WO2013072770A2

WO2013072770A2 - Pharmaceutical formulations comprising atorvastatin and glimepiride

Info

Publication number: WO2013072770A2
Application number: PCT/IB2012/002860
Authority: WO
Inventors: Maheshwar KOLLURI; Rajesh Dubey; Rajeev Singh Raghuvanshi
Original assignee: Dr. Reddy's Laboratories Ltd.
Priority date: 2011-11-15
Filing date: 2012-11-14
Publication date: 2013-05-23
Also published as: IN2014CN04119A; RU2014124118A; EP2779999A2; WO2013072770A3; ZA201403735B

Abstract

Aspects of the present application relate to pharmaceutical formulations comprising atorvastatin or pharmaceutically acceptable salts thereof, and glimepiride as active agents, wherein both atorvastatin or pharmaceutically acceptable salts thereof, and glimepiride are in immediate release form.

Description

PHARMACEUTICAL FORMULATIONS COMPRISING ATORVASTATIN AND

GLIMEPIRIDE

INTRODUCTION

The present application relates to pharmaceutical formulations comprising atorvastatin or pharmaceutically acceptable salts thereof, and glimepiride as active agents, wherein both atorvastatin or pharmaceutically acceptable salts thereof, and glimepiride are in immediate release form.

The present application also relates to pharmaceutical formulations comprising atorvastatin or pharmaceutically acceptable salts thereof, or atorvastatin or pharmaceutically acceptable salts thereof in the form of a premix, and glimepiride for the treatment of elevated blood glucose in type II diabetes mellitus associated with dyslipidaemia, wherein both atorvastatin or pharmaceutically acceptable salts thereof, or atorvastatin or pharmaceutically acceptable salts thereof in the form of a premix, and glimepiride are in immediate release form.

BACKGROUND

The drug having the International Nonproprietary Name (INN) "atorvastatin" is a synthetic lipid-lowering agent. Atorvastatin is an inhibitor of 3-hydroxy-3- methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis.

Atorvastatin calcium has a chemical name [R-(R^*,R^*)]-2-(4-fluorophenyl)- b,d-dihydroxy-5-(1 -methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1 H-pyrrole-1 - heptanoic acid, calcium salt (2:1 ) trihydrate.

A commercially available product containing atorvastatin calcium is sold as LIPITOR® oral tablets, by Pfizer. LIPITOR® tablets are available in the dosages of 10, 20, 40, and 80 mg atorvastatin acid equivalent, and are indicated for prevention of cardiovascular diseases and hypercholesterolemia.

U.S. Patent No. 4,681 ,893 discloses certain trans-6-[2-{3- or 4- carboxamido-substituted-pyrrol-1 -yl)alkyl]-4-hydroxy-pyran-2-ones, including frans-(±)-5-(4-fluorophenyl)-2-(1 -methylethyl)-N,4-diphenyl-1 -[(2-tetrahydro-4- hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1 H-pyrrole-3-carboxamide.

U.S. Patent No. 5,273,995 discloses the enantiomer having the "R form" of the ring-opened acid of frans-5-(4-fluorophenyl)-2-(1 -methylethyl)-N,4-diphenyl-1 - [(2-tetrahydro-4 -hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1 H-pyrrole-3-carboxamide, i.e., [R-(R^*,R^*)]-2-(4-fluorophenyl)- ,5-dihydroxy-5-(1 -methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-1 H-pyrrole-1 -heptanoic acid.

International Application Publication No. WO1994/016693 describes an oral pharmaceutical composition for treating hypercholesterolemia or hyperlipidemia containing an advantageous formulation for stabilizing the HMG-CoA (coenzyme A) inhibitor, CI-981 hemi-calcium with effective amounts of calcium carbonate. A method for preparing a CI-981 stabilizing composition is described.

International Application Publication No. WO2004/1 10431 describes a wet granulated pharmaceutical composition comprising atorvastatin.

International Application Publication No. WO2008/039894 describes pharmaceutical formulations of atorvastatin, processes for preparing the same, and their methods of use, treatment and administration. International Application Publication No. WO2004/1 10407 discloses a composition of amorphous atorvastatin calcium, wherein the amorphous atorvastatin is layered around a core.

International Application Publication Nos. WO2006/006021 , WO2004/071402, WO2004/032920, WO2003/068191 , WO2003/097039, WO2001/076566, WO2001/093859, WO2001/093860 and WO2000/035425 disclose various stabilized pharmaceutical compositions of atorvastatin or its pharmaceutically acceptable salts.

The drug having the International Nonproprietary Name (INN) "glimepiride" is an oral blood-glucose-lowering drug of the sulfonylurea class. Glimepiride is a white to yellowish-white, crystalline, odorless to practically odorless powder.

A chemical name for glimepiride is 1 -[[p-[2-(3-ethyl-4-methyl-2-oxo-3- pyrroline-1 -carboxamido)ethyl]phenyl]sulfonyl]-3-(trans-4-methylcyclohexyl)urea.

A commercially available product containing glimepiride is AMARYL® oral tablets, from Sanofi Aventis. AMARYL® tablets are available in dosage strengths of 1 mg, 2 mg, 3 mg and 4 mg of glimepiride. U.S. Patent No. 4,379,785 discloses a 1 -[[p-[2-(3-ethyl-4-methyl-2-oxo-3- pyrroline-1 carboxamido)ethyl]phenyl]sulfonyl]-3-(trans-4-methylcyclohexyl)urea, pharmaceutical composition and use in the treatment of diabetes.

Active pharmaceutical ingredients comprising a sulphonylurea moiety have proven to be a class of potent drugs for treating diabetes. These drugs lower blood glucose primarily by stimulating the secretion of insulin from functional pancreatic beta cells. In this way they exert a long-term effect of reducing the blood glucose levels. In addition, extra-pancreatic effects may also play a role in the activity of sulfonylureas. A particular active pharmaceutical ingredient comprising sulphonylurea moiety is glimepiride. This is supported by both preclinical and clinical studies demonstrating that glimepiride administration can lead to increased sensitivity of peripheral tissues to insulin. However, the characteristic low solubility of active pharmaceutical ingredients comprising sulphonylurea moiety poses great difficulty in providing pharmaceutical formulations with suitable solubility or dissolution rates. In such case, when active pharmaceutical ingredient is not soluble or only sparingly soluble in a neutral or acidic pH region, the dissolution is poor and a sufficient blood concentration of active pharmaceutical ingredient cannot be properly obtained.

Attempts have been made to improve the aqueous solubility of sulfonylureas, for example, by increasing the surface area of sulfonylureas by particle size reduction.

International Application Publication No. WO2006/087919 describes a composition containing a poorly water soluble substance such as a sulfonylurea, comprising: (i) the poorly water soluble substance; and (ii) polyvinylpyrrolidone or a copolymer of vinylpyrrolidone and vinyl acetate and having a median diameter of 1 μιτι or smaller; and (iii) an auxiliary dispersion stabilizer and having a median diameter of 1 m or smaller.

International Application Publication No. WO2007/072218 describes formulations and dosage units containing glimepiride of defined particle size that are useful for the treatment of diabetes. U.S. Patent Application Publication No. 2004/0147564 discloses a pharmaceutical composition for oral administration comprising glimepiride that has a mean particle size of less than about 30 μιτι and a particle size distribution such that at least 90% of glimepiride particles are less than about 75 μιτι. U.S. Patent No. 4,696,815 discloses an oral antidiabetic formulation comprising a sulfonylurea, a basic excipient such as sodium hydroxide or ammonium hydroxide and polyvinylpyrrolidone. International Application Publication No. WO2000/045818 describes use of a statin drug in the improvement of diabetic neuropathy, specifically in improving nerve conduction velocity and nerve blood flow in patients suffering from diabetes, in particular to pharmaceutical combinations of the statin drug and other agents known to improve diabetic neuropathy such as an aldose reductase inhibitor (ARI), an angiotensin converting enzyme (ACE) inhibitor, or an angiotensin II (All) antagonist, which combinations are useful in the prevention and treatment of the complications of diabetes.

International Application Publication No. WO2002/015892 describes a combination, especially a pharmaceutical composition, comprising (a) an insulin secretion enhancer or a pharmaceutically acceptable salt thereof, and (b) at least one of the active ingredients selected from the group consisting of: (i) HMG-Co-A reductase inhibitors or pharmaceutically acceptable salts thereof; and (ii) ACE inhibitors or pharmaceutically acceptable salts thereof; and, in case of a pharmaceutical composition, a pharmaceutically acceptable carrier.

International Application Publication No. WO2003/075933 describes a pharmaceutical composition which is a combination of an insulin-secretion stimulant and a HMG-CoA reductase inhibitor. Suitable insulin-secretion stimulants include the sulfonylurea drugs, and suitable HMG-CoA reductase inhibitors include the statin drugs. The composition may be formulated to provide extended-release characteristics of one or both of the active components.

When poorly soluble drugs like glimepiride are formed into tablets, the process used to prepare the tablets may further reduce the disintegrating or dissolving properties of such drugs. A tableting process generally requires high compression forces that hinder the disintegration and wetting of the interior portion of the tablet thereby reducing the disintegrating or dissolving properties of the tablet. Thus, to increase the dissolution rate, tablets are commonly formulated with relatively large amounts of disintegrant and carrier materials. However, increasing the amount of disintegrant and carrier material deleteriously affects either the size of the tablet or the drug loading of the tablet.

When atorvastatin or pharmaceutically acceptable salts thereof and glimepiride are combined in a single dosage form, there are challenges to be addressed by a formulation scientist. Some of the key challenges are maintaining optimum chemical, physical and polymorphic stability of atorvastatin or its pharmaceutically acceptable salts during the manufacturing process and also during storage, improving the solubility and dissolution rates of glimepiride, and designing an easy-to-prepare but patient-compliant dosage form. There is still an unmet need for new formulations comprising an atorvastatin or pharmaceutically acceptable salts thereof and glimepiride.

Surprisingly, the inventors of the present invention after extensive research and experimentation have found that when atorvastatin or pharmaceutically acceptable salts thereof and glimepiride are combined to make a pharmaceutical composition in the form of a multiple layered solid dosage form such as bi-layer tablets, such compositions possess optimum chemical, physical and polymorphic stability of the active agents particularly atorvastatin or its pharmaceutically acceptable salts, during the manufacturing process and also during storage of the formulation. Further the compositions of the present invention provide desirable dissolution rates of atorvastatin and glimepiride, and are also in the form of easy- to-prepare patient-compliant dosage forms.

SUMMARY

Aspects of the present application relate to a composition comprising atorvastatin or pharmaceutically acceptable salts thereof, or atorvastatin or pharmaceutically acceptable salts thereof in the form of a premix, and glimepiride as active agents, wherein both atorvastatin or pharmaceutically acceptable salts thereof, or atorvastatin or pharmaceutically acceptable salts thereof in the form of a premix, and glimepiride are in immediate release form.

Aspects of the present application relate to pharmaceutical formulations comprising atorvastatin or pharmaceutically acceptable salts thereof, or atorvastatin or pharmaceutically acceptable salts thereof in the form of a premix, and glimepiride, together with one or more pharmaceutically acceptable excipients, wherein both atorvastatin or pharmaceutically acceptable salts thereof, or atorvastatin or pharmaceutically acceptable salts thereof in the form of a premix, and glimepiride are in immediate release form. Aspects of the present application relate to a layered tablet comprising: (i) a first layer comprising atorvastatin or pharmaceutically acceptable salts thereof, or atorvastatin or pharmaceutically acceptable salts thereof in the form of a premix, and at least one pharmaceutically acceptable excipient; (ii) a second layer comprising glimepiride and at least one pharmaceutically acceptable excipient, wherein both atorvastatin or pharmaceutically acceptable salts thereof, or atorvastatin or pharmaceutically acceptable salts thereof in the form of a premix, and glimepiride are in immediate release form; optionally with a coating on the said layered tablet.

Aspects of the present application relate to pharmaceutical formulations in the form of a bi-layer tablet comprising atorvastatin or pharmaceutically acceptable salts thereof, or atorvastatin or pharmaceutically acceptable salts thereof in the form of a premix, and glimepiride in each of the two layers, together with one or more pharmaceutically acceptable excipients, wherein both atorvastatin or pharmaceutically acceptable salts thereof, or atorvastatin or pharmaceutically acceptable salts thereof in the form of a premix, and glimepiride are in immediate release form.

Aspects of the present application relate to processes for preparing pharmaceutical formulations comprising atorvastatin or pharmaceutically acceptable salts thereof, or atorvastatin or pharmaceutically acceptable salts thereof in the form of a premix, and glimepiride, wherein both atorvastatin, or pharmaceutically acceptable salts thereof, or atorvastatin or pharmaceutically acceptable salts thereof in the form of a premix, and glimepiride are in immediate release form.

Aspects of the present application relate to methods of treatment using combinations comprising atorvastatin or pharmaceutically acceptable salts thereof, or atorvastatin or pharmaceutically acceptable salts thereof in the form of a premix, and glimepiride, wherein both atorvastatin or pharmaceutically acceptable salts thereof, or atorvastatin or pharmaceutically acceptable salts thereof in the form of a premix, and glimepiride are in immediate release form.

Aspects of the present application relate to methods of treatment using pharmaceutical formulations comprising atorvastatin or pharmaceutically acceptable salts thereof, or atorvastatin or pharmaceutically acceptable salts thereof in the form of a premix, and glimepiride, wherein both atorvastatin or pharmaceutically acceptable salts thereof, or atorvastatin or pharmaceutically acceptable salts thereof in the form of a premix, and glimepiride are in immediate release form.

Aspects of the present application provide methods of treating elevated blood glucose in type II diabetes mellitus associated with dyslipidaemia, using pharmaceutical formulations comprising atorvastatin or pharmaceutically acceptable salts thereof and glimepiride, wherein both atorvastatin or pharmaceutically acceptable salts thereof, and glimepiride are in immediate release form.

Aspects of the present application relate to methods of treating subjects by administering a combination comprising atorvastatin or pharmaceutically acceptable salts thereof, and glimepiride, wherein both atorvastatin or pharmaceutically acceptable salts thereof and glimepiride are in immediate release form.

Aspects of the present application relate to pharmaceutical formulations in the form of solid oral dosage forms comprising atorvastatin or pharmaceutically acceptable salts thereof, and glimepiride, optionally with a coating, wherein both atorvastatin layer and glimepiride layer are in immediate release form.

Aspects of the present application relate to multiple layered tablets comprising atorvastatin layer, glimepiride layer and optionally at least one inert layer between atorvastatin layer and glimepiride layer, wherein both atorvastatin or pharmaceutically acceptable salts thereof, and glimepiride are in immediate release form, and wherein the said multiple layered tablets are optionally coated.

Aspects of the present application relate to triple layered tablets comprising atorvastatin layer, glimepiride layer and inert layer between atorvastatin layer and glimepiride layer and optionally the said triple layered tablets are coated, wherein both atorvastatin or pharmaceutically acceptable salts thereof and glimepiride are in immediate release form.

Aspects of the present application relate to bi-layer tablets comprising atorvastatin layer and glimepiride layer and optionally, the said bi-layer tablets being coated, wherein both atorvastatin or pharmaceutically acceptable salts thereof and glimepiride are in immediate release form.

Aspects of the present application relate to processes for preparing bi-layer tablets comprising atorvastatin or pharmaceutically acceptable salts thereof in a first layer, glimepiride in a second layer, and optionally a coating over the tablets, wherein both atorvastatin or pharmaceutically acceptable salts thereof and glimepiride are in immediate release form.

Aspects of the present application provide pharmaceutical formulations that are stable for commercially relevant period and provide the desired therapeutic concentration of the active agents for the intended duration.

An aspect of the present application provides pharmaceutical formulations comprising atorvastatin or pharmaceutically acceptable salts thereof and glimepiride, wherein polymorphic stability of the atorvastatin or its salt is achieved during the preparation of the formulations and also during the shelf-life of the formulations.

An aspect of the present application provides pharmaceutical formulations comprising atorvastatin or pharmaceutically acceptable salts thereof and glimepiride, wherein atorvastatin or its salt and glimepiride are chemically stable during preparation of the formulations and also during the shelf-life of the formulations.

An aspect of the present application relates to solid dosage forms comprising atorvastatin or pharmaceutically acceptable salts thereof, and glimepiride, wherein the percentage of atorvastatin or its pharmaceutically acceptable salts thereof is released in an amount not less than about 50% within about 30 minutes when subjected to an in vitro dissolution study or administered in vivo.

An aspect of the present application relates to solid dosage forms comprising atorvastatin or pharmaceutically acceptable salts thereof, and glimepiride, wherein the percentage of glimepiride released is not less than about 50% within about 30 minutes when subjected to an in vitro dissolution study or administered in vivo.

An aspect of the present application relates to solid dosage forms comprising atorvastatin or pharmaceutically acceptable salts thereof, and glimepiride, wherein atorvastatin or its salt is present in an amount of about 1 mg to about 80 mg and glimepiride is present in an amount of about 0.5 mg to about 20 mg.

An aspect of the present application relates to solid dosage forms comprising atorvastatin or pharmaceutically acceptable salts thereof, and glimepiride, wherein methods for preparing said dosage forms include one or more of the steps of mixing, dry granulation, wet granulation, fluidized bed granulation, drying, sifting, blending, lubrication, compression and coating.

An aspect of the present application relates to solid dosage forms comprising atorvastatin or pharmaceutically acceptable salts thereof, and glimepiride, wherein a dosage form is packaged in a strip or a blister or a HDPE container optionally together with a desiccant and/or oxygen absorbent.

BRIEF DESCRIPTION OF THE DRAWING

Figure 1 shows PXRD patterns of glimepiride (denoted as A), atorvastatin (denoted as B), a placebo according to Example 3 (denoted as C), bi-layer tablets of Example 3, as prepared (denoted as D), bi-layer tablets of Example 3, after storage at 40°C and 75% relative humidity (RH) for 6 months in a closed HDPE container (denoted as E), and bi-layer tablets of Example 3, after storage at 40°C and 75% RH for 6 months in aluminum foil blisters (denoted as F).

DETAILED DESCRIPTION

Aspects of the present application relate to a composition comprising atorvastatin or pharmaceutically acceptable salts thereof, or atorvastatin or pharmaceutically acceptable salts thereof in the form of a premix, and glimepiride, wherein both atorvastatin or pharmaceutically acceptable salts thereof, or atorvastatin or pharmaceutically acceptable salts thereof in the form of a premix, and glimepiride are in immediate release form.

Aspects of the present application relate to pharmaceutical formulations comprising atorvastatin or pharmaceutically acceptable salts thereof, or atorvastatin or pharmaceutically acceptable salts thereof in the form of a premix, and glimepiride, together with one or more pharmaceutically acceptable excipients, wherein both atorvastatin or pharmaceutically acceptable salts thereof, or atorvastatin or pharmaceutically acceptable salts thereof in the form of a premix, and glimepiride are in immediate release form.

As used herein, the terms "pharmaceutically acceptable salts of atorvastatin" or "atorvastatin" include metal and amine salts. The term "pharmaceutically acceptable metal salt" includes, but is not limited to, sodium, potassium, lithium, calcium, magnesium, aluminum, iron, and zinc salts. Such salts may be derived from bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide, aluminum hydroxide, ferrous or ferric hydroxide, etc. The term "pharmaceutically acceptable amine salt" includes, but is not limited to, salts formed by reaction with ammonium hydroxide or organic amines such as for example methylglucamine, choline, arginine, 1 -deoxy-2-(methylamino)-D-glucitol, and the like.

Further, as used herein, "pharmaceutically acceptable salts of atorvastatin" includes pharmaceutically acceptable salts of atorvastatin alone or in the form of a premix. The "premix" is prepared by treating the atorvastatin or pharmaceutically acceptable salts of atorvastatin with one or more excipients by using processes known in the art, for example, by dispersing/dissolving the atorvastatin or a pharmaceutically acceptable salt of atorvastatin in a solvent or a mixture of solvents and spraying it onto a substrate comprising one or more excipients. Another method involves dispersing/dissolving the atorvastatin or a pharmaceutically acceptable salt of atorvastatin along with one or more excipients in a solvent or a mixture of solvents and spraying it onto a substrate, or spray- drying it in a Spray-Dryer. Still another method involves intimately mixing the atorvastatin or a pharmaceutically acceptable salt of atorvastatin along with one or more excipients to obtain the desired premix.

Atorvastatin or pharmaceutically acceptable salts thereof may exist as premixes with antioxidants like sodium sulfite, sodium ascorbate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tocopherol, citric acid, malic acid, ascorbic acid, and any combinations thereof. Atorvastatin or pharmaceutically acceptable salts thereof may also be in the form of premix prepared using one or more diluents, binders, disintegrants, lubricants or glidants.

Aspects of the present application provide processes for preparing pharmaceutical formulations comprising atorvastatin or pharmaceutically acceptable salts thereof, or atorvastatin or pharmaceutically acceptable salts thereof in the form of a premix, and glimepiride, wherein both atorvastatin or pharmaceutically acceptable salts thereof, or atorvastatin or pharmaceutically acceptable salts thereof in the form of a premix, and glimepiride are in immediate release form. Aspects of the present application provide methods of treatment using a combination comprising atorvastatin or pharmaceutically acceptable salts thereof, or atorvastatin or pharmaceutically acceptable salts thereof in the form of a premix, and glimepiride, wherein both atorvastatin, or pharmaceutically acceptable salts thereof, and glimepiride are in immediate release form.

Aspects of the present application provide methods of treatment using pharmaceutical formulations comprising atorvastatin or pharmaceutically acceptable salts thereof, and glimepiride, wherein both atorvastatin or pharmaceutically acceptable salts thereof, and glimepiride are in immediate release form.

Aspects of the present application provide methods of treating elevated blood glucose in type II diabetes mellitus associated with dyslipidaemia, using pharmaceutical formulations comprising atorvastatin or pharmaceutically acceptable salts thereof, and glimepiride, wherein both atorvastatin or pharmaceutically acceptable salts thereof, and glimepiride are in immediate release form.

In embodiments, formulations of the present application are highly stable chemically and also exhibit appreciable physical and polymorphic stability during the preparation of the formulations and also during their shelf-life.

Embodiments of the present application provide pharmaceutical formulations in the form of a solid oral dosage forms comprising atorvastatin or pharmaceutically acceptable salts thereof, or atorvastatin or pharmaceutically acceptable salts thereof in the form of a premix, and glimepiride, and one or more pharmaceutically acceptable excipients, wherein the said solid dosage form is optionally coated, and wherein both atorvastatin or pharmaceutically acceptable salts thereof, or atorvastatin or pharmaceutically acceptable salts thereof in the form of a premix, and glimepiride, are in immediate release form.

In one embodiment, the present application provides a layered tablet comprising: (i) a first layer comprising atorvastatin or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient; (ii) a second layer comprising glimepiride and at least one pharmaceutically acceptable excipient, wherein both atorvastatin or pharmaceutically acceptable salts thereof, and glimepiride are in immediate release form; optionally with a coating on the said layered tablet. In embodiments, the present application provides multiple layered tablets comprising atorvastatin layer, glimepiride layer and optionally at least one inert layer between atorvastatin layer and glimepiride layer, wherein both atorvastatin or pharmaceutically acceptable salts thereof, and glimepiride are in immediate release form.

In embodiments, the present application provides multiple layered tablets comprising atorvastatin layer, glimepiride layer and optionally at least one inert layer between atorvastatin layer and glimepiride layer, the said multilayered tablets being coated, wherein both atorvastatin or pharmaceutically acceptable salts thereof, and glimepiride are in immediate release form.

In embodiments, pharmaceutical formulations comprising atorvastatin or pharmaceutically acceptable salts thereof, and glimepiride of the present application are in the form of layered tablets that can be bi-layer tablets or tri-layer tablets.

In embodiments, the present application provides triple layered tablets comprising atorvastatin layer, glimepiride layer and inert layer between atorvastatin layer and glimepiride layer and optionally the said triple layered tablets being coated, wherein both atorvastatin or pharmaceutically acceptable salts thereof, and glimepiride are in immediate release form.

In embodiments, the present application provides bi-layer tablets comprising atorvastatin layer and glimepiride layer, wherein both atorvastatin or pharmaceutically acceptable salts thereof and glimepiride are in immediate release form.

In embodiments, the present application provides bi-layer tablets comprising atorvastatin layer and glimepiride layer, the said bi-layer tablets being coated, wherein both atorvastatin or pharmaceutically acceptable salts thereof and glimepiride are in immediate release form.

In embodiments, the present application provides bi-layer tablets comprising: (i) a first layer comprising atorvastatin or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient; (ii) a second layer comprising glimepiride and at least one pharmaceutically acceptable excipient, wherein both atorvastatin or pharmaceutically acceptable salts thereof and glimepiride are in immediate release form; optionally with a coating on the said bi-layer tablet. In embodiments, the present application provides layered tablets comprising atorvastatin or pharmaceutically acceptable salts thereof in one layer and glimepiride in another layer, wherein the glimepiride containing layer is coated onto the atorvastatin containing layer. In specific embodiments, the glimepiride containing layer is provided as a spray coated layer or a compression coated layer, wherein both atorvastatin or pharmaceutically acceptable salts thereof, and glimepiride are in immediate release form.

In embodiments, the present application provides tablet-in-tablet formulations comprising atorvastatin or pharmaceutically acceptable salts thereof, and glimepiride, wherein an inner tablet contains glimepiride and an outer tablet contains atorvastatin or pharmaceutically acceptable salts thereof. In embodiments, the tablet is coated.

In embodiments, the present application provides pharmaceutical formulations in the form of solid oral dosage forms comprising atorvastatin or pharmaceutically acceptable salts thereof and glimepiride, and one or more pharmaceutically acceptable excipients, wherein the solid dosage forms are in the form of inlay tablets.

In embodiments, the present application provides pharmaceutical coated tablet formulations comprising atorvastatin or pharmaceutically acceptable salts thereof and glimepiride, wherein the coating is in the form of a film coat or sugar coat.

Embodiments of the present application provide pharmaceutical formulations that are stable for commercially relevant periods and provide desired therapeutic concentrations of the active agents atorvastatin and glimepiride for intended duration.

Embodiments of the present application provide processes for preparing layered tablets comprising atorvastatin or pharmaceutically acceptable salts thereof in one layer, and glimepiride in another layer, optionally wherein the tablets are coated, and wherein both atorvastatin or its salt and glimepiride are in immediate release form.

In embodiments, the present application provides a process for preparing a bi-layer tablet comprising: (1 ) a first layer comprising atorvastatin or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient; (2) a second layer comprising glimepiride and at least one pharmaceutically acceptable excipient, optionally with a coating on the said bi- layer tablet; wherein the said first layer is prepared by wet granulation and/or fluid bed granulation method and the said second layer is prepared by wet granulation method as given below: i) Dry mixing of glimepiride and at least one pharmaceutically acceptable excipient; ii) Preparation of granulating fluid containing a binder; iii) Granulating step i) with step ii) and drying the wet granules to obtain the desired sizes; iv) Optionally milling of dried granules followed by mixing with at least one pharmaceutical excipient and lubricant.

In embodiments, the present application provides a process for preparing of a bi-layer tablet comprising: (1 ) a first layer comprising atorvastatin or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient; (2) a second layer comprising glimepiride and at least one pharmaceutically acceptable excipient; optionally with a coating on the said bi- layer tablet; wherein the said first layer is prepared by wet granulation and/or fluid bed granulation method and the said second layer is prepared by wet granulation method as given below: i) Dry mixing of glimepiride, disintegrant and optionally at least one pharmaceutically acceptable excipient; ii) Preparation of granulating fluid containing a binder; iii) Granulating step i) with step ii) and drying the wet granules to obtain the desired sizes; iv) Optionally milling of dried granules followed by mixing with disintegrant and optionally at least one pharmaceutical excipient, and lubricant.

In embodiments, the present application provides a process for preparing of a bi-layer tablet comprising: (1 ) a first layer comprising atorvastatin or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient; (2) a second layer comprising glimepiride and at least one pharmaceutically acceptable excipient; optionally with a coating on the said bi- layer tablet; wherein the said first layer is prepared by wet granulation and/or fluid bed granulation method and the said second layer is prepared by wet granulation method as given below: i) Dry mixing of at least one pharmaceutically acceptable excipient; ii) Preparation of granulating fluid containing glimepiride and a binder; iii) Granulating step i) with step ii) and drying the wet granules; iv) Optionally milling of dried granules followed by mixing with at least one pharmaceutical excipient and lubricant; wherein both atorvastatin or pharmaceutically acceptable salts thereof, and glimepiride are in immediate release form.

In embodiments, the present application provides a process for preparing of a bi-layer tablet comprising: (1 ) a first layer comprising atorvastatin or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient; (2) a second layer comprising glimepiride and at least one pharmaceutically acceptable excipient, optionally with a film coating on the said bi- layer tablet; wherein the said first layer is prepared by wet granulation and/or fluid bed granulation method and the said second layer is prepared by wet granulation method as given below: i) Dry mixing of disintegrant and at least one pharmaceutically acceptable excipient; ii) Preparation of granulating fluid containing glimepiride and a binder; iii) Granulating step i) with step ii) and drying the wet granules; iv) Optionally milling of dried granules followed by mixing with disintegrant and at least one pharmaceutical excipient, and lubricant; wherein both atorvastatin or pharmaceutically acceptable salts thereof, and glimepiride are in immediate release form.

In embodiments, the present application provides a process for preparing bi-layer tablets comprising atorvastatin or pharmaceutically acceptable salts thereof, in one layer and glimepiride in another layer, wherein atorvastatin containing granules are prepared by using wet granulation or fluidized bed granulation method. In embodiments, the present application provides a process for preparing bi-layer tablets comprising atorvastatin or pharmaceutically acceptable salts thereof in one layer and glimepiride in another layer, wherein the atorvastatin layer includes two fractions of granules prepared using granulation methods such that one fraction contains about 75-95% of the total atorvastatin content and is prepared using a wet granulation method and the other fraction contains about 5- 25% of the total atorvastatin content and is prepared using a fluidized bed granulation method.

In embodiments, the present application provides a process for preparing bi-layer tablets comprising atorvastatin or pharmaceutically acceptable salts thereof in one layer and glimepiride in another layer, wherein the glimepiride layer includes compressed granules prepared using a wet granulation process, the granules containing a glidant material in an intragranular portion and the same glidant or a different glidant in an extragranular portion. In an embodiment, the glidant material comprises colloidal silicon dioxide.

Embodiments of the present application provide bi-layer tablets comprising atorvastatin or pharmaceutically acceptable salts thereof, in one layer and glimepiride in another layer, wherein atorvastatin or a pharmaceutically acceptable salt thereof is added in the form of a premix. In embodiments, a premix contains atorvastatin calcium and butylated hydroxyanisole. In embodiments, a premix is prepared by dissolving or dispersing atorvastatin or a salt thereof, and a compound such as butylated hydroxyanisole in a suitable solvent and evaporating the solvent.

The amounts of an active ingredient in the pharmaceutical formulations of the present application will be therapeutically effective amounts. Generally, a therapeutically effective amount of an active ingredient can range from about 0.05% to about 70%, or from about 1 % to about 60%, or from about 5% to about 50%, by weight, based on the total weight of the pharmaceutical composition.

Since atorvastatin calcium is susceptible to oxidation, antioxidants can be incorporated for enhancing its stabilization. Non-limiting examples of antioxidants useful in the present application include butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), citric acid, alpha-tocopherol, gallic acid, and the like, including any mixtures thereof. A combination of atorvastatin calcium and an antioxidant may be called an "atorvastatin calcium-antioxidant premix." For example, "atorvastatin calcium-BHA premix" refers to a combination of atorvastatin calcium and BHA in the context of the present application.

In aspects, the present application relates to processes for preparing premix compositions of atorvastatin calcium and antioxidant, wherein embodiments of a process comprise:

a) dissolving atorvastatin calcium in a solvent;

b) combining an antioxidant with the solution; and

c) removing the solvent.

In embodiments, the active agents namely atorvastatin or salts thereof, or atorvastatin or salts in the form of a premix, and glimepiride are present in amorphous form or crystalline form or mixtures thereof.

"Amorphous" for purposes of the application, includes "substantially amorphous" drug substances having less than about 10 percent, or less than about 8, 5, 4, 3, 2, or 1 percent, by weight of a crystalline form. In certain embodiments, the drug will have less than a detectable amount of crystallinity, such as can be determined by a suitable analytical method such as an X-ray powder diffraction analysis, and therefore is considered to be completely amorphous. The process of preparing atorvastatin calcium-BHA premix is disclosed in International Application Publication No. WO 2006/039441 .

"Crystalline" for purposes of the application, includes "substantially crystalline" drug substances having less than about 10 percent, or less than about 8, 5, 4, 3, 2, or 1 percent, by weight of amorphous form.

In aspects, the atorvastatin or salts thereof present in the pharmaceutical compositions of the present invention is in a crystalline form similar to the forms disclosed in the U.S. Patent No. 7,074,818 and U.S. Patent No. 5,969,156. In another aspect, the atorvastatin or salts thereof present in the pharmaceutical compositions of the present invention is in any crystalline form known in the art.

As used herein, the active agents atorvastatin or pharmaceutically acceptable salts thereof and glimepiride include the compounds and prodrugs thereof, active metabolites of the compounds and the prodrugs thereof, their salts, polymorphic forms, solvates, and hydrates, and single enantiomers thereof.

The term "excipient" or "pharmaceutically acceptable excipient" means a component of a pharmaceutical product that is not an active ingredient, such as a filler, diluent, carrier, etc. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic, and neither biologically nor otherwise undesirable, and are acceptable for veterinary use as well as human pharmaceutical use. An "excipient" or a "pharmaceutically acceptable excipient" as used in the specification includes both one and more than one such excipient.

The term "immediate release form" means that the active agents are released from the formulation fairly rapidly upon in vitro dissolution testing or upon in vivo administration.

The term "inert layer" means a layer which does not contain a pharmaceutically active agent or drug substance.

The term "stability" as used herein includes chemical stability, physical stability and polymorphic stability. The term "stability" or "stable for commercially relevant period" is defined as the ability of a drug substance or drug product to remain within the established specifications to maintain its identity, strength, quality, and purity at least until its expiration date. The term "chemical stability" means the tendency of drug to resist changes or decomposition due to chemical reactions, or due to the effects of oxygen, heat, light, pressure, etc. The term "polymorphic stability" means the tendency of drug to retain its original polymorphic form throughout the product shelf life. The term "physical and polymorphic stability" refers to maintaining the physical and polymorphic form of the active agents, such as crystalline, amorphous, or mixtures thereof, and "chemical stability" refers to maintaining acceptable concentrations of drug-related impurities.

The term "shelf life" is the time that finished products can be stored after manufacturing, during which the defined quality of a specified proportion of the product remains acceptable under expected (or specified) conditions of distribution, storage, and display.

The selection of appropriate particle sizes of the active agents as well as of excipients is within the scope of the application. D10, D50, and D90 values are useful ways for indicating a particle size distribution. D90 is the size value where at least 90 volume percent of the particles have sizes smaller than the value. Likewise, a D10 value refers to 10 volume percent of the particles having sizes smaller than the value. A D50 value refers to 50 volume percent of the particles having sizes smaller than the value, and a D[4,3] value refers to the mean particle size. Methods for determining D10, D50, D90, and D[4,3] include laser diffraction techniques, such as using equipment from Malvern Instruments Ltd., Malvern, Worcestershire, United Kingdom, or from Horiba.

In embodiments, compositions of the present application are prepared using active agents atorvastatin or pharmaceutically acceptable salts thereof, and glimepiride having particle size distributions wherein D90 is about 1 μιτι to about 1000 μιτι, or about 1 μιτι to about 500 μιτι; and D50 is from about 1 μιτι to about 500 μιτι, or about 1 μιτι to about 250 μιτι.

In embodiments, the compositions contain the active agents in amounts less than about 98%, or less than about 80%, or less than about 50%, by weight of the total composition.

In embodiments, the formulation of the present application is a bi-layer tablet comprising: (i) first layer comprising about 2 to 8% w/w atorvastatin or pharmaceutically acceptable salts thereof, about 0.5 to 2% w/w binder, about 1 to 5%w/w alkalizing agent, about 0.1 to 1 .5% w/w acid solubilizing agent, about 70 to 85% w/w diluents, about 1 to 5% w/w surfactant, and about 0.5 to 1 % w/w lubricant by weight of first layer; and

(ii) second layer comprising about 0.5 to 4% w/w glimepiride, about 80 to 95%w/w diluents, about 5 to 10% w/w disintegrant, about 0.5 to 2% w/w binder, and about 0.5 to 1 % w/w lubricant, by weight of second layer.

Useful pharmaceutically acceptable excipients include, for example, any one or more of diluents, binders, stabilizers, lubricants, glidants, disintegrating agents, anti-oxidants, alkalizing agents, surfactants, film coating materials, plasticizers, pigments, opacifiers, and coloring agents, and any other materials that are commonly used in solid pharmaceutical dosage form preparations.

Excipients present in pharmaceutical formulations according to the application include diluents such as calcium sulfate, cellulose acetate, dextrates, dextrin, dextrose, fructose, kaolin, lactitol, maltitol, maltodextrin, maltose, polymethacrylates, sodium chloride, sucrose, talc, starches, lactose, mannitol, cellulose derivatives, and the like. Different grades of lactose include, but are not limited to, lactose monohydrate, lactose DT (direct tableting), lactose anhydrous, Flowlac™, Pharmatose™ and others. Different grades of starches include, but are not limited to, maize starch, potato starch, rice starch, wheat starch, pregelatinized starch, Starch 1500, Starch 1500 LM grade (low moisture content grade), fully pregelatinized starch, and others. Various cellulose compounds that can be used include crystalline cellulose, powdered cellulose, and cellulose acetate. Examples of crystalline cellulose products include, but are not limited to, CEOLUS™ KG801 , Avicel™ PH101 , PH102, PH301 , PH302, and PH-F20, microcrystalline cellulose 1 14, silicified microcrystalline cellulose, and microcrystalline cellulose 1 12. Other useful diluents include, but are not limited to, carmellose, sugar alcohols such as mannitol, sorbitol, and xylitol, calcium carbonate, magnesium carbonate, sodium carbonate, sodium bicarbonate, light magnesium oxide, heavy magnesium oxide, sodium hydrogen phosphate, calcium sulfate, disodium hydrogen phosphate, basic calcium phosphate, and tribasic calcium phosphate.

Pharmaceutical formulations according to the application can also include binders, such as carboxymethylcelluloses, hydroxyethylcelluloses, dextrin, gelatin, maltodextrin, polyethylene oxides, sodium alginate, hydroxypropylcelluloses, hydroxypropyl methylcelluloses, polyvinylpyrrolidones or povidone (e.g., PVP-K25, PVP-K29, PVP-K30, and PVP-K90D), powdered acacia, gelatin, guar gum, carbomers (e.g., a Carbopol™ product), methylcelluloses, polymethacrylates, starches, and the like, and mixtures thereof.

Disintegrants can also be present in the formulation, such as carmellose calcium, carboxymethylstarch sodium, croscarmellose sodium, crospovidones, examples of commercially available crospovidone products including but not being limited to crosslinked povidone, KOLLIDON™ CL, POLYPLASDONE™ XL, XI-10, and INF-10, and low-substituted hydroxypropylcelluloses. Examples of low- substituted hydroxypropylcelluloses include, but are not limited to, low-substituted hydroxypropylcellulose LH1 1 , LH21 , LH31 , LH22, LH32, LH20, LH30, LH32, and LH33. Other useful disintegrants include sodium starch glycolate (type A or type B), colloidal silicon dioxide and starches.

In embodiments, disintegrants can be combined with other excipients in a process of granulating, i.e., intragranularly, and/or in the preparation of a compression mixture, i.e., extragranularly.

Lubricants can also be present as excipients, such as stearic acid, magnesium stearate, calcium stearate, sodium laurylsulphate, hydrogenated vegetable oil, hydrogenated castor oil, sodium stearyl fumarate, talc, glyceryl behenate, glyceryl monostearates, palmitic acid, carnauba wax, calcium soaps, zinc stearate, polyoxyethylene monostearates, calcium silicate, silicon dioxide, macrogols, and any mixtures thereof.

Alkanizing agents that can be used as excipients herein include one or more of alkaline earth metal salts, alkali metal salts, and organic alkalizing agents. Alkaline earth metal salts include, for example, calcium carbonate, calcium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate, aluminum magnesium hydroxide, and the like. Alkali metal salts include, for example, disodium hydrogen orthophosphate, sodium silicate, sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium aluminate, sodium or potassium citrate, carbonate, bicarbonate, phosphate, sulfate, benzoate, ascorbate, and the like. Examples of organic alkalizing agents include amines; specific examples of amines including N- methylglucamine, guanine, and arginine.

Antioxidants used herein include sodium sulfite, sodium ascorbate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tocopherol, citric acid, malic acid, ascorbic acid, and any mixtures thereof.

One or more glidant materials which improve the flow of powder blends, pellets, or mini-tablets, and minimize dosage form weight variations can be present as excipients, such as colloidal silicon dioxide, silica derivatives, and talc.

In embodiments of the present application, and acid solubility enhancing excipient comprises a pharmaceutically acceptable polymer that is water soluble, water swellable, water insoluble, pH dependent, pH independent, or mixtures thereof. Pharmaceutically acceptable polymers in the context of the application include, but are not limited to, polyethylene glycols (e.g., molecular weight less than about 400), hydroxymethyl celluloses, hydroxyethyl celluloses, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, methylcelluloses, carboxymethylcelluloses (CMC), sodium CMC, carboxyethyl celluloses, carboxy polymethylenes, hydroxypropyl methyl phthalates, polyvinylpyrrolidones, cellulose acetates, sodium alginate, gums such as acacia gum, guar gum, tragacanth gum, and xanthan gum, methacrylic acid copolymers such as poly(butylmethacrylate), (2-dimethylaminoethyl)methacrylates, methylmethacrylates, Eudragit™ products designated as E100 or E12.5 or EPO, polyvinyl acetal diethylaminoacetate (available as AEA supplied by Sankyo Co. Limited), chitosan, and the like, including any mixtures thereof. Formulations can also contain wetting agents to improve the wettability of one or both active agents. Various useful surfactants include, but are not limited to, sodium lauryl sulfate, cetrimide, polysorbates such as polysorbate 80, poloxamers such as poloxamer 188 and poloxamer 407, sodium carboxymethylcelluloses, hydrogenated oils, polyoxyethylene glycols, polyoxypropylene glycols, sorbitan fatty acid esters (e.g., SPAN® surfactants), polyoxyethylene sorbitan fatty acid esters (e.g., TWEEN® surfactants), polyglycolized glycerides, available commercially such as GELUCIRE® 40/14, GELUCIRE® 42/12, and GELUCIRE® 50/13, Vitamin E TGPS, and any mixtures thereof.

Coloring agents can include, but are not limited to, iron oxides, lake of sunset yellow, lake of quinoline yellow, lake of erythrosine, titanium dioxide, FD&C colorants, and the like.

Various solvents can be used in processes of preparing pharmaceutical formulations of the present application including, but not limited to, water, methanol, ethanol, acidified ethanol, acetone, diacetone, polyols, polyethers, oils, esters, alkyl ketones, methylene chloride, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulphoxide, Ν,Ν-dimethylformamide, tetrahydrofuran, and any mixtures thereof.

In embodiments, formulations of the present application are in the form of film-coated tablets. Useful coating compositions comprise pre-formulated film- coating materials such as OPADRY® products (manufactured by COLORCON), including OPADRY® White OY58900, OPADRY® White AMB OYB28920, etc.), other hydrophilic or hydrophobic substances, and mixtures thereof. Useful components for coating include, but are not limited to, film formers, plasticizers, antiadherents, opacifiers, solvents, and optionally colorants, lubricants, pigments, antifoam agents, and polishing agents.

In an aspect, a film coating composition contains the following components: polymer as film former, plasticizer, colourant or opacifier, and vehicle. In film coating suspensions, minor quantities of flavours, surfactants, and waxes can be included. In embodiments, polymers used in film coating are cellulose derivatives, such as cellulose ethers, or acrylic polymers and copolymers. High molecular weight polyethylene glycols, polyvinylpyrrolidones, polyvinyl alcohols, and waxy materials can also be used.

Typical cellulose ethers include hydroxyethylcelluloses, hydroxypropylcelluloses, hydroxypropyl methylcelluloses, and methylcelluloses. Suitable acrylic polymers include synthetic polymers with diverse functionalities. They may be further modified to enhance swelling and permeability by the incorporation of materials such as water soluble cellulose ethers and starches in order to ensure a more complete disintegration or dissolution of the film.

Plasticizers include materials such as polyethylene glycols (PEG), propylene glycols, cetanol, triacetin, citric acid esters such as, for instance, those sold under the trade name CITROFLEX® (Pfizer, New York), phthalic acid esters, dibutyl succinate, castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, triethyl citrate, and the like. Suitable plasticizers for use in the coating materials can be categorized into three groups: polyols (e.g., glycerol, propylene glycol, and macrogols), organic esters (e.g., pthalate esters, dibutyl sebacetate, citrate esters, and triacetin) and, oils or glycerides (e.g., castor oil, acetylated monoglycerides, and fractionated coconut oil).

Pigments, opacifiers such as titanium dioxide, talc, and other additives may also be included in coating compositions. The quantities of the coating applied may vary from about 0.1 -20%, or about 0.5-5%, by weight of the total weight of a core composition. In embodiments, a coating is applied either directly onto the cores or onto sub-coated cores, using conventional coating techniques such as, for instance, pan coating or fluidized bed coating methods.

Antiadherents are frequently used in film coating processes to avoid sticking effects during film formation and drying. An example of a useful antiadhesive for this purpose is talc. The antiadherent is frequently present in a film coating in amounts of about 0.5% (w/w) to 15% (w/w), based upon the total weight of the coating.

Suitable colorants/opacifiers can be selected from several groups such as organic dyes and lacquers, inorganic colors and natural colors.

Film coating dispersions can be prepared using various vehicles, such as water, alcohols, ketones, esters, chlorinated hydrocarbons, and any mixtures thereof. In embodiments, tablet compositions of the present application may comprise a sub-coating, onto which a film coating is provided.

In embodiments, compositions may be prepared by extrusion and spheronization, or using a melt granulation technique. Compositions may be presented as uncoated, film coated, sugar coated, compression coated, or powder coated forms.

The descriptions of excipients are illustrative and are not intended to be exhaustive or limiting. Those skilled in the art will be aware of many other substances that are useful in the practice of the application, and the use of such substances is specifically included in this application.

In embodiments, compositions of the present application are made into suitable pharmaceutical dosage forms. The different pharmaceutical dosage forms include solid oral dosage forms such as, but not limited to, tablets, capsules, and sachets.

In embodiments, the compositions of the present invention can be in the form of multiparticulates such as bilayered minitablets, which can be filled into a capsule.

Pharmaceutical compositions in embodiments of the present application include tablets including an active agent/ingredient, coated with another active agent/ingredient using a film coating and/or compression coating technique.

Pharmaceutical formulations in embodiments of the present application include multi-layered tablets, optionally with coatings. In embodiments, multi- layered tablets of the present application may be bi-layer tablets or triple layer tablets.

The different physicochemical properties of the active agent as well as of excipients are to be considered, as these properties affect processing and formulation aspects. Various important physicochemical properties include, but are not limited to, particle sizes, density (bulk density and tapped density), compressibility index, Hausner's ratio, angle of repose, etc. Particle sizes of active pharmaceutical ingredients can affect the solid dosage form in numerous ways. For example, content uniformity (CU) of pharmaceutical dosage units can be affected by particle sizes and size distributions. Also, particle sizes can play an important role in the dissolution of active agent from the final dosage forms, because of their solubility. Hence, these physicochemical properties not only affect the processes of preparing the pharmaceutical formulations but also affect the performance of the pharmaceutical products, both in vitro and in vivo.

In embodiments, granules have Carr's indices in the range of about 1 -40%. This indicates superior handling capabilities during processing into pharmaceutical dosage forms. Flowability of materials can be measured and represented using the Carr's Index. The Carr's Index is the percent ratio of the difference between tapped density and bulk density to tapped density, mathematically described as: Carr's Index = [(Tapped density - Bulk density) ÷ Tapped density] χ 100.

Densities can be determined using test method 616 "Bulk Density and Tapped Density" of United States Pharmacopeia 29, United States Pharmacopeial Convention, Inc., Rockville, Maryland, U.S.A., 2005. Carr's Index values below about 15% represent materials with very good flow properties and values above about 40% represent materials with very poor flow properties.

In embodiments, tablets have hardness values in the range of about 5-50 kiloponds (KP), or about 5-30 KP.

In embodiments, tablets have friability less than 5%, or less than 2%, or less than 1 % w/w, by weight of the tablets.

In embodiments, tablet compositions have "loss-on-drying" (LOD) values less than about 15%, or less than about 10%, by weight of the composition after manufacturing and during their shelf-life.

In embodiments, humidity conditions for the processing areas are controlled, such that the processes are carried out below about 70% relative humidity (RH) at about 25°C. Low moisture contents are useful to impart improved polymorphic stability to the active agents contained in the pharmaceutical formulations of the present invention. Excipients having moisture content less than about 10%, or less than about 5% by weight, are also useful to aid in preventing drug polymorphic conversions.

In embodiments, pharmaceutical compositions are prepared using any of methods including direct compression, dry granulation, wet granulation, roller compaction, slugging-deslugging, fluidized bed granulation, or combinations of such methods.

An aspect of the present application relates to direct compression methods, in which an active agent and excipients are mixed together and compressed. An aspect of the present application relates to granulation methods, for example, wet granulation methods, in which a binder and a solvent are added to a powder mixture and granulation is conducted, dry granulation methods, in which granulation is carried out by compacting/decompacting or slugging/deslugging a powder mixture, and melt granulation methods, in which a substance that melts on heating is mixed with an active agent and granulation is carried out.

There are no particular limitations on granulation solvents, which comprises water or any of various organic solvents, for example, lower alcohols such as methanol and ethanol, ketones such as acetone and methyl ethyl ketone, methylene chloride, or any mixtures thereof.

Further, for granulation, operations such as mixing granulation methods using a planetary mixer, a screw mixer and the like; high-speed mixing granulation methods using a Henschel mixer, a Super mixer and the like; extruding granulation methods using a cylindrical granulator, a rotary granulator, a screw extruding granulator, a pellet mill type granulator and the like; wet high-shear granulation methods; fluidized-bed granulation methods; compression granulation methods; crushing granulation methods; and spraying granulation methods can be used.

After granulation, drying using an oven dryer, a fluidized bed dryer, and the like, crushing, and sieving can be carried out to obtain granules or fine granules for use. Moreover, a granulation solvent may be used when preparing the composition according to the present application.

Equipment suitable for processing pharmaceutical compositions include any one or more of rapid mixer granulators, planetary mixers, mass mixers, ribbon mixers, fluid bed processors, mechanical sifters, blenders, roller compacters, extrusion-spheronizers, compression machines, capsule filling machines, rotating bowls or coating pans, tray dryers, fluid bed dryers, rotary cone vacuum dryers, and the like, multi-mills, fluid energy mills, ball mills, colloid mills, roller mills, hammer mills, and the like, equipped with a suitable screen.

In embodiments, pharmaceutical formulations of the present application are intended for oral administration to a subject in need thereof.

In aspects, the application provides methods of prophylaxis, amelioration, or treating diseases and/or disorders by administering a therapeutically effective amount of a formulation according to the present application to subjects in need thereof.

The term "solubility enhanced form" refers to atorvastatin or its salts having a solubility that has been enhanced by any means.

The term "acid solubility enhancing excipient" refers to any excipient which is able to dissolve in acid media and release atorvastatin from the dosage form.

The term "related substances" or "impurities" mean the degradation impurities or active ingredient process related impurities of drug materials.

Atorvastatin or pharmaceutically acceptable salts thereof, related impurities include one or more of the following:

Atorvastatin lactone: 5-(4-Fluorophenyl)-1 -{2-[(2R,4R)-4-hydroxy-6- oxotetrahydro-2H-pyran-2-yl]ethyl}-2-isopropyl-N,4-diphenyl-1 H-pyrrole-3- carboxamide.

Diepoxide Impurity: 3-(4-fluorobenzoyl)-2-isobutyryl-3-phenyl-oxirane-2- carboxylic acid phenylamide.

Atorvastatin lactam impurity.

Atorvastatin hydroxyl expoxy oxazinine impurity.

Glimepiride related substances or impurities include the following:

Impurity A (Cis isomer): 1 -[4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1 - carboxamido) ethyl] phenylsulfonyl]-3-(4-cis-methylcyclohexyl)urea.

Impurity B (PBS— III): N-[4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1 - carboxamido) ethyl] benzene sulfonamide.

Impurity D (Meta isomer): 1 -[[m-[2-(3-Ethyl-4-methyl-2-oxo-3-pyrroline-1 - carboxamido) ethyl]phenyl]sulfonyl]-3-(trans-4-methylcyclohexyl)urea.

The term "intragranular" refers to formulation components that are included before or during a granulation step.

The term "extragranular" refers to formulation components that are added after or following a granulation step.

In embodiments, the present application provides solid dosage forms comprising atorvastatin or a pharmaceutically acceptable salt thereof, and glimepiride, prepared using methods including any one or more of the steps of mixing, dry granulation, wet granulation, fluidized bed granulation, drying, sifting, blending, compression, and coating. In embodiments, there are provided processes for the preparation of bi- layer tablets comprising atorvastatin or a pharmaceutically acceptable salts thereof in one layer and glimepiride in another layer, wherein an atorvastatin layer is prepared by a process including the following:

A. Preparation of granules by fluid bed granulation.

1 . Sift diluents through a sieve and separately sift an acid solubility enhancing excipient through a sieve.

2. Dissolve atorvastatin or a salt thereof, or atorvastatin or a salt thereof in the form of a premix in a solvent and add an acid solubility enhancing excipient.

3. Granulate diluents with the drug-acid solubility enhancing excipient solution in a fluid bed granulator and dry the granules thus obtained.

B. Preparation of granules in a rapid mixer granulator.

1 . Mix a surfactant with water to form a thick paste.

2. Sift atorvastatin or a salt thereof, or atorvastatin or a salt thereof in the form of a premix, alkalizing agent, diluent, disintegrant, and any other excipients through a sieve and mix in a rapid mixer granulator.

3. Granulate the dry mixture with the surfactant paste and dry the granules.

C. Blending.

1 . Combine granules from A, granules from B, and sifted extragranular ingredients (except lubricant).

2. Add a lubricant and mix.

In embodiments, there are provided a process for the preparation of bi- layer tablets comprising atorvastatin or a pharmaceutically acceptable salt thereof in one layer and glimepiride in another layer, wherein the glimepiride layer is prepared by a process including the following:

1 . Sift and mix diluent, disintegrant, and wetting agent components in a rapid mixer granulator.

2. Dissolve a binder in a solvent and add glimepiride.

3. Granulate the dry mixture with the drug-binder mixture and dry the granules.

4. Blend the granules with a disintegrant and then blend with a lubricant. Embodiments of the present application relate to processes for preparing bi-layer tablets comprising atorvastatin or pharmaceutically acceptable salts thereof in one layer and glimepiride in another layer, wherein a glimepiride layer contains granules that are prepared by a wet granulation process, and wherein colloidal silicon dioxide is present intragranularly with other excipients and also is present extragranularly with other excipients in the said bi-layer tablets.

Embodiments of the present application provide bi-layer tablets comprising atorvastatin or pharmaceutically acceptable salts thereof in one layer and glimepiride in another layer, wherein the glimepiride layer contains granules that are prepared by a wet granulation process wherein part of disintegrating agent is present intragranularly and part of disintegrating agent is present extragranularly.

Embodiments of the present application provide methods of use, prevention, treatment and administration by administering pharmaceutical formulations comprising atorvastatin or pharmaceutically acceptable salts thereof and glimepiride.

Embodiments of the present application provide pharmaceutical formulations comprising atorvastatin or pharmaceutically acceptable salts thereof and glimepiride, wherein polymorphic stability of the atorvastatin or its salt is achieved during the preparation of the formulations and also during their shelf-life.

Embodiments of the present application provide pharmaceutical formulations comprising atorvastatin or pharmaceutically acceptable salts thereof and glimepiride, wherein atorvastatin or its salt and glimepiride are chemically stable during the preparation of the formulations and also during their shelf-life.

In embodiments, the present application provides solid dosage forms comprising atorvastatin or pharmaceutically acceptable salts thereof and glimepiride, wherein the chemical stability and/or polymorphic stability of atorvastatin or its pharmaceutically acceptable salt are maintained during storage at 40°C and 75% RH for 3 months, or for 6 months.

In embodiments, the solid dosage forms of the present application comprising atorvastatin or pharmaceutically acceptable salts thereof and glimepiride contain any one or more of the atorvastatin-related substances such as atorvastatin lactone, lactam impurity, and hydroxy expoxy oxazinine impurity each in amounts less than about 5%, and their total in amounts less than about 8% during storage at 40°C and 75% RH for 3 months, or at 30°C and 65% RH for 6 months, or at 25°C and 60% RH for 12 months.

In embodiments, solid dosage forms of the present application comprising atorvastatin or pharmaceutically acceptable salts thereof and glimepiride contain the glimepiride related substances such as Impurity A, Impurity B, and Impurity D each in amounts less than about 5%, and their total in amounts less than about 8% during storage at 40°C and 75% RH for 3 months, or at 30°C and 65% RH for 6 months, or at 25°C and 60% RH for 12 months.

Drug-related impurity contents are expressed in this application as percentages of the label content of the respective drug/active agent.

In embodiments, the present application relates to bi-layer tablets comprising atorvastatin or pharmaceutically acceptable salts thereof and glimepiride having polymorphic stability and/or chemical stability of atorvastatin or its salt and/or glimepiride during storage at 40°C and 75% RH for 3 months, or at 30°C and 65% RH for 6 months, or at 25°C and 60% RH for 12 months.

The dosage forms can be subjected to in vitro dissolution testing, such as according to Test 71 1 "Dissolution" in United States Pharmacopeia 29, United States Pharmacopeial Convention, Inc., Rockville, Maryland, 2005 ("USP"), to determine the rate at which the active agents are released from the dosage forms, and content of active agents can be determined in dissolution media using techniques such as high performance liquid chromatography (HPLC).

In embodiments, the present application provides solid dosage forms comprising atorvastatin or pharmaceutically acceptable salts thereof and glimepiride, wherein the release of atorvastatin or its pharmaceutically acceptable salt is not less than about 50% in 30 minutes when tested in USP type 2 (paddle) apparatus with 900 ml of 0.05 M phosphate buffer (pH 6.8) as the dissolution medium at 37°C, at 75 rpm paddle speed.

In embodiments, the present application provides solid dosage forms, comprising atorvastatin, or a pharmaceutically acceptable salt thereof, and glimepiride, wherein the release of glimepiride is not less than about 50% in 30 minutes, when tested in USP type 2 (paddle) apparatus with 900 ml of 0.05 M phosphate buffer (pH 6.8) as the dissolution medium at 37°C, at 75 rpm paddle speed.

In embodiments, the present application provides percentage release of a bi-layer tablet comprising: (1 ) a first layer comprising atorvastatin or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient; (2) a second layer comprising glimepiride and at least one pharmaceutically acceptable excipient; optionally a film coating on the said bi- layer tablet; wherein the release of atorvastatin or its pharmaceutically acceptable salt is not less than about 80% in 30 minutes, when tested in USP type 2 (paddle) apparatus with 900 ml of 0.05 M phosphate buffer (pH 6.8) as the dissolution medium at 37°C, at 75 rpm paddle speed and the release of glimepiride is not less than about 80% in 60 minutes when tested in USP type 2 (paddle) apparatus with 900 ml of 0.05 M phosphate buffer (pH 6.8) as the dissolution medium at 37°C, at 75 rpm paddle speed.

In embodiment, the term "about" refers to quantitative terms plus or minus 10%, or in another embodiment plus or minus 5%.

In embodiments, the present application provides solid dosage forms comprising atorvastatin or pharmaceutically acceptable salts thereof and glimepiride, wherein the release of atorvastatin or its pharmaceutically acceptable salt is not less than about 50% in 30 minutes from the said dosage form when subjected to an in vitro dissolution study or administered in vivo.

In embodiments, the present application provides solid dosage forms, comprising atorvastatin or pharmaceutically acceptable salts thereof and glimepiride, wherein the release of glimepiride is not less than about 50% in 30 minutes from the said dosage form when subjected to an in vitro dissolution study or administered in vivo.

Embodiments of the present application provide bi-layer tablets comprising atorvastatin or pharmaceutically acceptable salts thereof in one layer and glimepiride in another layer, wherein the bi-layer tablets exhibit a substantially comparable glimepiride release with the commercial product AMARYL^® (glimepiride) tablets and/or a substantially comparable atorvastatin release with the commercial product LIPITOR^® (atorvastatin calcium) tablets.

It is known that the amount of a drug released at a particular target site plays a role in its dissolution, absorption and/or bioavailability. Therefore, definite amounts of atorvastatin and glimepiride should be released at a specific site or pH in order to provide the desired dissolution, absorption and/or bioavailability. The compositions of the present application comprising atorvastatin or its salts thereof and glimepiride are designed to provide desired release of each of the active agents as required for providing a pharmacological effect without substantial toxicity when administered to a subject in need thereof. In embodiments, the present application provides solid dosage forms, comprising atorvastatin or pharmaceutically acceptable salts thereof and glimepiride, wherein atorvastatin or pharmaceutically acceptable salts thereof is present in amounts about 1 mg to about 80 mg and glimepiride is present in amounts about 0.5 mg to about 20 mg.

An aspect of the present application relates to bi-layer tablets comprising atorvastatin or pharmaceutically acceptable salts thereof in one layer and glimepiride in another layer, wherein a bi-layer tablet contains 10 to 80 mg of atorvastatin, or its pharmaceutically acceptable salt, and 1 to 4 mg of glimepiride. In embodiments, pharmaceutical formulations contain the following amounts of atorvastatin/glimepiride: 20 mg/1 mg; 20 mg/2 mg; 20 mg/3 mg; 20 mg/4 mg; 10 mg/1 mg; 10 mg/2 mg; 10 mg/3 mg; and 10 mg/4 mg.

In embodiments, the present application provides solid dosage forms comprising atorvastatin or pharmaceutically acceptable salts thereof and glimepiride, which can be administered to a subject in need thereof with or without regard to meals.

In embodiments, the present application provides solid dosage forms comprising atorvastatin or pharmaceutically acceptable salts thereof and glimepiride, wherein dosage forms are packaged in strips or blisters or a polymeric container, optionally together with desiccant and/or oxygen absorbent.

The application includes the use of packaging materials such as containers including closures composed of polyethylene and/or polypropylene and/or glass, and blisters or strips composed of aluminum or high-density polypropylene, or polyvinyl chloride, or polyvinyl chloride coated with polyvinyl idene dichloride, generally termed PVC/PVDC. In embodiments, the application includes the use of oxygen absorbers and/or desiccants with packaging materials.

Embodiments of the present application provide primary packaging for compositions comprising atorvastatin or pharmaceutically acceptable salts thereof and glimepiride, wherein the packages are HDPE containers including an oxygen absorber.

Embodiments of the present application relate to bi-layer tablets comprising atorvastatin or pharmaceutically acceptable salts thereof in one layer and glimepiride in another layer, wherein bi-layer tablets are packed in HDPE containers together with Stabilox® as an oxygen absorber. Embodiments of the present application provide primary packaging for bi- layer tablets comprising atorvastatin or pharmaceutically acceptable salts thereof in one layer and glimepiride in another layer, wherein the packages are aluminum foil blisters.

In embodiments, tablets can be formed in any shapes and sizes such as round, elongated, capsule-shaped, etc. In embodiments, tablets can be embossed or debossed. To form tablets, compression punches can be coated or uncoated punches and plain, concave, or convex in shape.

Embodiments of the present application provide formulations comprising atorvastatin or pharmaceutically acceptable salts thereof, and glimepiride, which can be administered once daily, twice daily, three times daily, or four times daily to a subject in need thereof.

Embodiments of the present application provide formulations comprising atorvastatin or pharmaceutically acceptable salts thereof and glimepiride, which can be administered once daily, twice daily, three times daily, or four times daily to a subject in need thereof.

The following examples further describe certain specific aspects and embodiments of the application. These examples are provided solely for the purpose of illustration, and should not be construed as limiting the scope of the disclosure in any manner.

EXAMPLES

EXAMPLE 1 : Preparation of atorvastatin calcium-BHA premix.

160 g of atorvastatin calcium was mixed with 1600 ml of ethyl acetate, followed by heating to a temperature of about 65-75°C to obtain a clear solution, then the clear solution was cooled to about 25-30°C. 0.2 g of butylated hydroxyanisole ("BHA") was added to the solution, followed by stirring for about 5- 10 minutes and filtration through a Celite bed. The bed was washed with 160 ml of ethyl acetate. The filtrate was passed through an agitated thin-film dryer at about 73-78°C under vacuum of about 650 mmHg. The solid material obtained from the agitated thin film dryer was micronized in a jet mill. The solid material was then dried using a fluid bed dryer at 68-75°C for about 4 hours. The atorvastatin calcium-BHA premix is an amorphous material. EXAMPLE 2: Comparative example of Monolithic tablets and Bi-layer tablets containing atorvastatin calcium 80 mg and glimepiride 4 mg.

Table-1 : Composition of Atorvastatin Layer

^* Evaporates during processing.

Manufacturing process:

Fluid bed granulation

1 . Microcrystalline cellulose and lactose monohydrate were sifted together through appropriate mesh sieve.

2. Dissolved the atorvastatin calcium premix in methanol, added basic butylated methacrylate copolymer (previously through appropriate mesh sieve), and stirred to obtain a clear solution. 3. Materials of step 1 were granulated in a fluid bed processor with the solution of step 2, then the granules were dried at 40±5°C for 15 minutes to a loss on drying (LOD) of 3% w/w or less and sifted through appropriate mesh sieve.

Wet granulation

1 . Sodium lauryl sulphate was mixed with water to form a thick paste.

2. Atorvastatin calcium-BHA premix, sodium bicarbonate, lactose monohydrate and microcrystalline cellulose were sifted through appropriate mesh sieve and mixed in a rapid mixer granulator.

3. With continued mixing, sodium lauryl sulphate paste of step 1 was slowly added to form granules.

4. The wet granules were dried at 60°C, until the LOD is below 3% w/w.

5. The granules were sifted through appropriate mesh sieve and the retained granules were milled with a Quadra Comill/ comminuting mill fitted with a 0.5 mm screen, passed through appropriate mesh sieve, and combined with the previously sifted granules.

Extragranular

1 . Hydroxypropyl cellulose and crospovidone were sifted through appropriate mesh sieve.

2. Fluid bed granules, wet granulation granules, and extragranular materials were mixed in a double cone blender.

Lubrication

1 . Magnesium stearate was sifted through appropriate mesh sieve and mixed with the blend of granules and extragranular materials.

Table-2: Composition of Glimepiride layer

Ingredients mg/tablet

Glimepiride 4.00

Lactose monohydrate (Impalpable) 78.59

Microcrystalline cellulose

16.50

(Avicel® PH101 )

Sodium starch glycolate 4.40

Ferric oxide red 0.1 1

Polyvinyl pyrrol idone (PVP K-30) 1 .10

Water^* q.s Sodium starch glycolate 4.40

Magnesium stearate 0.90

Total weight 1 10

^* Evaporates during processing.

Manufacturing process:

1 . Glimepiride, lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (first quantity) and red iron oxide were sifted and mixed in a rapid mixer granulator.

2. PVP K30 was dissolved in water.

3. The mixture from step 1 was granulated with the binder of step 2 in the rapid mixer granulator.

4. The granules were dried and then sifted and optionally the dried granules were milled to obtain desired sizes.

5. The dried granules were blended with sodium starch glycolate (second quantity); then magnesium stearate was added and mixed.

Bilayer Tablets: Atorvastatin lubricated blend equivalent to atorvastatin calcium 20 mg and Glimepiride lubricated blend equivalent to glimepiride 4 mg were compressed in a bilayer compression machine using appropriate punches.

Monolithic tablets: Required quantity of Atorvastatin blend equivalent to atorvastatin calcium 20 mg and Glimepiride blend equivalent to glimepiride 4 mg were mixed and compressed in a compression machine using appropriate punches.

Bi-layer tablets and monolithic tablets of Example 2, containing 20 mg of atorvastatin and 4 mg of glimepiride, were subjected to a direct exposure study at 40°C for 4 weeks. The initial and stored samples were analyzed using HPLC for drug-related impurities of atorvastatin calcium.

Impurity analysis results are shown in the table-3 below. Values are percentages of the respective label drug content for the formulation.

Table-3: Impurity analysis data

Initial 40°C/4 Weeks Initial 40°C /4 Weeks (Direct Exposure) (Direct Exposure)

Atorvastatin Lactone Total impurities Bi-layer tablets 0.08 0.25 0.60 0.96

Monolithic tablets 0.10 0.53 0.75 1 .67

Results of direct exposure study show that after 4 weeks the chemical purity of atorvastatin calcium is inferior in monolithic tablets as compared to bi- layer tablets.

EXAMPLE 3: Bi-layer tablets containing atorvastatin calcium 20 mg and glimepiride.

Table-4: Composition of Atorvastatin Layer

Evaporates during processing.

Manufacturing process: Fluid bed granulation

2. Dissolved the atorvastatin calcium premix in methanol, added basic butylated methacrylate copolymer (previously sifted through appropriate mesh sieve), and stirred to obtain a clear solution.

3. Materials of step 1 were granulated in a fluid bed processor with the solution of step 2, and then the granules were dried at 40±5°C for 15 minutes to a loss on drying (LOD) of 3% w/w or less and sifted through appropriate mesh sieve.

Wet granulation

1 . Sodium lauryl sulphate was mixed with water to form a thick paste.

2. Atorvastatin calcium-BHA premix, sodium bicarbonate, lactose monohydrate and crospovidone were sifted through appropriate mesh sieve and mixed in a rapid mixer granulator.

4. The wet granules were dried at 60°C, until the LOD is below 3% w/w.

Extragranular

Lubrication

1 . Magnesium stearate was sifted through appropriate mesh sieve and mixed with the blend of granules and extragranular materials. Table-5: Composition of Glimepiride Layer

^* Evaporates during processing.

Manufacturing process:

2. PVP K30 was dissolved in water.

3. The mixture from step 1 was granulated with the binder from step 2 in the rapid mixer granulator.

5. The dried granules were blended with sodium starch glycolate (second quantity), and then magnesium stearate was added and mixed.

Tablets

1 . Bi-layer tablets were compressed using the atorvastatin layer composition and one of the glimepiride layer compositions to obtain a core tablet. Weight of a core tablet weight = 41 1 .5 mg (Atorvastatin layer = 301 .5 mg; Glimepiride layer = 1 10 mg)

2. The bi-layer tablets were coated using the following composition stated in table-6 to obtain coated tablets^*. Table-6: Coating composition

^*weight of coated tablet = 421 .8 mg *^* Evaporates during processing.

^*** Opadry® White OY58900 is a product of Colorcon containing hydroxypropyl methyl cellulose, PEG400 and titanium dioxide.

Packaging

The bi-layer tablets were packaged in HDPE bottles with closures together with Stabilox® as an oxygen adsorbent, or were packaged in aluminum foil blister packaging.

A dissolution study was conducted using the prepared tablets containing atorvastatin calcium 20 mg and glimepiride 1 mg, commercially available LIPITOR® 20 mg tablets, and commercially available AMARYL® 1 mg tablets. The study conditions were: 900 ml of phosphate buffer medium, pH 6.8 for atorvastatin dissolution and pH 7.8 for glimepiride dissolution; USP apparatus 2 (paddle) with 75 rpm stirring; and temperature 37°C. Results are shown in the tables-7 & 8.

Table-7: Comparative Dissolution profile for Atorvastatin

Table-8: Comparative Dissolution profile for Glimepiride

The results of the dissolution study show that the release of atorvastatin and glimepiride from the compositions of the present invention is comparable to LIPITOR® tablets and AMARYL® tablets respectively.

Tablets of Example-3 containing 1 mg of glimepiride were stored in closed HDPE bottles at 40°C and 75% RH for 6 months. The initial and stored samples were analyzed for drug polymorphic conversion using PXRD and for drug-related impurities using HPLC.

Tablets of Example-3 stored in aluminum foil blister packages also were stored at 40°C and 75% RH for 6 months. The initial and stored samples were analyzed to check polymorphic conversion of active agents if any using PXRD and for drug-related impurities using HPLC.

A placebo composition similar to the Example-3 formulation was prepared for use in the PXRD study. The placebo composition contains the same excipients, and lactose was used in place of the active ingredients.

Results of the PXRD study are shown in Figure 1 . The amorphous form of the atorvastatin calcium and the polymorphic form of glimepiride were retained in the formulation during storage and there was no evidence of polymorphic conversion. This demonstrates the polymorphic stability of the active ingredients used in the formulation.

Impurity analysis results are shown in the tables-9 & 10. Values are percentages of the respective label drug content for the formulation. Table-9: Impurity analysis for Atorvastatin

Table-10: Impurity analysis for Glimepiride

^* ND: Not detected.

A two-way crossover pharmacokinetic study was conducted involving administration of the bi-layer tablets of Example 3 (20 mg/1 mg of atorvastatin and glimepiride respectively) as a test product and the commercial products LIPITOR® 20 mg tablets and AMARYL® 1 mg tablets as reference products with 21 healthy human volunteers in the fasting state and plasma concentrations of the drug compounds were determined at desired intervals after dosing. Pharmacokinetic data obtained in the study is shown in the following tables-1 1 & 12.

Table-1 1 : Pharmacokinetic data for Atorvastatin

Pharmacokinetic data AUCo-t AUCo Cmax

LIPITOR® 20mg Tablets 57.32 60.91 5.61

(Reference product, R) ng.hr/ml ng.hr/ml ng.hr/ml Example-3 tablets 55.68 59.22 5.51

(Test product, T) ng.hr/ml ng.hr/ml ng.hr/ml

Ratio of Least square 99.14 99.18 94.24

means (T/R) %

90% confidence intervals (T/R) %

Lower limit 91 .44 91 .65 78.17

Upper limit 107.49 107.34 1 13.62

Table-12: Pharmacokinetic data for Glimepiride

Pharmacokinetic data AUCo-t AUCo Cmax

AMARYL® 1 mg Tablets 495.27 515.21 72.07

(Reference product, R) ng.hr/ml ng.hr/ml ng.hr/ml

Example-3 tablets 499 516.08 56.28

(Test product, T) ng.hr/ml ng.hr/ml ng.hr/ml

Ratio of Least square 99.59 99.23 80.08

means (T/R) %

90% confidence intervals (T/R) %

Lower limit 94.18 94.22 72.20

Upper limit 105.32 104.50 88.84

Based on the above study, it can be concluded that the formulation of example-3 containing atorvastatin and glimepiride are individually bio-equivalent to the commercially marketed LIPITOR® tablets and AMARYL® tablets respectively.

EXAMPLE 4: Bi-layer tablets containing atorvastatin calcium 20 mg and glimepiride 1 mg.

Atorvastatin Layer composition and manufacturing procedures were same as described in Example 3.

Table-13: Composition of Glimepiride Layer

Ingredient mg/tablet

Lactose monohydrate 79.49

Microcrystalline cellulose 16.50 Sodium starch glycolate 4.40

Colloidal silica anhydrous 1 .00

Iron oxide red 0.1 1

Glimepiride 1 .00

Polyvinylpyrrolidone (PVP K-30) 2.20

Water^* q.s.

Sodium starch glycolate 4.40

Magnesium stearate 0.90

Total weight 110.00

^* Evaporates during processing.

Manufacturing procedure of Glimepiride layer:

1 . Colloidal silica anhydrous, lactose monohydrate, microcrystalline cellulose, and sodium starch glycolate (first quantity) were sifted and mixed in a rapid mixer granulator.

2. PVP K30 was dissolved in water and then glimepiride was dispersed in the solution.

3. The mixture from step 1 was granulated with the suspension from step 2 in the rapid mixer granulator.

4. The granules were dried, then sifted and optionally milled to obtain the desired particle sizes.

5. Dried granules were blended with sodium starch glycolate (second quantity), and magnesium stearate was added and mixed.

Preparation of Tablets:

1 . The atorvastatin layer blend and the glimepiride layer blend were compressed into bi-layered tablets and the tablets were coated with a dispersion of coating materials in water.

2. Bi-layer tablets were coated using the following composition in table-14.

Table-14: Tablet coating composition

Ingredient mg/tablet

Opadry® White OY 58900^** 10.30

Dichloromethane^* q.s. Isopropyl alcohol^* q.s.

Water^* q.s.

Coated tablet weight 421.80

^* Evaporates during processing.

^** Opadry® White OY58900 is a product of Colorcon containing hydroxypropyl methyl cellulose, PEG400 and titanium dioxide.

The bilayer tablets were packaged in HDPE bottles with closures together with Stabilox® as an oxygen adsorbent, and also in blister packs and aluminium pouches.

A dissolution study was conducted using the prepared tablets, commercially available LIPITOR® 20 mg tablets, and commercially available AMARYL® 1 mg tablets. The study conditions were: 900 ml of phosphate buffer medium, pH 6.8 for atorvastatin dissolution and pH 7.8 for glimepiride dissolution; USP apparatus 2 (paddle) with 75 rpm stirring; and temperature 37°C. Results are shown in the following tables 15 and 16.

Table-15: Comparative Dissolution profile for Atorvastatin

Table-16: Comparative Dissolution profile for Glimepiride

The results of the dissolution study show that the release of atorvastatin and glimepiride from the compositions of the invention is comparable to LIPITOR® and AMARYL® respectively.

EXAMPLE 5: This provides a bi-layer tablet containing atorvastatin calcium 20 mg and glimepiride 1 mg. Atorvastatin Layer composition and manufacturing procedure was same as described in Example-3 except that instead of Atorvastatin calcium (BHA Premix), the Atorvastatin layer contains Amorphous Atorvastatin calcium only. The composition and manufacturing process of Glimepiride Layer was same as described in Example-4.

EXAMPLE 6: This provides a bi-layer tablet containing atorvastatin calcium 20 mg and glimepiride 1 mg. Atorvastatin Layer composition and manufacturing process was same as described in Example-3 except that instead of Atorvastatin calcium (BHA Premix), the Atorvastatin layer contains Atorvastatin calcium crystalline Form-VI or Form-VII described in U.S. Patent No. 7,074,818. The composition and manufacturing process of Glimepiride Layer was same as described in Example-4.

EXAMPLE 7: This provides a bi-layer tablet containing atorvastatin calcium 20 mg and glimepiride 1 mg. Atorvastatin Layer composition and manufacturing process was same as described in Example-3 except that instead of Atorvastatin calcium (BHA Premix), the Atorvastatin layer contains Atorvastatin calcium crystalline Form-I, II or IV described in U.S. Patent No. 5,969,156. The composition and manufacturing process of Glimepiride Layer was same as described in Example-4.

EXAMPLE 8: Tri-layer Tablet of Atorvastatin and Glimepiride

Table-17: Composition of Atorvastatin Layer

Layer 1 - Atorvastatin Layer Ingredients mg/tablet

Atorvastatin calcium (BHA Premix) 20.68

Basic butylated methacrylate copolymer 2.50

Lactose anhydrous 1 10.00

Microcrystalline cellulose 108.00

Methanol^* q.s.

Lactose monohydrate 39.00

Crospovidone 12.00

Sodium hydrogen carbonate 15.00

Sodium lauryl sulphate 12.00

Purified water^* q.s.

Hydroxy propyl cellulose 4.02

Magnesium stearate 4.00

Weight of Atorvastatin layer (mg) 327.20

Layer 2 - Inert Layer

Lactose Monohydrate 59.00

Microcrystalline cellulose 139.00

Magnesium stearate 2.00

Weight of Inert Layer (mg) 200.00

Layer 3 - Glimepiride Layer

Glimepiride 2.00

Lactose monohydrate 74.85

Microcrystalline cellulose 21 .04

Crospovidone 5.80

Colloidal silica anhydrous 2.00

Iron oxide red 0.1 1

Hydroxypropyl methylcellulose 1 .50

Purified water^* q.s.

Crospovidone 1 .80

Magnesium stearate 0.90

Weight of Glimepiride Layer (mg) 1 10.00

Total weight of tri-layer tablet 637.20

^*lost during processing Manufacturing process:

Preparation of Atorvastatin Granules:

Atorvastatin granules were prepared as per process described in Example-

3

(Atorvastatin Part)

Preparation of Inert layer:

1 ) Lactose monohydrate and microcrystalline cellulose were sifted through appropriate sieve.

2) Magnesium stearate was sifted through appropriate sieve.

3) The mixture of Step 1 and 2 were mixed in a double cone blender.

4) Step 3 blend was used as an Inert layer.

Preparation of Glimepiride Granules:

Glimepiride granules were prepared as per process described in Example 4 (Glimepiride Part), wherein Sodium starch glycolate was replaced by crospovidone, Povidone K30 was replaced by Hydroxypropyl methylcellulose. Also the amount of the active agent Glimepiride was increased by 1 mg and the same was compensated by reducing 1 mg of Lactose monohydrate.

Preparation of Tri-layer tablets:

The Atorvastatin layer blend, the Inert layer blend and the Glimepiride layer blend were compressed into tri-layer tablets. The tablets were coated with a coating dispersion of Example-4 and by using the process described in Example-4 hereinbefore

EXAMPLE 9: This provides a bi-layer tablet containing atorvastatin calcium 20 mg and glimepiride 1 mg. Atorvastatin Layer composition and manufacturing process was same as described in Example-3. The compositions of each of the Glimepiride layers having different compositions as described in A-H of Table-18 are combined with the Atorvastatin layer to obtain the bi-layer tablets with different compositions.

Table-18: Composition of Glimepiride Layer

mg/tablet

Ingredient A B C D E F G H Glimepiride 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00

Lactose monohydrate 75.85 75.80 75.80 79.49 81.50 78.00 75.00 81.77

Microcrystalline

cellulose 21.04 22.00 21.00 16.50 17.09 18.00 15.00 14.02

Sodium starch

glycolate - 5.80 3.00 4.40 3.80 5.00 -

Crospovidone 5.80 - - - - - 10.00 4.70

Colloidal silica

anhydrous 2.00 1.50 1.50 1.00 1.00 1.99 1.00 1.50

Iron oxide red 0.11 0.11 0.11 0.11 0.11 0.11 0.11 0.11

Polyvinylpyrrolidone

(PVP K-30) - - - 2.20 1.80 2.00 - - hydroxy propyl Methyl

cellulose 1.50 1.49 1.50 - - - 3.00 2.00

Water^* q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.

Sodium starch

glycolate - - - 4.40 2.80 3.00 -

Crospovidone 1.80 1.40 4.00 - - 3.99 5.00

Magnesium stearate 0.90 0.90 0.90 0.90 0.90 0.90 0.90 0.90

Total weight 110 110 108.8 110 110 110 110 110

The manufacturing process of Glimepiride Layers was same as described in Example-4 hereinbefore.

Claims

What is claimed is:

1 ) A layered tablet comprising (i) atorvastatin or pharmaceutically acceptable salts thereof, or atorvastatin or pharmaceutically acceptable salts thereof in the form of a premix, and at least one pharmaceutically acceptable excipient; (ii) glimepiride and at least one pharmaceutically acceptable excipient, wherein both atorvastatin and glimepiride are in immediate release form.

2) The layered tablet according to claim 1 , which is in the form of a tri-layer tablet or a bi-layer tablet.

3) The tri-layer tablet according to claim 2 comprising: (i) a first layer comprising atorvastatin or pharmaceutically acceptable salts thereof, or atorvastatin or pharmaceutically acceptable salts thereof in the form of a premix, and at least one pharmaceutically acceptable excipient; (ii) a second inert layer (iii) a third layer comprising glimepiride and at least one pharmaceutically acceptable excipient, wherein both atorvastatin and glimepiride are in immediate release form.

4) The bi-layer tablet according to claim 2 comprising: (i) a first layer comprising atorvastatin or pharmaceutically acceptable salts thereof, or atorvastatin or pharmaceutically acceptable salts thereof in the form of a premix, and at least one pharmaceutically acceptable excipient; (ii) a second layer comprising glimepiride and at least one pharmaceutically acceptable excipient, wherein both atorvastatin and glimepiride are in immediate release form.

5) The bi-layer tablet according to claim 2 comprising: (i) a first layer comprising atorvastatin or pharmaceutically acceptable salts thereof, or atorvastatin or pharmaceutically acceptable salts thereof in the form of a premix, and at least one pharmaceutically acceptable excipient; (ii) a second layer comprising glimepiride and at least one pharmaceutically acceptable excipient; wherein the said first layer is prepared by wet granulation and/or fluid bed granulation method and the said second layer is prepared by wet granulation method as given below:

i) Dry mixing of glimepiride and at least one pharmaceutically acceptable excipient;

ii) Preparation of granulating fluid containing a binder;

iii) Granulating step i) with step ii) and drying the wet granules to obtain the desired sizes; iv) Optionally milling of dried granules followed by mixing with at least one pharmaceutical excipient and lubricant.

6) The bi-layer tablet according to claim 2 comprising: (1 ) a first layer comprising atorvastatin or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient; (2) a second layer comprising glimepiride and at least one pharmaceutically acceptable excipient; wherein the said first layer is prepared by wet granulation and/or fluid bed granulation method and the said second layer is prepared by wet granulation method as given below: i) Dry mixing of glimepiride, disintegrant and optionally at least one pharmaceutically acceptable excipient;

ii) Preparation of granulating fluid containing a binder;

iii) Granulating step i) with step ii) and drying the wet granules to obtain the desired sizes;

iv) Optionally milling of dried granules followed by mixing with disintegrant and optionally at least one pharmaceutical excipient and lubricant.

7) The bi-layer tablet according to claim 2 comprising: (1 ) a first layer comprising atorvastatin or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient; (2) a second layer comprising glimepiride and at least one pharmaceutically acceptable excipient; wherein the said first layer is prepared by wet granulation and/or fluid bed granulation method and the said second layer is prepared by wet granulation method as given below: i) Dry mixing of at least one pharmaceutically acceptable excipient;

ii) Preparation of granulating fluid containing glimepiride and a binder;

iii) Granulating step i) with step ii) and drying the wet granules

iv) Optionally milling of dried granules followed by mixing with at least one pharmaceutical excipient and lubricant.

8) A bi-layer tablet comprising: (i) a first layer comprising atorvastatin or pharmaceutically acceptable salts thereof, or atorvastatin or pharmaceutically acceptable salts thereof in the form of a premix, and at least one pharmaceutically acceptable excipient; (ii) a second layer comprising glimepiride and at least one pharmaceutically acceptable excipient; wherein the release of atorvastatin or its pharmaceutically acceptable salt is not less than about 80% in 30 minutes, when tested in USP type 2 (paddle) apparatus with 900 ml of 0.05 M phosphate buffer (pH 6.8) as the dissolution medium at 37°C, at 75 rpm paddle speed and the release of glimepiride is not less than about 80% in 60 minutes, when tested in USP type 2 (paddle) apparatus with 900 ml of 0.05 M phosphate buffer (pH 6.8) as the dissolution medium at 37°C, at 75 rpm paddle speed.

9) The bi-layer tablet according to claim 8 comprising: (i) first layer comprising about 2 to 8% w/w atorvastatin or pharmaceutically acceptable salts thereof, about 0.5 to 2% w/w binder, about 1 to 5% w/w alkalizing agent, about 0.1 to 1 .5% w/w acid solubilizing agent, about 70 to 85% w/w diluent, about 1 to 5% w/w surfactant and about 0.5 to 1 % w/w lubricant by weight of first layer; and ii) second layer comprising about 0.5 to 4% w/w glimepiride, about 80 to 95% w/w diluent, about 5 to 10% w/w disintegrant, about 0.5 to 2% w/w binder and about 0.5 to 1 % w/w lubricant by weight of second layer.

10) The layered tablet according to any of the preceding claims 1 -9 comprising (i) atorvastatin or pharmaceutically acceptable salts thereof, or atorvastatin or pharmaceutically acceptable salts thereof in the form of a premix, and at least one pharmaceutically acceptable excipient; (ii) glimepiride and at least one pharmaceutically acceptable excipient, wherein atorvastatin and glimepiride are contained in the following amounts of atorvastatin/glimepiride: 20 mg/1 mg; 20 mg/2 mg; 20 mg/3 mg; 20 mg/4 mg; 10 mg/1 mg; 10 mg/2 mg; 10 mg/3 mg; and 10 mg/4 mg.

1 1 ) The layered tablet according to any of the preceding claims 1 -10 comprising a coating.

12) The layered tablet according to any of the preceding claims 1 -1 1 comprising (i) atorvastatin or pharmaceutically acceptable salts thereof, or atorvastatin or pharmaceutically acceptable salts thereof in the form of a premix, and at least one pharmaceutically acceptable excipient; (ii) glimepiride and at least one pharmaceutically acceptable excipient, wherein the chemical stability and/or polymorphic stability of atorvastatin or its pharmaceutically acceptable salt is maintained during storage at 40°C and 75% RH for 3 months, or for 6 months.

13) The layered tablet according to any of the preceding claims 1 -1 1 comprising (i) atorvastatin or pharmaceutically acceptable salts thereof, or atorvastatin or pharmaceutically acceptable salts thereof in the form of a premix, and at least one pharmaceutically acceptable excipient; (ii) glimepiride and at least one pharmaceutically acceptable excipient, wherein the said formulation contains any one or more of the atorvastatin-related substances atorvastatin lactone, lactam impurity, and hydroxy expoxy oxazinine impurity each in amounts less than about 5%, and their total in amounts less than about 8% during storage at 40°C and 75% RH for 3 months or at 30°C and 65% RH for 6 months or at 25°C and 60% RH for 12 months.

14) The bi-layer tablet according to claim 13 comprising (i) a first layer of atorvastatin or pharmaceutically acceptable salts thereof, or atorvastatin or pharmaceutically acceptable salts thereof in the form of a premix, and at least one pharmaceutically acceptable excipient; (ii) a second layer of glimepiride and at least one pharmaceutically acceptable excipient, wherein the said formulation contains any one or more of the atorvastatin-related substances atorvastatin lactone, lactam impurity, and hydroxy expoxy oxazinine impurity each in amounts less than about 5%, and their total in amounts less than about 8% during storage at 40°C and 75% RH for 3 months or at 30°C and 65% RH for 6 months or at 25°C and 60% RH for 12 months.

15) The layered tablet according to any of the preceding claims 1 -1 1 comprising (i) atorvastatin or pharmaceutically acceptable salts thereof, or atorvastatin or pharmaceutically acceptable salts thereof in the form of a premix, and at least one pharmaceutically acceptable excipient; (ii) glimepiride and at least one pharmaceutically acceptable excipient, wherein the said composition contains the glimepiride related substances Impurity A, Impurity B, and Impurity D each in amounts less than about 5%, and their total in amounts less than about 8% during storage at 40°C and 75% RH for 3 months or at 30°C and 65% RH for 6 months or at 25°C and 60% RH for 12 months.

16) The bi-layer tablet according to claim 15 comprising (i) a first layer of atorvastatin or pharmaceutically acceptable salts thereof, or atorvastatin or pharmaceutically acceptable salts thereof in the form of a premix, and at least one pharmaceutically acceptable excipient; (ii) a second layer of glimepiride and at least one pharmaceutically acceptable excipient, wherein the said composition contains the glimepiride related substances Impurity A, Impurity B, and Impurity D each in amounts less than about 5%, and their total in amounts less than about 8% during storage at 40°C and 75% RH for 3 months or at 30°C and 65% RH for 6 months or at 25°C and 60% RH for 12 months.

17) The layered tablet according to any of the preceding claims 1 -16 comprising (i) atorvastatin or pharmaceutically acceptable salts thereof and at least one pharnnaceutically acceptable excipient; (ii) glimepiride and at least one pharnnaceutically acceptable excipient, wherein the pharnnaceutically acceptable excipient include one or more of diluents, binders, stabilizers, lubricants, glidants, disintegrating agents, anti-oxidants, alkalizing agents, surfactants, film coating materials, plasticizers, pigments, opacifiers and coloring agents.

18) The layered tablet according to claim 17 comprising (i) atorvastatin or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient; (ii) glimepiride and at least one pharmaceutically acceptable excipient, wherein the said formulation comprises a binder selected from a group comprising carboxymethylcelluloses, hydroxyethylcelluloses, dextrin, gelatin, maltodextrin, polyethylene oxides, sodium alginate, hydroxypropylcelluloses, hydroxypropyl methylcelluloses, polyvinylpyrrolidones, povidone, powdered acacia, gelatin, guar gum, carbomers, methylcelluloses, polymethacrylates, starches and mixtures thereof.

19) The layered tablet according to any of the preceding claims 1 -18 comprising (i) atorvastatin or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient; (ii) glimepiride and at least one pharmaceutically acceptable excipient, wherein the said composition comprises a disintegrant selected from the group comprising carmellose calcium, carboxymethylstarch sodium, croscarmellose sodium, crospovidones, low- substituted hydroxypropylcelluloses, sodium starch glycolate, colloidal silicon dioxide, starches, and mixtures thereof.

20) The layered tablet according to any of the preceding claims 1 -19 comprising (i) atorvastatin or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient; (ii) glimepiride and at least one pharmaceutically acceptable excipient, wherein the said formulation comprises alkanizing agent which include one or more of alkaline earth metal salts, alkali metal salts and organic alkalizing agents.

21 ) The layered tablet according to any of the preceding claims 1 -20 comprising (i) atorvastatin or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient; (ii) glimepiride and at least one pharmaceutically acceptable excipient, wherein the said formulation comprises antioxidants selected from the group comprising sodium sulfite, sodium ascorbate, butylated hydroxyanisole, butylated hydroxytoluene, tocopherol, citric acid, malic acid, ascorbic acid, and any mixtures thereof.

22) The layered tablet according to any of the preceding claims 1 -21 comprising (i) atorvastatin or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient; (ii) glimepiride and at least one pharmaceutically acceptable excipient, wherein the said formulation contains one or more wetting agents selected from the group comprising sodium lauryl sulfate, cetrimide, polysorbates, poloxamers, sodium carboxymethylcelluloses, hydrogenated oils, polyoxyethylene glycols, polyoxypropylene glycols, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyglycolized glycerides, Vitamin E TGPS, and mixtures thereof.

23) The layered tablet according to any of the preceding claims 1 -22 comprising (i) atorvastatin or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient; (ii) glimepiride and at least one pharmaceutically acceptable excipient, wherein the said tablet formulation is highly stable chemically and also exhibit appreciable physical and polymorphic stability during the preparation of the formulations and also during their shelf-life.

24) A method of using the pharmaceutical formulations comprising atorvastatin or pharmaceutically acceptable salts thereof, or atorvastatin or pharmaceutically acceptable salts thereof in the form of a premix, and glimepiride according to any of the preceding claims 1 -23 for the treatment of elevated blood glucose in type II diabetes mellitus associated with dyslipidaemia.