Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • 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
  • 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
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0043—Nose
• • 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
  • A61P25/28—Drugs for disorders of the nervous system 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

Definitions

• the invention relates to pharmaceutical compositions suitable for nasal administration.
• the invention relates to a pharmaceutical composition comprising levodopa (i.e., L-Dopa) or a pharmaceutically acceptable salt thereof for treating nervous system disorders (e.g., Parkinson’s disease) through nasal administration.
• levodopa i.e., L-Dopa
• nervous system disorders e.g., Parkinson’s disease
• Parkinson's disease is a progressive nervous system disorder that affects movement of a patient.
• neurons in the brain gradually break down or die. It is believed that many of the symptoms are due to a loss of neurons that produce dopamine, a chemical messenger in the brain.
• Parkinson's disease When dopamine levels decrease, it causes abnormal brain activity, leading to impaired movement and other symptoms of Parkinson's disease. Symptoms start gradually, sometimes starting with a barely noticeable tremor in just one hand. Tremors are common, but the disorder also commonly causes stiffness or slowing of movement. Although Parkinson's disease cannot be cured at this moment, pharmacological treatment may significantly improve symptoms.
• Levodopa was approved to treat Parkinson's disease over 50 years ago and today it remains the primary treatment.
• Levodopa (also known as “L-Dopa”) is in a class of medications referred to as dopaminergic antiparkinsonism agents and works by being converted to dopamine in the brain. It is commonly co-administered with a decarboxylase inhibitor, such as carbidopa, to limit the proportion of the dose converted to dopamine outside of the brain and to prevent the levodopa from being broken down before it reaches the brain.
• a decarboxylase inhibitor such as carbidopa
• the invention which in certain embodiments is directed to a method of treating Parkinson’s disease comprising administering to the olfactory region of the nose of a patient in need thereof a pharmaceutical composition comprising a therapeutically effective amount of levodopa or a pharmaceutically acceptable salt thereof, and at least one positively charged amino acid.
• the levodopa and the positively charged amino acid form a complex.
• the invention is directed to a pharmaceutical composition
• a pharmaceutical composition comprising a therapeutically effective amount of levodopa or a pharmaceutically acceptable salt thereof, a positively charged amino acid, and a pharmaceutically acceptable nasal vehicle, wherein the pH value of the pharmaceutical composition is from about 7 to about 8.
• the invention is directed to a pharmaceutical composition
• a pharmaceutical composition comprising a therapeutically effective amount of levodopa or a pharmaceutically acceptable salt thereof, a positively charged amino acid and a pharmaceutically acceptable nasal vehicle.
• the molar ratio of the positively charged amino acid to the levodopa or pharmaceutically acceptable salt thereof is greater than 2: 1.
• the invention is directed to a system comprising a device adapted to deliver a payload to the olfactory region of a human nose and a nasal composition wherein the nasal composition comprises a therapeutically effective amount of levodopa or a pharmaceutically acceptable salt thereof, at least one positively charged amino acid and a pharmaceutically acceptable nasal vehicle.
• the invention is directed to a method of delivering levodopa or a pharmaceutically acceptable salt thereof to a patient identified as in need of levodopa therapy, comprising administering to the olfactory region of the nose of the patient (e.g., a human) a pharmaceutical composition comprising levodopa or pharmaceutically acceptable salt thereof and a positively charged amino acid, wherein said method selectively delivers a therapeutically effective amount of the levodopa or pharmaceutically acceptable salt thereof to the brain tissues of the patient.
• a pharmaceutical composition comprising levodopa or pharmaceutically acceptable salt thereof and a positively charged amino acid
• the invention is directed to a process for manufacturing a pharmaceutical composition as disclosed herein comprising combining in any order, levodopa or a pharmaceutically acceptable salt thereof, a positively charged amino acid and a nasally acceptable vehicle.
• the invention is directed to a process for manufacturing a system comprising containing a pharmaceutical composition as disclosed herein in a device adapted to deliver a payload to the olfactory region of a human nose.
• Figure 1 depicts individual plasma concentrations of levodopa after intranasal administration of levodopa (1.2 mg/kg) and 10% arginine in male Sprague-Dawley rats.
• Figure 2 depicts average plasma concentrations of levodopa after intranasal administration of levodopa (1.2 mg/kg) and 10% arginine in male Sprague-Dawley rats.
• Figure 3 depicts average plasma concentrations of levodopa after intranasal administration of levodopa (1.2 mg/kg) and 10% arginine in male Sprague-Dawley rats.
• Figure 4 depicts average brain tissue concentrations of dopamine after intranasal administration of levodopa (1.2 mg/kg) and 10% arginine in male Sprague-Dawley rats.
• Figure 5 depicts average plasma concentrations of levodopa after intranasal administration of levodopa (2.4 mg/kg) and 10% arginine in male Sprague-Dawley rats.
• Figure 6 depicts average brain tissue concentrations of levodopa after intranasal administration of levodopa (2.4 mg/kg) and 10% arginine in male Sprague-Dawley rats.
• Figure 7 depicts average plasma concentrations of levodopa after intranasal administration of levodopa (3.6 mg/kg) with 10% arginine in male Sprague-Dawley rats.
• Figure 8 depicts average brain tissue concentrations of levodopa after intranasal administration of levodopa (3.6 mg/kg) with 10% arginine in male Sprague-Dawley rats.
• Figure 9 depicts average plasma concentrations of levodopa after intranasal administration of levodopa (2.4 mg/kg) with 5% arginine in male Sprague-Dawley rats.
• excipient includes a single excipient as well as a mixture of two or more different excipients, and the like.
• the term “about” in connection with a measured quantity or time refers to the normal variations in that measured quantity or time, as expected by one of ordinary skill in the art in making the measurement and exercising a level of care commensurate with the objective of measurement.
• the term “about” includes the recited number ⁇ 10%, such that “about 10” would include from 9 to 11, or “about 1 hour” would include from 54 minutes to 66 minutes.
• active agent refers to any material that is intended to produce a therapeutic, prophylactic, or other intended effect, whether or not approved by a government agency for that purpose.
• This term with respect to a specific agent includes the pharmaceutically active agent, and all pharmaceutically acceptable salts, solvates and crystalline forms thereof, where the salts, solvates and crystalline forms are pharmaceutically active.
• the terms "therapeutically effective” and an “effective amount” refer to that amount of an active agent or the rate at which it is administered needed to produce a desired therapeutic result.
• the term “patient” means a subject (preferably a human) who has presented a clinical manifestation of a particular symptom or symptoms suggesting the need for treatment, who is treated preventatively or prophylactically for a condition, or who has been diagnosed with a condition to be treated.
• subject is inclusive of the definition of the term “patient” and inclusive of the term “healthy subject,” which refers to an individual (e.g., a human) who is entirely normal in all respects or with respect to a particular condition.
• treatment of and “treating” include the administration of an active agent(s) to lessen the severity of a condition.
• prevention of and “preventing” include the avoidance of or delay the onset of a condition by a prophylactic administration of an active agent.
• a dose of one agent is administered prior to the end of the dosing interval of another agent.
• a dose of nasal levodopa with a particular dosing interval is considered as concurrently administered with oral levodopa when the nasal dose is administered within the dosing interval of the oral levodopa.
• the term “simultaneously” as used herein means that a dose of one agent is administered approximately at the same time as another agent, regardless of whether the agents are administered separately via the same or different routes of administration or in a single pharmaceutical composition or dosage form.
• a dose of nasal levodopa may be administered separately from, but at the same time as, a dose of oral levodopa.
• the term “sequentially” as used herein means that a dose of one agent is administered first and thereafter another dose of a same or different agent is administered second.
• a dose of oral levodopa may be administered first, and thereafter a dose of nasal levodopa may be administered second.
• the subsequent administration of the second agent may be inside or outside the dosing interval of the first agent.
• a method of managing the symptoms of Parkinson’s disease in a patient by nasal administration of a levodopa pharmaceutical composition is directed to the olfactory region of the nose of the patient, and thus provides a route for the delivery of levodopa directly to the patient’s brain, where it is metabolized to dopamine.
• systemic delivery of levodopa according to the method of the present invention is minimal or non-detectable, making it not necessary to co-administer a decarboxylase inhibitor. Although co-administration of a decarboxylase inhibitor is contemplated in certain embodiments of the invention.
• the invention is directed to a method of treating Parkinson’s disease comprising administering to the olfactory region of the nose of a subject or patient in need thereof a pharmaceutical composition comprising a therapeutically effective amount of levodopa or a pharmaceutically acceptable salt thereof and at least one positively charged amino acid.
• the pharmaceutical composition contacts the olfactory nerves of the subject or patient during administration.
• the invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of levodopa or a pharmaceutically acceptable salt thereof and a positively charged amino acid, wherein the pH value of the pharmaceutical composition is from about 7 to about 8.
• the invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of levodopa or a pharmaceutically acceptable salt thereof and a positively charged amino acid, wherein the molar ratio of the positively charged amino acid to the levodopa or pharmaceutically acceptable salt thereof is greater than about 2:1.
• the invention is directed to a system comprising a device adapted to deliver a payload to the olfactory region of a human nose and a nasal composition comprising a therapeutically effective amount of levodopa or a pharmaceutically acceptable salt thereof and a positively charged amino acid.
• the pharmaceutical composition further comprises a nasally acceptable vehicle.
• vehicle can be, e.g., an aqueous solution, an organic solvent (e.g., ethanol, propylene glycol, polyethylene glycols), a suspension, an ointment, a cream, a gel, or a combination thereof.
• the vehicle is an aqueous solution that contains greater than about 50% water, greater than about 60% water, greater than about 75% water; greater than about 90% water, or greater than about 95% water.
• the vehicle is a saline solution.
• the levodopa or pharmaceutically acceptable salt thereof is dissolved or partially dissolved in the nasally acceptable vehicle. In other embodiments, the levodopa or pharmaceutically acceptable salt(s) thereof is suspended or partially suspended in the nasally acceptable vehicle.
• the suspension could be either homogeneous or heterogeneous.
• the positively charged amino acid is dissolved or partially dissolved in the nasally acceptable vehicle. In other embodiments, the positively charged amino acid is suspended or partially suspended in the nasally acceptable vehicle.
• the pharmaceutical composition comprises solid particles comprising the levodopa and the positively charged amino acid and is administered without a liquid vehicle (e.g., as a dry powder).
• the solid particles may comprise an excipient, including a polymer (e.g., polylactic glycolic acid).
• the positively charged amino acid is lysine, arginine, histidine or a combination thereof.
• the positively charged amino acid comprises arginine (also known as, L-arginine).
• the pharmaceutical composition does not comprise a decarboxylase inhibitor (e.g., carbidopa). In certain embodiments, the composition does not comprise a decarboxylase inhibitor as there is a minimal amount levodopa that is delivered to systemic plasma.
• a decarboxylase inhibitor e.g., carbidopa
• the composition does not comprise a decarboxylase inhibitor as there is a minimal amount levodopa that is delivered to systemic plasma.
• the pharmaceutical composition of the invention includes a decarboxylase inhibitor (e.g., carbidopa).
• the decarboxylase inhibitor can be administered by the same route or a different route than the levodopa.
• the decarboxylase inhibitor can be administered orally.
• the pH of the pharmaceutical composition of the invention is from about 6 to about 9; from about 6.5 to about 8.5; from about 7 to about 8; or about 7.5.
• the levodopa or pharmaceutically acceptable salt thereof is present in the pharmaceutical composition at a concentration of greater than about 4 mg/mL; greater than about 6 mg/mL; greater than about 12 mg/mL; greater than about 15 mg/mL; greater than about 18 mg/mL; greater than about 22 mg/mL; from about 6 mg/mL to about 30 mg/mL; from about 15 mg/mL to about 25 mg/mL; from about 16 mg/mL to about 25 mg/mL; from about 10 mg/mL to about 20 mg/mL; from about 20 mg/mL to about 30 mg/mL; from about 6 mg/mL to about 10 mg/mL; from about 7 mg/mL to about 9 mg/mL; or about 8 mg/mL.
• the levodopa or pharmaceutically acceptable salt thereof is administered in an amount of greater than about 0.5 mg/kg; greater than about 1 mg/kg; greater than about 2 mg/kg; greater than about 3 mg/kg; from about 0.5 mg/kg to about 10 mg/kg; from about 1 mg/kg to about 9 mg/kg; from about 2 mg/kg to about 8 mg/kg; from about 3 mg/kg to about 7 mg/kg; from about 1 mg/kg to about 2 mg/kg; from about 1 mg/kg to about 3 mg/kg; from about 1 mg/kg to about 5 mg/kg; from about 2 mg/kg to about 3 mg/kg; from about 1 mg/kg to about 4 mg/kg; or at about 1.2 mg/kg, at about 2.4 mg/kg, or at about 3.6 mg/kg.
• the positively charged amino acid e.g., arginine
• the pharmaceutical composition at a concentration of greater than about 0.1%; greater than about 0.5%; greater than about 1%; greater than about 5%; greater than about 10%; greater than about 20%; from about 0.5% to about 20%; from 1% to about 10%; from about 5% to about 15%; or at about 5% or at about 10% based on the weight of the pharmaceutical composition.
• the ratio (w/w) of the positively charged amino acid to the levodopa or pharmaceutically acceptable salt thereof is greater than about 2: 1; greater than about 5: 1; greater than about 8: 1; greater than about 10: 1; greater than about 12: 1; greater than about 25 : 1 ; or greater than about 50: 1.
• the ratio (w/w) of the positively charged amino acid to the levodopa or pharmaceutically acceptable salt thereof is from about 2: 1 to about 50: 1; from about 5: 1 to about 20: 1; from about 8:1 to about 18: 1; from about 10: 1 to about 15: 1; or about 12.5: 1.
• the nasally administered pharmaceutical composition of the invention is concurrently, simultaneously or sequentially administered with orally administered levodopa or a pharmaceutically acceptable salt thereof and a decarboxylase inhibitor, which can be administered orally or by a different route.
• the nasal composition of the present invention is administered to treat “off periods” or breakthrough symptoms associated with an oral levodopa treatment in the patient in need thereof.
• the nasal administration is the sole levodopa therapy without associated oral levodopa administration.
• the methods of the invention provide a therapeutically effective amount of levodopa or metabolite thereof (e.g., dopamine) to the brain of the patient.
• levodopa or metabolite thereof e.g., dopamine
• the systemic plasma level of dopamine, attributed by the nasal administration, is minimal, i.e., below detectable limits.
• the methods of the invention provide a ratio of dopamine maximum concentration in the brain to dopamine maximum concentration in the systemic plasma at a value greater than about 10: 1, greater than about 50: 1; greater than about 100: 1; greater than about 500: 1; greater than about 1,000: 1; greater than about 5,000: 1; or greater than about 10,000: 1. In other embodiments, the ratio is from about 10: 1 to about 10,000: 1; from about 50: 1 to about 5,000: or from about 100: 1 to about 1,000: 1.
• a dose of the pharmaceutical compositions of the invention may be administered one time a day, two times a day, three times a day or four times a day.
• a dose may be administered every 72 hours, every 48 hours, every 24 hours, every 12 hours, every 8 hours, every 6 hours or every 4 hours.
• the dose may be administered once weekly, twice weekly, three times weekly, four times weekly or five times weekly.
• the dose is administered as needed for breakthrough symptoms of oral levodopa therapy.
• the pharmaceutical compositions of the present invention are administered from a nasal device adapted to deliver the composition to the olfactory region of the nose.
• the nasal device can include a suitable container (e.g., made of glass or plastic) to contain the pharmaceutical compositions disclosed herein.
• the device can be a nasal spray applicator, a squeeze bottle, a dropper bottle with pipette, a rhinyl catheter with a squirt tube, or a metered-dose spray pump.
• the device can be single use or provide multiple doses.
• An example of a nasal device that can be used in certain embodiments of the invention is described in U.S. Patent No. 10,507,295.
• the invention is directed to a method of delivering levodopa or a pharmaceutically acceptable salt thereof to a patient identified as in need of levodopa therapy, comprising administering to the olfactory region of the nose of the patient a pharmaceutical composition comprising levodopa or pharmaceutically acceptable salt thereof and a positively charged amino acid, wherein said method selectively delivers a therapeutically effective amount of the levodopa or pharmaceutically acceptable salt thereof to the brain tissues of the patient.
• the method thereby effectively treats diseases or disorders (such as Parkinson’s disease) treatable or manageable by a levodopa therapy in the patient.
• the delivery systems and pharmaceutical compositions disclosed herein include levodopa or a pharmaceutically acceptable salt thereof as a therapeutically active agent.
• Pharmaceutically acceptable salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate and the like; organic acid salts such as formate, acetate, trifluoroacetate, maleate, tartrate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like; and metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt and the like.
• the positively charged amino acids of the invention may be lysine, arginine, histidine, and the like, or a combination thereof.
• the positively charged amino acid comprises arginine (i.e., L-arginine) or derivatives thereof.
• the arginine is delivered as arginine glutamate or arginine alpha-ketoglutarate.
• other amino acids that may be incorporated into a composition of the invention include both natural and synthetic amino acid compounds that carry positive charges (e.g., protonated).
• compositions according to the invention may comprise one or more pharmaceutically acceptable vehicles, carriers and other excipients appropriate for nasal administration.
• pharmaceutically acceptable vehicles, carriers and other excipients are described in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (6 th Edition, 2009 Publication), which is incorporated by reference herein.
• Vehicles, carriers and other excipients suitable for nasal formulations include, but are not limited to, antioxidants, buffering agents, diluents, surfactants, solubilizers, stabilizers, hydrophilic polymers, additional absorption or permeability enhancers, preservatives, osmotic agents, isotonicity agents, pH adjusting agents, solvents, co-solvents, viscosity agents, gelling agents, suspending agents or combinations thereof.
• Suitable surfactants for the formulations disclosed herein include, but are not limited to Polysorbate 80 NF, polyoxyethylene 20 sorbitan monolaurate, polyoxyethylene (4) sorbitan monolaurate, polyoxyethylene 20 sorbitan monopalmitate, polyoxyethylene 20 sorbitan monostearate, polyoxyethylene (4) sorbitan monostearate, polyoxyethylene 20 sorbitan tristearate, polyoxyethylene (5) sorbitan monooleate, polyoxyethylene 20 sorbitan trioleate, polyoxyethylene 20 sorbitan monoisostearate, sorbitan monooleate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan trilaurate, sorbitan trioleate, sorbitan tristearate, and the like, and combinations thereof.
• Suitable isotonicity agents for the pharmaceutical compositions disclosed herein include, but are not limited to dextrose, lactose, sodium chloride, calcium chloride, magnesium chloride, sorbitol, sucrose, mannitol, trehalose, raffinose, various polyethylene glycol (PEG), hydroxyethyl starch, glycine, and the like, and combinations thereof.
• Suitable suspending agents for the formulations disclosed herein include, but are not limited to microcrystalline cellulose, carboxymethylcellulose sodium NF, polyacrylic acid, magnesium aluminum silicate, xanthan gum, and the like, and mixtures thereof.
• Suitable preservatives include phenylethyl alcohol, benzalkonium chloride, benzoic acid, or benzoates such as sodium benzoate.
• L-Dopa nasal composition was prepared by adding about 0.9 mL of sterile water to a powder mixture of 8 mg of L-Dopa and 100 mg of L-arginine. After measuring pH, acetic acid was used to adjust the solution to pH of 7.5. Finally, water was added until a total volume of 1.0 mL was reached.
• the measured dosing solution concentration is shown in Table 1.
• the dosing solution was diluted into rat plasma and analyzed in triplicate. All concentrations are expressed as mg/mL. The nominal dosing level was used in all calculations.
• Plasma and brain samples were extracted and analyzed using the methods described below.
• Brain samples were homogenized with a Virsonic 100 ultrasonic homogenizer. Each brain sample was first weighed, and then 2 mL of 20:80 methanol: water was added to each gram of sample. Samples were then homogenized on ice, and stored frozen until analysis.
• Tables 2, 3 and 4. The data are expressed as ng/mL of either L-Dopa or dopamine. Brain tissue concentrations are shown in Table 5. The data are expressed as ng of L-Dopa or dopamine per gram tissue. Samples that were below the limit of quantification were not used in the calculation of averages. Plasma concentrations versus time data are plotted in Figure 1 through Figure 3. Brain tissue concentrations versus time data are plotted in Figure 4.
• Pharmacokinetic parameters were calculated from the time course of the plasma and brain tissue concentrations and are presented in Tables 2, 3 and 4. Pharmacokinetic parameters were determined with Phoenix WinNonlin (v8.0) software using a non-compartmental model with or without sparse sampling. The sparse sampling option uses the mean concentration of the triplicate samples at each time point. This was used because of the limited number of samples per subject. The maximum plasma concentration (Cmax) and the time to reach maximum plasma concentration (tmax) after IN dosing were observed from the data. The area under the timeconcentration curve (AUC) was calculated using the linear trapezoidal rule with calculation to the last quantifiable data point, and with extrapolation to infinity if applicable.
• Plasma and brain halflife were calculated from 0.693/slope of the terminal elimination phase.
• Mean residence time was calculated by dividing the area under the moment curve (AUMC) by the AUC. Any samples below the limit of quantitation were treated as zero for the pharmacokinetic data analysis.
• ND not determined
• NA not applicable
• BLOQ below the limit of quantitation (5.00 ng/mL).
• ND not determined
• BLOQ below the limit of quantitation (5.00 ng/mL).
• the average ( ⁇ SE) Cmax of L-Dopa in plasma following sparse sampling was 15.0 ⁇ 2.30 ng/mL, the tmax was 30 minutes, the half-life could not be determined, the exposure based on the average ( ⁇ SE) dose normalized AUCiast was 16.2 ⁇ 2.30 hr*kg*ng/mL/mg. All L-Dopa concentrations in brain tissue were below the limit of quantitation.
• Group (1) L-Dopa (2.4 mg/kg) + 10% Arginine
• Group (2) L-Dopa (3.6 mg/kg) + 10% Arginine
• Group (3) L-Dopa (2.4 mg/kg) + 5% Arginine.
• a 16 mg/mL L-Dopa nasal composition was prepared by adding about 0.9 mL of sterile water to a powder mixture of 16 mg of L-Dopa and 100 mg of L-arginine. After measuring pH, acetic acid was used to adjust the solution to pH of 7.5. Finally, water was added until a total volume of 1.0 mL was reached.
• a 24 mg/mL L-Dopa nasal composition was prepared by adding about 0.9 mL of sterile water to a powder mixture of 24 mg of L-Dopa and 100 mg of L-arginine. After measuring pH, acetic acid was used to adjust the solution to pH of 7.5. Finally, water was added until a total volume of 1.0 mL was reached.
• the dose for Group (3) was prepared as follows, a 16 mg/mL L-Dopa nasal composition was prepared by adding about 0.9 mL of sterile water to a powder mixture of 16 mg of L-Dopa and 50 mg of L-arginine. After measuring pH, acetic acid was used to adjust the solution to pH of 7.5. Finally, water was added until a total volume of 1.0 mL was reached.
• Brain samples were homogenized with a Virsonic 100 ultrasonic homogenizer. Each brain sample was first weighed, and then 2 mL of 20:80 methanol: water was added to each gram of sample. Samples were then homogenized on ice, and stored frozen until analysis.
• Example 1 The samples were analyzed as described in Example 1.
• C C,,,,,,,: maximum plasma concentration
• t max time of maximum plasma concentration
• ti/2 half-life, data points used for half-life determination are in bold
• MRTi ast mean residence time, calculated to the last observable time point
• AUCi ast area under the curve, calculated to the last observable time point
• AUC area under the curve, extrapolated to infinity
• ND not determined
• BLOQ below the limit of quantitation (5.00 ng/mL).
• ND not determined
• NA not applicable
• BLOQ below the limit of quantitation (5.00 ng/mL).
• C C,,,,,,,: maximum plasma concentration
• t max time of maximum plasma concentration
• ti/2 half-life, data points used for half-life determination are in bold
• MRTi ast mean residence time, calculated to the last observable time point
• AUCi ast area under the curve, calculated to the last observable time point
• AUC area under the curve, extrapolated to infinity
• ND not determined
• BLOQ below the limit of quantitation (5.00 ng/mL).
• ND not determined
• NA not applicable
• BLOQ below the limit of quantitation (5.00 ng/mL).
• C C,,,,,,,: maximum plasma concentration
• t max time of maximum plasma concentration
• ti/2 half-life, data points used for half-life determination are in bold
• MRTi ast mean residence time, calculated to the last observable time point
• AUCi ast area under the curve, calculated to the last observable time point
• AUC area under the curve, extrapolated to infinity
• ND not determined
• BLOQ below the limit of quantitation (5.00 ng/mL).
• ND not determined
• NA not applicable
• BLOQ below the limit of quantitation (5.00 ng/mL).
• X includes A or B is intended to mean any of the natural inclusive permutations. That is, if X includes A; X includes B; or X includes both A and B, then “X includes A or B” is satisfied under any of the foregoing instances.
• Reference throughout this specification to “an embodiment”, “certain embodiments”, or “one embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrase “an embodiment”, “certain embodiments”, or “one embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment and are non-limiting.

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• 2021
  • 2021-08-30 WO PCT/US2021/048218 patent/WO2022047298A1/en not_active Ceased
  • 2021-08-30 EP EP21862913.7A patent/EP4203939A4/en active Pending
  • 2021-08-30 US US18/017,767 patent/US20230181508A1/en active Pending
  • 2021-08-30 JP JP2023509769A patent/JP2023538859A/ja active Pending

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