WO2013007360A1

WO2013007360A1 - Controlled release pharmaceutical composition of non-ergoline dopamine agonist

Info

Publication number: WO2013007360A1
Application number: PCT/EP2012/002831
Authority: WO
Inventors: Evangelos Karavas; Efthimios Koutris; Vicky Samara; Anastasia Kalaskani; Georgios GOTZAMANIS; Dimitrios Bikiaris
Original assignee: Pharmathen SA
Current assignee: Pharmathen SA
Priority date: 2011-07-13
Filing date: 2012-07-05
Publication date: 2013-01-17
Anticipated expiration: 2014-01-13
Also published as: GR1007629B; EP2731592A1

Abstract

The present invention relates to a controlled release formulation of solid dosage forms for oral administration comprising a therapeutically effective amount of a non-ergoline dopamine agonist or a pharmaceutically acceptable salt, derivative or polymorph thereof, in particular Ropinirole in combination with an effective amount of a non swellable agent, a gelling agent, and an amphiphillic compound. It also relates to a process for the preparation thereof.

Description

CONTROLLED RELEASE PHARMACEUTICAL COMPOSITION OF NON-ERGOLINE DOPAMINE AGONIST

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a controlled release pharmaceutical formulation for oral administration comprising a therapeutically effective quantity of a non-ergoline dopamine agonist such as Ropinirole, or pharmaceutical acceptable salt, derivative or polymorph thereof and a method for the preparation thereof. BACKGROUND OF THE INVENTION

Solid oral medications are administered as immediate or controlled release dosage forms. Immediate release dosage forms are easier to manufacture but the frequency of drug administration and the fluctuation of drug level in plasma, are two major disadvantages of this type of medications. Controlled release preparations are designed to deliver the active ingredient in a way that drug level in plasma is maintained within a therapeutic window and therefore effective and safe blood levels are achieved.

An ideal controlled release dosage form is designed to deliver the drug at a constant rate as it passes through the gastrointestinal tract. The release from this ideal formulation is described to follow zero order release kinetics. Nevertheless, this is not always the case. Water soluble active ingredients formulated in a controlled release dosage form tend to release rapidly on the initial stage of the dissolution test and gradually decrease during time. This type of release behavior deviates significantly from the ideal zero order release kinetics.

An additional problem that might occur especially with a water soluble active substance is the dose dumping phenomenon. Dose dumping appears when the controlled release product, releases the drug prematurely and at a greater rate leading to adverse effects and possible drug induced toxicity. The phenomenon usually takes place when patients take their medication at the same time when ingesting other substances like fatty meals or alcohol. These substances may act on the composition to speed up drug release, or they may stimulate the body's absorptive surfaces to increase the rate of drug uptake.

In order to overcome these problems, various methods are already known for the industrial preparation of oral dosage forms comprising a water soluble active ingredient:

(a) Beads to immobilize the water soluble active ingredient

(b) Osmotic pump dosage forms

(c) Coated particles, beads, pellets or spheroids

(d) In-situ intra-gel chemical reactions

(e) Multi-layer matrix tablets

All of the above techniques tend to have an approximate zero order release kinetic for a water soluble active ingredient, however, the prior art has encountered substantial difficulties in the production of the oral solid formulations of a desirable stability. The multi-layer matrix tablets, also known as Geomatrix technology, is the manufacturing process that draws most attention the recent few years. Nevertheless, reproducibility and in-vitro in-vivo data fluctuations, as well as slow production rates, difficulties in monitoring the production process and cohesiveness of the different layers related to this formulation, makes the need of a controlled release pharmaceutical composition that is cheaper and easier to manufacture essential. Ropinirole is a non-ergoline dopamine agonist and is indicated for the treatment of Parkinson disease. It's a high water soluble active substance, therefore all the problems described above regarding the formulation in a controlled release dosage form are applicable in that case.

Further, Ropinirole is a potent CNS active non-ergoline dopamine agonist with high relative in vitro specificity and full intrinsic activity at the D₂ and D₃ dopamine receptor subtypes, binding with a higher affinity to D₃ than to D₂ receptor subtypes. Additionally, Ropinirole presents a moderate affinity for opioid receptors and a negligible in vitro affinity for 5-HT_l5 5-HT₂, Dopamine D_l5 benzodiazepine, GAB A, muscarinic, alphaj, alpha₂ and beta adrenoceptors. Ropinirole hydrochloride is a white to pale greenish-yellow powder with a melting range of 243 C to 250°C and a solubility of 133mg/ml in water. It is also soluble in methanol, slightly soluble in ethanol and very slightly soluble in acetonitrile.

Various methods are already known for the industrial preparation of controlled release dosage forms of Ropinirole. However, prior art formulations are manufactured by using expensive and time consuming techniques or provide insufficient release.

EP 1 272 167 discloses a multilayer controlled release pharmaceutical dosage form wherein one layer has Ropinirole as active ingredient and one or more additional barrier layers.

EP 1 656 118 discloses controlled release simple matrix formulations of Ropinirole that do not achieve a 24 hour continuous release of the active substance.

Although each of the above patents represents an attempt to overcome the problems associated with pharmaceuticals compositions for controlled release comprising of a water soluble salt such as Ropinirole, there still exists a need for improving the stability and release rate over a 24 hour time period of said pharmaceutical compositions without producing unwanted pharmaceutical effects and with low production costs. SUMMARY OF THE INVENTION

It is, therefore, an object of the present invention to provide an improved solid dosage formulation for controlled oral administration of a of non-ergoline dopamine agonist such as Ropinirole or pharmaceutically acceptable salt, derivative or polymorph thereof, as the active ingredient, which overcomes the deficiencies of the prior art and provides a predictable and reproducible drug release for 24 hours.

It is another object of the present invention to provide a controlled release solid dosage formulation for oral administration containing a non-ergoline dopamine agonist such as Ropinirole or pharmaceutically acceptable salt, derivative or polymorph thereof, as the active ingredient, which is simple to manufacture, cost effective and does not involve time consuming techniques such as partial layering coatings. Further object of the present invention is to provide a solid dosage form for oral administration containing Ropinirole or pharmaceutical acceptable salt, derivative or polymorph thereof, which can be formulated into dosage forms of different strengths by proportionally adjusting the amounts of the pharmaceutically acceptable excipients, as well as the active compound Ropinirole without influencing the release characteristics.

Still an object of the present invention is to provide a controlled release formulation of a non- ergoline dopamine agonist such as Ropinirole or pharmaceutically acceptable salt, derivative or polymorph thereof that is stable during prolonged storage time, avoids degradation of the active ingredient and is effective with sufficient self-life and good pharmacotechnical properties

A further object of the present invention is to provide a method for the preparation of a stable controlled release solid dosage formulation for oral administration containing Ropinirole that overcomes the water solubility problems of the active ingredient and has acceptable pharmacotechnical properties.

In accordance with the above objects of the present invention, a controlled release pharmaceutical composition for oral administration is provided comprising a non-ergoline dopamine agonist such as Ropinirole or a pharmaceutical acceptable salt, derivative or polymorph thereof as an active ingredient and an effective amount of at least one excipient selected from a non swellable agent, a gelling agent, and an amphiphillic compound. According to another embodiment of the present invention, a process for the preparation of a controlled release pharmaceutical composition comprising a non-ergoline dopamine agonist such as Ropinirole or a pharmaceutical acceptable salt, derivative or polymorph thereof as an active ingredient and an effective amount of at least one excipient selected from a non swellable agent, a gelling agent, and an amphiphillic compound is provided, which comprises:

- forming a homogenous mixture by mixing the active ingredient with the gelling agent, the non swellable agent, the amphiphillic compound and a part of a binder until complete homogeneity;

- kneading the above mixture with a solvent selected from ethanol, acetone, isopropyl alcohol, water or mixtures thereof and then drying the wetted mass;

- sieving the dried mass and adding to the sieved mixture the remaining part of the binder and at least one optional excipient such as a glidant or a lubricant and mixing until uniformity;

- formulating the resulting mixture in a solid dosage form either by compressing into a desired tablet form or filling capsules;

- optionally film coating the tablets formed.

Preferred embodiments of the present invention are set out in dependent claims 2 to 12, 14 and 15. Other objects and advantages of the present invention will become apparent to those skilled in the art in view of the following detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 shows a comparative dissolution profile at pH=4, of 2mg and 8mg tablets prepared according to example 1 of the present invention. Fig. 2 shows a comparative dissolution profile at pH=4, of tablets prepared according to example 1 of the present invention and tablets of Requip^® XL.

Fig. 3 shows a comparative dissolution profile at pH=4, of compositions prepared according to example 2 of the present invention.

DETAILED DESCRIPTION OF THE INVENTION It has been surprisingly found that the object of the present invention is achieved by a pharmaceutical formulation in the form of a tablet or mini-tablets incorporated in a capsule. Each tablet of said delivery system contains a water soluble non-ergoline dopamine agonist and in particular Ropinirole or pharmaceutically acceptable salt, derivative or polymorph thereof forming a functional core and each core comprises:

(a) The active ingredient

(b) One or more of high viscosity gelling agents

(c) A non swellable (monolithic or plastic) agent or system comprising at least one or a mixture of water insoluble, non swelling polymers and an amphiphillic compound (d) Other pharmaceutically excipients such as lubricants, glidants, binders and diluents as long as their properties do not affect the performance of the system,

(e) Optionally, the core can be coated with a film that does not affect the release properties from the functional core. The core is obtained through a wet granulation and compression process, in order to optimize the cohesiveness of the core. In a preferred embodiment, the active ingredient, the gelling agent, the non swelling polymer(s), the amphiphillic compound and a part of a binder are mixed together and then submitted to wet granulation with a solvent or mixture of solvents able to develop the interactions between said excipients.

Preferably the solvent is selected from ethanol, acetone, isopropyl alcohol, water and mixtures thereof. The wet granulation step is followed by drying, adding the remaining portion of the binders quantity, optionally mixing with another gelling agent and then with other excipients such as glidants, lubricants. Finally the granular/powder mixture is compressed into tablets. Alternatively the non swelling polymer(s) is dissolved into an appropriate solvent and this solution or uniform dispersion is used for the wet granulation step of the remaining excipients. Any additional diluents or binders may be added in this step. The granular mass is dried and mixed with excipients such as glidants, lubricants and the binder and finally is compressed into tablets or mini-tablets filled in a capsule.

This interaction, combined with the observation of the modified matrices during the dissolution test is indicative of the potential mechanism underlying the release from the innovative dosage form. This mechanism involves the development of interactions between the components of the matrix, and/or an appropriate orientation of the hydrophobic parts of the constituents that possibly results in the modification of the diffusion layer throughout the dissolution test.

The amphiphillic compound functions as a conjunction agent, and forms bonds between the gelling agents and/or the non swellable agent and/or the active pharmaceutical ingredient, causing interactions between the ingredients of the core that have negative effect at the release and result in the predictable and manipulable behaviour of the system. Said amphiphillic compound exhibits a strong interaction with the non swellable excipient that potentially results in the appropriate orientation of the polymeric system that causes or strengthens the restriction of the diffusion of the water soluble active pharmaceutical ingredient from the matrix tablet. This is the main reason why the amphiphillic compound is considered the most important factor.

In a preferred embodiment the novel controlled release formulation comprises a ratio of non swellable agent to amphiphillic compound from about 0.5 to about 3.0.

The gelling agent is selected from Hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxycellulose phthalate, poly(ethyleneoxide), polylactic acid, xanthan gum, alginates, sodium and calcium carboxymethylcellulose, carrageen, carbomer, carbopol (oral use), methylhydroxyethylcellulose, propylhydroxyethylcellulose, polyhema, methylcellulose, alginates and other swellable polymers. The non-swellable agent is selected from poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 :2:0.1, commerced as Eudragit RS 100, vinylpyrrolidone-vinyl acetate copolymer commerced as Kollidon VA 64, ethyl cellulose, cellulose acetate propionate, cellulose acetate, poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 :2:0.2 copolymer, commercially available as Eudragit RL, polyvinylpyrrolidone acetate, polyvinyl chloride, polyvinyl acetate, polyethylene, and others or mixtures thereof.

The amphiphillic compound is usually anionic and selected from sodium lauryl sulphate, sodium docusate, sodium cetostearyl sulphate and triethanolamine lauryl sulphate. The proposed formulation could also enable common excipients, such as lubricants and glidants, binders and diluents, as long as their properties allow them to replace the functional constituents without affecting the performance of the system. The classical excipients used for the preparation of the core should exhibit low solubility in water and free of disintegrant properties. Binders may be, for example, acacia mucilage, alginic acid, carbomer, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, ethyl cellulose, gelatin, liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, Kollidon VA 64, maltodextrin, methylcellulose, polydextrose, polyethylene oxide, povidone, sodium alginate, starch paste, pregelatinized starch and sucrose.

Glidants may be, for example, calcium silicate, powdered cellulose, starch, talc, colloidal silicon dioxide. Lubricants may be polyethylene glycol 4000, polyethylene glycol 6000, starch, magnesium stearate, talc. The following examples illustrate preferred embodiments in accordance with the present invention without limiting the scope or spirit of the invention.

EXAMPLES Example 1

Table 1: Com ositions of exam le 1

Tablets of the above formulation were prepared according to the following manufacturing process: sieving and mixing until complete homogeneity the total quantities of Ropinirole HC1, Eudragit RS 100, HPMC K100M and SLS and a part of Kollidon VA 64. Wet granulating the mixture with Ethanol. Drying the mixture and subsequently sieving. Adding the remaining amount of Kollidon VA 64 and mixing until complete homogeneity. The total quantity of magnesium stearate is added and mixed until a homogenous granule is obtained. Finally, the granule is compressed into tablets, optionally coated. As it can be seen the binder is added both intra and extragranurarly and the amounts added are adjusted according to the strength of the tablet.

The compositions presented in table 1 above, are linear regarding the strength versus the weight of the tablet. Tablets of 2mg and 8 mg according to example 1 of the present invention and a commercially available composition (Requip^® XL) of Ropinirole were compared with respect to their dissolution profile. The conditions used were a USP Apparatus II (paddles), at 200 rpm having as dissolution medium citrate buffer of pH=4.

Table 2: Dissolution profiles of 2mg and 8mg tablets according to example 1 and of Requip

From Table 2 and Figure 1, it is apparent that the linearity between strength and weight of the tablets of example 1 , has minimal effect on the release characteristics of the tablets.

Tablets of the above example were tested in comparison to a commercially available composition (Requip^® XL) for their dissolution profile under the same conditions. From the dissolution profile of Table 2, it derives that the composition of example 1 is similar to that of the commercially available product (fig. 2).

The composition of example 1 , according to the present invention provided a controlled release dosage form with similar properties to the commercially available product by using an easier, faster and cost effective manufacturing process.

Additionally, a single-dose crossover comparative bioavailability study at fasted and single-dose replicate crossover comparative bioavailability study at fed state conditions has been conducted in healthy volunteers using a formulation prepared according to example 1 of the present invention.

The reference product, namely a 2mg Requip^® XL tablet, consists of the active ingredient, carboxymethylcellulose sodium, colloidal silicon dioxide, glyceryl behenate, hydrogenated castor oil, hypromellose, lactose monohydrate, magnesium stearate, maltodextrin, mannitol, povidone, and one or more of the following: FD & C Yellow No. 6 aluminum lake, FD & C Blue No. 2 aluminum lake, ferric oxides (black, red, yellow), polyethylene glycol 400, titanium dioxide.

Each patient received an oral 2mg dose of composition of example 1 and a tablet of the reference composition equal to 2 mg of active ingredient, at different times. Blood samples were taken at different times and the plasma concentrations of Ropinirole were determined. Table 3 shows the main pharmacokinetic parameters obtained from the test.

Table 3: Pharmacokinetic analysis of composition of the example 1 of the present invention versus reference product (Requip^® XL)

wherein:

C max=(peak concentration) is the highest concentration reached by the drug in plasma after dosing;

AUCo-t =(area under the curve) The area under the plasma concentration versus time curve, from time 0 to the last measurable concentration, as calculated by the linear trapezoidal method.

AUCo-inf =(area under the curve) The area under the plasma concentration versus time curve from time 0 to infinity. AUCinf is calculated as the sum of AUCo-_t plus the ratio of the last measurable plasma concentration to the elimination rate constant. The in vitro and in vivo data show that the properties of the dose dumping phenomenon does not take place for the composition of the present invention and that both formulations are comparable with respect to their main pharmacokinetic parameters.

In addition, the pharmaceutical composition of the present invention remains stable for a long period of storage time. Therefore, tablets of composition of example 1 were exposed to normal (25°C±2°C/60%±5% RH) intermediate (30°C±2°C/65%±5% RH) and accelerated (40°C±2°C/75%±5% RH) stability studies according to the current ICH guidelines.

The stability results are shown in Table 4. It is apparent that the composition of example 1 of the present invention is remarkably stable. Table 4: Stability results of composition of example 1 after preparation and after 6 months of storage in normal, intermediate and accelerated conditions

Example 2

Table 5: Compositions of example 2

Ingredients mg per tablet

Composition 1 Composition 2 Composition 3

Ropi irole HC1 (equiv. to

2.28 2.28 2.28

2mg Ropinirole base)

Eudragit RS 100 5.28 8.67 18.62

HPMC K100M 80.00 70.83 66.67

SLS 8.25 3.17 3.50

Kollidon VA 64 40.14 34.00 40.00

Mg Stearate 1.10 1.10 1.10

Total weight uncoated 137.05 120.05 132.17 Several compositions have been tested in order to optimize the ratio of the non swellable agent to the amphiphillic compound. The results of the compositions tested are shown in Table 5.

The tablets of all compositions of example 2 were prepared according to the same manufacturing process of example 1 of the present invention.

The three compositions were tested regarding their drug release behavior. The conditions used were a USP Apparatus II (paddles), at 200 rpm having as dissolution medium citrate buffer of pH=4.

Table 6: Dissolution profiles of compositions 1, 2 and 3 according to example 2

From Table 6 and Figure 3, it derives that when the ratio of the non swellable agent to the amphiphillic compound, in the composition according to the present invention, is from about 0.5 to about 3.0, the release of the active ingredient lies within the desired levels. A higher ratio, as in composition 3 of example 2, reveals undesired faster drug release.

While the present invention has been described with respect to the particular embodiments, it will be apparent to those skilled in the art that various changes and modifications may be made in the invention without departing from the spirit and scope thereof, as defined in the appended claims.

Claims

1. A controlled release pharmaceutical composition comprising a non-ergoline dopamine agonist such as Ropinirole or a pharmaceutical acceptable salt, derivative or polymorph thereof as an active ingredient and an effective amount of at least one excipient selected from a non swellable agent, a gelling agent, and an amphiphillic compound.

2. The controlled release pharmaceutical composition according to claim 1, wherein said non-ergoline dopamine agonist is Ropinirole or salt thereof.

3. The controlled release pharmaceutical composition according to claim 1, wherein the non-swellable agent is selected from poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 :2:0.1, vinylpyrrolidone-vinyl acetate copolymer, ethyl cellulose, cellulose acetate propionate, cellulose acetate, poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 :2:0.2 copolymer, polyvinylpyrrolidone acetate, polyvinyl chloride, polyvinyl acetate, and polyethylene or mixtures thereof.

4. The controlled release pharmaceutical composition according to claim 1, wherein the non-swellable agent is poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1 :2:0.1.

5. The controlled release pharmaceutical composition according to claim 1, wherein the amphiphillic compound is selected from sodium lauryl sulphate, sodium docusate, sodium cetostearyl sulphate and triethanolamine lauryl sulphate.

6. The controlled release pharmaceutical composition according to claim 1, wherein the amphiphillic compound is sodium lauryl sulphate.

7. The controlled release pharmaceutical composition according to claim 1, wherein the gelling agent is selected from Hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxycellulose phthalate, poly(ethyleneoxide), polylactic acid, xanthan gum, alginates, sodium and calcium carboxymethylcellulose, carrageen, carbomer, carbopol, methylhydroxyethylcellulose, propylhydroxyethylcellulose, polyhema, methylcellulose, alginates and other swellable polymers.

8. The controlled release pharmaceutical composition according to claim 1, wherein the gelling agent is hydroxypropylmethylcellulose.

9. The controlled release pharmaceutical composition according to claim 1, wherein the ratio of the non swellable agent to the amphiphillic compound is from about 0.5 to about 3.0.

10. The controlled release pharmaceutical composition according to claim 1, wherein it further comprises excipients, such as lubricants, glidants, binders and diluents.

11. The controlled release pharmaceutical composition according to any preceding claim, wherein it comprises by weight 1% to 5% Ropinirole or salt thereof, 1% to 5% Eudragit^® RSI 00, 55% to 65% Methocel® K100M, 2% to 7% sodium lauryl sulfate, 25% to 35% Kollidon® VA-64 and 0.5% to 3% magnesium stearate

12. The controlled release pharmaceutical composition according to claim 1, wherein said composition is in the form of tablets or mini tablets filled in a gelatine capsule.

13. A process for the preparation of a controlled release pharmaceutical composition a non- ergoline dopamine agonist such as Ropinirole or a pharmaceutical acceptable salt, derivative or polymorph thereof as an active ingredient and an effective amount of at least one excipient selected from a non swellable agent, a gelling agent, and an amphiphillic compound, which comprises:

- optionally film coating the tablets formed.

14. The process according to claim 12, wherein the ratio of the non swellable agent to the amphiphillic compound is from about 0.5 to about 3.0.

15. The process according to claim 12, wherein the kneading solvent is ethanol.