FIELD OF INVENTION

The present invention relates to oral solid dosage forms comprising a combination of ezetimibe and HMG-CoA reductase inhibitor.

Particularly, the present invention relates to oral solid dosage forms comprising a combination of ezetimibe and HMG-CoA reductase inhibitor, in the form of inlay-tablet or compression-coated tablet.

BACKGROUND OF THE INVENTION

Ezetimibe, chemically, (3R, 4S)-l-(4-fluorophenyl)-3-[3(S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-2-azetidinone; is a cholesterol absorption inhibitor. The therapeutic uses of ezetunibe and related compounds, and their preparations were disclosed in U.S. Patent No. 5,767,115.

Ezetimibe is commercially available as 10 mg tablets. It is sold m the U.S. under the brand name ZETIA™.

Simvastatin, chemically, 2,2-dimethylbutarioic acid (lS,3R,7S,8S,8aR)-l ,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-[(2R,4R)-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-l-naphthalenyl ester; is a HMG-CoA reductase inhibitor. The therapeutic uses of simvastatin and related compoimds, and their preparations were disclosed in U.S. Patent No, 4,444,784.

Simvastatin is commercially available as 5 mg, 10 mg, 20 mg, 40 mg and 80 mg tablets. It is sold in the U.S. under the brand name ZOCOR™.

A combination of ezetimibe and simvastatin is presently marketed in the U.S. under the trade name VYTORINTM; in order to provide improved medication in the treatment and/or prevention of atherosclerosis and related conditions.

The marketed VYTORINTM tablet is a monolithic tablet dosage form.

The present inventors hereby disclose solid oral dosage forms comprising a combination of ezetimibe and HMG-CoA reductase inhibitor in the form of inlay-tablet or compression-coated tablet.

SUMMARY AND OBJECTIVES OF THE INVENTION

The present invention relates to oral solid dosage form comprising a combination of ezetimibe and HMG-CoA reductase inhibitor.

Particularly, the present invention relates to an oral solid dosage form comprising a combination of ezetimibe and HMG-CoA reductase inhibitor, in the form of inlay-tablet or compression-coated tablet.

In an embodiment of the invention, there is provided an oral solid dosage form comprising a combination of ezetimibe and HMG-CoA reductase inhibitor.

In an embodiment of the invention, there is provided an oral solid dosage form comprising a combination of ezetimibe and HMG-CoA reductase inhibitor in the form of tablet prepared by compression-coating technique.

In an another embodiment of the invention, there is provided an oral solid dosage form comprising a combination of ezetimibe and HMG-CoA reductase inhibitor in the form of inlay-tablet.

In an another embodiment of the invention, there is provided an oral solid dosage form comprising a combination of ezetimibe and HMG-CoA reductase inhibitor in the form of inlay-tablet or compression-coated tablet, wherein ezetimibe is present as the core tablet while HMG-CoA reductase inhibitor is present as an external layer.

In an another embodiment of the invention, there is provided an oral solid dosage form comprising a combination of ezetimibe and HMG-CoA reductase inhibitor in the form of inlay-tablet or compression-coated tablet, wherein HMG-CoA reductase is present as the core tablet while ezetimibe is present as an external layer.
In a further embodiment of the invention, there is provided a process of preparing an inlay-tablet comprising a combination of ezetimibe and HMG-CoA reductase inhibitor.

In a further embodiment of the invention, there is provided a process of preparing a compression-coated tablet comprising a combination of ezetimibe and HMG-CoA reductase inhibitor.

In a further embodiment of the invention, there is provided for the oral solid pharmaceutical composition comprising a combination of ezetimibe and simvastatin in the form of inlay-tablet or compression-coated tablet, wherein the in-vitro dissolution release profile matches with the commercially available VYTORIN ™.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to oral solid dosage form comprising a combination of ezetimibe and HMG-CoA reductase inhibitor.

Particularly, the present invention relates to oral solid dosage form comprising a combination of ezetimibe and HMG-CoA reductase inhibitor, m the form of inlay-tablet or compression-coated tablet.

In context of the present invention, the terms like "active" or "active ingredient" or "drug" or "drug substance" or "pharmacologically active agent" or "active substance" may be used interchangeably and synonymously for ezetimibe or HMG-CoA reductase inhibitors or both.

The term "HMG-CoA reductase inhibitors" as used herein refers to include the family of statins. Examples of statins include fluvastatin, cerivasatm, mevastatin,pitavastatin, pravastatin,simvastatin, lovastatin, atorvastain, rosuvastatin, as well as any others which may be known in the art (including all pharmaceutically acceptable salts of any of the foregoing). Any of the foregoing, either alone or in combination, can function as the HMG-CoA reductase inhibitor component of the combination drug of the invention. Simvastatin and atorvastatin are mostly preferred.

Apart from HMG-CoA reductase inhibitors; in an embodiment of the present invention there is also provided other active agents/medicaments used in the treatment and/or prevention of atherosclerosis and related conditions, to be used in combination with ezetimibe. Such active agents/medicaments are selected from fenofibrate, niacin, gemfibrozil, etofibrate, orlistat, colestipol, cholestyramine and the likes.

The term "core" as used herein refers to a component that is at least partially or fully surrounded or covered by another component.

The term "inlay-tablet" as used herein refers to a tablet that comprises at least an inlay core and an outer layer.

According to the invention, the two components are usually "adjacent" which implies that the two components (core and the outer layer) are in physical proximity with each other. Preferably, the two components are in direct contact at least at one point.

The term "compression-coating" as used herein refers to the technique of preparing a tablet dosage form, wherein a tablet is inlayed within an another tablet or it also refers to a solid core comprising the active ingredient, which solid core is substantially covered with a compression coating. It may be used interchangeably and synonymously for "press-coated", "inlay-tablet", '*tablet-m-tablet" and the like.

The core, usually in the form of a tablet comprises an active ingredient and any other pharmaceutically acceptable carriers or excipients. The excipients or carriers are selected from the group comprising fillers/ diluents, stabilizers, antioxidants, buffers, pH modifiers, disintegrants, lubricants, glidants, colorants and other customary ingredients well known in the art. It may farther include other components which are necessary to meet appropriate drug release characteristic and/or for manufacturing purposes, such as binders, surfactants, wetting agents and the likes.

The outer layer surrounding partially or fully the core comprises an active ingredient and any other pharmaceutically acceptable carriers or excipients. The excipients or carriers are selected from the group comprising diluents/ fillers, binders, stabilizers, anti-oxidants, buffers, pH modifiers, disintegrants, lubricants, glidants, colorants and other customary ingredients well known in the art. It may further include other components which are necessary to meet appropriate drug release characteristic and/or for manufacturing purposes, such as surfactants, wetting agents, flavorants and the likes.

Diluents/ Fillers are selected from the group comprising microcrystalline cellulose (MCC), silicified MCC, lactose, starch, pre-gelatinized starch, mannitol, sorbitol, dextrates, dextrin, calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide and the like.

Binders are selected from the group comprising polyvinylpyrrolidone, cellulose derivatives such as hydroxyl propyl cellulose, hydroxyl propyl methyl cellulose, carboxy methyl cellulose sodium, starch and the likes.

Suitable disintegrants include sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose, starch, calcium carboxymethlycellulose, croscarmeliose sodium and the like.

Suitable lubricants include magnesium stearate, sodium stearate, calcium stearate, sodium stearyl fumarate, talc or silica and the like.

Stabilizers may be selected from the group comprising butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate, ascorbic acid, citric acid, edetate disodium and calcium metabisulphite, propyl gallate and combinations thereof.

A preferred embodiment of the present invention relates to a compression-coated tablet comprising a core tablet containing an effective amount of ezetimibe and compression-coat comprising HMG-CoA reductase inhibitor surrounded over the core tablet.

Another preferred embodiment of the present invention relates to an inlay-tablet comprising a core tablet containing an effective amount of ezetimibe and an outer layer of HMG-CoA reductase inhibitor partially covering the core tablet.

To form the tablet core, granulation techniques such as dry granulation or wet granulation is employed. In the dry granulation, the ingredients are blended in dry form, made denser by slugging or compaction and reduced to granules by grinding or milling, using suitable equipments. The ground particles or granules are then compressed into tablet form in conventional manner using lubricants, glidants, etc., which can take any of the conventional shapes, e.g., round, elongated, oval, etc.

The outer layer may be applied to the core by technique involving compressing-coating. The result is a layer of coating material comprising HMG-CoA reductase inhibitor or ezetimibe around the core tablet. Since the coating is compressed around the core in a manner similar to that used to make a tablet, specialized tableting machinery is employed to compress the external coating over the core.

Depending on the principles of the compression-coating machinery, the core can be made in one tablet forming machine and then transferred to another tableting machine for application of the coat. The core may also be transferred to a compression-coating machine for the compression coating process. Alternatively the core can be made on one side of the machine, and instantaneously transferred to the other side of the machine for the application of compression coating. An example of this type of machinery is the Manesty DryCota tableting machine from Casburt Limited.

The following examples illustrate specific aspects and embodiments of the invention and demonstrate the practice and advantages thereof. It is to be understood that the examples are given by way of illustration only and are not intended to limit the scope of the invention in any manner.

Brief Manufacturing Process:

Simvastatin layer:

1. Granulate sifted simvastatin, lactose monohydrate, croscarmellose sodium, hypromellose, citric acid, ascorbic acid with BHA solutions until desired consistency of wet mass is achieved.

2. Dry the wet mass of step no, 1 and mill to get suitable granules.

3. Lubricate the granules of step no. 2 with magnesium stearate' for 5 minutes in a blender.

Ezetimibe Core:

1. Granulate sifted ezetimibe, lactose monohydrate, croscarmellose sodium, hypromellose, citric acid, with SLS solutions until desired consistency of wet mass is achieved.

2. Dry the wet mass of step no. 1 and mill to get suitable granules.

3. Lubricate the granules of step no. 2 with magnesium stearate for 5 minutes in a blender.

4. Compress the lubricated blend to tablets using suitable punches.

5. Compress the ezetimibe tablets along with simvastatin blend into mlay-tablets.

Brief Martufacturing Process: Simvastatin layer:

1. Granulate sifted Simvastatin, lactose monohydrate, croscarmellose sodium, hypromellose, citric acid, ascorbic acid with BHA solutions until desired consistency of wet mass is achieved.

2. Dry the wet mass of step no. 1 and mill to get suitable granules.

3. Lubricate the granules of step 2 with magnesium stearate for 5 minutes in a blender.

Ezetimibe Core:

1. Granulate sifted ezetimibe, lactose monohydrate, croscarmellose sodium, hypromellose, citric acid, with SLS solutions until desired consistency of wet mass is achieved.

2. Dry the wet mass of step no. 1 and mill to get suitable granules.

3. Lubricate the granules of step no. 2 with magnesium stearate for 5 minutes in a blender.

4. Compress the lubricated blend to tablets using suitable punches.

5. Compress the ezetimibe tablets along with simvastatin blend into inlay-tablets.

Brief Manufacturing Process: Simvastatin layer:

1. Granulate sifted simvastatin, lactose monohydrate, croscarmellose sodium, hypromellose, citric acid, ascorbic acid with BHA solutions until desired consistency of wet mass is achieved.

2. Dry the wet mass of step no. 1 and mill to get suitable granules.

3. Lubricate the granules of step no. 2 with magnesium stearate for 5 minutes in a blender.

Ezetimibe Core:

1. Granulate sifted ezetimibe, lactose monohydrate, croscarmellose sodium, hypromellose, citric acid, with SLS solutions until desired consistency of wet mass is achieved.

2. Dry the wet mass of step no. 1 and mill to get suitable granules.

3. Lubricate the granules of step no. 2 with magnesium stearate for 5 minutes in a blender.

4. Compress the lubricated blend into tablets.

5. Ezetimibe tablets are collected into suitable hopper and the tablets are transferred into compression machine turret followed by the blend of simvastatin where the ezetimibe tablets are surrounded by the simvastatin blend to form a tablet in tablet dosage form.

Brief Manufacturing Process: Atorvastatin layer:

1. Granulate sifted atorvastatin calcium, lactose monohydrate, croscarmellose sodium, hypromellose, starch-1500; light calcium carbonate with BHA solutions until desired consistency of wet mass is achieved.

2. Dry the wet mass of step no. 1 and mill to get suitable granules.

3. Lubricate the granules of step no. 2 with magnesium stearate for 5 minutes in a blender.

Ezetimibe Core:

1. Granulate sifted ezetimibe, lactose monohydrate, croscarmellose sodium, hypromellose, ascorbic acid, and citric acid with SLS solutions until desired consistency of wet mass is achieved.

2. Dry the wet mass of step no. 1 and mill to get suitable granules.

3. Lubricate the granules of step 2 with magnesium stearate for 5 minutes in a blender.

4. Compress the lubricated blend into inlay-tablets using suitable punches.

Brief Manufacturing Process: Fenofibrate layer:

1. Melt granulate sifted fenofibrate, povidone, soya lecithin to form granules.

2. Add lactose, hypromellose, croscarmellose sodium, microcrystalline cellulose and blend the granules.

3. Lubricate the granules of step no. 2 with magnesium stearate for 5 minutes in a blender.

Ezetimibe Core:

1. Granulate sifted ezetunibe, lactose monohydrate, croscarmellose sodium, hypromellose, ascorbic acid, and citric acid with SLS solutions until desired consistency of wet mass is achieved.

2. Dry the wet mass of step no. 1 and mill to get suitable granules.

3. Lubricate the granules of step no. 2 with magnesium stearate for 5 minutes
in a blender.

4. Compress the lubricated blend into inlay-tablets using suitable punches.

Brief manufacturing process:

Rosuvastatin layer:

1. Granulate sifted Rosuvastatin, lactose monohydrate, croscarmellose sodium, hypromellose, povidone, starch with isopropyl alcohol and water mixed solutions until desired consistency of wet mass is achieved.

2. Dry the wet mass of step no. 1 and mill to get suitable granules.

3. Lubricate the granules of step 2 with magnesium stearate for 5 minutes in a blender.
£zetimibe Core:

1. Granulate sifted ezetimibe, lactose monohydrate, croscarmellose sodium, hypromellose, citric acid, with SLS solutions until desired consistency of wet mass is achieved.

2. Dry the wet mass of step no. 1 and mill to get suitable granules.

3. Lubricate the granules of step no. 2 with magnesium stearate for 5 minutes in a blender.

4. Compress the lubricated blend into inlay-tablets using suitable punches.

Physical Parameters of the Inlay-tablets:

Tablets prepared accordmg to Example 1 had the following physical parameters:

Dissolution Studies:

The inlay-tablets/ compression coated tablets according to the invention were studied for drug release m the given following dissolution conditions and were compared with that of the commercially available Vytorin 10/80 mg tablets; which is tabulated below:

Dissolution Media: pH 7.0 phosphate buffer with 0.5% Sodium Lauryl Sulphate

Dissolution Media Volume: 900 mL

Dissolution Apparatus: USP Apparatus II [Paddle]

Paddle Rotation Speed: 50 rpm

CLAIM:

1. A compression-coated tablet comprising an effective amount of cholesterol absorption inhibitor and an effective amount of HMG-CoA reductase inhibitor and one or more pharmaceutically acceptable excipient.

2. An inlay-tablet comprising an effective amount of cholesterol absorption inhibitor and an effective amount of HMG-CoA reductase inhibitor and one or more pharmaceutically acceptable excipient.

3. A pharmaceutical composition in the form of compression-coated tablet comprising a core containing an effective amount of cholesterol absorption inhibitor and a pharmaceutically acceptable excipient, coated with a compression coating containing an effective amount of HMG-CoA reductase inhibitor and a pharmaceutically acceptable excipient.

4. A pharmaceutical composition in the form of compression-coated tablet comprising a core containing an effective amount of HMG-CoA reductase inhibitor and a pharmaceutically acceptable excipient, coated with a compression coating containing an effective amount of cholesterol absorption inhibitor and a pharmaceutically acceptable excipient.

5. A pharmaceutical composition in the form of inlay-tablet comprising a core containing an effective amount of cholesterol absorption inhibitor and a pharmaceutically acceptable excipient, partially coated with a compression coating containing an effective amount of HMG-CoA reductase inhibitor and a pharmaceutically acceptable excipient.

6. A pharmaceutical composition in the form of inlay-tablet comprising a core containing an effective amount of HMG-CoA reductase inhibitor and a pharmaceutically acceptable excipient, partially coated with a compression coating containing an effective amount of cholesterol absorption inhibitor and a pharmaceutically acceptable excipient.

7. The tablet according to any of the preceding claims, wherein said cholesterol absorption inhibitor is ezetimibe.

8. The tablet according to any of the preceding claims, wherein said HMG-CoA reductase inhibitor is a statin.

9. The tablet according to claim 8, wherein said statin is selected from the group consisting of simvastatin, lovastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin and pitavastatin.

10. A compression-coated tablet comprising ezetimibe and simvastatin, as herein disclosed and exemplified.