WO2005099678A1 - Compositions pharmaceutiques et procede d'utilisation de levodopa et de carbidopa - Google Patents

Compositions pharmaceutiques et procede d'utilisation de levodopa et de carbidopa Download PDF

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Publication number
WO2005099678A1
WO2005099678A1 PCT/US2005/009303 US2005009303W WO2005099678A1 WO 2005099678 A1 WO2005099678 A1 WO 2005099678A1 US 2005009303 W US2005009303 W US 2005009303W WO 2005099678 A1 WO2005099678 A1 WO 2005099678A1
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Prior art keywords
composition
carbidopa
levodopa
acid
less
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PCT/US2005/009303
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English (en)
Inventor
Julius Remenar
Orn Almarsson
Anthony J. Meehan
Zhong Zhang
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Transform Pharmaceuticals, Inc.
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Priority claimed from US10/926,702 external-priority patent/US20050070608A1/en
Application filed by Transform Pharmaceuticals, Inc. filed Critical Transform Pharmaceuticals, Inc.
Publication of WO2005099678A1 publication Critical patent/WO2005099678A1/fr

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    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K31/13—Amines
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids

Definitions

  • This invention relates to stable compositions of levodopa and carbidopa.
  • Parkinson's disease is a neurodegenerative disorder chara-cterized by a progressive degeneration of the dopaminergic pathway in the brain. Parkinson's patients often have symptoms of bradykinesia, rigidity, tremor, poor balance and difficulty walking. Simple movements such as making breakfast or coffee can be very difficult for Parkinson's disease patients. In particular, manipularting small items such as a pill can be very difficult.
  • levodopa functions to cross the blood brain barrier, convert to dopamine, and to replace or supplement low levels of dopamine in the brain.
  • Parkinson's disease patients often take between 200 nxg and 2 g of levodopa per day with late stage Parkinsons patients taking toward the latex end of this range.
  • Monotherapy with levodopa is often accompanied by unpleasant side effects such as nausea and vomiting.
  • Administration of a combination of levodopa and a dopa decarboxylase inhibitor such as carbidopa decreases the patient side effects while increasing drug efficacy.
  • One of the disadvantages with levodo a/carbidopa tablets is that Parkinson's patients often experience episodes of "wearing off.” During these episodes, patients become frozen or have rigid movements. These freezing episodes have significant detrimental consequences to the quality of life for Parkinson's patients.
  • Unstable liquid levodopa/carbidopa suspension is a home remedy Parkinson's patients have employed. Patients take a sip of the unstable liquid levodopa/carbidopa suspension when they feel their levodopa levels decreasing. Thus, patients self dose their levodopa concentrations and subsequently their Parkinson's symptoms. Methods of making unstable liquid levodopa/carbidopa are available in the literature. Typically, patients grind up a pill of levodopa/carbidopa and add a liquid such as orange juice or ginger ale. One of the disadvantages of this procedure is the grinding process. A patient entering a "wearing off episode can have significant difficulty in grinding a pill.
  • the present invention provides for a dry, solid, tablet, or powder formulation of carbidopa and levodopa which can be mixed with a liquid to form a stable pharmaceutical product.
  • the present invention provides for a method of treating a
  • a pharmaceutical composition comprises levodopa, carbidopa, acid and a metal chelator.
  • metal chelators include EDTA and deferoxamine mesylate.
  • the EDTA may be in the form of a salt or its free base. In one aspect, EDTA concentration is at least 0.01 mg/ml.
  • the acid can be selected from a carboxylic acid, a mineral acid, citric acid, tartaric acid, ascorbic acid, dehydroascorbic acid, acetic acid, 5 formic acid, methanoic acid, butanoic acid, ethanoic acid, benzoic acid, butyric acid, malic acid, propionic, epoxysuccinic acid, muconic acid, furanacrylic acid, citramalic acid, capric acid, stearic acid, caprioc acid, malonic acid, succinic acid, diethylacetic acid, methylbutryic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, or sulfuric acid.O
  • the composition is a stable liquid of levodopa and carbidopa.
  • the stable liquid has less than 10% of carbidopa degradation at 25°C after 7 days. In another aspect, the stable liquid has less than 5% of carbidopa degradation at 25°C after 7 days. In further aspect, the stable liquid has less than 10% of carbidopa degradation at 25°C after 30 days. In an additional aspect, the stable liquid 5 has less than 5% of carbidopa degradation at 25°C after 4 days. In another aspect, the stable liquid has less than 5% of carbidopa degradation at 4°C after 30 days. In one aspect, the stable liquid has less than 5% of carbidopa degradation at 25°C after 250 days. In a further aspect, the stable liquid has less than 5% of carbidopa degradation at 4°C after 360 days.
  • the stable liquid has less than 10% ofO carbidopa degradation at 25°C after 9 days.
  • a pharmaceutical composition comprises levodopa, carbidopa and acid wherein the pH of said composition is less than or about 3.0. In one aspect, this composition has less than 10% of carbidopa degradation at 25°C after 7 days. In another aspect, this composition has less than 5% of carbidopa5 degradation at 25°C after 7 days. In further aspect, this composition has less than 10% of carbidopa degradation at 25°C after 30 days. In an additional aspect, this composition has less than 5% of carbidopa degradation at 25°C after 4 days.
  • this composition has less than 5% of carbidopa degradation at 4°C after 30 days. In one aspect, this composition has less than 5% of carbidopa degradation at 25°C after0 250 days. In a further aspect, this composition has less than 5% of carbidopa degradation at 4°C after 360 days. In an additional aspect, this composition has less than 10% of carbidopa degradation at 25°C after 9 days. In a further aspect, this composition further comprises further an artificial sweetener or a preservative. In another embodiment, an aqueous composition comprises levodopa and carbidopa wherein the levodopa is at a concentration of between 2.5 mg/ml and 9mg/ml.
  • the levodopa is at a concentration of about 4 mg/ml. In one aspect, this composition has less than 10% of carbidopa degradation at 25°C after 7 days. In another aspect, this composition has less than 5% of carbidopa degradation at 25°C after 7 days. In further aspect, this composition has less than 10% of carbidopa degradation at 25°C after 30 days. In an additional aspect, this composition has less than 5% of carbidopa degradation at 25°C after 4 days. In another aspect, this composition has less than 5% of carbidopa degradation at 4°C after 30 days. In one aspect, this composition has less than 5% of carbidopa degradation at 25°C after 250 days.
  • this composition has less than 5% of carbidopa degradation at 4°C after 360 days. In an additional aspect, this composition has less than 10% of carbidopa degradation at 25°C after 9 days. In a further aspect, this composition further comprises further an artificial sweetener or a preservative. In a further embodiment, a composition comprises levodopa, carbidopa, acid, and a metal chelator wherein less than 1.2% of the carbidopa has degraded after 24 hours at 25°C. Examples of metal chelators include EDTA and deferoxamine mesylate.
  • Additional compositions of this invention comprise stable formulations with low levels of degradants.
  • a degradant of hydrazine is lower than currently available levodopa/carbidopa suspensions.
  • a liquid pharmaceutical composition comprises levodopa and carbidopa at about 0.4 to 1.5 mg/ml, wherein hydrazine levels are below 0.07ug/ml after 24 hours at 25°C.
  • a liquid pharmaceutical composition comprisises levodopa and carbidopa at about 0.4 to 1.5 mg/ml, wherein hydrazine levels are below 0.32ug/ml after 3 days at 25°C.
  • a liquid pharmaceutical composition comprises levodopa and carbidopa at about 0.4 to 1.5 mg/ml, wherein hydrazine levels are below 1.6ug/ml after 7 days at 25°C.
  • a liquid pharmaceutical composition comprises levodopa and carbidopa at about 0.4 to 1.5 mg/ml, wherein hydrazine levels are below 0.06ug/ml after 7 days at 4°C.
  • a liquid formulation of levodopa, carbidopa, acid and a metal chelator is clear or translucent.
  • a pharmaceutical composition comprises levodopa, carbidopa, acid and a thioether compound.
  • the thioether functions to stabilize the carbidopa. Examples of thioethers include methionine, cysteine, glutathione, thiogylcerol, sodium thiosulfate, and n-acetylmethionine.
  • a composition comprises levodopa, carbidopa, acid, a thioether and a metal chelator.
  • One embodiment contains a pharmaceutical composition
  • a pharmaceutical composition comprising levodopa at about 2.5 to 6 mg/ml, carbidopa at about 0.625 to 1.5 mg/ml, citric acid at about 5mg/ml to 10 mg/ml, and EDTA at greater than about 0.25 mg/ml.
  • This composition may additionally contain aspartame at about 0.1 mg/ml to about 1 mg/ml or sodium benzoate at about 0.01 mg/ml to about 1 mg/ml.
  • a pharmaceutical composition comprises levodopa at about 2.5 to 6 mg/ml, carbidopa at about 0.25 to 0.6 mg/ml, citric acid at about 5mg/ml to 10 mg/ml, and EDTA at greater than about 0.25 mg/ml.
  • This composition may additionally contain water, aspartame at about 0.1 mg/ml to about 1 mg/ml, or sodium benzoate at about 0.01 mg/ml to about 1 mg/ml.
  • a pharmaceutical composition comprises levodopa of about 500 mg to about 1500 mg, carbidopa of about 125 mg to about 375 mg, citric acid of about 1065 mg to about 3195 mg and EDTA of about 13 mg to about 41 mg.
  • composition may be in the form of a dispersible tablet or in the form of a powder or granules for mixing with a liquid.
  • a pharmaceutical composition comprises levodopa of about 1O00 mg, carbidopa of about 250 mg, citric acid of about 2130mg, and EDTA of about 27 mg.
  • the composition can further comprise water, aspartame or sodium benzoate.
  • One embodiment comprises a pharmaceutical composition of levodopa, carbidopa, acid, a metal chelator, and sugar wherein the sugar comprises less than 1% of the composition.
  • One embodiment comprises a method of dosing levodopa and carbidopa wherein a dry or solid formulation of levodopa and carbidopa is added to a liquid; the formulation is mixed for less than 10 minutes and the formulation is adminstered to a patient.
  • the administration of the formulation is the first morning dose for a Parkinson's disease patient.
  • a liquid composition is capable of dissolving levodopa at about 2.5 to 6 mg/ml and carbidopa at about 0.25 to 0.6 mg/ml. In one aspect, this composition has less than 10% of carbidopa degradation at 25°C after 7 days.
  • this composition has less than 5% of carbidopa degradation at 25°C after 7 days. In further aspect, this composition has less than 10% of carbidopa degradation at 25°C after 30 days. In an additional aspect, this composition has less than 5% of carbidopa degradation at 25°C after 4 days. In another aspect, this composition has less than 5% of carbidopa degradation at 4°C after 30 days. In one aspect, this composition has less than 5% of carbidopa degradation at 25°C after 250 days. . In a further aspect, this composition has less than 5% of carbidopa degradation at 4°C after 360 days. In an additional aspect, this composition has less than 10% of carbidopa degradation at 25°C after 9 days.
  • a f rther embodiment of this invention is a method of making a pharmaceutical composition to treat a dopamine disorder comprising the steps of combining levodopa, carbidopa, acid, a metal chelator; and water.
  • a liquid composition comprises levodopa and carbidopa wherein the total metal ion concentration is less than 1 ppm.
  • the free metal ion concentration is less than 1 ppm.
  • the composition further comprises an acid.
  • One example of a relevant acid is hydrochloric acid.
  • the total metal ion concentration may be below 0.1 ppm, 0.1 ppm, 0.01 ppm, or 1 ppb.
  • a formulation of levodopa and carbidopa comprises one or more excipients or active agents and these excipients or active agents are subjected to chromatography to remove metal ions.
  • metal ions to remove include iron, lead, zinc or aluminum
  • Additional aspects of this invention comprise administering a composition of this invention to a patient.
  • FIGURE 1 Demonstrates the solubility of levodopa in citrate buffer as a function of pH and levodopa concentration.
  • DETAILED DESCRIPTION OF THE INVENTION The present invention provides for stable pharmaceutical compositions comprising carbidopa and levodopa. Prior compositions of levodopa and carbidopa are not sufficiently stable or functional for Parkinson's disease patients. Compositions of this invention can provide advantages over currently marketed levodopa and carbidopa formulations and the current homemade versions of liquid levodopa/carbidopa.
  • Liquid levodopa/carbidopa is defined to be a formulation of levodopa, carbidopa and a liquid wherein one or more tablets of levodopa/carbidopa are combined with a liquid.
  • Parkinson's disease patient is defined to be any person diagnosed by a physician to be suffering from Parkinson's Disease or any person diagnosed to be suffering from a dopamine disorder who could benefit from levodopa treatment. Improvements in stabilizing compositions of levodopa and carbidopa have been found. One method of improving stability involves reducing the free metal concentration in compositions of levodopa and carbidopa.
  • Another method of improving stability involves reducing the pH of a liquid composition of levodopa and carbidopa.
  • a further method of improving stability involves selecting preferred acids for the stability of levodopa and carbidopa.
  • Additional methods of improving stability of levodopa and carbidopa formulations include avoiding light exposure, addition of sulfides to the composition, and elimination or reduction in aldehydes and ketones in the composition (such as sugars).
  • This invention provides for formulations of carbidopa and levodopa which have advantages over the prior art in stability and ease of use. It has been found that the currently used homemade versions of liquid levodopa/carbidopa produce multiple degradation products.
  • At least one of these degradation products is hydrazine, a potential carcinogen.
  • Current practice by late stage Parkinson's patients who take lg of levodopa per day in the form of liquid levodopa/caribdopa could be exposed to toxic levels of hydrazine.
  • these homemade formulations expose patients to a potential carcinogen.
  • This potential carcinogen has been linked with cancer. (“Toxological Profile for Hydrazines," US Department of Health and Human Services, September 1997).
  • the degradation of carbidopa to hydrazine results in lost carbidopa potency, thereby decreasing the shelf life of a product.
  • One embodiment of this invention contains levodopa, carbidopa, and a metal chelator. Without being bound to any theory, metal ions are believed to cause carbidopa degradation (Example 12).
  • chelators include, but are not limited to, EDTA, deferoxamine mesylate, EGTA, fumaric acid, and malic acid.
  • EDTA include both free acid and salt forms of EDTA.
  • free acid or salt forms of EDTA include editic acid, disodium edetate, dipotassium edetate, edetate calcium disodium, sodium edetate, and trisodium edetate. Any of editic acid, disodium edetate, dipotassium edetate, edetate calcium disodium, sodium edetate, and trisodium edetate may be excluded from some embodiments of this invention.
  • EDTA concentration is at least 0.01 mg/ml, at least 0.O5 mg/ml, at least 0.1 mg/ml, between 0.01 and 0.5 mg/ml, between 0.05 mg/ml and 0.3 mg/ml, between 0.05 mg/ml and 0.2 mg/ml or about 0.1 mg/ml.
  • the metal chelator is a salt.
  • compositions of this invention contain low levels of metal, no detectable metal, low levels of free metal ions, or no detectable free metal ions.
  • low levels of metal are less than 10 ppm of metal ion, 8 ppm of metal ion, 5 ppm of metal ion, 3 ppm of metal ion, 2 ppm of metal ion, 1 ppm of metal ion, less than 0.9 ppm of metal ion, less than 0.8 ppm of metal ion, less than 0.7 ppm of metal ion, less than 0.6 ppm of metal ion, less than 0.5 ppm of metal ion, less than 0.4 ppm of metal ion, less than 0.3 ppm of metal ion, less than 0.2 ppm of metal ion, less than 0.1 ppm of metal ion, less than 0.08 ppm of metal ion, less than 0.05 ppm of metal ion, less than O.02 ppm of metal ion, less than 0.01 ppm of metal ion, less than 8 ppb of metal ion, less than
  • compositions with low levels of metal ions contain from lppm of metal ions to lppb metal ions, from lppm of metal ions to lOppb metal ions, from lppm of metal ions to O.Olppm metal ions, from 0.5ppm of metal ions to lppb metal ions, from 0.5ppm of metal ions to O.Olppm metal ions, from 0.5ppm of metal ions to lOppb metal ions, from 2ppm of metal ions to lppb metal ions, or from 0.8ppm of metal ions to lppb metal ions.
  • compositions with low levels of free metal ions contain from lppm of free metal ions to lppb free metal ions, from lppm of free metal ions to lOppb free metal ions, from lppm of free metal ions to O.Olppm free metal ions, from 0.5ppm of free metal ions to lppb free metal ions, from 0.5ppm of free metal ions to O.Olppm free metal ions, from 0.5ppm of free metal ions to lOppb free metal ions, from 2ppm of free metal ions to lppb free metal ions, or from 0.8ppm of free metal ions to lppb free metal ions.
  • compositions may have low levels of specific metal ions.
  • the ranges listed for metal ions are intended to be applicable to specific metal ions also.
  • a composition may have less than lppm of iron.
  • a composition of this invention may have between lppm and lppb of iron.
  • metal ions include, but are not limited to, iron, calcium, magnesium, cobalt, copper, iron, manganese, molybdenum, selenium, zinc, aluminum, arsenic, barium, cadmium, chromium, lead, mercury, selenium and silver.
  • a composition of levodopa and carbidopa contains less than 1 ppm of a metal ion. In a further embodiment, a composition of levodopa, carbidopa and acid contains less than 1 ppm of a metal ion. In a still further embodiment, a composition of levodopa and carbidopa contains less than 0.1 ppm of a metal ion. In another embodiment, a composition of levodopa, carbidopa and acid contains less than 0.1 ppm of a metal ion.
  • the total metal concentration is below a specific level and in other embodiments the total free metal ion concentration is below a specific level.
  • Free metal ions are metal ions which are not bound chemically to other molecules, excluding water. Metal ions occur in trace amounts in many pharmaceutical preparations including in commercially available preparations of levodopa and carbidopa. In addition, metal ions are present in liquids which could be used in making liquid formulations of levodopa and carbidopa. Methods of this invention remove metal ions from active ingredients, excipients, such as binders, acids, flavors, and from diluents such as water. In one embodiment, compositions of this invention are made by removing metal ions by chromatography.
  • compositions of this invention are made by subjecting all or some excipients and active agents to chromatography. In a further embodiment, compositions of this invention are made by subjecting all or some excipients and active agents to chromatography such that the total metal ion concentration of the resulting composition is less than 1 ppm, less than 0.5 ppm, less than 0.1 ppm, less than 0.01 ppm, or less than 1 ppb.
  • a composition of levodopa and carbidopa is subjected to chromatography to remove metal ions. Metal ions can be removed from a final composition or from each individual excipient or active from a composition.
  • metal ions could be removed from a formulation of levodopa, caribidopa, and hydrochloric acid or metal ions could be removed from levodopa, carbidopa, and hydrochloric acid individually.
  • levodopa and carbidopa are mixed with deionized water.
  • thioether compounds have been found to stabilize the carbidopa molecule thereby decreasing the degradant formation. Examples of thioethers include, but are not limited to, methionine, cysteine, glutathione, thioglycerol, sodium thiosulfate, and n-acetylmethionine.
  • Additional embodiments of this invention contain both a thioether and a chelator.
  • the combination of a thioether and a chelator functions to significantly lower the level of carbidopa degradation in compositions of carbidopa and levedopa.
  • this invention includes carbidopa, levodopa and one or more agents selected from a metal chelator or a thioether.
  • a further aspect of this invention is a formulation of carbidopa, levodopa and one or more agents selected from a chelator or a thioether wherein less than 10 ⁇ o of carbidopa degrades after 7 days at 25°C.
  • compositions of this invention are stable. Stable compositions have less than 10% carbidopa degradation at 25°C after 7 days, less than
  • Embodiments of this invention enable formulations with degradant levels below 1 part per million (ppm), below 0.5 ppm, below 0.2 ppm, below 0.1 ppm, below 0.05 ppm, or below 0.01 ppm after storage for 24 hours at room temperature.
  • ppm part per million
  • Embodiments of this invention enable formulations with one specific degradant such as hydrazine with levels below 1 part per million (ppm), below 0.5 ppm, below 0.2 ppm- below 0.1 ppm, below 0.05 ppm, or below 0.01 ppm after storage for 48 hours at room temperature.
  • Embodiments of this invention enable formulations with hydrazine levels below 1 part per million (ppm), below 0.5 ppm, below 0.2 ppm, below 0.1 ppm, below 0.05 ppm, or below 0.01 ppm after storage for one week at 4 degrees Celcius.
  • liquid formulations of this invention have less than 15%, 10%, 5%, 3%, 2%, 1%, 0.5%, or 0.25% degradation of carbidopa after one day at 25°C. In another embodiment, liquid formulations of this invention have less than 15%, 10%, 5%, 3%, 2%, 1%, 0.5%, or 0.25% degradation of carbidopa after three days at 25°C. In one embodiment, liquid formulations of this invention have less than 15%, 10%, 5%, 3%, 2%, 1%, 0.5%, or 0.25% degradation of carbidopa after one week at 25°C.
  • liquid formulations of this invention have less than 15%, 10%, 5%, 3%, 2%, 1%, 0.5%, or 0.25% degradation of carbidopa after one month at 25°C.
  • carbidopa monohydrate is used to aid in carbidopa stability.
  • the compositions of the present invention comprising levodopa are suitably stable for pharmaceutical use.
  • the levodopa, carbidopa or formulations thereof in the form of a liquid of the present invention are stable such that when stored at room temperature for 24 hours, less than 1 % of any one degradant is formed.
  • degradant refers herein to product(s) of a single type of chemical reaction.
  • compositions when stored at 4 degrees C for one week, contain less than 5 % of any one degradant is formed. Alternatively, when stored at room temperature for 24 hours, compositions of this invention contain less than 10 %, less than 5 %, less than 3 %, less than 2 %, less than 1 %, less than 0.5
  • the relative humidity (RH) may be specified as ambient RH,
  • compositions of this invention have improved stability over current practice.
  • compositions of this invention have 100 times less carbidopa degradation than current practice of mixing ginger ale with Sinemet tablets (at lmg/ml) after storage at 25°C for 24 hours.
  • compositions of this invention have 3 times less carbidopa degradation than current practice of mixing orange juice with Sinemet tablets (at lmg/ml) after storage at 25°C for 24 hours.
  • compositions of this invention have 15 times less carbidopa degradation than current practice of mixing orange juice with Sinemet tablets (at lmg/ml) after storage at 25°C for 3 days. In an additional example, compositions of this invention have 60 times less carbidopa degradation than current practice of mixing orange juice with Sinemet tablets (at lmg/ml) after storage at 25°C for 7 days. In some embodiments of this invention, the compositions have lower levels of carbidopa degradation compared to current practice. It has been found that the currently used liquid levodopa/carbidopa has carbidopa degradants in the homemade formulation (see Example 3 and 6).
  • levodopa/carbidopa tablet with orange juice, which contains ascorbic acid to dissolve the levodopa/carbidopa tablet.
  • the ascorbic acid can cause a reaction which creates a carbidopa degradant.
  • degradants may cause negative biological affects and decreased drug potency because degraded drug in no longer functional.
  • Experiments with other acids have demonstrated that other carbidopa degradants are possible.
  • Two specific degradents which can form in liquid levodopa/carbidopa formulations are hydrazine and 3,4-dihydroxyphenylacetone (DHPA).
  • compositions of this invention decrease the levels of these degradents.
  • compositions of this invention may prevent formation of these degradents or keep formation of these degradents below 0.05%, below 0.1%, below 0.2%, below 0.3%, below 0.5%), below 1%, below 2%, below 5Y , or below 10% after storage at 25°C for one week.
  • the compositions of the present invention comprising levodopa are suitably stable for pharmaceutical use.
  • the levodopa, carbidopa or formulations in a solid dosage form thereof of the present invention are stable such that when stored at 30 degrees C for 2 years, less than 0.2 % of any one degradant is formed.
  • degradant refers herein to product(s) of a single type of chemical reaction. For example, if a hydrolysis event occurs that cleaves a molecule into two products, for the purpose of the present invention, it would be considered a single degradant. More preferably, when stored at 40 degrees C for 2 years, less than 0.2 % of any one-degradant is formed.
  • the relative humidity (RH) may be specified as ambient RH, 75 % RH, or as any single integer between 1 to 99 % RH.
  • One embodiment of this invention comprises compositions of carbidopa, levodopa and one or more acids.
  • acids include, but are not limited, to carboxylic acids, mineral acid salts, citric acid, tartaric acid, ascorbic acid, dehydroascorbic acid, acetic acid, formic acid, methanoic acid, butanoic acid, ethanoic acid, benzoic acid, butyric acid, malic acid, propionic, epoxysuccinic acid, muconic acid, furanacrylic acid, citramalic acid, capric acid, stearic acid, caprioc acid, malonic acid, succinic acid, diethylacetic acid, methylbutryic acid, hydrochloric acid, hydrohromic acid, phosphoric acid, nitric acid, and sulfuric acid.
  • Acid can be added at molar ratios of from about 0.5 moles of levodopa to about 20 moles of acid, from about 0.5 moles of levodopa to about 2 moles of acid, from about 1 mole of levodopa to about 5 moles of acid, from about 1 mole of levodopa to about 7 moles of acid, from about 1 ole of levodopa to about 10 moles of acid, from about 1 mole of levodopa to about 3 moles of acid, or from about 1 mole of levodopa to about 4 moles of acid.
  • One skilled in the art can increase the acid concentration to increase the level of carbidopa or levodopa which can be dissolved in a liquid.
  • a solid, powder or granule composition comprises levodopa, carbidopa, and an anhydrous acid.
  • a solid, powder or granule composition comprises levodopa, carbidopa, and anhydrous citric acid.
  • any specific acid can be excluded from compositions of this invention.
  • acids which can be specifically excluded include, but are not limited to, carboxylic acids, citric acid, tartaric acid, ascorbic acid, dehydroascorbic acid, acetic acid, formic acid, methanoic acid, butanoic acid, ethanoic acid, benzoic acid, butyric acid, malic acid, propionic, epoxysuccinic acid, muconic acid, furanacrylic acid, citramalic acid, capric acid, stearic acid, caprioc acid, diethylacetic acid, methylbutryic acid, hydrochloric acid, malonic acid, succinic acid, phosphoric acid, and sulfuric acid.
  • Adjustments of ionic strength can be done to affect stability.
  • Example 7 illustrates that salt can have a slightly negative effect on carbidopa stability.
  • ionic strength is adjusted to maintiain optimal stability.
  • salt concentration is less than 1 Molar, less than 0.75 Molar, less than 0.5 Molar, less than 0.3 Molar, less than 0.2 Molar, or less than 0.1 Molar.
  • the pH of a liquid levodopa/carbidopa formulation can affect the stability of the formulation. As demonstrated in Example 8, lowering pH can increase stability of the formulation.
  • compositions of this invention can have a pH between 1 and 10, between 1 and 8, between 2 and 8, between 2 and 6, between 2 and 4, between 2.5 and 4.5, between 2.5 and 4, between 2.5 and 3.5, between 3 and 8, between 3 and 6, between 3 and 5, between 3 and 4, between 1 and 4, between 1.5 and 3.5, between 2 and 3 or less than 5, less than 4, less than 3, less than 2.9, less than 2.8, less than 2.7, less than 2.6, less than 2.5, less than 2.4, less than 2.3, less than 2.2, less than 2.1, or less than 2.
  • a composition of this invention comprises levodopa, carbidopa, and acid wherein the pH of said composition is between 1 and 3.
  • a composition of this invention comprises levodopa, carbidopa, and acid wherein the pH of said composition is between 1 and 2.8. In another embodiment, a composition of this invention comprises levodopa, carbidopa, and acid wherein the pH of said composition is between 1.8 and 2.8. Pharmaceutical compositions of this invention may comprise levodopa, carbidopa, and one, two, three, four or more additional excipients or additives.
  • Excipients or additives may be inert or may be active and may affect other composition components.
  • Excipients or additives can include, but are not limited to, acids, bases, salts, surfactants, emulsifiers, detergents, binders, wetting agents, salts, polymers, solvents, antimicrobials, preservatives, fillers, sugars, alcohols, colorants, flavors, and buffers.
  • Excipients can act to stabilize a formulation or to decrease or eliminate degradation of the active agents.
  • compositions which contain any known excipients including those disclosed in the Handbook of Pharmaceutical Additives compiled by Michael and Irene Ash, Gower Publishing, 1995. In some embodiments, any one or more specific agents can be excluded.
  • agents which can be excluded include, but are not limited to, acids, bases, salts, surfactants, emulsifiers, detergents, binders, wetting agents, salts, polymers, solvents, antimicrobials, preservatives, fillers, sugars, alcohols, or additives disclosed in the Handbook of Pharmaceutical Additives. Additional excipients may include a granulation binder. Specific granulation binders include, but are not limited to hydroxypropylcellulose and hydroxypropylmethylcellulose, and polyvinlypyrolidone. In one embodiment, a water soluble granulation binder is used in formulations of this invention.
  • compositions of this invention between 3 and 10 % by weight, 4 and 6 ° ⁇ by weight, or 4 and 5 % by weight binder is used.
  • additional agents are added to the composition to prevent the formation of degradants. Any agent that suffices to limit, reduce, or inhibit the formation of degradants in compositions of this invention is envisioned.
  • compositions of carbidopa and levodopa ⁇ vhich can be used to treat a Parkinson's patient.
  • a liquid version of carbidopa and levodopa is more beneficial than other dosing forms.
  • patients often require continually higher doses of levodopa to maintain movement capabilities. These high level dosing requirements often leave patients more susceptible to freezing episodes.
  • late stage Parkinson's patients often require high levels of levodopa to avoid freezing episodes.
  • Some embodiments of this invention will be particularly useful to late stage Parkinson's patients to avoid freezing episodes or to quickly emerge from a freezing episode by providing high concentrations of levodopa to the patient quickly.
  • the present invention relates to formulations of levodopa and carbidopa can be produced as powders, tablets or granules and mixed with liquid to create a stable liquid formulation. These formulations can be used, for example, for administration to
  • levodopa and carbidopa are formulated as a dry packet which can be mixed with a liquid.
  • the levodopa and carbidopa are formulated as a pill or tablet which can be mixed with a liquid.
  • the levodopa and carbidopa can be formulated as any dosage form which can be mixed into a liquid. Examples of applicable dosage forms include, but are not limited to, powders, granules, tablets, capsules, dispersions, solutions, and gels. Currently marketed levodopa and carbidopa drug products are in solid forms.
  • compositions of this invention may provide a faster onset of action thereby decreasing freezing time.
  • 80% or more of a composition of this invention may pass through the stomach and begin intestinal absorption within 1, 2, 3, 4, 5, 10, 15, 20, 25 or 30 minutes, or within 1 to 30, 1 to 20, 3 to 20, 3 to 15, 5 to 10, 10 to 30, 10 to 20, or 20 to 30 minutes, thereby speeding absorption into the body.
  • compositions of this invention may pass through the stomach and begin intestinal absorption within 1, 2, 3, 4, 5, 10, 15, 20, 25 or 30 minutes, or within 1 to 30, 1 to 20, 3 to 20, 3 to 15, 5 to 10, 10 to 30, 10 to 20, or 20 to 30 minutes, thereby speeding absorption into the body.
  • compositions of this invention may also include agents which increase stomach motility.
  • One side effect of Parkinson's disease or Parkinson's disease drug therapy is decreased stomach motility.
  • a formulation of levodopa, carbidopa, and a stomach motility modulator could provide Parkinson's disease patients with a fast acting drug. Examples of applicable drugs include, but are not limited to, dopamine antagonists such as cisapride and domperidone.
  • stomach modulator can function to relax the pyloric sphincter and to allow the stomach contents to enter the intestine.
  • Drug formulations which increase stomach motility could allow dosage of levodopa and carbidopa with food.
  • Many Parkinson' s disease patients avoid eating food at a time close to their levodopa dosing schedule.
  • Food is known to decrease levodopa absorption.
  • a formulation of levodopa and carbidopa with a stomach motility agent could allow a patient to eat food while taking their necessary drug dose.
  • one embodiment entails dosing a formulation of this inventions comprising levodopa, carbidopa and a stomach motility agent 1, 2, 3, 4, 5, 10, 20, 25, or 30 minutes before eating to decrease the effect food can have on levodopa bioavailability.
  • Embodiments of this invention with and without stomach motility agents may provide faster and more predictable levodopa absorption in the digestive system.
  • one aspect of this invention entails administering an embodiment of this invention with food or in close time proximity to a feeding period.
  • levodopa absorption may not be affected by food in some embodiments of this invention.
  • a further embodiment includes compositions which are administered with food or within on hour of eating.
  • the bioavailability of the compositions of this invention may be higher than currently available marketed products. Higher bioavailability can result in a faster onset of action.
  • the compositions of this invention may increase the concentration of levodopa in the plasma to above 1 nMoles/ml, to above 2 nMoles/ml, to above 3nMoles/ml, to above 4nMoles/ml, to above 5nMoles/ml to above 6 nMoles/ml, or to above 10 nMoles/ml.
  • compositions above 1 nMoles/ml, above 2 nMoles/ml, above 3nMoles/ml, above 4nMoles/ml, above 5nMoles/ml, above 6 nMoles/ml, or above 10 nMoles/ml of levodopa may prevent, decrease or stop a freezing episode.
  • compositions can decrease or stop a freezing episode.
  • a composition of this invention can reach a level of 3 nMoles/ml of levodopa in plasma within 10 minutes of ingesting the composition, can reach a level of of 3 nMoles/ml of levodopa in plasma within 15 minutes of ingesting the composition, can reach a level of of 3 nMoles/ml of levodopa in plasma within 20 minutes of ingesting the composition, can reach a level of of 4 nMoles/ml of levodopa in plasma within 10 minutes of ingesting the composition, can reach a level of of 4 nMoles/ml of levodopa in plasma within 15 minutes ofingesting the composition, or can reach a level of 4 nMoles/ml of levodopa in plasma within 20 minutes of ingesting the composition.
  • Patient reliance on levodopa varies.
  • compositions of this invention can decrease, prevent, or stop a freezing episode by dosing to create an adequate levodopa plasma concentration.
  • a doctor, pharmacist, or patient can adjust a dose of a formulation of this invention depending upon the particular circumstances of the Parkinson's disease patient. Parkinson's patients often have difficulty swallowing a pill.
  • Liquid formulations of levodopa and carbidopa can function to decrease or eliminate the difficulty of administering the medication.
  • the current liquid levodopa/carbidopa homemade doses do not dissolve well in the liquid as described in the art. Thus, patients do not know if the carbidopa and levodopa are fully dissolved.
  • compositions of this invention can address these needs.
  • Compositions of this invention can contain higher levels of levodopa or carbidopa than homemade liquid levodopa/carbidopa doses described in the art.
  • the liquid formulation may contain a concentration of levodopa up to about 0.5 mg/ml, of up to about 1 mg/ml, of up to about 2 mg/ml, of up to about 3 mg/ml, of up to about 4 mg/ml, of up to about 5 mg/ml, of up to about 10 , mg/ml, of up to about 20 mg/ml, of up to about 30 mg/ml or from about 0.5 mg/ml to 30 mg/ml, from about 0.5 mg/ml to 1 mg/ml, from about 1 mg/ml to 5 mg/ml, from about 1 mg/ml to 4 trig, ml, from about 1.5 mg/ml to 2 mg/ml, from about 1.5 mg/
  • the liquid formulations of this invention may contain a concentration of carbidopa of up to 0.5 mg/ml, of up to about lmg/ml, of up to about 2mg/ml, of up to about 3 mg/ml, of up to about 4g/ml, of up to about 5 mg/ml, of up to about 10 mg/ml, of up to about 20, mg/ml, of up to about 30 mg/ml or from about 0.5 mg/ml to 30 mg/ml, from about 0.5 mg/ml to 1 mg/ml, from about 1 mg/ml to 5 mg/ml, from about 1 mg/ml to 4 mg/ml, from about 1.5 mg/ml to 2 mg/ml, from about 1.5 mg/ml to 4 mg/ml, from about 2 mg/ml to 5 mg/m, from about 2 mg/ml to 7 mg/m, from about 3 mg/ml to 8 mg/ml, from about 5 mg/ml to 10 mg/m,
  • compositions of this invention can. change the ratio of carbidopa to levodopa to decrease or eliminate degradents in the formulation and increase stability (see Example 5).
  • the ratio of carbidopa to levodopa can function to stabilize carbidopa.
  • Prior products contain ratios of 1 :4 and 1 :1 0 carbidopa: levodopa.
  • Compositions of this invention can use other
  • the ratio of carbidopa to levodopa will be from one mole equivalent of carbidopa to three mole equivalents of levodopa, from one mole equivalent of carbidopa to four mole equivalents of levodopa, from one mole equivalent of carbidopa to five mole equivalents of levodopa, from one mole equivalent of carbidopa to six
  • compositions of this invention also comprise a thickening or
  • Thickening or gelling agents can function to ease swallowing for Parkinson's disease patient.
  • thickening or gelling agents include, but are not limited to, dextrin, ethyl cellulose, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hypromellose, methylcellulose, polyethylene glycol, pectin, xantham gum, or zinc stearate.
  • compositions of this invention allow easy swallowing of the formulation.
  • Compositions may be mixed with aqueous or water based liquids.
  • liquids include, but are not limited to, water, juice, tea, milk, carbonated beverages, saline, and dextrose solutions. Liquids which are commonly available in a home provide easy mixing and use.
  • compositions of this invention may require minimal dosing volume.
  • liquids do not contain sugar or contain less than 1% sugar. Examples of sugar include fructose and sucrose.
  • patients can drink 100 mg of levodopa in a volume from about 5ml to 500 ml, from about 5 ml to 100ml, from about 10 ml to 75 ml, from about 15 ml to 50 ml, from about
  • compositions are mixed with a liquid or water which has had its oxygen content depleted or reduced.
  • Compositions of this invention provide added stability beyond the stability of0 liquid levodopa/carbidopa. Examples 3 and 6 illustrate the stability problems associated with prior liquid levodopa/carbidopa formulations.
  • Stable liquid formulations contain no phase separation, drug or excipient separation, and have minimal drug degradation.
  • Compositions of the present invention can remain stable at 4 degrees Celsius for at least 2 hours, at least 4 hours, at least 6 hours, at least 12 hours, 5 at least 24 hours, at least 36 hours, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least one week or at least one month.
  • some compositions of this invention can be stable at room temperature (22 degrees Celsius) for at least 2 hours, at least 4 hours, at least 6 hours, at least 12 hours, at least 24 hours, at least 36 hours, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least one week,0 or at least one month.
  • One embodiment of the invention comprises a composition additionally containing a preservative, antibacterial, antimicrobial or bacteriostatic agent.
  • Preservative, antibacterial, antimicrobial, and bacteriostatic agents can function to preserve the compositions both before mixing in liquid and after mixing in liquid.
  • preservative, antibacterial, antimicrobial, or bacteriostatic agents include, but are not limited to, benzyl alcohol, metabisulf ⁇ te, benzoic acid, butylparaben, chlorocresol, dimethylsulfoxide, ethylparaben, glacial acetic acid, imidurea, methylparaben, and propylparaben.
  • One embodiment of this invention contains the preservative sodium benzoate.
  • compositions of this invention do ⁇ 0 not have any antibacterial or antimicrobial agent.
  • additional agents can be added to improve the taste of the composition. Artificial sweeteners can be used to improve the taste of a composition.
  • compositions of this invention use less than 1% sugar.
  • Some artificial sweeteners can be used to improve the taste of a formulation of this invention without causing the stability problems of sugars.
  • Examples of artificial sweeteners includes aspartame, saccharin, sucralose, neotame and acesulfame potassium.
  • One embodiment contains compositions with aspartame. Included within this invention are compositions of levodopa and carbidopa in different physical forms.
  • compositions of this invention may include a salt of levodopa or carbdopa to increase stability of the formulation.
  • a salt such as HC1 could function to lower the pH of the formulation and thereby increase stability of the formulation as shown in Example 11.
  • Examples of inorganic acid addition salts for levodopa or carbidopa include hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids.
  • Examples of organic acid addition salts for levodopa or carbidopa include maleic, fumaric, benzoic, ascorbic, succinic, oxcalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, and benzenesulfonic acids.
  • a composition comprises levodopa HC1, carbidopa and an acid. In another embodiment, a composition comprises levodopa, carbidopa HO, and an acid. Compositions of this invention may also contain a third, fourth, fifth active ingredient, or more. An additional active ingredient can function to augument or improve the treatment or conditions associated with Parkinson's disease.
  • additional active ingredients include selegiline, COMT inhibitors such as entacapone or tolcapone, and dopamine agonists such as bromocriptine, ropinirole, pergolide, rotigotine, or pramipexole, dopamine decarboxylase inhibitors such as benserazide, and stomach motility modulators such as cisapride or domperidone.
  • Carbidopa functions as a peripheral dopamine decarboxylase inhibitor. Thus, carbidopa prevents or limits decarboxylation of levodopa in the peripheral system of the body, thereby allowing most levodopa to cross the blood brain barrier.
  • compositions can contain levodopa and/or carbidopa derivatives.
  • Compositions can contain pro drugs such as levodopa and/or carbidopa ester derivatives.
  • levodopa derivatives include, but are not limited to, levodopa esters including levodopa methyl ester, levodopa ethyl ester, and the like.
  • carbidopa derivatives include, but are not limited to, esters including carbidopa methyl ester and carbidopa ethyl ester.
  • Another aspect of this invention provides for a composition of levodopa without any carbidopa.
  • a composition of levodopa without any carbidopa.
  • plasma levels of carbidopa may be sufficient or patients may be taking other medications which contain carbidopa.
  • carbidopa can be removed from any of the compositions of this invention.
  • Patients can take a pill of carbidopa or benserazide and use a liquid formulation of levodopa.
  • An additional embodiment comprises compositions of carbidopa without levodopa.
  • One embodiment of this invention comprises levodopa, carbidopa and a thioether. Specific examples of this thioether could include, hut are not limited to, methionine or cysteine.
  • Another embodiment comprises levodopa, carbidopa and a metal chelator.
  • metal chelators could include, but are not limited to, EDTA and deferoxamine mesylate.
  • a further embodiment comprises levodopa, carbidopa, a thioether and a chelator.
  • compositions of the invention comprise levodopa, carbidopa and acid.
  • the composition comprises levodopa, carbidopa, and an acid wherein said acid is hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric acid, maleic, fumaric, benzoic, succinic, oxalic, bis- methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, or benzenesulfonic acid.
  • said acid is hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric acid, maleic, fumaric, benzoic, succinic, oxalic, bis- methylenes
  • said acids are anhydrous acids.
  • Another embodiment comprises compositions of levodopa, carbidopa, acid and a thioether.
  • An additional embodiment comprises compositions of levodopa, carbidopa, acid and a chelator.
  • a further embodiment comprises levodopa, carbidopa, acid, a thioether and a chelator.
  • compositions of the invention comprise levodopa, carbidopa and an acid: a.
  • said acid is hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric acid, maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis- methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, or benzenesulfonic acid; and b.
  • compositions of the invention comprise levodopa, carbidopa and an acid: a.
  • said acid is hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric acid, maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis- methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, or benzenesulfonic acid; b.
  • compositions of the invention comprise levodopa, carbidopa and acid: a.
  • said acid is hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric acid, maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis- methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, or benzenesulfonic acid; b. .
  • compositions of the invention comprise levodopa, carbidopa and acid: a.
  • said acid is hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric acid, maleic, fu aric, benzoic, ascorbic, succinic, oxalic, bis- methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, or benzenesulfonic acid; and b. wherein the pH between 1 and 10, between 1 and 8, between 2 and 8, between 2 and 6, between 2 and 4, between 2.5 and 4.5, between 2.5 and 4, between 2.5 and 3.5, between 3 and 8, between 3 and 6, between 3 and 5,between 3 and 4, between
  • compositions of the invention comprise levodopa, carbidopa and an acid: a.
  • said acid is hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric acid, maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis- methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, or benzenesulfonic acid; and b. wherein the concentration of levodopa is greater than 2.5 mg/ml, greater than 3 mg/ml, greater than 4 mg/ml, greater than 5 mg/ml, greater than 6 mg/ml, greater than
  • compositions of the invention comprise levodopa, carbidopa and an acid: a. wherein said acid is hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric acid, maleic, fu aric, benzoic, ascorbic, succinic, oxalic, bis- methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, or benzenesulfonic acid; and b.
  • said acid is hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric acid, maleic, fu aric, benzoic,
  • compositions of the invention comprise levodopa, carbidopa and an acid: a.
  • said acid is hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric acid, maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis- methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, or benzenesulfonic acid; and b.
  • the formulation comprises levodopa at between 1 and 5 mg/ml, carbidopa at between 0.25 and 1.25 mg/ml, an acid, and a metal chelator. In another embodiment, the formulation comprises levodopa at between 1 and 5 mg/ml, carbidopa at between 0.25 and 1.25 mg/ml, an acid, and EDTA. In another embodiment, the formulation comprises levodopa at between 1 and 5 mg/ml, carbidopa at between 0.25 and 1.25 mg/ml, citric acid, and EDTA.
  • the formulation comprises levodopa at between 1 and 5 mg/ml, carbidopa at between 0.25 and 1.25 mg/ml, citric acid at between 3 and 10 mg/ml, and EDTA. In a still further embodiment, the formulation comprises levodopa at between 1 and 5 mg/ml, carbidopa at between 0.25 and 1.25 mg/ml, citric acid at between 3 and 10 mg/ml, and EDTA of at least 0.025ug/ml.
  • the metal chelator is a salt.
  • the formulation comprises levodopa at between 2.5 and 5 mg/ml, carbidopa at between 0-625 and 1.25 mg/ml, an acid, and a metal chelator. In one embodiment, the formulation comprises levodopa at between 2.5 and 5 mg/ml, carbidopa at between 0.625 and 1.25 mg/ml, an acid, and EDTA. In another embodiment, the formulation comprises levodopa at between 2.5 and 5 mg/ml, carbidopa at between 0.625 and 1.25 mg/ml, citric acid, and EDTA.
  • the formulation comprises levodopa at between 2.5 and 5 mg/ml, carbidopa at between 0.625 and 1.25 mg/ml, citric acid at between 3 and 10 mg/ml, and EDTA.
  • the formulation comprises levodopa at between 2.5 and 5 mg/ml, carbidopa at between 0.625 and 1.25 mg/ml, citric acid at between 3 and 10 mg/ml, and EDTA of at least O.Q25ug/ ml.
  • the formulation comprises levodopa at about 4 mg/rnl, carbidopa at between about 1 mg/ml, an acid, and a metal chelator.
  • the formulation comprises levodopa at about 4 mg/ml, carbidopa at between about 1 mg/ml, an acid, and EDTA. In another embodiment, the formulation comprises levodopa at about 4 mg/ml mg/ml, carbidopa at about 1 mg/ml mg/ml, citric acid, and EDTA. In a further embodiment, the formulation comprises levodopa at about 4 mg/ml mg/ml, carbidopa at about 1 mg/ml mg/ml, citric acid at between 3 and 10 mg/ml, and EDTA.
  • the formulation comprises levodopa at about 4 mg/ml mg/ml, carbidopa at about 1 mg/ml mg/ml, citric acid at between 3 and 10 mg/ml, and EDTA of at least 0.025ug/ml.
  • the formulation comprises levodopa at about 4 mg/ml mg/ml, carbidopa at about 1 mg/ml mg/ml, citric acid at between 3 and 10 mg/ml, EDTA of at least 0.025ug/ml and between 0.5 and 7% of a binder.
  • the formulation comprises levodopa at about 4 mg/ml mg/ml, carbidopa at about 1 mg/ml mg/ml, citric acid at between 3 and 10 mg/ml, EDTA of at least 0.025ug/ml, between 0.5 and 7% of a binder, and a flavor enhancer.
  • Compositions of this invention can be produced by combining the different agents together and mixing. Agents of this invention are available from commercial sources.
  • Carbidopa can be purchased from Sigma- Aldrich (2002-2003 Biochemicals and Reagents Catalog, page 368).
  • Levodopa can be purchased from Sigma-Aldrich (2002-2003 Biochemicals and Reagents Catalog, page 693).
  • Combinations of levodopa and carbidopa can be found in currently marl eted pharmaceuticals. Methods of making levodopa and carbidopa are known in the art. Other stated agents (active and inactive) are available from commercial sources. Dissolution of a composition of this invention in liquid can occur by any methods known in the art. In some instances, dissolution can occur by mixing, stirring, blending, or homogenizing. Dissolution of compositions of this invention can provide significant advantages to Parkinson's disease patients. Fast dissolution of components of a composition could aid a patient who suffers from rigidity, tremors and frozen episodes. Faster dissolution can occur by altering particle size of the composition and by granulating the certain compositions.
  • a composition of levdopa, carbidopa, and a binder has a particle size diameter of between about 5 and 20 um.
  • binders include polyvinylpyrollidone and hydroxypropylcellulose.
  • Compositions also obtain faster dissolution by granulation in the presence of a binder and in some embodiments an liquid. Wet granulation, as opposed to dry granulation, results in a composition with improved dissolution speed.
  • compositions of this invention dissolve at least 3 mg/ml of levodopa in a liquid within 5 minutes.
  • compositions of this invention dissolve at least 4 mg/ml of levodopa in a liquid within 5 minutes.
  • One suitable liquid is water.
  • the compositions of this invention can be packaged in a variety of ways.
  • compositions of this invention can be packaged in individual packets, multiuse vials, multiuse contains or containers of various sizes, configurations or materials.
  • compositions of this invention are packaged such that exposure to light is minimized.
  • compositions of this invention specifically exclude detergents.
  • compositions of this invention can form stable formulations with only levodopa and not with a derivative of levodopa.
  • compositions of this invention can form stable formulations with only a derivatative of levodopa and not with levodopa.
  • compositions of this invention comprise simple formulations of two, three or four different agents without requiring combinations of five or more agents.
  • compositions of this invention do not require any type of gelling component.
  • gelling components are, but are not limited to, hydrox ⁇ propylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol or gelatin. It should be understood to those skilled in the art that various changes in the form and details described in this application may be made without departing form the scope of the invention. This invention will now be described in further detail, by way of example only, with reference to the accompanying examples.
  • EXAMPLE 1 Solubility of Levodopa in citrate buffer at varying pH and buffer strength
  • a 1.0 M citric acid solution was made by weighing out 19.2 g Citric acid (FW 192.1) into a 100 mL volumetric flask and diluting with F ⁇ PLC grade water. This was repeated with the Sodium Citrate (FW 294.1), by weighting out 29.4 g of sodium citrate in into a 100 mL volumetric flask and diluting to 1 00 mL with water.
  • FW 294.1 Sodium Citrate
  • a series of 8 of 20 mL scintillation vials were then labeled and prepared as follows: For 1.0 molar samples of pH 1.5 (pure citric + IHCl), 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0 were made.
  • EXAMPLE 2 STABILITY OF LEVODOPA AND CARBIDOPA Sample preparation: A formulation of: Levodopa / Citric acid / C rbidopa / Sucrose mix at molar ratio of 1:3:0.2:1. This powder mixture was dissolved in water at a concentration of 5.5 mg/ml of levodopa. This solution was filter through a 0.22 micrometer filter (with PVDF membrane) and then stored at temperatures of 4 degrees C, 25 degrees C and 40 degrees C. A formulation of Levodopa / Ascorbic acid f Carbidopa mix at molar ratio of 1:3:0.25. This powder mixture was dissolved in water at concentration of 1.0 mg/ml of levodopa.
  • EXAMPLE 3 CARBIDOPA DEGRADENT Samples of levodopa/carbidopa/citric acid and levodopa/carbidopa/ascorbic acid at a molar ratio of 4: 1 : 1 were made. Samples were kept at 25 degrees Celsius for 24 hours. After 24 hours, samples were assayed on an HPLC. Analysis was carried out on Waters Alliance HPLC system equipped with 2695 separation module and 2996 PDA detector. Reversed phase HPLC method was utilizing Waters Atlantis dC18 column (4.6 x 150 mm, 5um) operated at 30 C and a two component gradient mobile phase. Run time was 30 min at flow rate 1.0 mL/min.
  • DHPA 3,4-dihyiroxyphenylacetone
  • EXAMPLE 4 STABILITY OF LEVODOPA AND CARBIDOPA FORMULATIONS Formulations of levodopa, carbidopa and an acid at various pHs were tested for carbidopa stability. Four grams of levodopa and one gram of carbidopa were dissolved with 3 Molar equilavents of various acids relative to levodopa and water as shown in the table below. The pH of each solution was adjusted 1 N E1C1 or 1 N NaOH. Area levodopa, area carbidopa, % carbdopa remaining and area °/ of DHPA were calculated. The "%carbidopa remaining was calculated accordin-g to the following equations:
  • carbT and LevT refer to carbidopa and levodopa area values for the acid, temperature, and pH being studied
  • lev4C and carb4C are the area values of the levodopa and carbidopa samples at 4°C for the pH and acid being studied.
  • EXAMPLE 5 RATIO OF CARBIDOPA TO LEVODOPA Samples of 1/ 3 /l Levodopa / citric acid/ sucrose were prepared at 4 mg/ml of levodopa and carbidopa was added at w/w ratios of 0.5, 0.125, and 0.05 relative to levodopa. The samples were diluted for HPLC analysis after 24 hours at 4C, 25C, and 40C.
  • the data indicates that the ratio of carbidopa to levodopa effects carbidopa stability.
  • EXAMPLE 6 STABILITY OF LEVODOPA AND CARBIDOPA IN GINGER ALE The stability of a formulation of levodopa and carbidop a was tested with ginger ale. A formulation of 4 mg/ml of levodopa and lmg/ml of carbidopa was combined with 100 ml of ginger ale. The formulation was kept at 4 °C, 25 °C and 40 °C for 24 hours. After 24 hours the samples were diluted and assayed by HPLC. The HPLC sample chamber was maintained at 5°C. Analysis was carried out on Waters Alliance HPLC system equipped with 2695 separation module and 2996 PDA detector.
  • EXAMPLE 7 AFFECT OF IONIC STRENGTH A formulation of Levodopa / carbidopa / citric acid/ sucrose at a molar ratio of 1/ 0.25/ 3 /l was prepared at 4 mg/ml of levodopa in NaCl solution with [NaCl] of 0.00, 0.05, 0.125, 0.250, and 0.5 M. After 24 hours the samples were diluted and assayed by HPLC (as described earlier). The HPLC sample chamber was maintained at 5°C. Area % 3, 4-dihydroxyphenylacetone relative to carbidopa area as a function of temperature and ionic strength is shown as a representation of carbidopa stability.
  • Salt appears to have a negative impact on carbidopa stability, which could be due to heavy metal contaminents in the salt.
  • EXAMPLE 8 AFFECT OF pH ON STABILITY Samples of carbidopa and citric acid were made. Samples were kept at 4 °C, 25 °C and 40 °C for 24 hours. After 24 hours the samples were diluted and assayed by HPLC. Analysis was carried out on Waters Alliance HPLC system equipped with 2695 separation module and 2996 PDA detector. Reversed phase HPLC method was utilizing Waters Atlantis dC18 column (4.6 x 150 mm, 5um) operated at 30 C and a two component gradient mobile phase. Run time was 30 min at flow rate 1.0 mL/min. Carbidopa impurities and degradation products were detected by absorbance at 280 nm and reported as their percent area relative to the parent peak. The HPLC sample chamber was maintained at 5°C. Area % 3.4- dihydroxyphenylacetone relative to carbidopa area as a function of temperature and pH is shown as a representation of carbidopa stability.
  • EXAMPLE 9 EFFECT OF SUGAR ON STABILITY Effect of sugars on the formation of DHPA over 24 hours for samples of 4 mg/ml levodopa + 1 mg/ml carbidopa + 3 equiv of citric acid (relative to levodopa) stored at 4, 25, and 40°C. Values reported are "area % DHPA" relative to carbidopa
  • EXAMPLE 10 EFFECT OF PRESERVATIVES ON STABILITY Samples of 1/ 0.25/ 3 /l Levodopa / carbidopa / citric acid/ sucrose were prepared at 5.0 mg/ml of levodopa in water and the preservatives sodium benzoate and potassium sorbate were added to the solutions. The preservatives were added at the maximum allowable concentration of 0.1 % each. The solutions were placed on stability for 24 hours and assayed by HPLC. Analysis was carried out on Waters Alliance HPLC system equipped with 2695 separation module and 29_ 6 PDA detector.
  • the peak accounts for 0.19 _% of the area. Placebos were prepared in order to determine whether the new peak is related to the potassium sorbate itself or from an interaction between potassium sorbate and levodopa or carbidopa.
  • the second placebo contains 14.5 mg/ml of citric acid and 1/3 molar equivalents of sucrose (relative to citric acid).
  • sodium benzoate had no effect to a slightly negative effect on the area % of 3 ,4-dihydroxyphenylacetone (0.71 % with vs 0.88 % without), while the size of the degradate doubled in the sample containing potassium sorbate.
  • potassium sorbate increases the rate of 3,4-dibydroxyphenylacetone formation over preservative-free or sodium benzoate-containing solutions.
  • EXAMPLE 11 EFFECT OF CITRIC ACID CONCENTR-ATION The effects of citric acid content and a HCl salt of levodopa on the rate of carbidopa degradation to 3, 4-dihydroxyphenylacetone were analyzed. Samples of levodopa HCl salt or free form levodopa at 4 mg/ml, carbidopa at lmg/ml and sucrose at 4mg/ml were made. As detailed in the chart below, between 0 and 3 equilavents of citric acid (in relation to levodopa) were added. Effects of citric acid concentration on the 24 hour stability of carbidopa were analyzed by looking for formation of 3,4- dihydroxyphenylacetone. The below table list DHPA Area %.
  • This hydrazine assay protocol has detection limitation of hydrazine at level of 0.27ppm when 0.10ml of sample was assayed.
  • the sample size was increased to 0.50ml in order to decrease the lower limit of the quantitation to below O.lOppm.
  • the limit of detection of the larger sample volume is 0.05ppm.
  • the following data indicated a linear correlation between UV absorption and volume of tested sample solution.
  • carbidopa is the source of hydrazine formation in the levedopa carbidopa formulation solutions. It is believed that DHPA is the main degradant of cabidopa in acidic solution, and a co -product of hydrazine formation. DHPA can be detected by HPLC assay. The following data indicated that there is a good correlation between the % of DHPA and the amount of hydrazine in ppm.
  • TPI-926 contains:
  • TPI-926 0.5 mg/ml of aspartame
  • the total volume of TPI-926 was lOOm-l of water.
  • Liquid formulations of levodopa at lmg/ml and carbidopa at 0.25 mg/rnl were made in orange juice and ginger ale by grinding 1 levodopa/carbidopa tablet (100:25) and combining with 100ml of orange juice or ginger ale.
  • a formulation of levodopa, carbidopa and ascorbic acid was made by grinding 1 levodopa/carbidopa tablet 100:25) and combining with 100ml of water and 2 mg/ml of ascorbic acid. Samples were kept at 4 and 25 degrees C for 24 hours, 3 days, and 7 days.
  • DHPA is a degradent of carbidopa. Thus, DHPA is at a 1 :1 ratio compared to degraded carbidopa. A 1% level of DHPA in a sample is expected to correlate with a 1% level of carbidopa degradation.
  • concentration per day was calculated by dividing the amount of hydrazine or DHPA of the longest duration sample divided by the number of days.
  • TPI-926 100 ml of TPI-926 created 3.7 meg of DHPA per day. Since DHPA and carbidopa are in molar equilavents, this correspond with 5mcg of carbidopa degradation per day.
  • One tablet of Sinemet contains 25,0O0mcg of carbidopa. Thus, TPI-926 has a 0.02% degradation rate of carbidopa per day for every 250mg.
  • ascorbic acid sample 100 ml of the ascorbic acid sample created 238 meg of DHPA per day. Since DHPA and carbidopa are in molar equilavents, this correspond with 323 meg of carbidopa degradation per day.
  • One tablet of Sinemet contains 25, OOOmcg of carbidopa.
  • ascorbic acid sample has a 1.2% degradation rate of carbidopa per day for every 250mg dose.
  • Levodopa/Carbidopa in Orange Juice 100 ml of the orange juice sample created 3013 meg of DHPA per day. Since DHPA and carbidopa are in molar equilavents, this correspond with 4083 meg of carbidopa degradation per day.
  • One tablet of Sinemet contains 25,000mcg of carbidopa. Thus, this orange juice sample has a 16.3% degradation rate of carbidopa per day for every
  • EXAMPLE 14 Levedopa solubility in ascorbic acid solution an ascorbic acid concentration of 3.5 mg/ml was tested. A sample of 3.5 mg/ml ascorbic acid was made by adding 70.0mg of ascorbic acid into 20ml of water. Then, 80.0mg of levodopa powder was dissolved into the 3.5 mg/ml ascorbic sample by stirring for 24 hour at RT. The projected levodopa concentration was 4 mg/ml. The sample was filtered through a 0.22 ⁇ PVDF filter to remove the insoluble levodopa. The filtration was assayed by by HPLC at 10X dilution with water. The HPLC data indicated the concentration of levodopa in the filtration was 2.0mg/ml. Thus, maximum solubility of levodopa in 3.5 mg/ml ascorbic acid solution was 2mg/ml.
  • EXAMPLE 15 A formulation of levodopa and carbidopa with low levels of metal ions was made.
  • a deionization procedure with a cation removal cartridge (Hose Nipple Cartridge D8905 from Bamstead International) was utilized for water purification. After all components were dissolved in the purified water, a dialysis step with Chelex-100® was conducted. The pH of the solution was adjusted to within 2.0 ⁇ 2.3. The level of carbidopa degradation was measured for this formulation. At time 0, 0.125 % of carbidopa had degraded. After two weeks at room temperature (25°C) 0.196% carbidopa had degraded. After one month at room temperature, 0.233 % carbidopa had degraded. After two weeks at 40°C, 0.618% carbidopa had degraded. After one month at 40°C, 1.276 % carbidopa had degraded.
  • EXAMPLE 16 Rate of formulation dissolution was tested.
  • Levodopa as purchased has a mean particle size of 76 um, where 50% of the particles are less than 67um, 90% of the particles are less than 1 6 um, and 100% of the particles are less than 364 um.
  • a particle size of between 7 and 13 um showed fast dissolution.
  • a binder such aspolyvinlypyrollidone or hydroxypropylcellulose increase dissolution speed.
  • EXAMPLE 17 CHELATION OF HEAVY METAL IONS BY ADDITION OF EDTA EDTA (at 0.9mg/ml as the sodium salt) was added to a formulation (levodopa at 4 mg/ml, carbidopa at lmg/ml, citric acid at 7.79 mg/ml, aspartame at 0.5 mg/ml, sodium benzoate at 0.25 mg/ml) with and without the addition of iron (Fe(III) citrate at 0.3ppm) and copper (CuSO 4 at lppm).
  • the metal concentrations were chosen to match those of the EPA secondary guideline for drinking water.
  • the measured pH of all solutions at the initial time was 2.67 ⁇ 0.05.
  • Area % DHPA values are reported relative to carbidopa area. As described earlier, %DHPA correlates with carbidopa degradation and hydrazine formation. The samples were stored at 25°C for 20 hours and assayed using HPLC

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Abstract

Cette invention se rapporte à des compositions stables de levodopa et de carbidopa, à des procédés pour traiter des patients avec ces compositions, et à des procédés de préparation de ces compositions.
PCT/US2005/009303 2004-04-06 2005-03-17 Compositions pharmaceutiques et procede d'utilisation de levodopa et de carbidopa WO2005099678A1 (fr)

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US10/926,702 US20050070608A1 (en) 2003-08-29 2004-08-26 Pharmaceutical compositions and method of using levodopa and carbidopa
US10/926,702 2004-08-26
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US11844754B2 (en) 2020-11-17 2023-12-19 Neuroderm, Ltd. Methods for treatment of Parkinson's disease
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US9901640B2 (en) 2007-12-28 2018-02-27 Impax Laboratories, Inc. Controlled release formulations of levodopa and uses thereof
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EP3326615A1 (fr) * 2010-11-15 2018-05-30 Neuroderm Ltd Administration continue d'inhibiteurs de la l-dopa, d'inhibiteurs de la dopa décarboxylase et d'inhibiteurs de la catéchol-o-méthyle transférase et compositions correspondantes
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