to the tablet.

In one embodiment, active ingredient can also be incorporated extra granularly either in the powdered form or in separately granulated form. The multi -unit tablet can optionally be film coated to impart aesthetic appeal to the tablet.

In general, manufacturing process involves mixing coated multi-unit pellets with diluent, binder, disintegrant, optionally surfactant and cushioning agent, and water is added during mixing to granulate the coated multi-unit pellets. Once the granulate was homogeneous, it was dried in the Fluid bed processor. Appropriate size dried granulate is lubricated in suitable blender and resulting blend is compressed into tablets using suitable tooling.

Determination of Blend uniformity and Content uniformity and Relative Standard Deviation (RSD)

Average blend uniformity and content uniformity of the tablets were determined. Average blend uniformity of each batch of the granulate was determined by taking 10 samples that represent the upper, middle and lower layer of each batch of the final blend (before tableting,) performing an HPLC assay to measure the amount of active ingredient in the samples, and comparing the amount of active ingredient in each sample to the labeled amount of active ingredient. The standard deviation and relative standard deviation were then determined according to the following formulae:

In the above formulae, s is the standard deviation; RSD is the relative standard deviation; x₁, X₂, X₃ . . . x_n are individual amounts of the tested samples expressed as percentages of the labeled amount of drug substance in each sample; X (bar) is the mean of the values obtained from the samples tested, expressed as a percentage of the labeled amount of drug substance in each sample; and n is the number of units tested.

Content uniformity of the tablets was determined using 10 random tablets, by performing an HPLC assay to quantify the amount of active ingredient in each tablet, and comparing the amount of active substance in each tablet to the labeled amount of active ingredient. The standard deviation and relative standard deviation were determined as above as mentioned in the formula.

Following examples are described to further illustrate the invention without limiting the scope of the invention.

Example 1: Multi-unit Pellets

Manufacturing Process:

A. Drug Coating-I:-

1 Hydroxypropyl methylcellulose was added in purified water to form clear solution.

2 Metoprolol succinate was added in step 1 A to form clear solution.

3 Talc was added to step 2A under stirring to form homogeneous dispersion.

4 Dispersion of Step 3 A was sifted.

5 Seal coated pellets Celphere CP-20 were coated with drug coating dispersion of step 4A and continued till desired weight gain was achieved.

6 Drug coated pellets were dried.

B. Extended Release Coating-I: -

1 Hydroxy propyl cellulose was added in isopropyl alcohol and methylene chloride mixture to formed homogeneous dispersion.

2 Ethyl cellulose was added to step IB to form clear solution.

3 Talc was added to step 2B under stirring, to form homogeneous dispersion.

4 Dispersion of Step 3B was sifted appropriate mesh.

5 Drug coated pellets of step 6A, were coated with extended release Coating- I dispersion of step 4B, till desired weight gain was achieved.

6 Extended release coated-I pellet of step 5B were dried.

C. Drug Coating-II: -

1 Hydroxy propyl methylcellulose was added to purified water to form clear solution.

2 Metoprolol succinate was added to step 1C to form clear Solution.

3 Talc was added to step 2C under stirring, to form homogeneous dispersion.

4 Dispersion of Step 3C was sifted through appropriate size mesh.

5 Extended Release -I coated pellets of step 6B, were coated with drug coating dispersion of step 4C, until desired weight gain was achieved. 6 Drug coated pellet-II of step 5C were dried

D. Extended Release Coating-II:

1 Hydroxy propyl cellulose was added to Isopropyl alcohol and Methylene chloride mixture to form clear solution.

2 Ethyl cellulose was added to step ID to form clear solution.

3 Talc was added to step 2D under stirring, to form homogeneous dispersion.

4 Dispersion Step 3D was sifted through appropriate size mesh.

5 Drug coated-II pellets of step 6C, were coated with extended release coating-II dispersion of step 4D, until desired weight gain achieved.

6 Extended Release -II a coated pellet of step 5D were dried.

E. Cushion (Protected) Coating: -

1 Hydroxy propyl cellulose was added to purified water and acetone mixture to form clear solution.

2 Polyethylene glycol was added to step IE to form clear solution.

3 Talc was added to step 2E under stirring, to form homogeneous dispersion.

4 Dispersion of Step 3E was sifted through appropriate size mesh.

5 Extended Release I & II pellets of steps 5B & 6D were coated with cushion coating dispersion of step 4E, until desired weight gain was achieved.

6 Cushion coated pellets was dried.

Example 2 - MUPS compression without granulation of the multi-unit pellets:

*eq. to 190 mg Metoprolol Succinate

Manufacturing Process: -

1) Croscarmellose sodium, colloidal silicon dioxide, polyethylene glycol 6000 and Silicified Microcrystalline cellulose were co-sifted through appropriate size mesh

2) The material of step 2.1 co-sifted with protective coated pellets and blended in blender.

3) The blend of Step 2.2 was lubricated with sodium stearyl fumarate.

4) Lubricated blend of step 2.3 (700 mg) were compressed into tablets.

Example 3: MUPS compression into tablet with granulation of the multi- unit pellets: -

*eq. to 190 mg Metoprolol Succinate

** Evaporates during processing

Manufacturing Process: -

1) Silicified microcrystalline cellulose, Crospovidone, Polyethylene glycol 6000 and polyvinyl pyrollidone were co-sifted through appropriate size mesh.

2) Step 3.1 materials co-sifted with Protective coated pellets and granulated with Purified water in Fluid bed granulator followed by drying of granules.

3) The dried granules of step 3.2 were milled and Pre-lubricated with colloidal silicon dioxide and Crospovidone.

4) Pre-lubricated granules of step 3.3 were lubricated with sodium stearyl fumarate and Lubricated bled (703.4 mg) was compressed into tablets. Example 4: MUPS compression into tablet without granulation of the multi-unit pellets:

*eq. to 23.75 mg Metoprolol Succinate

Manufacturing Process: -

1) Croscarmellose sodium, Colloidal silicon dioxide, Polyethylene glycol 6000 and Silicified Microcrystalline cellulose were co-sifted through appropriate size mesh.

2) The material of step 4.1 co-sifted with protective coated pellets and blended in blender through appropriate size mesh.

3) The blend of Step 4.2 lubricated with sodium stearyl fumarate and lubricated blend (87.5 mg) compressed into tablets. Example 5: MUPS compression into tablet with granulation of the multi- unit pellets:

*eq. to 23.75 mg Metoprolol Succinate

** Evaporates during processing

Manufacturing Process: -

2) Step 5.1 materials co-sifted with Protective coated pellets and granulated with Purified Water Fluid bed granulator followed by drying of granules. 3) Dried granules of Step 5.2 milled and Pre-lubricated with colloidal silicon dioxide and crospovidone.

4) Pre-lubricated granules of step 5.3 were lubricated with sodium stearyl fumarate and lubricated blend (87.5 mg) compressed into tablets.

Example 6: MUPS compression into tablet with granulation of the multi- unit pellets: -

*eq. to 47.5 mg Metoprolol Succinate

** Evaporates during processing

Manufacturing Process: -

1) Silicified microcrystalline cellulose, Crospovidone, Polyethylene glycol 6000 and polyvinyl pyrollidone were co-sifted through appropriate size mesh. 2) Step 6.1 materials were co-sifted with Protective coated pellet and granulated with Purified water in Fluid bed granulator followed by drying of granules.

3) Dried granules Step 6.2 milled and Pre-lubricated with colloidal silicon dioxide and Crospovidone.

4) Pre-lubricated granules of step 6.3 were lubricated with sodium stearyl fumarate and lubricated blend (175. mg) was compressed into tablets.

Example 7: Comparison of Content Uniformity, %RSD and Acceptance value data

It is clearly evident from the above data that MUPS tablets manufactured with granulation of multi-unit pellets have significantly improved Content uniformity and Acceptance value.

Claims

We Claim,

1. A Pharmaceutical composition of the MUPS tablets comprising multiunit pellets, one or more pharmaceutical active ingredients and tableting excipients, wherein multiunit pellets are granulated with pharmaceutically acceptable excipients comprising one or more diluent, binder, disintegrant, and wherein the ratio of intragranular component to extragranular component is from 80: 20 to 95: 05.

2. A Pharmaceutical composition of the MUPS tablets comprising multiunit pellets, one or more pharmaceutical active ingredients and tableting excipients, wherein multiunit pellets are granulated with pharmaceutically acceptable excipients comprising one or more diluent, binder, disintegrant, and wherein the ratio of intragranular component to extragranular component is from 70: 30 to 97: 03.

3. A pharmaceutical composition as claimed in claim 1, wherein pharmaceutical composition has content uniformity between 95% to 105% and acceptance value of less than 15 as per USP <905> uniformity of dosage unit.

4. A pharmaceutical composition as claimed in claim 1, wherein granulated multi-unit pellets are mixed with extragranular components consisting of active ingredient, diluent, binder, disintegrant, cushioning agents, lubricant, and glidant.

5. A pharmaceutical composition as claimed in claim 1, wherein pharmaceutically active ingredient is metoprolol succinate.

6. A pharmaceutical composition of the MUPS tablet as claimed in claim 1, wherein diluent is selected from group consisting of microcrystalline cellulose, lactose and silicified microcrystalline cellulose, powdered cellulose, polyethylene glycol, Dibasic calcium phosphate.

7. A pharmaceutical composition of the MUPS tablet as claimed in claim 1, wherein binder is selected from group consisting of povidone, hydroxy propyl cellulose, sodium carboxy methylcellulose, hydroxypropyl methylcellulose, and copovidone Pharmaceutical composition of the MUPS tablet as claimed in claim 1, wherein disintegrant is selected from group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, and pregelatinized starch. Pharmaceutical composition of the MUPS tablet as claimed in claim 1, wherein extragranular components are selected from the group consisting of binder, disintegrant, lubricant, glidant, cushioning agent and anti- adherent. A pharmaceutical composition as claimed in claim 1, wherein method of preparing the composition comprises the steps of: a. preparation of the multiunit pellets comprising one of or pharmaceutical active ingredient; b. granulation of the multiunit pellets with one or more diluent, binder, disintegrant using suitable solvent; c. mixing the granulated multiunit pellets with one or more lubricant, diluent, binder, disintegrant, lubricant and glidant; d. compressing the blend of step (c) to form a tablet e. optionally film coating the tablet of step (d).