Description: FIELD OF THE INVENTION
This invention relates to a tablet dosage form comprising (i) 70-95% of one or more active ingredient(s) and (ii) 5-30% of rate controlling matrix forming polymer and pharmaceutically acceptable excipients(s); wherein the amount of active ingredient(s) in a unit dosage form is 500mg to 1200mg; the total weight of the tablet does not exceed 130%±5% of the weight of the active ingredient(s); the longer axis of the tablet is less than or equal to 17mm and shorter axis is less than or equal to 6mm and the tablet provides a extended release of active ingredients for at least 8 hours. The compositions of the invention easily palatable and have improved storage stability. The invention also includes a process of preparing such compositions.

BACKGROUND OF THE INVENTION
The oral route of drug administration is the most convenient for patients, with tablets emerging as the most popular solid oral dosage form used today. Standard compressed, immediate release, controlled-release, uncoated and coated tablets are the most common form of solid oral dosages. A wide range and diversity of active pharmaceutical ingredients (“API”) are often included in tablet formulations.

Tablet formulations typically consist of drug substance and excipients. If the Tablet formulations are intended for extended or controlled release, the formulation would typically involve rate controlling polymers along with excipients to control the release of the drug. The amount of excipients and rate controlling polymer used in the formulation typically increases the weight of the tablet, making it bulky. It becomes even more challenging to control the weight of the tablet when a high dose active pharmaceutical ingredient is used. The challenges are even greater when the amount of API to be used in the formulation is high i.e. more than 500mg. If the higher dose active pharmaceutical ingredient is highly soluble, it adds further challenge as to control its release from the unit dosage form you need higher amount of rate controlling polymer. The development and production of tablets containing a high dose of active ingredients is a complex and extensive technological challenge.

One of the most commonly used high dose highly soluble active ingredient is Metformin. The daily recommended oral dose of Metformin for treatment of diabetes is very high - 500 mg to 850 mg for children and maximum 3 grams daily for adults, taken in three divided doses. As the daily dose of metformin is considerably very high, the final weight of any dosage form comprising 500mg to 1g of metformin along with excipients will be considerably more and the tablet formed will be of very large size and shape. Furthermore, Metformin Hydrochloride is water soluble drug, for sustaining the release of Metformin or pharmaceutically acceptable salt thereof from a dosage form for an extended period requires use of considerable amount of rate controlling polymers to control the release of the drug from the matrix. Higher dose of Metformin and higher amount of rate controlling polymers and excipients, both, results in formation of tablets with larger size and shape. This large size, shape and weight of the dosage forms containing metformin often leads to patient non-compliance and unacceptability of medication regimens. This large size of tablets is major reason of non-compliance in geriatric or patients. There are many other such high dose active ingredients, which pose same kind of problem.

The major challenge is to use minimum amount of rate controlling polymer and excipients with high dose of the active pharmaceutical ingredient so that ultimately the size and shape of the tablet remains acceptable to patients.

Tablet size, shape, and surface coating influence the patient’s ability to swallow and consequently, the medicine’s acceptability. Thus, while formulating the unit dosage form of any active ingredient it is essential to keep in mind the preference and ease of swallowing in individuals. Many people, even healthy subjects, sometimes find that they have difficulty swallowing medications, mainly tablets. Tablets with a smaller radius of curvature are reportedly easier to swallow in terms of subject preference. Most patients taking larger size tablets have already experienced difficulty swallowing tablets and this is one of the main related complaints leading to patient non-compliance.

Body position, fluid intake, and the presence of certain medical conditions (e.g., multiple sclerosis, muscular dystrophy, Parkinson's disease) may also affect a patient’s ability to swallow tablets and capsules. It is more difficult for geriatric, parkinson’s patient and patients with problem of dysphagia to swallow tablets of larger size. Children and elderly are more likely to have difficulty swallowing tablets or capsules.

The weight of the tablet or capsule also may affect transit time, with heavier tablets having faster transit times compared to similarly-sized, lighter tablets. The weight of the unit dosage form coupled other technical features of formulation such as disintegration time, hardness, amount of rate controlling polymer have the potential to affect the performance of the drug product for its intended use.

Larger tablets and capsules have been shown to have a prolonged esophageal transit time. This can lead to disintegration of the product in the esophagus and/or cause injury to the esophagus, resulting in pain and localized esophagitis and the potential for serious sequelae including ulceration, stricture, and perforation. Other adverse events such as pain, gagging, choking, and aspiration are related to swallowing difficulties in the oropharyngeal phase of swallowing and increasingly occur at larger tablet and capsule sizes.

It has been reported in guidance issues by United States Food and Drug Administration on Size, Shape, and Other Physical Attributes of Generic Tablets and Capsules Guidance June 2015 that in adults evaluating the effect of tablet and capsule size on ease of swallowing suggest that increases in size are associated with increases in patient complaints related to swallowing difficulties at tablet sizes greater than approximately 8 mm in diameter.

Various attempts have been made in past to prepare formulations containing high dose active ingredients.

US Patent No. 6,488,962 describe a controlled-release oral drug dosage form comprising a solid monolithic matrix with said drug contained therein.

PCT Publication No. 2004012700A1 discloses a dosage form of combination of high dose high solubility active ingredient, as modified release and low dose active ingredient as immediate release.

PCT Publication No. 2011045775A1 discloses a delayed release pharmaceutical composition of mesalamine comprising: (a) granules, comprising mesalamine or pharmaceutically acceptable salts thereof and a hydrophilic polymer; and (b) extragranular excipients selected from the group consisting of hydrophilic polymers, glidants, lubricants, diluents and disintegrants; wherein the pharmaceutical composition is further coated with a single layer of polymer.

European Patent Application 2621477A1 discloses n oral pharmaceutical tablet for controlled release of mesalazine or a pharmaceutically acceptable salt thereof as active ingredient with a core and a gastro-resistant outer coating.

U.S. Patent No. 6,340,475 describes tablets in which the drugs are incorporated into hydrophilic swellable polymeric matrices that swell upon uptake of water to a size that is large enough to cause retention of the tablet in the stomach.

PCT Patent Publication No. 2004110422 discloses extended release metformin tablets, which comprise 5-25% w/w of rate controlling polymers. The use of lesser amounts of rate controlling polymers ensures that the total weight of the dosage form is low, and a single dosage unit is sufficient to provide the therapeutic dosage of the drug.
Indian Patent Application No. 965/MUM/2007 discloses an extended release pharmaceutical composition comprising; a) a high dose and high solubility active agent b) a hydrophilic or hydrophobic polymer c) a gum d) magnesium aluminometasilicate as release modifying agent and optionally other pharmaceutical excipients.

Though there are various attempts to minimize the amount of rate controlling polymer and excipients in the formulation, the size of the compressed tablets is large and unacceptable to patients. Therefore, there is a need for developing a unit dosage form which though contains high dose active pharmaceutical ingredients ie.e more than 500mg yet is smaller in size and is able to control the release of the active pharmaceutical ingredient by use of minimum amount of rate controlling polymer and excipients. The unit dosage form has flexibility to add additional active agent(s) without increasing the overall size of the tablet. The tablet of the invention should be palatable and easily swallowable.

Hence, it is an object of the invention to provide a tablet composition comprising 70-95% of high dose active ingredient(s) and minimum amount of rate controlling matrix forming polymer and/or pharmaceutically acceptable excipients(s); such that the total weight of the tablet does not exceed 130%±5% of the weight of the active ingredient(s); the longer axis of the tablet is less than or equal to 17mm and shorter axis is less than or equal to 6mm and the tablet provides a extended release of active ingredients for at least 8 hours, and tablet has suitable size and shape which aids in swallowing and thereby increases the patient compliance.

SUMMARY OF THE INVENTION
One aspect of the present invention relates to a tablet dosage form comprising (i) 70-95% of high dose active ingredient(s) and (ii) 5-30% of rate controlling matrix forming polymer and pharmaceutically acceptable excipients(s); wherein the amount of high dose active ingredient(s) per unit dosage form is 500mg to 1200mg; the total weight of the tablet does not exceed 130%±5% of the weight of the active ingredient(s); the longer axis of the tablet is less than or equal to 17mm and shorter axis is less than or equal to 6mm and the tablet provides a extended release of active ingredients for at least 8 hours.

Another aspect of the present invention relates to a tablet dosage form comprising a core comprising (i) 70-95% of high dose active ingredient(s) and (ii) 5-30% of rate controlling matrix forming polymer and pharmaceutically acceptable excipients(s) and an outer coating over the core containing low dose active ingredient(s); wherein the high dose active ingredient(s) per unit dosage form is 500mg to 1200mg; the total weight of the tablet does not exceed 130%±5% of the weight of the active ingredient(s); the longer axis of the tablet is less than or equal to 17mm and shorter axis is less than or equal to 6mm and the tablet provides a extended release of active ingredients for at least 8 hours.

Another aspect of the present invention relates to a wet granulated tablet dosage form comprising (a) granules comprising (i) 70-95% of high dose active ingredient(s) and (ii) 5-25% of rate controlling matrix forming polymer, binder and pharmaceutically acceptable excipients(s); (b) 0-10% extragranular portion consisting of glidant, lubricants and/or anti-adherent, wherein the amount of active ingredient(s) per unit dosage form is 500mg to 1200mg; the total weight of the tablet does not exceed 130%±5% of the weight of the active ingredient(s); the longer axis of the tablet is less than or equal to 17mm and shorter axis is less than or equal to 6mm and the tablet provides a extended release of active ingredients for at least 8 hours.

Another aspect of the present invention relates to wet granulated tablet dosage form comprising core comprising (a) granules comprising (i) 70-95% of high dose active ingredient(s) and (ii) 5-25% of rate controlling matrix forming polymer, binder and pharmaceutically acceptable excipients(s), (b) 0-10% extragranular portion consisting of glidant, lubricants and/or anti-adherent, and an outer coating over the core containing low dose active ingredient(s), wherein the total amount of high dose and low dose active ingredient(s) per unit dosage form is 500mg to 1400mg; the total weight of the tablet does not exceed 130%±5% of the weight of the active ingredient(s); the longer axis of the tablet is less than or equal to 17mm and shorter axis is less than or equal to 6mm and the tablet provides a extended release of active ingredients for at least 8 hours.

Another aspect of the present invention relates to a unit dosage form comprising 70-95% of active ingredient(s), rate controlling polymer, and pharmaceutically acceptable excipients(s); wherein the total amount of active ingredient(s) per unit dosage form is 500mg to 1400mg; the total weight of the rate controlling polymer and excipients in unit dosage form is not more than 30% of the total weight of the active ingredients in the formulation; total weight of the tablet does not exceed 130%±5% of the weight of the active ingredient(s); the longer axis of the tablet is less than or equal to 17mm and shorter axis is less than or equal to 6mm and the tablet provides a extended release of active ingredients for at least 8 hours.

Another aspect of the present invention relates to a unit dosage form comprising 70-95% of active ingredient(s), matrix forming rate controlling polymer, and pharmaceutically acceptable excipients(s); wherein the total amount of active ingredient(s) per unit dosage form is 500mg to 1400mg; the total weight of the rate controlling polymer and excipients in unit dosage form is not more than 30% of the total weight of the active ingredients in the formulation; total weight of the tablet does not exceed 130%±5% of the weight of the active ingredient(s); the longer axis of the tablet is less than or equal to 17mm and shorter axis is less than or equal to 6mm and the tablet provides a extended release of active ingredients for at least 8 hours and wherein the excipients are devoid of binder.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a tablet dosage form comprising (i) 70-95% of high dose active ingredient(s) and (ii) 5-30% of rate controlling matrix forming polymer and pharmaceutically acceptable excipients(s); wherein the amount of high dose active ingredient(s) per unit dosage form is 500mg to 1200mg; the total weight of the tablet does not exceed 130%±5% of the weight of the active ingredient(s); the longer axis of the tablet is less than or equal to 17mm and shorter axis is less than or equal to 6mm and the tablet provides a extended release of active ingredients for at least 8 hours.

It was observed by inventors of the present invention that the major problem with the marketed composition containing high dose active pharmaceutical ingredients is their weight and size. To control the release of API from the dosage form and to convert the API into a suitable dosage form, it is essential to use rate controlling polymer and excipients. Use of these rate controlling polymer and excipients leads to increase in the overall weight of the tablet and consequentially larger size of the tablets. The common problem associated with these bulky is their swallowability. Due to large size and shape, these tablets are difficult to swallow especially for geriatric patients. This leads to patient non-compliance.

While working on the development of a composition comprising high dose API, the major challenges that the inventors faced were (i) to prepare a easy swallowable palatable small size tablet containing higher amount of active ingredients especially along with rate controlling polymers and/or excipients, (ii) to keep the amount of excipients and rate controlling polymers to minimum yet provide extended release of API for atleast 8 hours, (iii) to keep the flexibility in the dosage form to incorporate one or more low dose active ingredients yet keeping the size same; and (iv) to keep the size and shape of the tablet to minimum so that it is easy to swallow but at the same time the tablet should expand in-vivo so that it is retained in the upper part of intestine where maximum absorption of most of the drugs occurs.

After numerous attempts, Inventors of the present invention surprisingly found that when high dose active pharmaceutical substance are mixed with 5-30% of rate controlling matrix forming polymer and pharmaceutically acceptable excipients and then wet granulated and compressed as a single layer extended release matrix tablet, the inventors of the present invention were able to prepare a easy swallowable small size tablet compared to marketed formulations, which not only an extended release of active ingredients for at least 8 hours but also has a low weight, acceptable size and shape and exhibits superior chemical and physical stability. The total weight of the tablet does not exceed 130%±5% of the weight of the active ingredient(s); the longer axis of the tablet is less than or equal to 17mm and shorter axis is less than or equal to 6mm. The selection of rate controlling polymer varied as per the physical characteristics of the active pharmaceutical ingredient.

As used herein the terms “pharmaceutical composition” or “dosage form” as used herein are used interchangeably and are defined to mean a pharmaceutical composition, preparation or system in which doses of medicine or active drug are included.

As used herein the terms “active ingredient(s)” or “active pharmaceutical ingredient(s)” or “API” as used herein are used interchangeably and are defined to mean one or more active pharmaceutical substance which has therapeutic effects. The said term are used to represent one active ingredient or two or more pharmaceutically active ingredients.

As used herein the term “immediate release” refers to the dosage forms which provide a substantially immediate rate of release of the active drug when administered in gastrointestinal tract.

As used herein, the term “sustained/ extended/controlled release” refers to a pharmaceutical composition which exhibit a “extended release”, “extended release”, or “controlled release” of the active drug, as used herein are used interchangeably and defined to mean dosage forms that provide a release of the active drug over an extended period of time compared to an immediate release dosage form, such that plasma concentrations of the active drug are maintained for a longer time at a therapeutic level, and provides a therapeutic benefit over a period of time (e.g. a 12-hour or 24-hour period).

The term “core” as used herein is defined to mean a solid vehicle in which at least one active drug is uniformly or non-uniformly dispersed.

As used herein, the term “functional coating” as used herein refers to a coating that containing active drug(s). The term “non-functional coating” as used herein refers to a coating which does not contain any active drug.

As used herein, the term "treatment" refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder.

As used herein, the term "one or more" as used herein refers to one or more than one i.e two, three and so on.

As used herein, the term "atleast" as used herein refers to the minimum quantity and intends to encompass all concentrations which are more than that minimum quantity.

As used herein, the term "not more than" as used herein refers to the maximum quantity and intends to encompass all concentrations or amounts which are less than that maximum quantity.

The term “high dose” as used herein refers to the weight of active ingredient in unit dosage form according to the invention is from 500 mg to 1500 mg.

The term “low dose” as used herein refers to the weight of the active ingredient in unit dosage form according to the invention is less than or equal to 50 mg.

The term “high solubility” as used herein in relation to high dose active ingredient means that from less than 1 part to 30 parts of the water will require dissolving 1 part of active ingredient.

The high dose active ingredients are comprises of the following therapeutic classes but not limited to antidiabetic agents, anti-histamines, anti-depressants, anti-viral agents, anesthetics, antacids, anti-arthritis, antibiotics, anti-psychotics, anti- spasmodics, anxiolytic agents, appetite suppressants, cardiovascular agents, cough suppressants, emollients, gastro-intestinal agents, growth regulators, respiratory stimulants, vitamins, angiotensin converting enzyme inhibitors, anti-asthmatics, anti- cholesterolemics, anti-convulsants, anti-depressants,'anti-diarrhea preparations, anti- infective, anti-inflammatory agents, anti-nauseants, anti-stroke agents, anti-tumor drugs, anti-tussives, anti-uricemic drugs, amino-acid preparations, antiemetics, antiobesity drugs, antiparasitics, antipyretics, appetite stimulants, cerebral dilators, chelating agents, cholecystokinin antagonists, cognition activators, deodorants, dermatological agents, diuretics, erythropoietic drugs, fertility agents, synthetic hormones, laxatives, mineral supplements, neuroleptics, neuromuscular agents, peripheral vaso-dilators, prostaglandins, vaginal preparations, vaso-constrictors, vertigo agents, and biguanides. The high dose active pharmaceutical ingredients can be selected from the group comprising of Paracetamol, Metformin, Gabapentin, Imeglimin, Eslicarbazepine Acetate, Azithromycin, Gemfibrozil, Oxcarbazepine, Ibuprofen, Sevelamer Carbonate, Tinidazole, Sulfadoxine, Telbivudine, Metformin, Levetiracetam, Magnesium Valporate, Calcium Carbonate, Oxaprozin, Methylcobalamin, Sucralfate, Chlorzoxazone, Levocarnitine, Naproxen, Ursodeoxycholic Acid, Fenbendazole, Calcium Dobesilate Monohydrate, Tranexamic Acid, Valproic Acid, Calcium Carbonate, Linezolid, Acetylcysteine, Taurine, Dapagliflozin, Mecobalamin, Calcium, L-Carnitine, Etamsylate, Levofloxacin, Nabumetone, Levocarnitine, Citicoline, Griseofulvin, Ranolazine, Vitamin C, Magnesium Hydroxide, Calcium Polycarbophil, Sodium Bicarbonate, Sodium Valproate, Niacin, Stiripentol, Dihydrocodeine, Hydrogen Tartrate, Betamethasone, mesalamine, Sodium Phosphate, Acetylcysteine Sodium, Hydrogen Carbonate, Carbocisteine, Quetiapine Fumarate, Calcium Citrate, Ascorbic Acid, Pirfenidone, Favipiravir, Acetyl Salicylic Acid, Oxaceprol, Abacavir, Efavirenz, Darunavir Ethanolate, Glucosamine, Guaiphenesin or combinations thereof.

The low dose active ingredients are comprises of the following therapeutic classes but not limited to antidiabetic agents, anti-histamines, anti-depressants, anti-viral agents, anesthetics, antacids, anti-arththriics, antibiotics, anti-psychotics, anti-spasmodics, anxiolytic agents, appetite suppressants, cardiovascular agents, cough suppressants, emollients, gastro-intestinal agents, growth regulators, respiratory stimulants, vitamins, angiotensin converting enzyme inhibitors, anti-asthmatics, anti-cholesterolemics, anti- convulsants, anti-depressants, anti-diarrhea preparations, anti-infective, anti-inflammatory agents, anti-nauseants, anti-stroke agents, anti-tumor drugs, anti-tussives, anti-uricemic drugs, amino-acid preparations, antiemetics, antiobesity drugs, antiparasitics, antipyretics, appetite stimulants, celebral dilators, chelating agents, cholecystokinin antagonists, cognition activators, deodorants, dermatological agents, diuretics, erythropoietic drugs, fertility agents, synthetic hormones, laxatives, mineral supplements, neuroleptics, neuromuscular agents, peripheral vaso-dilators, prostaglandins, vaginal preparations, vaso- constrictors, vertigo agents, sulphonylurease, meglitinides, PPAR gama agonist [insulin sensitisers (thiazolidinedione)], PPAR alpha gamma agonist and alpha-glucosidase inhibitors. Examples of low dose active ingredients comprises of but not limited to zafirlukast, quinapril hydrochloride, isotretinoin, rabeprazole sodium, estradiol (e2), norethindrone acetate, risedronate sodium, pioglitazone HC1, amphetamine, anagrelide hydrochloride, biperiden HC1, mephalan, alprazolam, ramipril, naratriptan hydrochloride, leflunomide, anastrozole, exemestane, paroxetine mesylate, candesartan cilexetil, almotriptan, cerivastatin, betaxolol hydrochloride, bisoprolol fumarate, deloratadine, clonazepam, clorazepate dipotassium, clozapine, methylphenidate HC1, carvedilol, warfarin sodium, norgestrel, ethinyl estradiol, cyclophosphamide, pemoline, liothyronine sodium, misoprostol, tolterodine tartrate, dextroamphetamine sulfate, dicyclomine hydrochloride, digoxin, oxybutynin chloride, doxazosin mesylate, ethacrynate sodium, venlafaxine HC1, enalapril maleate, estradiol, estropipate, famotidine, letrozole, fludrocortisone acetate, fluoxetine, dexmethylphenidate hci, alendronate sodium, ziprasidone, glipizide, glyburide, miglitol, guanabenz acetate, haloperidol, doxercalciferol, zalcitabine, hydrochlorothiazide, hydromorphone HC1, indapamide, estradiol, nitric oxide, ketorolac tromethamine, clonazepam, granisetron, lamotrigine, fluvastatin sodium, levonorgestrel, levothyroxine sodium, atorvastatin calcium, lisinopril, minoxidil, loperamide, loratidine, lorazepam, lovastatin, pravastatin sodium, fluvoxamine maleate, acetaminophen, acyclovir, aminocaproic acid, pitavastatin, rosuvastatin, dalvastatin, sertraline, pitavastatin, rosuvastatin, dalvastatin, escetalopram; sertraline, celecoxib, parecoxib, valdecoxib, glibenclamide (glyburide), glipizide, gliclazide, glimepiride, tolazamide, tolbutamide, clorpropamide, gliquidone, nateglinide, glyburide, glisoxepid, glibornuride, phenbutamide, tolcyclamide, repaglinide, reglitazar troglitazone, ciglitazone, pioglitazone, englitazone, acarbose, voglibose, emiglitate, miglitol, farglitazar, Netoglitazone, Tesaglitazar, Ragaglitazar, (S)-2-ethoxy-3- [4- (2- {4- methanesulfonyloxyphenyl} ethoxy) phenyl] propanoic acid, 3-{4-[2-(4-. tert- butoxycarbonylaminophenyl) ethoxy] phenyl}-(S)-2-ethoxy propanoic acid and L-6766892.

In one aspect of the present invention, the high dose active ingredient is Metformin or pharmaceutically acceptable salts thereof. The low dose active ingredient is glimepiride and/or voglibose. The effective amount of metformin or salt thereof used in the pharmaceutical compositions is 500 mg to 1500g, preferably 500mg to 1000mg. The effective amount of Voglibose, Glimepiride or salt thereof used in the pharmaceutical compositions is 0.1 mg to 10mg. The API(s) used in formulation is micronized.

The high-dose tablet means a tablet of a high dose of an active substance. In the present invention, a high dose particularly means an amount of 500 mg to 1500 mg, preferably between 500 and 1100 mg and especially preferred about 1000 mg of the active substance.

In one of the aspect of the present invention, the pharmaceutical composition or dosage form is tablet or caplet. The tablet may be oval, oblong, boat shaped or parallelogram in shape.

In one aspect of the present invention, the inner core provides extended release of the high dose active ingredient and outer portion or coating provides immediate release of the low dose active ingredient.

In another embodiment provided a pharmaceutical composition; wherein the high dose active ingredient or pharmaceutically acceptable salt thereof is present in the range of 70% w/w to 90% w/w of the total weight of the composition or dosage form. In preferred embodiment of the present invention, the high dose active ingredient or pharmaceutically acceptable salt thereof is present in the range of 80 % w/w to 90% w/w of the total weight of the composition or dosage form.

In another embodiment provided a pharmaceutical composition; the total amount of rate controlling polymer and excipients used in the invention are not more than 35% of the total weight of the composition or dosage form. In preferred embodiment of the present invention the total amount of rate controlling polymer and excipients used in the invention are in range of 10 to 20% of the total weight of the composition or dosage form.

The rate controlling polymer used in the composition of present invention are selected from the group consisting of carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, methacrylic acid copolymers, a salt of a homopolymer of acrylic acid, hydroxyacrylic acid or methacrylic acid, methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate, butyl acrylate or combinations thereof. The “cellulose”, “cellulosic” or “hydrophilic cellulose polymer” that can be used in the pharmaceutical compositions according to the invention can be selected from but not limited to hydroxypropyl methylcellulose (HPMC) (e.g. Pharmacoat® 606 or Hypromellose), hydroxypropyl cellulose (HPC), methyl cellulose, hydroxyethyl cellulose, or hydroxyethyl methylcellulose. The polyacrylate polymer can be selected from the group consisting of methacrylic acid copolymers, a salt of a homopolymer of acrylic acid, hydroxyacrylic acid or methacrylic acid, or a copolymer thereof containing at least about 80% by weight of units derived from said acids and the remainder of said units being derived from the group consisting of vinyl chloride, vinyl alcohol, furan, acrylonitrile, methacrylonitrile, vinyl acetate, methyl acrylate, methyl methacrylate, styrene, alpha-methylstyrene, vinyl methyl ether, vinyl ethyl ether, vinyl propyl ether, ethylene, propylene, 3-butenoic acid, and mixtures thereof.

The rate controlling polymers used in the compositions of present invention are hydroxypropyl methylcellulose or hydroxypropylcellulose.

Pharmaceutical excipients that can be used in the pharmaceutical composition of the invention can be selected from a group comprising binders, diluents, matrix forming agents, lubricants, disintegrating agents, glidants, stabilizers, and surface-active agents.

The binders that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising carboxymethyl cellulose sodium, ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminum silicate, maltodextrin, methyl cellulose, povidone, polyvinyl alcohol, copovidone, starch or combinations thereof.

The diluents that can be used in the pharmaceutical compositions according to the invention can be selected from a group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch and starch derivatives, sodium chloride, sucrose, talc, xylitol or the combinations thereof.

The lubricants that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulphate, talc, stearic acid, zinc stearate, glyceryl behenate or combinations thereof.

The disintegrating agent that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, chitosan, starch, sodium starch glycolate or combinations thereof.

The glidants that can be used in the pharmaceutical compositions according to the invention can be selected from but not limited to colloidal silicon dioxide, calcium silicate, magnesium silicate, silicon hydrogel, magnesium trisilicate, corn starch, talc and the like or combinations thereof.

The surface-active agent that can be used in the pharmaceutical compositions according to the invention can be selected from but not limited to poloxamer, dioctyl sodium sulfosuccinate (DSS), triethanolamine, polysorbates, sodium lauryl sulphate (SLS), polyoxy ethylene sorbitan and poloxalkol derivatives or quaternary ammonium salts.

In another embodiment the compressed core of the present invention are prepared by the process wet granulation, dry granulation or melt granulation process. In preferred embodiment, the tablets are wet granulated and compressed. In another embodiment, the matrix core of the composition is single layer compressed tablets. In another embodiment, the coating layer is applied by spray coating; perforated pan coaters or fluid bed coaters can be used. In another embodiment of the present invention the compressed cores are coated with seal coat before any functional coating. In another embodiment the compressed core of the present invention, the compositions of the present invention are not multilayer compressed tablets or caplets. In another embodiment of the present invention the core comprised two or more actives optionally coated with functional or non functional coating. The size of the tablets so obtained was less than the marketed tablets.

In another embodiment, there is provided an extended release pharmaceutical formulation as per the present invention is intended for oral administration to a subject in need thereof.

In another embodiment the extended release dosage form of the present invention expands in size when placed in an aqueous environment in vivo.

The composition of present invention upon oral administration to a patient, provides extended release of an effective amount of the metformin to at least one region of the patient's upper gastrointestinal tract for atleast 8hours, preferably for atleast 12h.

In another embodiment of present invention provides a process of preparation of an extended release tablet composition, wherein the process comprising the steps of:
i. preparing granules comprising high dose active ingredient(s), rate controlling polymer and one or more pharmaceutically acceptable excipients,
ii. granules obtained in step (i) was compressed to form core of the tablet;
iii. compressed core of step (ii) was then coated with one or more functional coating containing low dose API(s).

The invention has been described with reference to specific embodiment which is merely illustrative and not intended to limit the scope of the invention as defined in the claims.

The invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.

EXAMPLES
Example 1: Coated Tablets
Each film coated tablet contains: Glimepiride 1mg, Voglibose 0.2mg, and Metformin Hydrochloride 500mg (In sustained-release form)
Table 1: Pharmaceutical Composition
Core Tablet
Sr. No Ingredients Quantity/Tablet (mg)
1 Metformin Hydrochloride 500.00
2 Carboxy Methyl Cellulose Sodium 39.63
3 Methyl Paraben 1.30
4 Propyl Paraben ALTA LABOR 0.05
5 Purified Water q.s
6 Colloidal Silicon Dioxide 6.50
7 Magnesium Stearate 4.30
8 H.P.M.C. VISCOSITY: 2,00,000 CPS 123.22
Avg. weight 675.00
Stage-1 Coating (Seal Coating) Optional
Sr. No Ingredients Qty. For Batch
8 Insta Moistshield White 2.000 kg
10 Isopropyl Alcohol 14.000 L
11 Dichloromethane 21.000 L
Stage-2 Coating (Functional Coating)
Sr. No Ingredients Qty. For Batch
12 Voglibose 0.024 kg
13 H.P.M.C. (E-5) 0.601 kg
14 P.E.G - 6000 0.150 kg
15 Purified Talc 0.125 kg
16 Titanium Dioxide 0.100 kg
17 Purified Water 10.000 L
Stage-3 Coating
Sr. No Ingredients Qty. For Batch
18 Glimepiride Micronized 0.120 kg
19 H.P.M.C. (E-15) 0.505 kg
20 P.E.G - 6000 0.150 kg
21 Purified Talc 0.125 kg
22 Titanium Dioxide 0.100 kg
23 Isopropyl Alcohol 10.000 L
24 Dichloromethane (Methylene Chloride) 20.000 L
Batch size is 1,00,000 Tablets
Process of Preparation
Preparation of Core:
1. Metformin and carboxymethyl cellulose were sifted and loaded in a rapid granulator mixer.
2. Binder solution was prepared by boiling hot water and adding HPMC, methylparaben and propylparaben to the said boiling water with continuous stirring.
3. The powder of Step 1 was granulated by spraying the binder solution of step 2.
4. The granules so obtained were semidried in fluidized bed drier and then milled through 4.00 mm perforated screen and then finally dried. The granules so formed are checked for Loss on drying (LOD). LOD of dried granules should between 3-4%w/w/w.
5. The dried granules of Step 4 were lubricating with colloidal silicon dioxide and magnesium stearate.
6. The mixture of Step 5 was compressed into tablets using punch size of 16.00 X 8.00 mm. The physical properties of the tablet so obtained were measured.
Coating:
Coating 1: (Seal Coating; Optional)
7. Insta moistshield white (cellulose based coating system) was suspended in isopropyl alcohol solution. To this suspension dichloromethane was added with slow stirring.
8. Core tablets obtained in Step 6 were loaded into coating pan and were coated with coating solution of step 7.
9. The physical parameters of coated tablet were evaluated.
Coating 2: (API Functional Coating)
10. Voglibose is dissolved in purified water
11. HPMC was dissolved in purified water.
12. Solution of Step 10 and 11 were mixed.
13. To the Solution of Step 12, PEG6000 was added under mechanical stirring
14. Titanium dioxide and purified talc were shifted and added in purified water under continuous stirring to make slurry.
15. The slurry of Step 14 was added to solution of Step 12
16. Coated tablets were loaded into coating pan and were coated with coating solution of step 16.
Coating 2: (API Functional Coating)
17. Glimepiride was dissolved in dichloromethane
18. HPMC was dissolved in isopropyl alcohol and dichloromethane
19. Solution of Step 17 and 18 were mixed
20. To the solution of Step 19, PEG6000 was added under mechanical stirring
21. Titanium dioxide and purified talc were shifted and dissolved in Isopropyl alcohol to make slurry
22. The slurry of step 21 is added to Solution of Step 20
23. Coated tablets obtained from Step 16 were then loaded into a clean, dry coating pan and dry for 10 minutes at 0.5 rpm at 30?C - 40?C

Table 2: Physical properties of Coated Tablet of Example 1
The physical properties of coated tablets of Example 1 were measured using standard procedures known in the field of invention. The results are produced below in Table 2.

Table 2: Physical properties of Coated Tablet of Example 1
S. No. PARAMETERS OBSERVED RESULT
1. Description White coloured, biconvex, elongated, film coated tablets, scored on one side and plain on other side.
2. Average Weight of tablets 705.0 mg
3. Group weight of 20 Tablets 14.10 gm
4. Uniformity of Tablet weight 705.0 mg
5. Length: 16.20 mm
6. Width: 8.20 mm
7. Thickness 5.90 mm

Example 3: Dissolution profile:
The dissolution profile of coated tablets of Example 1 was obtained by placing the tablets in USP type I apparatus containing 1000ml of phosphate buffer pH 6.8 at 37°C, 100rpm. The dissolution profile of formulation of Example 1 was compared with dissolution profile of marketed fixed dose products containing same API in same quantity. The dissolution profile of formulation of Example 1 was found to be comparable with the marketed fixed dose products.
Example 4: Comparison of Marketed Products with Composition of Present Invention
A. Measurement of Physical Parameters
The length (longer axis), width and height (shorter axis) of marketed fixed dose products and dosage form of Example 1 were measured using vernier calliper. The results are provided in Table 3.
Table 3: Marketed Products with Windlas Product
S. No. Brand Name L W H
1 AMARYL MV 1 TABLETS 20.10 mm 9.40 mm 6.75 mm
2 VOGS-GM 1 TABLETS 18.10 mm 8.10 mm 6.40 mm
3 VOGLYSON GM 1 TABLETS 18.10 mm 8.10 mm 6.40 mm
4 JUBIGLIM MV 1 TABLETS 18.10 mm 8.10 mm 6.20 mm
5 ZUVOG TRIO 1 TABLETS 20.10 mm 9.40 mm 6.60 mm
6 WINDLAS 16.20 mm 8.20 mm 5.90 mm

B. Pictorial Comparison of Marketed Products Vs Tablets of Present Invention
Tablets of Marketed Products containing the fixed dose combination of Metformin, Voglibose and Glimipiride in same dose as compositions of present invention were photographed along with Tablets of present invention (Windlas). Figure 1 provides Top and side view of the said tablets. Figure 2 provides the Longitudinal View of the said tablets.

Example 5: Dapagliflozin and Metformin Hydrochloride Sustained Release tablets
Table 1: Dapagliflozin 10 mg and metformin hydrochloride (SR) 500 mg tablets
Core Tablet
Sr. No Ingredients Quantity/Tablet (mg)
1 Metformin Hydrochloride 500.00
2 Carboxy Methyl Cellulose Sodium 39.63
3 Methyl Paraben 1.30
4 Propyl Paraben ALTA LABOR 0.05
5 Purified Water q.s
6 Colloidal Silicon Dioxide 6.50
7 Magnesium Stearate 4.30
8 H.P.M.C. VISCOSITY: 2,00,000 CPS 123.22
Avg. weight 675.00
Coating
9 Dapagliflozin propanediol monohydrate 12.15
10 Hydroxypropyl methylcellulose (E-15) 11.35
11 PEG 6000 3.00
12 Purified talc 0.50
13 Isopropyl Alcohol qs
14 Dichloromethane qs
Total Weight 27.00

Process of Preparation
Preparation of Core:
1. Metformin and carboxymethyl cellulose were sifted and loaded in a rapid granulator mixer.
2. Binder solution was prepared by boiling hot water and adding HPMC, methylparaben and propylparaben to the said boiling water with continuous stirring.
3. The powder of Step 1 was granulated by spraying the binder solution of step 2.
4. The granules so obtained were semidried in fluidized bed drier and then milled through 4.00 mm perforated screen and then finally dried. The granules so formed are checked for Loss on drying (LOD). LOD of dried granules should between 3-4%w/w/w.
5. The dried granules of Step 4 were lubricating with colloidal silicon dioxide and magnesium stearate.
6. The mixture of Step 5 was compressed into tablets using punch size of 16.00 X 8.00 mm. The physical properties of the tablet so obtained were measured.
Coating: (API Functional Coating)
7. Dapagliflozin propanediol monohydrate was dissolved in isopropyl alcohol.
8. HPMC was dissolved in isopropyl alcohol
9. Solution of Step 7 and 8 were mixed
10. To the solution of Step 9, dichloromethane was added under mechanical stirring
11. Purified talc was shifted and dissolved in Isopropyl alcohol to make slurry.
12. The slurry of step 11 and PEG6000 were added to Solution of Step 10.
13. Core tablets were loaded into coating pan and were coated with coating solution of step 12.
14. The diameter and thickness of coated tablets were 16.1 X 8.1 mm (approx.) and 5.8 mm (approx.) respectively.

Claims: We Claim:
1. A tablet dosage form comprising
a) 70-95% of high dose active ingredient(s),
b) 5-30% of rate controlling matrix forming polymer and pharmaceutically acceptable excipients(s);
wherein the amount of high dose active ingredient(s) per unit dosage form is 500mg to 1200mg; the total weight of the tablet does not exceed 130%±5% of the weight of the active ingredient(s); the longer axis of the tablet is less than or equal to 17mm and shorter axis is less than or equal to 6mm and the tablet provides a extended release of active ingredients for at least 8 hours.

2. The tablet dosage form as claimed in claim 1, wherein the rate controlling polymer is selected from the group consisting of carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, methacrylic acid copolymers, a salt of a homopolymer of acrylic acid, hydroxyacrylic acid or methacrylic acid, methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate, butyl acrylate or combinations thereof.

3. The tablet dosage form as claimed in claim 2, wherein the rate controlling polymer is hydroxylpropyl methylcellulose.

4. The tablet dosage form as claimed in claim 1, wherein the high dose active ingredient(s) is metformin.

5. The tablet dosage form as claimed in claim 1, wherein total weight of the rate controlling polymers and other excipients in the tablet is 10% w/w to 20% w/w of the total weight of the coated tablet.

6. The tablet dosage form as claimed in claim 1, wherein the tablet is additionally coated with a seal coat and functional coat(s) containing low dose active ingredient(s).

7. The tablet composition as claimed in claim 1, wherein the tablet is prepared by the process of wet granulation of granules and compressed as single layer tablet.

8. A wet granulated tablet dosage form comprising
a) granules comprising (i) 70-95% of high dose active ingredient(s) and (ii) 5-25% of rate controlling matrix forming polymer, binder and pharmaceutically acceptable excipients(s);
b) 0-10% extragranular portion consisting of glidant, lubricants and/or anti-adherent,
wherein the amount of active ingredient(s) per unit dosage form is 500mg to 1200mg; the total weight of the tablet does not exceed 130%±5% of the weight of the active ingredient(s); the longer axis of the tablet is less than or equal to 17mm and shorter axis is less than or equal to 6mm and the tablet provides a extended release of active ingredients for at least 8 hours

9. A unit dosage form comprising a composition consisting 70-95% of active ingredient(s), rate controlling polymer, and pharmaceutically acceptable excipients(s); wherein the total amount of active ingredient(s) per unit dosage form is 500mg to 1400mg; the total weight of the rate controlling polymer and excipients in unit dosage form is not more than 30% of the total weight of the active ingredients in the formulation; total weight of the tablet does not exceed 130%±5% of the weight of the active ingredient(s); the longer axis of the tablet is less than or equal to 17mm and shorter axis is less than or equal to 6mm and the tablet provides a extended release of active ingredients for at least 8 hours.

10. A tablet dosage form comprising a core comprising (i) 70-95% of high dose active ingredient(s) and (ii) 5-30% of rate controlling matrix forming polymer and pharmaceutically acceptable excipients(s) and an outer coating over the core containing low dose active ingredient(s); wherein the high dose active ingredient(s) per unit dosage form is 500mg to 1200mg; the total weight of the tablet does not exceed 130%±5% of the weight of the active ingredient(s); the longer axis of the tablet is less than or equal to 17mm and shorter axis is less than or equal to 6mm and the tablet provides a extended release of active ingredients for at least 8 hours.