DESC:CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority to and the benefit of Indian Patent Application No. 202321032709, filed May 09, 2023.
FIELD OF THE INVENTION
The present invention relates to a stable controlled release pharmaceutical compositions of carbidopa (CD) and levodopa (LD) and at least one pharmaceutically acceptable excipient and process for preparing thereof.
BACKGROUND OF THE INVENTION
Carbidopa, an inhibitor of aromatic amino acid decarboxylation, an enzyme important in the biosynthesis of L-tryptophan to serotonin and in the biosynthesis of L-DOPA to dopamine. Carbidopa inhibits the decarboxylation of peripheral levodopa and does not cross the blood-brain barrier. Carbidopa inhibits the decarboxylation of peripheral levodopa, making more levodopa available for delivery to the brain.
The drug substance used in the drug product formulation is the monohydrate form of carbidopa, also known by the US accepted name of Carbidopa (CD) and is chemically described as (–)-L-a-hydrazino-a-methyl-ß-(3,4-dihydroxy-benzene) propanoic acid monohydrate with a molecular weight of 244.3. Its empirical formula is C10H14N2O4?H2O and its structural formula is:

Levodopa, is an amino acid and also known as a dopamine agonists or metabolic precursor of dopamine, does cross the blood-brain barrier, and presumably is converted to dopamine in the brainis. This is important for the relieves symptoms of Parkinson's disease.
The drug substance used in the drug product formulation is the free base of levodopa, also known by the US accepted name of Levodopa (LD) and is chemically described as (–)-L-a-amino-ß-(3,4-dihydroxybenzene) propanoic acid with a molecular weight of 197.2. Its empirical formula is C9H11NO4 and its structural formula is:

Parkinson's disease (PD) is a progressive neurodegenerative disorder, which is characterized by motor symptoms such as tremor, rigidity, slowness of movement and problems with gait. Motor symptoms are often accompanied with fatigue, depression, pain and cognitive problems. Parkinson disease is the second-most common neurodegenerative disorder that affects 2–3% of the population =65 years of age. Parkinson disease is clinically defined by the presence of bradykinesia and at least one additional cardinal motor feature (rigidity or rest tremor), as well as additional supporting and exclusionary criteria.
Combinations of carbidopa (CD) and levodopa (LD) to treat Parkinson's disease (PD) are well known in the pharmaceutical art and are considered by many to be the 'gold standard' treatment for symptoms of PD. Currently, several formulations containing a combination of CD and LD are commercially available, e.g., SINEMET®, SINEMET® CR, STALEVO®, PARCOPA®, ATAMET® and RYTARY®. The approved multiple controlled release/ extended absorption commercial formulations of Carbidopa and Levodopa are available in a 1:4 ratio of carbidopa to levodopa. The controlled release oral dosage forms are available in the form of extended release tablet (SINEMET® CR) and extended release capsule (RYTARY®). The extended release composition or enteric coated composition contain at least two components or multiparticulate i.e. immediate release component, controlled release component and enteric coated component and those components are filled capsule shell.
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 is 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 extended 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 requires more frequent dosing and are associated with more fluctuating plasma LD concentrations.
Over time patients treated with LD exhibit symptoms of “wearing off,” where a single dose of levodopa no longer lasts as long as in the early days of levodopa therapy (usually 5-10 years after start of levodopa therapy). Such patients may develop motor fluctuations characterized by end-of-dose failure, peak dose dyskinesia, and akinesia. The advanced form of motor fluctuations (also commonly referred to as the ‘on-off’ phenomenon) is characterized by unpredictable swings from mobility to immobility. Although the causes of these motor fluctuations are not completely understood, advanced patients generally benefit from treatment regimens that produce steady plasma levels of LD, such as through intestinal infusion of LD as such delivery method may mimic normally tonic endogenous dopamine. However, intestinal infusion of LD is restrictive, invasive and cumbersome. Oral delivery of LD is preferred, but plasma concentration levels remain difficult to control via oral delivery.
Carbidopa and Levodopa is available in the United States of America as RYTARY® (carbidopa; levodopa) extended release capsules and is indicated for the treatment of Parkinson's disease, post-encephalitic parkinsonism, and parkinsonism that may follow carbon monoxide intoxication or manganese intoxication. RYTARY® is available in four strengths i.e. 23.75mg;95mg, 36.25mg;145mg, 48.75mg;195mg and 61.25mg;245mg and RYTARY®’s composition contains microcrystalline cellulose, mannitol, tartaric acid, ethyl cellulose, hypromellose, sodium starch glycolate, sodium lauryl sulfate, povidone, talc, methacrylic acid copolymers, triethyl citrate, croscarmellose sodium, and magnesium stearate as inactive ingredients and capsule shell contains gelatin and titanium dioxide.
US4983400 patent discloses the controlled release solid oral dosage formulation consisting essentially of a uniform dispersion of 5-300 mg of carbidopa, 20-1200 mg of levodopa in a polymer vehicle of 2 to 120 mg of polymethyl methacrylate, whereby following administration the carbidopa and levodopa are released slowly and simultaneously from the formulation.
US6531153 patent discloses a pharmaceutical composition comprising a therapeutically effective amount of levodopa and of carbidopa, dispersed in a hydrophilic matrix, said composition further comprising an organic acid. Also, discloses a process for preparing the composition, comprising granulation, in particular in a fluidized bed, of the various components and compression of the granules obtained.
WO2003101432 patent application further discloses Dosage form having an immediate release and a controlled release component, both components comprising a ratio of Carbidopa to Levodopa of 1:1 to 1:50.
US20070003621 patent application discloses plurality of pellets comprising carbidopa, levodopa, wherein one portion of pellets are coated with bioadhesive polymers.
WO2009085306 patent application discloses a Controlled release oral solid formulation comprising: a) Levodopa; b) a decarboxylase inhibitor, preferably Carbidopa and; c) a carboxylic acid that is not Levodopa or Carbidopa, for the treatment of Parkinson's disease and its related movement disorders.
US10292935 patent discloses controlled release pharmaceutical compositions of levodopa (LD) and esters of levodopa or salts thereof, formulated with a muco-adhesive polymer and a rate-controlling material that will contribute to the controlled release of the levodopa and/or ester of levodopa or salts thereof and applied as an undercoating the muco-adhesive polymer coating further coated with enteric coating polymer.
Despite the existence of prior art solid pharmaceutical formulations of levodopa and carbidopa mentioned above, there is still a need for an oral pharmaceutical composition of levodopa and carbidopa with prolonged absorption capable of stabilising the composition and providing a prolonged and consistent pharmacokinetic property without the use of a mucoadhesive polymer layer over the core.
It has now been found surprisingly that a pharmaceutical composition containing an immediate release component of levodopa and a decarboxylase inhibitor, such as carbidopa, as well as a controlled release core component of levodopa, has been found to be coated with a release rate control polymer and externally coated with an enteric polymer without the use of a mucoadhesive polymer layer over the core and such composition was stable and also provided prolonged absorption and consistent pharmacokinetic properties. The controlled release component is critical for achieving the desired pharmacokinetic characteristics and consequently the extended absorption.
OBJECT OF THE INVENTION
It is an object of the present invention to provide a stable controlled release pharmaceutical composition of levodopa and carbidopa, and at least one pharmaceutically acceptable excipient and processes for preparing thereof.
It is also another object of the present invention to provide a stable multiparticulate controlled release pharmaceutical composition for oral administration comprising: (a) a plurality of controlled release component which comprises: i) a core comprising levodopa, and at least one pharmaceutically acceptable excipient; ii) a controlled release coating layer surrounding the core comprising of cellulose acetate, pectin or combinations thereof, and iii) an enteric coating layer surrounding the controlled release coating; and (b) an immediate release component comprising levodopa and carbidopa; and at least one pharmaceutically acceptable excipient.
It is also another object of the present invention to provide a stable multiparticulate controlled release pharmaceutical composition for oral administration comprising: (a) a plurality of controlled release component which comprises: i) a core comprising levodopa, and diluent, surfactant and binder; ii) a controlled release coating layer surrounding the core comprising of cellulose acetate, pectin or combination thereof, and iii) an enteric coating layer surrounding the controlled release coating; and (b) an immediate release component comprising levodopa and carbidopa; and disintegrant, binder and lubricant.
It is yet another object of the present invention is to provide a stable multiparticulate controlled release pharmaceutical composition for oral administration comprising: (a) a plurality of controlled release component which comprises: i) a core comprising levodopa, and diluent, surfactant and binder; ii) a controlled release coating layer surrounding the core comprising of cellulose acetate; and iii) an enteric coating layer surrounding the controlled release coating; and (b) an immediate release component comprising levodopa and carbidopa; and disintegrant, binder and lubricant.
It is also another object of the present invention provide a stable multiparticulate controlled release pharmaceutical composition for oral administration comprising: (a) a plurality of controlled release component which comprises: i) a core comprising levodopa, and diluent, surfactant and binder; ii) a controlled release coating layer surrounding the core comprising of cellulose acetate, pectin or combination thereof; and iii) an enteric coating layer surrounding the controlled release coating; and (b) an immediate release component comprising levodopa and carbidopa; and disintegrant, binder and lubricant, wherein process comprises: (a) Preparation of controlled release component comprising: i) a core containing levodopa pellets prepared by using povidone binder solution are mixed with levodopa, diluent as microcrystalline cellulose, mannitol & surfactant as sodium lauryl sulfate and blend was extruded and spheronized; ii) a core coated with a layer of release controlling membrane contains cellulose acetate, pectin or combination thereof; and iii) an enteric coating layer of Eudragit L100 surrounding the layer of release controlling membrane; and (b) Preparation of immediate release component by using povidone binder solution mixed with carbidopa, levodopa and disintegrant as croscarmellose sodium, lubricant as magnesium stearate in rapid mixing granulator, to form dried levodopa, carbidopa granules.
It is also another object of the present invention to provide a stable multiparticulate controlled release pharmaceutical composition for oral administration comprising: (a) a plurality of controlled release component which comprises: i) a core comprising levodopa, and at least one pharmaceutically acceptable excipients; ii) a controlled release coating layer surrounding the core comprising of cellulose acetate, and iii) another controlled release coating layer surrounding the release controlling polymer layer iv) an enteric coating layer surrounding the core and the release controlling polymer layers; and (b) an immediate release component comprising levodopa and carbidopa; and at least one pharmaceutically acceptable excipient.
It is also another object of the present invention to provide a stable multiparticulate controlled release pharmaceutical composition for oral administration comprising: a) a plurality of controlled release component which comprises: i) a core comprises about 46% w/w levodopa, about 3.2% w/w microcrystalline cellulose, about 3.1% w/w mannitol, about 3.1% w/w sodium lauryl sulfate and about 1.1% w/w povidone K90, optionally carbidopa; ii) a controlled release coating layer surrounding the core comprises about 1.6% w/w cellulose acetate, about 1.6% w/w copovidone; iii) controlled release coating layer surrounding the layer of step ii) comprises about 3% w/w pectin, about 0.3% w/w talc and about 0.3% w/w glycerin; iv) an enteric coating layer surrounding the core and the release controlling polymer layers comprises about 4.8% w/w eudragit L100, about 1.4% w/w triethyl citrate, about 0.7% w/w talc and about 0.3% w/w of magnesium stearate; and (b) an immediate release component which comprises about 11.4% w/w levodopa, about 15.4% w/w carbidopa, about 1.5% croscarmellose sodium, about 1.3% w/w povidone and about 0.2% w/w magnesium stearate.
It is also another object of the present invention to provide a stable multiarticulate controlled release pharmaceutical composition for oral administration comprising: (a) a plurality of controlled release component which comprises: i) a core comprising levodopa, diluent, surfactant and binder; ii) a controlled release coating layer surrounding the core comprising of cellulose acetate, and iii) another controlled release coating layer surrounding the release controlling polymer layer iv) an enteric coating layer surrounding the core and the release controlling polymer layers; and (b) an immediate release component comprising levodopa, carbidopa, disintegrant, binder and lubricant, wherein process comprises: a) Preparation of controlled release component comprising: i) a core containing levodopa pellets prepared by using povidone binder solution which is mixture of diluent as microcrystalline cellulose, mannitol, surfactant as sodium lauryl sulfate and blend was extruded and spheronized. ii) a core coated with release controlling coating/layer which comprises cellulose acetate. iii) above core is further coated with another release controlling coating which comprises pectin; iv) an enteric coating layer comprising eudragit L100 surrounding the controlled release coating comprising pectin. b) Immediate release component pellets were prepared by using povidone binder solution mixed with carbidopa, levodopa, disintegrant as croscarmellose sodium, and lubricant as magnesium stearate in rapid mixing granulator, to form dried levodopa and carbidopa granules. The granules obtained in a) and b) further filled in suitable size capsule.
It is yet another object of the present invention provides a stable controlled release pharmaceutical composition of levodopa and carbidopa and processes for preparing thereof and one or more pharmaceutically acceptable excipients, which uses a novel and improved formulation and yet is bioequivalent to the compositions (“IPX203) disclosed in the patent US10292935 and also to the submitted 505(b)(2) NDA to the U.S. FDA approval for the treatment of Parkinson’s disease (PD).
SUMMARY OF THE INVENTION
The present invention provides a stable controlled release pharmaceutical composition of levodopa and carbidopa and processes for preparing thereof and one or more pharmaceutically acceptable excipients.
In one aspect of the present invention, there is provided a stable multiparticulate controlled release pharmaceutical composition for oral administration comprising: (a) a plurality of controlled release component which comprises: i) a core comprising levodopa, and at least one pharmaceutically acceptable excipient; ii) a controlled release coating layer surrounding the core comprising of cellulose acetate, pectin or combination thereof; and iii) an enteric coating layer surrounding the controlled release coating; and (b) an immediate release component comprising levodopa and carbidopa; and at least one pharmaceutically acceptable excipient.
In one aspect of the present invention, there is provided a stable multiparticulate controlled release pharmaceutical composition for oral administration comprising: (a) a plurality of controlled release component which comprises: i) a core comprising levodopa, and diluent, surfactant and binder; ii) a controlled release coating layer surrounding the core comprising of cellulose acetate, pectin or combination thereof; and iii) an enteric coating layer surrounding the controlled release coating; and (b) an immediate release component comprising levodopa and carbidopa; and disintegrant, binder and lubricant.
In another aspect of the present invention, there is provided a stable multiparticulate controlled release pharmaceutical composition for oral administration comprising: (a) a plurality of controlled release component which comprises: i) a core comprising levodopa, and diluent, surfactant and binder; ii) a controlled release coating layer surrounding the core comprising of cellulose acetate; and iii) an enteric coating layer surrounding the controlled release coating; and (b) an immediate release component comprising levodopa and carbidopa; and disintegrant, binder and lubricant.
In one another aspect of the present invention, there is provided a stable multiparticulate controlled release pharmaceutical composition for oral administration comprising: (a) a plurality of controlled release component which comprises: i) a core comprising levodopa, and diluent, surfactant and binder; ii) a controlled release coating layer surrounding the core comprising of cellulose acetate, pectin or combination thereof; and iii) an enteric coating layer surrounding the controlled release coating; and (b) an immediate release component comprising levodopa and carbidopa; and disintegrant, binder and lubricant, wherein process comprises: a) Preparation of controlled release component comprising: i) a core containing levodopa pellets prepared by using povidone binder solution are mixed levodopa, diluent as microcrystalline cellulose, mannitol, surfactant as sodium lauryl sulfate and blend was extruded and spheronized; ii) a core coated with a layer of release controlling membrane contains cellulose acetate, pectin or combination thereof; and iii) an enteric coating layer containing Eudragit L100 surrounding the layer of release controlling membrane; and b) Preparation of immediate release component by using povidone binder solution mixed with carbidopa, levodopa, disintegrant as croscarmellose sodium and lubricant as magnesium stearate in rapid mixing granulator, to formed dried levodopa, carbidopa granules.
It is also another object of the present invention to provide a stable multiparticulate controlled release pharmaceutical composition for oral administration comprising: (a) a plurality of controlled release component which comprises: i) a core comprising levodopa, and at least one pharmaceutically acceptable excipients; ii) a controlled release coating layer surrounding the core comprising of cellulose acetate, and iii) another controlled release coating layer surrounding the release controlling polymer layer iv) an enteric coating layer surrounding the core and the release controlling polymer layers; and (b) an immediate release component comprising levodopa and carbidopa; and at least one pharmaceutically acceptable excipient.
It is also another object of the present invention to provide a stable multiparticulate controlled release pharmaceutical composition for oral administration comprising: a) a plurality of controlled release component which comprises: i) a core comprises about 46% w/w levodopa, about 3.2% w/w microcrystalline cellulose, about 3.1% w/w mannitol, about 3.1% w/w sodium lauryl sulfate and about 1.1% w/w povidone K90, optionally carbidopa; ii) a controlled release coating layer surrounding the core comprises about 1.6% w/w cellulose acetate, about 1.6% w/w copovidone; iii) controlled release coating layer surrounding the layer of step ii) comprises about 3% w/w pectin, about 0.3% w/w talc and about 0.3% w/w glycerin; iv) an enteric coating layer surrounding the core and the release controlling polymer layers comprises about 4.8% w/w eudragit L100, about 1.4% w/w triethyl citrate, about 0.7% w/w talc and about 0.3% w/w of magnesium stearate; and (b) an immediate release component which comprises about 11.4% w/w levodopa, about 15.4% w/w carbidopa, about 1.5% croscarmellose sodium, about 1.3% w/w povidone and about 0.2% w/w magnesium stearate.
It is also another object of the present invention to provide a stable multiparticulate controlled release pharmaceutical composition for oral administration comprising: (a) a plurality of controlled release component which comprises: i) a core comprising levodopa, diluent, surfactant and binder; ii) a controlled release coating layer surrounding the core comprising of cellulose acetate, and iii) another controlled release coating layer surrounding the release controlling polymer layer iv) an enteric coating layer surrounding the core and the release controlling polymer layers; and (b) an immediate release component comprising levodopa, carbidopa, disintegrant, binder and lubricant, wherein process comprises: a) Preparation of controlled release component comprising: i) a core containing levodopa pellets prepared by using povidone binder solution which is mixture of diluent as microcrystalline cellulose, mannitol, surfactant as sodium lauryl sulfate and blend was extruded and spheronized ii) a core coated with release controlling coating/layer which comprises cellulose acetate. iii) above core is further coated with another release controlling coating which comprises pectin; iv) an enteric coating layer comprising eudragit L100 surrounding the controlled release coating comprising pectin. b) Immediate release component pellets were prepared by using povidone binder solution mixed with carbidopa, levodopa, disintegrant as croscarmellose sodium, and lubricant as magnesium stearate in rapid mixing granulator, to form dried levodopa and carbidopa granules. The granules obtained in a) and b) further filled in suitable size capsule.

DETAILED DESCRIPTION OF THE INVENTION
Before the present process and methods are described, it is to be understood that this invention is not limited to particular compounds, formulas or steps described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the invention.
Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.
It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a formulation” includes a plurality of compounds. Thus, for example, reference to "a compound" includes a plurality of such compounds and reference to "the step" includes reference to one or more step and equivalents thereof known to those skilled in the art, and so forth.
The publications discussed herein are provided solely for their availability to the applicant prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed
The term “composition” as used herein is intended to encompass a product comprising the specified ingredients (and in the specified amount, if indicated), as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By “pharmaceutically acceptable” it is mean that the diluent, excipient or carrier must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The term "extended release" as used herein refers to a release, which is not immediate release. Further, the term "extended release" as used herein refers to the release of an active ingredient from a pharmaceutical composition or dosage form, in which the active ingredient is released over an extended period of time and / or at particular location and is taken to encompass sustained release, controlled release, modified release, prolonged release, delayed release and the like.
The term “immediate release” as used herein refers to a pharmaceutical formulation which, in Simulated gastric fluid (SGF) at 25°C using the basket test (75 rpm), releases at least 80% of the active pharmaceutical ingredient within 30 minutes or less after administration.
The term, "controlled release" as used herein refers to a dosage form that is deliberately modified to protract the release rate of the drug substance compared to that observed for an immediate-release dosage form. After the therapeutic plasma level of levodopa is obtained by the immediate release component, the controlled release component(s) should provide and/or maintain a therapeutic plasma level of levodopa over a period of thereof at least 4-12 hours, preferably 6-12 hours and most preferably 5, 6, 7, 8, 9, 10, 11 or 12 hours after administration. The controlled release component as used herein refers to a pharmaceutical formulation which, in Simulated gastric fluid (SGF) and 50mM phosphate buffer, pH 7.0 at 25°C using the basket test (75 rpm), releases 20% of the active pharmaceutical ingredient within 30 minutes or less after administration.
The term “multiparticulate pharmaceutical composition” as used herein refers to a pharmaceutical composition in the form of multiple solid units, such as, powder, pellets, bead, mini-tablets, granules, and/or mixtures thereof.
The term “pharmaceutically acceptable” as used herein refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of animals, in particular human beings, without excessive toxicity, irritation, allergic response, or other problematic complications commensurate with a reasonable benefit/risk ratio.
The term "coating" as used herein refers to adherence, and/or adsorption, preferable uniformly, of at least one solution, dispersion or suspension coating material onto a substrate. The coating material on the substrate may be of any thickness. Preferably the coating material is a thin and uniform film applied onto the substrate. A thin and uniform film can be of the type of a "film coating" or/and an "isolating film coating" or/and an "external film coating".
In accordance with the present invention, the "carbidopa" unless indicated otherwise in the specification refers to carbidopa in the form of free base or its pharmaceutically acceptable salt, amorphous, crystalline or any isomer or derivative, hydrate or solvate, prodrug or combinations thereof. Preferably carbidopa is in the form of carbidopa as a crystalline carbidopa monohydrate. Carbidopa inhibits the decarboxylation of peripheral levodopa, making more levodopa available for delivery to the brain.
In accordance with the present invention, the "levodopa" unless indicated otherwise in the specification refers to levodopa in the form of free base or its pharmaceutically acceptable salt, amorphous, crystalline or any isomer or derivative, hydrate or solvate, ester of levodopa, prodrug or combinations thereof. Preferably levodopa is in the form of levodopa as a crystalline levodopa free base. Levodopa, is an amino acid and also known as a dopamine agonists or metabolic precursor of dopamine, does cross the blood-brain barrier, and presumably is converted to dopamine in the brainis. This is important for the relieves symptoms of Parkinson's disease.
The term "therapeutically effective amount" is defined to mean the amount or quantity of the active drug carbidopa and levodopa, which is sufficient to elicit an appreciable biological response when administered to the patient. A person skilled in the art can easily determine such an amount by routine experimentation and with an undue burden. Therapeutically effective amount of carbidopa and levodopa are present in the formulation of the invention in a weight ratio of about 1:1 to 1:10, preferably 1:4 ratio of carbidopa to levodopa and the doses with respect of this invention are usually range between 35mg to 175 mg of carbidopa and 140mg to 700mg of levodopa, usually administered twice, thrice or four times a day, although amounts outside this range and different frequencies of administration are feasible for use in therapy under prescribed medical conditions. As mentioned, dosage forms of the present invention are useful, inter alia, in the treatment of subjects with advanced Parkinson's disease (PD) who have motor fluctuations.
The present invention provides a levodopa and carbidopa or its pharmaceutically acceptable salt thereof, wherein levodopa may be present in an amount of about 5 % w/w to about 70 % w/w, preferably about 10 % w/w to about 65 % w/w, more preferably about 20 % w/w to about 60 % w/w of the total weight of composition, and carbidopa may be present in an amount of about 5 % w/w to about 30 % w/w, preferably about 10 % w/w to about 25 % w/w, more preferably about 12 % w/w to about 20 % w/w of the total weight of composition.
The therapeutically effective amount of carbidopa and levodopa, or a pharmaceutically acceptable salt thereof, used in the pharmaceutical composition ranges from about 1:4 weight ratio of carbidopa to levodopa which includes: 35mg/140mg, 45mg/180mg, 52.5mg/210, 70mg/280mg, 87.5mg/350mg, 105mg/420mg, 140mg/560mg and 175mg/700mg of the pharmaceutical composition. An important aspect of the present invention provides a stable compositions of controlled release pharmaceutical composition of levodopa and carbidopa and processes for preparing thereof.
The term “stable” as used herein refers to the chemical stability of the Pharmaceutical compositions of the present invention wherein the total impurities formed for each of drugs Carbidopa and Levodopa is Not More Than (NMT) 2%, when the Pharmaceutical composition is subjected to the stability conditions of 25ºC /60% RH and 40ºC /75% RH for at least 1 month. Pharmaceutical compositions of the present invention comprising controlled release levodopa and carbidopa composition are found to be stable. The term “Mucoadhesive polymer” is defined to mean the polymers used in the formulation to improve gastrointestinal retention via adherence of the formulation to the walls of the GI tract. As used herein "mucoadhesive" generally refers to the ability of a material to adhere to a biological surface for an extended period of time. Mucoadhesion requires contact between a mucoadhesive material and a surface (e.g. tissue and/or cells).
Another important aspect of the present invention provides a stable controlled release pharmaceutical composition of levodopa and carbidopa prepared by granulation process and extrusion spheronization, preferably immediate release granules are prepared by rapid mixing granulator and controlled release pellets are prepared by granulation and extrusion spheronization.
The composition(s) according to the present invention, when tested for in- vitro dissolution profile, exhibits dissolution such that the amount of the levodopa equivalent to 22 % dissolves within 1 hour, 77 – 80 % dissolve within 4 hour and 92 -97 % dissolve within 6 hours. To study the dissolution profile of the pharmaceutical compositions of the invention, the suitable dissolution test is selected and it is carried out in an aqueous media simulated gastric fluid and phosphate buffer to a pH range (1 to 7.8) found in the gastrointestinal tract and controlled at 37°C (± l0°C), that maintain a physiological relevance. Various dosage forms such as tablets, capsules can be studied for dissolution profile, in a standard prescribed manner. When the dosage form is a capsule, typically USP I basket are used and rotating at 50-75 rpm are used to test the dissolution rate of the Capsule. The amount of dissolved active drug can be determined using suitable analytical techniques such as UV or HPLC.
The term "composition" or "formulation" or "dosage form" as used herein synonymously include solid dosage forms such as granules, multiunit particulate systems (MUPS), pellets, spheres, tablets, capsules, mini-tablets, layered tablets (e.g. bilayer or trilayer), beads, particles and the like; and liquid dosage forms such as solutions, suspensions, emulsions, colloids and the like, meant for oral administration. The preferred composition is in the form of a capsule containing multiparticulates.
The term "excipient" as used herein means a pharmacologically inactive component such as, but not limited to, a diluent or filler, binder, disintegrant, release controlling agent, release retarding agent, release modifying agent, lubricant, plasticizer, surfactant, or the like. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and are acceptable for human use.
“Diluents or fillers” may be selected from, but not limited to, carbohydrates, confectioners’ sugar, compressible sugars, dextrose, dextrin, fructose, lactitol, xylitol, sorbitol, microcrystalline cellulose, mannitol, lactose, sucrose, maltose, starch, calcium carbonate, calcium sulfate, calcium hydrogen phosphate, or combinations thereof. Fillers or diluents may be used in the range of about 1% w/w to about 30 % w/w, preferably about 3% w/w to about 20% w/w, more preferably about 5% w/w to about 15%w/w of total weight of stable oral pharmaceutical composition. In an embodiment of the present invention, microcrystalline cellulose and mannitol are preferred diluent or filler.
“Solvent or solubilizing agents” used in the composition of the present invention is selected from but are not limited to, ethanol, propanol, isopropanol, acetone, purified water, propylene glycol, polyethylene glycol of various molecular weights, dichloromethane, dimethylisosorbide, ethyl lactate, N-methylpyrrolidones, glycofurol, decaglycerol mono-, dioleate, triglycerol monooleate, polyglycerol oleate, mixed diesters of Caprylic/Capric acid and propylene glycol, ethyl oleate, glyceryl monooleate, Vitamin E TPGS, alpha tocopherol, or mixtures thereof. The preferred solvent or solubilizing agents is purified water, Iso-propyl alcohol and acetone.
“Binders” may be selected from, but not limited to, potato starch, wheat starch, com starch, microcrystalline cellulose, celluloses such as hydroxy propyl cellulose, hydroxy propyl methylcellulose, povidone, hydroxy ethyl cellulose, sodium carboxy methyl cellulose, natural gums like acacia, alginic acid, guar gum, liquid glucose, dextrin, povidone, syrup, polyethylene oxide, polyvinyl pyrrolidone, poly-N-vinyl amide, polyethylene glycol, gelatin, poly propylene glycol, tragacanth, or combinations thereof. Binders may be used in the range of about 0.1% w/w to about 15. % w/w, preferably about 1% w/w to about 10 % w/w, more preferably about 2% w/w to about 8% w/w of total weight of stable oral pharmaceutical composition. The preferred Binder is povidone K-90.
“Disintegrants” may be selected from, but not limited to, alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, crospovidone, guar gum, magnesium aluminium silicate, sodium alginate, sodium starch glycolate, starches or combinations thereof. Disintegrants may be used in the range of about 0.1% w/w to about 15% w/w, preferably about 0.5% w/w to about 10% w/w, more preferably about 1% w/w to about 5%w/w of total weight of stable oral pharmaceutical composition. The preferred disintegrating agent is croscarmellose sodium.
“Surfactants” are compounds which are capable of improving the wetting of the drug and/or enhancing the dissolution. The surfactants can be selected from, but not limited to, hydrophilic surfactants or lipophilic surfactants or mixtures thereof. The surfactants can be anionic, nonionic, cationic, and zwitterionic surfactants. Surfactants according to the present invention are selected from, but not limited to, polyoxyethylene alkylaryl ethers, polyethylene glycol (PEG) fatty acid esters; polyoxyethylene sorbitan fatty acid ester such as polysorbate 40, polysorbate 60, polysorbate 80; sorbitan fatty acid mono esters such as sorbitan monolaurate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, polyoxyethylene castor oil derivates such as polyoxyl castor oil, polyoxyl hydrogenated castor oil, sodium lauryl sulfate and the like, used either alone or in combination thereof. Surfactants may be used in the range of about 0.01% w/w to about 15% w/w, preferably about 1% w/w to about 10% w/w, more preferably about 2% w/w to about 5% w/w of total weight of stable oral pharmaceutical composition. The preferred Surfactant is sodium lauryl sulfate.
“Rate-controlling polymers” slows the release of active agent from the dosage form, and extending the release and absorption of active agent. The rate-controlling polymers can be selected from, but not limited to, ethylcellulose, cellulose acetate, Eudragit® E, Eudragit® RS, Eudragit® RL, and Eudragit® NE, chitosan, pectin, glycerin, alginate, polysaccharide or mixtures thereof. The rate-controlling polymers may be used in the range of about 0.1% w/w to about 207% w/w, preferably about 1% w/w to about 15% w/w, more preferably about 2% w/w to about 7% w/w of total weight of stable oral pharmaceutical composition. The preferred rate-controlling polymer insoluble in water at neutral pH. Preferred, the rate-controlling polymer is cellulose acetate and/or pectin or combination thereof. Additionally, release retarding agents (flux enhancer) are added to the release controlling agent to adjust the release rate of active agent. Release retarding agent may be used in range of about 0.01% w/w to about 15% w/w, preferably about 0.1% w/w to about 10% w/w, more preferably about 1% w/w to about 5% w/w of the total weight of the stable oral pharmaceutical composition. The preferred release retarding agent is copovidone.
“Enteric coating polymer” are polymers that delay the release of the active agents until the dosage form has passed through the stomach and into the small intestine. Enteric coating polymers are well known in the art. In general, enteric coating polymers are designed to prevent drug release from an oral solid dosage form in the low pH environment of the stomach, thereby delaying drug release until the dosage form reaches the small intestine. The enteric coating polymers can be selected from, but not limited to shellac (esters of aleurtic acid), cellulose acetate phthalate (CAP), poly(methacrylic acid-co-methyl methacrylate), poly(methacrylic acid-co-ethyl methacrylate), cellulose acetate trimellitate (CAT), poly(vinyl acetate phthalate) (PVAP), hydroxypropyl methylcellulose phthalate (HPMCP) and hydroxypropyl methylcellulose acetate succinates. The preferred enteric polymers release at a pH of greater than or equal to pH 5.5. Examples include Eudragit® L100 or Eudragit® L100-55, Eudragit® L 30 D-55, Eudragit® L 12,5, Eudragit® S 100, Eudragit® S 12,5, Eudragit® S 30 D. The Enteric coating polymer may be used in the range of about 1% w/wto about 20% w/w, preferably about 2% w/w to about 15% w/w, more preferably 3% w/w to about 10% w/w of total weight of stable oral pharmaceutical composition. The preferred enteric coating polymer is Eudragit® L100.
“Lubricants” may be selected from, but not limited to, aluminium stearate, zinc stearate, calcium stearate, magnesium stearate, polyethylene glycol, mineral oil, talc, hydrogenated vegetable oil, stearic acid, magnesium aluminum silicate, sodium stearyl fumarate, glyceryl behenate, sodium benzoate or mixtures thereof. Lubricant may be used in the range of about 0.01% w/w to about 15% w/w, preferably 0.05% w/w to about 10% w/w, more preferably 0.1% w/w to about 5%w/w of total weight of stable oral pharmaceutical composition. The preferred lubricating agent is magnesium stearate.
“Anti-tacking agent” may be selected from, but not limited to, tribasic calcium phosphate, talc, powdered cellulose, magnesium stearate, sodium bicarbonate, magnesium silicate, calcium phosphate, silicon hydrogel or mixtures thereof. Anti-tacking agent may be used in the range of about 0.01 - 10% w/w, preferably about 0.05% w/w to about 5% w/w, more preferably about 0.1% w/w to about 3% w/w of total weight of stable oral pharmaceutical composition. The preferred anti-tacking agent is micronized talc.
“Plasticizers” may be selected from, but not limited to, diethyl phthalate, triethyl citrate, triacetin, tributyl sebecate, glycerin or polyethylene glycol. Plasticizer may be used in the range of about 0.1% w/w to about 10% w/w, preferably about 0.5% w/w to about 7% w/w, more preferably about 1% w/w to about 5% w/w of total weight of stable oral pharmaceutical composition. The preferred plasticizers are glycerin and triethyl citrate.
The compositions in accordance with the present invention can also be prepared by using a granulation method including but not limited to wet granulation or dry granulation and extrusion spheronization, which may comprise rapid mixing granulator, fluid bed drier, and capsule filling machine.
Another aspect of the present invention provides that the compositions comprising carbidopa and levodopa may be packed or stored in the bottle or blister pack or pouch or any corresponding packing known to a person skilled in the art in which the dosage form or the pharmaceutical compositions are packed or stored. In an embodiment of the present invention, carbidopa and levodopa compositions are packed or stored in the bottle or blister pack or pouch which comprises a desiccant. The term "desiccant" as used herein refers to a substance used to remove or suppress or decrease the odor or to absorb moisture which prevents degradation and/or decomposition of the active agent(s). The desiccant may be placed in the internal space of the package containing the composition, in an amount sufficient to remove the odorous material or to suppress or reduce the smell. In one embodiment, the desiccants are selected from, but not limited to, a synthetic zeolite, silica gel, silica-alumina, an active carbon, metallic oxide such as calcium oxide and the like used either alone or in combinations thereof.
An aspect of the present invention provides a stable controlled release pharmaceutical composition comprising levodopa and carbidopa for the treatment of Parkinson’s disease and associated disorders. Another aspect of the present invention further provides a method of using the compositions of present invention comprising therapeutically effective amount of carbidopa and levodopa or a pharmaceutically acceptable salt thereof for the treatment of Parkinson’s disease and associated disorders. It should be appreciated that the invention can be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will convey the scope of the invention to those skilled in the art. Other features and embodiments of the invention will become apparent from the following examples, which are given for illustration of the invention rather than for limiting its intended scope.
The pharmaceutical compositions of the present invention may be prepared by the conventional processes such as wet granulation, extrusion spheronization, coating, milling, sieving, lubricating and filling as known to those skilled in the art.
The following examples are intended to illustrate the scope of the present invention in all its aspects but not to limit it thereto. The composition strengths 35mg/140mg, 45mg/180mg, 52.5mg/210mg, 70mg/280, 87.5mg/350mg, 105mg,420mg, 140mg,560mg and 175mg/700mg are dose proportional to the active and inactive or excipients.
The present invention is illustrated below by reference to the following examples. However, one skilled in the art will appreciate that the specific methods and results discussed are merely illustrative of the invention, and not to be construed as limiting the invention, as many variations thereof are possible without departing from the spirit and scope of the invention.
EXAMPLES
Example 1: Compositions of Carbidopa and Levodopa (Strength: 87.5mg /350mg)
Sr. No. Ingredients mg/ capsule % W/W
A. Immediate release component
1 Carbidopa monohydrate 94.48 15.56
2 Levodopa 70.00 11.54
3 Croscarmellose sodium 9.52 1.57
4 Povidone 4.00 0.66
5 Magnesium stearate 1.00 0.16
B. Controlled release component
B1 Preparation of pellets (Extrusion /Spheronization)
6 Levodopa 280.00 46.12
6 Microcrystalline cellulose 19.04 3.14
7 Mannitol 18.93 3.12
8 Sodium lauryl sulfate 18.90 3.11
9 Povidone 7.30 1.20
10 Purified water Q.s. Q.s.
B2 Release controlling coating
11 Cellulose acetate 8.50 1.40
12 Pectin 18.03 2.97
13 Copovidone 10.40 1.71
14 Talc 1.83 0.30
15 Glycerin 1.83 0.30
16 Acetone Q.s. Q.s.
17 Isopropyl alcohol Q.s. Q.s.
18 Purified water Q.s. Q.s.
B3 Enteric coating
19 Eudragit L 100 29.18 4.81
20 Triethyl citrate 8.30 1.37
21 Talc 4.17 0.68
22 Acetone Q.s. Q.s.
23 Isopropyl alcohol Q.s. Q.s.
B4 Lubrication
24 CR component pellets 426 70.17
25 Magnesium stearate 1.63 0.26
Capsule fill (IR + CR) component 607.04 100.00
Manufacturing Procedure:
A. Preparation of IR component:
1) Povidone was dissolved in water,
2) Carbidopa, levodopa, croscarmellose sodium was charged into rapid mixing granulator and mixed for 10 minutes.
3) Material of step 2 was granulated with binder of step 1 and Carbidopa, levodopa granules were dried in fluidized bed dryer.
4) The above granules were milled and sifted through 20 mesh screen and sifted granules were lubricated with magnesium stearate.
B. Preparation of Controlled release component:
B.1: Preparation of pellets:
1) Povidone was dissolved in water.
2) Levodopa, Mannitol and sodium lauryl sulfate was charged into rapid mixture granulator and mixed for 10 minutes.
3) Materials of step 2 was granulated with binder solution of step 1.
4) Material obtained in step 3 was extruded by 1 mm screen and spheronized using 2 mm Chequered plate and pellets obtained were dried in fluidized bed dryer.
5) The dried pellets were sifted through 14 mesh and 24 mesh sieve.
B.2: Release controlling membrane/layer coating:
6) Pellets of step 5 were loaded in fluidized bed processor.
7) Cellulose acetate and co-povidone were dissolved in acetone and isopropyl alcohol.
8) pellets of step 6 were coated with coating solution of step 7, after target amount of coating solution was sprayed the coated pellets were dried in fluidized bed processor for 15 minutes.
B.3: Pectin coating:
9) Pectin was dissolved in water along with glycerin under continuous stirring for 15 minutes.
10) To the material of step 9, talc was added under stirring and mixing was continued until completely dissolved.
11) Coated pellets obtained in step 8 were loaded in fluidized bed processor and coated with solution obtained in step 10.
12) After target amount of coating solution was sprayed, the coated pellets were dried in the fluidized bed processor for 15 minutes.
B.4: Enteric coating:
13) Eudragit L100 was added to the mixture of acetone and isopropyl alcohol under continuous stirring till material completely dissolved. Triethyl citrate and talc was added to the solution under continuous stirring.
14) Pectin coated pellets of step 12 were loaded in fluidized bed processor and coated with dispersion of step 13.
15) After target amount of coating solution was sprayed, the coated pellets were dried in the fluidized bed processor for 15 minutes.
B.5: Lubrication:
16) The pellets of step 15 were lubricated with magnesium stearate.
C. Capsule filling:
1) IR component pellets of step 4 and controlled release component pellets of step 15 were filled into hard gelatin capsule.
Example 2: Compositions of Carbidopa and Levodopa
Sr. No. Ingredients mg/ capsule % W/W
A. Immediate release component
1 Carbidopa monohydrate 94.48 16.14
2 Levodopa 70.00 11.95
3 Croscarmellose sodium 9.52 1.63
4 Povidone 4.00 0.68
5 Magnesium stearate 1.00 0.17
B. Controlled release component
B1 Preparation of pellets (Extrusion /Spheronization)
6 Levodopa 280.00 47.84
7 Microcrystalline cellulose 19.04 3.25
8 Mannitol 18.93 3.23
9 Sodium lauryl sulfate 18.90 3.23
10 Povidone 7.30 1.25
11 Purified water Q.s. Q.s.
B2 Release controlling coating
12 Cellulose acetate 8.50 1.45
13 Copovidone 10.40 1.78
14 Acetone Q.s. Q.s.
15 Isopropyl alcohol Q.s. Q.s.
B4 Enteric coating
16 Eudragit L 100 29.18 4.99
17 Triethyl citrate 8.30 1.42
18 Talc 4.17 0.71
19 Acetone Q.s. Q.s.
20 Isopropyl alcohol Q.s. Q.s.
B5 Lubrication
21 CR component pellets 406 69.36
22 Magnesium stearate 1.63 0.27
Capsule fill (IR + CR) component 585.35 100.00
Manufacturing procedure:
A. Preparation of Immediate Release (IR) Component:
a) Binder solution: Povidone was dissolved in purified water.
b) Levodopa, Carbidopa, and croscarmellose sodium were charged into rapid mixing granulator and mixed for ten minutes and granulate the mixture using povidone binder solution.
c) Levodopa, Carbidopa, granules were dried in fluid bed drier after that dried granules were milled and shifted through 20 mesh screens.
d) Milled Levodopa, Carbidopa, granules are lubricated with magnesium stearate by blending
e) Lubricated Levodopa, Carbidopa, granules were mixed properly and used for capsule filling.
B. Preparation of Controlled Release (CR) Component:
B1. Preparation of levodopa pellets:
• Binder solution: Povidone was dissolved in purified water.
• Levodopa, mannitol and sodium lauryl sulfate were charged into rapid mixing granulator and mixed for ten minutes and granulate the mixture using povidone binder solution.
• Levodopa granules are extruded by 1.00 mm screen and spheronized using 2.00 mm chequered plate.
• Levodopa pellets were dried in fluid bed drier after that dried levodopa pellets were pass through 14 mesh screen and retained on 24 mesh screen, retained fraction of levodopa pellets used for further coating.
B2. Release controlling membrane /layer coating:
• Levodopa pellets were coated with using cellulose acetate and co-povidone solution in fluidized bed processor and after the specified amount of coating solution sprayed, the coated levodopa pellets were dried in fluidized bed processor for 30 minutes.
B3. Enteric coating
• Acetone and isopropyl alcohol were dispensed at wt. ratio of 80:20 into container and stirred.
• While stirring Eudragit L100 and triethyl citrate was added under continuous stirring and stirred for 15 minutes and afterwards talc was added under stirring and mixing until solution becomes completely dispersed.
• Release controlling layer coated levodopa pellets were loaded into fluidized bed processor and coated with enteric solution (Eudragit L100) and after the specified amount of enteric solution sprayed, the coated levodopa pellets were dried in fluidized bed processor for 20 minutes.
B4. Lubrication:
• Enteric coated levodopa pellets are lubricated with using magnesium stearate.
Encapsulation:
Immediate release component and Controlled release component were filled into 00 size hard gelatin capsule.
Stability Data: Example 1 & Example 2
Example 1 Example 2 Limit %
Related Substances (%) Initial 1 M
40°C /75% 1 M
25°C /60% Initial 1 M
40°C /75% 1 M
25°C /60%
For Carbidopa
Carbidopa Impurity A 0.258 0.147 0.17 0.224 0.216 0.154 NMT 0.5
Carbidopa Impurity B ND ND ND ND ND ND NMT 0.2
Carbidopa Impurity D/E ND ND ND ND ND ND NMT 0.2
Carbidopa Impurity H - - - - - - NMT 0.2
Specified impurity at RRT 1.6 0.212
(RRT 1.61) 0.184 0.222 0.192
(RRT 1.62) 0.225 0.198 NMT 0.8
Any unspecified degradation product - - - - - - NMT 0.2
Total impurities carbidopa 0.508 0.445 0.532 0.446 0.543 0.409 NMT 2.0
For Levodopa
Levodopa Impurity A ND ND ND ND ND ND NMT 0.15
L-Tyrosine 0.021 0.009 0.03 0.019 0.026 0.02 NMT 0.15
Any unspecified degradation product ND ND ND ND ND ND NMT 0.10
Total impurities levodopa 0.021 0.009 0.03 0.019 0.026 0.02 NMT 1.0
Water content (by KF) 2.12 2.39 2.35 2.53 2.24 2.42 NMT 4.0
ND: Not Detected, NMT: Not more than
All the impurity data at initial and 1 Month at 25°C /60% RH and 40°C /75% RH stability were found to be satisfactory.
Dissolution Study:
The composition(s) according to the present invention, the in-vitro release profile of example 1 and example 2 were measured using USP I (Basket)-Basket dissolution apparatus at agitation speed 75 RPM (revolutions per minute) in Simulated gastric fluid (SGF) [pH 1.0] for first 2 hours and followed by in 50mM Phosphate Buffer (pH 7.0) up to 7 hours.
Dissolution Data:
Dissolution medium Time point (min) Example 1 Example 2 Limit Levodopa LD (%)
Initial 1 month
(40°C/75%) 1 month
(25°C/60%) Initial 1 month
(40°C/75%) 1 month
(25°C/60%)
Simulated gastric fluid (SGF) 0 CD LD CD LD CD LD CD LD CD LD CD LD -
30 94 20 99 21 97 20 96 21 97 21 93 20 -
60 94 21 99 21 93 20 96 22 97 22 93 21 -
120 94 25 99 25 92 23 97 24 97 24 93 23 NLT 15 & NMT 40
50mM Phosphate Buffer, pH 7.0 135 - 37 - 37 - 35 - 35 - 36 - 35 -
150 - 48 - 48 - 45 - 46 - 47 - 47 -
180 - 63 - 63 - 62 - 62 - 63 - 63 NLT 52 & NMT 72
210 - 75 - 74 - 72 - 72 - 74 - 73 -
240 - 83 - 82 - 80 - 81 - 83 - 81 -
300 - 94 - 92 - 88 - 91 - 92 - 92 -
360 - 98 - 97 - 92 - 97 - 97 - 96 NLT 80
420 - 100 - 97 - 93 - 99 - 99 - 97 -
NLT: Not less than; NMT: Not more than
Carbidopa (Specifications): NLT 80% in 30 minutes
All the dissolution data at initial and 1 Month timepoints, at 25°C /60% RH and 40°C /75% RH for the stability loaded compositions were found to be satisfactory.
Example 3:
Sr. No. Ingredients Mg/ Capsule %w/w
A. Immediate release component
1 Carbidopa as carbidopa monohydrate 94.48 15.46
2 Levodopa 70.00 11.46
3 Crosscarmellose sodium 9.52 1.56
4 Povidone 8.00 1.31
5 Magnesium stearate 1.000 0.16
Granules weight 183.000 -
B. Controlled release component
Preparation of pellets (Extrusion / Spheronization)
6 Levodopa 280.000 45.83
7 Microcrystalline Cellulose 19.740 3.23
8 Mannitol 18.930 3.10
9 Sodium lauryl sulfate 18.900 3.09
10 Povidone 6.600 1.08
11 Purified water Q.s -
Pellets Weight 344.170 -
Release controlling coating
12 Cellulose acetate 9.4500 1.55
13 Copovidone 9.4500 1.55
14 Acetone Q.s -
15 Isopropyl alcohol Q.s -
Pellets weight 363.070
Pectin coating
16 Pectin 18.030 2.95
17 Talc 1.830 0.30
18 Glycerin 1.830 0.30
19 Purified water Q.s -
Pellets weight 384.760 -
Enteric coating
20 Eudragit L100 29.180 4.78
21 Triethyl citrate 8.300 1.36
22 Talc 4.170 0.68
23 Acetone Q.s -
24 Isopropyl alcohol Q.s -
Wt of CR component (Pellets) 426.410 -
Lubrication - -
25 CR component (Pellets) 426.410 -
26 Magnesium Stearate 1.590 0.26
Wt of lubricated CR pelelts 428.000 -
Capsule Shell Size 00
Capsule Fill Weight (mg) (IR part +CR part) 611.000 100

The capsule composition in example 3 were prepared using manufactured using the manufacturing process as described in example 1.
Stability data: Example 3
Carbidopa and Levodopa ER cap 87.5/350 mg (Test product)
## Parameters
Releated Substances (%) (By HPLC,w/w)
Condition Initial 1 month
(400C/75%) 1 month
(250C/60%)
For Carbidopa
Carbidopa Impurity A 0.258 0.147 0.17
Carbidopa Impurity B ND ND ND
Carbidopa Impurity D/E ND ND ND
Carbidopa Impurity H - - -
Specified impurities at RRT 1.6 0.212
(RRT:1.61) 0.184 0.222
Any unspecified degradation product for Carbidopa
Total impurities of Carbidopa 0.508 0.445 0.532
For Levodopa
Levodopa Impurity A ND ND ND
L-Tyrosine 0.021 0.009 0.03
Any unspecified degradation product for Levodopa ND ND ND
Total Impurities of Levodopa 0.021 0.009 0.03
ND: Not Detected, NMT: Not more than
All the impurity data at initial and 1 Month at 25°C /60% RH and 40°C /75% RH stability were found to be satisfactory.
Dissolution Study: The composition(s) according to the present invention, the in-vitro release profile of example 3 was measured using USP I (Basket) dissolution apparatus.

Dissolution Data:
Carbidopa and Levodopa ER cap 87.5/350 mg (Test product)
Sr No
2 Dissolution (Min) SGF/pH 7.0, 50 mm phosphate buffer
(% Cumulative release)
Condition Initial 1 month
(40oC/75%) 1 month
(25oC/60%)
SGF - CD LD CD LD CD LD
30 94 20 99 21 97 20
60 94 21 99 21 93 20
120 94 25 99 25 92 23
Buffer 135 - 37 - 37 - 35
150 - 48 - 48 - 45
180 - 63 - 63 - 62
210 - 75 - 74 - 72
240 - 83 - 82 - 80
300 - 94 - 92 - 88
360 - 98 - 97 - 92
420 - 100 - 97 - 93
3 Water content (by
KF) 2.12 2.39 2.35
CD: Carbidopa, LD: Levodopa. NLT: Not less than, NMT: Not more than
Carbidopa (Specifications): NLT 80% in 30 minutes
All the dissolution data at initial and 1 Month timepoints, at 25°C /60% RH and 40°C /75% RH for the stability loaded compositions were found to be satisfactory.
Although the inventions herein have been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and application of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described.
All publications, patents, and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated herein by reference.

,CLAIMS:We claim:

1. A stable multiparticulate controlled release oral solid composition comprising: (a) a plurality of controlled release particles comprising: i) a core comprising levodopa, optionally carbidopa, and at least one pharmaceutically acceptable excipient, ii) a layer or coating surrounding the core comprising the release controlling polymer iii) a layer or coating surrounding the release controlling polymer layer, and iv) an enteric coating surrounding the core and the release controlling polymer layers; and b) an immediate release component comprising levodopa, optionally carbidopa.
2. The multiparticulate composition as claimed in claim 1, wherein the controlled release particles are a mini-tablet, bead, pellet, or granule.
3. The multiparticulate composition as claimed in claim 1, wherein the immediate release component is a powder, mini-tablet, bead, pellet, granule, a coating applied to the controlled release particles, or a combination thereof.
4. The multiparticulate composition as claimed in claim 1, wherein the controlled release particles and immediate release component are in a capsule.
5. The multiparticulate composition as claimed in claim 1, wherein the controlled release coating polymers are cellulose acetate and pectin.
6. The multiparticulate composition as claimed in claim 1, wherein the enteric release coating polymer is Eudragit L100.
7. The stable composition as claimed in claim 1, wherein the pellets are manufactured using wet granulation method/extrusion and spheronization process.
8. A multiparticulate controlled release oral solid composition comprising: (a) a plurality of controlled release particles comprising: i) a core comprising levodopa, optionally carbidopa, and at least one pharmaceutically acceptable excipient, ii) a layer or coating surrounding the core comprising the cellulose acetate iii) a layer or coating comprising pectin surrounding the release controlling polymer layer, and iv) an enteric coating comprising eudragit L100 surrounding the core and the release controlling polymer layers; and b) an immediate release component comprising levodopa, optionally carbidopa.
9. A stable multiparticulate controlled release oral solid composition comprising: a) a plurality of controlled release component which comprises: i) a core comprises about 46% w/w levodopa, about 3.2% w/w microcrystalline cellulose, about 3.1% w/w mannitol, about 3.1% w/w sodium lauryl sulfate and about 1.1% w/w povidone K90, optionally carbidopa; ii) a controlled release coating layer surrounding the core comprises about 1.6% w/w cellulose acetate, about 1.6% w/w copovidone; iii) controlled release coating layer surrounding the layer of step ii) comprises about 3% w/w pectin, about 0.3% w/w talc and about 0.3% w/w glycerin; iv) an enteric coating layer surrounding the core and the release controlling polymer layers comprises about 4.8% w/w eudragit L100, about 1.4% w/w triethyl citrate, about 0.7% w/w talc and about 0.3% w/w of magnesium stearate; and (b) an immediate release component which comprises about 11.4% w/w levodopa, about 15.4% w/w carbidopa, about 1.5% croscarmellose sodium, about 1.3% w/w povidone and about 0.2% w/w magnesium stearate.
10. The stable composition as claimed in preceding claims, wherein the composition is indicated for the treatment of Parkinson’s disease.