WO2013166114A1

WO2013166114A1 - Oral tablet formulation consisting of fixed combination of atorvastatin and ezetimibe

Info

Publication number: WO2013166114A1
Application number: PCT/US2013/039012
Authority: WO
Inventors: Marie Charmaine DIAS
Original assignee: Althera Life Sciences, Llc
Priority date: 2012-05-01
Filing date: 2013-05-01
Publication date: 2013-11-07

Abstract

The present invention is an orally consumed fixed combination formulation of both atorvastatin and ezetimibe in one tablet that is expected to have same Area Under Curve as two active ingredients taken together individually orally, and pharmaceutically acceptable additives suitable for the preparation. In preferred embodiments of this invention, the atorvastatin is in the form of atorvastatin calcium and the pharmaceutically acceptable additives are selected from the diluents, disintegrants, glidants, lubricants, colorants and combinations thereof.

Description

ORAL TABLET FORMULATION CONSISTING OF FIXED COMBINATION OF

ATORVASTATIN AND EZETIMIBE

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application Serial No.

61/641,012, filed on May 1, 2012. The entire teachings of the above application are incorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of invention

The present invention is directed to solid dosage formulations containing a combination of atorvastatin and ezetimibe, as well as to methods of making such solid dosage forms and method of treating patients with fixed combination solid dosage forms of atorvastatin and ezetimibe.

2. Related background Art

Cardiovascular disease is one of the largest causes of death in the US, Europe, and also developing nations such as Brazil, Mexico, Russia, China, Turkey and India.

Throughout the WHO European Region, cardiovascular disease is estimated to account for more than 5 million deaths as well as almost one-quarter of the region's disease burden; WHO estimates 8.7% of the total disease burden in Europe is due to high blood cholesterol, and presence of high levels of Low Density lipids (LDL). Atorvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA reductase inhibitor) that works by inhibiting the enzyme HMG CoA reductase; HMG CoA is one of the key regulators of cholesterol synthesis in the liver and blockade of the enzyme leads to substantial reduction in total cholesterol (TC), low density lipoprotein cholesterol (LDL- C) and very low density lipoprotein cholesterol (VLDL-C). Ezetimibe is a compound that also reduces TC and LDL-C but by a different mechanism as it binds cholesterol in the intestine, thereby reducing intestinal absorption of cholesterol. The atorvastatin and ezetimibe molecules may be selected from any of those disclosed in U.S. Pat. Nos. US 5,273,995; 5,969, 156; 6, 126,971 ; 5,686,104; 5,688,990; 5,656,624; 5,624,920;

5,698,548; 5,627, 176; 5,633,246; 5,688,785; 5,688,787; 5,744,467; 5,756,470; 5,767,1 15 which are incorporated herein by reference. It has been seen in clinical studies that the patients treated with both atorvastatin and ezetimibe achieve higher levels of LDL reduction compared to individual therapy of atorvastatin or ezetimibe alone. Hence there is significant value in a fixed combination of atorvastatin and ezetimibe if such a formulation can be shown as the same Area Under Curve (AUC) as each of the two components taken together, which is demonstrated in bioequivalence (BE) studies. As used herein, "fixed-combination" refers to a combination of two drugs or active ingredients presented in a single dosage unit such as tablet or a capsule; further as used herein, "free-combination" refers to a combination of two drugs or active ingredients dosed simultaneously but as two dosage units. Such a fixed combination in comparison to individual consumption of the two active ingredients will improve ease of administration, create convenience for the patients that need both the individual drugs and improves compliance in patients who cannot be controlled on either product alone. This formulation, when used will increase the compliance in reduction of LDL and thereby reduce the cardiovascular risk of patients consuming this formulation compared to the monotherapy consumption of either atorvastatin or ezetimibe alone.

Accordingly, a fixed combination solid dosage formulation of atorvastatin and ezetimibe that is bioequivalent to corresponding free-combination would be desirable.

SUMMARY OF THE INVENTION

In a first aspect, the present invention is an orally consumed fixed combination formulation of both atorvastatin and ezetimibe in one tablet that is expected to have same Area Under Curve as two active ingredients taken together individually orally, and pharmaceutically acceptable additives suitable for the preparation. In preferred embodiments of this invention, the atorvastatin is in the form of atorvastatin calcium and the pharmaceutically acceptable additives are selected from the diluents, disintegrants, glidants, lubricants, colorants and combinations thereof.

In the preferred embodiments of this invention, the solid dosage form is a bi-layer tablet. The amount of atorvastatin employed in such bi-layer tablets preferably ranges from 0.5 mg, such as 2.5mg, to 40mg, including 5mg, lOmg and 20mg. The amount of ezetimibe ranges from 5mg to 20mg, preferably lOmg.

In a second aspect, the present invention leads to creation of a novel formulation that overcomes significant problems encountered during the formulation of combining atorvastatin and ezetimibe in an oral solid dosage form due to inherent characteristics of atorvastatin and ezetimibe enumerated as follows: (a) Atorvastatin calcium is prone to oxidative and moisture mediated degradation both leading to formation of a lactone impurity. This reaction can be arrested in presence of basic milieu, (b) Ezetimibe is practically insoluble in water. While cellulose is the normal excipient that would be used for formulations with atorvastatin, there is a significant interaction of microcrystalline cellulose with ezetimibe, which makes use of such excipient difficult. Microcrystalline cellulose was found to bind with ezetimibe thereby retarding the drug release from the formulation, which would make it not bioequivalent to individually consumed ezetimibe. (c) While atorvastatin is more stable in near neutral to alkaline pH, the same is detrimental to ezetimibe. Hence it is important to separate the two individual molecules, which creates a significant product development challenge, (d) Solubility issues of ezetimibe raise the challenge of creating a formulation that achieves the right level of in-vitro dissolution as well as is bioequivalent in a combination form to the individual ezetimibe consumption.

Considering above challenges, the invention describes a novel approach which separates the two active ingredients - atorvastatin and ezetimibe in two almost completely separate parts, uses microcrystalline cellulose for the formulation of atorvastatin, but keeps it separate from ezetimibe and follows a unique process of dissolving ezetimibe and mounting it on lactose to enhance the solubility of ezetimibe when used in combination with atorvastatin to create a formulation that is bioequivalent and has similar Cmax and area under curve as two individual tablets of atorvastatin and ezetimibe consumed together. This approach then creates a bi-layer tablet, which has one solid layer of ezetimibe composition and a solid layer of atorvastatin. This formulation then overcomes the above significant development challenges and enables a fixed combination formulation that has simultaneously: a) similar dissolution profile to individual active ingredients, which leads to bioequivalence of the two individual active ingredients compared to consumption of two separate tablets of atorvastatin and ezetimibe, b) A stable formulation despite the incompatibilities of two component molecules - atorvastatin and ezetimibe, and c) enables the benefit of reducing the cholesterol levels in patients and reducing the cardiovascular risk in patients compared to monotherapies.

In a third aspect, the present invention is directed to a method of making a solid dosage bi-layer form of atorvastatin and ezetimibe comprising the steps of: (a) Blending atorvastatin calcium with calcium carbonate, microcrystalline cellulose, croscarmellose sodium and lactose with a lubricant such as magnesium stearate to create the atorvastatin layer blend, (b) Mixing ezetimibe with a wetting agent such as Sodium Lauryl Sulphate, and disperse material in sufficient quantity of Iso propyl alcohol and dicholoromethane mixture, (c) Absorbing the dispersion on lactose, and mix thoroughly, (d) Air drying the dispersion, passing through sieve, mix with croscarmellose sodium, and blend (e) Granulating the mix with Polyvinylpyrolidone solution and dry to obtain the ezetimibe granules, (f) Creating the desired bi-layer tablet by compressing the two distinctly different set of granules as desired in the second aspect of the invention in a bi-layer compression machine, followed by film coating the oral dosage form.

In a fourth aspect, this invention is directed to solid dosage forms of atorvastatin and ezetimibe made according to the method of the third aspect.

A fifth aspect of this invention is directed to a method of treating hyperlipidemia, cardiovascular diseases, congestive heart failure, myocardial infarction, atherosclerosis comprising administering a solid dosage form of atorvastatin and ezetimibe in combination to a patient in need of such a treatment. In a preferred embodiment, the solid dosage form is orally administered to the subject.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to solid dosage formulations containing a

combination of atorvastatin and ezetimibe, as well as to methods of making such solid dosage forms and method of treating patients with fixed combination solid dosage forms of atorvastatin and ezetimibe.

The first embodiment of the invention is a fixed combination orally consumed formulation of both atorvastatin and ezetimibe in one tablet that is expected to have same Area Under Curve as two active ingredients taken together individually orally, and pharmaceutically acceptable additives suitable for the preparation. In preferred embodiments of this invention, the atorvastatin is in the form of atorvastatin calcium and the pharmaceutically acceptable additives are selected from the diluents, disintegrants, glidants, lubricants, colorants and combinations thereof. The preferred solid dosage form is a bi-layer tablet.

Atorvastatin and ezetimibe suitable for use in the present invention can be purchased from commercial sources or can be prepared according to known methods. Any form of atorvastatin or ezetimibe may be used for this invention.

The amount of atorvastatin employed in such bi-layer tablets preferably ranges from 2.5mg (e.g., 10 mg) to 40mg, including 5mg, lOmg and 20mg. The amount of ezetimibe ranges from 5mg to 20mg, and is preferably lOmg. In a second embodiment, the present invention leads to creation of a novel formulation that overcomes significant problems encountered during the formulation of combining atorvastatin and ezetimibe in an oral solid dosage form due to inherent characteristics of atorvastatin and ezetimibe enumerated as follows: (a) Atorvastatin calcium is prone to oxidative and moisture mediated degradation both leading to formation of a lactone impurity. This reaction can be arrested in presence of basic milieu, (b) Ezetimibe is practically insoluble in water. While cellulose is the normal excipient that would be used for formulations with atorvastatin, there is a significant interaction of microcrystalline cellulose with ezetimibe, which makes use of such excipient difficult. Microcrystalline cellulose was found to bind with ezetimibe thereby retarding the drug release from the formulation, which would make it not bioequivalent to individually consumed ezetimibe. (c) While atorvastatin is more stable in near neutral to alkaline pH, the same is detrimental to ezetimibe. Hence it is important to separate the two individual molecules, which creates a significant product development challenge, (d) Solubility issues of ezetimibe raise the challenge of creating a formulation that achieves the right level oi in-vitro dissolution as well as is bioequivalent in a combination form to the individual ezetimibe consumption.

The above challenges were proven by a number of dissolution tests conducted on the formulation described in Table 1 and Table 2, which demonstrate the challenge in creating a formulation that is similar to the individually consumed tablets.

TABLE 1: COMPARATIVE DISSOLUTION PROFILE OF EZETIMIBE IN

ATORVASTATIN 20 mg & EZETIMIBE 10 mg TABLETS

Directly

Formulation DC DC DC DC

compressible

details formula 2 formula 3 formula 4 formula 5

(DC) l

Time in min /

2 tablets 2 tablets 2 tablets 6 tablets 6 tablets No of tablets

5 29 42 53 27 20

10 53 64 72 45 40

20 72 80 86 62 62

30 79 84 90 69 71

45 - - - 74 80 TABLE 2: ACCELERATED STABILITY (40°C/75%RH) WITHOUT NOVEL

FORMULATION

Considering above challenges, the invention describes a novel approach which separates the two active ingredients - atorvastatin and ezetimibe in two almost completely separate parts or layers and uses microcrystalline cellulose for the formulation of atorvastatin, but keeps it separate from ezetimibe and follows a unique process of dissolving ezetimibe and mounting it on lactose to enhance the solubility of ezetimibe when used in combination with atorvastatin to create a formulation that is bioequivalent and has similar Cmax and area under curve as two individual tablets of atorvastatin and ezetimibe consumed together. This approach then creates a bi-layer tablet, which has one solid layer of ezetimibe composition and a solid layer of atorvastatin. This formulation then overcomes the above significant development challenges and enables a fixed combination formulation that has simultaneously: a) similar dissolution profile to individual active ingredients, which leads to bioequivalence of the two individual active ingredients compared to consumption of two separate tablets of atorvastatin and ezetimibe, b) a stable formulation despite the incompatibilities of two component molecules - atorvastatin and ezetimibe, and c) enables the benefit of reducing the cholesterol levels in patients and reducing the cardiovascular risk in patients compared to monotherapies.

In this embodiment, the formulation with the atorvastatin layer, that is the top layer consists of atorvastatin as the active ingredient, with excipients as calcium carbonate precipitated 1-10% of the weight of the atorvastatin layer, Croscarmellose Sodium 1-10% of the weight of the formulation with the atorvastatin layer, that is the top layer consists of _L atorvastatin as the active ingredient, with excipients as calcium carbonate precipitated 1-10% of the weight of the atorvastatin layer, Croscarmellose Sodium 1-10% of the weight of the atorvastatin layer, lactose 20-95% of the weight of the atorvastatin layer, Microcrystalline cellulose 2-20% of the weight of the atorvastatin layer, and lubricants such as magnesium stearate 0.1 -2% of the weight of the atorvastatin layer. In addition the layer may contain an antioxidant such as butylated hydroxy anisole 0.05 to 2% of the weight of atorvastatin layer and a dispersion agent such as Aerosil 1-10% of the atorvastatin layer. This formulation in a separate layer of atorvastatin enables a good dissolution of atorvastatin at the same time avoids the oxidative effects leading to degeneration into lactone, thereby making the atorvastatin layer more stable while placing the layer on top of the ezetimibe layer.

In this aspect, the formulation with the ezetimibe layer, that is the bottom layer consists of ezetimibe as the active ingredient, with excipients as a surfactant such as sodium lauryl sulphate 2-20% of the ezetimibe layer, lactose 20-90% of the ezetimibe layer, a disintegrant such as Croscarmellose 5-30% of the ezetimibe layer, a binder such as Polyvinylpyrrolidone 0.5-10% of the ezetimibe layer, and Magnesium Stearate 0.2-5% of the ezetimibe layer.

METHOD

In a third embodiment, the present invention is directed to a method of making a solid dosage bi-layer form of atorvastatin and ezetimibe comprising the five steps enumerated below.

(a) Blending atorvastatin calcium with calcium carbonate, microcrystalline cellulose, croscarmellose sodium and lactose with a lubricant such as magnesium stearate. In the preferred embodiment of this step, atorvastatin calcium is passed through a sieve followed by Calcium carbonate, Croscarmellose sodium, Lactose monohydrate and microcrystalline cellulose, which is blended in a blender, then lubricated and blended with Magnesium stearate.

(b) Mixing ezetimibe with a wetting agent such as Sodium Lauryl Sulphate, and disperse material in sufficient quantity of Isopropyl alcohol and dicholoromethane mixture. Also in the preferred embodiment, the material of ezetimibe mixed with Sodium Lauryl Sulphate is slowly added to the mixture of isopropyl alcohol and dicholoromethane. This step is important to avoid crystallization of ezetimibe, which may adversely affect dissolution of ezetimibe.

(c) Absorbing the dispersion on lactose, and mix thoroughly. In the preferred embodiment of this step, the solution containing ezetimibe is added to the lactose in a slow process to ensure ezetimibe solution is fully absorbed on lactose, which results on full mounting of ezetimibe on lactose without loss of assay.

(d) Air drying the dispersion, passing through sieve, and mix with croscarmellose sodium and blend. In the preferred embodiment of this step, the ezetimibe solution mounted on lactose is dried evenly at temperatures between 30 degrees Celsius and 55 degrees Celsius. The temperature _L range avoids crystallization of ezetimibe that can adversely impact the dissolution of ezetimibe granules once process is fully complete. Additionally the ezetimibe mounted on lactose should be air dried rather than oven dried to ensure an even flow of the ezetimbe mounting on lactose.

(e) Mixing with Polyvinylpyrolidone solution and dry to obtain the ezetimibe granules. In the preferred embodiment the granules should be dried between 30 and 75 degrees Celsius.

(f) Creating the desired bi-layer tablet by compressing the two distinctly different set of granules as desired in the second aspect of the invention in a bi-layer compression machine, followed by film coating the oral dosage form.

EXAMPLE 1: fixed combination tablet of atorvastatin 20mg and ezetimibe lOmg

Below is an example of the formulation of a bi-layer tablet with atorvastatin 20mg and ezetimibe lOmg.

The method of above formulation is undertaken in three stages as follows:

Stage A. Atorvastatin granules: The steps followed to create the atorvastatin granules are as follows.

1. Pass Atorvastatin through sieve followed by, Calcium carbonate, and Croscarmellose sodium, Lactose monohydrate and microcrystalline cellulose.

2. Load the Step 1 material blend to Octagonal blender and blend.

3. Pass Magnesium stearate through sieve, load in to Step 2 material and blend. _L

Stage B. Ezetimibe granules: The steps followed to create the ezetimibe granules are as follows.

1. Pass Ezetimibe and sodium lauryl sulphate through sieve and mix.

2. Disperse Step-1 material in quantity sufficient of isopropyl alcohol and dichloromethane mixture.

3. The prepared Step -2 dispersion adsorb on Lactose, mix thoroughly and dried.

4. The Step-3 dried adsorb pass through sieve and mix with previously passed croscarmellose sodium in octagonal blender or suitable container attached to octagonal blender.

5. The Step-4 mixed materials granulate with Polyvinylpyrrolidone solution and dried.

6. The Step-5 dried granule pass through sieve and the passed granules lubricate with Magnesium stearate in octagonal blender or suitable container attached to the blender.

Stage C. Combination of two layers

The Atorvastatin granules and Ezetimibe bed layer granules compressed in bilayer compression machine. Compressed tablet is coated under continuous stirring. EXAMPLE 2: fixed combination tablet of atorvastatin lOmg and ezetimibe lOmg

Below is an example of the formulation of a bi-layer tablet with atorvastatin lOmg and ezetimibe lOmg:

Ingredients Weight per tablet in mg

Atorvastatin Calcium Trihydrate 11.35

Calcium carbonate precipitated and Croscarmellose

Sodium 9.75

Lactose monohydrate (Super 11 SD) 130

Microcrystalline cellulose (Avicel pH 102) and

Magnesium stearate 5.0

Total weight of the layer 156.1

Ingredients Weight per tablet

Ezetimibe 10.08

Sodium lauryl sulphate and Croscarmellose 30

Lactose 80

Polyvinylpyrrolidone and Magnesium Stearate 2.92

Total weight of the layer 123 _L

The method of above formulation is undertaken in three stages as follows:

2. Load the Step 1 material blend to Octagonal blender and blend.

3. Pass Magnesium stearate through sieve, load in to Step 2 material and blend.

Stage B. Ezetimibe granules: The steps followed to create the ezetimibe granules are as follows. 1. Pass Ezetimibe and sodium lauryl sulphate through sieve and mix.

3. The prepared Step -2 dispersion adsorb on Lactose, mix thoroughly and dried.

6. The Step-5 dried granule pass through sieve and the passed granules lubricate with Magnesium stearate in octagonal blender or suitable container attached to the blender. Stage C. Combination of two layers

The Atorvastatin granules and Ezetimibe bed layer granules compressed in bilayer compression machine. Compressed tablet is coated under continuous stirring.

DISSOLUTION RESULTS

Dissolution is a well-established method to test pharmacoequivalence of two products. The pharmacoequivalence of the fixed-combination dosage forms of the present invention was compared with that of the corresponding free-combinations. Table 2 and Table 3 list the results from the Example described earlier and of multiple tests that were undertaken between the test (fixed-combination) and the reference (free-combination) dosage forms. _L

TABLE 2: COMPARATIVE DISSOLUTION PROFILE OF LIPITOR 20 MG AND ATORVASTATIN CALCIUM FROM ATORVASTATIN 20 mg & EZETIMIBE 10 mg TABLETS

TABLE 3: COMPARATIVE DISSOLUTION PROFILE OF EZETROL 10 MG AND EZETIMIBE FROM ATORVASTATIN 20 mg & EZETIMIBE lOmg TABLETS

STABILITY RESULTS

To test the stability of the formulation, inventors undertook stability test of the formulation. Following are the results of accelerated stability studies of formulations. The tablets were exposed to accelerated stability conditions such as 40°C/75%RH in unsealed HDPE containers (open condition) for the period of two months. Samples were analyzed each week for degradation products and assay. The results of the novel formulation delivered stable products and the stability studies depicted stabilization potential of the formulation as well as the improved absorption and dissolution of ezetimibe with the novel process.

In a fourth embodiment, this invention is directed to solid dosage forms of atorvastatin and ezetimibe made according to the method of the third embodiment.

A fifth embodiment of this invention is directed to a method of treating hyperlipidemia, cardiovascular diseases, congestive heart failure, myocardial infarction, atherosclerosis comprising administering a solid dosage form of atorvastatin and ezetimibe in combination to a _L patient in need of such a treatment. In a preferred embodiment, the solid dosage form is administered to the subject.

While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims

CLAIMS What is claimed is:

1. A solid dosage form of atorvastatin and ezetimibe combined in one tablet comprising atorvastatin, ezetimibe, and pharmaceutically acceptable additives suitable for the preparation of solid dosage forms of a combination of atorvastatin and ezetimibe.

2. The solid dosage form of claim 1, wherein the orally consumed fixed combination formulation of both atorvastatin and ezetimibe in one tablet is expected to have same Area Under Curve as two active ingredients taken together individually orally.

3. The solid dosage form of claim 1, wherein atorvastatin and ezetimibe are prepared in a bi- layer formulation.

4. The solid dosage form of claim 3, wherein the atorvastatin dosage ranges from 2.5mg to 40mg, and ezetimibe ranges from 5mg to 20mg.

5. The solid dosage form of claim 3 that allows a stable composition of atorvastatin and ezetimibe with impurities within the limits prescribed by pharmacopeia.

6. The solid dosage form of claim 3 that consists of an atorvastatin layer and an ezetimibe layer wherein the atorvastatin layer consists of atorvastatin calcium, calcium carbonate precipitated 1-10% by weight, Croscarmellose Sodium 1-10% by weight, lactose 20-95% by weight, Microcrystalline cellulose 2-20% by weight, and a lubricant, such as magnesium stearate, 0.1-2% by weight of the atorvastatin layer and, optionally an antioxidant, such as Butylated hydroxy Anisole, 0.05 to 2% by weight or a dispersion agent, such as Aerosil, 1-10% by weight.

7. The solid dosage form of claim 6, wherein the ezetimibe layer consists of ezetmibe, a surfactant, such as Sodium lauryl sulphate, 2-20% by weight, lactose 20-90% by weight a disintegrant, such as Croscarmellose, 5-30% by weight, a binder, such as Polyvinylpyrrolidone, 0.5-10% by weight, and Magnesium Stearate 0.2-5%, by weight.

8. The method of making a solid oral dosage form of atorvastatin and ezetimibe comprising the steps of: a. Blending atorvastatin calcium with calcium carbonate, microcrystalline cellulose, croscarmellose sodium and lactose with a lubricant such as magnesium stearate to create the atorvastatin layer blend,

b. Mixing ezetimibe with a wetting agent such as Sodium Lauryl Sulphate, and disperse material in sufficient quantity of Isopropyl alcohol and dicholoromethane mixture,

c. Absorbing the dispersion on lactose, and mix thoroughly,

d. Air drying the dispersion, passing through sieve, mix with croscarmellose sodium, and blend,

e. Granulating the mix with Polyvinylpyrolidone solution and dry to obtain the ezetimibe granules,

f. Creating the desired bi-layer tablet by compressing the two distinctly different set of granules as desired in the second aspect of the invention in a bi-layer compression machine, followed by film coating the oral dosage form.

9. A method of treating hyperlipidemia, cardiovascular diseases, congestive heart failure, myocardial infarction, atherosclerosis comprising simultaneously administering a solid dosage form of atorvastatin and ezetimibe to a patient in need of such a treatment.