US20130137729A1 - Use of levodopa, carbidopa and entacapone for treating parkinson's disease - Google Patents

Use of levodopa, carbidopa and entacapone for treating parkinson's disease Download PDF

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US20130137729A1
US20130137729A1 US13/582,427 US201113582427A US2013137729A1 US 20130137729 A1 US20130137729 A1 US 20130137729A1 US 201113582427 A US201113582427 A US 201113582427A US 2013137729 A1 US2013137729 A1 US 2013137729A1
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carbidopa
dosage form
entacapone
levodopa
proportion
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Juha Rouru
Mikko Kuoppamäki
Juha Ellmen
Pekka Männistö
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Orion Oyj
Kromek Ltd
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    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets

Definitions

  • the present disclosure relates to a method for the treatment of Parkinson's disease as well as to pharmaceutical dosage forms used in said method.
  • Levodopa (( ⁇ )-L-alpha-amino-beta-(3,4-dihydroxybenzene)propanoic acid) is a commonly used drug in the treatment of Parkinson's disease (PD). It is commercially available as a combination with an aromatic amino acid decarboxylase (AADC) inhibitor such as carbidopa (( ⁇ )-L-alpha-hydrazino-alpha-methyl-beta-(3,4-dihydroxybenzene)propionic acid) monohydrate) or benserazide hydrochloride (N-DL-seryl)-N′-(2,3,4-trihydroxy-benzyl)hydrazine hydrochloride).
  • AADC aromatic amino acid decarboxylase
  • levodopa with carbidopa is sold under, for instance, the trademarks SINEMET®, DUODOPA® and PARCOPA® and the combination with benserazide hydrochloride is sold under, for instance, the trademark MADOPAR®.
  • Entacapone (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N-diethyl-2 propenamide) is a catechol-O-methyl transferase (COMT) inhibitor that is used in combination with levodopa and carbidopa or benserazide to treat Parkinson's disease.
  • CCT catechol-O-methyl transferase
  • the proportion of levodopa to carbidopa (when calculated as anhydrate) or benserazide hydrochloride in commercial formulations is 4:1 (or sometimes also 10:1 with carbidopa) by weight and the proportion of entacapone to carbidopa or benserazide hydrochloride, respectively, is at least 4:1 by weight.
  • Tolcapone (3,4-dihydroxy-4′′-methyl-5-nitro-benzophenone) is another COMT inhibitor that is used as a 100 mg or 200 mg stand-alone formulation administered three times daily as an adjunct to the levodopa/carbidopa or levodopa/benserazide treatment, the proportions of levodopa to the AADC inhibitor being the same as those used with entacapone.
  • Tolcapone is sold under trademark TASMAR® and its preparation has been disclosed in EP 0 237 929.
  • WO 2007/013830 discloses several COMT inhibitors including BIA 9-1067 (5-[3-(2,5-dichloro-4,6-dimethyl-1-oxypyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol), which is undergoing clinical evaluation.
  • BIA 9-1067 (5-[3-(2,5-dichloro-4,6-dimethyl-1-oxypyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol), which is undergoing clinical evaluation.
  • WO 2000/37423 discloses BIA 3-201 (1-(3,4-dihydroxy-5-nitrophenyl)-2-phenyl-ethanone, nebicapone).
  • WO 2007/010085 discloses new COMT inhibitor such as (3-chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophen-2-yl)-morpholin-4-yl-methanone, 3-chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carboxylic acid diethylamide, (3-chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophen-2-yl)-piperidin-1-yl-methanone, 3-chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carboxylic acid phenylamide, 3-[(3-chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carbonyl)-amino]-benzoic acid, 4-[(3-chloro-5,6-dihydroxy-7-nitro-benzo[b]thiophene-2-carbonyl)-amin
  • the COMT inhibitors disclosed in WO 2007/010085 as well as BIA 9-1067 are considered to belong to a class of “highly potent COMT inhibitors.”
  • the predicted standard dose (the dose recommended to be used together with the above mentioned conventional proportion of levodopa to carbidopa) for a highly potent COMT inhibitor ranges from 0.1 mg to 50.
  • tolcapone and other such COMT inhibitors are considered to belong to a class of “moderately potent COMT inhibitors.”
  • the present disclosure provides a method for the treatment of Parkinson's disease (PD) comprising simultaneously or sequentially administering to a patient in need of treatment of Parkinson's disease
  • PD Parkinson's disease
  • levodopa in an amount ranging from 50 mg to 300 mg
  • carbidopa in an amount ranging from 25 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor
  • entacapone in an amount ranging from 50 mg to 300 mg
  • the proportion of entacapone to carbidopa ranges from 0.33:1.0 to 3.2:1.0 by weight
  • a moderately potent COMT inhibitor in an amount ranging from 25 mg to 200 mg
  • the proportion of said COMT inhibitor to carbidopa ranges from 0.16:1.0 to 3.08:1.0 by weight
  • a highly potent COMT inhibitor in an amount ranging from 1 mg to 100 mg, wherein the proportion of said COMT inhibitor to carbidopa ranges from 0.006:1.0 to 1.54:1.0 by weight.
  • the present disclosure also provides a dosage form comprising
  • levodopa in an amount ranging from 50 mg to 300 mg
  • carbidopa in an amount ranging from 25 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor
  • entacapone in an amount ranging from 50 mg to 300 mg
  • the proportion of entacapone to carbidopa in said dosage form ranges from 0.33:1.0 to 3.2:1.0 by weight
  • a moderately potent COMT inhibitor in an amount ranging from 25 mg to 200 mg
  • the proportion of said COMT inhibitor to carbidopa in said dosage form ranges from 0.16:1.0 to 3.08:1.0 by weight
  • a highly potent COMT inhibitor in an amount ranging from 1 mg to 100 mg
  • the proportion of said COMT inhibitor to carbidopa in said dosage form ranges from 0.006:1.0 to 1.54:1.0 by weight.
  • Patients that may benefit the most from the invention are those whose Parkinson's disease symptoms or motor complications such as on/off fluctuations have not been adequately controlled with their existing levodopa-AADC inhibitor therapy.
  • a typical patient to be treated is an adult patient with Parkinson's disease having symptoms of end-of-dose wearing off.
  • FIG. 1 shows the mean levodopa plasma concentrations (ng/ml) by study treatments:
  • FIG. 2 shows the mean carbidopa plasma concentrations (ng/ml) by study treatments:
  • FIG. 3 shows mean levodopa concentrations in human with increased carbidopa dose and with increasing COMT-inhibition either by increasing the entacapone dose or by using the moderately potent COMT inhibitor, tolcapone.
  • Parkinson's Disease The most effective therapy for symptom control in Parkinson's Disease is levodopa therapy.
  • PD patients With disease progression and long-term levodopa treatment, PD patients frequently experience motor complications, including wearing-off symptoms such as “end-of-dose wearing off” symptoms, “early morning dystonia” and “on/off fluctuations,” and dyskinesia.
  • a PD patient with “end-of-dose wearing off” or “on/off fluctuations” may experience poor gastrointestinal tract mobility and swallowing difficulties.
  • the wearing-off symptoms may also include non-motor symptoms such as anxiety and pain.
  • non-motor symptoms such as anxiety and pain.
  • the reasons for the fluctuation episodes are not completely understood but may be, in part, related to oscillating plasma levels of levodopa in turn leading to intermittent or pulsatile stimulation of striatial dopamine receptors in the brain.
  • End-of-dose wearing off symptoms or on/off fluctuations comprise alternations between periods of relatively good mobility (“on” periods) and periods of relatively impaired motor function (“off” periods) often associated with simultaneous non-motor symptoms.
  • Dyskinesia are involuntary movements in the body of a PD patient often associated with high maximum or peak concentrations of a PD drug, such as levodopa.
  • AADC inhibition is not saturated by the currently used carbidopa dose, as with levodopa-carbidopa combination alone, but may be further enhanced by increased carbidopa doses, which may lead to improved levodopa pharmacokinetics and metabolism and subsequently may lead to improved control of PD symptoms and motor complications.
  • levodopa/carbidopa ratio such as 4:1
  • increased carbidopa doses may potentiate the pharmacodynamic effect on the AADC inhibition and subsequently may increase levodopa AUC throughout the dosing period despite the decreasing carbidopa plasma concentrations towards the end of said period. This is because by the increased carbidopa dose in the presence of a COMT inhibitor Cmin and AUC of levodopa are significantly increased.
  • the COMT-inhibitor dose can also be reduced without significantly reducing AUC of levodopa. Reducing the amount of COMT-inhibitor would allow a smaller tablet size which would in turn benefit especially patients with swallowing difficulties. This would also be advantageous to reduce the risk of COMT inhibitor related gastrointestinal irritation and urine discoloration.
  • the COMT-inhibitor dose or potency can also be increased to an extent that will not significantly increase Cmax but will increase AUC of levodopa.
  • Increasing the COMT-inhibitor potency would allow better control of PD symptoms. This would be advantageous to PD patients with wearing-off symptoms such as end-of-dose wearing off, early morning dystonia, and on/off fluctuations.
  • the present disclosure provides a method for the treatment of Parkinson's disease comprising simultaneously or sequentially administering to a patient in need of treatment of Parkinson's disease
  • levodopa in an amount ranging from 50 mg to 300 mg
  • carbidopa in an amount ranging from 25 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor
  • entacapone in an amount ranging from 50 mg to 300 mg
  • the proportion of entacapone to carbidopa ranges from 0.33:1.0 to 3.2:1.0 by weight
  • a moderately potent COMT inhibitor in an amount ranging from 25 mg to 200 mg
  • the proportion of said COMT inhibitor to carbidopa ranges from 0.16:1.0 to 3.08:1.0 by weight
  • a highly potent COMT inhibitor in an amount ranging from 1 mg to 100 mg, wherein the proportion of said COMT inhibitor to carbidopa ranges from 0.006:1.0 to 1.54:1.0 by weight.
  • the patient to be treated is an adult patient with Parkinson's disease experiencing symptoms of end-of-dose wearing off.
  • the present disclosure also provides a dosage form comprising
  • levodopa in an amount ranging from 50 mg to 300 mg
  • carbidopa in an amount ranging from 25 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor
  • entacapone in an amount ranging from 50 mg to 300 mg
  • the proportion of entacapone to carbidopa in said dosage form ranges from 0.33:1.0 to 3.2:1.0 by weight
  • a moderately potent COMT inhibitor in an amount ranging from 25 mg to 200 mg
  • the proportion of said COMT inhibitor to carbidopa in said dosage form ranges from 0.16:1.0 to 3.08:1.0 by weight
  • a highly potent COMT inhibitor in an amount ranging from 1 mg to 100 mg
  • the proportion of said COMT inhibitor to carbidopa in said dosage form ranges from 0.006:1.0 to 1.54:1.0 by weight.
  • the present disclosure also provides levodopa, an aromatic amino acid decarboxylase inhibitor, and entacapone for use in a method of treatment of Parkinson's disease by simultaneous or sequential administration to a patient of
  • levodopa in an amount ranging from 50 mg to 300 mg
  • carbidopa in an amount ranging from 25 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor
  • entacapone in an amount ranging from 50 mg to 300 mg
  • the proportion of entacapone to carbidopa ranges from 0.33:1.0 to 3.2:1.0 by weight
  • a moderately potent COMT inhibitor in an amount ranging from 25 mg to 200 mg
  • the proportion of said COMT inhibitor to carbidopa ranges from 0.16:1.0 to 3.08:1.0 by weight
  • a highly potent COMT inhibitor in an amount ranging from 1 mg to 100 mg
  • the proportion of said COMT inhibitor to carbidopa ranges from 0.006:1.0 to 1.54:1.0 by weight, optionally wherein carbidopa is replaced by a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor.
  • the present disclosure also provides use of levodopa, an aromatic amino acid decarboxylase inhibitor, and entacapone in the manufacture of a medicament for the treatment of Parkinson's disease by simultaneous or sequential administration to a patient of (i) levodopa in an amount ranging from 50 mg to 300 mg,
  • carbidopa in an amount ranging from 25 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor
  • entacapone in an amount ranging from 50 mg to 300 mg, wherein the proportion of entacapone to carbidopa ranges from 0.33:1.0 to 3.2:1.0 by weight, a moderately potent COMT inhibitor in an amount ranging from 25 mg to 200 mg, wherein the proportion of said COMT inhibitor to carbidopa ranges from 0.16:1.0 to 3.08:1.0 by weight, or a highly potent COMT inhibitor in an amount ranging from 1 mg to 100 mg, wherein the proportion of said COMT inhibitor to carbidopa ranges from 0.006:1.0 to 1.54:1.0 by weight, optionally wherein carbidopa is replaced by a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor.
  • the present disclosure also provides a dosage form comprising
  • levodopa in an amount ranging from 50 mg to 300 mg
  • carbidopa in an amount ranging from 25 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor
  • entacapone in an amount ranging from 50 mg to 300 mg
  • the proportion of entacapone to carbidopa in said dosage form ranges from 0.33:1.0 to 3.2:1.0 by weight
  • a moderately potent COMT inhibitor in an amount ranging from 25 mg to 200 mg
  • the proportion of said COMT inhibitor to carbidopa in said dosage form ranges from 0.16:1.0 to 3.08:1.0 by weight
  • a highly potent COMT inhibitor in an amount ranging from 1 mg to 100 mg
  • the proportion of said COMT inhibitor to carbidopa in said dosage form ranges from 0.006:1.0 to 1.54:1.0 by weight, for simultaneous or sequential use in the treatment of Parkinson's disease.
  • the present disclosure also provides a kit for simultaneous or sequential administration of levodopa, carbidopa or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor, and entacapone, a moderately potent COMT inhibitor, or a highly potent COMT inhibitor, comprising:
  • levodopa in an amount ranging from 50 mg to 300 mg; (ii) carbidopa in an amount ranging from 25 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor; and (iii) entacapone in an amount ranging from 50 mg to 300 mg, wherein the proportion of entacapone to carbidopa in said administration ranges from 0.33:1.0 to 3.2:1.0 by weight, a moderately potent COMT inhibitor in an amount ranging from 25 mg to 200 mg, wherein the proportion of said COMT inhibitor to carbidopa in said administration ranges from 0.16:1.0 to 3.08:1.0 by weight, or a highly potent COMT inhibitor in an amount ranging from 1 mg to 100 mg, wherein the proportion of said COMT inhibitor to carbidopa in said administration ranges from 0.006:1.0 to 1.54:1.0 by weight, wherein the kit may further comprise instructions for the simultaneous or sequential administration of the levodopa, carbidopa or
  • levodopa is present in an amount ranging from 50 mg to 200 mg
  • carbidopa is present in an amount ranging from 65 mg to 125 mg
  • entacapone is present in an amount ranging from 100 mg to 200 mg, wherein the proportion of entacapone to carbidopa ranges from 0.8:1.0 to 3.08:1.0 by weight.
  • levodopa is present in an amount ranging from 75 mg to 175 mg
  • carbidopa is present in an amount ranging from 65 mg to 105 mg
  • entacapone is present in an amount ranging from 100 mg to 200 mg, wherein the proportion of entacapone to carbidopa ranges from 0.95:1.0 to 3.08:1.0 by weight.
  • levodopa is present in an amount ranging from 50 mg to 300 mg, for instance from 50 mg to 200 mg, such as from 75 mg to 125 mg, for example 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, or 200 mg, for example 75 mg, 100 mg, 125 mg, 150 mg.
  • carbidopa is present in an amount ranging from 65 mg to 150 mg, for instance from 65 mg to 125 mg, such as from 65 mg to 105 mg, for example 65 mg, 80 mg, 85 mg, 105 mg, or 125 mg.
  • entacapone is present in an amount ranging from 50 mg to 300 mg, for instance from 50 mg to 200 mg, such as from 100 mg to 200 mg, for example 100 mg, 150 mg or 200 mg.
  • the moderately potent COMT inhibitor such as tolcapone
  • the highly potent COMT inhibitor such as BIA 9-1067
  • carbidopa is replaced by a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor, such as for instance with benserazide.
  • the treatment and/or the dosage form is oral.
  • the treatment comprises administering orally a solid combination formulation.
  • the oral dosage form is an oral solid combination formulation
  • the proportion of entacapone to carbidopa ranges from 0.33:1.0 to 3.08:1.0 by weight, for instance from 0.8:1.0 to 2.35:1.0 by weight.
  • the proportion of entacapone to carbidopa is 0.66:1.0, 0.80:1.0, 0.95:1.0, 1.18:1.0, 1.33:1.0, 1.54:1.0, 1.6:1.0, 1.9:1.0, 2.35:1.0, 2.5:1.0, or 3.08:1.0 by weight.
  • the proportions of entacapone and carbidopa are 100 mg:125 mg, 100 mg:105 mg, 100 mg:85 mg, 100 mg:80 mg, 100 mg:65 mg, 200 mg:125 mg, 200 mg:105 mg, 200 mg:85 mg, 200 mg:80 mg, 200 mg:65 mg.
  • the proportion of levodopa to carbidopa ranges from 0.4:1.0 to 3.1:1.0 by weight, for instance from 0.48:1.0 to 1.91:1.0 by weight.
  • the proportions of levodopa and carbidopa are 50 mg:45 mg, 50 mg:65 mg, 50 mg:80 mg, 50 mg:85 mg, 50 mg:105 mg, 50 mg:125 mg, 75 mg:45 mg, 75 mg:65 mg, 75 mg:80 mg, 75 mg:85 mg, 75 mg:105 mg, 75 mg:125 mg, 100 mg:45 mg, 100 mg:65 mg, 100 mg:80 mg, 100 mg:85 mg, 100 mg:105 mg, 100 mg:125 mg, 125 mg:45 mg, 125 mg:65 mg, 125 mg:80 mg, 125 mg:85 mg, 125 mg:105 mg, 125 mg:125 mg, 150 mg:45 mg, 150 mg:65 mg, 150 mg:80 mg, 150 mg:85 mg, 150 mg:105 mg, 150 mg:125 mg, 150 mg:80 mg, 150 mg:85 mg, 150 mg:105 mg, 150 mg:125 mg, 200 mg:65 mg, 200 mg:80 mg, 200 mg:85 mg, 200 mg:105 mg, or 200 mg
  • the proportions of levodopa, carbidopa and entacapone are 50 mg:65 mg:200 mg, 50 mg:80 mg:200 mg, 50 mg:85 mg:200 mg, 50 mg:105 mg:200 mg, 50 mg:125 mg:200 mg, 75 mg:65 mg:200 mg, 75 mg:80 mg:200 mg, 75 mg:85 mg:200 mg, 75 mg:105 mg:200 mg, 75 mg:125 mg:200 mg, 100 mg:65 mg:200 mg, 100 mg:80 mg:200 mg, 100 mg:85 mg:200 mg, 100 mg:105 mg:200 mg, 100 mg:125 mg:200 mg, 125 mg:65 mg:200 mg, 125 mg:80 mg:200 mg, 125 mg:85 mg:200 mg, 125 mg:105 mg:200 mg, 125 mg:125 mg:200 mg, 150 mg:65 mg:200 mg, 150 mg:80 mg:200 mg, 150 mg:85 mg:200 mg, 150 mg:105 mg:200 mg, 150 mg:125 mg:200 mg, 150
  • the proportions of levodopa, carbidopa and entacapone are 50 mg:65 mg:200 mg, 50 mg:80 mg:200 mg, 50 mg:85 mg:200 mg, 50 mg:105 mg:200 mg, 75 mg:65 mg:200 mg, 75 mg:80 mg:200 mg, 75 mg:85 mg:200 mg, 75 mg:105 mg:200 mg, 100 mg:65 mg:200 mg, 100 mg:80 mg:200 mg, 100 mg:85 mg:200 mg, 100 mg:105 mg:200 mg, 125 mg:65 mg:200 mg, 125 mg:80 mg:200 mg, 125 mg:85 mg:200 mg, 125 mg:105 mg:200 mg, 150 mg:65 mg:200 mg, 150 mg:80 mg:200 mg, 150 mg:85 mg:200 mg, 150 mg:105 mg:200 mg, 200 mg:65 mg:200 mg, 200 mg:80 mg:200 mg, 200 mg:85 mg:200 mg, or 200 mg:105 mg:200 mg.
  • the proportions of levodopa, carbidopa and entacapone are 75 mg:65 mg:200 mg, 75 mg:85 mg:200 mg, 75 mg:105 mg:200 mg, 100 mg:65 mg:200 mg, 100 mg:85 mg:200 mg, 100 mg:105 mg:200 mg, 125 mg:65 mg:200 mg, 125 mg:85 mg:200 mg, 125 mg:105 mg:200 mg, 150 mg:65 mg:200 mg, 150 mg:85 mg:200 mg, or 150 mg:105 mg:200 mg.
  • the daily dose of levodopa ranges from 150 mg to 1500 mg, for instance from 300 mg to 1250 mg, such as from 300 mg to 900 mg, wherein the total number of daily doses ranges from 3 to 10, for instance from 3 to 7, such as from 4 to 6, such as 4 or 5 or 6.
  • the daily dose of carbidopa ranges from 135 mg to 1250 mg, for instance from 195 mg to 1050 mg, such as form 255 mg to 850 mg, wherein the total number of daily doses ranges from 3 to 10, for instance from 3 to 7, such as from 4 to 6, such as 4 or 5 or 6.
  • the highly potent COMT inhibitor is BIA 9-1067 (5-[3-(2,5-dichloro-4,6-dimethyl-1-oxypyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-3-nitrobenzene-1,2-diol)
  • the daily dose of BIA 9-1067 is 25 mg or 50 mg given once-a-day.
  • BIA 9-1067 is a poorly soluble drug.
  • WO 2009/108077 discloses a solid dosage form for the release of a poorly soluble active pharmaceutical ingredient such as BIA 9-1067.
  • the proportion of BIA 9-1067 to carbidopa ranges from 0.01:1.0 to 0.16:1.0 by weight, for instance from 0.02:1.0 to 0.1:1.0 by weight.
  • the proportions of BIA 9-1067 and carbidopa are 2.5 mg:65 mg, 2.5 mg:85 mg, 2.5 mg:105 mg, 5.0 mg:65 mg, 5.0 mg:85 mg, 5.0 mg:105 mg, 10.0 mg:65 mg, 10.0 mg:85 mg or 10.0 mg:105 mg.
  • the proportions of levodopa, carbidopa and BIA 9-1067 are 75 mg:65 mg:2.5 mg, 75 mg:85 mg:2.5 mg, 75 mg:105:2.5 mg, 100 mg:65 mg:2.5 mg, 100 mg:85 mg:2.5 mg, 100 mg:105 mg:2.5 mg, 125 mg:65 mg:2.5 mg, 125 mg:85 mg:2.5 mg, 125 mg:105 mg:2.5 mg, 150 mg:65 mg:2.5 mg, 150 mg:85 mg:2.5 mg, 150 mg:105 mg:2.5 mg, 75 mg:65 mg:5.0 mg, 75 mg:85 mg:5.0 mg, 75 mg:105:5.0 mg, 100 mg:65 mg:5.0 mg, 100 mg:85 mg: 5.0 mg, 100 mg:105 mg:5.0 mg, 125 mg:65 mg:5.0 mg, 125 mg:85 mg:5.0 mg, 125 mg:105 mg:5.0 mg, 150 mg:65 mg:5.0 mg, 150 mg:85 mg:5.0 mg, 150 mg:65 mg:5.0 mg, 150 mg:85 mg:5.0 mg,
  • the daily dose of entacapone ranges from 150 mg to 2000 mg, for instance from 300 mg to 2000 mg, such as from 300 mg to 1600 mg, wherein the total number of daily doses ranges from 3 to 10, for instance from 3 to 8, such as from 4 to 6, such as 4 or 5 or 6.
  • the daily dose of tolcapone or another moderately potent COMT inhibitor ranges from 75 mg to 1200 mg, for instance from 150 mg to 800 mg, such as from 300 mg to 600 mg, wherein the total number of daily doses ranges from 3 to 10, for instance from 3 to 7, such as from 3 to 5, such as 3 or 4 or 5.
  • the daily dose of a highly potent COMT inhibitor ranges from 1 mg to 500 mg, for instance from 5 mg to 100 mg, such as from 10 mg to 100 mg, wherein the total number of daily doses ranges from 1 to 10, for instance from 1 to 7, such as from 1 to 3, such as 1 or 2 or 3.
  • treatment of Parkinson's Disease refers to relieving and/or delaying of the worsening of one of more of the symptoms and/or motor complications related to idiopathic Parkinson's Disease, e.g. bradykinesia, rigidity, and resting tremor.
  • adult patient means a patient 18 years of age or older.
  • symptoms of end-of-dose wearing-off refers to the shortening of the duration of the motor response after a PD drug intake and increasing the severity of e.g. bradykinesia, rigidity, and resting tremor.
  • the term comprises the so-called predictable end-of-dose motor fluctuations characterised by end-of-dose failure of the symptom control.
  • End-of-dose wearing-off symptoms may also include fluctuating non-motor symptoms, such as anxiety and pain. Motor complications may also include rapid and unpredictable swings from mobility to immobility (“on-off” phenomenon).
  • entacapone may be administered as a separate dosage form and levodopa and carbidopa may be administered in a combination formulation, or carbidopa may be administered, followed by levodopa, then by entacapone.
  • typically administration of the last drug substance is begun an hour or less, generally 30 minutes or less, after administration of the first drug substance is begun.
  • oral solid dosage form refers to a single or multi-unit solid oral dosage form.
  • a single oral dosage form may be a combination formulation, such as a tablet, which comprises two or more of the drug substances.
  • the single oral dosage form is a combination formulation, such as a tablet, which comprises all of the drug substances.
  • a multi-unit solid oral dosage form may be a dosage form comprising a plurality of oral solid units in the form of small particles (for instance a capsule or sachet filled with minitablets, granules or pellets) which, when taken simultaneously or sequentially, provide a unit dose.
  • the terms “multiple-unit” or “multi-particulate” oral dosage form may also be used to refer to such a multi-unit solid oral dosage form.
  • the particles may be also be used as such in a so-called sprinkle form that can be sprinkled directly onto food or liquids for easy ingestion.
  • Multiple-unit dosage forms have been accepted to provide advantages over single unit dosage forms.
  • the pharmacokinetics of the drug release from a multiple unit dosage form is more uniform than from the single unit dosage form, because the pharmacokinetics of the drug release from a multiple unit dosage form is the average value of the kinetics of the drug release from individual subunits.
  • a multi-unit solid oral dosage form may be individual tablets that contain the drug substances.
  • a multi-unit solid oral dosage form can include entacapone in one tablet and a separate tablet containing levodopa and carbidopa.
  • the terms “repeated dose” and “in a repeated manner” refers to multiple administration of a drug during a day, usually from at least 3 up to 10 times a day depending on the severity of the disease of a patient with Parkinson's Disease and on the subsequent need of levodopa.
  • levodopa is usually administered in a repeated manner and simultaneously or sequentially with an AADC inhibitor.
  • a highly potent COMT inhibitor may be administered in combination with repeated dose levodopa and AADC inhibitor only once a day or even less frequently and a moderately potent COMT inhibitor may be administered one to three times per day.
  • the “standard dose” may be used to determine whether a COMT inhibitor may be considered to be a highly potent inhibitor or a moderately potent inhibitor. As potency increases, less inhibitor is required to reach 80% inhibition of soluble COMT in human erythrocytes (Shultz, E. and Nissinen, E., Biomedical Chromatography, Vol. 3, No. 2, 1989, 64-67 and Nohta, H. et al, Journal of Chromatography, 308 (1984) 93-100). For example, a moderately potent COMT inhibitor will require more than 200 mg in a single dose to reach 80% inhibition, typically from more than 200 mg to 800 mg in a single dose.
  • a highly potent inhibitor will need 200 mg or less in a single dose to reach 80% inhibition. A more potent inhibitor will also provide effective inhibition for a longer period of time. Thus, a moderately potent inhibitor when administered in a 200 mg dose will maintain 40% or more effective inhibition of soluble COMT in human erythrocytes for from 2 hours to less than 8 hours, typically from 3 to 6 hours. A highly potent inhibitor when administered in a dose of 100 mg will maintain 40% or more effective inhibition of soluble COMT in human erythrocytes for 8 hours or more. Suitable conditions for measuring effective inhibition of soluble COMT in human erythrocytes are described in Keränen, T. et al, Eur. J. Clin. Pharmcol (1994) 46:151-157 andumblemanse, J. et al, Clinical Pharmacology & Therapeutics, May 1995, 508-517).
  • pharmaceutically acceptable salt refers to a salt of a compound that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • pharmaceutically acceptable salts include, but are not limited to, acid addition salts with inorganic or organic acids, for instance, chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, methane sulfonates, formates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates, acetates, and oxalates.
  • the pharmaceutically acceptable form can be in the form of an anhydrate or a hydrate.
  • prodrug refers to a derivative of a drug substance which releases said active parent drug substance in vivo when such prodrug is administered to a patient.
  • levodopa methyl ester has been under development by Chiesi under trademark LEVOMET®
  • an ethylester has been disclosed in U.S. Pat. No. 5,607,969 and more complex esters have been disclosed in EP 0 309 827 B, WO 2005/121069 and WO 2007/067495.
  • various carbidopa prodrugs have been disclosed e.g. in GB 940,596 and WO 2004/052841.
  • esters refers to an ester of a compound that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • esters may be prepared by known methods using pharmaceutically acceptable acids that are conventional in the field of pharmaceuticals.
  • Non-limiting examples of these esters include esters of aliphatic or aromatic alcohols.
  • Representative examples of pharmaceutically acceptable esters include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and benzyl esters.
  • a therapeutically equivalent amount refers to an amount of an aromatic amino acid decarboxylase inhibitor other than carbidopa that is capable of causing a similar therapeutic response as the dose of carbidopa, when used according to the present disclosure.
  • an aromatic amino acid decarboxylase inhibitor other than carbidopa that is capable of causing a similar therapeutic response as the dose of carbidopa, when used according to the present disclosure.
  • 50 mg of benserazide hydrochloride is considered to be capable of causing a similar therapeutic response as 50 mg of carbidopa, when used according to the present disclosure.
  • substantially separated and substantially separation refer to that a considerable or ample amount of said drug substance is kept apart from the other drug substance(s), for example, that a considerable amount of carbidopa is kept apart from entacapone.
  • separation may be several ways to accomplish said separation, for example, by granulating all or at least one of the drug substances separately. No specific separation layer is needed to cause said substantial separation. It is also to be noted that even though all drug substances would be granulated separately, there will always be small amounts of said drug substance as a powder. In one embodiment, before granulating and incorporating a drug substance in a single dosage unit with other drug substances, they may undergo pre-processing in a manner indicated below.
  • substantially portion refers to that at least 80% of said drug substance is handled using the technology in question. For instance, granulating a substantial portion of carbidopa means that from 80% to 100% is granulated. If 90% is granulated, then 10% is added as such.
  • granule refers to a pharmaceutical formulation whereby the ingredients have been mixed together in order to intimately and evenly disperse the drug substance(s) within some or all of the other ingredients and to increase the particle size.
  • Well known techniques are known in the pharmaceutical industry and can be selected from wet, melt granulation or dry granulation.
  • the terms “granulating” and “granulation” refer to methods, wherein one or more drug substances are brought into contact with at least one pharmaceutically acceptable excipient and granulated.
  • the granulation method may be any granulation method known in the art such as dry granulation, melt granulation or wet granulation or the like. All unit operations typically needed to perform granulation, such as sieving and drying are meant to be included in said granulation step in the context of this disclosure.
  • the drug substances to be used in the granulation method may be pre-processed before the granulation. Pre-processing may also generally be applied to drug substances before formulating into a dosage form without granulation. For example, a drug substance in the form of a powder may be pre-processed before formulation into a dosage form.
  • pre-processed and “pre-processing” refer to pre-treatment of each of the drug substances, either individually or together with another drug substance, before further processing, such as before granulation or before formulating a powder into a dosage form.
  • Suitable pre-processing methods can be, for example, sieving, de-dusting, gas treatment, conditioning, milling and optionally mixing, de-aggregation, de-agglomeration or treatment with pharmaceutically acceptable excipients, for example, with glidants such as colloidal silicon dioxide.
  • mixing and “preparing a mixture” refer to the meaning used in the art of manufacturing pharmaceutical dosage forms' Suitable mixing technologies have been described, for example in the above mentioned handbooks.
  • bilayered tablet refers to a tablet, wherein there are two layers horizontally on the top of each other or there is an inner core comprising either one or two of the drug substances and an outer layer comprising at least one drug substance.
  • an outer layer comprising carbidopa and levodopa or carbidopa alone and an inner core comprising entacapone and levodopa or entacapone alone.
  • carbidopa may be divided between the outer layer and the inner core.
  • trilayered tablet and “multilayered” tablets refer to tablets
  • inert layers e.g. layers prepared without separately adding a drug substance
  • inert inner core for instance, a non-pareil inside the tablet.
  • minitablet refers to a compressed pharmaceutical formulation that has dimensions of length and breadth (or, depending on its shape, a diameter) each equal to or less than 5 mm.
  • pellet refers to a substantially spherical solid particle whose diameter size may range from about 100 microns to about 3 mm that has been made by layering onto a particle (for instance, on a non-pareil) or extrusion optionally followed by spheronisation or other similar known techniques. Generally pellets are more spherical in appearance than mini-tablets.
  • immediate release refers to a pharmaceutical dosage form which releases levodopa immediately upon administration and will result in 80-100%, preferably 90-100% dissolution of the dose amount within one hour.
  • Dissolution method USP apparatus I: 50 rpm; medium: 0.1 N hydrochloric acid, 750 ml.
  • the pharmaceutical dosage forms of the present invention can be present in the form of monolayered or multilayered (for instance, bilayered or trilayered tablets), minitablets, capsules, granules, pellets, or minitablets, granules, pellets or a combination of the same in a capsule or the like.
  • One way to prepare a dosage form according to the invention is to first formulate carbidopa substantially separately from entacapone and levodopa before formulating into the dosage form, for example, in the manner disclosed in U.S. Pat. No. 6,500,867 describing fixed oral combinations of entacapone, levodopa and carbidopa, wherein carbidopa is substantially separated from entacapone and levodopa.
  • Another way is to first formulate entacapone substantially separately from levodopa and carbidopa before formulating into the dosage form.
  • One particular such way is to use separate entacapone-containing granules or granule mixtures, for example using the technologies disclosed in WO 2006/131591, and combine said granules or granule mixtures with levodopa and AADC inhibitor either in a fixed combination formulation or as two separate dosage forms.
  • a further way of preparing dosage forms according to the invention is to first formulate part of the levodopa content with entacapone and a further part of the levodopa content with carbidopa, before formulating into the dosage form optionally together with a further part of the levodopa content added as such.
  • a yet further way is to prepare a mixture of levodopa, carbidopa and entacapone, of which any part may optionally be pre-processed, before formulating into the dosage form.
  • entacapone and carbidopa are substantially separated from each other.
  • separation can be made, for instance, by granulating levodopa and entacapone together or separately and adding carbidopa as such (i.e. non-granulated carbidopa, for example, in powder form) and/or as granules; or by granulating levodopa and carbidopa and adding entacapone as such (i.e. non-granulated entacapone, for example, in powder form) or in the form of granules.
  • any known granulation method for example, wet granulation, melt granulation and dry granulation can be used, but preferably the granulation method is wet granulation.
  • Suitable granulation methods are known in the art and suitable excipients are listed in, for instance in WO 2006/131591.
  • levodopa in an amount ranging from 50 mg to 200 mg, (ii) carbidopa in an amount ranging from 65 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor, and (iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein the proportion of entacapone to carbidopa in said dosage form ranges from 0.66:1.0 to 3.08:1.0 by weight, is provided comprising (a) granulating substantial portion of entacapone and substantial portion of levodopa either together or separately (b) optionally granulating all or any portion of carbidopa (c) combining the product obtained in step (a) with the product of step (b) or carbidopa as such or a mixture thereof; and (d) formulating the product obtained in step (c) as well as the rest of entacapone and/or levodopa, if any, into tablets or minitablets or filling the
  • levodopa in an amount ranging from 50 mg to 200 mg
  • carbidopa in an amount ranging from 65 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor
  • entacapone in an amount ranging from 100 mg to 200 mg
  • the proportion of entacapone to carbidopa in said dosage form ranges from 0.66:1.0 to 3.08:1.0 by weight, is provided comprising (a) granulating entacapone and levodopa either together or separately (b) granulating carbidopa
  • levodopa in an amount ranging from 50 mg to 200 mg
  • carbidopa in an amount ranging from 65 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor
  • entacapone in an amount ranging from 100 mg to 200 mg
  • the proportion of entacapone to carbidopa in said dosage form ranges from 0.66:1.0 to 3.08:1.0 by weight, is provided comprising (a) granulating entacapone and levodopa either together or separately (b) granulating from 5 to 80% of carbidopa
  • c) combining the product obtained in step (a) with the product of step (b) and the rest of carbidopa as such; and (d) formulating the product obtained in step (c) into tablets or minitablets or filling the same directly into capsules, sachets or a dispenser.
  • levodopa in an amount ranging from 50 mg to 200 mg
  • carbidopa in an amount ranging from 65 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor
  • entacapone in an amount ranging from 100 mg to 200 mg
  • the proportion of entacapone to carbidopa in said dosage form ranges from 0.66:1.0 to 3.08:1.0 by weight, is provided comprising (a) granulating entacapone and levodopa either together or separately (b) granulating from 5 to 40% of carbidopa
  • c) combining the product obtained in step (a) with the product of step (b) and the rest carbidopa as such; and (d) formulating the product obtained in step (c) into tablets or minitablets or filling the same directly into capsules, sachets or a dispenser.
  • levodopa in an amount ranging from 50 mg to 200 mg
  • carbidopa in an amount ranging from 65 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor
  • entacapone in an amount ranging from 100 mg to 200 mg, wherein the proportion of entacapone to carbidopa in said dosage form ranges from 0.66:1.0 to 3.08:1.0 by weight, is provided comprising (a) granulating entacapone and levodopa either together or separately (b) granulating from 15 to 20% of carbidopa (c) combining the product obtained in step (a) with the product of step (b) and the rest carbidopa as such; and (d) formulating the product obtained in step (c) into tablets or minitablets or filling the same directly into capsules, sachets or a dispenser.
  • levodopa in an amount ranging from 50 mg to 200 mg
  • carbidopa in an amount ranging from 65 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor
  • entacapone in an amount ranging from 100 mg to 200 mg
  • the proportion of entacapone to carbidopa in said dosage form ranges from 0.66:1.0 to 3.08:1.0 by weight, is provided comprising (a) granulating entacapone and levodopa either together or separately (b) combining the product obtained in step (a) with carbidopa as such; and (c) formulating the product obtained in step (c) into tablets.
  • This method provides a simple manufacturing process and a good stability for the product.
  • levodopa in an amount ranging from 50 mg to 200 mg, (ii) carbidopa in an amount ranging from 65 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor, and (iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein the proportion of entacapone to carbidopa in said dosage form ranges from 0.66:1.0 to 3.08:1.0 by weight, is provided comprising (a) formulating a substantial portion of entacapone and a substantial portion of levodopa either together or independently into granules, minitablets or pellets (b) formulating a substantial portion of carbidopa into granules, minitablets or pellets; and (c) combining the product obtained in step (a) with the product of step (b) and the rest of the drug substances if any, and filling it into capsules, sachets or a dispenser.
  • levodopa in an amount ranging from 50 mg to 200 mg, (ii) carbidopa in an amount ranging from 65 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor, and (iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein the proportion of entacapone to carbidopa in said dosage form ranges from 0.66:1.0 to 3.08:1.0 by weight, is provided comprising (a) formulating a substantial portion of entacapone and a substantial portion of levodopa either together or independently into granules, minitablets or pellets (b) formulating a substantial portion of carbidopa into granules, minitablets or pellets; and (c) formulating the product obtained in step (a) and product of step (b) and the rest of the drug substances, if any, into a monolayered, bilayered, threelayered or a multilayered tablet.
  • levodopa in an amount ranging from 50 mg to 200 mg, (ii) carbidopa in an amount ranging from 65 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor, and (iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein the proportion of entacapone to carbidopa in said dosage form ranges from 0.66:1.0 to 3.08:1.0 by weight, is provided comprising (a) granulating substantial portion of levodopa and substantial portion of carbidopa either together or separately (b) optionally granulating all or any portion of entacapone (c) combining the product obtained in step a) with the product obtained in step (b), or entacapone as such or a mixture thereof; and (d) formulating the product obtained in step (c) an the rest of levodopa and/or carbidopa, if any, into tablets or minitablets or filling the same
  • levodopa in an amount ranging from 50 mg to 200 mg, (ii) carbidopa in an amount ranging from 65 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor, and (iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein the proportion of entacapone to carbidopa in said dosage form ranges from 0.66:1.0 to 3.08:1.0 by weight, is provided comprising (a) granulating levodopa and carbidopa either together or separately (b) granulating entacapone (c) combining the product obtained in step a) with the product obtained in step (b); and (d) formulating the product obtained in step (c) into tablets or minitablets or filling it or said minitablets into capsules, sachets or a dispenser.
  • levodopa and carbidopa are granulated together.
  • levodopa in an amount ranging from 50 mg to 200 mg
  • carbidopa in an amount ranging from 65 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor
  • entacapone in an amount ranging from 100 mg to 200 mg, wherein the proportion of entacapone to carbidopa in said dosage form ranges from 0.66:1.0 to 3.08:1.0 by weight, is provided comprising (a) granulating levodopa and carbidopa either together or separately (b) granulating from 5 to 100% of entacapone (c) combining the product obtained in step a) with the product obtained in step (b); and the rest of entacapone as such; and (d) formulating the product obtained in step (c) into tablets or minitablets or filling the same directly into capsules, sachets or a dispenser.
  • levodopa in an amount ranging from 50 mg to 200 mg
  • carbidopa in an amount ranging from 65 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor
  • entacapone in an amount ranging from 100 mg to 200 mg, wherein the proportion of entacapone to carbidopa in said dosage form ranges from 0.66:1.0 to 3.08:1.0 by weight, is provided comprising (a) granulating levodopa and carbidopa either together or separately (b) granulating from 10 to 75% of entacapone (c) combining the product obtained in step a) with the product obtained in step (b); and the rest of entacapone as such; and (d) formulating the product obtained in step (c) into tablets or minitablets or filling the same directly into capsules, sachets or a dispenser.
  • levodopa in an amount ranging from 50 mg to 200 mg
  • carbidopa in an amount ranging from 65 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor
  • entacapone in an amount ranging from 100 mg to 200 mg, wherein the proportion of entacapone to carbidopa in said dosage form ranges from 0.66:1.0 to 3.08:1.0 by weight, is provided comprising (a) granulating levodopa and carbidopa either together or separately (b) granulating from 15 to 50% of entacapone (c) combining the product obtained in step a) with the product obtained in step (b); and the rest of entacapone as such; and (d) formulating the product obtained in step (c) into tablets or minitablets or filling the same directly into capsules, sachets or a dispenser.
  • levodopa in an amount ranging from 50 mg to 200 mg
  • carbidopa in an amount ranging from 65 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor
  • entacapone in an amount ranging from 100 mg to 200 mg, wherein the proportion of entacapone to carbidopa in said dosage form ranges from 0.66:1.0 to 3.08:1.0 by weight, is provided comprising (a) granulating levodopa and carbidopa either together or separately (b) combining the product obtained in step (a) with entacapone as such; and (c) formulating the product obtained in step (b) into tablets or minitablets.
  • levodopa in an amount ranging from 50 mg to 200 mg
  • carbidopa in an amount ranging from 65 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor
  • entacapone in an amount ranging from 100 mg to 200 mg
  • the proportion of entacapone to carbidopa in said dosage form ranges from 0.66:1.0 to 3.08:1.0 by weight, is (a) formulating carbidopa and levodopa either together or independently into granules, minitablets or pellets
  • levodopa and carbidopa are formulated together.
  • WO 2010/108845 disclosing a dosage form comprising a) a first mixture of 10 to 75% by weight of the total amount of levodopa with all entacapone present in the composition and b) a second mixture of 25 to 90% by weight of total levodopa with all carbidopa present in the composition and c) optionally, a third mixture comprising the remaining levodopa, if any.
  • the two mixtures a) and b) are prepared such that they are not both in powder form.
  • the same principles, manufacturing processes and excipients as disclosed in WO 2010/108845 may be used to prepare the dosage form also according to the present invention.
  • a method for the preparation of a oral solid dosage form comprising
  • levodopa in an amount ranging from 50 mg to 200 mg, (ii) carbidopa in an amount ranging from 65 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor, and (iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein the proportion of entacapone to carbidopa in said dosage form ranges from 0.66:1.0 to 3.08:1.0 by weight, is provided comprising a) preparing a first mixture of 10 to 75% by weight of the total amount of levodopa with all entacapone present in the composition, b) preparing a second mixture of 25 to 90% by weight of total levodopa with all carbidopa present in the composition; and c) optionally preparing a third mixture comprising the remaining levodopa; and d) formulating the products obtained in steps (a) and (b) and optionally (c) independently into granules, tablets, minitable
  • levodopa in an amount ranging from 50 mg to 200 mg, (ii) carbidopa in an amount ranging from 65 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor, and (iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein the proportion of entacapone to carbidopa in said dosage form ranges from 0.66:1.0 to 3.08:1.0 by weight, is provided comprising a) granulating from 10 to 75% by weight of the total amount of levodopa with all entacapone present in the composition, b) granulating from 25 to 90% by weight of total levodopa with all carbidopa present in the composition; and c) optionally preparing a third mixture comprising the remaining levodopa; and d) formulating the products obtained in steps (a) and (b) and (c) if any into tablets or minitablets and optionally filling the said
  • levodopa in an amount ranging from 50 mg to 200 mg, (ii) carbidopa in an amount ranging from 65 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor, and (iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein the proportion of entacapone to carbidopa in said dosage form ranges from 0.66:1.0 to 3.08:1.0 by weight, is provided comprising a) preparing a first mixture of 30 to 90% by weight of the total amount of levodopa with all entacapone present in the composition, b) preparing a second mixture of 10 to 70% by weight of total levodopa with all carbidopa present in the composition; and c) optionally preparing a third mixture comprising the remaining levodopa; and d) formulating the products obtained in steps (a) and (b) and optionally (c) independently into granules, tablets, minitablet
  • levodopa in an amount ranging from 50 mg to 200 mg, (ii) carbidopa in an amount ranging from 65 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor, and (iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein the proportion of entacapone to carbidopa in said dosage form ranges from 0.66:1.0 to 3.08:1.0 by weight, is provided comprising a) preparing a first mixture of 50 to 80% by weight of the total amount of levodopa with all entacapone present in the composition, b) preparing a second mixture of 20 to 50% by weight of total levodopa with all carbidopa present in the composition; and c) optionally preparing a third mixture comprising the remaining levodopa; and d) formulating the products obtained in steps (a) and (b) and optionally (c) independently into granules, tablets, minitable
  • levodopa in an amount ranging from 50 mg to 200 mg, (ii) carbidopa in an amount ranging from 65 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor, and (iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein the proportion of entacapone to carbidopa in said dosage form ranges from 0.66:1.0 to 3.08:1.0 by weight, is provided comprising a) granulating 30 to 90% by weight of the total amount of levodopa with all entacapone present in the composition, b) granulating of 10 to 70% by weight of total levodopa with all carbidopa present in the composition; and c) optionally preparing a third mixture comprising the remaining levodopa; and d) formulating the products obtained in steps (a) and (b) and (c) if any, into tablets or minitablets and optionally filling the said gran
  • levodopa in an amount ranging from 50 mg to 200 mg, (ii) carbidopa in an amount ranging from 65 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor, and (iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein the proportion of entacapone to carbidopa in said dosage form ranges from 0.66:1.0 to 3.08:1.0 by weight, is provided comprising a) granulating 50 to 80% by weight of the total amount of levodopa with all entacapone present in the composition, b) granulating of 20 to 50% by weight of total levodopa with all carbidopa present in the composition; and c) optionally preparing a third mixture comprising the remaining levodopa; and d) formulating the products obtained in steps (a) and (b) and (c) if any, into tablets or minitablets and optionally filling the said
  • levodopa in an amount ranging from 50 mg to 200 mg
  • carbidopa in an amount ranging from 65 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor
  • entacapone in an amount ranging from 100 mg to 200 mg, wherein the proportion of entacapone to carbidopa in said dosage form ranges from 0.66:1.0 to 3.08:1.0 by weight, is provided comprising (a) preparing a mixture of optionally pre-processed levodopa, optionally pre-processed carbidopa and optionally pre-processed entacapone, (b) formulating the product obtained in step (a) into granules, tablets, minitablets, pellets and optionally filling said granules, minitablets or pellets into a capsule, sachet or a dispenser.
  • levodopa in an amount ranging from 50 mg to 200 mg
  • carbidopa in an amount ranging from 65 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor
  • entacapone in an amount ranging from 100 mg to 200 mg, wherein the proportion of entacapone to carbidopa in said dosage form ranges from 0.66:1.0 to 3.08:1.0 by weight, is provided comprising (a) preparing a mixture of optionally pre-processed levodopa, optionally pre-processed carbidopa and optionally pre-processed entacapone, (b) compressing the product obtained in step (a) into tablets.
  • This method provides a simple and robust manufacturing process, wherein also non-micronized drug substances (for instance, medium sized or coarse entacapone) may be used.
  • levodopa in an amount ranging from 50 mg to 200 mg
  • carbidopa in an amount ranging from 65 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor
  • entacapone in an amount ranging from 100 mg to 200 mg
  • the proportion of entacapone to carbidopa in said dosage form ranges from 0.66:1.0 to 3.08:1.0 by weight, allowing 80-100% of levodopa to be released within one hour in a dissolution test (USP apparatus I (baskets) 50 rpm, medium: 0.1N hydrochloric acid, volume 750 ml) from said dosage form.
  • levodopa in an amount ranging from 50 mg to 200 mg
  • carbidopa in an amount ranging from 65 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor
  • entacapone in an amount ranging from 100 mg to 200 mg
  • the proportion of entacapone to carbidopa in said dosage form ranges from 0.66:1.0 to 3.08:1.0 by weight, allowing from 90 to 100% of levodopa to be released within one hour in a dissolution test (USP apparatus I (baskets) 50 rpm, medium: 0.1N hydrochloric acid, volume 750 ml) from said dosage form.
  • levodopa in an amount ranging from 50 mg to 200 mg
  • carbidopa in an amount ranging from 65 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor
  • entacapone in an amount ranging from 100 mg to 200 mg
  • the proportion of entacapone to carbidopa in said dosage form ranges from 0.66:1.0 to 3.08:1.0 by weight, allowing from 20 to 100% of carbidopa to be released within one hour in a dissolution test (USP apparatus I (baskets) 50 rpm, medium: 0.1N hydrochloric acid, volume 750 ml) from said dosage form.
  • levodopa in an amount ranging from 50 mg to 200 mg
  • carbidopa in an amount ranging from 65 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor
  • entacapone in an amount ranging from 100 mg to 200 mg
  • the proportion of entacapone to carbidopa in said dosage form ranges from 0.66:1.0 to 3.08:1.0 by weight, allowing from 40 to 100% of carbidopa to be released within one hour in a dissolution test (USP apparatus I (baskets) 50 rpm, medium: 0.1N hydrochloric acid, volume 750 ml) from said dosage form.
  • levodopa in an amount ranging from 50 mg to 200 mg
  • carbidopa in an amount ranging from 65 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor
  • entacapone in an amount ranging from 100 mg to 200 mg
  • the proportion of entacapone to carbidopa in said dosage form ranges from 0.66:1.0 to 3.08:1.0 by weight, allowing from 20 to 100% of entacapone to be released within 60 minutes in a dissolution test (USP apparatus I (baskets) 125 rpm, medium: phosphate buffer pH 5.5, volume 900 ml) from said dosage form.
  • levodopa in an amount ranging from 50 mg to 200 mg
  • carbidopa in an amount ranging from 65 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor
  • entacapone in an amount ranging from 100 mg to 200 mg
  • the proportion of entacapone to carbidopa in said dosage form ranges from 0.66:1.0 to 3.08:1.0 by weight, allowing from 40 to 100% of entacapone to be released within 60 minutes in a dissolution test (USP apparatus I (baskets) 125 rpm, medium: phosphate buffer pH 5.5, volume 900 ml) from said dosage form.
  • the dosage form according to the invention may include, for instance one or more of fillers, binders, disintegrants, solubility enhancers, glidants, lubricants (if applicable, for example, if tabletting) as well as other pharmaceutical excipients.
  • the maximum amount of excipients is typically from 50 to 60% by weight of the dosage form.
  • the amounts of the excipients depend on the choice of technology in question and whether the same technology, for example, granulation is used to formulate all drug substances.
  • the amount of the binder is typically from about 0.1% by weight to about 50% by weight of the total weight of the dosage form.
  • the amount of disintegrant is typically from about 1% by weight to about 30% by weight of the total weight of the dosage form.
  • a typical amount of a solubility enhancer is from about 1% by-weight to about 40% by weight of the total weight of the dosage form.
  • a typical amount of a diluent or filler is from about 1% by weight to about 60% by weight of the total weight of the dosage form.
  • a typical amount of a glidant is from about 0.1% by weight to about 20% by weight of the total weight of the dosage form.
  • a typical amount of a lubricant is from about 0.1% by weight to about 10% by weight of the total weight of the dosage form.
  • a typical amount of a release rate controlling excipient is from about 0.1% by weight to about 60% by weight of the total weight of the dosage form.
  • a typical amount of a co-processed excipient is from about 1% by weight to about 60% by weight of the total weight of the dosage form.
  • the dosage form according to the invention comprises a diluents or a filler which may be used e.g. as a processing aid.
  • the diluents or filler may be, for instance one or more of calcium carbonate (Barcroft, Cal-Carb, CalciPure, Destab, MagGran, Millicarb, Pharma-Carb, Precarb, Sturcal, Vivapres Ca), calcium phosphate, dibasic anhydrous (A-TAB, Di-Cafos A-N, Emcompress Anhydrous, Fujicalin), calcium phosphate, dibasic dihydrate (Cafos, Calipharm, Calstar, Di-Cafos, Emcompress), calcium phosphate tribasic (Tri-Cafos, TRI-CAL WG, TRI-TAB), calcium sulphate (Destab, Drierite, Snow White, Cal-Tab, Compactrol, USG Terra Alba), cellulose powdered (Arbocel, Elce
  • the dosage form of the invention comprises a binder.
  • the binder may be, for instance one or more of following: acacia, alginic acid (Kelacid, Protacid, Satialgine H8), carbomer (Acritamer, Carbopol, Pemulen, Ultrez), carboxymethylcellulose sodium (Akucell, Aquasorb, Blanose, Finnfix, Nymcel, Tylose), ceratonia (Meyprofleur), cottonseed oil, dextrin (Avedex, Caloreen, Crystal Gum, Primogran W), dextrose (Caridex, Dextrofm, Lycedex PF, Roferose, Tabfine D-IOO), gelatin (Cryogel, Instagel, Solugel), guar gum (Galactosol, Meprogat, Meyprodor, Meyprofm, Meyproguar), hydrogenated vegetable oil type I (Akofine, Lubritab, Sterotex, Dynasan P60,
  • the binder is a binder suitable for use in hot melt granulation (hot melt binder).
  • a binder may be, for example one or more of the following: Polyethylene glycol (Breox PEG, Carbowax, Hodag PEG, Lutrol E), Stearic acid, Paraffin, Castor oil, hydrogenated (Castorwax, Castorwax MP 70, Castorwax MP 80, Opalwax, Sinulsol), Carnauba wax, Candelilla wax, Cottonseed oil, hydrogenated (Lubritab, Sterotex), glyceryl monostearate (Advawax 140, Atmul 67, Citomulgin M, Estol 603, Hodag GMS, Myvaplex 600P), acetylated glycerol monostearate, sorbitan monostearate (Capmul S, Liposorb S, Protachem SMS, Span 60), hexadecyl palmitate, oc
  • the dosage form according to the invention comprises a disintegrant.
  • the disintegrant maybe, for instance one or more of following: alginic acid (Kelacid, Protacid, Satialgine H8), calcium phosphate, tribasic (Tri-Cafos, TRI-CAL WG, TRI-TAB), carboxymethylcellulose calcium (ECG 505, Nymcel ZSC), carboxymethylcellulose sodium (Akucell, Aquasorb, Blanose, Finnfix, Nymcel Tylose CB), colloidal silicon dioxide (Aerosil, Cab-O-Sil, Cab-O-Sil M-5P, Wacker HDK), croscarmellose sodium (Ac-Di-Sol, Explocel, Nymcel ZSX, Pharmacel XL, Primellose, Solutab, Vivasol), crospovidone (Kollidon CL, Kollidon CL-M, Polyplasdone XL, Polyplasdone XL-10), docusate sodium, guar gum (Ga
  • the dosage form according to the invention comprises a solubility enhancer.
  • the solubility enhancer may be, for instance one or more of the following: cyclodextrins (Cavitron, Encapsin, Rhodocap, Kleptose), glyceryl monostearate (Abracol SLG, Admul, Myvaplex 600P), lecithin, poloxamer (Lutrol, Monolan, Pluronic), polyoxyethylene fatty acid esters (polysorbates) (Tween), polyoxyethylene castor oil derivatives (Cremophor series), docusate sodium (Cropol), sodium lauryl sulphate (Elfan 240, Maprofix 563), sorbitan esters (sorbitan fatty acid esters) (Span), polyvinyl pyrrolidone, polyethylene glycol (PEG), lauryl macrogol glyceride (Gelucire) and d-alpha-tocophenyl PEG succinate (Vitamin
  • the dosage form according to the invention comprises a release rate controlling excipient.
  • the release controlling excipient may be, for instance one or more of hydroxypropyl cellulose, hypromellose, hydroxy ethyl cellulose, ethyl cellulose, cellulose ethers, poly(ethylene oxide), microcrystalline cellulose, carbomer, carbomers, carbomer copolymer, povidone (Kollidon, Plasdone) polyvinyl acetate-povidone (Kollidon SR), fatty acids, fatty acid esters, magnesium stearate, calcium stearate, stearic acid, stearyl alcohol, glyceryl monostearate (Capmul GMS-50, Cutina GMS, Imwitor 191 and 900, Kessco GMS5 Lipo GMS 410, 450 and 600, Myvaplex 600P, Myvatex, Protachem GMS-450, Rita GMS, Stepan GMS, Tegin, Tegin 503 and 515
  • Suitable polymers include (but are not limited to) cellulose acetate, cellulose acetate phthalate, hypromellose phthalate, hypromellose acetate succinate, polyvinyl acetate, polyvinyl acetate phthalate, alginic acid and its salts like sodium alginate, potassium alginate, calcium alginate, propylene glycol alginate.
  • a release rate controlling agent may be acrylic acid polymers and copolymers like methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate with copolymers of acrylic and methacrylic acid esters (Eudragit NE, Eudragit RL, Eudragit RS, Eudragit FS30D, Eudrgit L, Eudragit S, Eudragit S100, Eudragit L100-55, RS30D, RL30D, NE30 D, Kollicoat MAE 30D, Kollicoat MAE 30DP, Acryl EZE, Acryl EZE-MP, Eastacryl 30D) and the like and any mixture or combination thereof, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate phthalate, polyvinyl acetate phthalates, hydroxypropyl methylcellulose phthalates, hydroxypropyl methylcellulose acetate succinates LF, hydroxypropyl methylcellulose a
  • the dosage form according to the invention comprises a glidant.
  • the glidant may be, for instance one or more of the following: tribasic calcium phosphate (Tri-Cafos, TRI-CAL, TRI-TAB), calcium silicate, cellulose, powdered (Arbocel, Elcema, Sanacel, Solka-Floc), colloidal silicon dioxide (Aerosil, Cab-O-Sil, Cab-O-Sil M-5P, Wacker HDK), magnesium silicate, magnesium trisilicate, starch (Aytex P, Fluftex W, Instant Pure-Cote, Melojel, Meritena, Paygel 55, Perfectamyl D6PH, Pure-Bind, Pure-Cote, Pure-Dent, Pure-Gel, Pure-Set, Purity 21, Purity 826, Tablet White) and talc (Altaic, Luzenac, Luzenac Pharma, Magsil Osmanthus, Magsil Star, Superiore).
  • the dosage form is a tablet or a core tablet and a lubricant may be used to improve the tabletting.
  • the lubricant may be for instance one or more of following: calcium stearate (HyQual), glycerine monostearate (Capmul GMS-50, Cutina GMS, Ilmwitor 191 and 900, Kessco GMS5 Lipo GMS 410, 450 and 600, Myvaplex 600P, Myvatex, Protachem GMS-450, Rita GMS, Stepan GMS, Tegin, Tegin 503 and 515, Tegin 4100, Tegin M, Unimate GMS), glyceryl behenate (Compritol 888 ATO), glyceryl palmitostearate Precirol ATO 5), hydrogenated castor oil (Castorwax, Castorwax MP 70, Castorwax MP 80, Croduret, Cutina HR, Fancol, Simulsol 1293), hydrogenated vegetable oil type I (
  • the dosage form according to the invention comprises as co-processed excipients any combinations of these components which by their functions for improve said properties.
  • Some of them are commercially available like cellulose and silicified microcrystalline (ProSolv) or microcrystalline cellulose—silicon dioxide—sodium starch glycolate and sodium stearyl fumarate (ProSolv EASYtab).
  • the tablet, minitablet, granule and/or the pellet disclosed herein may be coated.
  • the coating comprises one or more of the following polymers: a cellulose derivative, polyvinyl alcohol, polyethylene glycols, acrylate polymers or a sugar derivative.
  • a water based coating is used.
  • the coating may comprise plasticizers, dyes, colour lakes, or pigments, such as iron oxides, for instance yellow or red irons oxides and titanium dioxide.
  • Entacapone used in the dosage form of the invention is preferably a substantially pure (E)-isomeric form the preparation of which has been disclosed in U.S. Pat. No. 5,135,950.
  • the (E)-isomer may take different polymorphic forms, e.g. polymorph A disclosed in U.S. Pat. No. 5,135,950 or polymorph D disclosed in WO 2005/063696.
  • entacapone having reduced particle size i.e. at least 90% of entacapone particles have a diameter less than 55 microns e.g. less than 35 microns
  • SSA specific surface area
  • a method for the preparation of a oral solid dosage form comprising
  • levodopa in an amount ranging from 50 mg to 200 mg
  • carbidopa in an amount ranging from 65 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor
  • entacapone in an amount ranging from 100 mg to 200 mg, wherein the proportion of entacapone to carbidopa in said dosage form ranges from :1.0 to 3.08:1.0 by weight, is provided, wherein in the preparation of said dosage form entacapone has been used having specific surface area of from 2 m 2 /g to 20 m 2 /g.
  • levodopa in an amount ranging from 50 mg to 200 mg
  • carbidopa in an amount ranging from 65 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor
  • entacapone in an amount ranging from 100 mg to 200 mg, wherein the proportion of entacapone to carbidopa in said dosage form ranges from 0.66:1.0 to 3.08:1.0 by weight, is provided, wherein in the preparation of said dosage form entacapone has been used having specific surface area of from 2.2 m 2 /g to 7 m 2 /g.
  • Entacapone particles of reduced particle size have tended to cause manufacturing problems.
  • Potential problems related to fine particle size include poor flowability and agglomeration which may result in compromised content uniformity (i.e. the reproroducible amount of entacapone between different units).
  • the use of coarser particle size would therefore be beneficial.
  • Such a coarser particle size could be used, for example, in direct compression which is advantageous, as direct compression is an inexpensive and efficient manufacturing process. It has now been surprisingly found out by the applicants that is not necessary (but it is still possible) to use such a small particle size of entacapone when preparing the dosage forms according to the invention.
  • a method for the preparation of a oral solid dosage form comprising
  • levodopa in an amount ranging from 50 mg to 200 mg
  • carbidopa in an amount ranging from 65 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor
  • entacapone in an amount ranging from 100 mg to 200 mg, wherein the proportion of entacapone to carbidopa in said dosage form ranges from 0.66:1.0 to 3.08:1.0 by weight, is provided, wherein in the preparation of said dosage form entacapone has been used having specific surface area of from 0.2 m 2 /g to 1.0 m 2 /g.
  • levodopa in an amount ranging from 50 mg to 200 mg
  • carbidopa in an amount ranging from 65 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor
  • entacapone in an amount ranging from 100 mg to 200 mg, wherein the proportion of entacapone to carbidopa in said dosage form ranges from 0.66:1.0 to 3.08:1.0 by weight, is provided, wherein in the preparation of said dosage form entacapone has been used having specific surface area of from 0′01 to less than 0.2 m 2 /g.
  • Entacapone particles having a SSA from 0.01 m 2 to 0.2 m 2 are considered to consist mainly of coarse sized particles.
  • the particle size of levodopa for use in the dosage form of the present invention may be a particle size as typically used in formulations comprising levodopa.
  • the particle size of commercially available levodopa may generally be suitable.
  • levodopa in an amount ranging from 50 mg to 200 mg
  • carbidopa in an amount ranging from 65 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor
  • entacapone in an amount ranging from 100 mg to 200 mg, wherein the proportion of entacapone to carbidopa in said dosage form ranges from 0.66:1.0 to 3.08:1.0 by weight, is provided, wherein in the preparation of said dosage form entacapone has been used having specific surface area of from 0.1 to 0.2 m 2 /g.
  • levodopa in an amount ranging from 50 mg to 200 mg, (ii) carbidopa in an amount ranging from 65 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor, and (iii) entacapone in an amount ranging from 100 mg to 200 mg, wherein the proportion of entacapone to carbidopa in said dosage form ranges from 0.66:1.0 to 3.08:1.0 by weight, is provided, wherein in the preparation of said dosage form levodopa has been used having specific surface area of from 0.1 to 1.0 m 2 /g.
  • the particle size of carbidopa for use in the dosage form of the present invention may be a particle size as typically used in formulations comprising carbidopa.
  • levodopa in an amount ranging from 50 mg to 200 mg
  • carbidopa in an amount ranging from 65 mg to 150 mg or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor
  • entacapone in an amount ranging from 100 mg to 200 mg, wherein the proportion of entacapone to carbidopa in said dosage form ranges from 0.66:1.0 to 3.08:1.0 by weight, is provided, wherein in the preparation of said dosage form carbidopa has been used having specific surface area of from 0.5 to 10 m 2 /g.
  • the SSA values are measured using three-point nitrogen gas adsorption according to the BET (Brunauer-Emmett-Teller) technique well known in the art (e.g. using Coulter SA3100, Coulter Corp. or TriStar 3000, Micromeritics, or other corresponding equipment).
  • BET Brunauer-Emmett-Teller
  • the entacapone particles used in the dosage form(s) as well as in the preparation thereof according to this disclosure can be produced by any method used in the art for obtaining particles with a desired specific surface area and/or particles size distribution. Thus, they may be obtained directly from the production scale processes (e.g. by direct crystallization) or reducing the particle size of said entacapone particles for example mechanically (e.g. by milling, for instance by a ball mill, a fluid energy attrition mill or a jet mill), by ultrasonic means and/or by fractionating.
  • a general textbook reference on providing particles of desired size as well as to manufacturing technologies mentioned herein a reference is made to Remington's Pharmaceutical Sciences, 18 th ed, 1990, Mack Publishing Company, Easton, Pa. 18042. Suitable manufacturing technologies may be also found in Pharmaceutics the Science of Dosage Form Design Ed. M. E. Aulton, 2000.
  • the particle size of aromatic amino acid decarboxylase inhibitor other than carbidopa and of COMT inhibitor other than entacapone may similarly be the size typically used in formulations comprising these substances, and commercially available materials may be of a suitable particle size.
  • the present invention also relates to dosage forms, particularly oral solid dosage forms, including single unit dosage forms and multiple-unit dosage forms, comprising granules, tablets, minitablets, pellets, capsules, sachets or dispensers obtainable by the methods described above, particularly the methods disclosed in any of paragraphs [085] to [110] or [132] to [143].
  • the present disclosure also provides a kit for simultaneous or sequential administration of levodopa, carbidopa or a therapeutically equivalent amount of another aromatic amino acid decarboxylase inhibitor, and entacapone, a moderately potent COMT inhibitor, or a highly potent COMT inhibitor in the amounts described above.
  • the kit may comprise the levodopa, aromatic amino acid decarboxylase inhibitor (such as carbidopa) and COMT inhibitor (such as entacapone) in any combination.
  • the kit may suitably be comprised of oral solid dosage forms in any combination of single and multi-unit dosage forms as defined above.
  • a kit may be comprised of all single oral dosage forms as defined above.
  • such a kit might comprise a number of tablets, each of which comprise levodopa, carbidopa and entacapone, for individual administration at set time intervals.
  • a kit may be comprised of all multi-unit dosage forms in the form of individual tablets containing the drug substances.
  • a kit could comprise entacapone in one tablet and a separate tablet containing levodopa and carbidopa for sequential administration.
  • a kit may comprise multi-unit dosage forms in the form of a plurality of oral solid units (i.e. multiple unit or multi-particulate dosage forms), e.g. a capsule, sachet or dispenser filled with minitablets, granules or pellets.
  • a kit may comprise one or more single oral dosage forms and one or more multi-unit dosage forms.
  • kits may comprise (1) a single oral dosage form comprising a COMT inhibitor, levodopa and carbidopa and (2) further oral solid dosage forms (single oral dosage forms or multi-unit dosage forms) for separate administration which comprise levodopa and carbidopa and optionally the same COMT inhibitor or a different COMT inhibitor, such as entacapone.
  • the primary objective of the study was to evaluate the effects of different carbidopa dose levels on the pharmacokinetics (PKs) of levodopa with and without concomitant administration of entacapone. This was the first study to evaluate the effect of the combinations in a repeated dose setting in human subjects. Pharmacokinetics of levodopa in the presence of AADC and COMT inhibition with substances like carbidopa and entacapone is complex and difficult to model based on single dose PK data in humans, or animal models.
  • G Levodopa 100 mg+carbidopa 100 mg
  • the primary objective of the study was to evaluate the effects of different carbidopa dose levels on the pharmacokinetics (PKs) of levodopa with concomitant administration of different entacapone dose levels and with the moderately potent COMT inhibitor tolcapone.
  • PKs pharmacokinetics
  • the study subjects were randomly allocated to receive either increasing doses of entacapone or standard dose of tolcapone combined with increasing doses of carbidopa in each treatment period, a total of 12 different dose combinations.
  • Entacapone was administered concomitantly with 100 mg of levodopa and 25 mg of carbidopa at 3.5-hour intervals 4 times a day and tolcapone 3 times a day.
  • the study subjects received increasing dose levels of carbidopa.
  • the levodopa plasma profile was assessed.
  • the levodopa plasma concentrations after entacapone dose escalation and tolcapone standard dose and with increased carbidopa dose are given in FIG. 3 .
  • entacapone/levodopa/carbidopa tablet formulations are described in Tables 1 to 2 (formulations 1 to 4).
  • the tablets are prepared by adding carbidopa separately as granules into the formulation. Accordingly, entacapone and levodopa are granulated together with maize starch, mannitol, croscarmellose sodium and povidone in a high shear mixer. Carbidopa is wet granulated separately with maize starch, mannitol, croscarmellose sodium, and povidone in a high shear mixer.
  • the dry entacapone/levodopa granules, the dry carbidopa granules, croscarmellose sodium, mannitol (and castor oil, hydrogenated, in formulations 3 to 4), and magnesium stearate are mixed together and the mass obtained are compressed to tablets and coated with HPMC-coating containing a color pigment.
  • Formulation 1 Formulation 2 Core tablet: mg/tablet mg/tablet Entacapone 100.0 200.0 Levodopa 100.0 100.0 Carbidopa monohydrate 86.5 86.5 (corresponds to anhydrate 80.0 mg)
  • Formulation 3 Formulation 4 Core tablet: mg/tablet mg/tablet Entacapone 100.0 200.0 Levodopa 100.0 100.0 Carbidopa monohydrate 86.5 86.5 (respond carbidopa 80.0 mg) Maize starch 77.0 107.0 Mannitol 152.7 173.7 Croscarmellose sodium 12.9 17.4 Castor oil, hydrogenated 3.0 4.0 Povidone 32.4 47.9 Magnesium stearate 8.5 10.5 Theoretical weight of the 573.0 747.0 core tablet HPMC-coating containing 17.0 21.0 color pigments Theoretical weight of the 590.0 768.0 coated tablet

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US17/064,759 Active 2031-12-31 US11771675B2 (en) 2010-03-04 2020-10-07 Use of levodopa, carbidopa and entacapone for treating Parkinson's disease
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US18/455,759 Pending US20240050394A1 (en) 2010-03-04 2023-08-25 Use of levodopa, carbidopa and entacapone for treating parkinson's disease

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CN112741808B (zh) * 2019-10-29 2024-02-06 南京济群医药科技股份有限公司 一种提高含盐酸苄丝肼口服固体组合物稳定性的方法
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US20210085635A1 (en) 2021-03-25
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