WO2015018794A1

WO2015018794A1 - A pharmaceutical composition containing ropinirole hcl administrable by oral route, and manufacturing method thereof

Info

Publication number: WO2015018794A1
Application number: PCT/EP2014/066729
Authority: WO
Inventors: Roberto Valducci; Serozh Avanessian
Original assignee: Valpharma International S.P.A.
Priority date: 2013-08-05
Filing date: 2014-08-04
Publication date: 2015-02-12
Also published as: ITFI20130189A1

Abstract

The present invention describes a sustained-release multilayer tablet for the oral administration of Ropinirole, said tablet wherein each layer includes Ropinirole and a retardant matrix comprising a hydrophobic lipid-waxy excipient with a melting temperature below 100° C.

Description

A PHARMACEUTICAL COMPOSITION CONTAINING ROPINIROLE HCL ADMINISTRABLE BY ORAL ROUTE, AND MANUFACTURING METHOD THEREOF. Field of the Invention

The present invention relates to the field of the pharmaceutical compositions containing Ropinirole, in particular it relates to a composition containing Ropinirole HCI in the form of tablets for oral administration.

State of the Art

Ropinirole, having chemical formula 4-[2-(dipropylamino)ethyl]-1 ,3-dihydro-2H- indol-2-one, is a non-ergoline dopamine agonist, and is therefore used in the treatment of Parkinson's disease. Because of the pathological aspects of the disease, formulations containing Ropinirole require a constant in-vitro release, to balance the dopamine deficit during the span of 24 hours; for this reason a zero- order release kinetics is required.

In WO01 /78688, three-layer tablets containing Ropinirole HCI, in which the active principle is present only in the inner layer, associated with two external barrier layers, are described. The tablets may be coated.

Said three-layer tablets comprise, in the inner layer, Ropinirole, hydroxypropylmethyl cellulose (HPMC), used as hydrophilic polymer component, in combination with hydrogenated castor oil, used as hydrophobic component, and further comprise, sodium carboxymethylcellulose (CMC), used as a viscosity regulator, lactose, used as a soluble diluent, and maltodextrin, used as a binder. Said three-layer tablets comprise, in the external barrier layers, Glyceryl Behenate, a hydrophobic lipid component, in association with hydroxypropyl methyl cellulose (HPMC), used as hydrophilic polymer. In order to increase the permeability, said external barrier layers further comprise mannitol or lactose, as soluble diluents. Essentially, considering the nature of the disease, the need to have formulations with extended release in time has to be noted. The dopamine deficiency has pathological profiles that change throughout the course of the disease itself; for this reason it is necessary to develop technologies and formulations quite malleable and easy to modify, in order to easily respond to the needs of the entire timeframe of the disease.

The purpose of this patent application is to provide a pharmaceutical composition, and manufacturing method thereof, for the oral administration of Ropinirole with a zero-order sustained-release {i.e. at constant rate).

Summary of the Invention

It is object of the present patent application a multilayer Ropinirole sustained- release tablet, said tablet comprising at least two layers, each of said layers comprising Ropinirole, or pharmaceutically acceptable salts thereof; wherein at least two of these layers contain different amounts of Ropinirole.

Each layer of the tablet has a retardant matrix comprising a hydrophobic lipid-waxy excipient with a melting temperature below 100°C.

The tablet of the invention is suitable for the oral administration of Ropinirole, or pharmaceutically acceptable salts thereof, with a zero-order sustained-release (i.e. constant release kinetics).

It is also subject-matter of the present invention a method of manufacturing a tablet as described above, said method comprising hot granulation of the components of each layer, without the addition of any solvents or binders.

Brief Description of the Drawings

Figure 1 schematically shows, in vertical section, two preferred embodiments of the tablet of the invention.

Detailed Description of the Invention

Preferably, the hydrophobic lipid-waxy excipient, with a melting temperature below 100°C, is selected from the group consisting of mono-, di- or tri-glycerides of fatty acids containing at least 16 carbon atoms such as, for example, glyceryl palmitostearate, glyceryl behenate, glyceryl monopalmitostearate, mono- or di- glyceryl behenate.

Preferably, each layer of the tablet has a retardant matrix comprising an association of a hydrophobic lipid-waxy excipient, with a melting temperature below 100 °C, and a hydrophilic polymer excipient. Preferred examples of hydrophilic polymer excipients are cellulose derivatives, such as hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxypropyl methyl cellulose (HPMC).

The retardant matrix preferably comprises an association of Glyceryl Behenate and HPMC, which is able to gel in contact with water; specifically, the matrix has a canalized structure: HPMC gels and then solubilises in contact with water, and leaves free channels within the insoluble structure of Glyceryl Behenate, from which the active principle can leak. The quantities of the two excipients are included in a weight ratio ranging from 1:1 to 1:3 of Glyceryl Behenate: HPMC. To further increase the permeability of the active principle, water soluble diluents {e.g. Maltodextrin and Mannitol) in a percentage ranging from 1 0% to 40% can be added.

Preferably, in the tablet according to the invention, Ropinirole is in the form of HCI salt.

The tablet of the invention can further comprise compression excipients, such as glidants and/or lubricants, and can optionally comprise colouring agents or pigments to differentiate the layers with different colours.

The compression excipients are preferably magnesium stearate (lubricant) and anhydrous colloidal silica (glidant). The colouring agent is preferably iron oxide (yellow) used for colouring the external layers (I) and (I I I).

The tablet object of the invention may optionally be coated.

The tablet object of the invention preferably comprises at least three layers, wherein at least two of said layers contain different amounts of Ropinirole.

Even more preferably, the tablet of the invention consists of three layers: possible geometric configurations representing preferred embodiments of the present invention are specifically shown in Fig.1 .

The three layers can have very similar excipient compositions, except that the amount of the active principle in the inner layer (I I) differs from the outer layers (I) and (I I I). The greater amount is in the central layer (I I); in the outer layers (I) and (I I I) smaller quantities are present, which may be the same or different between them, according to the formulation needs. Preferably, the tablet object of the invention has an inner layer (II), containing the higher amount of Ropinirole, having the following composition:

Preferably, the tablet object of the invention has the outer layers (I) and (III), containing the lower amount of Ropinirole, having the following composition:

Within the three layers mentioned above, the Active Principle (AP = Ropinirole) is present in different percentages. In the inner layer (II) the largest quantity of Ropinirole, which is responsible of the massive release during the last hours under examination, is found. Associated with and adjacent to the inner layer (II), there are the outer layers (I) and (III), in which Ropinirole is present in lower amounts, which serve to ensure a certain initial release of PA, which would otherwise be too low (almost zero) if it was only due to release by the central layer in contact with the outside.

Moreover, this formulation arises also from the need to overcome the issue of formulations having a too high release in the first hours, and too low releases at the end of the 24 hours. The basic principle of these three-layer tablets is then, precisely, to lower the early releases by decreasing the contact surface of the central layer (containing most of the active principle) with the exterior, thereby increasing subsequent releases, once the two outer layers will be fully hydrated. For the tablet according to the invention, the releases during the first hours will basically depend on the amount of Ropinirole in the outer layers, while the releases of the last hours will depend on the amount of Ropinirole in the inner layer.

From this concept, it can therefore be inferred that the release profile of the active principle, as well as depend on the nature of the formulation, as in any modified release formulation, depends also, and above all, on the different Ropinirole ratio between the inner layer and the outer layers. This feature not only ensures that it is possible to have a very wide range of release profiles, so that a variety of formulation requirements can be achieved, but it also provides the opportunity to develop, easily and with little modification, dosage forms suitable for every pathological step of the disease, characterised by a dopamine deficiency that changes during the course of the same.

Contrary to what reported in the literature (in particular in the patent WO01/78688), it has been unexpectedly noted that the combination of Glyceryl Behenate and Ropinirole in all layers has led to release profiles fully superimposable to those of the compositions known in the art (in particular those described in WO01 /78688). It is also an object of the present invention a manufacturing method of the tablet described above, said method being substantially different from any other known formulation.

The method according to the invention involves a hot granulation, without any addition of solvents and binders (such as PVP).

Preferably, the manufacturing method of the tablet of the invention comprises the following steps:

cold mixing (at a temperature between 15 and 30 °C) of the components of each layer;

heating each mixture, under stirring, up to a temperature not exceeding

100°C, leading to the melting of the hydrophobic lipid-waxy excipient, which therefore acts as a binder;

sieving each mixture, when still hot, to obtain the granulates for each layer, cooling each granulate;

optionally mixing each granulate with compression excipients;

compression of the granules to form the multilayer tablet. The %, both those above and those indicated below in the embodiment examples, are all % w/w referred to the total weight of each layer.

Examples of formulation and manufacturing methods thereof are reported below: EXAMPLE 1

Manufacturing of three-layer tablets comprising 9.12 mg of Ropinirole HCI (0.5 mg in the layer (I) - 8.12 mg in the layer (II) - 0.5 mg in the layer (III))

The starting granulates are prepared first. The (I) and (III) layer, having identical composition, are prepared together.

The granulates have the following compositions:

(I) - (III) layer

The Glyceryl Behenate and HPMC are in a ratio of 1:1.2, while the content of soluble excipients is of 24.85%.

(II) layer

The glyceryl behenate and HPMC are in a ratio of 1:1.22, while the content of soluble excipients is of 23.01%. Both granulates are produced in a double jacket heated cutter. The components are cold mixed, after which the product is heated, always under stirring, up to a product temperature of 75±5°C; by doing so, the glyceryl behenate melts, acting as a binder. The product is sieved, still hot, in a shale shaker and allowed to cool.

The granulates are then mixed with compression excipients, and compressed in a Manesty Layerpress three-layer press using punches having 13x7mm size.

Considering an AP quantity equal to 0.5 mg in the outer layers and 8.12 mg in the inner layer, tablets with the following composition are obtained:

FIRST LAYER (0.5 mg)

The tablets are then analysed with Basket at 100 rpm using Phosphate Buffer pH 6.8 / 900 ml as a medium, obtaining the following in vitro releases: Time %

lh 12.2

2h 19.1

4h 30.2

6h 39.3

8h 47.4

12h 61.5

16h 74.1

20h 84.6

24h 91.8

EXAMPLE 2

The granulates have the following compositions: (I) - (III) layer

The glyceryl behenate and HPMC are in a ratio of 1:1.36, while the content of soluble excipients is of 30.63%. (II) layer

The glyceryl behenate and HPMC are in a ratio of 1:1.46, while the content of soluble excipients is of 30.95%.

Both granulates are produced in a double jacket heated cutter. The components are cold mixed, after which the product is heated, always under stirring, up to a product temperature of 75±5°C; by doing so, the glyceryl behenate melts, acting as a binder. The product is sieved, still hot, in a shale shaker and allowed to cool.

The granulates are then mixed with compression excipients and compressed in a Manesty Layerpress three-layer press using punches having 13x7mm size.

Considering a AP quantity equal to 0.5 mg in the outer layers and 8.12 mg in the inner layer, tablets with the following composition are obtained:

FIRST LAYER (0.5 mg)

lh 14.4

2h 22.9

4h 34.3

6h 45.2

8h 51.3

12h 67.9

16h 82.4

20h 89.6

24h 94.8

EXAMPLE 3

Manufacturing of three-layer tablets comprising 9.12 mg of Ropinirole HCI (1 mg in the layer (I) - 7.12 mg in the layer (II) - 1 mg in the layer (III))

The granulates have the following compositions:

(I) - (III) layer

The glyceryl behenate and HPMC are in a ratio of 1:1.2, while the content of soluble excipients is of 24.85%. (II) layer

COMPONENT %

Ropinirole HCI 5.65

HPMC 39.59

Glyceryl behenate 31.75

Mannitol 9.52

Maltodextrin 13.49 The glyceryl behenate and HPMC are in a ratio of 1:1.25, while the content of soluble excipients is of 23.01%. Both granulates are produced in a double jacket heated cutter. The components are cold mixed, after which the product is heated, always under stirring, up to a product temperature of 75±5°C; by doing so, the glyceryl behenate melts, acting as a binder. The product is sieved, still hot, in a shale shaker and allowed to cool. The granulates are then mixed with compression excipients and compressed in a Manesty Layerpress three-layer press using punches having 13x7mm size.

Considering an AP quantity equal to 1 mg in the outer layers and 7.12 mg in the inner layer, tablets with the following composition are obtained:

FIRST LAYER (1 mg)

lh 15.3

2h 22.4

4h 32.1

6h 41.6

8h 48.1

12h 62.1

16h 76.3

20h 84.3

24h 92.4

EXAMPLE 4

The granulates have the following compositions: (I) - (III) layer

The glyceryl behenate and HPMC are in a ratio of 1:1.35, while the content of soluble excipients is of 30.63%. (II) layer

The glyceryl behenate and HPMC are in a ratio of 1:1.5, while the content of soluble excipients is of 30.95%.

Both granulates are produced in a double jacket heated cutter. The components are cold mixed, after which the product is heated, always under stirring, up to a product temperature of 75±5°C; by doing so, the glyceryl behenate melts, acting as a binder. The product is sieved, still hot, in a shale shaker and allowed to cool. The granulates are then mixed with compression excipients and compressed in a Manesty Layerpress three-layer press using punches having 13x7mm size.

FIRST LAYER (1 mg)

lh 18.3

2h 25.2

4h 36.4

6h 43.4

8h 51.2

12h 68.3

16h 81.2

20h 90.2

24h 95.3

EXAMPLE 5

Manufacturing of three-layer tablets comprising 9.12 mg of Ropinirole HCI (0.3 mg in the layer (I) - 8.52 mg in the layer (II) - 0.3 mg in the layer (III))

The granulates have the following compositions: (I) - (III) layer

The glyceryl behenate and HPMC are in a ratio of 1:1.21, while the content of soluble excipients is of 24.85%. (II) layer

The glyceryl behenate and HPMC are in a ratio of 1:1.21, while the content of soluble excipients is of 23.01%.

Considering an AP quantity equal to 0.3 mg in the outer layers and 8.52 mg in the inner layer, tablets with the following composition are obtained:

FIRST LAYER (0.3 mg)

lh 8.3

2h 15.2

4h 24.3

6h 32.9

8h 45.8

12h 63.4

16h 75.2

20h 83.9

24h 91.7

EXAMPLE 6

Manufacturing of three-layer tablets comprising 9.12 mg of Ropinirole HCI (0.3 mg in the layer (I) - 8.12 mg in the layer (II) - 0.5 mg in the layer (III))

The starting granulates are prepared first.

The granulates have the following compositions:

(I) layer

The glyceryl behenate and HPMC are in a ratio of 1:1.36, while the content of soluble excipients is of 30.63%.

(II) layer

The glyceryl behenate and HPMC are in a ratio of 1:1.45, while the content of soluble excipients is of 30.95%.

(Ill) layer

The granulates are produced in a double jacket heated cutter. The components are cold mixed, after which the product is heated, always under stirring, up to a product temperature of 75±5°C; by doing so, the glyceryl behenate melts, acting as a binder. The product is sieved, still hot, in a shale shaker and allowed to cool.

Considering an AP quantity equal to 0.3 mg and 0.7 mg in the outer layers and 8.12 mg in the inner layer, tablets with the following composition are obtained:

FIRST LAYER (0.3 mg)

The tablets are then analysed with Basket at 100 rpm using Phosphate Buffer pH 6.8 / 900 ml as a medium, obtaining the following in vitro releases: Time % lh 17.5

2h 24.3

4h 35.2

6h 41.2

8h 50.9

12h 67.3

16h 79.4

20h 88.5

24h 94.9

Claims

1 . A multilayer Ropinirole sustained-release tablet, said tablet comprising at least two layers, each of said layers comprising:

Ropinirole or salts thereof; and

a retardant matrix comprising a hydrophobic lipid-waxy excipient melting at a temperature lower than 100°C;

where at least two of said layers contain different amounts of Ropinirole.

2. The tablet according to claim 1 , wherein the retardant matrix of each layer comprises an association of a hydrophobic lipid-waxy excipient with a hydrophilic polymeric excipient.

3. The tablet according to claim 2, wherein the hydrophobic lipid-waxy excipient is glyceryl behenate and the hydrophilic polymeric excipient is hydroxypropyl methyl cellulose (HPMC).

4. The tablet according to claim 3, wherein the glyceryl behenate :H PMC ratio is in the range from 1 :1 to 1 :3 by weight.

5. The tablet according to any one of the claims 2-4, wherein the layers further comprise water-soluble diluents chosen from polyalcohols, or mixtures thereof, preferably maltodextrin, mannitol and mixtures thereof.

6. The tablet according to claim 5, wherein the content of water-soluble diluents is 10-40% w/w with respect to the total weight of each single layer.

7. The tablet according to any one of the claims 1 -6, wherein Ropinirole is in the form of HCI salt.

8. The tablet according to any one of the claims 1 -7, further comprising compression excipients, preferably magnesium stearate and anhydrous colloidal silica.

9. The tablet according to any one of the claims 1 -8, wherein different layers have different colors.

10. The tablet according to any one of the claims 1 -9, consisting of three layers: two external layers (I) and (III), and one internal layer (II).

1 1 . The tablet according to claim 10, wherein the inner layer (I) containing the higher amount of Ropinirole has the following composition: COMPONENT %

Ropinirole HCI 4- 10

HPMC 30-50

Glyceryl behenate 25-40

Mannitol 5- 15

Maltodextrin 10-20

Coloring 0- 1 and wherein the outer layers (I) and (I I I) containing the lower amount of Ropinirole has the following composition :

where the indicated percentages are % w/w referred to the total weight of each layer, excluding the compression excipients.

12. A method of manufacturing a tablet according to any one of the claims 1 -1 1 , said method comprising hot granulation of the components of each layer, without the addition of solvents or binders.