EP2227224A2 - Improved pharmaceutical composition containing non-ergoline dopamine agonist and method for the preparation thereof - Google Patents

Abstract

The present invention relates to a pharmaceutical formulation of solid dosage forms for oral administration comprising a therapeutically effective amount of a non-ergoline dopamine agonist or a pharmaceutical acceptable salt thereof, and especially Ropinirole or pharmaceutical acceptable salt thereof, in combination with an amino acid, as an antioxidant, and a process for the preparation thereof.

Description

IMPROVED PHARMACEUTICAL COMPOSITION CONTAINING NON-ERGOLINE DOPAMINE AGONIST AND METHOD FOR THE PREPARATION THEREOF

TECHNICAL FIELD OF THE INVENTION

The present invention relates to improved pharmaceutical compositions and in particular to a formulation for oral administration comprising a therapeutically effective quantity of a non- ergoline dopamine agonist, such as Ropinirole or pharmaceutical acceptable salt thereof, in combination with amino acids, such as Methionine, as an antioxidant and a process for the preparation thereof for the treatment of Parkinson's disease and Restless Legs Syndrome (RLS). BACKGROUND OF THE INVENTION

Ropinirole is a known non-ergoline dopamine agonist, a selective D2-agonist, employed for the treatment of Parkinson's disease with much less undesirable side effects than other dopaminergic agents. 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-HT₁, 5-HT₂, Dopamine D₁, benzodiazepine, GABA, muscarinic, alpha_! , alpha₂ and beta adrenoceptors.

Ropinirole used in the dosage form is in the form of the crystalline hydrochloride salt (4- (2-di-n- propylaminoethyl)-2 (3H)-indolone hydrochloride), which has been pharmaceutically approved for human use. Ropinirole hydrochloride is a white to pale greenish-yellow powder with a melting range of 243° to 250° and a solubility of 133mg/ml in water. It is also soluble in methanol, slightly soluble in ethanol and very slightly soluble in acetonitrile.

Ropinirole is known to be susceptible to degradation upon exposure to moisture and elevated temperatures. Additionally, it tends to interact with other tablet ingredients when exposed to stress conditions and decomposes. The degradation of the active ingredient results in reduced drug effectiveness and treatment failure.

The susceptibility to decomposition can be controlled by handling the compound and storing the final dosage form in a controlled environment, so as to preserve the therapeutic potency of the active pharmaceutical ingredient. Furthermore, the stability of pharmaceutical compositions containing a non-ergoline dopamine agonist and in particular, Ropinirole or pharmaceutical acceptable salt thereof can also be influenced by the selection of the excipients. The bioavailability and the release rate of the pharmaceutical dosage can also be enhanced by the selection of the excipients. In order to prevent the decomposition effect, certain stabilizing agents have been incorporated into pharmaceutical compositions containing Ropinirole. The amount of the stabilizing agent to be used in a particular formulation depends upon the dosage form itself, the size of the dosage form and the amount of active ingredient (strength) present in the dosage form. The pharmaceutical formulations of Ropinirole or salt thereof stabilized to oxidation are preferably formulations for oral administration. Such formulations include solid or liquid dosage forms such as for example tablets, capsules, powders and suspensions, including any sustained release preparations thereof.

Nevertheless, the poor flow properties of said non-ergoline dopamine agonist and in particular, Ropinirole or pharmaceutical acceptable salt thereof may also generate difficulties when it has to be formulated in dosage forms suitable for oral administration. Furthermore, another concern during development of such active compounds is the uniformity of the bulk and of the final composition since the active ingredient is found in low amounts in the tablet.

Various methods are already known for the industrial preparation of oral dosage forms comprising a non-ergoline dopamine agonist e.g. Ropinirole or salt thereof, as an active ingredient due to its useful properties. However, the prior art has encountered substantial difficulties in the production of the oral solid formulations of a desirable stability due to the degradation of said active ingredient and the low concentration of the active ingredient. EP 0 314 387 discloses a pharmaceutical composition which comprises a dopamine agonist, such as pergolide, which is susceptible to decomposition by light, and an amount of a stabilizing agent, such as PVP, a-tocopherol succinate and propyl gallate. The active ingredient and the stabilizing agent are comprised in an amount sufficient to achieve stabilization against degradation by light.

Although the prior art refers several attempts to overcome the decomposition problems associated with pharmaceuticals compositions comprising a non-ergoline dopamine agonist, there still exists a need for improving the stability of such pharmaceutical compositions. SUMMARY OF THE INVENTION

It is, therefore, an object of the present invention to provide an improved solid dosage formulation for oral administration containing a non-ergoline dopamine agonist, and in particular, Ropinirole, or pharmaceutical acceptable salt thereof as an active ingredient, which overcomes the deficiencies of the prior art and avoids the degradation of the active ingredient.

Another aspect of the present invention is to provide a solid dosage formulation for oral administration containing a non-ergoline dopamine agonist and in particular, Ropinirole or pharmaceutically acceptable salt thereof as an active ingredient, with low concentration of the active ingredient, which is bioavailable and effective with sufficient self-life and good pharmacotechnical properties.

Moreover, another aspect of the present invention is to provide a solid dosage formulation for oral administration containing a non-ergoline dopamine agonist, and in particular, Ropinirole or pharmaceutically acceptable salt thereof as an active ingredient, which can be prepared in dosage forms of different strength by proportionally adjusting the quantities of the excipients and the active ingredient, thereby providing a pharmacotechnical linearity, without affecting the dissolution profile and bioavailability of the active ingredient. A further aspect of the present invention is to provide a method for the preparation of a stable solid dosage formulation for oral administration containing a non-ergoline dopamine agonist, and in particular, Ropinirole or pharmaceutically acceptable salt thereof as an active ingredient, thereby avoiding the decomposition of said active ingredient and improving the pharmacotechnical characteristics of said composition.

In accordance with the above objects of the present invention, a pharmaceutical composition for oral administration is provided comprising a non-ergoline dopamine agonist, such a Ropinirole or pharmaceutical acceptable salt thereof as an active ingredient, and an effective amount of an amino acid such as Methionine as an antioxidant to inhibit oxidation and/or degradation.

According to another embodiment of the present invention, a process for the preparation of solid dosage forms for oral administration such as tablets, capsules and sachets containing a non- ergoline dopamine agonist, and in particular, Ropinirole or pharmaceutically acceptable salt thereof as an active ingredient is provided, which comprises: - Forming a homogenous mixture by mixing the total quantity of said active ingredient with a total quantity of amino acid such as Methionine as an antioxidant to inhibit oxidation and/or degradation;

- Sieving the above mixture through a sieve;

- Adding to the sieved mixture the total quantities of at least one optional excipient of the internal phase such as a binder, a diluent, a disintegrant and mixing until uniform,

- Adding to the uniformed mixture at least one optional excipient of the external phase such as glidant, a lubricant and mixing; and

- Formulating the resulting mixture in a solid dosage form either by compressing it into a desired tablet form or by filling capsules or sachets.

Further preferred embodiments of the present invention are defined in dependent claims 2 to 9 and 11 to 12.

Other objects and advantages of the present invention will become apparent to those skilled in the art in view of the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

For the purposes of the present invention, a pharmaceutical composition comprising a non- ergoline dopamine agonist (e.g. Ropinirole or pharmaceutical acceptable salt thereof) is considered to be "stable" if said ingredient degradates less or more slowly than it does on its own and/or in known pharmaceutical compositions.

An excipient is considered to be "incompatible" with an active ingredient (non-ergoline dopamine agonist e.g. Ropinirole or salt thereof) if it promotes the degradation of said active ingredient, that is to say, if said active ingredient degrades more or faster in the presence of said excipient when compared with the degradation of said active ingredient on its own. The terms "incompatibility", "compatible" and "compatibility" are defined accordingly.

The term "pharmaceutically acceptable" refers to a form that is acceptable to the patient from a pharmacological or toxicological point of view, including acceptable composition, formulation, stability, bioavailability and acceptance by the patient.

Although the pharmaceutical composition may be in various forms, the preferred solid forms are tablets, capsules and caplets.

The improved solid pharmaceutical composition of the present invention is characterized by physicochemical properties suitable for the tablet formulation by direct compression, the adequate release rate of the active ingredient (non-ergoline dopamine agonist e.g. Ropinirole or salt thereof) and the storage stability, by employing excipients practically devoiding the tendency to interact with the active ingredient, and possessing good compressibility properties.

As already mentioned non-ergoline dopamine agonist such as Ropinirole is susceptible to degradation / oxidation upon exposure to moisture and heat and its tendency gets stronger when formulated and mixed with excipients or other active substances

It has been surprisingly found that the object of the present invention is achieved by employing a an effective amount of an amino acid, such Methionine as an antioxidant.

Methionine is a sulphur-containing proteinogenic amino acid (α-amino acid). It is classified as non-polar, it is hydrophobic, practically insoluble in water, resistant to heat and stable during storage. Methionine has been used in the present invention as a racemate or pure D- or L- form. Preferably the antioxidant agent used herein is DL-Methionine.

The active ingredient (non-ergoline dopamine agonist such as Ropinirole or salt thereof) and a suitable amount of amino acid such as Methionine are being mixed to complete homogeneity. After sieving the mixture, any optional additional excipient is then added. The composition is then mixed until uniform. The resulting composition may then be compressed.

Moreover, any excipient may optionally be added to the above composition, provided that they are compatible with the active ingredient of the composition, in order to overcome problems associated with the unfavorable pharmacotechnical characteristics of these substances, and in order to increase the stability of the drug and the self-life of the pharmaceutical product, and provide a product exhibiting excellent bioavailability. The present invention can be applied in the formulation of tablets, capsules, caplets, sachets or other solid dosage forms for oral administration of an active ingredient having stability problems especially related with heat and/or humidity of the atmosphere.

Furthermore, it is possible to prepare dosage forms of different strength using appropriate quantity of the same composition, thereby limiting the cost of production and minimizing the number, and consequently the cost, of clinical studies required for the approval of the product by the authorities.

The manufacturing process for the preparation of the composition according to the present invention is simpler and inexpensive in comparison to any other conventional method. Thus, direct compression was the chosen manufacturing method because it is faster, easier, adds fewer steps to the process, more economical, and considering the fact that the active ingredient employed in the present invention is susceptible to degradation upon exposure to moisture and heat. In a first embodiment, the present invention provides a pharmaceutical composition comprising from about 0.05% to 50% by weight of Ropinirole or salt thereof and from about 0.05% to 5% by weight of Methionine. The weight ratio of the Ropinirole or salt thereof to Methionine is preferably 1000:1 to 1 :100. Preferred pharmaceutical compositions according to the present invention comprise Ropinirole or salt thereof in an amount approximately 0.05% to 40%, more preferably 0.05% to 25% and most preferably 0.05% to 15%. More preferred pharmaceutical compositions according to the present invention comprise Methionine in an amount approximately 0.05% to 2%, and most preferably 0.05% to 1.5%.

The preferred pharmaceutical compositions are in the form of solid dosage forms for oral or sublingual administration such as tablets, capsules, caplets, troches, pastilles, pills, lozenges and the like, in all shapes and sizes, coated or uncoated. All percentages stated herein are weight percentages based on total composition weight, unless otherwise stated.

Another embodiment of the present invention is the use of the direct compression process for the preparation of solid dosage forms such as tablets containing Ropinirole or salt thereof. Said direct compression process comprises:

- Sieving the total quantity of the active ingredient such as Ropinirole or salt thereof and the total quantity of the antioxidant such as Methionine and forming a homogenous mixture;

- Adding to the above mixture the total quantity of at least one optional excipient such as a binder, a diluent, a filler and/or a disintegrant; - Subsequently, adding a lubricant and/or a glidant and mixing until uniform;

- Formulating the resulting mixture in a solid dosage form either by compressing it into a desired tablet form or by filling capsules or sachets

- Optionally applying a film-coating The pharmaceutical compositions of the present invention are characterized by excellent pharmacotechnical properties, such as homogeneity, flowability and compressibility. Thanks to these properties, the solid dosage forms prepared by the above process exhibit excellent technical characteristics including disintegration time, dissolution rate, hardness, resistance to crashing, friability and stability, as better illustrated by the measurements during the stage of the development of the products.

The pharmaceutical compositions of the present invention may contain one or more formulation ingredients selected from a wide variety of excipients. According to the desired properties of the composition, any number of ingredients may be selected, alone or in combination, based upon their known uses in preparation of solid dosage form compositions.

Such ingredients include, but are not limited to, diluents, binders, compression aids, disintegrants, glidants, lubricants, flavours, water scavengers, colorants, sweetener, coating agents and preservatives.

Diluents may be, for example, calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate, microcrystalline cellulose, microcrystalline silicified cellulose, powdered cellulose, dextrates, dextrose, fructose, lactitol, lactose anhydrous, lactose monohydrate, lactose dihydrate, lactose trihydrate, mannitol sorbitol, starch, pregelatinized starch, sucrose, talc, xylitol, maltose maltodextrin, maltitol.

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, maltodextrin, methylcellulose, polydextrose, polyethylene oxide, povidone, sodium alginate, starch paste, pregelatinized starch and sucrose. Disintegrants may be, for example, alginic acid, carbon dioxide, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, croscarmellose sodium, crospovidone, sodium docusate, guar gum, hydroxypropyl cellulose, methylcellulose, polacrilin potassium, poloxamer, povidone, sodium alginate, sodium glycine carbonate, sodium lauryl sulfate, sodium starch glycolate, starch, pregelatinized starch.

Glidants may be, for example, calcium silicate, powdered cellulose, starch, talc, lubricants e.g. polyethylene glycol 4000, polyethylene glycol 6000, sodium lauryl sulfate, starch, 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: Tablet of 0.25 mg Ropinirole (Comp. 1)

Tablets of the above formulation were prepared according to the following manufacturing process: Ropinirole HCL, Microcrystalline cellulose, Microcellac and Croscarmellose sodium were admixed to complete homogeneity. The above mixture was passed through a sieve. The sieved mixture was then mixed with colloidal silicon dioxide. Finally magnesium stearate was added and mixed until complete homogeneity. The resulting granule was compressed into tablets.

The produced tablets were tested for hardness, friability, disintegration, and water content. All tests were performed according to European Pharmacopoeia 5.1 and were well within the specifications. However, the stability results were not satisfactory.

Example 2: Tablet of 0.25 mg Ropinirole (Comp. 21

Tablets of the above composition 2 were prepared according to the following manufacturing process: Ropinirole HCL and DL-Methionine were mixed together for sufficient time and then Microcrystalline cellulose, Microcellac and Croscarmellose sodium were added and mixed. Subsequently, Colloid silicon dioxide was added and mixed. Finally magnesium stearate was added and mixed until complete homogeneity. The resulting granule was compressed into tablets.

The stability results of composition 2 were acceptable and much more improved than of composition 1.

Example 3: Tablet of 0.25 mg Ropinirole (Comp. 3)

Tablets of the above composition 3 were prepared according to the manufacturing process of composition 2.

Both compositions 3 comprising a ratio of Ropinirole hydrochloride to DL-methionine 2:5 and

1 : 1 were tested.

The stability results for both compositions of example 3 were worse compared to the results of composition 2 of Example 2.

Example 4: Tablet of 0.25 mg Ropinirole (Comp. 4^*)

Tablets of the above composition 4 were prepared according to the following manufacturing process:

1. Ropinirole hydrochloride is sieved.

2. DL-Methionine is sieved and mixed with Ropinirole in a suitable mixer

3. Microcellac 100 is sieved.

4. An appropriate quantity of Microcellac 100 (Microcellac: Mix 1:1) is added in the mixture of step 2 and mixed. 5. An additional appropriate quantity of Microcellac 100 (Microcellac: Mix 1:1) is added in the mixture of step 4 and mixed. This procedure continues till the whole amount of Microcellac 100 is added.

6. The rest of the excipients of internal phase are sieved and mixed.

7. The mixture of step 6 is added to the mixture of step 5 for adequate time till suitable content uniformity is achieved.

8. The total quantity of Colloidal Silicon Dioxide is sieved and added to the mixture of step 7.

9. The total quantity of Magnesium Stearate is sieved and added to the mixture of step 8.

10. The bulk is compressed into tablets.

One of the most critical pharmacotechnical tests is the dissolution test as it is strongly correlated with the bioavailability of the product. For the dissolution method a Paddle Apparatus was used 50rpm, 37⁰C, time 30min, while as a dissolution medium 900ml of H₂O was used.

TABLE 1: Dissolution profiles of compositions of Example 2 and 4

The dissolution profile of the composition 4 showed a faster release profile and disintegration time. Also, the release at 30 minutes is over 95% compared to 92% of composition 2, showing that better homogeneity of these tablets.

Composition 4 showed improved pharmacotechnical characteristics such as lower disintegration time, increased release of the active ingredient release in the dissolution test and improved uniformity of the low content of the active ingredient.

Further, Composition 4 was investigated for its scalability, while a process validation was performed in order to prove the repeatability and accuracy of the manufacturing process and the proposed formulations. All the above mentioned characteristics were also investigated for formulations of 0,25mg, 0,5mg, lmg, 2mg and 5mg strength equivalent weight of Ropinirole per tablet and 3 batches per strength were used.

The validation process showed that the composition 4 and the manufacturing process are suitable in order to provide a repeatable and high quality product.

Another object of the present invention was to prepare a pharmaceutical composition that is stable and the active ingredient does not degradates for a long period of storage time. Therefore, tablets of composition 4, three batches of each strength, were packed in blisters and 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 under normal conditions for the five different strengths are shown in Table 2 below (one batch each strength).

TABLE 2: Stability results for composition 4 directly after preparation and after 12 months of storage in normal conditions

The results show a good stability of the product and compatibility between the drug substance and the excipients proposed by the present invention. The excellent results regarding the physicochemical characteristics, the excellent stability of the product as well as the simple and economic manufacturing process indicate the advantages of the present invention relative to the commonly used methods and excipients for the formulation of Ropinirole.

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

CLAIMS L A pharmaceutical composition for oral administration comprising a non-ergoline dopamine agonist, and in particular Ropinirole or a pharmaceutical acceptable salt thereof, as an active ingredient, and an effective amount of an amino acid, such as Methionine as an antioxidant to inhibit oxidation and/or degradation.

2. The pharmaceutical composition according to claim 1, wherein said amino acid is Methionine.

3. The pharmaceutical composition according to claim 2, wherein it comprises from about 0.05 to 50% by weight of said non-ergoline dopamine agonist or salt thereof, and from about 0.05 to 5.0 % by weight of said amino acid.

4. The pharmaceutical composition according to claim 2, wherein the weight ratio of said non- ergoline dopamine agonist or salt thereof to the amino acid is preferably 1000:1 to 1 :100.

5. The pharmaceutical composition according to any preceding claim, wherein said non-ergoline dopamine agonist is Ropinirole or a pharmaceutical acceptable salt thereof.

6. The pharmaceutical composition according to any preceding claim, wherein it further comprises at least one glidant, such as a colloidal silicon dioxide.

7. The pharmaceutical composition according to any preceding claim, wherein it further comprises at least one optionally excipient selected from the group consisting of diluents, binders, disintegrants, lubricants, and glidants.

8. The pharmaceutical composition according to any preceding claim, wherein it comprises Microcrystalline cellulose, Microcellac, Lactose monohydrate, Croscarmellose sodium, Colloidal silicon dioxide and Mg stearate.

9. The pharmaceutical composition according to any preceding claim, wherein said composition is in a solid dosage form such as a tablet, capsule or sachet comprising an active ingredient such as Ropinirole or salt thereof.

10. A process for the preparation of a solid dosage form for oral administration such as a tablet, capsule or sachet containing a non-ergot dopamine agonist or a pharmaceutical acceptable salt thereof as an active ingredient and an effective amount of an amino acid such as Methionine as an antioxidant to inhibit oxidation and/or degradation, which comprises:

- Forming a homogenous mixture by mixing the total quantity of said active ingredient with a total quantity of said antioxidant;

- Sieving the above mixture through a sieve; - Adding to the sieved mixture the total quantities of at least one optional excipient of the internal phase such as a binder, a diluent, a disintegrant and mixing until uniform,

- Adding to the uniformed mixture at least one optional excipient of the external phase such as glidant, a lubricant and mixing; and

- Formulating the resulting mixture in a solid dosage form either by compressing it into a desired tablet form or by filling capsules or sachets.

11. The process according to claim 11, wherein said active ingredient is Ropinirole or salt thereof.

12. The process according to claim 11, wherein said amino acid is Methionine.