[go: up one dir, main page]

US20110229566A1 - Single Unit Oral Dose Pharmaceutical Composition Comprising Levodopa, Carbidopa And Entacapone Or Salts Thereof - Google Patents

Single Unit Oral Dose Pharmaceutical Composition Comprising Levodopa, Carbidopa And Entacapone Or Salts Thereof Download PDF

Info

Publication number
US20110229566A1
US20110229566A1 US13/060,180 US200913060180A US2011229566A1 US 20110229566 A1 US20110229566 A1 US 20110229566A1 US 200913060180 A US200913060180 A US 200913060180A US 2011229566 A1 US2011229566 A1 US 2011229566A1
Authority
US
United States
Prior art keywords
entacapone
levodopa
carbidopa
salts
cellulose
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US13/060,180
Other languages
English (en)
Inventor
Yatendra Kumar Gupta
Girish Kumar Jain
Munish Talwar
Manoj Mashalkar
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=41259399&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20110229566(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Individual filed Critical Individual
Publication of US20110229566A1 publication Critical patent/US20110229566A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • a single unit oral dose pharmaceutical composition comprising a) levodopa or salts thereof from about 50 mg to about 300 mg in extended release form, b) carbidopa or salts thereof from about 10 mg to about 100 mg in extended release and c) entacapone or salts thereof from about 100 mg to about 1000 mg in immediate release form, optionally with other pharmaceutically acceptable excipients.
  • the invention also relates to process of preparation of such compositions.
  • Entacapone an inhibitor of catechol-O-methyltransferase (COMT), used in the treatment of Parkinson's disease as an adjunct to levodopa/carbidopa therapy.
  • the chemical name of entacapone is (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide. Its empirical formula is C 14 H 15 N 3 O 5 , and its structural formula is:
  • Carbidopa an inhibitor of aromatic amino acid decarboxylation
  • ( ⁇ )-L-( ⁇ -hydrazino-( ⁇ -methyl- ⁇ -(3,4-dihydroxybenzene) propanoic acid Its empirical formula is C 10 H 14 N 2 O 4 and its structural formula is:
  • Levodopa an aromatic amino acid
  • ( ⁇ )-L- ⁇ -amino- ⁇ -(3,4-dihydroxybenzene) propanoic acid Its empirical formula is C 9 H 11 NO 4 , and its structural formula is:
  • U.S. Pat. Nos. 6,500,867 and 6,797,732 disclose oral solid tablet compositions comprising entacapone, levodopa and carbidopa, or pharmaceutically acceptable salts or hydrates thereof, and a pharmaceutically acceptable excipient.
  • US 20080051459 discloses a method of treating Parkinson's disease comprising administering pharmaceutically effective amount of a composition comprising levodopa.
  • US 20070275060 disclose an extended release tablet comprising an extended release composition comprising levodopa; and an immediate or rapid release composition comprising carbidopa.
  • WO 07/073,702 discloses a multi-layered tablet providing three different release profiles.
  • US 20060173074 disclose a method for the treatment of restless legs syndrome in a mammal.
  • Entacapone is available as immediate release composition under the trade name Comtan®.
  • the marketed strength is 200 mg.
  • the triple combination of levodopa, carbidopa and entacapone is available as immediate release composition in different strengths.
  • Stalevo® 50 (containing 12.5 mg of carbidopa, 50 mg of levodopa and 200 mg of entacapone)
  • Stalevo® 75 (containing 18.75 mg of carbidopa, 75 mg of levodopa and 200 mg of entacapone)
  • Stalevo® 100 containing 25 mg of carbidopa, 100 mg of levodopa and 200 mg of entacapone
  • Stalevo® 125 31.2575 mg of carbidopa, 125 mg of levodopa and 200 mg of entacapone
  • Stalevo® 150 (containing 37.5 mg of carbidopa, 150 mg of levodopa and 200 mg of entacapone)
  • Stalevo® 200 (containing 50 mg of carbidopa, 200 mg of levodopa and 200 mg of ent
  • Parkinson's disease is a slowly progressive disease, in which the symptoms get worse over time. Therefore, the symptoms will change and evolve.
  • the pattern of symptoms can vary for each person. Over a number of years, however, some people may see changes in the way their medication controls their symptoms. These changes are commonly known as motor fluctuations. Over time, symptoms begin to come back before it is time to take next dose of levodopa medication. This change in symptoms is called “wearing-off.” As “wearing-off” becomes more noticeable, the amount of time for a good response to levodopa (known as “on” time) shortens and the time for poor response to levodopa (known as “off” time) may lengthen.
  • the brain In the early stages of the disease, the brain is able to store enough dopamine. This permits smoother release of dopamine in the brain. It also provides a more constant control of symptoms. However, as Parkinson's disease gets worse, the brain has fewer cells that can take up levodopa and store it as dopamine for release when levels are low. Because of this reduced ability to store dopamine in the brain, symptoms may return after shorter periods of time (e.g. “wearing-off”). If someone with a reduced ability to store dopamine is given too much levodopa, it may lead to side effects (e.g. dyskinesia).
  • side effects e.g. dyskinesia
  • dyskinesia e.g. twisting/turning movements
  • dystonia e.g. prolonged muscle cramping
  • the patients treated for Parkinson's disease may frequently develop motor fluctuations characterized by end-of-dose failure, peak dose dyskinesia and akinesia, with levodopa therapy (“wearing off”) in which the patient suffers from unpredictable swings from mobility to immobility. More than 50% of patients with Parkinson's disease develop motor response fluctuations (the “wearing off” phenomenon) after treatment with levodopa therapy.
  • Symptoms of wearing off include bradykinesia, dystonia, tremors, decreased manual dexterity, paresthesia, muscle pain, voice softness.
  • entacapone increases the bioavailability of levodopa by facilitating its passage across the blood-brain barrier.
  • entacapone is approved as an adjunct to levodopa therapy in Parkinson's disease.
  • the dosage of currently available formulation of carbidopa, levodopa and entacapone i.e. Stalevo® is given eight times a day. The frequent dosing of these formulations is associated with more fluctuating plasma entacapone concentrations. Further, this regimen is not patient compliant.
  • a single unit oral dose pharmaceutical composition comprising a) levodopa or salts thereof from about 50 mg to about 300 mg in extended release form, b) carbidopa or salts thereof from about 10 mg to about 100 mg in extended release and c) entacapone or salts thereof from about 100 mg to about 1000 mg in immediate release form, optionally with other pharmaceutically acceptable excipients.
  • a method of reducing the “wearing off” phenomena in Parkinson's patients comprising administering to patient in need thereof, a single unit oral dose pharmaceutical composition comprising a) levodopa or salts thereof from about 50 mg to about 300 mg in extended release form, b) carbidopa or salts thereof from about 10 mg to about 100 mg in extended release and c) entacapone or salts thereof from about 100 mg to about 1000 mg in immediate release form, optionally with other pharmaceutically acceptable excipients.
  • a process for preparing a single unit oral dose pharmaceutical composition comprising a) levodopa or salts thereof from about 50 mg to about 300 mg in extended release form, b) carbidopa or salts thereof from about 10 mg to about 100 mg in extended release and c) entacapone or salts thereof from about 100 mg to about 1000 mg in immediate release form, wherein the said process comprises of: a) coating or mixing levodopa, carbidopa with pharmaceutically acceptable rate controlling polymers; b) entacapone with one or more pharmaceutically acceptable excipients; c) mixing the blend of step a) and b) and converting it into suitable dosage form.
  • Embodiments of the pharmaceutical composition may include one or more of the following features.
  • the pharmaceutically acceptable excipients may include one or more of fillers, binders, lubricants, sweeteners, coloring and flavoring agents, glidants, disintegrants, and the like.
  • Sinemet CR and Comtan can be combined together in a single unit oral dose fixed combination without effecting bioavailability of any one active in presence of other. Even microcrystalline cellulose can also be used in the fixed dose combination without having any destabilizing effect on fixed dose composition. This fixed dose combination further leads to increase in patient compliance.
  • extended release refers to specific release of drug over a specified time period, which may extend from 4 hr to 24 hrs or more.
  • the extended release in the pharmaceutical composition may be achieved by one or more of coating or embedding in matrix using with hydrophilic or hydrophobic polymers or by attachment to ion-exchange resins. Further, extended release may be achieved by osmotic oral release technology also.
  • One tablet of the said composition exhibits no significant difference in rate and/or extent of absorption of entacapone as compared to 2-4 tablets of 200 mg of immediate release entacapone commercially marketed as Comtan® and levodopa and carbidopa as compared to one tablet of Sinemet® CR administered at the interval of 3-4 hours.
  • Bioequivalency is established by a 90% Confidence Interval (CI) of between 0.80 and 1.25 for both C max and AUC under USFDA regulatory guidelines, or a 90% CI for AUC of between 0.80 to 1.25 and a 90% CI for C max of between 0.70 to 1.43 under the European EMEA regulatory guidelines.
  • CI Confidence Interval
  • Confidence interval refers to a statistical range with a specified probability that a given parameter lies within the range.
  • variance refers to plain meaning known to ordinary skill in the art. It is a statistical measure of the variance of two random variables that are observed or measured in the same mean time period. This measure is equal to the product of the deviations of corresponding values of the two variables from their respective means.
  • the extended release pharmaceutical composition may include one or more of tablet, bilayered tablet, trilayered tablet, tablet in tablet, capsule, powder, disc, caplet, granules, pellets, granules in capsule, minitablets, minitablets in capsule, pellets in capsule, sachet and the like.
  • Levodopa, carbidopa or entacapone may be present in the form of powder, granules, pellets, beads, microtablets, minitablets and crystals.
  • the amount of entacapone in these pharmaceutical compositions varies from about 100 mg to about 1000 mg.
  • the amount of levodopa in these pharmaceutical compositions varies from about 50 mg to about 300 mg.
  • the amount of carbidopa in these pharmaceutical compositions varies from about 10 to about 100 mg.
  • Suitable rate controlling hydrophilic or hydrophobic polymers comprise one or more of polyvinyl acetate, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, ethyl cellulose, a fatty acid, a fatty acid ester, an alkyl alcohol, a wax, shellac, rosin, zein (prolamine from corn), povidone, kollidon SR, a poly(meth)acrylate, microcrystalline cellulose or poly(ethylene oxide), polyuronic acid salts, cellulose ethers, xanthan gum, tragacanth gum, gum karaya, guar gum, acacia, gellan gum locust bean gum, alkali metal salts of alginic acid or pectic acid, sodium alginate, potassium alginate, ammonium alginate, hydroxypropyl cellulose, hydroxy ethyl cellulose, hydroxypropyl methyl cellulose, carboxyvinyl polymers, poly
  • the extended release pharmaceutical composition may comprise one or more pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients may include diluents, binders, disintegrants, surfactants, lubricants, glidants and the like.
  • Suitable binder may one or more of, povidone, starch, stearic acid, gums, hydroxypropylmethyl cellulose and the like. Binder may be used from 0.1% to 40% by weight of the composition
  • Suitable diluent may be one or more of, microcrystalline cellulose, mannitol, calcium phosphate, calcium sulfate, kaolin, dry starch, powdered sugar and the like. Diluent may be used from 1 to 50% by weight of the composition.
  • Suitable disintegrant may be one or more of starch, croscarmellose sodium, crospovidone, sodium starch glycolate and the like. Disintegrant may be used from 2-20% by weight of the composition.
  • Suitable lubricant may be one or more of magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil, glyceryl behenate and the like. Lubricant may be used from 0.1-5% by weight of the composition.
  • Suitable glidant may be one or more of colloidal silicon dioxide, talc or cornstarch and the like. Glidant may be used from 0.1-5% by weight of the composition.
  • the pharmaceutical composition may be prepared by mixing entacapone with pharmaceutically acceptable excipients to form an entacapone blend.
  • Levodopa and carbidopa may be mixed with one or more pharmaceutically acceptable polymers and excipients to form levodopa carbidopa blend.
  • the entacapone blend and levodopa-carbidopa blend may be mixed with other pharmaceutically acceptable excipients and converted into suitable dosage form.
  • composition of batches is provided in Table 1 to 23. Following formulations are representatives of the preferred compositions of the invention. The preparation of example is detailed below.
  • composition of the invention Ingredients % w/w Entacapone IR layer/Portion Entacapone 38.41 Mannitol 6.73 Sodium starch glycolate 3.85 Corn Starch 9.42 Croscarmellose sodium 4.62 Povidone 1.51 Purified water q.s. Extragranular Ingredients Magnesium stearate 0.77 Levodopa and Carbidopa CR layer/Portion Levodopa 19.22 Carbidopa 5.19 Microcrystalline Cellulose 4.62 Povidone 3.46 Purified Water q.s. Extragranular Ingredients Poly Vinyl Pyrrolidone 1.73 Magnesium Stearate 0.38
  • Entacapone and mannitol were co-milled and sifted.
  • Cornstarch, croscarmellose sodium and sodium starch glycolate were co-sifted separately.
  • the materials were placed in granulator and mixed.
  • Povidone was dissolved in purified water and granulated with the mixed material.
  • the granulated contents were dried.
  • Magnesium stearate was sifted and mixed with the dried granules.
  • Levodopa, Carbidopa and microcrystalline cellulose were co-sifted and mixed.
  • Povidone was dissolved in Purified water and granulate with above mixed contents. The granulated contents were dried.
  • Magnesium stearate was sifted with polyvinyl pyrrolidone and mixed with the dried granules.
  • Both the entacapone layer/portion and Levodopa and Carbidopa layer/portion were compressed into bilayered tablets or into tablet in tablet with entacapone surrounding the levodopa-carbidopa inlay tablet.
  • Table 2 provides the dissolution data of composition prepared as per formula given in table 1.
  • USP Type 2 Apparatus rpm 50
  • 900 ml of pH 5.5 phosphate buffer at 37° C. ⁇ 0.5° C. was used as medium.
  • USP Type 2 Apparatus rpm 50
  • 900 ml of 0.1 N HCl at 37° C. ⁇ 0.5° C. was used as medium.
  • composition of the invention Ingredients % w/w Entacapone layer/Portion Entacapone 28.57 Mannitol 5.00 Sodium starch glycolate 2.86 Corn Starch 7.00 Croscarmellose sodium 3.43 Povidone 1.14 Purified water q.s. Extragranular Ingredients Magnesium stearate 0.57 Levodopa and Carbidopa CR layer/Portion Levodopa 28.57 Carbidopa 7.71 Microcrystalline Cellulose 6.86 Povidone 5.14 Purified Water q.s. Extragranular Ingredients PVP 2.57 Magnesium Stearate 0.57
  • Entacapone and mannitol were co-milled and sifted.
  • Corn starch, croscarmellose sodium and sodium starch glycolate were co-sifted separately.
  • the materials were placed in granulator and mixed.
  • Povidone was dissolved in purified water and granulated with the mixed material.
  • the granulated contents were dried.
  • Magnesium stearate was sifted and mixed with the dried granules.
  • Levodopa, Carbidopa and microcrystalline cellulose were co-sifted and mixed.
  • Povidone was dissolved in Purified water and granulate with above mixed contents. The granulated contents were dried. Magnesium stearate was sifted with Poly Vinyl Pyrrolidone and mixed with the dried granules.
  • Both the entacapone layer/portion and Levodopa and Carbidopa layer/portion were compressed into bilayered tablets or into tablet in tablet with entacapone surrounding the levodopa-carbidopa inlay tablet.
  • Table 4 provides the dissolution data of composition prepared as per formula given in table 3.
  • USP Type 2 Apparatus rpm 50
  • 900 ml of pH 5.5 phosphate buffer at 37° C. ⁇ 0.5° C. was used as medium.
  • USP Type 2 Apparatus rpm 50
  • 900 ml of 0.1 N HCl at 37° C. ⁇ 0.5° C. was used as medium.
  • composition of the invention Ingredients % w/w Entacapone IR layer/Portion Entacapone 36.36 Mannitol 21.27 Povidone 3.27 Crospovidone 4.36 Magnesium stearate 0.54 Extragranular Ingredients Talc 0.90 Magnesium stearate 0.54 Levodopa and Carbidopa CR layer/Portion Levodopa 18.18 Carbidopa 4.90 Microcrystalline Cellulose 4.36 Povidone 3.27 Purified Water q.s. Extragranular Ingredients PVP 0.16 Magnesium Stearate 0.03
  • Entacapone and mannitol were co-milled and sifted.
  • Povidone, crospovidone and mannitol were co-sifted separately.
  • the materials were mixed to form a bulk.
  • Magnesium stearate was sifted and mixed with the above bulk. This was compacted and crushed.
  • Magnesium stearate and talc were sifted separately and was mixed with the crushed material.
  • Levodopa, Carbidopa and microcrystalline cellulose were co-sifted and mixed.
  • Povidone was dissolved in Purified water and granulate with above mixed contents. The granulated contents were dried. Magnesium stearate was sifted with Poly Vinyl Pyrrolidone and mixed with the dried granules.
  • Both the entacapone layer/portion and Levodopa and Carbidopa layer/portion were compressed into bilayered tablets or into tablet in tablet with entacapone surrounding the levodopa-carbidopa inlay tablet.
  • composition of the invention Ingredients % w/w Entacapone IR layer/Portion Entacapone 27.39 Mannitol 21.27 Povidone 2.47 Crospovidone 3.29 Magnesium stearate 0.41 Extragranular Ingredients Talc 0.68 Magnesium stearate 0.41 Levodopa and Carbidopa CR layer/Portion Levodopa 27.39 Carbidopa 7.39 Microcrystalline Cellulose 6.58 Povidone 4.93 Purified Water q.s. Extragranular Ingredients PVP 2.46 Magnesium Stearate 0.54
  • Entacapone and mannitol were co-milled and sifted.
  • Povidone, crospovidone and mannitol were co-sifted separately.
  • the materials were mixed to form a bulk.
  • Magnesium stearate was sifted and mixed with the above bulk. This was compacted and crushed.
  • Magnesium stearate and talc were sifted separately and was mixed with the crushed material.
  • Levodopa, Carbidopa and microcrystalline cellulose were co-sifted and mixed.
  • Povidone was dissolved in Purified water and granulate with above mixed contents. The granulated contents were dried. Magnesium stearate was sifted with Poly Vinyl Pyrrolidone and mixed with the dried granules.
  • Both the entacapone layer/portion and Levodopa and Carbidopa layer/portion were compressed into bilayered tablets or into tablet in tablet with entacapone surrounding the levodopa-carbidopa inlay tablet.
  • composition of the invention Ingredient % w/w Inner LC-ER core tablet Levodopa 30.77 Carbidopa 8.31 Hydroxy Propyl cellulose 4.62 Mannitol 1.54 Povidone K90 0.46 Isopropyl alcohol 0.00 Dichloromethane 0.00 Magnesium stearate 0.46 Inner ER core tablet Weight External Entacapone IR granules Entacapone 30.77 Mannitol 25 5.38 Sodium starch glycolate 3.08 Croscarmellose sodium 3.69 Corn starch 7.54 Povidone K30 1.23 water 0.00 Sodium starch glycolate 1.54 Magnesium stearate 0.62 External Entacpone IR granules Weight Total Tablet weight
  • step 1 Levodopa, Carbidopa, Hydroxy Propyl cellulose & mannitol were co-sifted and mixed.
  • Povidone K90 was dissolved in Isopropyl alcohol & Dichloromethane.
  • the bulk of step 1 was granulated using step 2 solution and granules were dried.
  • Magnesium stearate was added to prepared granules and lubricated granules were compressed to obtain core tablets.
  • Table 8 provides the dissolution data of composition prepared as per formula given in table 7.
  • USP Type 2 Apparatus rpm 50
  • 900 ml of pH 5.5 phosphate buffer at 37° C. ⁇ 0.5° C. was used as medium.
  • USP Type 2 Apparatus rpm 50
  • 900 ml of 0.1 N HCl at 37° C. ⁇ 0.5° C. was used as medium.
  • Table 9 provides bio profile of LC ER and Entacapone IR combination tablets prepared as per example V under fasting condition versus Reference product Comtan® 200 mg+one tablet of Sinemet CR (Manufacturer: Merck; Levodopa 200+Carbidopa 50 mg ER tablet. Study design include fasting two-way cross-over bioequivalence study in 15 normal, adult, human subjects under fed condition
  • composition of the invention Ingredient % w/w Inner LC ER core tablet Levodopa 30.30 Carbidopa 8.18 Hydroxy Propyl cellulose 4.55 Mannitol 1.97 Methacrylic acid copolymer 1.52 Isopropyl alcohol — Dichloromethane — Magnesium stearate 0.45 External Entacpone IR granules Entacapone 30.30 Mannitol 25 5.30 Sodium starch glycolate 3.03 Croscarmellose sodium 3.64 Corn starch 7.42 Povidone K30 1.21 water — Sodium starch glycolate 1.52 Magnesium stearate 0.61 Total Tablet weight
  • step 1 Levodopa, Carbidopa, Hydroxy Propyl cellulose & mannitol were co-sifted and mixed. Methacrylic acid copolymer was dissolved in Isopropyl alcohol & Dichloromethane. The bulk of step 1 was granulated using step 2 solution and granules were dried. Magnesium stearate was added to the bulk of step 3 and mixed. The bulk of step 4 was granulated using suitable punches to obtain core tablets.
  • Entacapone & mannitol were mixed and milled.
  • Sodium starch glycolate, Croscarmellose sodium, Corn starch were co-sifted and mixed.
  • Povidone K30 in was dissolved in purified water.
  • the bulk of step 7 was granulated using step 8 solution and granules were dried.
  • Sodium starch glycolate was added to the bulk of step 9 and mixed.
  • Magnesium stearate was added to the bulk of step 10 and mixed.
  • Tablet in tablet dosage form was prepared using inner LC ER core tablets & external Entacpone IR granules using suitable compression machine.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Psychology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)
US13/060,180 2008-08-22 2009-08-22 Single Unit Oral Dose Pharmaceutical Composition Comprising Levodopa, Carbidopa And Entacapone Or Salts Thereof Abandoned US20110229566A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
IN1779MU2008 2008-08-22
IN1779/MUM/2008 2008-08-22
PCT/IB2009/053699 WO2010020970A1 (fr) 2008-08-22 2009-08-22 Composition pharmaceutique monodose par voie orale comprenant de la lévodopa, de la carbidopa et de l’entacapone ou leurs sels

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2009/053699 A-371-Of-International WO2010020970A1 (fr) 2008-08-22 2009-08-22 Composition pharmaceutique monodose par voie orale comprenant de la lévodopa, de la carbidopa et de l’entacapone ou leurs sels

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US13/482,258 Continuation US8895065B2 (en) 2008-08-22 2012-05-29 Single unit oral dose pharmaceutical composition comprising levodopa, carbidopa and entacapone or salts thereof

Publications (1)

Publication Number Publication Date
US20110229566A1 true US20110229566A1 (en) 2011-09-22

Family

ID=41259399

Family Applications (2)

Application Number Title Priority Date Filing Date
US13/060,180 Abandoned US20110229566A1 (en) 2008-08-22 2009-08-22 Single Unit Oral Dose Pharmaceutical Composition Comprising Levodopa, Carbidopa And Entacapone Or Salts Thereof
US13/482,258 Expired - Fee Related US8895065B2 (en) 2008-08-22 2012-05-29 Single unit oral dose pharmaceutical composition comprising levodopa, carbidopa and entacapone or salts thereof

Family Applications After (1)

Application Number Title Priority Date Filing Date
US13/482,258 Expired - Fee Related US8895065B2 (en) 2008-08-22 2012-05-29 Single unit oral dose pharmaceutical composition comprising levodopa, carbidopa and entacapone or salts thereof

Country Status (15)

Country Link
US (2) US20110229566A1 (fr)
EP (1) EP2326311B1 (fr)
KR (1) KR20110046555A (fr)
CN (1) CN102170869A (fr)
AU (1) AU2009283814B2 (fr)
BR (1) BRPI0918408A2 (fr)
CA (1) CA2735050C (fr)
ES (1) ES2476792T3 (fr)
IL (1) IL211343A0 (fr)
MX (1) MX2011002016A (fr)
NZ (1) NZ591328A (fr)
RU (1) RU2519159C2 (fr)
UA (1) UA102111C2 (fr)
WO (1) WO2010020970A1 (fr)
ZA (1) ZA201101440B (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5718937B2 (ja) * 2009-12-25 2015-05-13 イノファーマックス インコーポレイテッド パーキンソン病を治療するための医薬組成物及びその調製方法
KR101868326B1 (ko) 2010-03-04 2018-06-19 오리온 코포레이션 파킨슨병의 치료를 위한 레보도파, 카르비도파 및 엔타카폰의 용도
DE102010023828A1 (de) * 2010-06-15 2011-12-15 IIP - Institut für industrielle Pharmazie, Forschungs- und Entwicklungsgesellschaft mbH Pharmazeutisches Präparat, welches Entacapon, Levodopa und Carbidopa enthält
CN102578564A (zh) * 2011-11-01 2012-07-18 江苏江山制药有限公司 速崩直压型颗粒甘露醇制剂的制备方法
US20150140084A1 (en) * 2012-05-21 2015-05-21 Capsugel Belgium Nv Acid resistant banding solution for two piece hard capsules
CN103845317B (zh) * 2012-11-28 2018-05-08 北京生命科学研究所 恩他卡朋在预防或治疗肥胖等代谢综合征中的应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6500867B1 (en) * 1999-06-30 2002-12-31 Orion Corporation Pharmaceutical composition comprising entacapone, levodopa, and carbidopa
US20030161878A1 (en) * 2000-07-11 2003-08-28 Dagmar Jasprova Tablet obtained by direct compression comprising 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid as active ingredient
US20040166159A1 (en) * 2002-05-29 2004-08-26 Chien-Hsuan Han Pharmaceutical dosage forms having immediate and controlled release properties that contain an aromatic amino acid decarboxylase inhibitor and levodopa
WO2008053297A2 (fr) * 2006-10-30 2008-05-08 Wockhardt Research Centre Compositions pharmaceutiques comprenant l'entacapone, la lévodopa, et la carbidopa
US20080118556A1 (en) * 1998-11-02 2008-05-22 Elan Corporation, Plc Modified Release of Compositions Containing a Combination of Carbidopa, Levodopa and Entacapone

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BRPI0620863A8 (pt) * 2005-12-29 2018-01-16 Osmotica Kereskedelmi Es Szolgaltato Kft comprimido em camadas com combinação de liberação tripla
RU2485947C2 (ru) * 2008-02-06 2013-06-27 Вокхардт Рисерч Сентер Фармацевтические композиции энтакапона, леводопы и карбидопы с улучшенной биодоступностью

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080118556A1 (en) * 1998-11-02 2008-05-22 Elan Corporation, Plc Modified Release of Compositions Containing a Combination of Carbidopa, Levodopa and Entacapone
US6500867B1 (en) * 1999-06-30 2002-12-31 Orion Corporation Pharmaceutical composition comprising entacapone, levodopa, and carbidopa
US20030161878A1 (en) * 2000-07-11 2003-08-28 Dagmar Jasprova Tablet obtained by direct compression comprising 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid as active ingredient
US20040166159A1 (en) * 2002-05-29 2004-08-26 Chien-Hsuan Han Pharmaceutical dosage forms having immediate and controlled release properties that contain an aromatic amino acid decarboxylase inhibitor and levodopa
WO2008053297A2 (fr) * 2006-10-30 2008-05-08 Wockhardt Research Centre Compositions pharmaceutiques comprenant l'entacapone, la lévodopa, et la carbidopa

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
AHTILA (Ahtila et al., Effect of Entacapone, a COMT Inhibitor, on the Pharmacokinetics and Metabolism of Levodopa After Administration of Controlled-Release Levodopa-Carbidopa in Volunteers, Clin. Neuropharm. 18 (1995) 46-57). *
PICCINI (Piccini et al., The catechol-O-methyltransferase (COMT) inhibitor entacapone enhances the pharmokinetic and clinical response to Sinemet CT in Parkinson's disease, J. Neurol. Neurosurg. Psychiatry, 68 (2000) 589-594). *
RINNE (Rinne, et al., Entacapone enhances the response to levodopa in parkinsonian patients with motor fluctuations Neurology, 51 (1998) 1309-1314). *

Also Published As

Publication number Publication date
IL211343A0 (en) 2011-05-31
EP2326311B1 (fr) 2014-06-04
CN102170869A (zh) 2011-08-31
BRPI0918408A2 (pt) 2015-11-24
ES2476792T3 (es) 2014-07-15
UA102111C2 (uk) 2013-06-10
CA2735050A1 (fr) 2010-02-25
WO2010020970A1 (fr) 2010-02-25
RU2519159C2 (ru) 2014-06-10
CA2735050C (fr) 2016-07-26
EP2326311A1 (fr) 2011-06-01
AU2009283814B2 (en) 2014-05-01
RU2011110756A (ru) 2012-09-27
US20120231051A1 (en) 2012-09-13
MX2011002016A (es) 2011-05-19
AU2009283814A1 (en) 2010-02-25
KR20110046555A (ko) 2011-05-04
NZ591328A (en) 2012-11-30
ZA201101440B (en) 2012-05-30
US8895065B2 (en) 2014-11-25

Similar Documents

Publication Publication Date Title
US9289392B2 (en) Extended release pharmaceutical composition of entacapone or salts thereof
US20240050394A1 (en) Use of levodopa, carbidopa and entacapone for treating parkinson's disease
KR20210014168A (ko) 글루코키나제 활성화제 및 비구아니드 혈당 저하 약물을 함유하는 약제학적 병용물, 조성물, 및 병용 제제, 및 이의 제조 방법 및 용도
US8895065B2 (en) Single unit oral dose pharmaceutical composition comprising levodopa, carbidopa and entacapone or salts thereof
WO2011151708A1 (fr) Formes posologiques à rétention gastrique d'analogues de gaba
WO2010026467A2 (fr) Forme pharmaceutique à libération prolongée de principe actif hautement soluble
EP3976014A1 (fr) Combinaison comprenant de l'alogliptine et de la metformine
EP2801351B1 (fr) Formulations pharmaceutiques de lacosamide
US20060159751A1 (en) Controlled release pharmaceutical compositions of carbidopa and levodopa
US20090263481A1 (en) Levetiracetam formulations
EP2480234B1 (fr) Composition de ranolazine à libération prolongée
US20070160667A1 (en) Controlled release formulation of divalproex sodium
WO2007081341A1 (fr) Formule à libération contrôlée d'acide divalproïque et ses dérivés
EP1815850A1 (fr) Formulation à libération contrôlée comprenant acide valproique et ses dérivés

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION