INTRODUCTION OF THE INVENTION
Aspects of the present invention provide controlled release formulations comprising levodopa, carbidopa, and a carboxylic acid and methods of preparing such formulations for treating neurological diseases or conditions associated with reduced or impaired dopamine levels. Further aspect of the invention provides a stable controlled release formulation comprising levodopa, carbidopa, and a carboxylic acid. Another aspect of the present invention provides multiparticulate, controlled release formulations comprising levodopa, carbidopa, and a carboxylic acid and methods of preparing such formulations. Another aspect of the present invention provides a controlled release formulation comprising levodopa, carbidopa and carboxylic acid components, wherein the carboxylic acid component is not present as a separate or distinct component from the levodopa and carbidopa components.
BACKGROUND OF THE INVENTION
Combinations of carbidopa (CD) and levodopa (LD) to treat Parkinson's disease are known in the pharmaceutical arts. Several products currently on the North American market, including SINEMET® (Merck Co.) and SINEMET CR® (Merck Co.) contain combinations of carbidopa and levodopa in immediate release and controlled release forms, respectively.
The carbidopa and levodopa combination is used to treat the symptoms of Parkinson's disease, which is characterized by abnormally low levels of dopamine. Dopamine is a neurotransmitter having significant influence over the mobility and control of the skeletal muscular system. Patients suffering from Parkinson's disease frequently have periods in which their mobility becomes difficult, often resulting in an inability to move.
Administering dopamine is not effective to treat Parkinson's disease because dopamine does not cross the blood brain barrier. To resolve this failure, Parkinson's patients are administered levodopa, the metabolic precursor of dopamine. Levodopa crosses the blood brain barrier and is rapidly converted to

dopamine, thereby alleviating the symptoms of Parkinson's disease caused by reduced levels of dopamine. Levodopa is problematic because of its rapid decarboxylation by tissues other than the brain. Thus, when levodopa is administered alone, large doses are required because only a small portion is transported to the brain unchanged.
Patients treated with levodopa therapy for Parkinson's disease may frequently develop motor fluctuations characterized by end-of-dose failure, peak dose dyskinesia and akinesia. An advanced form of motor fluctuations is known as the "on-off effect" in which the patient suffers from unpredictable swings from mobility to immobility. It is believed that the on-off effect can be minimized in some patients with a treatment regimen which produces narrow ranges of plasma levels of levodopa.
Carbidopa (CD) inhibits the decarboxylation of levodopa (LD) by a patient's body tissues outside of the brain. Small doses of carbidopa administered in conjunction with levodopa allow a larger percentage of levodopa to reach the brain unchanged for later conversion to dopamine. The carbidopa and levodopa combination allows for lower doses of levodopa with a concordant reduction of side effects.
Currently available controlled release formulations of CD/LD are meant to allow for a continuous release of drug over a prolonged period of time in an attempt to maintain tight LD plasma ranges. However, the use of these controlled release dosage forms are problematic in that many PD patients wake up in the morning having little or no mobility due to the wearing off of the dose taken the day/evening before. Once the previous dose has worn off, such patients are usually unwilling, or even unable, to wait for the controlled period of time required for a controlled release dosage form to deliver the necessary plasma levels of LD.
While the use of an immediate release formulation of LD can reduce this 'wait time', the use of an immediate release formulation of LD require more frequent dosing and are associated with more fluctuating plasma LD concentrations. DUODOPA®, an intraduodenal infusion therapy approved outside

of the United States, demonstrates significantly reduced motor complications and reduced 'off time. The cumulative experiences from DUODOPA® and experimental infusion studies show that the maintenance of stable plasma LD concentrations and the avoidance of low trough levels appear to be effective in reducing 'off time, increasing 'on' time without disabling dyskinesia, and reduce the severity of dyskinesia in comparison to the standard oral formulations. However, such infusion therapies are extremely inconvenient to the patient.
The results of infusion therapies, such as DUODOPA®, strongly suggest a rationale for the development of a LD treatment that provide constant, or relatively steady, LD plasma concentrations to optimize relief of PD symptoms and to minimize 'off times and dyskinesias. Indeed, a need remains for a more convenient, i.e., oral, dosage form that will improve the administration of LD to PD patients by narrowing blood plasma ranges of LD, which in turn will result in reduced 'off times', prolonged 'on time', and decreased time to 'on'.
A number of approaches have been described in the literature to provide controlled release formulations of levodopa.
U.S. Patent No. 6,238,699 discloses bi-layer compositions of levodopa and carbidopa, wherein the sustained and immediate release layers of carbidopa and levodopa are separated by a drug free excipient layer.
U.S. Patent No. 7,094,427 discloses pharmaceutical compositions of levodopa and carbidopa having an immediate release component and a controlled release component with specific invitro dissolution profiles.
US Patent Application Publication No. 2010/0298268 discloses controlled release oral solid formulations of levodopa comprising levodopa, carbidopa, and carboxylic acid components, wherein the carboxylic acid component is present as a separate or distinct component from the levodopa and carbidopa components. The pharmaceutical formulations of the invention provide a superior plasma levodopa profile to a patient than the currently available oral pharmaceutical formulations.

There remains, however, a continuing need for immediate and controlled release carbidopa and levodopa products which will improve the administration of levodopa to parkinson's patients by narrowing blood plasma ranges of levodopa and reducing side effects.
SUMMARY OF THE INVENTION
Aspects of the present invention provide controlled release oral solid formulations comprising levodopa, carbidopa, and a carboxylic acid and methods of preparing such formulations for treating neurological diseases or conditions associated with reduced or impaired dopamine levels.
In embodiments, the invention provides a controlled release formulation comprising levodopa, carbidopa and carboxylic acid components, wherein the carboxylic acid component is not present as a separate or distinct component from the levodopa and carbidopa components.
Another embodiment provides a stable controlled release formulation comprising levodopa, carbidopa and carboxylic acid components, wherein the carboxylic acid component is not present as a separate or distinct component from the levodopa and carbidopa components.
Yet another embodiment provides stable multiparticulate, controlled release solid formulations comprising levodopa, carbidopa and carboxylic acid components, wherein the carboxylic acid component is not present as a separate or distinct component from the levodopa and carbidopa components.
Yet another embodiment provides a stable controlled release formulation, wherein levodopa and carbidopa are in the form of immediate, delayed or/and controlled release components and carboxylic acid is in the form of delayed or/and controlled release components.
Yet another embodiment provides a stable controlled release formulation, wherein levodopa and carbidopa are in the form of immediate, delayed or/and controlled release components and carboxylic acid is in the form of an immediate release component.

Yet another embodiment provides a stable controlled release formulation of levodopa, wherein the extended-release carboxylic acid component further comprises levodopa.
Yet another embodiment provides a stable controlled release formulation of levodopa, wherein the extended-release carboxylic acid component further comprises carbidopa.
Another embodiment provides a stable controlled release formulation, wherein the extended-release carboxylic acid component further comprises immediate-release levodopa or/and carbidopa in the core or in the form of a coating over carboxylic acid core.
Another embodiment provides a stable controlled release formulation, wherein the controlled release components of levodopa and carbidopa further comprises carboxylic acid in the core or in the form of a coating over the core.
Further embodiment provides a stable controlled release formulation comprising levodopa, carbidopa and a carboxylic acid, wherein the carboxylic acid is tartaric acid or citric acid.
Yet another embodiment provides controlled release formulation, wherein levodopa, carbidopa and tartaric acid are in the form of controlled release components and further carbidopa and levodopa are coated onto the controlled release component of tartaric acid.
Another embodiment provides controlled release formulation, wherein levodopa, carbidopa and tartaric acid are in the form of controlled release components and controlled release component of tartaric acid further comprises carbidopa and levodopa in the core.
Yet another embodiment provides controlled release formulation, wherein levodopa, carbidopa and tartaric acid are in the form of controlled release components and further tartaric acid is coated onto controlled release components of carbidopa and levodopa.
Another embodiment provides controlled release formulation, wherein levodopa, carbidopa and tartaric acid are in the form of controlled release

components and controlled release components of carbidopa and levodopa further comprises tartaric acid in the core.
DETAILED DESCRIPTION
The current invention provides a multiparticulate, controlled release oral solid formulations of levodopa comprising: i) a component comprising a mixture of levodopa, carbidopa and a rate controlling excipient; ii) a carboxylic acid component and a rate controlling excipient; and iii) an immediate release component comprising a mixture of levodopa and carbidopa. The current invention additionally provides a stable controlled release formulation of levodopa providing a relatively steady levodopa plasma or serum concentration profile over a prolonged period of time.
The active agents for use in dosage forms according to the present invention include levodopa and carbidopa their salts, derivatives and pro-drugs. The terms "levodopa" and "carbidopa" are meant to embrace these chemical compounds themselves, pro-drugs thereof, N-oxides thereof, the pharmaceutically acceptable salts thereof, derivatives thereof, and the solvates thereof, e.g. hydrates, where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits.
The term "derivative" means a chemically modified compound wherein the modification is considered routine by the ordinary skilled chemist, such as an ester or an amide of an acid, protecting groups, such as a benzyl group for an alcohol or thiol, and tert-butoxycarbonyl group for an amine.
The term "effective amount" means an amount of a compound/composition according to the present invention effective in producing the desired therapeutic effect.
The term "analogue" means a compound which comprises a chemically modified form of a specific compound or class thereof, and which maintains the pharmaceutical and/or pharmacological activities characteristic of said compound or class.

The term "acid" refers to a chemical compound that, when dissolved in water, gives a solution with a pH less than 7. The "acid" can be organic. It can have a pKa in the range of e.g., 2-5. Examples of acids suitable for the invention include, but are not limited to, tartaric acid, adipic acid, succinic acid, citric acid, benzoic acid, acetic acid, ascorbic acid, edetic acid, fumaric acid, lactic acid, malic acid, oleic acid, sorbic acid, stearic acid, palmitic and boric acid or mixtures thereof.
The term "stable" refers to formulations that substantially retain the label amount of the therapeutically active ingredient during storage for commercially relevant times, and the drug-related impurities in the formulations remain low.
The term "label amount" refers to the dosage amount of therapeutically active ingredient present in a pharmaceutical product.
The term "pharmaceutically acceptable" as used herein means substances that are suitable for use in contact with the tissues of humans and other animals without undue toxicity, irritation, allergic response, and the like, in keeping with a reasonable benefit/risk ratio.
The term "immediate-release", as used herein, refers to a conventional or non-modified release dosage form which releases greater than or equal to about 75% of the active agent within about two hours after immersion into an aqueous fluid, or within about one hour after immersion.
The terms "controlled-release" or "sustained-release" or "extended-release", as used herein, refers to a dosage form in which the release of the active agent is controlled or modified over a period of time or refer to dosage forms that release the contained active agent at such a rate that steady state blood (e.g., plasma) levels are maintained within a therapeutic range, but below toxic levels, for at least about 8 hours, or at least about 12 hours after administration. The term "steady-state" means that a plasma level for a given active agent has been achieved and which is maintained with subsequent doses of the drug at levels at or above the minimum effective therapeutic level and below the minimum toxic plasma level for a given active agent.

The term "delayed-release", as used herein, refers to a dosage forms for which there is a time-delay after administration, before significant plasma levels of the active agent are achieved. A delayed-release formulation of the active agent can avoid an initial burst of the active agent, or can be formulated so that release of the active agent in the stomach is avoided and systemic absorption occurs in the small intestine.
The term "formulation" or "dosage form" or "composition" for purposes of the present invention includes solid pharmaceutical products such as tablets, capsules, sachets, pills, or granules, which may be matrix based formulations, reservoir based formulations, multi-particulate based formulations, multi-layer formulations, resin formulations, osmotic formulations, gastro-retentive formulations, etc.
The term "mini-tablet" as used herein refers to any tablet having a maximum dimension between about 2 mm and about 5 mm.
The term "pH-independent" indicates that the release characteristic is virtually the same in different pH media.
The term "pH-dependent" refers to a release to the active substance in a manner that is substantially dependent upon the pH of the surrounding medium within the pH ranges normally found in the human gastrointestinal (Gl) tract.
As used herein the term "particulate" includes granules, spheroids, beads, pellets, and mini-tablets.
The term "layer" in its broadest sense also includes a coating or a film partly or fully surrounding material containing an active pharmaceutical ingredient and having a defined thickness.
A "tablet" or "pill" comprises a pharmaceutical formulation pressed into a form. The form can be in any shape, for example, round, oblong, triangular or other shapes.
A "capsule" comprises a pharmaceutical formulation in which the pharmaceutical formulation is encased in a hard or soft soluble container. The container can be in the form of gelatin or other material.

The term "hydrophilic" for purposes of the present invention relates to excipients that are soluble and/or swellable in water, or have affinity toward water.
The term "water soluble" for purposes of the present invention relates to excipients that dissolve to the extent required, in aqueous fluids having pH values in the range of about 1 to about 8, and is not particularly limited.
The term "water swellable" for purposes of the present invention relates to excipients that are relatively insoluble in water, but which can absorb at least two times their weight in water.
The term "enteric" for purposes of the present invention relates to excipients that do not dissolve or decompose to a significant extent in aqueous fluids having pH values about 4 or less, in an in vitro test, however, they will dissolve or decompose in aqueous fluids having pH values about 5 or greater, such as in the range of about 5 to 7, in the range of about 5 to 6, or in the range of about 5 to 5.5. In general, enteric polymers are intended to remain intact while in the highly acidic environment of the stomach, but not in higher pH environments such as the intestines.
The terms "release controlling excipient" or "rate controlling excipient" may be used interchangeably. Release excipients or rate controlling excipients include all excipients and/or polymers that control the release of a pharmaceutical agent(s), e.g., LD, CD and in this case acid, after administration in a subject. Examples of release excipients or rate controlling excipients include, but are not limited to, hypromellose, hydroxypropyl cellulose, ethyl cellulose and prop-2-enoic acid. Delayed-release polymers, as a subset of release excipients or rate controlling excipients, are used to delay the release of a pharmaceutical agent(s) after administration to a subject. Examples of delay release polymers include, but are not limited to, enteric polymers and/or neutral methacrylic polymers such as Eudragit®L100-55, Eudragit®S100 or Eudragit®FS30D (Rohm).
The term "hydrophobic material" for purposes of the present invention relates to excipients that are insoluble in water, which are water repellent, or which lack affinity toward water.

Certain formulations described herein may be "coated." The coating can be a suitable coating, such as a functional or a non-functional coating, or multiple functional and/or non-functional coating. "Functional coating" is meant to include a coating that modifies the release properties of the total formulation, for example, an enteric or sustained-release coating. "Non-functional coating" is meant to include a coating that is not a functional coating, for example, a cosmetic coating. A non¬functional coating can have some impact on the release of the active agent due to the initial dissolution, hydration, perforation of the coating, etc., but would not be considered to be a significant deviation from the non-coated composition.
Enhancing or maintaining dopamine levels in a subject can treat the subject suffering from a condition associated with reduced or impaired dopamine levels. Examples of conditions associated with reduced or impaired dopamine levels include, but is not limited to, Alzheimer's disease, dystonia, schizophrenia, and Parkinson's disease.
Patients treated with levodopa therapy for Parkinson's disease may frequently develop motor fluctuations characterized by end-of-dose failure, peak dose dyskinesia and akinesia. An advanced form of motor fluctuations is known as the "on-off effect" in which the patient suffers from unpredictable swings from mobility to immobility. It is believed that the on-off effect can be minimized in some patients with a treatment regimen which produces narrow ranges of plasma levels of levodopa.
The present invention provides methods for reducing motor fluctuations in a patient suffering from Parkinson's disease, reducing off time in a patient suffering from Parkinson's disease, increasing on time in a patient suffering from Parkinson's disease, reducing time to 'on' in a patient suffering from Parkinson's disease and otherwise enhancing dopamine levels in a subject suffering from a disease associated with reduced or impaired dopamine levels.
The skilled artisan will appreciate that daily dosages having an amount of active agent sufficient to treat Parkinson's disease will generally contain from about 25 mg to about 4,000 mg of levodopa in combination with from about 5 mg to about

600 mg of carbidopa. Dosage forms according to the present invention may also contain from about 25 or preferably 100 mg to about preferably 300 or 600 mg of levodopa in combination with from about 12.5 or preferably 50 mg to about preferably 75 or 200 mg of carbidopa. Preferred dosage forms include 95 mg LD + 23.75 mg CD; 145 mg LD + 36.25 mg CD; 195 mg LD + 48.75 mg CD and 245 mg LD + 61.25 mg CD. Dosage unit compositions may also contain amounts of levodopa and carbidopa in percentages of these dosages as may be used to make up the daily dose. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including body weight, general health, gender, diet, time and route of administration, rates of absorption and excretion, combination with other drugs, and the severity of the particular disease being treated.
The controlled release oral solid formulation of the present invention may comprise one portion having delayed release particles and another portion having immediate release, controlled release, or combinations of immediate and controlled release particles, filled into capsules or sachets or tableted into finished dosage forms. In an embodiment of the invention, the multiparticulates are encapsulated. In another embodiment, the multiparticulates are not encapsulated. Alternatively, the multiparticulates may be in a sprinkle form that can be sprinkled directly onto food or liquids for easy ingestion.
The controlled release oral solid formulation of levodopa contains carbidopa and levodopa in a ratio of about 1:1 to about 1:10. In one embodiment, the ratio of carbidopa to levodopa is 1:4. Carbidopa might be present in the form of monohydrate or dihydrate.
The controlled release oral solid formulation of the present invention further comprises a carboxylic acid. Suitable examples of carboxylic acids include, but are not limited to, tartaric acid, adipic acid, succinic acid, citric acid, benzoic acid, acetic acid, ascorbic acid, edetic acid, fumaric acid, lactic acid, malic acid, oleic acid, sorbic acid, stearic acid, palmitic acid and boric acid or mixtures thereof. The

pharmaceutical formulations of the present invention can include a single acid or a mixture of acids. In a particular embodiment, the dicarboxylic acid is a tartaric acid.
Tartaric acid pellets are directly available in the market which could be used directly in the formulation rather than formulating tartaric acid into pellets.
The controlled release oral solid formulation of the invention may have a ratio of moles of dicarboxylic acid to levodopa of less than 4:1. In one embodiment, the ratio of moles of dicarboxylic acid to levodopa is greater than 1:4 and less than 3:2. In another embodiment, the ratio of moles of dicarboxylic acid to levodopa is greater than 1:2 and less than 4:3. In yet another embodiment, the ratio of moles of dicarboxylic acid to levodopa is greater than 2:3 and less than 5:4. In a further embodiment, the ratio of moles of dicarboxylic acid to levodopa is greater than 1:1 and less than 4:3.
Pharmaceutical formulations of the present invention may be in the form of tablets, such as layered or monolithic tablets, mini-tablets, capsules, pellets, granules (synonymously, "beads" or "particles"), nonpareil, patches, powders, and other dosage forms suitable for oral administration. In embodiments, the formulations of the present application are in the form of layered or monolithic tablets, or mini-tablets. Also contemplated are controlled release pellets, wherein the active ingredient is embedded within a matrix or layered onto an inert core. The formulations may also be formulated as layered tablets comprising at least two layers, wherein layers may exhibit the same or different release profiles, or as a mantle formulation wherein one layer completely surrounds the other layer. The formulations may also be in the form of reservoir systems, wherein a functional coating controls the release of the active ingredient.
The capsules used may be a hard gelatin or Hydroxypropylmethylcellulose (HPMC) capsules. A hard gelatin capsule has gelatin and a water dispersible or water-soluble plasticizer as principal components, and may contain other suitable additives such as preservatives, coloring agents, and/or opacifiers that are present to stabilize the capsule and/or impart a specific characteristic such as color or other appearance attribute to the capsule. The hard gelatin capsules can also be banded

to prevent leakage. Various methods can be used to band the hard gelatin capsules which include, but are not limited to, banding using a gelatin band and sealing using a hydroalcoholic solution.
Equipment suitable for processing the pharmaceutical formulations of the present application include rapid mixer granulators, planetary mixers, mass mixers, ribbon mixers, fluid bed processors, mechanical sifters, homogenizers, blenders, roller compacters, extrusion-spheronizers, compression machines, capsule filling machines, rotating bowls or coating pans; tray dryers, fluid bed dryers, rotary cone vacuum dryers, or the like, multimills, fluid energy mills, ball mills, colloid mills, roller mills, hammer mills, or the like, equipped with a suitable screen.
The formulations can be prepared by direct compression, dry compression (slugging), or by wet or melt granulation. Tablets can be prepared using a direct compression technique, with powder blends. Granules can be formed by any processes, using operations such as one or more of dry granulation, wet granulation, extrusion-spheronization, and the like. The granulation of the active ingredient, optionally together with one or more pharmaceutically acceptable excipients such as diluents or fillers, is usually carried out in equipment such as planetary mixers, rapid mixer granulators (RMG), fluid bed processors, and the like. Alternatively, powder blends can be compacted using a roller compactor and then milled to produce granules that are suitable for compression. The granules or pellets obtained may further be compressed into tablets or filled into capsules. Tablets and mini-tablets can be filled into capsules using techniques known in the art. The granules, or the dry blends formed, may have bulk densities ranging from about 0.2-0.6 g/ml_, tapped densities ranging from about 0.5-0.8 g/ml_, and Carr indexes ranging from about 20-40%.
Melt extrusion is achieved using either hydrophilic or lipophilic substances with melting points between about 40°C and 120°C. Some examples are polyethylene glycol 2000-10000, poloxamer 188, carnauba wax, hydrogenated castor oil, stearyl alcohol, cetyl alcohol, and mixtures thereof. In order to achieve

the desired release rates, other excipients such as lactose, microcrystalline cellulose, starch, etc., can be added.
Tablets of the present invention can be of any suitable size and shape, for example round, oval, polygonal, or pillow-shaped, and optionally bear nonfunctional surface markings. According to embodiments of the present application, controlled release tablets are white to off-white and of oval, round, or biconvex, shape.
Immediate or Controlled release pellets of the present invention can be of sizes between about 0.2 and 3 mm, or between about 0.5 and 1.5 mm, or between about 0.7 and 1 mm. The controlled release capsules can be of any size and shape and color and can be compressed into tablets or can be directly filled into capsules. The capsule shells frequently are made from hydroxypropyl methylcellulose (HPMC), vegetable-derived materials, or gelatin.
Pellets can be prepared by extrusion-spheronization process. Extrusion can be defined as the process of forcing a material through an orifice or die under controlled conditions thus forming cylinders or strands called extrudates. During spheronization, these extrudates are broken into small cylinders and consequently rounded into spheres (pellets).
Alternatively, pharmacologically inert pellets, beads, or cores that can be used include, but are not limited to: water-soluble particles such as sugar spheres, lactose, and the like; and water-insoluble particles such as celluloses, including microcrystalline cellulose, silicon dioxide, calcium carbonate, dicalcium phosphate anhydrous, dicalcium phosphate monohydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, and the like can be used. Active substances may be layered onto inert particles to prepare drug-containing core.
In embodiments, water-soluble core materials such as sugar spheres may be coated with a seal coating layer. The purpose of sealing is to offer an initial protection and to prevent some core ingredients from migrating into the coating. Sealing may be accomplished by the application of polymer based coating material on the surface of the core particles. Examples of the polymers that might be used

include shellac, zein, hydroxypropyl cellulose (HPC), hydroxyethylcellulose (HEC), hydroxypropyl methylcellulose (HPMC), polyvinyl acetate phthalate (PVAP) and cellulose acetate phthalate (CAP). This sealing agent may be dissolved in an appropriate aqueous or non-aqueous solvent.
Coating involves the deposition of a thin, substantially uniform film onto the surface of a solid dosage form such as a tablet, powder, granule, nonpareil, capsule, or the like. Coatings are generally applied continuously to a moving bed of material, usually by means of a spray technique, although manual application procedures can be used. The coated dosage forms are then sometimes cured at an elevated temperature to provide a finished product.
The coatings employed in the present application may be aqueous, non-aqueous, or hydro-alcoholic systems. The solvents used to prepare a non-aqueous coating formulation include dehydrated alcohol, isopropyl alcohol, ethylene chloride, acetone, or any other solvent known in the art for such use, or mixtures thereof.
Suitable polymers for use in coating include ethylcellulose, hydroxypropylcelluloses, hydroxyethylcelluloses, hydroxypropyl methylcelluloses, methyl hydroxy ethyl-celluloses, methylcelluloses, ethylcelluloses, cellulose acetates, sodium carboxymethylcelluloses, polymers or copolymers of acrylic acid and methacrylic acid or esters thereof (e.g., Eudragit RL™, Eudragit RS™, Eudragit L100™, Eudragit S100™, Eudragit NE™), Acryl-eze™ acrylic coating from Colorcon, polyvinylpyrrolidones, or polyethylene glycols. The polymers can be combined with water-soluble polymers, such as HPMCs or polyethylene glycols to form pores or channels in the coating to modify the release rate.
In an embodiment, the controlled release formulation of the present invention comprises immediate, delayed and controlled release components of levodopa, carbidopa or carboxylic acid.
Another embodiment of the present invention comprises immediate, delayed or/and controlled release components of carbidopa and levodopa and delayed

or/and controlled release components of carboxylic acid, wherein the carboxylic acid component is not present as a separate or distinct component.
In a further embodiment, the controlled release formulation of the present invention comprises levodopa, carbidopa and carboxylic acid components, wherein the immediate release component of carbidopa and levodopa is coated onto the delayed or/and controlled release components of carboxylic acid.
Yet another embodiment provides a controlled release formulation, wherein delayed or/and controlled release components of carboxylic acid are coated onto the delayed or/and controlled release components of carbidopa and levodopa.
Another embodiment provides a controlled release formulation, wherein levodopa, carbidopa and carboxylic acid are coformulated as a single component.
Yet another embodiment provides a controlled release multiparticulate formulation comprising immediate, delayed and controlled release components of carbidopa and levodopa and a delayed or/and controlled release component of carboxylic acid, wherein the carboxylic acid component is not present as a separate or distinct component.
Another embodiment provides a controlled release formulation comprising levodopa, carbidopa and carboxylic acid, wherein the carboxylic acid is tartaric acid or citric acid.
Yet another embodiment provides controlled release formulation, wherein levodopa, carbidopa and tartaric acid are in the form of controlled release components and further tartaric acid is coated onto the controlled release components of carbidopa and levodopa.
Another embodiment provides controlled release formulation, wherein levodopa, carbidopa and tartaric acid are in the form of controlled release components and controlled release components of carbidopa and levodopa further comprises tartaric acid in the core.
Another embodiment provides controlled release formulation, wherein levodopa, carbidopa and tartaric acid are in the form of controlled release

components and controlled release components of carbidopa and levodopa further comprises tartaric acid in the core.
Another embodiment provides controlled release formulation, wherein levodopa, carbidopa and tartaric acid are in the form of controlled release components and controlled release component of tartaric acid further comprises levodopa and carbidopa in the core.
Yet another embodiment provides a multiparticulate, controlled release formulation comprising: i) a component comprising levodopa, carbidopa and a rate controlling excipient; ii) a component comprising tartaric acid, levodopa, carbidopa and a rate controlling excipient, wherein levodopa and carbidopa present in the component (ii) may be in the form of coating or in the core.
Another embodiment provides a multiparticulate, controlled release formulation comprising: i) a component comprising levodopa, carbidopa, tartaric acid and a rate controlling excipient; ii) a component comprising tartaric acid and a rate controlling excipient, wherein tartaric acid present in the component (i) may be in the form of coating or in the core.
Another embodiment provides a multiparticulate, controlled release formulation comprising: i) a component comprising levodopa, carbidopa and a rate controlling excipient ii) a component comprising tartaric acid, levodopa and a rate controlling excipient, wherein levodopa present in the component (ii) may be in the form of coating or in the core.
Another embodiment provides a multiparticulate, controlled release formulation comprising: i) a component comprising levodopa, carbidopa and a rate controlling excipient ii) a component comprising tartaric acid, carbidopa and a rate controlling excipient, wherein carbidopa present in the component (ii) may be in the form of coating or in the core.
Dosage forms can be made according to well known methods in the art. Some preferred methods are described below.
Matrix dosage forms have an active agent incorporated therein. Upon exposure to a dissolution media, channels are formed in the solid material so that

the active agent can escape. Dosage forms may be in the form of coated or uncoated matrices.
The skilled artisan will appreciate that the matrix material can be chosen from a wide variety of materials which can provide the desired dissolution profiles. Materials can include, for example, one or more gel forming polymers such as polyvinyl alcohol, cellulose ethers including, for example, hydroxy propyl alkyl, celluloses such as hydroxypropyl methyl cellulose, hydroxy alkyl celluloses such as hydroxy propyl cellulose, natural or synthetic gums such as guar gum, xanthan gum, and alginates, as well as, ethyl cellulose, polyvinyl pyrrolidone, fats, waxes, polycarboxylic acids or esters such as the Carbopol® (Noveon) series of polymers, methacrylicacid copolymers, and methacrylate polymers.
The controlled release portion is in intimate contact with at least one release rate-controlling material. The rate-controlling material is a material that permits release of the active agent at a controlled fashion into an aqueous medium. The release rate-controlling material can be associated with the formulation either in the form of a matrix or a coating, wherein rate-controlling component is hydrophilic, hydrophobic, lipophilic, or combinations thereof. Methods of making matrix dosages are well known in the art and any known method of making such dosages which yields the desired immediate release and controlled release dissolution profiles can be used. One such method involves the mixture of the levodopa and carbidopa combination with a solid polymeric material and one or more pharmaceutically acceptable excipients which are then blended and compressed in controlled release tablet cores. Such tablet cores can be used for further processing as bi-layer tablets, press coated tablets, or film coated tablets.
A coating containing the immediate release carbidopa or carbidopa and levodopa in combination can be added to the outside of the controlled release cores to produce a final dosage form. Such an immediate release coating can be spray coated onto the tablet cores.
The immediate release/delayed release/controlled release components of the present invention can also take the form of pharmaceutical particles. The

dosage forms can include immediate release particles in combination with controlled release particles in a ratio sufficient to deliver the desired dosages of active agents. The controlled release particles can be produced by coating the immediate release particles.
The particles can be produced according to any of a number of well known methods for making particles. The immediate release particles comprise the active agent combination and a disintegrant. Suitable disintegrants include, for example, starch, low-substitution hydroxypropyl cellulose, croscarmellose sodium, calcium carboxymethyl cellulose, hydroxypropyl starch, and microcrystalline cellulose. In addition to the above-mentioned ingredients, a controlled release matrix may also contain suitable quantities of other materials, for example, diluents, lubricants, binders, granulating aids, colorants, flavorants, and glidants that are conventional in the pharmaceutical arts. The quantities of these additional materials are sufficient to provide the desired effect to the desired formulation. A controlled release matrix incorporating particles may also contain suitable quantities of these other materials such as diluents, lubricants, binders, granulating aids, colorants, flavorants, and glidants that are conventional in the pharmaceutical arts in amounts up to about 75% by weight of the particulate, if desired.
Particles can assume any standard structure known in the pharmaceutical arts. Such structures include, for example, matrix particles, non-pareil cores having a drug layer and active or inactive cores having multiple layers thereon. A controlled release coating can be added to any of these structures to create a controlled release particle.
The term particle as used herein means a granule having a diameter of between about 0.01 mm and about 5.0 mm, preferably between about 0.1 mm and about 2.5 mm, and more preferably between about 0.5 mm and about 2 mm. The skilled artisan will appreciate that particles according to the present invention can be any geometrical shape within this size range and so long as the mean for a statistical distribution of particles falls within the particle sizes enumerated above,

they will be considered to fall within the contemplated scope of the present invention.
The release of the therapeutically active agent from the controlled release formulation of the present invention can be further influenced, i.e., adjusted to a desired rate, by the addition of one of more release-modifying agents. The release-modifying agent may be organic or inorganic and include materials that can be dissolved, extracted, or leached from the coating in the environment of use. The pore-formers may comprise one or more hydrophilic materials such as hydroxypropyl methylcellulose. The release-modifying agent may also comprise a semi-permeable polymer. In certain preferred embodiments, the release-modifying agent is selected from hydroxypropyl methylcellulose, lactose, metal stearates, and mixtures thereof.
The controlled release particles of the present invention slowly release the ingredients when ingested and exposed to gastric fluids, and then to intestinal fluids. The controlled release profile of the formulations of the invention can be altered, for example, by increasing or decreasing the thickness of the retardant coating, i.e., by varying the amount of overcoating. The resultant solid controlled release particles may thereafter be placed in a gelatin capsule in an amount sufficient to provide an effective controlled release dose when ingested and contacted by an environmental fluid, e.g., gastric fluid, intestinal fluid or dissolution media. The particles may be overcoated with an aqueous dispersion of a hydrophobic or hydrophilic material to modify the release profile. The aqueous dispersion of hydrophobic material preferably further includes an effective amount of plasticizer, e.g. triethyl citrate.
Suitable hydrophilic materials comprise water soluble or water swellable materials. Examples of such materials include hydroxyalkyl celluloses, hydroxyalkyl alkylcelluloses, carboxyalkyl cellulose esters, for example, hydroxypropyl methylcelluloses (hypromelloses or HPMC), hydroxypropylcelluloses (HPC), hydroxyethylcellulose (HEC), polyvinyl porollidones, for example, various grades like PVP-K25, PVP-K29, PVP-K30, PVP-K90, etc and combinations comprising

one or more of the foregoing materials. For the purposes of this invention, the release-controlling agent may be present in a matrix, or in a coating covering a core containing atcive agent. For the purposes of this invention, the concentration of hydrophilic material ranges from about 5% to about 50% by weight of the formulation.
In embodiments, hydrophilic materials include polyalkylene oxides, polysaccharide gums, and crosslinked polyacrylic acids. Polysaccharide gums, both natural and modified (semi-synthetic), can be used. Examples are dextran, xanthan gum, gellan gum, welan gum and rhamsan gum.
In embodiments, formulations include a rate-controlling material that is an "enteric polymer," being insoluble in highly acidic environments such as the stomach, but being dissolved or decomposed in higher pH environments such as the intestines. Examples include polyvinylacetate phthalates (PVAP), alginic acid and its derivatives, hydroxypropyl methylcellulose acetate succinates (HPMCAS), cellulose acetate phthalates (CAP), methacrylic acid copolymers, hydroxypropyl methylcellulose succinates, cellulose acetate succinates, cellulose acetate hexahydrophthalates, hydroxypropyl methylcellulose hexahydrophthalates, hydroxypropyl methylcellulose phthalates (HPMCP), cellulose propionate phthalates, cellulose acetate maleates, cellulose acetate trimellitates, cellulose acetate butyrates, cellulose acetate propionates, methacrylic acid/methacrylate polymers (e.g., acid number 300 to 330 and also known as EUDRAGIT™ L from Evonik Industries, Germany, which is an anionic copolymer based on methacrylate, available as a powder, and also known as methacrylic acid copolymer, type A NF), methacrylic acid-methyl methacrylate copolymers, ethyl methacrylate-methylmethacrylate-chlorotrimethylammonium ethyl methacrylate copolymers, and the like, and combinations comprising one or more of the foregoing enteric polymers.
In embodiments, pharmaceutically acceptable excipients include, but are not limited to, any one or more of diluents, disintegrants, binders, glidants, lubricants, colouring agents, coating materials, and the like.

Diluents include, but are not limited to, starches, lactose, Pearlitol™ SD 200, celluloses, confectioners' sugar, and the like. Different grades of lactose include, but are not limited to, lactose monohydrate, lactose DT (direct tabletting), lactose anhydrous, Flowlac™ (available from Meggle Products), Pharmatose™ (available from DMV), and others. Different grades of starches include, but are not limited to, maize starch, potato starch, rice starch, wheat starch, pregelatinized starches and Starch 1500, Starch 1500 LM grade (low moisture content grade) from Colorcon, fully pregelatinized starches and others. Different celluloses that can be used include crystalline celluloses and powdered celluloses. Examples of crystalline cellulose products include, but are not limited to, CEOLUS™ KG801, Avicel™ PH101, PH102, PH301, PH302 and PH-F20, microcrystalline cellulose ("MCC") 114, and microcrystalline cellulose 112.
Disintegrants may be incorporated into intragranular or extragranular
blends, or both. Various useful disintegrants include, but are not limited to,
carmellose calcium, carboxymethylstarch sodium, croscarmellose sodium,
crospovidones, examples of commercially available crospovidone products
including but not limited to crosslinked povidone and low-substituted
hydroxypropylcelluloses ("L-HPC"). Examples of low-substituted
hydroxypropylcelluloses include but are not limited to low-substituted hydroxypropylcellulose. Other useful disintegrants include sodium starch glycolate, colloidal silicon dioxide, starches, and any combinations thereof.
Binders include, but are not limited to, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, polyvinylpyrrolidones, copovidones, powdered acacia, carrageenan, gelatin, guar gum, carbomers (e.g. Carbopol™ products), methylcelluloses, polymethacrylates, starches, and any combinations thereof.
Direct compression vehicles include, but are not limited to, lactose, modified starch, cellulose derivatives, sucrose, dextrose, sorbitol, mannitol, maltodextrin, corn flour, dicalcium phosphate dihydrate, and any combinations thereof.
Solvents that are useful in processing include, but are not limited to, water, methanol, ethanol, isopropanol, butanols, acidified ethanol, acetone, diacetone,

polyols, polyethers, oils, esters, alkyl ketones, methylene chloride, methyl acetate, ethyl acetate, isopropyl acetate, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulphoxide, dimethylformamide, tetrahydrofuran, and any combinations thereof.
Glidants or anti-sticking agents can be used, including but not limited to talc, silica derivatives, colloidal silicon dioxide, and the like, or any mixtures thereof, and lubricants that can be used include, but are not limited to, stearic acid and stearic acid derivatives such as magnesium stearate, calcium stearate, zinc stearate, sucrose esters of fatty acid, polyethylene glycol, talc, sodium stearyl fumarate, zinc stearate, castor oils, waxes, and any combinations thereof.
An effective amount of any pharmaceutically acceptable tableting lubricant can be added to assist with compressing tablets. Useful tablet lubricants include magnesium stearate, glyceryl monostearates, palmitic acid, talc, carnauba wax, calcium stearate sodium, sodium or magnesium lauryl sulfate, calcium soaps, zinc stearate, polyoxyethylene monostearates, calcium silicate, silicon dioxide, hydrogenated vegetable oils and fats, stearic acid, and any combinations thereof.
Various useful colourants include, but are not limited to, Food Yellow No. 5, Food Red No. 2, Food Blue No. 2, and the like, food lake colorants, iron oxides, and any combinations thereof. If desired, an outer continuous phase in the form of a film coating may be used, optionally containing additional adjuvants for coating processing such as plasticizers, polishing agents, colorants, pigments, antifoam agents, opacifiers, antisticking agents, the like, including any combinations thereof.
Various plasticizers include, but are not limited to, castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycols, propylene glycol, triacetin, triethyl citrate. Also, mixtures of plasticizers may be utilized. The type of plasticizer depends upon the type of coating agent.
An opacifier like titianium dioxide may also be present, in amounts ranging from about 10% to about 20%, based on the total weight of the coating. When

colored tablets are desired then the colour is frequently applied in the coating. Consequently, colouring agents and pigments may be present in the film coating.
Anti-adhesives are frequently used in film coating processes to avoid sticking effects during film formation and drying. An example of an anti-adhesive for this purpose is talc. Useful polishing agents include, but are not limited to, polyethylene glycols of differing molecular weights or mixtures thereof, talc and surfactants (e.g. glycerol monostearate and poloxamers), fatty alcohols (e.g., stearyl alcohol, cetyl alcohol, lauryl alcohol and myristyl alcohol) and waxes (e.g., carnauba wax, candelilla wax and white wax).
Suitable alkaline stabilizers include, but are not limited to, sodium, potassium, calcium, magnesium and aluminum salts of phosphoric acid, carbonic acid, citric acid and aluminum/magnesium compounds such as AI203»6 MgOC02'12H20, MgO'AI203'2Si02»nH20, where n is an integer of 2 or higher. In addition, the alkaline material may be an antacid material such as aluminum hydroxides, calcium hydroxides, magnesium hydroxides, and magnesium oxide.
The capsules or tablets prepared as above can be subjected to in vitro dissolution evaluations according to Test 711 "Dissolution" in United States Pharmacopoeia 29, United States Pharmacopeial Convention, Inc., Rockville, Maryland, 2005 ("USP") to determine the rate at which the active substance is released from the dosage forms, and content of active ingredient can conveniently be determined in solutions by techniques such as high performance liquid chromatography.
Formulations according to the present application release the contained active ingredient over a period of at least 4 hours, at least 8 hours, at least 12 hours, at least 18 hours, or at least 24 hours. In embodiments, the drug is completely released between about 12 hours and about 24 hours. As used herein, the total dose is defined as from about 80% to about 125% of the incorporated amount of active ingredient, according to a suitable assay.
In embodiments, the invention includes the use of packaging materials such as containers and closures of high-density polyethylene (HDPE), low-density

polyethylene (LDPE) and/or polypropylene and/or glass, and blisters or strips composed of aluminum, high-density polypropylene, polyvinylchloride, polyvinylidine dichloride, etc.
The following examples further describe certain specific aspects and embodiments of the invention and demonstrate the practice and advantages thereof. It is to be understood that the examples are provided for purposes of illustration only and are not intended to limit the scope of the invention in any manner.

Methacrylic Acid Copolymer Type A Eudragit L100 3.42
Methacrylic Acid Copolymer Type B Eudragit S 100 7.02
Triethyl citrate 3.01
Talc 1.99
Purified Water q.s
Isopropyl alcohol q.s
Component-Ill
Tartaric acid 132.53
Microcrystalline cellulose 33.07
Ethyl cellulose 15.27
Hypromellose type 2910 3.23
Methacrylic Acid Copolymer Type A Eudragit L100 10.63
Methacrylic Acid Copolymer Type B Eudragit S 100 21.52
Triethyl citrate 9.25
Talc 2.89
Water q.s
Isopropyl alcohol q.s
Drug layering
Carbidopa monohydrate 13.43
Levodopa 53.71
Hydroxypropyl starch 18
Purified water q.s
Lubrication
Talc 2.89
Hard gelatin Capsule Size "00el"
Manufacturing process: Component-I:
-27-

1. Dispensing & Sifting: Carbidopa monohydrate, levodopa, microcrystalline cellulose/ crospovidone/modified starch, mannitol, sodium starch glycolate, sodium lauryl sulphate, povidone, methacrylic acid copolymer Type A and Type B, triethyl citrate and talc are dispensed and sifted through #20 mesh.
2. Granulation: The sifted ingredients are mixed in a rapid mixer granulator for specified time and granulated using purified water.
3. Extrusion & Spheronization: The granulated mass is extruded in an extruder with 0.8mm screen and extrudes are spheronized to obtain pellets.
4. Drying: The spheroid mass is dried in fluid bed drier (FBD) at appropriate inlet temperature. Dried granules are sifted through#18 and #30mesh and #18/#30 fractions are collected.
5. Enteric coating: The dried granules are coated in fluid bed processor (FBP) with enteric coating dispersion prepared by adding methacrylic acid copolymer Type A and Type B, triethyl citrate and talc in hydro-alcoholic solution.
Component-ll:
6. Dispensing: Carbidopa monohydrate, levodopa, microcrystalline cellulose/ carrageenan/modified starch, methacrylic acid copolymer Type A and Type B, triethyl citrate and talc are dispensed and carbidopa, levodopa and microcrystalline cellulose are sifted through #20 mesh.
7. Granulation: The sifted ingredients are mixed in a rapid mixer granulator for specified time and granulated using purified water.
8. Extrusion & Spheronization: The granulated mass is extruded in an extruder with 0.9 mm screen and the extrudes are spheronized to obtain pellets.
9. Drying: The spheroid mass is dried in FBD at appropriate inlet temperature. Dried granules are sifted through#16 and #24mesh and #16/#24 fractions are collected.
10. Enteric Coating: The dried granules are coated in fluid bed processor (FBP) with
enteric coating dispersion prepared by adding methacrylic acid copolymer Type A and
Type B, triethyl citrate and talc in hydro-alcoholic solution.
Component-Ill:

11. Dispensing: Tartaric acid, microcrystalline cellulose, methacrylic acid copolymer, Type A and Type B, triethyl citrate and talc are dispensed and microcrystalline cellulose and tartaric acid are sifted through #20 mesh.
12. Granulation: The sifted ingredients are mixed in a rapid mixer Granulator for specified time and granulated using purified water.
13. Extrusion & Spheronization: The granulated mass is extruded in an extruder with 0.8mm screen and the extrudes are spheronized to obtain pellets.
14. Drying: The spheroid mass is dried in FBD at appropriate inlet temperature. Dried granules are sifted through#16 and #24mesh and #16/#24 fractions are collected.
15. Coating:
(i) Seal-coating: The dried granules are coated with seal coating dispersion prepared by adding hydroxypropyl methylcellulose and ethyl cellulose in hydro-alcoholic solution.
(ii) Controlled-release coating: The seal coated granules of step 15 (i) are coated in fluid bed processor (FBP) using controlled release dispersion prepared by mixing eudragit L 100 & eudragit S 100 along with talc and triethyl citrate in hydro-alcoholic solution.
(iii) Drug-layering: The enteric coated granules of step 15 (ii) are coated in a Fluid Bed Processor (FBP) using a dispersion prepared by mixing carbidopa monohydrate and levodopa along with hydroxypropyl starch in water.
The three components are filled into a capsule after lubricating with talc.

Sodium starch glycolate 3.21
Sodium lauryl sulphate 3.21
Povidone K30 0.63
Methacrylic Acid Copolymer Type A Eudragit L100 0.79
Methacrylic Acid Copolymer Type B Eudragit S 100 1.57
Triethyl citrate 0.67
Talc 0.68
Purified Water q.s
Isopropyl alcohol q.s
Component-ll
Carbidopa monohydrate 38.91
Levodopa 144.17
Microcrystalline cellulose /carrageenan/modified starch 50.13
Methacrylic Acid Copolymer Type A Eudragit L100 3.42
Methacrylic Acid Copolymer Type B Eudragit S 100 7.02
Triethyl citrate 3.01
Talc 1.99
Purified Water q.s
Isopropyl alcohol q.s
Component-Ill
Tartaric acid 132.53
Microcrystalline cellulose 33.07
Carbidopa monohydrate 3.31
Levodopa 12.25
Ethyl cellulose 15.27
Hypromellose type 2910 3.23
Methacrylic Acid Copolymer Type A Eudragit L100 10.63
Methacrylic Acid Copolymer Type B Eudragit S 100 21.52
Triethyl citrate 9.25
-30-

Manufacturing process: Component-I:
1. Dispensing & Sifting: Carbidopa monohydrate, levodopa, microcrystalline cellulose/crospovidone/modified starch, mannitol, sodium starch glycolate, sodium lauryl sulphate, povidone, methacrylic acid copolymer Type A and Type B, triethyl citrate and talc are dispensed and sifted through #20 mesh.
2. Granulation: The sifted ingredients are mixed in a rapid mixer granulator for specified time and granulated using purified water.
3. Extrusion & Spheronization: The granulated mass is extruded in an extruder with 0.8mm screen and extrudes are spheronized to obtain pellets.
4. Drying: The spheroid mass is dried in fluid bed drier (FBD) at appropriate inlet temperature. Dried granules are sifted through#18 and #30mesh and #18/#30 fractions are collected.
5. Enteric coating: The dried granules are coated in fluid bed processor (FBP) with enteric coating dispersion prepared by adding methacrylic acid copolymer Type A and Type B, triethyl citrate and talc in hydro-alcoholic solution.
Component-ll:

6. Dispensing: Carbidopa monohydrate, levodopa, microcrystalline
cellulose/carrageenan/modified starch, methacrylic acid copolymer Type A and
Type B, triethyl citrate and talc are dispensed and carbidopa, levodopa and
microcrystalline cellulose are sifted through #20 mesh.
7. Granulation: The sifted ingredients are mixed in a rapid mixer granulator for specified time and granulated using purified water.
8. Extrusion & Spheronization: The granulated mass is extruded in an extruder with 0.9 mm screen and the extrudes are spheronized to obtain pellets.
9. Drying: The spheroid mass is dried in FBD at appropriate inlet temperature. Dried granules are sifted through#16 and #24mesh and #16/#24 fractions are collected.
10. Enteric coating: The dried granules are coated in fluid bed processor (FBP) with
enteric coating dispersion prepared by adding methacrylic acid copolymer Type A and
Type B, triethyl citrate and talc in hydro-alcoholic solution.
Component-Ill:
11. Dispensing: Tartaric Acid, microcrystalline cellulose, carbidopa monohydrate, levodopa, methacrylic acid copolymer Type A and Type B, triethyl citrate and talc are dispensed.
12. Sifting: Tartaric acid, microcrystalline cellulose, carbidopa monohydrate and levodopa are sifted through #20 mesh.
13. Mixing: The sifted ingredients are mixed for specified time in a rapid mixer granulator.
14. Granulation: The mixture is granulated using purified water.
15. Extrusion: The granulated mass is extruded in an extruder and the extrudes are spheronized to obtain pellets.
16. Drying: The spheroid mass is dried in a fluid bed drier at appropriate inlet temperature. The dried granules are sifted through#16 and #24mesh and #16/#24 fractions are collected.
17. Coating

(i) Seal-coating: The dried granules are coated with seal coating dispersion prepared by adding hydroxypropyl methylcellulose and ethyl cellulose in water and isopropyl alcohol solution.
(ii) Controlled-release coating: The seal coated granules of step 17 (i) are coated in a FBP using controlled release dispersion prepared by mixing Eudragit L 100 & Eudragit S 100 along with talc and triethyl citrate in water and isopropyl alcohol solution.
(iii) Drug-layering: The enteric coated granules of step 17 (ii) are coated in a FBP using dispersion prepared by mixing carbidopa monohydrate and levodopa along with hydroxypropyl starch in water. The three components are filled into a capsule after lubricating with talc.

Carbidopa monohydrate 42.22
Levodopa 156.42
Microcrystalline cellulose /carrageenan/modified starch 50
Ethyl cellulose 15.27
Hypromellose type 2910 3.23
Tartaric acid 10.0
Methacrylic Acid Copolymer Type A Eudragit L100 3.42
Methacrylic Acid Copolymer Type B Eudragit S 100 7.02
Triethyl citrate 3.01
Talc 1.99
Purified Water q.s
Isopropyl alcohol q.s
Component-Ill
Tartaric acid pellets 112.53
Ethyl cellulose 32.82
Hypromellose type 2910 6.94
Methacrylic Acid Copolymer Type A Eudragit L100 21.35
Methacrylic Acid Copolymer Type B Eudragit S 100 43.22
Triethyl citrate 18.58
Talc 5.8
Water q.s
Isopropyl alcohol q.s
Drug layering
Carbidopa monohydrate 13.43
Hydroxypropyl starch 5
Purified water
Lubrication
Talc 2.89
Hard gelatin Capsule Size "00el"
-34-

Manufacturing process: Component-I:
1. Dispensing & Sifting: Carbidopa monohydrate, levodopa, tartaric acid,
microcrystalline cellulose/crospovidone/modified starch, mannitol, sodium starch
glycolate, sodium lauryl sulphate, povidone, methacrylic acid copolymer Type A
and Type B, triethyl citrate and talc are dispensed as per the composition and
sifted through #20 mesh.
2. Granulation: The sifted ingredients are mixed in a rapid mixer granulator for specified time and granulated using purified water.
3. Extrusion & Spheronization: The granulated mass is extruded in an extruder with 0.8mm screen and extrudes are spheronized to obtain pellets.
4. Drying: The spheroid mass is dried in fluid bed drier (FBD) at appropriate inlet temperature. Dried granules are sifted through#18 and #30mesh and #18/#30 fractions are collected.
5. Enteric coating: The dried granules are coated in fluid bed processor (FBP) with enteric coating dispersion prepared by adding methacrylic acid copolymer Type A and Type B, triethyl citrate and talc in hydro-alcoholic solution.
6. Drug-layering: Enteric coated granules of step 5 are coated in a FBP using a dispersion prepared by mixing carbidopa monohydrate and levodopa along with hydroxypropyl starch in water.
Component-ll:
7. Dispensing: Carbidopa monohydrate, levodopa, tartaric acid, microcrystalline
cellulose/carrageenan/modified starch, methacrylic acid copolymer Type A and
Type B, triethyl citrate and talc are dispensed as per the composition and
carbidopa, levodopa and microcrystalline cellulose are sifted through #20 mesh.
9. Granulation: The sifted ingredients are mixed in a rapid mixer granulator for
specified time and granulated using purified water.
10. Extrusion & Spheronization: The granulated mass is extruded in an extruder with
0.9 mm screen and the extrudes are spheronized to obtain pellets.

11. Drying: The spheroid mass is dried in FBD at appropriate inlet temperature. Dried granules are sifted through#16 and #24mesh and #16/#24 fractions are collected.
12. Enteric coating: The dried granules are coated in fluid bed processor (FBP) with enteric coating dispersion prepared by adding methacrylic acid copolymer Type A and Type B, triethyl citrate and talc in hydro-alcoholic solution.
Component-Ill:
13. Coating
(i) Seal-coating: Coat the tartaric acid pellets with seal coating dispersion prepared by adding hydroxypropyl methylcellulose and ethyl cellulose in water and isopropyl alcohol solution.
(ii) Controlled-release coating: Coat the seal coated granules of step 13 (i) in FBP using controlled release dispersion prepared by mixing Eudragit L 100 & Eudragit S 100 along with talc and triethyl citrate in water and isopropyl alcohol solution. The three components are filled into a capsule after lubricating with talc.

Tartaric Acid 10.0
Talc 0.68
Purified Water q.s
Isopropyl alcohol q.s
Component-ll
Carbidopa monohydrate 42.22
Levodopa 156.42
Microcrystalline cellulose /carrageenan/modified starch 85.13
Methacrylic Acid Copolymer Type A Eudragit L100 3.42
Methacrylic Acid Copolymer Type B Eudragit S 100 7.02
Triethyl citrate 3.01
Tartaric Acid 10.0
Talc 1.99
Purified Water q.s
Isopropyl alcohol q.s
Component-Ill
Tartaric acid 112.53
Microcrystalline cellulose 33.07
Ethyl cellulose 15.27
Hypromellose type 2910 3.23
Methacrylic Acid Copolymer Type A Eudragit L100 10.63
Methacrylic Acid Copolymer Type B Eudragit S100 21.52
Triethyl citrate 9.25
Talc 2.89
Water q.s
Isopropyl alcohol q.s
Drug layering
Carbidopa monohydrate 13.43
Levodopa 53.71
-37-

Manufacturing process: Component-I:
1. Dispensing: Carbidopa monohydrate, levodopa, microcrystalline
cellulose/crospovidone/modified starch, mannitol, sodium starch glycolate, sodium
lauryl sulphate, povidone, methacrylic acid copolymer Type A and Type B, triethyl
citrate, tartaric Acid and talc are dispensed.
2. Sifting: Carbidopa, levodopa, microcrystalline cellulose, mannitol, sodium starch glycolate, sodium lauryl sulphate and povidone are sifted through #20 mesh.
3. Mixing: The sifted ingredients are mixed for specified time in a rapid mixer granulator.
4. Granulation: The above mixture is granulated using purified water.

5. Extrusion & Spheronization: The granulated mass is extruded with 0.8mm screen and spheronized to obtain pellets.
6. Drying: The spheroid mass is dried in fluid bed drier at appropriate inlet temperature. The dried granules are sifted through #18 and #30 mesh and #18/#30 fractions are collected.
7. Enteric coating: The dried granules are coated in FBP with enteric coating dispersion prepared by adding methacrylic Acid copolymer Type A and Type B, triethyl citrate and talc in hydro-alcoholic solution.
8. Tartaric acid coating: The enteric coated granules are coated in FBP with a dispersion prepared by adding tartaric acid in water.
Component-ll:

9. Dispensing: Carbidopa monohydrate, levodopa, microcrystalline
cellulose/carrageenan/modified starch, methacrylic acid copolymer Type A and
Type B, triethyl citrate, tartaric acid and talc are dispensed.
10. Sifting: Carbidopa monohydrate, levodopa and microcrystalline cellulose are sifted
through #20 mesh.
11. Mixing: The sifted ingredients are mixed for specified time in a rapid mixer
granulator.
12. Granulation: The above mixture is granulated using purified water.
13. Extrusion & Spheronization: The granulated mass is extruded in an extruder with 0.9 mm screen then spheronized to get pellets.
14. Drying: The spheroid mass is dried in a fluid bed drier at appropriate inlet temperature. The dried granules are sifted through #16 and #24mesh and #16/#24 fractions are collected.
15. Enteric coating: The dried granules are coated in a FBP with enteric coating dispersion prepared by adding methacrylic acid copolymer Type A and Type B, triethyl citrate and talc in hydro-alcoholic solution.
16. Tartaric acid coating: The dried granules are coated in FBP with a dispersion prepared by adding tartaric acid in water.
Component-Ill:
17. Dispensing: Microcrystalline cellulose, tartaric Acid, methacrylic acid copolymer Type A and Type B, triethyl citrate and talc are dispensed.
18. Sifting: Microcrystalline cellulose and tartaric acid are sifted through #20 mesh.
19. Mixing: The sifted ingredients are mixed for specified time in a rapid mixer
granulator.
20. Granulation: The above mixture is granulated using purified water.
21. Extrusion: The granulated mass is extruded and spheronized to form pellets.
22. Drying: The spheroid mass is dried in fluid bed drier at appropriate inlet temperature. The dried granules are sifted through#16 and #24mesh and #16/#24 fractions are collected.
23. Coating:

(i) Seal-coating: The dried granules are coated with a dispersion prepared by adding hydroxypropyl methylcellulose and ethyl cellulose in hydro-alcoholic solution.
(ii) Controlled-release coating: The seal coated granules of step 23 (i) are coated using controlled release dispersion prepared by mixing Eudragit L 100 & Eudragit S 100 along with talc and triethyl citrate in hydro-alcoholic solution.
(iii) Drug-layering: The enteric coated granules of step 23 (ii) are coated in FBP using a dispersion prepared by mixing carbidopa monohydrate and levodopa along with hydroxypropyl starch in water. The three components are filled into a capsule after lubricating with talc.

WE CLAIM:
1. A controlled release oral solid formulation of levodopa comprising i) an
extended-release component comprising levodopa, carbidopa and a rate-
controlling excipient; and ii) an extended-release component comprising a
carboxylic acid, levodopa, carbidopa and a rate-controlling excipient.
2. The controlled release oral solid formulation of claim 1, wherein the carboxylic
acid is selected from a group consisting of tartaric acid, adipic acid, succinic acid,
citric acid, benzoic acid, acetic acid, ascorbic acid, edetic acid, fumaric acid, lactic
acid, malic acid, oleic acid, sorbic acid, stearic acid, palmitic acid and boric acid or
mixtures thereof.
3. The controlled release oral solid formulation of claims 1-2, wherein the
carboxylic acid is tartaric acid.
4. The controlled release oral solid formulation of claims 1-3, wherein levodopa and carbidopa of component (ii) may be present in the form of coating over tartaric acid core or present in the core along with tartaric acid.
5. The controlled release oral solid formulation of claims 1-3, wherein tartaric acid of component (ii) may be present in the form of coating over levodopa/carbidopa core or present in the core along with levodopa/carbidopa.
6. The controlled release oral solid formulation of claims 1-5, wherein carbidopa and levodopa are present in the formulation in a ratio of about 1:1 to about 1:10.
7. The controlled release oral solid formulation of claims 1-6, wherein the rate controlling excipient is an enteric polymer or a mixture of more than one type of enteric polymer.