WO2010015911A1

WO2010015911A1 - Sustained release pharmaceutical compositions of ropinirole and process for preparation thereof

Info

Publication number: WO2010015911A1
Application number: PCT/IB2009/006437
Authority: WO
Inventors: Navin Ishwarlal Vaya; Badal Kumar Sasmal; Praful Mahadeorao Giradkar
Original assignee: Torrent Pharmaceuticals Ltd
Current assignee: Torrent Pharmaceuticals Ltd
Priority date: 2008-08-06
Filing date: 2009-08-04
Publication date: 2010-02-11
Anticipated expiration: 2011-02-06

Abstract

The present invention relates to sustained release pharmaceutical compositions of ropinirole, process for preparing such compositions and method of using such compositions. More particularly, the present invention relates to a single layer sustained release pharmaceutical composition comprising ropinirole and a rate controlling polymer selected from a hydrophilic polymer or a mixture of hydrophilic and hydrophobic polymer.

Description

SUSTAINED RELEASE PHARMACEUTICAL COMPOSITIONS OF ROPINIROLE AND PROCESS FOR PREPARATION THEREOF

FIELD OF THE INVENTION

BACKGROUND OF THE INVENTION

Ropinirole hydrochloride (4-(2-di-n-propylaminoethyl)-2(3H)-indolone hydrochloride) is approved in most territories for the treatment of Parkinson's disease under the tradename Requip^® and has also been disclosed as being of potential use in the treatment of a variety of other conditions, such as Restless Legs Syndrome (RLS; Ekbom Newsletter, July 1997), fibromyalgia (U.S. Pat. No. 6,277,875), acute CNS injury (Medico, M. et al., (2002), European Neuropsychopharmacology 12, 187- 194), various sleep related disorders such as apneas, hypopneas and snoring events (Saletu, M. et al., (2000), Neuropsychobiology 41, 190-199) and chronic fatigue syndrome (U.S. Pat. No. 6,300,365).

Ropinirole hydrochloride has previously only been disclosed as either an immediate release formulation or a 24-hour controlled release formulation (WO 01/78688). WO 01/78688 discloses multi-layer controlled release tablet of ropinirole hydrochloride comprising a mixed matrix of hydrophilic and lipophilic components. According to WO 01/78688, the multi-layer tablet can be prepared as two-layer tablets, three-layer tablets or even greater numbers of layers. One of the layers contains the active substance to be released from the tablet and at least one layer contains a barrier or support layer with respect to the active substance containing layer. US 2007/059365 describes novel formulations of ropinirole for oral administration and their use in the treatment of diseases which can prevent or disturb sleep, particularly Restless Legs Syndrome (RLS). It discloses a controlled release oral dosage form having monolith or a multi-component system with different release rate from each component. The dosage form disclosed therein has dissolution profile such that greater than 80% (by weight) ropinirole released by 10 hours. The dosage form is also characterized in such a way that the mean duration taken to achieve the half peak plasma concentration (l/2C_max) or ropinirole in-vivo is less than 3 hours after administration of the dosage form. According to the invention described in this application, an RLS patient taking ropinirole in the early evening is provided with relatively rapidly relief of initial symptoms to allow onset of sleep (as indicated by a short duration to reach half peak plasma concentration (l/2C_max) of ropinirole) followed by a sustained period wherein plasma concentration is maintained above l/2C_max to prevent RLS symptoms disturbing sleep.

There is still a need in the art for alternative sustained release composition of ropinirole, which can provide a release of ropinirole for a period of more than 12 hours, preferably for a period of 24 hours. We have surprisingly found that sustained release pharmaceutical composition of ropinirole can be prepared as single layer matrix composition.

SUMMARY OF THE INVENTION

In one aspect, the invention discloses a single layer sustained release pharmaceutical composition comprising: (i) ropinirole,

(ii) a rate controlling polymer, and (iii) one or more pharmaceutically acceptable excipients.

In another aspect, it discloses a process for preparation of a single layer sustained release pharmaceutical composition, wherein the process comprises: (i) mixing ropinirole, optionally a rate controlling polymer and one or more pharmaceutically acceptable excipients,

(ii) granulating the mixture of step (i) with a granulating solvent or a solution, (iii) drying the granules of step (ii), (iv) mixing the granules of step (iii) with a rate controlling polymer and one or more pharmaceutically acceptable excipients, and (v) compressing the mixture of step (iv) into a tablet.

In still another aspect, it discloses a process for preparation of a single layer sustained release pharmaceutical composition, wherein the process comprises:

(i) mixing ropinirole, a rate controlling polymer and one or more pharmaceutically acceptable excipients,

(ii) granulating the mixture of step (i) with a granulating solvent or a solution, (iii) drying the granules of step (ii), (iv) mixing the granules of step (iii) with optionally a rate controlling polymer and one or more pharmaceutically acceptable excipients, and (v) compressing the mixture of step (iv) into a tablet.

In further aspect, the invention discloses a method for the treatment of parkinson's disease, Restless Legs Syndrome (RLS) and/or fibromyalgia, wherein the method comprises administering to a patient in need thereof a single layer sustained release pharmaceutical composition of ropinirole.

DETAILED DESCRIPTION OF THE INVENTION

The term "ropinirole" as used herein refers to ropinirole free base or pharmaceutically acceptable salts, hydrates, solvates and enantiomers thereof or mixtures thereof. The preferred salt of ropinirole is ropinirole hydrochloride. Ropinirole may be present in an amount ranging from 0.01 % to 20 % by weight of the composition.

The term "single layer sustained release pharmaceutical composition" as used herein refers to the composition which releases not more than 80% by weight of ropinirole within 10 hours. The composition provides the desired therapeutic effect of ropinirole for a period of more than 12 hours, preferably for a period of 24 hours. The composition as described herein is a single layer matrix composition.

The term "rate controlling polymer" as used herein and appended claims refers to a hydrophilic polymer or a mixture of hydrophilic and hydrophobic polymer. Suitable hydrophilic polymers may be selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl ethylcellulose, methyl cellulose, carboxymethylcellulose, carbopol, polyethylene oxide, polyvinylpyrrolidone, sodium alginate, xanthan gum, carrageenan, polyvinyl alcohol, locust bean gum, alginic acid, methacrylate copolymer or mixtures thereof. Suitable hydrophobic polymer is selected from a natural fat as such or totally or partially hydrogenated, beeswax, a mono-, bi- or tri-substituted glyceride, glyceryl palmitostearate, glyceryl behenate, diethyleneglycol palmitostearate, a polyethyleneglycol stearate, a polyoxyethyleneglycol palmitostearate, glyceryl monopalmitostearate, cetyl palmitate, polyethyleneglycol palmitostearate, mono- or di-glyceryl behenate, a fatty alcohol associated with a polyethoxylate fatty alcohol, cetyl alcohol, stearic acid, a saturated or unsaturated fatty acid or a hydrogenated derivative thereof, hydrogenated castor oil, certain grades of methacrylate copolymer, ethyl cellulose or mixtures thereof. The rate controlling polymer may be present intragranularly, extragranularly or both. The rate controlling polymer provides the sustained release of ropinirole for a period of more than 12 hours, preferably 24 hours. Preferably, rate controlling polymer comprises a hydrophilic polymer.

The pharmaceutical compositions as described herein may comprise of one or more pharmaceutically acceptable excipients selected from diluent, binder, disintegrant, lubricant and mixtures thereof.

Diluent may be selected from microcrystalline cellulose, starch, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, dextrose, kaolin, magnesium carbonate, magnesium oxide; sugars such as lactose or sucrose; sugar alcohols such as mannitol, sorbitol or erythritol; and mixtures thereof. The diluent may be present in an amount ranging from 5 % to 80 % by weight of the composition. Binder may be selected from hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomers, dextrin, ethyl cellulose, methylcellulose, gelatin, polymethacrylates, polyvinylpyrrolidone, pregelatinized starch, sodium alginate, gums, synthetic resins and the like. The binder may be present in an amount ranging from 0.1 % to 8 % by weight of the composition.

Disintegrant may be selected from croscarmellose sodium, sodium starch glycolate, pregelatinized starch, sodium carboxymethyl cellulose, microcrystalline cellulose, cross-linked polyvinylpyrrolidone and mixtures thereof. The disintegrant may be present in an amount ranging from 1 % to 10 % by weight of the composition.

Lubricant / glidant may be selected from talc, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; colloidal silicon dioxide, finely divided silicon dioxide, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, glyceryl behenate, polyethylene glycols, sodium stearyl fumarate, sodium benzoate, mineral oil, magnesium trisilicate; and mixtures thereof. The lubricant / glidant may be present in an amount ranging from 0.1 % to 8 % by weight of the composition.

Granulating solvent may be selected from water, isopropyl alcohol, ethanol, methanol, acetone, methylene chloride or mixtures thereof. Granulating solution may be a mixture of any binder in the granulating solvent.

The pharmaceutical composition may be further coated using suitable coating techniques known in the art which do not affect the dissolution properties of the final formulation. The film coat may comprise of film-forming polymer such as hydroxypropyl methylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, polyvinyl pyrrolidone, and the like; a plasticizer such as glyceryltriacetate, dibutyl sebacate, diethylphthalate, polyethylene glycol, propylene glycol, glycerol, castor oil, copolymers of propylene oxide and ethylene oxide, and the like; an opacifying agent such as titanium dioxide, iron oxides, and the like.

In one embodiment, the invention provides the process for preparing a single layer sustained release pharmaceutical composition wherein the process comprises the steps of: mixing ropinirole, a rate controlling polymer and one or more pharmaceutically acceptable excipients, granulating the mixture to obtain granules, drying the granules, mixing the dried granules with a rate controlling polymer and one or more pharmaceutically acceptable excipients, and compressing the mixture into a tablet.

In another embodiment, the invention provides the process for preparing a single layer sustained release pharmaceutical composition wherein the process comprises the steps of: mixing ropinirole, a rate controlling polymer and one or more pharmaceutically acceptable excipients, granulating the mixture to obtain granules, drying the granules, mixing the dried granules with one or more pharmaceutically acceptable excipients, and compressing the mixture into a tablet.

In another embodiment, the invention provides the process for preparing a single layer sustained release pharmaceutical composition wherein the process comprises the steps of: mixing ropinirole, and one or more pharmaceutically acceptable excipients, granulating the mixture to obtain granules, drying the granules, mixing the dried granules with a rate controlling polymer and one or more pharmaceutically acceptable excipients, and compressing the mixture into a tablet.

In another embodiment, the invention provides the process for preparing a single layer sustained release pharmaceutical composition wherein the process comprises the steps of: mixing ropinirole, a rate controlling polymer and one or more pharmaceutically acceptable excipients, and compressing the mixture into a tablet.

The term "reference product" as used herein refers to the compositions containing ropinirole hydrochloride, which release ropinirole for an extended period of time of about 12 hours or about 24 hours. The preferred reference product is 2 / 4 / 6 / 8 / 12 mg Requip^® XL prolonged-release tablet marketed by SmithKline Beecham.

The pharmaceutical compositions as described herein may be illustrated by the following examples which are not to be construed as limiting the scope of the invention:

EXAMPLE 1

PROCEDURE: Ropinirole hydrochloride, lactose monohydrate and microcrystalline cellulose were sifted and mixed using suitable mixer to get a uniformly mixed blend. Hydroxypropyl methylcellulose was dissolved in purified water to get binder solution. The blend was granulated by using binder solution. The granules were dried and mixed with carbopol and purified talc. The blend was lubricated with magnesium stearate. The lubricated blend was compressed into tablets using appropriate punches and dies.

EXAMPLE 2

PROCEDURE: Ropinirole hydrochloride, lactose monohydrate and microcrystalline cellulose were sifted and mixed using suitable mixer to get a uniformly mixed blend. Hydroxypropyl methylcellulose was dissolved in purified water to get binder solution. The blend was granulated by using binder solution. The granules were dried and mixed with xanthan gum and purified talc. The blend was lubricated with magnesium stearate. The lubricated blend was compressed into tablets using appropriate punches and dies.

EXAMPLE 3

PROCEDURE: Ropinirole hydrochloride, lactose monohydrate and microcrystalline cellulose were sifted and mixed using suitable mixer to get a uniformly mixed blend. Hydroxypropyl methylcellulose was dissolved in purified water to get binder solution. The blend was granulated by using binder solution. The granules were dried and mixed with sodium carboxymethylcellulose and purified talc. The blend was lubricated with magnesium stearate. The lubricated blend was compressed into tablets using appropriate punches and dies.

EXAMPLE 4

PROCEDURE: Ropinirole hydrochloride, lactose monohydrate and microcrystalline cellulose were sifted and mixed using suitable mixer to get a uniformly mixed blend. Hydroxypropyl methylcellulose was dissolved in purified water to get binder solution. The blend was granulated by using binder solution. The granules were dried and mixed with sodium alginate and purified talc. The blend was lubricated with magnesium stearate. The lubricated blend was compressed into tablets using appropriate punches and dies.

EXAMPLE 5

PROCEDURE: Ropinirole hydrochloride, lactose monohydrate and microcrystalline cellulose were sifted and mixed using suitable mixer to get a uniformly mixed blend. Hydroxypropyl methylcellulose was dissolved in purified water to get binder solution. The blend was granulated by using binder solution. The granules were dried and mixed with polyethylene oxide and purified talc. The blend was lubricated with magnesium stearate. The lubricated blend was compressed into tablets using appropriate punches and dies.

EXAMPLES 6 AND 7

PROCEDURE: Ropinirole hydrochloride, lactose monohydrate and microcrystalline cellulose were sifted and mixed using suitable mixer to get a uniformly mixed blend. Hydroxypropyl methylcellulose (low-viscosity grade) was dissolved in purified water to get binder solution. The blend was granulated by using binder solution. The granules were dried and mixed with hydroxypropyl methylcellulose (High-viscosity grade) and purified talc. The blend was lubricated with magnesium stearate. The lubricated blend was compressed into tablets using appropriate punches and dies.

EXAMPLE 8

PROCEDURE: Ropinirole hydrochloride, lactose monohydrate, microcrystalline cellulose and hydroxypropyl methylcellulose were sifted and mixed using suitable mixer to get a uniformly mixed blend. Polyvinylpyrrolidone was dissolved in purified water to get binder solution. The blend was granulated by using binder solution. The granules were dried and mixed with purified talc. The blend was lubricated with magnesium stearate. The lubricated blend was compressed into tablets using appropriate punches and dies. Table 1; Dissolution profile of Example 8 in USP Type II apparatus, 50 rpm, 500 ml of pH 4.5 citrate buffer; 37 ± 0.5⁰C

EXAMPLE 9

PROCEDURE: Ropinirole hydrochloride and lactose monohydrate were sifted and mixed using suitable mixer to get a uniformly mixed blend. Methacrylic copolymer was dissolved in methylene chloride to get binder solution. The blend was granulated by using binder solution. The granules were dried and mixed with hydroxypropyl methylcellulose. The blend was lubricated with colloidal silicon dioxide and magnesium stearate. The lubricated blend was compressed into tablets using appropriate punches and dies. Table 2: Dissolution profile of Example 9 in USP Type II apparatus, 100 rpm, 500 ml of pH 4.5 citrate buffer; 37 ± 0.5⁰C

PROCEDURE: Ropinirole hydrochloride, lactose monohydrate, Hydroxypropyl methylcellulose and colloidal silicon dioxide were sifted and mixed using suitable mixer to get a uniformly mixed blend. Polyvinyl pyrrolidone was dissolved in isopropyl alcohol to get binder solution. The blend was granulated by using binder solution. The granules were dried and mixed with polyvinyl pyrrolidone and hydroxypropyl methylcellulose. The blend was lubricated with colloidal silicon dioxide and magnesium stearate. The lubricated blend was compressed into tablets using appropriate punches and dies.

Table 3: Dissolution profiles of Examples 10, 11 and 12 in USP Type Il apparatus, 100 rpm, 500 ml of pH 4.5 citrate buffer; 37 ± 0.5⁰C

EXAMPLE 13

PROCEDURE: Ropinirole hydrochloride, lactose monohydrate and ethyl cellulose were sifted and mixed using suitable mixer to get a uniformly mixed blend. The powder mix was granulated by adding methylene chloride and isopropyl alcohol. The granules were dried. Hydroxypropyl methylcellulose, colloidal silicon dioxide and magnesium stearate were sifted and blended with the dried granules as obtained above. Glyceryl behenate and colloidal silicon dioxide were sifted, added to the blend as obtained above and mixed in a suitable blender. The lubricated blend was compressed into tablets using appropriate punches and dies. The tablets were coated with aqueous solution of film coating materials and pharmaceutically acceptable colorants.

The pharmaceutical compositions as described herein are expected to be bio-equivalent to the reference product.

Claims

We claim:

1. A single layer sustained release pharmaceutical composition comprising:

(i) Ropinirole or its pharmaceutically acceptable salts, hydrates, solvates and enahtiomers thereof or mixtures thereof,

2. The composition of claim 1, wherein the rate controlling polymer is selected from a hydrophilic polymer, a hydrophobic polymer or mixtures thereof.

3. The composition of claim 2, wherein the hydrophilic polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose,^' hydroxyethyl cellulose, hydroxypropyl ethyl cellulose, methyl cellulose, carboxymethylcellulose, carbopol, polyethylene oxide, polyvinylpyrrolidone, sodium alginate, xanthan gum, carrageenan, polyvinyl alcohol, locust bean gum, alginic acid, methacrylate copolymer or mixtures thereof.

4. The composition of claim 2, wherein the hydrophobic polymer is selected from the group consisting of a natural fat as such or totally or partially hydrogenated, beeswax, a mono-, bi- or tri-substituted glyceride, glyceryl palmitostearate, glyceryl behenate, diethyleneglycol palmitostearate, a polyethyleneglycol stearate, a polyoxyethyleneglycol palmitostearate, glyceryl monopalmitostearate, cetyl palmitate, polyethyleneglycol palmitostearate, mono- or di-glyceryl behenate, a fatty alcohol associated with a polyethoxylate fatty alcohol, cetyl alcohol, stearic acid, a saturated or unsaturated fatty acid or a hydrogenated derivative thereof, hydrogenated castor oil, certain grades of methacrylate copolymer, ethyl cellulose or mixtures thereof.

5. The composition according to claim 1, wherein the rate controlling polymer is present extragranularly.

6. The composition according to claim 1, wherein the rate controlling polymer is present intragranularly.

7. The composition according to claim 1, wherein the rate controlling polymer is present both intragranularly and extragranularly.

8. The composition according to claim 1, wherein the excipient is selected from diluent, binder, disintegrant, lubricant or mixtures thereof.

9. A process for preparation of a single layer sustained release pharmaceutical composition, wherein the process comprises: (i) mixing ropinirole, optionally a rate controlling polymer and one or more pharmaceutically acceptable excipients,

(ii) granulating the mixture of step (i) with a granulating solvent or a solution,

(iii) drying the granules of step (ii),

(iv) mixing the granules of step (iii) with a rate controlling polymer and one or more pharmaceutically acceptable excipients, and (v) compressing the mixture of step (iv) into a tablet.

10. A process for preparation of a single layer sustained release pharmaceutical composition, wherein the process comprises: (i) mixing ropinirole, a rate controlling polymer and one or more pharmaceutically acceptable excipients, (ii) granulating the mixture of step (i) with a granulating solvent or a solution,

(iii) drying the granules of step (ii), (iv) mixing the granules of step (iii) with optionally a rate controlling polymer and one or more pharmaceutically acceptable excipients, and (v) compressing the mixture of step (iv) into a tablet.

11. A method for treating signs and symptoms of idiopathic Parkinson's disease comprising administering a pharmaceutical composition of claim 1 to a patient in need thereof.