MX2014011167A

MX2014011167A - Oral tablet formulation consisting of immediate release rosuv astatin and extended release metformin.

Info

Publication number: MX2014011167A
Application number: MX2014011167A
Authority: MX
Inventors: Marie Charmaine Dias
Original assignee: Althera Life Sciencies Llc
Priority date: 2012-03-19
Filing date: 2013-03-15
Publication date: 2014-11-14
Also published as: WO2013142314A1; EP2844067A1; EP2844067A4

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

FORMULATION OF SOLID ORAL TABLET OF ROSUVASTATIN OF IMMEDIATE RELEASE AND METFORMINE OF PROLONGED RELEASE.

DESCRIPTION OBJECT OF THE INVENTION The present invention is directed to a solid dosage product whose formulation contains a fixed combination of rosuvastatin and metformin, such that rosuvastatin is immediately administered to the patient and metformin is administered in a controlled manner over a long period of time, also described as prolonged release, as well as the methods of making the solid dosage forms and the use of the solid dose form containing a fixed combination of rosuvastatin and metformin in the manufacture of a medicament useful in the treatment of patients with fixed combinations of solid dosage forms of immediate-release rosuvastatin and extended-release metformin.

BACKGROUND.

Large-scale clinical studies, epidemiological studies and population reviews conducted by different organizations such as the International Diabetes Federation (IDF), The European Association for the Study of Diabetes (European Association for the Study of Diabetes Diabetes (EASD)), the World Health Organization (World Health Organization (WHO)), the National Cholesterol Education Program (NCEP) and the Center for Disease Control (Center for Disease Control) (CDC)) have identified Diabetes as the major risk factor related to cardiovascular events and mortality. The monitoring of the cohort mortality of EUROASPIRE I showed that in addition to smoking, diabetes is the most important risk factor for coronary artery diseases and subsequently cardiovascular morbidity and mortality. In sum, cardiovascular events are the leading 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 the recommended lipid ranges in relation to low density lipoproteins (LDL-C), high density lipoproteins (HDL-C) or apolipoproteins (ApoB) recommended by the American Diabetes Association (ADA), the National Cholesterol Education Program (NCEP) and the European Union Working Group of the European Society of Cardiology (ESC) and the European Association for the Diabetes Study (European Association for the Study of Diabetes (EASD)), therefore maintaining these patients at high risk for premature cardiovascular diseases and death.

There is significant evidence that fixed combination dosing products improve adherence to medication and patient compliance due to a reduced load of pills and the improvement in the ease of administration. It has been demonstrated that the adherence to medication in cardiovascular diseases and in particular to hyperlipidemia is lower than desired, which frequently results in an inability to reach the objectives of the treatment as recommended by the European Society of Cardiology (ESC) and the National Program of Education on Cholesterol (NCEP) ATP III.

Adherence to anti-diabetic medications is also a major problem in patients with type 2 diabetes who frequently need 2-4 different anti-diabetic drugs to lower their HbA levels to the recommended levels. To worsen the burden of pills even more, many patients with diabetes and hyperlipidemia also suffer from hypertension since many of these patients suffer at least some degree of metabolic syndrome. Therefore, any action that can reduce the load of pills and facilitate adherence to medication could be very beneficial.

The development of this invention needs to be observed within this context. Adherence to the patient's medication has shown to be significantly greater with a regimen of a single pill compared to a regimen of two pills, or with a regimen of two pills compared to a regimen of three or four pills. Concerns about increasing the burden of pills to the patient often result in doctors' reluctance to add more medications to the patient's current regimen despite the potential for therapeutic benefits.

Accordingly, a solid dose formula of a fixed combination of metformin and rosuvastatin which is bioequivalent and corresponds to a free combination would be highly desirable for the benefit of the patients.

US 2008/0187581 A1, refers to delivery systems in the form of solid compositions such as, for example, tablets or capsules. In one embodiment, a unit dose composition of more than two active ingredients is provided wherein the active ingredients have different release profiles, various active agents or a mixture thereof fall within the scope of this invention, however unlike the invention of the present application is not simple to choose the combination metformin-rosuvastatin since the list of possible active ingredients is very large, which makes the invention object of the present application is a new and inventive combination, compared to that described in the document, coupled with the fact that the document does not specify the doses of the active ingredients, nor which is controlled release and which immediate release.

US 2006/0240095 A1 discloses that the combination of metformin with a statin leads to a significant improvement of hyperglycemia in a diabetic patient. The combination of metformin with a statin has never been described in the prior art. The invention relates to a pharmaceutical composition comprising, as active ingredients, (i) metformin, and (ii) a statin, in combination with one or more excipients pharmaceutically acceptable This composition is particularly suitable for reducing hyperglycemia in patients with non-insulin-dependent diabetes and for improving insulin resistance. It can also be used in non-dyslipidemic patients or in dyslipidemic patients. In the composition described, if rosuvastatin is used, the amount is between 4 to 80 mg, more preferably 10 to 20 mg per day. The method and combination of the combination are useful for the prevention, inhibition and treatment of hyperglycemia, non-insulin dependent diabetes, dyslipidemia, hyperlipidemia, hypercholesterolemia, obesity and cardiovascular diseases. However, in the document the choice of rosuvastatin is made from the statin family, that is, it is an option of a group of compounds, besides it does not describe that rosuvastatin is immediate release and metformin prolonged release.

US 2006/0024365, relates to modified release compositions in general and describes all medicaments of less than 500 mg in immediate release form, and all therapeutic classes (eg, the description of any drug for any disease) and hundreds of molecules that may be relevant, however, it does not disclose rosuvastatin and does not provide any specific oral doses for rosuvastatin, therefore it is not a relevant document for the invention described in the present application.

BRIEF DESCRIPTION OF THE FIGURES.

Figure 1: shows the average release pattern of Metformin and Rosuvastatin concentration when administered to 10 healthy human volunteers, on the X axis the time is plotted and on the Y axis the percent concentration of relative Metformin or Rosuvastatin absorbed is represented at the maximum concentration on variable points of time from 0 to 96 hours.

In Figure 2: Comparison of the release and concentration pattern of Metformin is shown when administering the composition of the invention and GLUCOPHAGE® in 10 healthy human volunteers.

Figure 3 shows the comparison of the release and concentration pattern of Rosuvastatin when administering the composition of the invention and CRESTOR® in 10 healthy human volunteers.

DETAILED DESCRIPTION OF THE INVENTION.

In a first aspect, the present invention is a fixed combination product of oral administration consisting of immediate-release rosuvastatin and prolonged-release metformin, that is, metformin is administered to the patient for a prolonged period of time as indicated for simultaneous treatment of type 2 diabetes and hyperlipidemia or for risk reduction cardiovascular. This novel product simultaneously provides treatment for diabetes and hyperlipidemia overcoming a significant difference in dosage between the two individual ingredients and provides a novel product that reduces low density cholesterol (LDL), the potential cardiovascular risk and glucose levels in patients with diabetes when simultaneously treating hyperglycemia and hyperlipidemia.

In a second aspect, the present invention is a new formulation consisting of immediate-release rosuvastatin and extended-release metformin in such a manner that both rosuvastatin and extended-release metformin in a single tablet have the same area under the curve as two active ingredients that are taken orally together individually and the pharmaceutically acceptable additives convenient for the preparation. In the preferred embodiments of this invention, 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 present invention overcomes the challenge of significantly formulating two different drugs with two different release times.

In the preferred embodiments of this invention, the solid dosage form is a two-layer or two-layer tablet. The amount of rosuvastatin used in said bilayer tablets preferably ranges from 5 mg to 40 mg, including 10 mg and 20mg The amount of metformin ranges from 250mg to 2000mg, including 500mg, 750mg, 850mg, 1000mg, 1250mg and 1500mg.

In a third aspect, the present invention is directed to a method for preparing a dosage form of bilayer of rosuvastatin to be released immediately and metformin for prolonged release. The first stage is to develop the extended release metformin layer with the following steps: (a) Mix the intragranular ingredients in the granulator and granulate the above mixture with a binding agent; (b) Partially dry the granules, pass them through the mill and dry the calibrated granules until an optimum desired level (LOD) is obtained; (c) Pass the dried granules through the mill and sift the granules to a size and mix the granules; and d) lubricating the above granules with magnesium stearate. In the second stage, a layer of rosuvastatin is created by mixing the excipients with rosuvastatin in a mixer and lubricating the ingredients with lubricants such as magnesium stearate. In the third stage, the above mixtures are compressed into double layer tablets with careful pressure control. Finally, the bilayer tablets are coated with a film.

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

The fifth aspect of this invention is directed to the use of the invention (oral solid dose form) in the treatment of hyperlipidemia, diseases cardiovascular, simultaneously with type 2 diabetes comprising the administration of a solid dosage form of rosuvastatin and metformin to a patient in need of such treatment. In a preferred embodiment, the solid dosage form is administered orally to the subject.

The present invention is directed to a solid dosage form whose formulation contains a fixed combination of rosuvastatin and metformin in such a way that rosuvastatin is immediate release and metformin is released in a controlled manner for a long period of time, also known as metformin of prolonged release, as well as to methods of preparing such solid dosage forms and to the use of the dosage form to which the present invention relates in the treatment of patients with fixed combination of solid dosage forms of immediate-release rosuvastatin and metformin prolonged release.

The first embodiment of the invention is a fixed combination which provides metformin in prolonged form and rosuvastatin immediately to the patient. A number of clinical studies have shown that a substantial proportion of patients with diabetes do not reach the recommended lipid ranges in relation to low density lipoproteins (LDL-C), high density lipoproteins (HDL-C) or apolipoproteins (ApoB) recommended by the American Diabetes Association (ADA, the National Cholesterol Education Program (NCEP) and the European Union Working Group of the European Society of Cardiology (ESC) and the European Association for the Study of Diabetes (EASD), therefore keeping these patients at high risk for diseases premature cardiovascular diseases and death. There is significant evidence that fixed combination dosing products improve adherence to medication and patient compliance due to a reduced load of pills and that ease of administration is improved. It has been demonstrated that the adherence to medication in cardiovascular diseases and in particular to hyperlipidemia is lower than desired, which frequently results in an inability to reach the objectives of the treatment as recommended by the European Society of Cardiology (ESC) and the National Program of Education on Cholesterol (NCEP) ATPIII. Adherence to anti-diabetic medications is also a major problem since patients with type 2 diabetes often need 2 to 4 different anti-diabetic drugs to lower their HbAlc levels to the recommended levels. To worsen the burden of pills even more, many patients with diabetes and hyperlipidemia also suffer from hypertension since many of these patients suffer at least some degree of metabolic syndrome. Therefore, any action that can reduce the load of pills and facilitate adherence to medication could be very beneficial. The development of this invention needs to be observed considering this purpose. The patient's adherence to medication has been shown to be significantly greater with a regimen of a single pill compared to a regimen of two pills, or at a regimen of two pills compared to a regimen of three or four pills. The concern about increasing the burden of pills to the patient often results in the doctors' resistance in adding more drugs to the patient's current regimen despite the potential for therapeutic benefits.

Metformin and rosuvastatin are 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 a day. However, metformin is indicated to be consumed multiple times varying from 6 to 8 hours during the day. Given the difference in the dosage pattern, this invention created a new product where the product releases rosuvastatin immediately when it is consumed by the patient, and where metformin is released in a controlled manner for a longer period of time and thus achieving the Multiple dosage requirements of metformin. Therefore, this invention creates a new product that treats both diabetes and hyperlipidemia with a single oral dose so that the patient consumes it once daily.

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

The second embodiment of this invention is a new formulation consisting of immediate-release rosuvastatin and extended-release metformin and, like both, rosuvastatin and prolonged-release metformin in a single tablet, they are expected to have the same area under the curve as two active ingredients that are taken orally together individually and with the pharmaceutically acceptable additives and convenient for the preparation. In the preferred embodiments of this invention, rosuvastatin is in the form of calcium rosuvastatin and pharmaceutically acceptable additives which are selected from diluents, disintegrants, binding agents, lubricants, colorants and the resulting combinations. The present invention overcomes the challenge of significantly formulating two different drugs with two different release times. In the preferred embodiments of this invention, the solid dosage form is a two-layer tablet. The amount of rosuvastatin used in such two-layer tablets preferably ranges from 5 mg to 40 mg, including 10 mg and 20 mg. The amount of metformin ranges from 250mg to 2000mg, including 500mg, 750mg, 850mg, 1000mg, 1250mg and 1500mg.

The creation of a tablet that has two different times of release of rosuvastatin and metformin is a significant challenge. Recognizing this challenge, the inventors developed a strategy using two layers of metformin and one of rosuvastatin. The strategy included rosuvastatin in the upper or outer layer of the tablet such that the release of the active ingredient from rosuvastatin precedes the metformin layer. And the metformin layer that includes granules that control the release of metformin in the human stomach.

In this embodiment, the rosuvastatin layer of the formulation consists of rosuvastatin as the active ingredient with excipients such as starch 1-5% by weight of the rosuvastatin layer, dicalcium phosphate 0.5-5% by weight of the rosuvastatin layer , cellulose 20-90% by weight of the rosuvastatin layer, crospovidone 2-30% by weight of the rosuvastatin layer and lubricants such as sodium stearyl fumarate 0.1-2% by weight of the rosuvastatin layer. In this modality the metformin granules are created by combining metformin with cellulose 0.5-5% by weight of the metformin layer, a polymer 5-50% by weight of the metformin layer and organically soluble water and cellulose such as hydroxypropylcellulose 0.5-5% of the weight of the metformin layer. These granules are also packed in the polymer to the weight of 5-30% by weight of the metformin layer together with a lubricant such as magnesium stearate 0.2-5% by weight of the metformin layer.

In a third embodiment, the present invention is directed to a method of preparing a bilayer dosage form of rosuvastatin to be released immediately and metformin to be released in a prolonged manner. The first stage is to develop the prolonged release layer of metformin with the following steps: (a) Mix the intragranular ingredients in the granulator and granulate the above mixture with a ligation agent; (b) Partially dry the granules, pass them through the mill and dry the calibrated granules until an optimum (LOD) level is obtained; (c) Pass the granules dry through mill and sift the granules to a size and mix the granules; and d) lubricating the above granules with magnesium stearate.

In the second stage, a rosuvastatin layer mixture is created by mixing the excipients with rosuvastatin in a mixer and lubricating the ingredients with lubricants such as magnesium stearate. In the third stage, the above mixtures are compressed into double layer tablets with careful pressure control. Finally, the bilayer tablets are coated with a film.

A key element of the embodiment of this invention is the compression pressure in 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 the other ingredient of the tablet to be extended release, the one that can be produced and compressed at the same time meant significant challenges. For example, when the compression pressure was higher, the immediate-release component of rosuvastatin would release more slowly than optimal and if the compression pressure was too low, prolonged-release metformin would release too quickly.

An example of this problem is described in Table 1, which compares the release of a reference monotherapy tablet from rosuvastatin (established as CRESTOR® 20mg) compared to a test tablet established as E111 (T750 / 20).

TABLE 1: RELEASE OF ROSUVAST ATINA IN THE TEST PRODUCT WITH VARIABLE COMPRESSION COMPARED TO THE REFERENCE PRODUCT (CRESTOR).

The above problem was solved by adjusting the compression pressure of the double-layer machine to an optimal release pattern, which is an important part of the third embodiment of this invention. The compression pressure range varies between 200 KiloNewtons and 500 KiloNewtons.

The final embodiment of this invention is directed to the use for treating hyperlipidemia, cardiovascular diseases, simultaneously with type 2 diabetes which comprises manufacturing a drug in solid dosage form of immediate-release rosuvastatin and extended-release metformin, to administer this form solid dose to a patient in need of such treatment. In a preferred embodiment, the solid dosage form is orally administered to the subject.

EXAMPLES EXAMPLE 1: Fixed combination of one tablet of rosuvastatin 20mg and metformin 750mg.

The above ingredients were used to produce a tablet according to the third embodiment of this invention, where the steps that were carried out were: In the first stage, the extended-release metformin layer was developed with the following steps: (a) The intragranular ingredients were mixed in the granulator and the above mixture was granulated with a binding agent; (b) The granules were partially dried, passed through the mill and the calibrated granules dried until an optimum desired level (LOD) was obtained; (c) The dried granules were passed through the mill and the calibrated granules were sieved and the granules were mixed: and (d) The above granules were lubricated with magnesium stearate.

In the second stage, a rosuvastatin layer mixture was created by mixing the excipients with rosuvastatin in a mixer and lubricating the ingredients with lubricants such as magnesium stearate.

In the third stage, the above mixtures are compressed into double-layer (bilayer) tablets with careful pressure control. Finally, the bilayer tablets are coated with a film.

EXAMPLE 2: Fixed combination of a tablet of rosuvastatin 10mg and metformin 500mg.

The above ingredients were used to produce a tablet according to the third embodiment of this invention, where the steps that were carried out were: In the first stage the prolonged release layer of metformin was developed with the following steps: (a) mixed the intragranular ingredients in the granulator and granulated the above mixture with a binding agent; (b) The granules were partially dried, passed through the mill and the calibrated granules dried until an optimum desired level (LOD) was obtained; (c) The dried granules were passed through the mill and the calibrated granules were sieved and the granules were mixed: and (d) The above granules were lubricated with magnesium stearate.

RESULTS OF DISSOLUTION AND EQUIVALENCE.

Dissolution is a recognized method for testing the drug-equivalence of two products. The drug equivalence of the fixed combination dosage forms of the present invention was compared to that of the corresponding free combinations.

Below are the results of the example described above and the multiple tests that were carried out between the test (fixed-combination) and the reference products (individual products) available on the market © GLUCOPHAGE SR and CRESTOR®, respectively.

TABLE 2: Dissolution profile of Metformin-HCl in pH 4.5 medium.

TABLE 3: Dissolution profile of Rosuvastatin calcium in pH 6.6 medium.

As is evident from the dissolution results, the invention is capable of creating a stable formulation having similar profiles for the release of the drug rosuvastatin and metformin since metformin is released in extended-release form and rosuvastatin is immediate-release.

The individual components in the invention were also tested against the individual reference drugs and found to have similar release patterns. These are provided and illustrated in Figures 2 and 3.

While this invention has been particularly exemplified and described with references to preferred embodiments, consequently those of ordinary skill in the art and skill in the art will understand that various changes in form and detail can be made without departing from the scope of the invention. application of the invention encompassed by the appended claims.

Claims

CLAIMS. Having sufficiently described my invention, I consider it a novelty and therefore claim as my exclusive property, what is contained in the following clauses:

1 . - A combined solid dosage form of metformin and rosuvastatin in a single tablet characterized, because the dose of rosuvastatin is 5 mg to 40 mg and the dose of metformin is 250 mg to 2000 mg, and where rosuvastatin is immediate release and metformin is provided in the form of granules that release metformin for a long time.

2. - The solid dosage form according to claim 1, wherein the rosuvastatin and the metformin are prepared in a bilayer formulation.

3. - The solid dosage form according to claim 2, wherein the rosuvastatin and the metformin are in a double layer tablet.

4. - The solid dosage form according to claim 2, characterized in that the rosuvastatin layer of the formulation consists of rosuvastatin as the active ingredient, with excipients such as starch of 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 rosuvastatin layer, and lubricants such as sodium stearyl fumarate 0.1- 2% of the weight of the rosuvastatin layer.

5. - The solid dosage form according to claim 2, characterized in that it comprises metformin granules which are created by the combination of metformin with cellulose 0.5-5% by weight of the layer of metformin, a polymer of 5-20% by weight of the metformin layer, and organically soluble water and cellulose, such as hydroxypropylcellulose 0.5-5% by weight of the metformin layer.

6 -. 6 - The solid dosage form according to claim 1, made by the manufacturing process characterized by the following steps: a) First stage or formation of the prolonged release layer of metformin with the following steps: i. Mix the intragranular ingredients in granulator, and granulate the above mixture with the binding agent; ii. Dry the granules partially, pass through the mill and dry the granules of calibrated size until obtaining an optimum desired level (LOD); iii. Pass the dried granules through mill and sift granules of size, and mix the granules iv. Lubricate the above granules with magnesium stearate. b) In the second stage, a mixture of the rosuvastatin layer is created by mixing the excipients with rosuvastatin in a mixer, and lubricating the ingredients with lubricants such as magnesium stearate, c) In the third stage, the above mixtures are compressed into double layer tablets with carefully controlled compression pressure ranging from 200 kiloNewtons to 500 kiloNewtons. d). A fourth stage in which the double layer tablets are coated with a film.

7. - The use of a combination dosage form of metformin and rosuvastatin according to claim 1, for the manufacture of a medicament for the treatment of hyperlipidemia and cardiovascular diseases, simultaneously with type 2 diabetes, characterized in that a Combined oral dose form of metformin and rosuvastatin, where the dose of rosuvastatin is immediate release and comprises from 5 mg to 40 mg and prolonged-release metformin from 250 mg to 2000 mg.