(19)
(11)EP 2 844 233 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
06.05.2020 Bulletin 2020/19

(21)Application number: 13785009.5

(22)Date of filing:  01.05.2013
(51)International Patent Classification (IPC): 
A61K 9/24(2006.01)
A61K 31/397(2006.01)
A61K 31/505(2006.01)
(86)International application number:
PCT/US2013/039018
(87)International publication number:
WO 2013/166117 (07.11.2013 Gazette  2013/45)

(54)

ORAL TABLET FORMULATION CONSISTING OF FIXED COMBINATION OF ROSUVASTATIN AND EZETIMIBE FOR TREATMENT OF HYPERLIPIDEMIA AND CARDIOVASCULAR DISEASES

ORALE TABLETTENFORMULIERUNG AUS EINER FIXIERTEN KOMBINATION AUS ROSUVASTATIN UND EZETIMIB ZUR BEHANDLUNG VON HYPERLIPIDÄMIE UND HERZ-KREISLAUF-ERKRANKUNGEN

FORMULATION DE COMPRIMÉ ORAL CONSTITUÉE D'UNE COMBINAISON FIXE DE ROSUVASTATINE ET D'ÉZÉTIMIBE POUR LE TRAITEMENT DE L'HYPERLIPIDÉMIE ET DE MALADIES CARDIOVASCULAIRES


(84)Designated Contracting States:
AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

(30)Priority: 01.05.2012 US 201261641013 P

(43)Date of publication of application:
11.03.2015 Bulletin 2015/11

(73)Proprietor: Althera Life Sciences, LLC
Morristown, NJ 07960 (US)

(72)Inventor:
  • DIAS, Marie, Charmaine
    Morristown, NJ 07960 (US)

(74)Representative: Berggren Oy, Helsinki & Oulu 
P.O. Box 16 Eteläinen Rautatiekatu 10A
00101 Helsinki
00101 Helsinki (FI)


(56)References cited: : 
WO-A1-2010/021608
WO-A2-2009/024889
WO-A2-2011/139256
US-A1- 2004 126 423
US-A1- 2010 247 645
WO-A1-2012/064307
WO-A2-2011/019326
US-A1- 2003 072 800
US-A1- 2010 204 195
US-A1- 2011 262 497
  
      
    Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


    Description

    BACKGROUND OF THE INVENTION


    1. Field of invention



    [0001] The present invention is directed to solid dosage formulations containing a combination of rosuvastatin and ezetimibe, as well as to methods of making such solid dosage forms and such a formulation for use in treatment of hyperlipidemia, cardiovascular diseases, congestive heart failure, myocardial infarction, atherosclerosis in a patient in need of such a treatment.

    2. Related background Art



    [0002] 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). Rosuvastatin 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 rosuvastatin and ezetimibe molecules may be selected from any of those disclosed in U.S. Pat. Nos. RE 37,721; 5,260,440; 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; 5,767,115.

    [0003] WO2009/024889 A2 discloses pharmaceutical combination preparations comprising a HMG-CoA reductase inhibitor and ezetimibe.

    [0004] It has been seen in clinical studies that the patients treated with both rosuvastatin and ezetimibe achieve higher levels of LDL reduction compared to individual therapy of rosuvastatin or ezetimibe alone. Hence there is significant value in a fixed combination of rosuvastatin 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 improve 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 rosuvastatin or ezetimibe alone.

    [0005] Accordingly, a fixed combination solid dosage formulation of rosuvastatin and ezetimibe that is bioequivalent to corresponding free-combination would be desirable.

    SUMMARY OF THE INVENTION



    [0006] In a first aspect, the present invention is an orally consumed bilayer tablet formulation comprising one solid layer of rosuvastatin formulated with microcrystalline cellulose, one separate solid layer of ezetimibe formulated without microcrystalline cellulose by dissolving ezetimibe and mounting it on lactose, and pharmaceutically acceptable additives suitable for the preparation of such solid dosage forms. This formulation is expected to have the 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 rosuvastatin is in the form of rosuvastatin calcium and the pharmaceutically acceptable additives are selected from diluents, disintegrants, glidants, lubricants, colorants and combinations thereof The amount of rosuvastatin employed in such bi-layer tablets preferably ranges from 2.5mg, preferably 5mg, to 40mg, including 5mg, 10mg and 20mg. The amount of ezetimibe ranges from 5mg to 20mg, preferably 10mg.

    [0007] A novel bilayer tablet formulation is created, comprising one solid layer of rosuvastatin formulated with microcrystalline cellulose, one separate solid layer of ezetimibe formulated without microcrystalline cellulose by dissolving ezetimibe and mounting it on lactose, and pharmaceutically acceptable additives suitable for the preparation of such solid dosage forms, that overcomes significant problems encountered during the formulation of combining rosuvastatin and ezetimibe in an oral solid dosage form due to inherent characteristics of rosuvastatin and ezetimibe enumerated as follows: (a) Rosuvastatin 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 rosuvastatin, 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 rosuvastatin 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.

    [0008] Considering the above challenges, the invention describes a novel approach which separates the two active ingredients - rosuvastatin and ezetimibe in two almost completely separate parts, uses microcrystalline cellulose for the formulation of rosuvastatin, 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 rosuvastatin to create a formulation that is bioequivalent and has similar Cmax and area under curve as two individual tablets of rosuvastatin 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 rosuvastatin. This formulation then overcomes the above significant development challenges and enables the Inventor to create 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 rosuvastatin and ezetimibe, b) a stable formulation despite the incompatibilities of two component molecules - rosuvastatin and ezetimibe, and c) enables the benefit of reducing the cholesterol levels in patients and reducing the cardiovascular risk in patients compared to monotherapies.

    [0009] In a second aspect, the present invention is directed to a method of making a solid dosage bi-layer form of rosuvastatin and ezetimibe comprising the steps of: (a) Blending Rosuvastatin Calcium with Pre-gelatinized starch, Calcium Hydrogen Phosphate Dihydrate, microcrystalline cellulose and Crospovidone, passing through sieve and lubricating the blend with lubricant such as Sodium stearyl fumarate to create the rosuvastatin 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.

    [0010] The solid dosage forms of rosuvastatin and ezetimibe of the present invention can be made according to the method of the second aspect.

    [0011] A third aspect of this invention is directed to a bilayer tablet formulation comprising one solid layer of rosuvastatin formulated with microcrystalline cellulose, one separate solid layer of ezetimibe formulated without microcrystalline cellulose by dissolving ezetimibe and mounting it on lactose and pharmaceutically acceptable additives suitable for the preparation of such solid dosage forms, for use in treating hyperlipidemia, cardiovascular diseases, congestive heart failure, myocardial infarction, atherosclerosis in a patient in need of such a treatment. In a preferred embodiment, the solid dosage form is orally administered to the subject.

    DESCRIPTION OF THE FIGURE



    [0012] The FIGURE: Average Release pattern of Concentration of Rosuvastatin and Ezetimibe when administered to healthy human volunteers, X-Axis depicts time, and Y-axis depicts % concentration of rosuvastatin or ezetimibe absorbed relative to maximum concentration over varying time points from 0 to 96 hours.

    DETAILED DESCRIPTION OF THE INVENTION



    [0013] The present invention relates to bilayer tablet formulations comprising one solid layer of rosuvastatin formulated with microcrystalline cellulose, one separate solid layer of ezetimibe formulated without microcrystalline cellulose by dissolving ezetimibe and mounting it on lactose and pharmaceutically acceptable additives suitable for the preparation of such solid dosage forms, as well as to methods of making such solid dosage forms and such solid dosage form for use in treating patients. The first embodiment of the invention is a bilayer tablet formulation comprising one solid layer of rosuvastatin formulated with microcrystalline cellulose, one separate solid layer of ezetimibe formulated without microcrystalline cellulose by dissolving ezetimibe and mounting it on lactose and pharmaceutically acceptable additives suitable for the preparation of such solid dosage forms. The formulation is expected to have same Area Under Curve as two active ingredients taken together individually orally. In preferred embodiments of this invention, the rosuvastatin is in the form of rosuvastatin calcium and the pharmaceutically acceptable additives are selected from the diluents, disintegrants, glidants, lubricants, colorants and combinations thereof. Rosuvastatin 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 rosuvastatin or ezetimibe may be used for this invention.

    [0014] The amount of rosuvastatin employed in such bi-layer tablets preferably ranges from 2.5mg, preferably 10 mg, to 40mg, including 5mg, 10mg and 20mg. The amount of ezetimibe ranges from 5mg to 20mg, and is preferably 10mg. In a second embodiment, the present invention leads to a novel formulation that overcomes significant problems encountered during the formulation of combining rosuvastatin and ezetimibe in an oral solid dosage form due to inherent characteristics of rosuvastatin and ezetimibe enumerated as follows: (a) Rosuvastatin 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 rosuvastatin, 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 rosuvastatin 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.

    [0015] The above challenges were proven by a number of dissolution tests conducted on the formulation described in Table 1, which demonstrates the challenge in creating a formulation that is similar to the individually consumed tablets.
    TABLE 1: COMPARATIVE DISSOLUTION PROFILE OF EZETIMIBE IN ROSUVASTATIN 20 mg & EZETIMIBE 10 mg TABLETS
    Appearance of the tablet White colored Round shaped tablets
    Formulation details Dry granulation of Rosuvastatin and lubricated with mag-stearate and Wet granulation of Ezetimibe
    # Basket at 75 RPM
    Time in min/ No of tablets 6 tablets
    5 45
    10 81
    20 87
    30 89
    45 91


    [0016] Considering above challenges, the invention describes a novel approach which separates the two active ingredients - rosuvastatin and ezetimibe in two almost completely separate parts or layers, uses microcrystalline cellulose for the formulation of rosuvastatin, 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 rosuvastatin to create a formulation that is bioequivalent and has similar Cmax and area under curve as two individual tablets of rosuvastatin 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 rosuvastatin. This formulation then overcomes the above significant development challenges and enables the Inventor to create 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 rosuvastatin and ezetimibe, b) a stable formulation despite the incompatibilities of two component molecules - rosuvastatin and ezetimibe, and c) enables the benefit of reducing the cholesterol levels in patients and reducing the cardiovascular risk in patients compared to monotherapies.

    [0017] In this embodiment, the formulation with the rosuvastatin layer, that is the top layer that consists of rosuvastatin as the active ingredient, with excipients as starch 1-15% of the weight of the rosuvastatin layer, dicalcium phosphate 0.5-10% of the weight of the rosuvastatin layer, Cellulose 20-90% of the weight of the rosuvastatin layer, Crospovidone 2¬30% of the weight of the rosuvastatin layer, and lubricants such as sodium stearyl fumarate 0.1-2% of the weight of the rosuvastatin layer. In addition the layer may contain an anti¬oxidant such as Butylated hydroxy Anisole 0.05 to 2% of the weight of rosuvastatin layer and a dispersion agent such as Aerosil 1-10% of the rosuvastatin layer. This formulation in a separate layer of rosuvastatin enables a good dissolution of rosuvastatin at the same time avoids the oxidative effects leading to degeneration into lactone, thereby making the rosuvastatin layer more stable while placing the layer on top of the ezetimibe layer.

    [0018] 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



    [0019] In a second embodiment, the present invention is directed to a method of making a solid dosage bi-layer form of rosuvastatin and ezetimibe comprising the five steps enumerated below.
    1. (a) Blending Rosuvastatin Calcium with Pre-gelatinized starch, Calcium Hydrogen Phosphate Dihydrate, microcrystalline cellulose and Crospovidone, passing through sieve and lubricating the blend with lubricant such as Sodium stearyl fumarate to create the rosuvastatin layer blend. In the preferred embodiment of this step, rosuvastatin calcium is passed through a sieve, followed by Pre-gelatinized starch, Calcium Hydrogen Phosphate Dihydrate, microcrystalline cellulose and Crospovidone and blended, and then lubricated and blended with sodium stearyl fumarate and passed through another sieve.
    2. (b) Mixing ezetimibe with a wetting agent such as Sodium Lauryl Sulphate, and disperse material in sufficient quantity of Isopropyl alcohol and dicholoromethane mixture. In the preferred embodiment, the mixture of isopropyl alcohol and dicholoromethane. 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.
    3. (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.
    4. (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 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.
    5. (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 rosuvastatin 20mg and ezetimibe 10mg



    [0020] Below is an example of the formulation of a bi-layer tablet with rosuvastatin 20mg and ezetimibe 10mg.
    IngredientsWeight per tablet
    Rosuvastatin 22.08
    Pre-gelatinized starch and Dicalcium phosphate 16.8
    Microcrystalline cellulose 140
    Crospovidone, Aerosil and Butylated hydroxy Anisole (BHA) 42.1
    Total weight of the layer 220.98
    IngredientsWeight 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


    [0021] The method of the above formulation is undertaken in three stages as follows:

    Stage A. Rosuvastatin granules: The steps followed to create the rosuvastatin granules are as follows:

    1. 1. Pass Rosuvastatin through sieve, followed by Pre-gelatinized starch, Calcium Hydrogen Phosphate Dihydrate, Microcrystalline Cellulose and Crospovidone through the sieve.
    2. 2. Load the Step 1 material blend to Octagonal blender and blend.
    3. 3. Pass Sodium stearyl fumarate 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. 1. Pass Ezetimibe and sodium lauryl sulphate through sieve and mix.
    2. 2. Disperse Step-1 material in quantity sufficient of isopropyl alcohol and dichloromethane mixture.
    3. 3. The prepared Step -2 dispersion adsorb on Lactose, mix thoroughly and dried.
    4. 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. 5. The Step-4 mixed materials granulate with Polyvinylpyrrolidone solution and dried.
    6. 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



    [0022] The Rosuvastatin granules and Ezetimibe bed layer granules compressed in bilayer compression machine. Compressed tablet is coated under continuous stirring.

    EXAMPLE 2: fixed combination tablet of rosuvastatin 10mg and ezetimibe 10mg



    [0023] Below is an example of the formulation of a bi-layer tablet with rosuvastatin 10mg and ezetimibe 10mg.
    IngredientsWeight per tablet
    Rosuvastatin 11.04
    Pre-gelatinized starch and Dicalcium phosphate 8.4
    microcrystalline cellulose 70
    Crospovidone, Aerosil and Butylated hydroxy 21.05
    Anisole (BHA)  
    Total weight of the layer 110.49
    IngredientsWeight 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


    [0024] The method of the above formulation is undertaken in three stages as follows:

    Stage A. Rosuvastatin granules: The steps followed to create the rosuvastatin granules are as follows:

    1. 1. Pass Rosuvastatin through sieve, followed by Pre-gelatinized starch, Calcium Hydrogen Phosphate Dihydrate, Microcrystalline Cellulose and Crospovidone through the sieve.
    2. 2. Load the Step 1 material blend to Octagonal blender and blend.
    3. 3. Pass Sodium stearyl fumarate 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. 1. Pass Ezetimibe and sodium lauryl sulphate through sieve and mix.
    2. 2. Disperse Step-1 material in quantity sufficient of isopropyl alcohol and dichloromethane mixture.
    3. 3. The prepared Step -2 dispersion adsorb on Lactose, mix thoroughly and dried.
    4. 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. 5. The Step-4 mixed materials granulate with Polyvinylpyrrolidone solution.
    6. 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



    [0025] The Rosuvastatin granules and Ezetimibe bed layer granules compressed in bilayer compression machine. Compressed tablet is coated under continuous stirring.

    DISSOLUTION RESULTS



    [0026] 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.
    TABLE 2: COMPARATIVE DISSOLUTION PROFILE OF CRESTOR 20 MG AND ROSUVASTATIN CALCIUM FROM ROSUVASTATIN 20 mg & EZETIMIBE 10 mg 10 TABLETS
    Time in minCrestor- 20 mg tablets (B.No: HV373) REFERENCERosuvastatin from the Test tablets of Inventor TESTWITHIN acceptable range to be comparable
    10 96 84 YES
    20 97 93
    30 97 95
    45 97 98
    TABLE 3: COMPARATIVE DISSOLUTION PROFILE OF EZETROL 10 MG AND EZETIMIBE FROM ROSUVASTATIN 20 mg & EZETIMIBE 10mg TABLETS
    Time in minEzetrol 10 mg tablets (B.No: 310688) REFERENCEEzetimibe from the Test tablets of Inventor TESTWITHIN acceptable range to be comparable
    10 95 78 YES
    20 95 83
    30 95 90
    45 95 95

    STABILITY RESULTS



    [0027] 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. Summary results are enumerated below in Table 4.
    TABLE 4: RELATED SUBSTANCE IMPURITIES FOR ROSUVASTATIN AND 5 EZETIMIBE
    Impurity NameLimit3 weeks6 weeks
    40°C/75% RH40°C/75% RH
    Rosuvastatin related Lactone Not more than 0.5% 0.06% 0.16%
    Rosuvastatin related Keto impurity Not more than 0.5% 0.15% 0.15%
    Ezetimibe related cyclic ether impurity Not more than 0.5% Not Detected Not Detected


    [0028] The results of above accelerated stability studies depict stabilization potential of the formulation as well as the improved absorption and dissolution of ezetimibe with the novel process.

    [0029] In a fourth embodiment, this invention is directed to solid dosage forms of rosuvastatin and ezetimibe made according to the method of the third embodiment.

    [0030] Fifth embodiment of this invention is directed to a bilayer tablet formulation comprising one solid layer of rosuvastatin formulated with microcrystalline cellulose, one separate solid layer of ezetimibe formulated without microcrystalline cellulose by dissolving ezetimibe and mounting it on lactose and pharmaceutically acceptable additives suitable for the preparation of such a solid dosage form for use in treating hyperlipidemia, cardiovascular diseases, congestive heart failure, myocardial infarction, atherosclerosis in a patient in need of such a treatment. In a preferred embodiment, the solid dosage form is orally administered to the subject.

    [0031] 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

    1. A solid dosage form of rosuvastatin and ezetimibe combined in one bilayer tablet formulation comprising one solid layer of rosuvastatin formulated with microcrystalline cellulose, one separate solid layer of ezetimibe formulated without microcrystalline cellulose by dissolving ezetimibe and mounting it on lactose, and pharmaceutically acceptable additives suitable for the preparation of solid dosage forms of a combination of rosuvastatin and ezetimibe.
     
    2. The solid dosage form of claim 1, wherein the rosuvastatin dosage ranges from 2.5mg to 40mg, and ezetimibe ranges from 5mg to 20mg.
     
    3. The solid dosage form of claim 1 that comprises a rosuvastatin layer consisting of rosuvastatin, starch 1-15% by weight, dicalcium phosphate 0.5-10% by weight, Cellulose 20-90% by weight, Crospovidone 2-30% by weight, and a lubricant, such as sodium stearyl fumarate, 0.1-2% by weight and, optionally, an anti-oxidant, such as Butylated hydroxy Anisole, 0.05-2% by weight or a dispersion agent, such as Aerosil, 1-10% by weight.
     
    4. The solid dosage form of claim 3 that comprises an ezetimibe layer consisting of ezetimibe, 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, by weight 0.5-10%, and Magnesium Stearate 0.2-5% by weight.
     
    5. The method of making a solid oral dosage form of rosuvastatin and ezetimibe according to claim 1, comprising the steps of:

    a) Blending Rosuvastatin Calcium with Pre-gelatinized starch, Calcium Hydrogen Phosphate Dihydrate, microcrystalline cellulose and Crospovidone, passing through sieve and lubricating the blend with lubricant such as Sodium stearyl fumarate to create the rosuvastatin 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 blending,

    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 in a bi-layer compression machine, followed by film coating the oral dosage form.


     
    6. A solid dosage form of rosuvastatin and ezetimibe according to any one of claims 1 to 4 for use in treatment of hyperlipidemia, cardiovascular diseases, congestive heart failure, myocardial infarction, atherosclerosis in a patient in need of such a treatment.
     


    Ansprüche

    1. Feste Dosierungsform von Rosuvastatin und Ezetimib kombiniert in einer zweischichtigen Tablettenformulierung, umfassend eine mit mikrokristalliner Cellulose formulierte feste Schicht von Rosuvastatin, eine separate, ohne mikrokristalline Cellulose durch Lösen von Ezetimib und dessen Aufbringen auf Lactose formulierte feste Schicht von Ezetimib und pharmazeutisch unbedenkliche, für die Herstellung fester Dosierungsformen einer Kombination von Rosuvastatin und Ezetimib geeignete Zusatzstoffe.
     
    2. Feste Dosierungsform nach Anspruch 1, wobei die Rosuvastatindosis im Bereich von 2,5 mg bis 40 mg liegt und Ezetimib im Bereich von 5 mg bis 20 mg liegt.
     
    3. Feste Dosierungsform nach Anspruch 1, umfassend eine aus Rosuvastatin, 1-15 Gew.-% Stärke, 0,5-10 Gew.-% Dicalciumphosphat, 20-90 Gew.-% Cellulose, 2-30 Gew.-% Crospovidon und 0,1-2 Gew.-% eines Schmiermittels wie Natriumstearylfumarat und gegebenenfalls 0,05-2 Gew.-% eines Antioxidationsmittels wie Butylhydroxyanisol oder 1-10 Gew.-% eines Dispersionsmittels wie Aerosil bestehende Rosuvastatinschicht.
     
    4. Feste Dosierungsform nach Anspruch 3, umfassend eine aus Ezetimib, 2-20 Gew.-% eines Tensids wie Natriumlaurylsulfat, 20-90 Gew.-% Lactose, 5-30 Gew.-% eines Sprengmittels wie Croscarmellose, 0,5-10 Gew.-% eines Bindemittels wie Polyvinylpyrrolidon und 0,2-5 Gew.-% Magnesiumstearat bestehende Ezetimibschicht.
     
    5. Verfahren zur Herstellung einer festen oralen Dosierungsform von Rosuvastatin und Ezetimib nach Anspruch 1, welches die folgenden Schritte umfasst:

    a) das Mischen von Rosuvastatin-Calcium mit vorgelatinisierter Stärke, Calciumhydrogenphosphat-dihydrat, mikrokristalliner Cellulose und Crospovidon, das Sieben und das Schmieren der Mischung mit einem Schmiermittel wie Natriumstearylfumarat unter Bildung der Rosuvastatinschichtmischung,

    b) das Mischen von Ezetimib mit einem Netzmittel wie Natriumlaurylsulfat und das Dispergieren des Materials in einer ausreichenden Menge an einer Mischung von Isopropylalkohol und Dichlormethan,

    c) das Absorbieren der Dispersion an Lactose und gründliches Mischen,

    d) das Lufttrocknen der Dispersion, das Sieben, das Mischen mit Croscarmellose-Natrium und das Mischen,

    e) das Granulieren der Mischung mit Polyvinylpyrrolidonlösung und das Trocknen unter Erhalt des Ezetimibgranulats,

    f) die Herstellung der gewünschten Zweischichttablette durch Verpressen der zwei deutlich verschiedenen Granulatmengen in einer Zweischichtpresse, gefolgt von dem Filmbeschichten der oralen Dosierungsform.


     
    6. Feste Dosierungsform von Rosuvastatin und Ezetimib nach einem der Ansprüche 1 bis 4 zur Verwendung bei der Behandlung von Hyperlipidämie, Herz-Kreislauf-Krankheiten, dekompensierter Herzinsuffizienz, Herzinfarkt, Atherosklerose in einem einer solchen Behandlung bedürftigen Patienten.
     


    Revendications

    1. Forme de dosage solide de rosuvastatine et d'ézétimibe combinés dans une formulation de comprimé bicouche comprenant une couche solide de rosuvastatine formulée avec de la cellulose microcristalline, une couche solide distincte d'ézétimibe formulée sans cellulose microcristalline par dissolution d'ézétimibe et montage de celui-ci sur du lactose, et des additifs pharmaceutiquement acceptables appropriés pour la préparation de formes de dosage solide ou d'une combinaison de rosuvastatine et d'ézétimibe.
     
    2. Forme de dosage solide selon la revendication 1, le dosage de rosuvastatine se situant dans la plage de 2,5 mg à 40 mg et le dosage d'ézétimibe se situant dans la plage de 5 mg à 20 mg.
     
    3. Forme de dosage solide selon la revendication 1 qui comprend une couche de rosuvastatine constituée de rosuvastatine, de 1 à 15 % en poids d'amidon, de 0,5 à 10 % en poids de phosphate dicalcique, de 20 à 90 % en poids de cellulose, de 2 à 30 % en poids de crospovidone, et de 0,1 à 2 % en poids d'un lubrifiant, tel que le fumarate de stéaryle sodique, et, éventuellement de 0,05 à 2 % en poids d'un antioxydant, tel que l'hydroxyanisole butylé ou de 1 à 10 % en poids d'un agent de dispersion, tel que l'Aérosil.
     
    4. Forme de dosage solide selon la revendication 3 qui comprend une couche d'ézétimibe constituée d'ézétimibe, de 2 à 20 % en poids d'un tensioactif, tel que le sulfate de lauryle sodique, de 20 à 90 % en poids de lactose, de 5 à 30 % en poids d'un désintégrant, tel que le croscarmellose, de 0,5 à 10 % en poids d'un liant, tel que la polyvinylpyrrolidone, et de 0,2 à 5 % en poids de stéarate de magnésium.
     
    5. Procédé de fabrication d'une forme de dosage oral solide de rosuvastatine et d'ézétimibe selon la revendication 1, comprenant les étapes de :

    a) mélangeage de rosuvastatine calcium avec de l'amidon pré-gélatinisé, du dihydrate d'hydrogénophosphate de calcium, de la cellulose microcristalline et de la crospovidone, passage à travers un tamis et lubrification du mélange avec un lubrifiant tel que le fumarate de stéaryle sodique pour créer le mélange de couche de rosuvastatine,

    b) mélange d'ézétimibe avec un agent mouillant tel que le sulfate de lauryle sodique, et dispersion du matériau dans une quantité suffisante d'un mélange d'alcool isopropylique et de dichlorométhane,

    c) absorption de la dispersion sur du lactose, et mélange soigneux,

    d) séchage à l'air de la dispersion, passage à travers un tamis, mélange avec du croscarmellose sodique, et mélangeage,

    e) granulation du mélange avec une solution de polyvinylpyrrolidone et séchage pour obtenir les granules d'ézétimibe,

    f) création du comprimé bicouche souhaité par compression des deux différentes séries distinctes de granules dans une machine de compression bicouche, suivie par le pelliculage de la forme de dosage oral.


     
    6. Forme de dosage solide de rosuvastatine et d'ézétimibe selon l'une quelconque des revendications 1 à 4 pour une utilisation dans un traitement de l'hyperlipidémie, de maladies cardiovasculaires, d'insuffisance cardiaque congestive, d'infarctus du myocarde, d'athérosclérose chez un patient ayant besoin d'un tel traitement.
     




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    Cited references

    REFERENCES CITED IN THE DESCRIPTION



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    Patent documents cited in the description