Pharmaceutical tablet formulation comprising levodopa and benserazide

Abstract

The invention relates to develop of a stable pharmaceutical fixed-dose formulation for oral administration comprising therapeutically effective amounts of levodopa and benserazide or pharmaceutically ассерtаblе salts thereof, wherein the levodopa containing and benserazide containing granules constituting the said tablet composition are prepared by separate granulation.

Description

[0001]PHARMACEUTICAL TABLET FORMULATION COMPRISING LEVODOPA AND BENSERAZIDE DESCRIPTION Technical field: The present invention relates to the development of a stable pharmaceutical fixed dose formulation for oral administration, comprising therapeutically effective amounts of levodopa and benserazide or pharmaceutically ассерtаblе salts thereof. The invention relates to a process for the preparation of the tablet. Prior Art: Levodopa, also known as L-dopa, is an aromatic amino acid that is the precursor of the neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline), which are collectively known as catecholamines. Its chemical name is (+L-α- amino-β-(3,4-dihydroxybenzene)propanoic acid, and its empirical formula is C9H11NO4with the following structural formula; Levodopa Benserazide is a peripherally acting aromatic L-amino acid decarboxylase or DOPA decarboxylase inhibitor that cannot cross the blood–brain barrier. It is used in the treatment of Parkinson's disease in combination with L-DOPA (levodopa) as a co-beneldopa (BAN). The chemical name is 2-amino-3-hydroxy-N′-(2,3,4-trihydroxybenzyl) propionohydrazide, and the empirical formula is C10H15N3O5with the following structural formula; Benserazide Parkinson’s disease (PD) is characterized by a progressive degeneration of the dopaminergic pathway resulting in reduced concentration of the neurotransmitter dopamine in the brain which manifests itself as symptoms of slowness of movement (e.g.,bradykinesia), rigidity, tremor and poor balance in the patient. Levodopa is an immediate metabolic precursor of dopamine that, unlike dopamine, is able to cross the blood-brain barrier, and is most commonly used for restoring the dopamine concentration in the brain. It is still the most important treatment for Parkinson's disease and intermittent oral Levodopa treatment achieves good relief of the symptoms at early stages of the disease. In spite of the massive loss of neurones there is still an adequate storage capacity, which makes possible an even release of dopamine into the synaptic spatium during interval dosage. Levodopa is a neutral amino acid, which must pass the blood-brain barrier before it reaches the central nervous system. This transport requires consuming. Levodopa has a short half- life of 30 to 60 minutes. Under the influence of the enzyme dopadecarboxylase (DDC), the greater part of Levodopa is metabolised to 90% in the first passage before reaching the brain. The metabolic transformation of levodopa to dopamine is catalyzed by the aromatic L-amino acid decarboxylase enzyme, a ubiquitous enzyme with particularly high concentrations in the intestinal mucosa, liver, brain and brain capillaries. Due to the possibility of extracerebral metabolism of levodopa, it is necessary to administer large doses of levodopa leading to high extracerebral concentrations of dopamine that cause nausea in some patients. In order to increase the bioavailability of Levodopa, and reduce its secondary effects on the system, Levodopa is therefore given by simultaneous administration in combination with a decarboxylase inhibitor carbidopa [L-2-hydrazino-3-(3,4-dihydroxyphenyl)-2- methylpropanoic acid] or benserazide [2-amino-3-hydroxy-N′-(2,3,4-trihydroxybenzyl) propionohydrazide], which both compete with Levodopa for the metabolising DDC—and thus allow more of the administered Levodopa to reach the brain before it is metabolised into dopamine. The combination with a decarboxylase inhibitor reduces by 60-80% the levodopa dose required for a clinical response, and thus prevents certain of its side effects by inhibiting the conversion of levodopa to dopamine outside the brain. The inhibition of dopadecarboxylase does not, however, increase the half-life for Levodopa very greatly, which points to the metabolising of Levodopa being shunted to the smaller COMT pathway. This leads to the formation of the metabolite 3-0-methyldopa (OMD) which because of its long half-life is accumulated in plasma and reaches manifestly higher levels as compared to Levodopa. The metabolite OMD is also a neutral amino acid and can therefore compete with Levodopa for the passage over the two barriers. Comparative studies of levodopa alone and in combination with an extracerebral decarboxylase inhibitor have shown advantages of combined treatment. With a combination, there are fewer peripheral side effects but equal incidence of central ones. Furthermore, improvement with combined treatment occurs sooner and is greater than improvement with levodopa alone. According to a study conducted by Da Prada (1987), the findings further support the view that benserazide is more potent than carbidopa as an inhibitor of peripheral AADC in both rats and humans. According to another study conducted by Rinne (1979), the effects of levodopa combined with benserazide (4:1 ratio) or with carbidopa (10:1 ratio) were compared in a controlled trial of 92 parkinsonian patients who had not previously been treated with levodopa. The dosage of levodopa and benserazide was increased in 6 weeks to a maximum daily dose of 800 mg of levodopa and 200 mg of benserazide, and the dosage of levodopa and carbidopa increased in 3 weeks to a maximum daily dose of 1500 mg of levodopa and 150 mg of carbidopa, except when serious side effects occurred. Both treatment schedules resulted in significant and equal clinical improvement of parkinsonism during follow-up for 6 months. Thus the more rapid dose increase with levodopa and carbidopa was not reflected in a quicker onset of action. However, nausea, vomiting, and involuntary movements were more frequent and more severe during levodopa-carbidopa treatment than during treatment with the levodopa-benserazide combination. Currently available oral drugs include Sinemet® and Sinemet® CR sustained-release tablets that include carbidopa or levodopa; Stalevo® tablets containing carbidopa, entacapone and levodopa; and Madopar® tablets containing levodopa and benserazide. In this present invention, Madopar® Tablets (Roche) are used as reference product. Madopar® is available in over 80 countries worldwide, and is an oral formulation of levodopa and the decarboxylase inhibitor benserazide. It is used to treat patients with Parkinson's disease and restless legs syndrome (RLS). The combination of Levodopa and decarboxylase inhibitor can increase dopamine content in brain cells, and improve Parkinson's disease. Meanwhile, benserazide can prevent dopa decarboxylase from being converted into dopamine before levodopa enters the brain, so that the dopamine in the brain is increased, the curative effect of the dopamine is enhanced, and peripheral adverse reactions of the dopamine are reduced. The compound preparation of levodopa and benserazide combination is used as a first-line medicament for treating the Parkinson disease or the Parkinson syndrome, and clinical practice shows that good curative effect can be obtained, the effect is the same as that of large-dose levodopa, and the tolerance is much better. With the combination therapy two major clinical advantages are obtained: increased bioavailability of Levodopa with marked reduction of the daily requirement of Levodopa, and improved tolerence due to the prevention of the formation of dopamine in peripheral tissues with a resulting marked reduction of side effects (nausea, vomiting and orthostatic hypotension). US20080051459 discloses a method of treating Parkinson's disease comprising administering pharmaceutically effective amount of a composition comprising levodopa. According to literature study on the stability and impurity analysis of the compound preparation of the benserazide, it is found that the benserazide hydrochloride is unstable to light and moisture, and three main degradation impurities are formed, namely, benserazide impurity A: (2RS) -2-amino-3-hydroxypropionyl hydrazide, benserazide impurity B: (2RS) - 2-amino-3-hydroxy-N, N-bis (2,3, 4-trihydroxybenzyl) propane hydrazide, benserazide impurity C: (2RS)-2-amino-3-hydroxy-N'- [(EZ)-(2,3,4-trihydroxyphenyl) methylene] propionylhydrazine. In the studies carried out in the present invention, it was determined that the degradation product known as impurity B increased significantly under stability conditions. Stability-related problems occur with a large number of active substances, including benserazide hydrochloride, under the influence of accelerated conditions. According to literature, benserazide is unstable especially in aqueous medium and undergoes oxidation processes which depend on the pH. Moreover, it was demonstrated that it undergoes a temperature-dependent equilibrium process (Figure 1). When benserazide is exposed to air and humidity, it undergoes structural degradation and changes in behaviour. Two main problems arise from this fact. The first problem is that the stability of the benserazide products developed is not at the desired level and their shelf life is shortened. The second problem is that benserazide inhibits the degradation of levodopa in the periphery at low levels and causes less penetration into the brain than the pharmaceutically effective amount. Degradation also leads to impurities in the formulation and the introduction of undesired components into the formulation. In the absence of a study on the degradation of compositions containing the active ingredients levodopa and benserazide in combination, there remains a need to develop a novel formulation of a composition containing levodopa and benserazide that is stable over the shelf life. Description of the Invention: It is an object of the present invention to provide a stable pharmaceutical tablet composition comprising pharmaceutically effective amount of levodopa and benserazide or pharmaceutically ассерtаblе salts thereof and one or more pharmaceutically acceptable excipients, wherein the said tablet composition comprises levodopa and benserazide granules; (i) levodopa granules are substantially free of benserazide, (ii) benserazide granules are substantially free of levodopa. Another aspect of the invention provides a stable pharmaceutical tablet composition comprising pharmaceutically effective amount of levodopa and benserazide hydrochloride and one or more pharmaceutically acceptable excipients, the said tablet composition comprises levodopa granules and benserazide granules; wherein the levodopa granules are prepared by wet granulation process and the benserazide granules are prepared by wet granulation or dry granulation process. Another aspect of the invention provides a stable pharmaceutical tablet composition comprising pharmaceutically effective amount of levodopa and benserazide hydrochloride and one or more pharmaceutically acceptable excipients, wherein said tablet composition comprises levodopa granules and benserazide granules comprising levodopa granules which are prepared by wet granulation process and benserazide granules which are prepared by dry granulation process. Another aspect of the invention provides a stable pharmaceutical tablet composition comprising pharmaceutically effective amount of levodopa and benserazide hydrochloride wherein said tablet composition comprises ethyl cellulose as a binder, prejelatenized starch as a disintegrant, combination of mannitol, calcium hydrogen phosphate and microcrystalline cellulose as filler / disintegrant, colloidal silicon dioxide as a glidant. Another aspect of the invention provides a stable pharmaceutical tablet composition comprising pharmaceutically effective amount of levodopa and benserazide hydrochloride, said tablet composition comprising granules characterised in that levodopa granules are prepared by the steps of (i) blending levodopa, mannitol, calcium hydrogen phosphate, pregelatinized starch, and ethyl cellulose in a granulator, (ii) wet granulating the resulting powder, (iii) and then drying in a fluid bed dryer; benserazide granules are prepared by the steps of (i) blending benserazide hydrochloride, mannitol, calcium hydrogen phosphate, microcrystalline cellulose, pregelatinized starch and ethyl cellulose in a granulator, (ii) wet granulating the resulting powder, (iii) and then drying in a fluid bed dryer. Another aspect of the invention provides a stable pharmaceutical tablet composition comprising pharmaceutically effective amount of levodopa and benserazide hydrochloride, said tablet composition comprising granules characterised in that levodopa granules are prepared by the steps of (i) blending levodopa, mannitol, calcium hydrogen phosphate, pregelatinized starch, and ethyl cellulose in a granulator, (ii) wet granulating the resulting powder, (iii) and then drying in a fluid bed dryer; benserazide granules are prepared by the steps of (i) blending benserazide hydrochloride, mannitol, calcium hydrogen phosphate, microcrystalline cellulose, pregelatinized starch, ethyl cellulose, colloidal silicon dioxide and magnesium stearate, (ii) dry granulating the resulting powder, (iii) and then sieving the obtained granules. In some embodiments, a stable pharmaceutical tablet composition comprises 200 mg to 100 mg of levodopa and 50 mg to 25 mg of a dopamine decarboxylase inhibitor, namely benserazide. There are three general methods of preparation of the materials to be included in the solid dosage form prior to compression: (1) dry granulation; (2) direct compression; and (3) wet granulation. Dry granulation procedures may be utilized where one of the constituents, either the drug or the diluent, has sufficient cohesive properties to be tableted. The method includes mixing the ingredients, slugging the excipients, dry screening, lubricating and finally compressing the excipients. In direct compression, the powdered material(s) to be included in the solid dosage form is compressed directly without modifying the physical nature of the material itself. The wet granulation procedure includes mixing the powders to be incorporated into the dosage form in and thereafter adding solutions of a binding agent to the mixed powders to obtain a granulation. Thereafter, the damp mass is screened, and then dried, the use of a fluid-bed dryer, spray-dryer, radio-frequency dryer, microwave, vacuum, or infra-red dryer. The term "active substance" or "active pharmaceutical ingredient" means any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or other animals. In the present invention, the active substances are levodopa and benserazide or their pharmaceutically acceptable salts, esters, and solvates thereof, preferably levodopa and benserazide hydrochloride. The term “therapeutically effective amount” refers to the amount of levodopa and benserazide or their pharmaceutically acceptable salts, esters, and solvates thereof, that is an amount sufficient to effect treatment, as defined herein, when administered to a subject in need of such treatment. In the present invention, tablet composition comprises 200 mg to 100 mg of levodopa and 50 mg to 25 mg of benserazide. As used herein, “stable” refers to a composition that substantially maintains its physical and chemical properties when stored. A pharmaceutical composition comprising an active ingredient is considered to be "stable" if said ingredient degrades less or more slowly than it does on its own and / or in known pharmaceutical compositions. As used herein, ‘fixed-dose’ refers to a combination of two or more active pharmaceutical ingredients (APIs) combined in a single dosage form, which is manufactured and distributed in fixed doses such as a tablet or oral dosage form. The term “decarboxylase inhibitor” refers to a dopa decarboxylase inhibitor, e.g., a drug that inhibits the peripheral metabolism of levodopa to dopamine by aromatic L-amino acid decarboxylase such as carbidopa and benserazide. In the present invention, benserazide is used as a dopa decarboxylase inhibitor. The expression “comprising” means “including, but not limited to”. Thus, other non- mentioned substances, additives, carriers, or steps may be present. In addition to the active or therapeutic substances, tablets may contain a number of inert materials known as excipients. The pharmaceutical compositions described herein can, if desired, include one or more pharmaceutically acceptable excipients. The term "excipient" herein means any substance, not itself a therapeutic agent, which may be used as a carrier or vehicle for delivery of a therapeutic agent to a subject or combined with a therapeutic agent (e.g., to create a pharmaceutical composition) to improve its handling or storage properties or to permit or facilitate formation of a dose unit of the composition. Excipients include, by way of illustration and not limitation, binders, disintegrants, taste enhancers, solvents, thickening or gelling agents (and any neutralizing agents, if necessary), penetration enhancers, solubilizing agents, wetting agents, antioxidants, lubricants, emollients, emulsifying agents, surfactants, substances added to mask or counteract a disagreeable odor, fragrances or taste, and substances added to improve appearance or texture of the composition. Any such excipients can be used in any dosage forms according to the present disclosure. The foregoing classes of excipients are not meant to be exhaustive but merely illustrative as a person of ordinary skill in the art would recognize that additional types and combinations of excipients could be used to achieve the desired goals for release and stability of levodopa - benserazide tablet composition. The excipients may be classified according to the role they play in the final tablet. The primary composition includes a filler / diluent, binder, lubricant, and glidant. Typically, excipients are added to a formulation to impart good flow and compression characteristics to the material being compressed. Such properties are imparted to these excipients through pretreatment steps, such as wet granulation, dry granulation, spray drying spheronization, or crystallization etc. The following examples represent various embodiments of the present invention. The examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention, as many variations thereof are possible without departing from the spirit and scope of the invention. Examples: The scope of present invention is the preparation of a stable pharmaceutical dosage form for oral administration comprising Levodopa and Benserazide, and exhibiting an immediate drug release profile. Also, the pharmaceutical composition shall be bioequivalent to reference product as per acceptance criteria indicated for generic products and must be stable under different storage conditions. Example 1. Production Methods – Selection of Production Method Formulation Trial – 1 F-01Levodopa 30-40 Benserazide HCl 8-15 Mannitol 15-25 Calcium hydrogen phosphate 10-20 Microcrystalline cellulose 5-10 Crospovidone 3-5 Pregelatinized starch 1-4 Ethyl cellulose 0.1-1 Docusate sodium 0.01-1 Aerosil 0.1-1 Magnezyum stearate 0.1-1.5 Required amounts of levodopa, benserazide hydrochloride, mannitol, microcrystalline cellulose, pregelatinized starch and ethyl cellulose are blended in a granulator and the prepared powder is wet granulated and dried in fluid bed dryer to obtain granules comprising levodopa and benserazide. The prepared granules are mixed with remained excipients. The final blends were compressed using a rotary tablet press. Formulation Trial - 2 F-02Levodopa Phase Levodopa 30-40 Mannitol 6-12 Calcium hydrogen phosphate 4-12 Pregelatinized starch 1-3 Ethyl cellulose 0.1-1 Benserazide Phase Benserazide HCl 8-15 Mannitol 6-12 Calcium hydrogen phosphate 4-12 Microcrystalline cellulose 6-8 Pregelatinized starch 1-3 Ethyl cellulose 0.1-1 Docusate sodium 0.01-1 Extragranular phase Crospovidone 3-5 Aerosil 0.1-1 Magnezyum stearate 0.1-1.5 In this formulation study, granules were prepared separately. Required amounts of levodopa, mannitol, calcium hydrogen phosphate, pregelatinized starch, and ethyl cellulose are blended in a granulator and the prepared powder is wet granulated and dried in fluid bed dryer to obtain levodopa granules. Required amounts of benserazide hydrochloride, mannitol, calcium hydrogen phosphate, microcrystalline cellulose, pregelatinized starch and ethyl cellulose are blended in a granulator and the prepared powder is wet granulated and dried in fluid bed dryer to obtain benserazide granules. The prepared levodopa granules and benserazide granules are mixed to obtain a homogeneous mixture and extragranular phase excipients are added. The final blends were compressed using a rotary tablet press. Formulation Trial - 3 F-03Levodopa Granule Levodopa 30-40 Mannitol 6-12 Calcium hydrogen phosphate 4-12 Pregelatinized starch 1-3 Ethyl cellulose 0.1-1 Docusate sodium 0.01-1 Benserazide Granule Benserazide HCl 8-15 Mannitol 6-12 Calcium hydrogen phosphate 4-12 Microcrystalline cellulose 6-8 Pregelatinized starch 1-3 Ethyl cellulose 0.1-1 Colloidal silicon dioxide Magnezyum stearate 0.01-1 Extragranular phase Crospovidone 3-5 Colloidal silicon dioxide 0.1-1 Magnezyum stearate 0.1-1.5 In this formulation study, granules were prepared separately. Required amounts of levodopa, mannitol, calcium hydrogen phosphate, pregelatinized starch and ethyl cellulose are mixed for 10 minutes. The prepared powder is wet granulated and dried in fluid bed dryer to obtain levodopa granules. Required amounts of benserazide hydrochloride, mannitol, calcium hydrogen phosphate, microcrystalline cellulose, pregelatinized starch, ethyl cellulose, colloidal silicon dioxide and magnesium stearate are blended for 10 minutes. The resulting powder mixture is passed through the compactor for dry granulation. The structure taken from the compactor should be in the form of thin wafers, strips that do not break easily when handled, are hard but can be broken with a little pressure (with a hardness above medium). The obtained granules are sieved to obtain benserazide granules. The prepared levodopa granules and benserazide granules are mixed to obtain a homogeneous mixture and external phase excipients are added. The final blends were compressed using a rotary tablet press. Example 2. In-Vitro Dissolution The in-vitro dissolution profile of Formulation Trials (F-01, F-02 and F-03) were recorded in Buffer 0.1 N HCl 100 RPM, 900 mL basket apparatus in comparison to reference product. An in-vitro comparative dissolution test was performed for the test (Formulations F01, F02 and F03) and the reference products (Madopar®), in accordance to the Guideline on Investigation of Bioequivalence, was performed using the chosen dissolution conditions (900 mL dissolution medium, basket at 100 rpm at 37oC ±0.5oC) at 0.1 N HCl medium). The above exemplified compositions (Formulations F-01, F02 and F-03) comprising levodopa and benserazide were tested in vitro and they were compared with a commercial reference product Madopar® Tablet. The dissolution profiles were compared; the dissolution profiles obtained were evaluated by similarity factor (f2) (Helmy & Bedaiwy, 2013). An value between 50 and 100 suggests that the two dissolution profiles are similar (EMEA Guideline on the Investigation of Bioequivalence, 2010). The similarity factor (f2) values of test products (Formulations F-01, F-02 and F-03) and reference product (Madopar® Tablet) for the different pH media are found between 50 and 100. Example 3. Stability Studies The stability of a drug substance is an important factor in the manufacture of safe and effective pharmaceutical products. Stability studies are required to be submitted by any applicant seeking approval for a new pharmaceutical product. The rules in force (e.g. "Note for Guidance on Impurities in New Drug Products" CPMP / ICH / 2738 / 99, issued by EMEA, European Medicines Agency) provide strict limitations for impurities, nevertheless it is better to prevent or reduce as possible the degradation to avoid the exposure of patients to substances. The stability of a pharmaceutical dosage form is related to maintaining its physical, chemical, microbiological, therapeutic, and toxicological properties when stored, i.e., in a particular container and environment. It is known that many drugs exhibit poor or modest shelf stability. The presence of degradation products of these drugs can give rise to efficacy or toxicity issues, but even if they do not, the diminution of the concentration of a drug as a result of its degradation is inherently undesirable, as it makes therapy with the drug less certain. Stability issues can be caused by environmental factors such as humidity, temperature and the like. However, degradation may result from, or be accelerated by, interactions of drug substances with pharmaceutical excipients such as fillers, binders, lubricants, glidants and disintegrating agents or impurities contained in any of these excipients. Accelerated stability tests are performed by storing a product in stress conditions. These tests allow predicting the shelf life of the product over the years when it will be stored in normal storage conditions. The accelerated stability test in this case was performed according to the EMEA Guideline on Stability Testing (CPMP / QWP / 122 / 02, rev 1), i.e. by maintaining the product in its container at a temperature of 40°C ± 2°C and 75% ± 5 %RH (Relative Humidity) for six months. Table 2. Stability results (assay) for Test products (F-01, F-02, F03) and reference product (Madopar®) initially and after 6 months at 40°C±2°C / 75%±5 %RH and 25°C±2°C / 60±5% Relative Humidity, RH±5% storage conditions. Assay (%) After 6 months *Levod: Levodopa & Bens: Benserazide According to the stability studies, the reference product (Madopar® Tablet) and test products (Formulations F-02 and F-03) gave appropriate results for assay test under 6- month stability conditions. In addition, no change was observed in the appearance tests between the initial conditions and the 6-month stability conditions. While stability conditions were examined in prior art documents, only the appearance and quantity determination tests of the products were compared. However, it is also very important to examine the degradation products formed for active substances that are prone to degradation. In this regard, impurity tests were carried out on both the reference product (Madopar® Tablet) and the test products (Formulations F-01, F-02 and F-03) under initial and stability conditions. Table 4. Stability results (degradation products of Levodopa and Benserazide) for Test products and reference product (Madopar®) initially and after 6 months at 40°C±2°C / 75%±5 %RH and 25°C±2°C / 60±5% Relative Humidity, RH±5% storage conditions. Degradation Product (%) After 6 months *Imp. B: Degradation product - Impurity B - of Benserazide It is known that the active substance Benserazid undergoes structural degradation and behavioural changes when exposed to air and humidity. As seen in the present invention, the fixed dose tablet composition comprising Levodopa and Benserazide undergoes degradation over time. Two main problems arise from this situation. The first problem is that the stability of the developed benserazide products is not at the desired level and their shelf life is shortened. The second problem is that benserazide inhibits the degradation of levodopa in the periphery at low levels, resulting in less penetration into the brain than the pharmaceutically effective amount. Degradation also leads to impurities in the formulation and the introduction of unwanted components into the formulation. The Test products (F-02 and F-03) surprisingly showed good stability according to stability test results. The degradation problem has been solved with the invented formulation; a stable pharmaceutical tablet composition comprising pharmaceutically effective amount of levodopa and benserazide, wherein said tablet composition are formed by producing levodopa and benserazide granules separately. FIGURES: Figure 1. The equilibrium reaction of benserazide observed in aqueous solution

Claims

CLAIMS 1. A stable pharmaceutical tablet composition comprising pharmaceutically effective amount of levodopa and benserazide or pharmaceutically ассерtаblе salts thereof, and one or more pharmaceutically acceptable excipients, wherein said tablet composition comprises levodopa granules and benserazide granules, (i) the levodopa granules are substantially free of benserazide, (ii) the benserazide granules are substantially free of levodopa.

2. The stable tablet composition according to claim 1, wherein the active substance is benserazide hydrochloride.

3. The stable tablet composition according to claim 1, wherein levodopa granules are prepared by wet granulation process.

4. The stable tablet composition according to claim 1, wherein benserazide granules are prepared by wet granulation process.

5. The stable tablet composition according to claim 1, wherein benserazide granules are prepared by dry granulation process.

6. The stable tablet composition according to claim 1, wherein one or more pharmaceutically acceptable excipients are selected from the group comprising, lubricants, binders, glidants, filler / diluents, disintegrants and coloring agents or mixtures thereof.

7. The stable tablet composition according to claim 1, wherein binder used in the composition is ethyl cellulose.

8. The stable tablet composition according to claim 1, wherein disintegrant used in the composition is pregelatinized starch.

9. The stable tablet composition according to claim 1, wherein filler / disintegrant used in the composition is a combination of mannitol, calcium hydrogen phosphate and microcrystalline cellulose.

10. The stable tablet composition according to claim 1, wherein glidant used in the composition is colloidal silicon dioxide.

11. The stable tablet composition according to claim 1, wherein levodopa granules comprising the steps of; (a) blending levodopa, mannitol, calcium hydrogen phosphate, pregelatinized starch, and ethyl cellulose in a granulator, (b) wet granulating the resulting powder, (c) and then drying in a fluid bed dryer.

12. The stable tablet composition according to claim 1, wherein benserazide granules comprising the steps of; (a) blending benserazide hydrochloride, mannitol, calcium hydrogen phosphate, microcrystalline cellulose, pregelatinized starch, and ethyl cellulose in a granulator, (b) wet granulating the resulting powder, (c) and then drying in a fluid bed dryer.

13. The stable tablet composition according to claim 1, wherein benserazide granules comprising the steps of; (a) blending benserazide hydrochloride, mannitol, calcium hydrogen phosphate, microcrystalline cellulose, pregelatinized starch, ethyl cellulose, colloidal silicon dioxide and magnesium stearate, (b) dry granulating the resulting powder, (c) and then sieving the obtained granules.

14. The stable tablet composition according to claim 1, wherein the composition comprises 200 mg or 100 mg of levodopa and 50 mg or 25 mg of a dopamine decarboxylase inhibitor, namely benserazide.

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