EP3236957A1

EP3236957A1 - Levodopa/carbidopa/entacapone pharmaceutical preparation and method for preparing the same

Info

Publication number: EP3236957A1
Application number: EP14838916.6A
Authority: EP
Inventors: Evangelos Karavas; Efthymios Koutris; Vasiliki SAMARA; Ioanna Koutri; Anastasia Kalaskani; Andreas KAKOURIS; George GOTZAMANIS
Original assignee: Pharmathen SA
Current assignee: Pharmathen SA
Priority date: 2014-12-23
Filing date: 2014-12-23
Publication date: 2017-11-01
Also published as: WO2016101969A1

Abstract

The present inventions relates to a solid pharmaceutical dosage form comprising Levodopa/Entacapone/Carbidopa, or pharmaceutically acceptable salts or hydrates thereof, characterized in that the active agents are stabilized with the use of dextrates.

Description

LEVODOPA/CARBIDOPA/ENTACAPONE PHARMACEUTICAL PREPARATION AND METHOD FOR PREPARING THE SAME

TECHNICAL FIELD OF THE INVENTION

The present invention belongs to the technical field of pharmaceutical dosage form preparation. In particular, it relates to a pharmaceutical composition comprising a combination of Levodopa / Carbidopa / Entacapone or pharmaceutically acceptable salts or hydrates thereof and manufacturing process for the preparation of the composition above.

BACKGROUND OF THE INVENTION

Parkinson's disease (PD) is a chronic and progressive neurodegenerative condition associated with considerable morbidity and social and economic consequences. Levodopa is the most effective treatment for the symptoms of PD. No other medial or surgical intervention has been shown to provide better antiparkinsonian efficacy. Levodopa is chemically designated as (-)-3-(3, 4-dihydroxyphenyl)-L-alanine-3-hydroxy-L-tyrosine and represented by FORMULA (I).

FORMULA (I)

However, chronic Levodopa therapy is associated with the development of potentially disabling motor complications, such as fluctuations in the motor response, involuntary movements, dyskinesias, which can result in disability and have a significant impact on a patient's quality of life.

A number of clinical trials indicated that Levodopa-associated motor complications are a result of high dosage and the non-continuous delivery of Levodopa to the brain. Levodopa is metabolized mainly by two enzymes: dopa decarboxylase (DDC) and catechol O- methyltransferase (COMT). A fixed dose combination of Levodopa/Entacapone/Carbidopa is currently marketed under the tradename of Stalevo^® by Novartis Pharmaceuticals Corporation, which is a pharmacokinetically (PK) optimized Levodopa formulation that peripherally inhibits both of the main pathways of Levodopa metabolism. Compared with conventional Levodopa, the PK profile of Levodopa with dual enzyme inhibition is markedly improved, increasing the half-life of Levodopa by up to 85% and the bioavailability of the drug by 35% in plasma.

The active pharmaceutical ingredients in Stalevo^®, in addition to Levodopa, are Carbidopa monohydrate, is which is chemically known as (aS)-a-hydrazino-3, 4-dihydroxy-a-methyl benzene propanoic acid monohydrate and represented by FORMULA (II), as a DDC- inhibitor, and

FORMULA (II)

Entacapone, which is chemically known as (E)-2-cyano-3-(3, 4-dkhydroxy-5-nitrophenyl)-N, N-diethyl-2-propenamide and represented by FORMULA (III), as a COMT-inhibitor.

FORMULA (III)

While a number of PK studies suggested that combination therapy of Levodopa / Entacapone / Carbidopa provide more consistent delivery of Levodopa to the brain, hence providing increased symptomatic benefits with fewer motor complications, a number of problems arise in adopting the current formulation. Outstanding issues include: (1) the difficulty to control the dissolution rate of three different active agents in a single dosage form; and (2) the difficulty to select suitable excipients that are effective in stabilizing three different active agents mainly to the fact that many of the pharmaceutical acceptable excipients have the tendency to react with the active agents, some accelerate the degradation of the active agents and some others stabilize the active agents.

EP 1189608 B 1 provides an oral solid pharmaceutical composition of Levodopa / Carbidopa / Entacapone combination, characterized in that substantial portion of Carbidopa is separated from Entacapone and Levodopa. Said composition comprises at least one pharmaceutically acceptable excipient being a sugar alcohol or starch, or a sugar alcohol and starch, wherein the preferred sugar alcohol is mannitol and the preferred starch is maize starch.

It is further disclosed in EP 1189608 Bl that many commonly used excipients are not suitable for solid composition containing Levodopa / Carbidopa / Entacapone. For example, microcrystalline cellulose destabilizes the formulation on long term storage, when all three active agents are combined together. US 2006/0222703 Al provides an oral solid pharmaceutical composition of Levodopa / Carbidopa / Entacapone combination, characterized in that the excipients include a long- chain polymer having an equilibrium moisture content of at least 2% by a solvent-free preparation method. Suitable long-chain polymers include microcrystalline cellulose, maize starch etc. It is suggested that wet granulation methods have a significant negative influence on the stability of the composition.

Although each of the patents above represents an attempt to overcome the physicochemical problems associated with pharmaceutical compositions comprising combination of Levodopa / Carbidopa / Entacapone, there still exists a need for an alternative pharmaceutical formulation that overcomes such problems.

SUMMARY OF THE INVENTION

It is, therefore, an object of the present invention to provide an oral solid pharmaceutical composition comprising a combination of Levodopa / Carbidopa / Entacapone, or pharmaceutically acceptable salts or hydrate thereof, in which the dissolution profile of each active agent is comparable to that of the reference product Stalevo®. Further object of the present invention is to provide an oral solid pharmaceutical composition comprising combination of Levodopa / Carbidopa / Entacapone, or pharmaceutically acceptable salts or hydrate thereof, which is stable under long-term storage. An additional object of the present invention is to provide a method for the preparation of the composition described above. The process for the preparation of a solid pharmaceutical dosage form comprising Levodopa, Entacapone, Carbidopa as active agents, comprises the steps of:

(1) preparing a dry mixture of Levodopa, Entacapone and dextrates with one or more optional pharmaceutically acceptable excipients to provide PART- A;

(2) preparing a dry mixture of Levodopa, Entacapone, Carbidopa and dextrates with one or more optional pharmaceutically acceptable excipients to provide PART-B;

(3) dry blending PART-A and PART-B together with any excipients of the external phase; and

(4) processing the mixture obtained in step (3) into the desired dosage form.

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

Parkinsonism medication needs to be taken several times a day to keep the patients without symptoms. The frequent medicament uptake and poor patient compliance let to fixed dose combination film-coated tablets of Levpdopa / Entacapone / Carbidopa as a replace dosage regime of Entacapone and Levovodopa / Carbidopa separate tablets. This is especially important for Parkinsonism patients with tremor and old age.

When tablets are formulated to contain more than one therapeutic ingredient, the possibility of interactions between the active substances should always be considered. Guideline on fixed combination medicinal products (CPMP/EWP/240/95) requires that "applicant must demonstrate that the various substances do not affect each other's respective pharmacokinetic patterns. Bioequivalence studies, the plasma concentration time curves, are frequently used to make critical decisions supporting the safety and efficacy of a medicinal product. The primary concern of bioequivalence assessment is to compare the bioavailability between a test and a reference product. Two products are considered bioequivalent if their bioavailability (rate and extent) after administration in the same molar dose lie within acceptable predefined limits.

During the development of a medicinal product, dissolution tests are conventionally used to identify formulation factors that may have an effect on the bioavailability of the drug. The dissolution test can be used to demonstrate bioequivalence by determining the similarity factor ^. An fi value between 50 and 100 suggests that the two dissolution profiles are similar. Therefore, dissolution studies can serve several purposes, including quality control of scale-up and of production batches to ensure batch-to-batch consistency and that the dissolution profiles remain similar to those pivotal clinical trial batches.

The inventors of the present application have surprisingly found that effective control of the dissolution profiles of three active agents, namely Levodopa, Entacapone, Carbidopa or pharmaceutically acceptable salts or a hydrate thereof, in a single solid pharmaceutical composition can be achieved with the present invention.

The incorporation of dextrates in the pharmaceutical composition of the present invention stabilizes the dosage of form in terms of undesirable impurities that could potentially affect the pharmacological result as well as the health of the patient. Furthermore, dextrates made possible to include in the composition other common pharmaceutically acceptable excipients such as microcrystalline cellulose that prior art considered as causing stability problems and degradation of the active pharmaceutical substances.

Additionally, the use of dextrates made possible to manufacture the dosage form with a dry granulation process which is faster since it avoids any drying steps and less expensive in comparison with wet granulation processes employed in prior art. The amount of dextrates in the composition of the present invention has been found to be effective in an amount of from 10% to 30% w/w of the total weight of the composition. The dry granulation process present herein comprises two main steps of dry mixing. The presence of dextrates allows the mixing of Carbidopa together with Entacapone and Levodopa which was unacceptable so far since the APIs were considered incompatible. The method is characterized in that the active agents are divided in two portions, each portion is granulated separately and subsequently the two granules are mixed together. Herein these two compositions are referred as PART-A and PART-B.

PART-A comprises dry granulation of approximately 20% by weight of the total amount of Levodopa in the composition, 90% by weight of the total amount by weight of Entacapone in the composition, 70% to 80% of by weight of the total amount of dextrates in the composition and other optional pharmaceutically acceptable excipients. Optionally, the granules are micronized to the desired particle size range by conventional methods known in the art, such as milling, grinding, etc. PART-B comprises dry granulation of the remaining amounts of Levodopa, Entacapone, dextrates, the total amount of Carbidopa and other optional pharmaceutically acceptable excipients. The two parts of the composition are dry granulated together with excipients of external phase and then formulated in the desired dosage form. In case the granules are compacted into tablets, the tablets can be optionally coated with a film coating in a mount of 2% to 5% of the total weight of the composition.

Excipients should be chosen carefully in order to provide optimized pharmacotechnical and physicochemical properties but mainly not to promote degradation of the active pharmaceutical ingredients. Sometimes, it is preferred to select excipients that promote stability of the active agents during long-term storage. It is suggested in the literature that thioether compounds, such as methionine, glutathione, thioglycerol, sodium thiosulfate, and metal chelators, such as disodium ethylene-diamine-tetra-acetate (EDTA), deferoxamine mesylate, stabilize the Carbidopa molecule. The inventors of the present application examined the stabilization effect of a number of the above mentioned compounds in composition comprising Carbidopa molecule. It was found that simply incorporating stabilizing agents in the specific composition cannot stabilize the Carbidopa in long-term storage. Method for preparing the composition has a significant effect on the stability of Carbidopa molecule. In particular, dry blending is most preferred because of the impurities profiles of both Levodopa and Carbidopa. In a preferred embodiment the current composition comprises dextrates in an amount of from 10% to 30% w/w, crospovidone in an amount of from 0.5% to 4% w/w, povidone in an amount of from 5% to 15% w/w, macrocrystalline cellulose in an amount of from 5% to 25% w/w and magnesium stearate in an amount of from 0.5% to 3% w/w of the total weight of the composition.

Thus, according to the present invention, an improved solid pharmaceutical dosage form comprising Levodopa/Entacapone/Carbidopa, or pharmaceutically acceptable salts or hydrates thereof, is developed. A combination of formulating process is also developed for the preparation of solid pharmaceutical dosage form of the present invention. The main advantages of the current formulation are excellent stability of the dosage form during long- term storage and fine-tuned dissolution profiles which provide therapeutic efficacy comparable to those of Stalevo®.

The following examples illustrate preferred embodiments in accordance with the present invention without limiting the scope or spirit of the invention.

EXAMPLES

Example 1 Solid dosage forms were prepared in accordance with the preferred embodiments of the present invention. The process for manufacturing the dosage forms of tables 1 and 2 below was:

Dry mixing the active agents and the excipients of Part A;

Separately dry mixing the active agents and the excipients of Part B;

Dry mixing granules of part A and B together with excipients of the external pha:

Compacting the granules in a tablet dosage form;

Optionally, film-coating the tablets. Tablets were prepared in all marketed dose strengths, i.e. 50 (75, 100, 125, 150, 175, 200)/12.5 (18.75, 25, 31.25, 37.5, 43.75, 50)/200 of Levodopa/Carbidopa/Entecapone respectively. The dosage forms were prepared in logic of keeping the tablets' total weight below 950mg. This value was considered essential since it could potentially enhance patient compliance. A tablet over lOOOmg would be relatively large in size and could present less appealing to any patient to take. On the other hand, a size over 500mg would result in a tablet of enough tablet size for a patient suffering from Parkinson disease to be able to hold and administer by himself.

Keeping in mind the above, two sets of tablets were prepared one with increasing amount of excipients & another with relatively constant amounts.

Table 1: Tablets prepared following an increasing amount of excipients

Table 2: Tablets prepared following a relatively constant amount of excipients

2.1 2.2 2.3 2.4 2.5 2.6 2.7

Internal phase Mg Mg Mg Mg Mg Mg Mg

/tablet /tablet /tablet /tablet /tablet /tablet /tablet

Part A

Levodopa 10,00 15,00 20,00 25,00 30,00 35,00 40,00

Entacapone 180,00 180,00 180,00 180,00 180,00 180,00 180,00

Dextrates 88,00 89,67 91,33 93,00 94,67 96,33 98,00

MCC 64,00 63,83 63,67 63,50 63,33 63,17 63,00

Povidone 31,20 32,42 33,63 34,85 36,07 37,28 38,50

Crospovidone 6,00 5,25 5,00 4,75 4,50 4,25 4,00

Part B

Levodopa 40,00 60,00 80,00 100,00 120,00 140,00 160,00

Entacapone 20,00 20,00 20,00 20,00 20,00 20,00 20,00

Carbidopa on anhydrous basis 12,50 18,75 25,00 31,25 37,5 43,75 50,00

Carbidopa 13,50 20,25 27,00 33,75 40,50 47,25 54,00

Dextrates 31,00 30,04 29,08 28,13 27,17 26,21 25,25

MCC 23,00 24,21 23,92 23,63 23,33 23,04 22,75

Povidone 15,60 16,50 17,40 18,30 19,20 20, 10 21,00

Crospovidone 5,00 3,83 3,67 3,50 3,33 3,17 3,00

External phase

Crospovidone 4,00 3,92 3,83 3,75 3,67 3,58 3,50

Mg Stearate 9, 10 9,63 10,15 10,68 11,20 1 1,73 12,25

Total weight of the core tablet 540,40 574,55 608,68 642,83 676,97 711,11 745,25 Stability of the formulation above according to the present invention was checked. Below are presented the results of tablets of the above formulations (125/31.25/200) under long term storage condition (25°C/60% RH), intermediate storage condition (30°C/60% RH) and accelerated storage condition (40°C/75% RH). According to the stability data, all three active agents are stable under all three storage conditions.

Table 3: Stability results of formulation 1.4

Table 4: Stability results of formulation 2.4

The compositions are tested for their dissolution profiles. The results of all the above formulations were comparable with the dissolution profile of Stalevo^®. Additionally, all formulation had adequate hardness, disintegration and flowability

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. An oral solid pharmaceutical composition comprising pharmacologically effective amounts of Entacapone, Levodopa and Carbidopa or pharmaceutically acceptable salts or hydrates thereof and comprising at least one pharmaceutically acceptable excipient being dextrates.

2. The composition according to claim 1 wherein dextrates are in an amount of from 10% to 30% w/w of the total weight of the composition.

3. The composition according to claim 1 wherein further comprises crospovidone in an amount of from 0.5% to 4% w/w of the total weight of the composition.

4. The composition according to claim 1 wherein further comprises povidone in an amount of from 5% to 15% w/w of the total weight of the composition.

5. The composition according to claim 1 wherein further comprises microcrystalline cellulose in an amount of from 5% to 25% w/w of the total weight of the composition.

6. The composition according to claim 1 wherein further comprises magnesium stearate in an amount of from 0.5% to 3% w/w of the total weight of the composition.

7. The composition according to claim 1 wherein further comprises an optional film coating in an amount of from 2% to 5% w/w of the total weight of the composition. 8. A solid pharmaceutical dosage form according to claim 1, which is film-coated tablets.

9. A process for the preparation of an oral solid pharmaceutical composition of Levodopa, Entacapone, Carbidopa as active agents, comprising the steps of:

(1) preparing a mixture of Levodopa, Entacapone and dextrates with one or more excipients and dry granulating the mixture to provide Part-A;

(2) preparing a mixture of Levodopa, Entacapone, Carbidopa and dextrates with one or more excipients by a dry granulation to provide Part-B;

(3) blending Part-A and Part-B together with excipients of external phase; and

(4) processing the mixture obtained in step (3) into the desired dosage form.

10. The process according to claim 9, wherein dextrates are in an amount of from 10% to

30% w/w of the total weight of the composition.

11. A process according to claim 9, wherein further excipients employed comprise crospovidone, povidone, microcrystalline cellulose and magnesium stearate.

2. Use of an oral solid pharmaceutical dosage form according to claim 1 in manufacture of a medicament for treatment of Parkinson's disease.