Orodispersible tablet composition containing carbidopa and levodopa

Abstract

An orodispersible solid pharmaceutical composition in tablet form is disclosed comprising a) carbidopa and levodopa or pharmaceutically acceptable salts thereof, b) one or more diluent, c) one or more

Description

Field of the Invention The technical field of the present invention relates to the pharmaceutical compositions of carbidopa and levodopa. The present invention more particularly relates to orodispersible tablets of carbidopa and levodopa or pharmaceutically acceptable salts thereof for oral administration. The present invention also provides an orodispersible tablet of carbidopa and levodopa for the treatment of Parkinson’s disease and the process for preparing the same. Background of the Invention Carbidopa was first disclosed in the U.S. Pat. No. 3462536 and levodopa was first disclosed in the U.S. Pat. No. 3253023 with the process of preparing the same. Parkinson's disease is a progressive, neurodegenerative disorder of the extrapy rami dal nervous system affecting the mobility and control of the skeletal muscular system. Its characteristic features include resting tremor, rigidity, and bradykinetic movements. A combination of both drugs is considered to be the most effective treatment for symptoms of Parkinson’s disease, which is associated with the depletion of dopamine from cells in the corpus striatum. Carbidopa presents a chemical denomination ofN-amino-alpha-methyl-3-hydroxy-L-tyrosine monohydrate. It potently inhibits aromatic amino acid decarboxylase (DDC) and due to its chemical properties, it does not cross the bloodbrain barrier. Due to its activity, carbidopa is always administered concomitantly with levodopa. When mixed with levodopa, carbidopa inhibits the peripheral conversion of levodopa to dopamine and the decarboxylation of oxitriptan to serotonin by aromatic L-amino acid decarboxylase. This results in an increased amount of levodopa and oxitriptan available for transport to the central nervous system. Carbidopa also inhibits the metabolism of levodopa in the GI tract, thus, increasing the bioavailability of levodopa. The presence of additional units of circulating levodopa can increase the effectiveness of the still functional dopaminergic neurons and it has been shown to alleviate symptoms for a time. The action of carbidopa is very important as levodopa is able to cross the blood-brain barrier while dopamine cannot. Hence the administration of carbidopa is essential to prevent the transformation of external levodopa to dopamine before reaching the mam action site in the brain. Carbidopa and levodopa are indicated in the treatment of Parkinson's disease, postencephalitic parkinsonism, and symptomatic parkinsonism that may follow carbon monoxide intoxication or manganese intoxication. Carbidopa, an inhibitor of aromatic amino acid decarboxylation, is slightly soluble in water, with a molecular weight of 244.24. It is designated chemically as (-)-L-a-hydrazino-a-methyl-P- (3,4-dihydroxybenzene) propanoic acid monohydrate. Its molecular formula is C10H14N2O4 ^0, and its structural formula is OH ^0 ""C Levodopa, USP an aromatic amino acid, slightly soluble in water, with a molecular weight of 197.19. It is designated chemically as (-)-L-a-amino-P-(3,4-dihydroxybenzene) propanoic acid. Its molecular formula is C9H11NO4, and its structural formula is: OH HO CW^OHOnOH OHg Carbidopa and levodopa are marketed as a capsule extended release, suspension, oral tablet, tablet extended release, and tablet orally disintegrating. The commercially marketed products of carbidopa and levodopa in capsule extended release available in strength of 23.75MG; 95MG, 36.25MG; 145MG, 48.75MG; 195MG, and 61.25MG; 245MG. The suspension is available in strength of 4.63MG / ML; 20MG / ML. The oral tablet and extended-release tablet are available in 10MG; 100MG, 25MG; 100MG, 25MG; 250MG, and 50MG; 200MG. Carbidopa belongs to BCS class III and levodopa belongs to BCS class I drug. Carbidopa allows patients treated for Parkinson's disease to use much lower doses of levodopa. Some patients who responded poorly to levodopa have improved on carbidopa and levodopa. This is most likely due to decreased peripheral decarboxylation of levodopa caused by the administration of carbidopa rather than by a primary effect of carbidopa on the nervous system. Carbidopa has not been shown to enhance the intrinsic efficacy of levodopa. Carbidopa may also reduce nausea and vomiting and permit more rapid titration of levodopa. Carbidopa reduces the amount of levodopa required to produce a given response by about 75% and, when administered with levodopa, increases both plasma levels and the plasma half-life of levodopa and decreases plasma and urinary dopamine and homovanillic acid. The plasma half-life of levodopa is about 50 minutes, without carbidopa. When carbidopa and levodopa are administered together, the half-life of levodopa is increased to about 1.5 hours. In clinical pharmacologic studies, simultaneous administration of carbidopa and levodopa produced greater urinary excretion of levodopa in proportion to the excretion of dopamine than administration of the two drugs at separate times. Pyridoxine hydrochloride (vitamin B), in oral doses of 10 mg to 25 mg, may reverse the effects of levodopa by increasing the rate of aromatic amino acid decarboxylation. Carbidopa inhibits this action of pyridoxine; therefore, carbidopa and levodopa can be given to patients receiving supplemental pyridoxine (vitamin B). There are some documents that disclose the formulations of Carbidopa and levodopa for the treatment of Parkinson’s. US4832957A discloses a matrix or monolithic drug delivery system for the controlled release tablet of carbidopa and levodopa oral dosage formulation comprising carbidopa, levodopa, tablet lubricant, and in a mixture thereof with a pharmaceutically acceptable dye, in a polymer vehicle comprising water-soluble hydroxypropyl cellulose polymer, and water-soluble polyvinyl acetate-crotonic acid copolymer, whereby following administration the carbidopa and levodopa are released slowly and simultaneously from the formulation. US5840756 discloses a matrix based on hydroxypropylmethylcellulose, hydroxypropyl cellulose, and a carboxy vinyl polymer containing different proportions of levodopa and carbidopa. This formulation is obtained by direct compression of the mixture of the constituents. The drawback of such a process lies in the difficulty of obtaining a uniform distribution of the active principles during direct compression. This formulation does not have good stability. EP0253490 discloses a formulation of levodopa and carbidopa uniformly dispersed in a polymeric matrix consisting of a mixture of two polymers, one of which is watersoluble, such as hydroxypropyl(methyl) cellulose, and the other of which is weakly soluble, such as polyvinyl acetate / crotonic acid copolymer. Such a formulation is, firstly, complex (it requires the steps of mixing the active compounds with an aqueous-alcoholic solution of the polymers, drying, grinding, mixing with the lubricant, and finally compressing into tablets), and secondly, there is no indication as to the stability of the preparation. The currently available solid dosage form of carbidopa and levodopa poses challenges for patients who struggle with swallowing, resulting in poor patient compliance. The fear of swallowing or choking on such solid formulation is still a concern in certain populations, especially in geriatrics. Solid dosage forms become sticky when wetted by saliva, and if the patient experiences difficulty in swallowing on the first attempt, then the tablet must often be discarded. Furthermore, if solid dosage forms partially dissolve in the patient's mouth due to unsuccessful swallowing or the solid dosage form gets stuck in an orthodontic appliance, the resulting unpleasant taste can discourage the patient from taking another dose. These challenges associated with solid dosage forms contribute to decreased patient compliance. Liquid dosage forms, on the other hand, present challenges such as bulkiness, difficulty in transport, and significant space occupation. Due to their inherent instability, liquid dosage forms often have shorter shelf lives. The accurate measurement of the exact volume by the patient determines whether the dose is administered appropriately, introducing a potential for variability. Therefore, alternative dosage forms that are easier to swallow and have a faster onset time need to be explored. An orodispersible tablet of the present invention is a pharmaceutical formulation specifically designed in such a way that the entire tablet disintegrates with saliva within a short time when put in the mouth, facilitating easy administration to patients. The orodispersible tablet of carbidopa and levodopa is the best-suited dosage form to formulate, as it offers several benefits, including precise dosing, fast disintegration in the oral cavity without the need for water, fast dissolution, and improved patient adherence who have difficulty swallowing, such as pediatrics and geriatrics suffering from dysphagia. The present invention solves all prior art problems and provides a pharmaceutical composition for oral administration comprising carbidopa and levodopa. Summary of the Invention The main aspect of the present invention is to provide the stable pharmaceutical compositions of carbidopa and levodopa. Another main aspect of the present invention is to provide an orodispersible tablet of carbidopa and levodopa for oral administration comprising carbidopa and levodopa or pharmaceutically acceptable salts thereof, at least one disintegrant, at least one diluent, at least one binder, and one or more pharmaceutically acceptable excipient selected from a sweetener, flavoring agent, coloring agent, and lubricant. Another aspect of the present invention relates generally to pharmaceutical dosage forms comprising carbidopa and levodopa. These dosage forms can be used in the treatment of medical conditions associated with reduced dopamine levels in a patient's brain. An aspect of the present invention is to provide an orodispersible tablet of carbidopa and levodopa prepared by a wet granulation process comprising: mixing levodopa, carbidopa, a binder, including a further diluent, a disintegrant, and / or a Sweetener to form a mixture; granulating the mixture with a Suitable Solvent to form granules, drying the resulting granules, milling oversized granules, blending the resulting granules with a lubricant, and compressing the product into a tablet. A further aspect of the present invention provides for carbidopa-levodopa orodispersible tablets, wherein the tablets disintegrate within about 45 seconds In-Vitro in a USP disintegration apparatus in 0.1 N HCL. In preferred embodiments, the ODT formulation disintegrates in less than about 35 Seconds In-Vitro in a USP disintegration apparatus in 0.1 N HCL. The other aspect of the present invention is to provide an orodispersible tablet of carbidopa and levodopa and a process of preparation thereof. Objects of the Invention The main object of the present invention is to provide an orodispersible tablet of carbidopa and levodopa or pharmaceutically acceptable salts thereof. Another object of the present invention is to provide an orodispersible tablet of carbidopa and levodopa which enhances the disintegration and dissolution of the drug for oral administration. Another object of the present invention is to provide an orodispersible tablet of carbidopa and levodopa which has taste-masking properties and presents pleasant palatability such that the administration of the orodispersible tablet is not unpleasant for pediatrics, geriatrics, or unconscious patients. Another further object of the present invention is to provide an orodispersible tablet of carbidopa and levodopa which is effective and very convenient for administration without the need for water or swallowing difficulties, which will improve patient compliance. A further object of the present invention is to provide a stable orodispersible tablet of carbidopa and levodopa or pharmaceutically acceptable salts thereof. Yet another object of the present invention is to provide an orodispersible tablet of carbidopa and levodopa which can effectively treat Parkinson's disease, postencephalitic parkinsonism, and symptomatic parkinsonism that may follow carbon monoxide intoxication or manganese intoxication. Detailed description of the Invention The detailed description set forth below is intended as a description of exemplary embodiments and is not intended to represent the only forms in which the exemplary embodiments may be constructed and / or utilized. The description sets forth the functions and the sequence of steps for constructing and / or operating the exemplary embodiments. However, it is to be understood that the same or equivalent functions and sequences that may be accomplished by different exemplary methods are also intended to be encompassed within the spirit and scope of the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. As stated herein, that it follows in a transitional phrase or in the body of a claim, the terms “comprise (s)” and “comprising” are to be interpreted as having an open ended meaning. That is, the terms are to be interpreted synonymously with the phrases “having at least” or “including at least”. When used in the context of a process, the term “comprising” means that the process includes at least the recited steps, but may include additional steps. When used in the context of a composition, the term “comprising” means that the composition includes at least the recited features or components, but may also include additional features or components. The term "Orodispersible tablet” as used herein means solid dosage form that disintegrates rapidly in the oral cavity of a patient after administration, without chewing. The term “excipient” as used herein refers to any pharmaceutical additive material that is used in the pharmaceutical dosage form other than the one or more pharmaceutically active substances. The term “about” is used herein to mean approximately, in the region of, roughly, or around. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term "about", as and when used in this specification, means ±10 % of the mentioned value. The term “% w / w” is intended to mean the percentage of an ingredient(s) / the total percentage by weight of the composition (100%). Here the % w / w is to be calculated against the total weight of the composition. The main embodiment of the present invention is to provide an orodispersible tablet formulation of carbidopa and levodopa. Another main embodiment of the present invention is to provide an orodispersible tablet formulation of carbidopa and levodopa comprising carbidopa and levodopa or pharmaceutically acceptable salts thereof, at least one disintegrant, at least one diluent, at least one binder and one or more pharmaceutically acceptable excipient selected from a coloring agent, sweetener, flavoring agent, and lubricant. In the present invention, an orodispersible tablet may contain other pharmaceutically acceptable excipients as needed, insofar as they do not reduce the effect of the present invention. The term pharmaceutically-acceptable salts can be used herein includes salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. Suitable pharmaceutically acceptable acid addition salts of carbidopa and levodopa may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoric acid. Appropriate organic acids may be selected from formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, p-hydroxybenzoic, salicyclic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic, sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, alginic, phydroxybutyric, malonic, galactaric and galacturonic acid. Preferably carbidopa and levodopa as used herein in the form of the free base. In the one embodiment of the present invention, the combination of carbidopa, and levodopa, or pharmaceutically acceptable salts thereof, are present in the range of about 40 %w / w to about 70 %w / w, preferably in the range of about 45 %w / w to about 65 %w / w. Carbidopa is present in the range from about 1 %w / w to about 20 %w / w, preferably from about 5 %w / w to about 15 %w / w, Levodopa is present in the range from about 35 %w / w to about 55 %w / w, preferably from about 40 %w / w to about 50 %w / w. In the one embodiment of the present invention, a suitable diluent for the present invention can be selected from the group consisting of a calcium carbonate, cellulose derivative, microcrystalline cellulose, microfme cellulose, sugar alcohols such as maltitol, xylitol, mannitol, sorbitol, erythritol, dextrose, lactose, maize starch, pregelatinized starch, and dextrin, or any combinations thereof. In the preferred embodiment of the present invention, the combination of microcrystalline cellulose 101, microcrystalline cellulose 102, and Maize starch is preferred as a diluent in the range of about 20 %w / w to about 50 %w / w, preferably in the range from about 25 %w / w to about 45 %w / w. Microcrystalline cellulose 101 is present in the range from about 10 %w / w to about 30 %w / w, preferably from about 15 %w / w to about 25 %w / w, microcrystalline cellulose 102 is present in the range from about 5 %w / wto about 20 %w / w, preferably from about 10 %w / w to about 15 %w / w and Maize starch is present in the range from about 0.5 %w / w to about 10 %w / w, preferably from about 1 %w / w to about 5 %w / w. In the one another embodiment of the present invention, a suitable disintegrant is selected from the group consisting of methylcellulose, Pregelatinised maize starch, alginic acid, guar gum, carboxymethylcellulose calcium, polacrilin potassium, croscarmellose sodium, carmellose calcium, crospovidone, calcium hydrogen phosphate, sodium carboxymethyl starch, poloxamer, and sodium starch glycolate, or any combination thereof. The lower concentration of pregelatinized maize starch is used as a disintegrant and the higher concentration is used as the binder. In the preferred embodiment of the present invention, the pregelatinised maize starch is preferred as a disintegrant in the range of about 0.1 %w / w to about 5 %w / w, preferably in the range from about 0.5 %w / w to about 1 %w / w. In the one more embodiment of the present invention, a suitable binder can be selected from the group consisting of Pregelatinised Maize Starch, starch, polyethylene glycol, polyvinylpyrrolidone, sugars such as sucrose, glucose, dextrose, molasses, lactose, dextrin, xylitol, sorbitol, polymethacrylates, acrylates such as Eudragits, natural and synthetic gums such as acacia, alginic acids, sodium alginate, gum tragacanth, irish moss extract, ghatti gum, guar gum, zein, cellulose derivatives hydroxypropyl cellulose, hydroxy ethyl cellulose and ethyl cellulose, polyvinylpyrrolidone, polyethylene glycol, magnesium aluminum silicate, bentonites or any combinations thereof. In the preferred embodiment of the present invention, Pregelatinised Maize Starch is preferred as the binder in the range from about 0.5 %w / w to about 10 %w / w, preferably in the range of about 1 %w / w to about 5 %w / w. In the one embodiment of the present invention, a suitable lubricant can be selected from the group consisting of magnesium stearate, sodium stearyl fumarate, leucine, sodium benzoate, sodium acetate, sodium lauryl sulfate, stearic acid, sodium stearate, sodium oleate, calcium stearate, waxes or any combination thereof. In the preferred embodiment of the present invention, magnesium stearate is preferred as a lubricant for the present invention and is present in the range from about 0.1 %w / w to about 5 %w / w, preferably in the range of about 0.5 %w / w to about 1 %w / w. In one more embodiment of the present invention, a sweetener can be selected from the group consisting of cyclamate, acesulfame potassium, monoammonium glycyrrhizinate, saccharin sodium, sucralose, saccharin, aspartame, or any combination thereof. In the preferred embodiment of the present invention, aspartame is preferred as a sweetener for the present invention and is present in the range of about 0.05 %w / w to about 1 %w / w, preferably in the range of about 0.1 %w / w to about 0.5 %w / w. In one another embodiment of the present invention, a flavoring agent can be selected from a group consisting of menthol, tutti frutti, floral fennel flavor, vanillin, raspberry flavor, orange flavor, or any combinations thereof. In the preferred embodiment of the present invention, Tutti Frutti flavor is preferred as a flavoring agent present in the range from about 0.05 %w / w to about l%w / w, preferably in the range of about 0.1 %w / w to about 0.5 %w / w. In the preferred embodiment, the present invention has been made to solve the above-mentioned problems, and its object is to use carbidopa and levodopa or a pharmaceutically acceptable salt thereof as an active ingredient, which provides a faster disintegration time and faster dissolution rate. Carbidopa and levodopa can effectively treat Parkinson's disease, post-encephalitic parkinsonism, and symptomatic parkinsonism that may follow carbon monoxide intoxication or manganese intoxication. In the one embodiment of the present invention, the orodispersible tablet comprising carbidopa and levodopa or pharmaceutically acceptable salts thereof, present in an amount from about 40 %w / w to about 70 %w / w, preferably in the range of about 45 %w / w to about 65 %w / w, a combination of diluents is present in the range of about 20 %w / w to about 50 %w / w, preferably in the range of about 25 %w / w to about 45 %w / w, disintegrants is present in the range from about 0.1 %w / w to about 5 %w / w, preferably in the range of about 0.5 %w / w to about 1 %w / w, binder is present in the range from about 0.5 %w / w to about 10 %w / w, preferably in the range of about 1 %w / w to about 5 %w / w, lubricant is present in the range from about 0.1 %w / w to about 5 %w / w, preferably in the range of about 0.5 %w / w to about 1 %w / w, the sweetener is present in the range of about 0.05 %w / w to about 1 %w / w, preferably in the range of about 0.1 %w / w to about 0.5 %w / w, the colouring agent is present in the range of about 0.05 %w / w to about 1% w / w, preferably in the range of about 0.1 %w / w to 0.5 %w / w, and the flavoring agent is present in the range from about 0.05 %w / w to about l%w / w, preferably in the range of about 0.1 %w / w to about 0.5 %w / w. In the preferred embodiment of the present invention, the orodispersible tablet comprising carbidopa and levodopa or pharmaceutically acceptable salts thereof, present in an amount from about 40 %w / w to about 70 %w / w, preferably in the range of about 45 %w / w to about 65 %w / w, a combination of Microcrystalline Cellulose -101, Microcrystalline Cellulose -102, and Maize starch is present in the range of about 20 %w / w to about 50 %w / w, preferably in the range of about 25 %w / w to about 45 %w / w, Pregelatinised Maize Starch as disintegrant is present in the range from about 0.1 %w / w to about 5 %w / w, preferably in the range of about 0.5 %w / w to about 1 %w / w, Pregelatinised Maize Starch as binder is present in the range from about 0.5 %w / w to about 10 %w / w, preferably in the range of about 1 %w / w to about 5 %w / w, Magnesium stearate is present in the range from about 0.1 %w / w to about 5 %w / w, preferably in the range of about 0.5 %w / w to about 1 %w / w, the Aspartame is present in the range of about 0.05 %w / w to about 1 %w / w, preferably in the range of about 0.1 %w / w to about 0.5 %w / w, the Quinoline yellow lake is present in the range of about 0.05 %w / w to about 1% w / w, preferably in the range of about 0.1 %w / w to 0.5 %w / w, and the Tutti Frutti flavor is present in the range from about 0.05 %w / w to about l%w / w, preferably in the range of about 0.1 %w / w to about 0.5 %w / w. In the one embodiment of the present invention is to manufacture an orodispersible tablet containing carbidopa and levodopa by wet granulation process, which is one of the most economical methods. Wet granulation enhances the flow properties of powders, making them easier to handle and ensuring a more uniform distribution during the tableting process. As per one another embodiment of the present invention, the disintegrating time of the carbidopa and levodopa orodispersible tablet is less than 45 seconds, preferably less than 35 seconds. As per another embodiment of the present invention, 85 % of the carbidopa and levodopa is released in 60 minutes, preferably more than 85 % is released within 50 minutes. As per one embodiment of the present invention, packaging material for an orodispersible tablet of carbidopa-levodopa is selected from the polypropylene bottle with silica canister, PP Bottle with an Oxygen scavenger, HDPE Bottle, HDPE Bottle with SAF, HDPE Bottle with CR cap, HDPE Bottle with Silica canister, HDPE Bottle with an Oxygen scavenger, Alu-Alu Blister and PVC / PVDC-Alu Film. In the present invention, the HDPE Bottle with a CR cap containing silica gel is preferred as packaging material to deliver the desired physicochemical parameters. As per one more embodiment, the wet granulation method is used to manufacture the orodispersible tablet. Carbidopa, levodopa, and Microcrystalline Cellulose 101 were sieved separately through a 30# sieve, and maize starch, Microcrystalline Cellulose 102, aspartame, pregelatinised maize starch, and tutti frutti flavor were sieved separately through a 40# sieve. The quinoline yellow lake was sieved separately through a 100# sieve. Magnesium stearate was sieved separately through a 60# sieve. In a rapid mixer granulator previously sifted carbidopa, levodopa, Microcrystalline Cellulose 101, and quinoline yellow lake were blended and mixed for 10 minutes. Pregelatinised maize starch was then dissolved in water with continuous stirring until a clear and viscous solution was obtained to prepare a binder solution. Subsequently, the binder solution obtained earlier was gradually added to the rapid mixer granulator at the slow speed of the impeller and chopper off, ensuring a homogeneous mixture with continuous mixing for 5 minutes. The granulated blend was then dried in a dryer at 50°C ± 5°C and the dry granules were passed through a 30# sieve retained granules were milled through a 1.5 mm screen, and the entire blend was subsequently passed through a 30# sieve. Further, the granules were mixed with previously sifted microcrystalline Cellulose-102, pregelatinised maize starch, maize starch, aspartame, and tutti frutti flavor added to the above blend and mixed for 10 minutes. At last, the previously sifted magnesium stearate was added to the above mixture and blended in a blender for 5 minutes. Finally, the lubricated mixture was compressed to form tablets. The prepared tablets were packed in HDPE bottles with CR cap containing silica gel preferred as packaging materials to deliver the desired physicochemical parameters. Embodiments of the present disclosure are now further illustrated on the basis of examples and a detailed description from which further features and advantages may be taken. It is to be noted that the following explanations are presented for the purpose of illustrating and description only, they are not intended to be exhaustive or to limit the disclosure to the precise forms disclosed. EXAMPLES Example 1: The orodispersible tablet was made according to the method defined below using the formulation having the ingredients shown in Table I for a Carbidopa / Levodopa in dose strength of 25mg / 100mg: TABLE-I Ingredients iiii® Carbidopa 11.364 Levodopa 45.455 Microcrystalline Cellulose -101 36.81 Maize starch 4.09 Aspartame 0.227 Pregelatinised Maize Starch 0.909 Tutti Frutti flavor 0.227 Magnesium stearate 0.909 Total 100 Manufacturing process: Carbidopa, levodopa, and Microcrystalline Cellulose 101 were sieved separately through a 30# sieve, and maize starch, aspartame, pregelatinised Maize starch, and tutti frutti flavor were sieved separately through a 40# sieve. Magnesium stearate was sieved 5 separately through a 60# sieve. In a blender previously sifted carbidopa, levodopa, and Microcrystalline Cellulose 101 were blended and mixed for 10 minutes. The previously sifted maize starch, Aspartame, pregelatinised maize starch, and tutti frutti flavor were added to the blender and blended for 15 minutes. At last, previously sifted magnesium stearate was added to the above blend and mixed for 5 minutes. .0 The blend flow was not good so, further compression activity was not performed. To optimize blend flow, the Microcrystalline Cellulose 101 is added. Test Parameters of blend Result Bulk Density (gm / ml) 0.269 Tap Density (gm / ml) 0.388 Carr’s Index (%) 30.67 Hausner’s Ratio 1.44 15 Example 2: The orodispersible tablet was made according to the method defined below using the formulation having the ingredients shown in Table II for a Carbidopa / Levodopa in dose strength of 25mg / 100mg: TABLE-II Ingredients %w / w Carbidopa 11.364 Levodopa 45.455 Microcrystalline Cellulose -101 24.77 Maize starch 4.09 Microcrystalline Cellulose -102 12.045 Aspartame 0.227 Pregelatinised Maize Starch 0.909 Tutti Frutti flavor 0.227 Magnesium stearate 0.909 Total 100 Manufacturing process: Carbidopa, levodopa, and Microcrystalline Cellulose 101 were sieved separately through a 30# sieve, and maize starch, Microcrystalline Cellulose 102, aspartame, pregelatinised maize starch, and tutti frutti flavor were sieved separately through a 40# sieve. Magnesium stearate was sieved separately through a 60# sieve. In a blender previously sifted carbidopa, levodopa, and Microcrystalline Cellulose 101 were blended and mixed for 10 minutes. The previously sifted maize starch, Microcrystalline Cellulose 102, Aspartame, pregelatinised maize starch, and tutti frutti flavor were added to the blender and blended for 15 minutes. At last, previously sifted magnesium stearate was added to the above blend and mixed for 5 minutes. Finally, the lubricated mixture was compressed to form tablets. The blend flow was not good so, further compression activity was not performed. In order to optimize blend, flow it was necessary to change the granulation process from direct compression to wet granulation. The tablets present the characteristics mentioned in the table below: Test Parameters of blend Result Bulk Density (gm / ml) 0.290 Tap Density (gm / ml) 0.395 Carr’s Index (%) 26.58 Hausner’s Ratio 1.36 Example 3: The orodispersible tablet was made according to the method defined below using the formulation having the ingredients shown in Table III for a Carbidopa / Levodopa in dose strength of 25mg / 100mg: 5 TABLE-111 Ingredients Carbidopa 11.364 Levodopa 45.455 Microcrystalline Cellulose -101 21.818 Quinoline yellow lake 0.227 Pregelatinised Maize Starch 2.727 Purified water Q.S Maize starch 4.091 Microcrystalline Cellulose -102 12.045 Aspartame 0.227 Pregelatinised Maize Starch 0.909 Tutti Frutti flavor 0.227 Magnesium stearate 0.909 Total 100.00 Manufacturing process: Carbidopa, levodopa, and Microcrystalline Cellulose 101 were sieved separately 10 through a 30# sieve, and maize starch, Microcrystalline Cellulose 102, aspartame, pregelatinised maize starch, and tutti frutti flavor were sieved separately through a 40# sieve. The quinoline yellow lake was sieved separately through a 100# sieve. Magnesium stearate was sieved separately through a 60# sieve. In a rapid mixer granulator previously sifted carbidopa, levodopa, Microcrystalline Cellulose 101 and 15 quinoline yellow lake were blended and mixed for 10 minutes. Pregelatinised maize starch was then dissolved in water with continuous stirring until a clear and viscous solution was obtained to prepare a binder solution. Subsequently, the binder solution obtained earlier was gradually added to the rapid mixer granulator at the slow speed of the impeller and chopper off, ensuring a homogeneous mixture with continuous mixing for 5 minutes. The granulated blend was then dried in a dryer at 50°C ± 5°C and the dry granules were passed through a 30# sieve retained granules were milled through a 1.5 mm screen, and the entire blend was subsequently passed through a 30# sieve. Further, the granules were mixed with previously sifted microcrystalline Cellulose-102, pregelatinised maize starch, maize starch, aspartame, and tutti frutti flavor added to the above blend and mixed for 10 minutes. At last, the previously sifted magnesium stearate was added to the above mixture and blended in a blender for 5 minutes. Finally, the lubricated mixture was compressed to form tablets. All the physical and chemical parameters of the tablets were found satisfactory. Test Parameters of blend Result Bulk Density (gm / ml) 0.450 Tap Density (gm / ml) 0.560 Carr’s Index (%) 19.64 Hausner’s Ratio 1.24 The tablets present the characteristics mentioned in the table below: Test Parameters Test Parameters Result Hardness 15-55N 37N Average weight 200 mg ± 7.5% 203mg Thickness 3.12 ±0.3 3.13mm Disintegration time NMT 3 min 3 3 sec Friability NMT 1.0% 0.31% Example 4: The Dissolution profile of the tablet prepared according to Example 3 The conditions of dissolution are the following: Apparatus: USP type II (paddle) Rate of rotation: 50 Volume: 750 ml Temperature: 37°C ± 0.5°C Detection: UV detector Detector: 282 nm 5 Dissolution medium: 0. IN HCL Carbidopa 25 mg Orodispersible tablet Time (Min) % Drug Release 10 98.1 15 100.8 20 100.2 30 100.3 45 99.6 60 98.9 Levodopa 100 mg Orodispersible tablet Time (Min) % Drug Release 10 79.7 15 91.8 20 94.0 30 98.3 45 97.9 60 97.8 Result: The Orodispersible Tablet of carbidopa and levodopa was tested for its 10 dissolution profile measured in 750 mL of water, at 50 RPM in USP II (Paddle) apparatus and the active ingredient of the tablet was released at more than 75 % in 10 minutes. Example 5: The tablets prepared according to example 3 were subjected to a stability 15 study of 25°C / 60% RH and 40°C / 75% RH for 1 month. Results are tabulated below. Carbidopa-levodopa 25 / 100 mg Orodispersible Tablets Test Specification Exp 4 (Initial) Exp 4 (After 1 month) liiiiill lllllllll % RH Average weight 220.00 mg ± 7.5% (203.50^236.50 mg) 221.0 219.8 220.6 Hardness 30Nto 80 N 55N 57N 54N Dissolution Carbidopa 75%(Q) in 45 minutes 88.4 89.1 89.5 Levodopa 75%(Q) in 45 minutes 100.3 101.5 101.9 Assay (%) Carbidopa 95.0% - 110.0% 97.10 98.2 97.9 Levodopa 95.0 - 105% 98.1 98.3 99.1

Claims

1. An orodispersible tablet of carbidopa and levodopa for oral administration, comprising:a) a combination of carbidopa and levodopa or pharmaceutically acceptable salts thereof, present in an amount ranging from about 40 %w / w to about 70 %w / w, preferably in the range of about 45 %w / w to about 65 %w / w;b) one or more diluents present in the range from about 20 %w / w to about 50 %w / w, preferably in the range of about 25 %w / w to about 45 %w / w;c) one or more disintegrants present in the range from about 0.1 %w / w to about 5 %w / w, preferably in the range of about 0.5 %w / w to about 1 %w / w;d) at least one lubricant present in the range from about 0.1 %w / w to about 5 %w / w, preferably in the range of about 0.5 %w / w to about 1 %w / w,(e) at least one binder presents in the range from about 0.5 %w / w to about 10 %w / w, preferably in the range of about 1 %w / w to about 5 %w / w; and(g) one or more pharmaceutically acceptable excipients.

2. The orodispersible tablet according to claim 1, wherein the carbidopa present in the range from about 1 %w / w to about 20 %w / w, preferably in the range of about 5 %w / w to about 15 %w / w.

3. The orodispersible tablet according to claim 1, wherein the levodopa present in the range from about 35 %w / w to about 55 %w / w, preferably in the range of about 40 %w / w to about 50 %w / w.

4. The orodispersible tablet according to claim 1, wherein the diluent is selected from the group consisting of a calcium carbonate, cellulose derivative, microcrystalline cellulose, microfine cellulose, sugar alcohols such as maltitol, xylitol, mannitol, sorbitol, erythritol, dextrates, dextrose, lactose, Maize starch, pregelatinized starch, and dextrin, or any combinations thereof.

5. The orodispersible tablet according to claim 4, wherein the diluent comprises the combination of powdered form of microcrystalline cellulose, granular form of microcrystalline cellulose, and Maize starch.

6. The orodispersible tablet according to claim 5, wherein the diluent maize starch present in the range from about 0.5 %w / w to about 10 %w / w, preferably in the range of about 1 %w / w to about 5 %w / w.

7. The orodispersible tablet according to claim 5, wherein the diluentmicrocrystalline cellulose powdered form is present in the range from about 10 %w / w to about 30 %w / w, preferably in the range of about 15 %w / w to about 25 %w / w.

8. The orodispersible tablet according to claim 5, wherein the diluent microcrystalline cellulose granular form is present in the range from about 5 %w / w to about 20 %w / w, preferably in the range of about 10 %w / w to about 15 %w / w.

9. The orodispersible tablet according to claim 1, wherein the disintegrant is selected from the group consisting of methylcellulose, Pregelatinised maize starch, alginic acid, guar gum, carboxymethylcellulose calcium, polacrilin potassium, croscarmellose sodium, carmellose calcium, crospovidone, calcium hydrogen phosphate, sodium carboxymethyl starch, poloxamer, and sodium starch glycolate, or any combination thereof.

10. The orodispersible tablet according to claim 9, wherein the pregelatinised maize starch is used in lower concentration as a disintegrant.

11. The orodispersible tablet according to claim 1, wherein the binder is selected from the group consisting of Pregelatinised Maize Starch, starch, polyethylene glycol, polyvinylpyrrolidone, sugars such as sucrose, glucose, dextrose, molasses, lactose, dextrin, xylitol, sorbitol, polymethacrylates, acrylates such as Eudragits, natural and synthetic gums such as acacia, alginic acids, sodium alginate, gum tragacanth, irish moss extract, ghatti gum, guar gum, zein, cellulose derivatives hydroxypropyl cellulose, hydroxy ethyl cellulose and ethyl cellulose,polyvinylpyrrolidone, polyethylene glycol, magnesium aluminum silicate, bentonites or any combinations thereof.

12. The orodispersible tablet according to claim 11, wherein the Pregelatinised Maize Starch is used as the binder in higher concentration.

13. The orodispersible tablet according to claim 1, wherein the lubricant is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, leucine, sodium benzoate, sodium acetate, sodium lauryl sulfate, stearic acid, sodium stearate, sodium oleate, calcium stearate, waxes or any combination thereof.

14. The orodispersible tablet according to claim 13, wherein the lubricant is magnesium stearate.

15. The orodispersible tablet according to claim 1, wherein the sweetener is selected from the group consisting of cyclamate, acesulfame potassium, monoammonium glycyrrhizinate, saccharin sodium, sucralose, saccharin, aspartame, or any combination thereof.

16. The orodispersible tablet according to claim 1, wherein the flavoring agent is Selected from the group consisting of menthol, tutti frutti, floral fennel flavor, vanillin, raspberry flavor, orange flavor, or any combinations thereof.

17. The orodispersible tablet according to claim 1, further comprises aspartame as a sweetener present in the range from about 0.05 %w / w to about 1 %w / w, preferably in the range of about 0.1 %w / w to about 0.5 %w / w, Tutti Frutti flavor as flavoring agent present in the range from about 0.05 %w / w to about l%w / w, preferably in the range of about 0.1 %w / w to about 0.5 %w / w.

18. The orodispersible tablet according to claim 1, further comprises quinoline yellow lake as a coloring agent present in the range of about 0.05 %w / w to about 1% w / w, preferably in the range of about 0.1 %w / w to 0.5 %w / w.

19. The process for preparing an orodispersible tablet by the wet granulation method according to claim 1, comprising the steps of:(a) Sieving carbidopa and levodopa or pharmaceutically acceptable salts thereof, and microcrystalline cellulose separately through a 30# sieve, maize starch separately through a 30# sieve, maize starch, microcrystalline cellulose, aspartame, pregelatinized maize starch, and tutti Frutti flavor were sieved separately through a 40# sieve. The quinoline yellow lake was sieved separately through a 100# sieve and magnesium stearate was sieved separately through a 60# sieve;(b) Dry mixing of carbidopa and levodopa or pharmaceutically acceptable salts thereof Microcrystalline Cellulose, and quinoline yellow lake in the rapid mixer granulator;(c) Dissolving pregelatinised maize starch in water with continuous stirring until it gets a clear viscous binder solution;(d) Adding binder solution gradually in step (c) dry mixed blend in rapid mixer granulator with continuance mixing;(e) Drying the granulated blend of step (d) in a dryer at 50°C ± 5°C;(f) Passing the dry granules of step (e) through a 30# sieve and retained granules milled through a 1.5 mm screen and pass all blend through a 30# sieve;(g) Mixing of granules with previously shifted microcrystalline Cellulose-102, pregelatinised maize starch, maize starch, aspartame, and tutti frutti flavor in the blender;(h) Mixing of the blend prepared in step (g) with magnesium stearate in a blender;(i) Compressing the resulting mixture into tablet dosage form; and(j) Packing of the tablet into an HDPE Bottle with CR cap containing silica gel.

20. The orodispersible tablet according to claim 1, wherein 85 % of the carbidopa and levodopa or pharmaceutically acceptable salts thereof, is released within 60 minutes, preferably more than 85 % is released within 50 minutes under the condition of 50 RPM and 750 ml 0.1 N HC1 dissolution media.

21. The orodispersible tablet according to claim 1, wherein the hardness of the orally disintegrating tablet is between about 30 N to about 70 N, preferably between 25 N to 60 N.

22. The orodispersible tablet according to claim 1, wherein the orally disintegrating tablet is disintegrated in the buccal cavity upon contact with saliva in not more than 45 seconds preferably less than 35 seconds.

23. The use of orodispersible tablets according to claim 1, for the treatment of Parkinson's disease, post-encephalitic parkinsonism, and symptomatic parkinsonism that may follow carbon monoxide intoxication or manganese intoxication.

24. The orodispersible tablet according to claim 1, wherein said tablet composition comprises:a) a combination of carbidopa and levodopa or pharmaceutically acceptable salts thereof present in the range from about 40 %w / w to about 70 %w / w, preferably in the range of about 45 %w / w to about 65 %w / w;b) 1 %w / w to about 20 %w / w, preferably from about 5 %w / w to about 15 %w / w of carbidopa;c) 35 %w / w to about 55 %w / w, preferably from about 40 %w / w to about 50 %w / w of levodopa;d) a combination of powdered microcrystalline cellulose, granular microcrystalline cellulose and Maize starch present in the range from about 20 %w / w to about 50 %w / w, preferably in the range of about 25 %w / w to about 45 %w / w;e) 0.5 %w / w to about 10 %w / w, preferably in the range of about 1 %w / w to about 5 %w / w of maize starch;f) 10 %w / w to about 30 %w / w, preferably in the range of about 15 %w / w to about 25 %w / w of powdered microcrystalline cellulose;g) 5 %w / w to about 20 %w / w, preferably in the range of about 10 %w / w to about 15 %w / w of granular microcrystalline cellulose;h) 0.1 %w / w to about 5 %w / w, preferably in the range of about 0.5 %w / w to about 1 %w / w of pregelatinised maize starch at lower concentration;i) 0.5 %w / w to about 10 %w / w, preferably in the range of about 1 %w / w to about 5 %w / w of pregelatinised maize starch at higher concentration;j) 0.1 %w / w to about 5 %w / w, preferably in the range of about 0.5 %w / w to about 1 %w / w of magnesium stearate;k) 0.05 %w / w to about 1 %w / w, preferably in the range of about 0.1 %w / w to about 0.5 % w / w of aspartame;1) 0.05 %w / w to about 1 %w / w, preferably in the range from about 0.1 % w / w to about 0.5 % w / w of tutti frutti flavor; andm) 0.05 %w / w to about 1% w / w, preferably in the range of about 0.1 %w / w to 0.5 %w / w of quinoline yellow lake.

25. The orodispersible tablet according to claim 1, wherein said tablet composition comprises:a) 11.364 % w / w of Carbidopa or pharmaceutical-acceptable salts thereof;b) 45.455 % w / w of Levodopa or pharmaceutical-acceptable salts thereof;c) 4.091 % w / w of maize starch, 21.818 % w / w powdered microcrystalline cellulose, and 12.045 % w / w of granular microcrystalline cellulose as a combination of diluents;d) 0.909 % w / w of pregelatinized maize starch as a disintegrates;e) 2.727 % w / w of pregelatinized maize starch as a binder;f) 0.227 % w / w of aspartame;g) 0.227 % w / w of Tutti Frutti flavor;h) 0.227 % w / w of quinoline yellow lake; andi) 0.909 % w / w of magnesium stearate.27