EP3244880A1

EP3244880A1 - A stable bilayer pharmaceutical tablet compositions comprising fixed dose of irbesartan and amlodipine

Info

Publication number: EP3244880A1
Application number: EP15705399.2A
Authority: EP
Inventors: Hatice Öncel; Yilmaz Çapan; Onur Pinarbasli; Aslihan Arslan; Nagehan Sarraçoglu
Original assignee: Ilko Ilac Sanayi ve Ticaret AS
Current assignee: Ilko Ilac Sanayi ve Ticaret AS
Priority date: 2015-01-12
Filing date: 2015-01-12
Publication date: 2017-11-22
Also published as: WO2016114725A1

Abstract

The present invention relates to a stable bilayer pharmaceutical tablet composition comprising the angiotensin II receptor antagonist irbesartan having particle size d90 less than 30 microns and the calcium channel blocker amiodipine besilate in different layers. The present invention also provides a method of producing said bilayer tablet.

Description

A STABLE BILAYER PHARMACEUTICAL TABLET COMPOSITIONS COMPRISING FIXED DOSE OF IRBESARTAN AND AMLODIPINE

DESCRIPTION

Technical field:

The present invention relates to a stable bilayer pharmaceutical tablet composition comprising one layer of the angiotensin II receptor antagonist irbesartan having particle size d90 less than 30 microns and also granulating alone or at least one pharmaceutically acceptable excipients and the other layer of the calcium channel blocker amiodipine besilate. The present invention also provides a method of producing said bilayer tablet.

Prior Art:

Amiodipine is a calcium channel blocker developed for the treatment of hypertension and other medical indications as disclosed in USP 4,572,909 and USP 4,879,303. Its chemical name is 3-ethyl-5-methyl-(+-)-2-[(2-aminoethoxy) methyl]-4-(2- chlorophenyl)-1 ,4-dihydro- 6-methylpyridine-3,5-di-carboxylate.

Amiodipine is marketed as the monobenzenesulfonate salt, amiodipine besilate under the trade name Norvasc® or Istin®. It is available as oral tablets in strengths of 2.5 mg, 5 mg and 10 mg. The inactive ingredients in the Norvasc® tablets include microcrystalline cellulose, dibasic calcium phosphate anhydrous, sodium starch glycolate and magnesium stearate.

Amiodipine besilate is slightly soluble in water and has an absolute bioavailability of 64- 90%.

Irbesartan is described in Bernhart et al., U.S. Patent No. 5,270,317, incorporated herein by reference. Irbesartan, is a potent, long-acting angiotensin II receptor antagonist which is particularly useful in the treatment of cardiovascular ailments such as hypertension and heart failure. Its chemical name is2-n-butyl-4-spirocyclopentane- 1 -[(2'-(tetrazol-5- yl)biphenyl-4-yl)methyl]-2-imidazolin-5-one. Irbesartan is marketed by under the trade name Aprovel® or Karvea®.

Irbesartan is insoluble in water. Irbesartan has a parabolic pH solubility profile in aqueous medium with minimum solubility between pH 2.0 and pH 6.0 and maximum solubility in 0.1 N HCI and pH 7.5 phosphate buffer.

Pharmaceutical fixed dose compositions comprising irbesartan and amiodipine besilate is first described in WO2011001202 A1 (Sanofi Aventis). WO2011001202 A1 discloses solid stable pharmaceutical fixed dose compositions comprising irbesartan, amiodipine besilate and pharmaceutically acceptable excipients, to their preparation and to their therapeutic application.

Combination therapy is often required in patients with hypertension, and fixed-dose single- pill combinations have been shown to provide an easier regimen for patients, improving adherence.

Irbesartan/amlodipine is an angiotensin-receptor blocker/calcium-channel blocker fixed- dose single-pill combination, whose constituent drugs exert additive effects when coadministered.

Fixed-dose combination therapy with irbesartan/amlodipine was more effective than continuation of irbesartan or amiodipine monotherapy in patients with hypertension not adequately controlled with initial irbesartan or amiodipine monotherapy.

However, a combination of active ingredients is with drawbacks. Certain physical properties of the drugs and specifically stability, present a challenge in developing formulations suitable for preparing a tablet having reduced levels of total impurities on long term stability. Irbesartan is, for example, a fluffy material, with relatively low bulk and tap densities. It is also a sticky and abrasive material. These properties make it difficult to formulate an effective amount of the drug into a small tablet with uniformity of weight, hardness, and other desirable tablet properties.

The very low aqueous solubility of irbesartan also presents a challenge, since only limited amounts of excipients may be added to facilitate wetting, disintegration, and ultimately, rapid and complete drug release.

The dissolution rate of poorly soluble drugs such as irbesartan is strongly related to the particle size distribution. The specific surface area increased with decreasing particle size of the drug, resulting in an increase in dissolution rate.

The addition of a second active ingredient such as amlodipine besilate, which is also a fluffy material exhibiting poor flow and low aqueous solubility, can further contribute to problems such as tableting or uniformity of dosage units.

Concerning formulations containing Amlodipine besilate alone, WO2006/059217 discloses that amlodipine is highly hygroscopic and absorbs moisture, which leads to degradation. One of the major routes of degradation is via a catalytic oxidative process, which is pH dependent. One of the major degradation products known in the art is 3-ethyl-5-methyl-2- [(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methylpyridine-3,5 dicarboxylate and called Impurity D.

WO2003/051364 discloses Amlodipine besilate tablets with improved stability of the active ingredient and reduced in weight containing microcrystalline cellulose, a lubricant and a disintegrating agent and the process for the preparation of said tablets.

WO2008/062435 discloses a stable solid dosage form of amlodipine besilate comprising polyols and having reduced levels of total impurities on stability and especially impurity D.

WO2011001202 A1 from Sanofi Aventis discloses solid stable pharmaceutical fixed dose compositions comprising irbesartan, amlodipine besilate and pharmaceutically acceptable excipients, wherein irbesartan is physically separated from amlodipine besilate.

WO2011001202 A1 from Sanofi Aventis discloses solid dosage form is particularly advantageous since amlodipine besilate does not undergo degradation and this combination product shows reduced and controlled impurities even lesser than with regards to individual reference products of same dose when subjected to stress studies and in finished pack. In addition, the dissolution profile of both irbesartan and amlodipine besilate is not compromised by comparison to the dissolution profile of each active ingredient alone. WO2011001202 A1 from Sanofi Aventis discloses irbesartan under the form of coated granules is embedded in an extragranular matrix comprising amlodipine besilate. Preferably the solid composition of the invention takes the form of a monolayer tablet, preferably film coated.

Description of the Invention:

The object of the present invention is based on the recognition, which is fixed dose a stable bilayer pharmaceutical tablet composition comprising one layer of irbesartan having particle size d90 less than 30 microns, preferably less than 5 microns and the other of layer amlodipine besilate having adequate drug stability, optimum drug release of both active ingredients and reliable manufacturing process.

The bilayer pharmaceutical tablet composition characterized in that the level of impurities (w/w %) after 6 months at 40 ±2°C, 75 ±5 % RH in the total composition:

a) The level of total impurities is less than 2.0% (w/w), preferably less than 1.0% (w/w), b) The level unknown impurities is less than 0.5% (w/w), preferably less than 0.1 %(w/w),

c) The level of impurity A for Irbesartan is less than 0.2%(w/w)

d) The level of impurity D for Amlodipine is less than 1.0% (w/w), preferably less than 0.5% (w/w).

The dissolution performances of the bilayer tablet containing the combination of irbesartan and amlodipine besilate of the invention are similar to the dissolution performances of the tablets containing each active ingredient irbesartan or amlodipine alone.

Preparation of composition of the invention wherein Irbesartan and Amlodipine besilate are physically separated by both separate wet granulations.

The solid composition of the invention takes the form of a bilayer tablet, preferably film coated.

In a preferred embodiment of the composition according to invention, the irbesartan represents between about 40% and about 70% by weight of the total composition.

In a preferred embodiment of the composition according to invention the amlodipine besilate represents between about 1% and about 10% by weight of the total composition.

In a preferred embodiment of the composition according to invention the pharmaceutically acceptable excipients are selected from the group consisting of diluent, disintegrant, antiadherent, binder, lubricant and mixture thereof. In a preferred embodiment of the composition according to invention the amount of Irbesartan is comprised 150 mg or 300 mg of the total weight of the tablet.

In a preferred embodiment of the composition according to invention the amount of amlodipine besilate is comprised 6,94 mg or 13,87 mg (equivalent to 5 mg or 10 mg Amlodipine) of the total weight of the tablet.

According to another object, the invention is related to a process for the preparation of a stable oral pharmaceutical composition in a form of a bilayer tablet comprising irbesartan and amlodipine besilate, wherein the process comprises the steps of:

i. granulating irbesartan alone or at least one pharmaceutically acceptable excipients, with water, to form granules,

ii. drying the granules;

iii. granulating amlodipine besilate and one or more pharmaceutically acceptable excipients, with aqueous solution containing a binder or with water to form granules.

iv. drying the granules;

v. lubricating the blend of step ii. and iv; optionally after a pre-lubricating step; and vi. compressing the bilayer tablet

vii. optionally coating the core bilayer tablet.

The two actives are present in a bilayer tablet form wherein irbesartan and amlodipine besilate is physically separated from each other.

Pharmaceutically acceptable additives suitable for use in the present invention with amlodipine besilate layer is selected from suitable diluents such as Microcrystalline cellulose, Calcium Hydrogen Phosphate, suitable disintegrants such as Crospovidone and suitable lubricants such as magnesium stearate, suitable binders such as povidone.

Pharmaceutically acceptable additives suitable for use in the present invention with Irbesartan layer is selected from suitable diluents such as Microcrystalline cellulose, suitable disintegrant such as Croscarmellose sodium, suitable antiadherent such as silicone dioxide, suitable lubricants such as Magnesium Stearate, suitable binders such as hypromellose.

In the composition of the invention, the reference composition of Amlodipine besilate layer is Norvasc® composition and reference composition of Irbesartan layer is Karvea® composition.

The bilayer tablet according to the present invention generally contains 150 to 300 mg, of irbesartan and 5 to 10 mg of amlodipine. Presently preferred forms are bilayer tablets comprising 300 mg/10 mg, 300 mg/5 mg and 150 mg/5 mg of irbesartan and amlodipine, respectively.

Irbesartan layer, composition generally comprises 40 to 80 wt.%, preferably 70 to 80 wt.%, of active ingredient; 5 to 20 wt.%, preferably 10 to 20 wt.%, of diluent; 1 to 10 wt. %, preferably 2 to 8 wt.%, of disintegrant, 1 to 5 wt. %, preferably 2 to 4 wt.%, of binder, 0.25 to 5 wt.% , preferably 0.5 to 1 wt.% of antiadherent 0.5 to 1.5 wt. %, preferably 1 wt.%, of lubricant.

Amlodipine layer, composition generally comprises 5 to 20 wt.%, preferably 5 to 12 wt.%, of active ingredient; 25 to 90 wt.%, preferably 50 to 85 wt.%, of diluent; 1 to 15 wt. %, preferably 1 to 10 wt.%, of disintegrant, 1 to 5 wt. %, preferably 2 to 4 wt.%, of binder, 0.5 to 1.5 wt. %, preferably 1 wt.%, of lubricant.

In a further aspect, the present invention relates to an improvement in bilayer tableting technology and provides a method of producing a bilayer pharmaceutical tablet comprising the steps of; granulating irbesartan alone or at least one pharmaceutically acceptable excipients, with water, to form granules, drying the granules; and granulating amlodipine besilate and one or more pharmaceutically acceptable excipients, with aqueous solution containing a binder, to form granules, drying the granules; lubricating step, then compressing the bilayer tablet, coating the core bilayer tablets.

Example 1

Amlodipine Besilate layer

Ingredient Component Quantity (w/w)

Amlodipin Besilate (equivalent to

Active ingredient 5 - 12 %

Amlodipine)

Calcium Hydrogen Phosphate Diluent 30 - 55 %

Microcrystalline Cellulose Diluent 30 - 55 %

Povidone Binder 2 - 4 %

Crospovidone Disintegrant 1 - 10 %

Magnesium Stearate Lubricant 1 %

Dissolution Profiles:

The dissolution profiles of the products of the invention are compared to the dissolution profiles of the references products. The present invention has a dissolution performance such that 85% or grater of the irbesartan and 85% or grater of the amlodipine contained in the bilayer tablet composition dissolves within 15 minutes, wherein the dissolution performance is measured using USP apparatus 2 placing the bilayer tablet in 900 mL of 0.1 N HCI at 37±0.5°C with a paddle speed of 75 rpm.

The results as illustrated in figures 1 and 2 show that the dissolution performances of the tablet containing the combination of irbesartan and amlodipine besilate of the invention are equivalent to the dissolution performances of the tablets containing each active ingredient irbesartan or amlodipine alone.

Stability Studies:

The oral pharmaceutical compositions of the present invention were subjected to accelerated stability studies at the following conditions; 40 ±2°C, 75 ±5 % relative humidity RH. These were evaluated on the basis of assay, in vitro dissolution, moisture content and related substances measured between initial and 6-months time points for irbesartan as well as amlodipine besilate. This test is carried on under the following conditions. The tablets were packed in to the Opaque duplex (PVC/PVdC) blister pack and such blister were further packed in to the cartons, and cartons were charged on to the stability as per ICH guidelines, and samples were taken out at each stability stage interval and submitted for analysis.

The stability results at 40 ±2°C, 75 ±5 % RH are provided in Table 1.

The bilayer pharmaceutical tablet composition has less than 2.0% and more preferably less that 1.0% (w/w) of total impurities in the total composition, less than 0.5% and more preferably less that 0.1 %(w/w) of unknown impurities in the total composition, less than 0.2%(w/w) of impurity A for Irbesartan and less than 1.0% more preferably less that 0.5% (w/w) of impurity D for Amlodipine is found in the composition of the invention after 6 months at 40 ±2°C, 75 ±5 % RH.

Table 1. The stability results at 40 ±2°C, 75 ±5 % RH (t=6 months)

Note: Impurity-A from Irbesartan, Impurity-D from Amlodipine, Unknown Impurities and Total Impurities are calculated in %w/w of the total composition

Claims

1. A stable solid oral pharmaceutical fixed dose composition in a form of a bilayer tablet comprising irbesartan and amiodipine besilate in different layers characterized in that irbesartan has particle size d90 less than 30 microns.

2. The pharmaceutical composition of claim 1 , wherein irbesartan has particle size d90 less than 5 microns.

3. The pharmaceutical composition of claim 1 , characterized in that the level of impurities (w/w%) after 6 months at 40 ±2°C, 75 ±5 % RH in the total composition

a) The level of total impurities is less than 2.0% (w/w),

b) The level of unknown impurities is less than 0.5% (w/w),

c) The level of impurity A for Irbesartan is less than 0.2%(w/w)

d) The level of impurity D for Amiodipine is less than 1.0% (w/w).

4. The pharmaceutical composition of claim 1 , characterized in that the level of impurities (w/w%) after 6 months at 40 ±2°C, 75 ±5 % RH in the total composition

a) The level of total impurities is less than 1.0% (w/w),

b) The level of unknown impurities is less than 0.1 %(w/w),

c) The level of impurity A for Irbesartan is less than 0.2%(w/w)

d) The level of impurity D for Amiodipine is less than 0.5% (w/w).

5. The pharmaceutical composition according to claim 1, wherein irbesartan is granulating alone or at least one pharmaceutically acceptable excipients with water.

6. The pharmaceutical composition according to claim 1 , wherein amiodipine besilate is granulating one or more pharmaceutically acceptable excipients with aqueous solution containing a binder.

7. The pharmaceutical composition according to claim 1 , wherein the amount of irbesartan is 150 mg or 300 mg in the bilayer tablet.

8. The pharmaceutical composition according to claim 1 , wherein the amount of amiodipine besilate is 6,94 mg or 13,87 mg (equivalent to 5 mg or 10 mg Amiodipine) in the bilayer tablet.

9. The pharmaceutical composition according to claim 1 , wherein it comprises 70 to 80 wt. irbesartan, 10 to 20 wt.% of microcrystalline cellulose, 2 to 8 wt.% of croscarmellose sodium, 0.5 to 1 wt.% of silicone dioxide, 2 to 4 wt.% of hypromellose and about 1 wt.% of magnesium stearate in irbesartan layer.

10. The pharmaceutical composition according to claim 1 , wherein it comprises 5 to 12 wt.% of amlodipine besilate, 50 to 85 wt.% of microcrystalline cellulose and/or calcium hydrogen phosphate, 1 to 10 wt.% of crospovidone, 2 to 4 wt.% of povidone and about 1 wt.% of magnesium stearate, in amlodipine layer.

11. The pharmaceutical composition of claim , it has a dissolution performance such that 85% or greater of the irbesartan and 85% or grater of the amlodipine within 15 minutes, wherein the dissolution performance is measured using USP apparatus 2 in 900 mL of 0.1 N HCI at 37±0.5°C with a paddle speed of 75 rpm.