EP2844067A1

EP2844067A1 - Oral tablet formulation consisting of immediate release rosuv astatin and extended release metformin

Info

Publication number: EP2844067A1
Application number: EP13765204.6A
Authority: EP
Inventors: Marie Charmaine DIAS
Original assignee: Althera Life Sciences LLC
Current assignee: Althera Life Sciences LLC
Priority date: 2012-03-19
Filing date: 2013-03-15
Publication date: 2015-03-11
Also published as: MX2014011167A; EP2844067A4; WO2013142314A1

Abstract

The present invention is directed to solid dosage product and formulation containing a fixed combination of rosuvastatin and metformin such that rosuvastatin is delivered immediately to the patient and metformin is delivered in a controlled fashion over a longer course of time, also described as extended release, as well as to methods of making such solid dosage forms and method of treating patients with fixed combination solid dosage forms of immediate release rosuvastatin and extended release metformin.

Description

ORAL TABLET FORMULATION CONSISTING OF IMMEDIATE RELEASE ROSUVASTATIN

AND EXTENDED RELEASE METFORMIN

RELATED APPLICATION

5 This application is related to U.S. Provisional Application No. 61/612,563, filed on

March 19, 2012 and US Provisional Application No. 61/640,971, filed May 1, 2012. The entire teachings of the above applications are incorporated herein by reference.

BACKGROUND OF THE INVENTION

0 1. Field of invention

The present invention is directed to solid dosage product and formulation containing a fixed combination of rosuvastatin and metformin such that rosuvastatin is delivered immediately to the patient and metformin is delivered in a controlled fashion over a longer course of time, also described as extended release, as well as to methods of5 making such solid dosage forms and method of treating patients with fixed combination solid dosage forms of immediate release rosuvastatin and extended release metformin.

2. Related background Art

Large scale clinical studies, epidemiological studies, and population reviews0 conducted by various organizations such as International Diabetes Federation (IDF), European Association for the Study of Diabetes (EASD), World Health Organization (WHO), National Cholesterol Education Program (NCEP), and Center for Disease Control (CDC) have identified Diabetes as a major risk factor for cardiovascular events and related mortality. The mortality follow-up of the EUROASPIRE I cohort showed that, apart from5 smoking, diabetes is the most important, single risk factor for coronary artery disease and subsequent cardiovascular morbidity and mortality. In addition, cardiovascular event is the main cause of death in patients with diabetes.

A number of clinical studies have shown that a substantial proportion of patients with diabetes do not reach recommended lipid targets with regard to Low Density

0 Lipoproteins (LDL-C), High Density Lipoprotein (HDL-C), or Apolipoprotein (ApoB) as recommended by American Diabetes Association (ADA), The National Cholesterol Education Program (NCEP) and The European joint Task force of European Society of Cardiology (ESC) and the European Association for the Study of Diabetes (EASD), thereby keeping these patients at a high risk for premature cardiovascular disease and death.

There is significant existing evidence that fixed dose combination products improve adherence to medication and patient compliance due to reduced pill burden and improved ease of administration. It is been demonstrated that the adherence to medication in cardiovascular disease and in particular hyperlipidemia is less than desirable, which often results in an inability to meet treatment goals as recommended by European Society of Cardiology (ESC) and National Cholesterol Education Program (NCEP) ATP III. Adherence to anti-diabetes medication is an equally large problem as patients with type 2 diabetes often need 2-4 different anti-diabetic drugs to bring their HbAlc levels down to recommended levels. To make the pill burden even worse, many patients with diabetes and hyperlipedemia also suffer from hypertension as many of these patients have at least some degree of metabolic syndrome. Hence, any approach that can reduce the pill burden and ease adherence to medication could be very beneficial. The development of this invention needs to be looked at within this context. Patient adherence to medication has been shown to be significantly greater with a single-pill regimen compared with a two-pill regimen, or a two-pill regimen compared to a three- or four-pill regimen. Concerns about increasing a patient's pill burden often result in reluctance from physicians in adding further medications to a patient's existing regimen despite potential therapeutic benefits.

Accordingly, a fixed combination solid dosage formulation of metformin and rosuvastatin that is bioequivalent to corresponding free-combination would be highly desirable for the benefit of patients. SUMMARY OF THE INVENTION

In a first aspect, the present invention is an orally consumed fixed combination product that consists of immediate release rosuvastatin and extended release metformin, that is, metformin delivered to patient over an extended period of time that is indicated for simultaneous treatment of type 2 diabetes and hyperlipidemia or reduction in

cardiovascular risk. This novel product delivers simultaneous treatment of diabetes and hyperlipidemia overcoming a significant dosing difference between the two individual ingredients and delivers a novel product that reduces low density cholesterol (LDL), potentially cardiovascular risk, and glucose levels in diabetes patients by simultaneously treating hyperglycemia and hyperlipidemia.

In a second aspect, the present invention is a novel formulation that consists of immediate release rosuvastatin and extended release metformin such that both rosuvastatin and extended release metformin in one tablet are 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 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. The present invention overcomes the significant formulation challenge of timing two different release timings of two different drugs.

In the preferred embodiments of this invention, the solid dosage form is a bi-layer tablet. The amount of rosuvastatin employed in such bi-layer tablets preferably ranges from 5mg to 40mg, including lOmg and 20mg. The amount of metformin ranges from 250mg to 2000mg, including 500mg, 750mg, 850mg, lOOOmg, 1250mg and 1500mg.

In a third aspect, the present invention is directed to a method of making a solid dosage bi-layer form of rosuvastatin to be released in immediate form and metformin to be released in extended release. First stage is to develop the metformin extended release layer with the following steps: (a) Mix the intragranular ingredients in granulator, and granulate the above blend with binding agent; (b) Dry the granules partially, pass through mill and dry the sized granules until optimum LOD obtained; (c) Pass the dried granules through mill and sift the sized granules, and blend the granules; and (d) Lubricate the above granules with magnesium stearate. In the second stage, a rosuvastatin layer blend is created by blending the excipients with rosuvastatin in a blender, and lubricating the ingredients with lubricants such as magnesium stearate. In the third stage the above blends are compressed in bi-layer tablets with carefully controlled compression pressure. Finally the bi-layer tablets are film-coated.

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

The fifth aspect of this invention is directed to a method of treating hyperlipidemia, cardiovascular diseases, simultaneously with type 2 diabetes comprising administering a solid dosage form of rosuvastatin and metformin to a patient in need of such a treatment. In a preferred embodiment, the solid dosage form is orally administered to the subject. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 : Average Release pattern of Concentration of Metformin and

Rosuvastatin when administered to 10 healthy human volunteers, X-Axis depicts time, and Y-axis depicts % concentration of Metformin or rosuvastatin absorbed relative to maximum concentration over varying time points from 0 to 96 hours.

Figure 2: Comparision of release pattern and concentration of Metformin in 10 healthy human volunteers between INVENTION and GLUCOPHAGE.

Figure 3: Comparision of release pattern and concentration or Rosuvastatin in 10 healthy human volunteers between INVENTION AND CRESTOR.

DETAILED DESCRIPTION OF THE INVENTION

The first embodiment of the invention is a fixed combination product that delivers metformin in an extended form and rosuvastatin in an immediate form to the patient. A number of clinical studies have shown that a substantial proportion of patients with diabetes do not reach recommended lipid targets with regard to Low Density Lipoproteins (LDL-C), High Density Lipoprotein (HDL-C), or Apolipoprotein (ApoB) as recommended by American Diabetes Association (ADA), The National Cholesterol Education Program (NCEP) and The European joint Task force of European Society of Cardiology (ESC) and the European Association for the Study of Diabetes (EASD), thereby keeping these patients at a high risk for premature cardiovascular disease and death. There is significant existing evidence that fixed dose combination products improve adherence to medication and patient compliance due to reduced pill burden and improved ease of administration. It is been demonstrated that the adherence to medication in cardiovascular disease and in particular hyperlipidemia is less than desirable, which often results in an inability to meet treatment goals as recommended by European Society of Cardiology (ESC) and National Cholesterol Education Program (NCEP) ATP III. Adherence to anti-diabetes medication is an equally large problem as patients with type 2 diabetes often need 2-4 different anti- diabetic drugs to bring their HbAlc levels down to recommended levels. To make the pill burden even worse, many patients with diabetes and hyperlipedemia also suffer from hypertension as many of these patients have at least some degree of metabolic syndrome. Hence, any approach that can reduce the pill burden and ease adherence to medication could be very beneficial. The development of this invention needs to be looked at within this context. Patient adherence to medication has been shown to be significantly greater with a single-pill regimen compared with a two-pill regimen, or a two-pill regimen compared to a three- or four-pill regimen. Concerns about increasing a patient's pill burden often result in reluctance from physicians in adding further medications to a patient's existing regimen despite potential therapeutic benefits.

Metformin and rosuvastatin are respectively well known treatments for diabetes and hyperlipidemia respectively. However, there is a significant challenge in combining the two products in one treatment. Rosuvastatin is indicated to be consumed or dosed once daily. However metformin is indicated for consumption at multiple points of time ranging as every 6-8 hours during the day. Given the difference in dosing pattern, this invention created a novel product where the product delivers rosuvastatin immediately when consumed by the patient, whereas metformin is released in a controlled fashion over a longer period of time thereby meeting the multiple dosing requirements of metformin. This invention hence creates a novel product that treats both diabetes and hyperlipidemia with a single oral dosage to be consumed by patients once daily.

The first embodiment of this invention is described in the release pattern of the two components of the product as depicted in Figure 1.

The second embodiment of this invention is a novel formulation that consists of immediate release rosuvastatin and extended release metformin such that both rosuvastatin and extended release metformin in one tablet are 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 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. The present invention overcomes the significant formulation challenge of timing two different release timings of two different drugs.

Creation of one tablet that has two different time-release of rosuvastatin and metformin is a significant challenge. Recognizing this challenge the inventors developed a strategy to use two layers - one of metformin and one of rosuvastatin. The strategy included rosuvastatin on the upper or outer layer of the tablet such that the release of rosuvastatin active ingredient is earlier than the metformin layer. And the metformin layer to include granules that control the release of metformin in the human stomach.

In this embodiment, the rosuvastatin layer of the formulation consists rosuvastatin as the active ingredient, with excipients such as starch 1-5% of the weight of the rosuvastatin layer, dicalcium phosphate 0.5-5% 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 this embodiment the metformin granules are created by combining metformin with cellulose 0.5-5% of the weight of the metformin layer, a polymer 5-50% of the weight of the metformin layer, and water and organically soluble cellulose such as hydroxypropyl cellulose 0.5-5% of the weight of the metformin layer. These granules are further packed in the polymer to the weight of 5-30% of the weight of the metformin layer along with a lubricant such as magnesium stearate 0.2-5% of the weight of the metformin layer.

In a third embodiment of the present invention is directed to a method of making a solid dosage bi-layer form of rosuvastatin to be released in immediate form and metformin to be released in extended release. First stage is to develop the metformin extended release layer with the following steps: (a) Mix the intragranular ingredients in granulator, and granulate the above blend with binding agent; (b) Dry the granules partially, pass through mill and dry the sized granules until optimum LOD obtained; (c) Pass the dried granules through mill and sift the sized granules, and blend the granules; and (d) Lubricate the above granules with magnesium stearate. In the second stage, a rosuvastatin layer blend is created by blending the excipients with rosuvastatin in a blender, and lubricating the ingredients with lubricants such as magnesium stearate. In the third stage the above blends are compressed in bi-layer tablets with carefully controlled compression pressure. Finally the bi-layer tablets are film-coated. A key element of this embodiment of this invention is the compression pressure at which this particular bi-layer tablet is compressed to form the tablet. Given the desire for one ingredient of the tablet to be immediate release and another ingredient of the tablet to be extended release, at the same time they may be manufactured and compressed at the same time created significant challenges. For example, when the compression pressure was higher, the immediate release component of the rosuvastatin would release slower than was optimal, and if the compression pressure was too low, the extended release component of the metformin would release too fast. Example of this problem are described in below Table 1, which compares the release of a reference monotherapy tablet of rosuvastatin (stated as Crestor 20mg) compared to a test tablet, stated as El 1 1

(T750/20).

TABLE 1: RELEASE OF ROSUVASTATIN IN THE TEST PRODUCT WITH VARIABLE COMPRESSION COMPARED TO REFERENCE PRODUCT

(CRESTOR)

The above problem was overcome by adjusting the compression pressure of the bi- layer machine to an optimum release pattern, which is an important part of the third embodiment of this invention, and ranges between 200 KiloNewtons and 500

KiloNewtons.

Final embodiment of this invention is directed to a method of treating

hyperlipidemia, cardiovascular diseases, simultaneously with type 2 diabetes comprising administering a solid dosage form of rosuvastatin and metformin to a patient in need of such a treatment. In a preferred embodiment, the solid dosage form is orally administered to the subject. EXAMPLES

EXAMPLE 1: fixed combination tablet of rosuvastatin 20mg and metformin 750mg

The above ingredients were used to manufacture a tablet in accordance with the third embodiment of this invention, where the steps undertaken were: First stage developed the metformin extended release layer with the following steps: (a) Mixed the intragranular ingredients in granulator, and granulated the above blend with binding agent; (b) Dried the granules partially, passed through mill and dried the sized granules until optimum LOD obtained; (c) Passed the dried granules through mill and sift the sized granules, and blended the granules; and (d) Lubricated the above granules with magnesium stearate. In the second stage, a rosuvastatin layer blend was created by blending the excipients with rosuvastatin in a blender, and lubricated the ingredients with lubricants such as magnesium stearate. In the third stage the above blends were compressed in bi-layer tablets with carefully controlled compression pressure. Finally the bi-layer tablets were film-coated. EXAMPLE 2: fixed combination tablet of rosuvastatin lOmg and metformin 500mg

The above ingredients were used to manufacture a tablet in accordance with the third embodiment of this invention, where the steps undertaken were: First stage developed the metformin extended release layer with the following steps: (a) Mixed the intragranular ingredients in granulator, and granulated the above blend with binding agent; (b) Dried the granules partially, passed through mill and dried the sized granules until optimum LOD obtained; (c) Passed the dried granules through mill and sift the sized granules, and blended the granules; and (d) Lubricated the above granules with magnesium stearate. In the second stage, a rosuvastatin layer blend was created by blending the excipients with rosuvastatin in a blender, and lubricated the ingredients with lubricants such as magnesium stearate. In the third stage the above blends were compressed in bi-layer tablets with carefully controlled compression pressure. Finally the bi-layer tablets were film-coated. DISSOLUTION AND EQUIVALENCE 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.

Below are the results from the Example described earlier and of multiple tests that were undertaken between the test (fixed-combination) and the reference products (individual products) available in the market - GLUCOPHAGE SR and CRESTOR respectively. Table 2: Dissolution profile of Metformin HCl in pit 4.5 media

NLT = Not Less Than

Table 3: Dissolution profile of Rosuvastatin Ca in ph 6.6 media

As is evident from the dissolution results, the invention is able to create a stable formulation that has similar drug release profiles for rosuvastatin and metformin such that metformin is released in an extended release fashion and rosuvastatin is released in an immediate release fashion.

The individual components in the invention were also tested against the individual reference drugs, and were found to be of similar release pattern. These are provided in the Figure 2 and Figure 3.

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 metformin and rosuvastatin combined in one tablet wherein rosuvastatin is released immediately and metformin is released in controlled fashion; comprising pharmaceutically acceptable additives suitable for the preparation of solid dosage forms of a combination of metformin in sustained release form and rosuvastatin.

2. The solid dosage form of claim 1, wherein rosuvastatin and metformin are prepared in a bi-layer formulation.

3. The solid dosage form of claim 1 , wherein the rosuvastatin ranges from 5mg to 40mg, and the metformin ranges from 250mg to 2000mg.

4. The solid dosage form of claim 2, wherein the rosuvastatin and metformin are in a bi-layer tablet.

5. The solid dosage form of claim 2, wherein a first layer comprises the rosuvastatin and excipients comprising starch in an amount of 1-5% of the weight of the rosuvastatin layer, dicalcium phosphate in an amount of 0.5-

5% of the weight of the rosuvastatin layer, Cellulose in an amount of 20- 90% of the weight of the rosuvastatin layer, crospovidone in an amount of 2-30% of the rosuvastatin layer, and lubricants, such as sodium stearyl fumarate, in an amount of 0.1-2% of the weight of the rosuvastatin layer.

6. The solid dosage form in claim 2, wherein a second layer comprises

metformin granules which are created by combining metformin with cellulose in an amount of 0.5-5% of the weight of the metformin layer, a polymer in an amount of 5-20% of the weight of the metformin layer, and a water and organically soluble cellulose such as hydroxypropyl cellulose in an amount of 0.5-5% of the weight of the metformin layer. The solid dosage form of claim 6, wherein the metformin granules are further packed in the polymer to the weight of 5-30% of the weight of the metformin layer along with a lubricant, such as magnesium stearate, in an amount of 0.2-5% of the weight of the metformin layer.

The solid dosage form in claim 1, made by process comprising:

a. A First stage to develop the metformin extended release layer with the following steps:

i. Mix the intragranular ingredients in granulator, and granulate the above blend with binding agent;

ii. Dry the granules partially, pass through mill and dry the sized granules until optimum LOD obtained;

iii. Pass the dried granules through mill and sift the sized granules, and blend the granules; and

iv. Lubricate the above granules with magnesium stearate and b. In a second stage, a rosuvastatin layer blend is created by blending the excipients with rosuvastatin in a blender, and lubricating the ingredients with lubricants such as magnesium stearate; and

c. In a third stage the above blends are compressed in bi-layer tablets with carefully controlled compression pressure; and

d. A Fourth stage wherein the bi-layer tablets are film-coated.

The process of manufacturing where Step c in claim 8 is a force for compression for manufacturing rosuvastatin and metformin in bi-layer formulation ranging between 200 KiloNewtons and 500 KiloNewtons is used.

A method of treating hyperlipidemia, cardiovascular diseases,

simultaneously with type 2 diabetes comprising administering a solid dosage form of rosuvastatin and metformin to a patient in need of such a treatment.