CONTROLLED RELEASE FORMULATIONS OF LEVODOPA AND USES THEREOF

• US 20100298268A1
• Filed: 12/26/2008
• Published: 11/25/2010
• Est. Priority Date: 12/28/2007
• Status: Active Grant

• Current Assignee: Impax Laboratories, LLC
• Original Assignee: Impax Laboratories Incorporated (Amneal Pharmaceuticals, LLC)
• Inventors: Kou, Jim H., Hsu, Ann, Alani, Laman
• Granted Patent: US 8,377,474 B2
• Time in Patent Office: Days
• US Class Current: 514/64
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/197 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 carnitine A61K31/205
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 47/38 Cellulose; Derivatives thereof
• CPC Class Codes: A61K 9/0002 Galenical forms characterised by the drug release technique; Application systems commanded by energy
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61K 9/2086 Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat active cores with a complete drug-free outer coat A61K9/28
• CPC Class Codes: A61K 9/2846 Poly(meth)acrylates
• CPC Class Codes: A61K 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5084 Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs tablets containing such a mixture A61K9/2077
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 229/36 : with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton

Abstract

The current invention provides a controlled release oral solid formulation of levodopa comprising levodopa, a decarboxylase inhibitor, and a carboxylic acid. Also provided by this invention is multiparticulate, controlled release oral solid formulations of levodopa comprising: i) a controlled release component comprising a mixture of levodopa, a decarboxylase inhibitor and a rate controlling excipient; ii) a carboxylic acid component; and iii) an immediate release component comprising a mixture of levodopa and a decarboxylase inhibitor.

Claims

1. A controlled release oral solid formulation of levodopa comprising:

a. levodopa,

b. a decarboxylase inhibitor, and

c. a carboxylic acid that is not (a) or (b).

2. The controlled release oral solid formulation of claim 1, wherein the carboxylic acid is selected from a group consisting of tartaric acid, adipic acid, succinic acid, citric acid, benzoic acid, acetic acid, ascorbic acid, edetic acid, fumaric acid, lactic acid, malic acid, oleic acid, sorbic acid, stearic acid, palmitic acid and boric acid or mixtures thereof.

4. The controlled release oral solid formulation of claim 1, wherein the carboxylic acid is a dicarboxylic acid.

6. The controlled release oral solid formulation of claim 1, wherein the decarboxylase inhibitor is carbidopa.

15. The controlled release oral solid formulation of claim 4, wherein the carbidopa and levodopa are present in the formulation in a ratio of about 1:

1 to about 1;

10.

16. The controlled release oral solid formulation of claim 15, wherein the ratio of carbidopa to levodopa is about 1:

4.

77. A method of reducing motor fluctuations in a patient suffering from Parkinson'"'"'s disease comprising administering to the patient an effective amount of any of the formulations of claim 1 thereby providing a plasma concentration of levodopa effective to reduce motor fluctuations in the patient.

78. A method of reducing off time in a patient suffering from Parkinson'"'"'s disease comprising administering to the patient an effective amount of any of the formulations of claim 1 thereby providing a plasma or serum concentration of levodopa effective to reduce off time in the patient.

79. A method of increasing on time in a patient suffering from Parkinson'"'"'s disease comprising administering to the patient an effective amount of any of the formulations of claim 1 thereby providing a plasma or serum concentration of levodopa effective to increase on time in the patient.

80. A method of reducing time to ‘

on’

in a patient suffering from Parkinson'"'"'s disease comprising administering to the patient an effective amount of any of the formulations of claim 1 thereby providing a plasma or serum concentration of levodopa effective to reduce the time to on in the patient.

81. A method of enhancing dopamine levels in a subject suffering from a disease associated with reduced or impaired dopamine levels comprising;

administering to a subject an effective amount of any of the formulations of claim 1 thereby providing a plasma or serum concentration of levodopa effective to enhance dopamine levels in the subject suffering from a disease associated with reduced or impaired dopamine levels.

82. The method of claim 77, wherein the plasma or serum concentration of levodopa comprises:

a controlled release oral solid formulation of levodopa having a levodopa plasma or serum concentration profile comprising;

a. a time of administration,

b. a first concentration, and

c. a second concentration,

wherein, said first concentration is equal to the maximum concentration of said profile;

said second concentration is the minimum concentration occurring at a time later than said first concentration and earlier than or equal to about six hours following said time of administration; and

wherein said second concentration is greater than or equal to about fifty percent of said first concentration.

91. A method of providing a therapeutically effective and stable median blood plasma level of levodopa in a subject comprising administering to the subject a therapeutically effective amount of any of the formulations of claim 1.

92. The method of claim 91, wherein the blood plasma level does not fluctuate more than 40% between 0.5 hours after administration and six hours after administration.

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27. A multiparticulate, controlled release oral solid formulation of levodopa comprising:

a. a controlled release component comprising a mixture of levodopa, a decarboxylase inhibitor and a rate controlling excipient;

b. a carboxylic acid component; and

c. an immediate release component comprising a mixture of levodopa and a decarboxylase inhibitor.

33. The multiparticulate, controlled release oral solid formulation of claim 27, wherein the carboxylic acid component comprises a carboxylic acid selected from the group consisting of tartaric acid, adipic acid, succinic acid, citric acid, benzoic acid, acetic acid, ascorbic acid, edetic acid, fumaric acid, lactic acid, malic acid, oleic acid, sorbic acid, stearic acid, palmitic acid and boric acid or mixtures thereof.

46. The multiparticulate, controlled release oral solid formulation of claim 27, having a ratio of moles of carboxylic acid to levodopa of less than 4:

1.

47. The multiparticulate, controlled release oral solid formulation of claim 27, having a ratio of moles of carboxylic acid to levodopa of greater than 1:

4 and less than 3;

2.

51. The multiparticulate, controlled release oral solid formulation of claim 27, comprising from about 25 mg to about 1000 mg levodopa.

52. The multiparticulate, controlled release oral solid formulation of claim 51 comprising about 50 to about 600 mg of levodopa.

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55. A controlled release oral solid formulation of levodopa having a levodopa plasma or serum concentration profile comprising:

a. a time of administration,

b. a first concentration, and

c. a second concentration,

wherein, said first concentration is equal to the maximum concentration of said profile;

said second concentration is the minimum concentration occurring at a time later than said first concentration and earlier than or equal to about six hours following said time of administration; and

wherein said second concentration is greater than or equal to about fifty percent of said first concentration.

58. The formulation of claim 55, wherein said concentration profile further comprises a third concentration, wherein said third concentration is greater than or equal to fifty percent of said first concentration and said third concentration occurs at a time earlier than said first concentration and within about ninety minutes of said time of administration.

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72. A controlled release oral solid formulation of levodopa having a median levodopa plasma or serum concentration profile comprising:

a. a time of administration;

b. a first concentration at a first time, that occurs within one hour of said time of administration;

c. a second concentration at a second time, that occurs after said first time;

d. a third concentration at a third time, that occurs at least four hours after said second time;

wherein, said second concentration is equal to the maximum concentration of said profile;

said first concentration is equal to about fifty percent of said second concentration;

said third concentration is equal to about fifty percent of said second concentration.

73. A controlled release oral solid formulation having a levodopa plasma or serum concentration profile substantially the same as levodopa formulation IPX066 in FIG. 1 for a 380 mg dose of levodopa, or having a levodopa plasma or serum concentration profile substantially proportional to said formulation in FIG. 1 for a dose other than 380 mg.

74. A controlled release oral solid formulation having a levodopa plasma or serum concentration profile such that the ratio of the maximum concentration of said profile to the concentration at any time between one hour and seven hours after administration of said formulation is less than or equal to 4:

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75. A controlled release oral solid formulation of levodopa having a median levodopa plasma or serum concentration profile comprising:

a. a first concentration at a first time;

b. a second concentration at a second time, that occurs within about one hour after said first time;

c. a third concentration at a third time, that occurs at least four hours after said second time; and

d. a maximum concentration,

wherein, said second concentration is equal to the maximum concentration of said profile;

said first concentration is equal to fifty percent of said second concentration;

said third concentration is equal to fifty percent of said second concentration.

76. A stable, controlled release oral solid formulation of levodopa comprising levodopa, a decarboxylase inhibitor and a dicarboxylic acid wherein no more than 1% by weight of the degradation product of levodopa is present after being stored for 3 months at 40 degrees Centigrade and 75% relative humidity.

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