Method for treatment of parkinson's disease

Abstract

This invention discloses a method for treating neurological or motor disorders, such as Parkinson's disease, in individuals in need, by non-enteral administration of levodopa and dopa decarboxylase inhibitors (DDCIs), such as carbidopa, benserazide, or any combination thereof, accompanied by oral administration of levodopa and DDCIs, such as carbidopa, benserazide, or any combination thereof.

Description

[Technical Field]

[0001] This invention provides a method for treating neurological or motor disorders, such as Parkinson's disease, by non-enteral administration of levodopa or its prodrug and dopa decarboxylase inhibitor (DDCI) or its prodrug, such as carbidopa, benserazide or any combination thereof, accompanied by oral administration of levodopa or its prodrug and dopa decarboxylase inhibitor (DDCI) or its prodrug, such as carbidopa, benserazide or any combination thereof. [Previous Technology]

[0002] Parkinson's disease is a degenerative disease characterized by a decrease in the concentration of the neurotransmitter dopamine in the brain. Levodopa (L-DOPA or L-3,4-dihydroxyphenylalanine) is a direct metabolic precursor of dopamine. Unlike dopamine, it can cross the blood-brain barrier and is most commonly used to restore dopamine concentration in the brain. For the past 40 years, levodopa has remained the most effective treatment for Parkinson's disease.

[0003] However, levodopa has a short half-life in plasma and causes pulsatile dopaminergic stimulation even under best current standards of care. Therefore, long-term therapy is complicated by fluctuations in efficacy and motor difficulties, which can represent a significant source of disability in some patients. A treatment strategy that ultimately delivers levodopa / dopamine to the brain in a more continuous and physiological manner would provide the benefits of standard levodopa with reduced motor complications, and is highly needed for patients with Parkinson's disease and other neurological or motor disorders. [Summary of the Invention]

[0004] This article particularly provides methods and pharmaceutical compositions for treating neurological or motor disorders, comprising non-enteral administration of levodopa, its prodrug or a salt thereof (e.g., a pharmaceutically acceptable prodrug or a salt thereof), and a composition comprising the foregoing (e.g., a pharmaceutically acceptable composition, such as a liquid pharmaceutical composition), and dopa decarboxylase inhibitor (DDCI), its prodrug or a salt thereof (e.g., a pharmaceutically acceptable prodrug or a salt thereof), and a composition comprising the foregoing (e.g., a pharmaceutically acceptable composition, such as a liquid pharmaceutical composition), accompanied by oral administration of an active agent selected from the group consisting of: levodopa, levodopa salt, levodopa prodrug, dopa decarboxylase inhibitor (DDCI), its prodrug or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), and a composition comprising the foregoing (e.g., a pharmaceutically acceptable composition, such as a liquid pharmaceutical composition). The present invention also discloses a kit for administering the described method, and a treatment regimen for administering the described method, specified by a time schedule and an amount of pharmaceutical composition.

[0005] An embodiment of the present invention relates to a method for treating Parkinson's disease in a patient in need, the method comprising: subcutaneously administering to the patient a medically acceptable liquid composition comprising levodopa and carbidopa over a subcutaneous infusion period of at least about 24 hours, wherein about 720 mg of levodopa and about 90 mg of carbidopa are delivered to the patient during the at least about 24 hours; and orally administering to the patient one or more direct-release tablets or capsules comprising 100 mg of levodopa before or during the subcutaneous infusion period.

[0006] According to some embodiments, the pharmaceutically acceptable liquid composition further comprises arginine. According to some embodiments, the pharmaceutically acceptable liquid composition further comprises at least one antioxidant. According to some embodiments, the direct-release tablets or capsules further comprise carbidopa.

[0007] According to some embodiments, after the subcutaneous administration and the oral administration, the area under the curve (AUC) of plasma levodopa in the patient from time 0 to the end of the infusion time is higher than the following combination: i) plasma levodopa AUC from time 0 to the end of the infusion time when the medically acceptable liquid composition is administered subcutaneously to the patient alone for at least about 24 hours; and ii) plasma levodopa AUC in patients who are administered oral levodopa alone.

[0008] Other embodiments of the present invention relate to a method for treating Parkinson's disease in a patient in need, the method comprising: subcutaneously administering to the patient, over a subcutaneous infusion period of at least about 24 hours or longer, a first pharmaceutically acceptable liquid composition comprising: levodopa, carbidopa, arginine and an antioxidant, wherein about 720 mg of levodopa and about 90 mg of carbidopa are delivered to the patient during the at least about 24 hours; and orally administering to the patient, before or during the subcutaneous infusion period, at least one oral formulation comprising levodopa.

[0009] According to some embodiments, the oral dosage form includes one of the following: 50 mg levodopa, 75 mg levodopa, 95 mg levodopa, 100 mg levodopa, 125 mg levodopa, 145 mg levodopa, 150 mg levodopa, 195 mg levodopa, 200 mg levodopa, 245 mg levodopa, or 250 mg levodopa.

[0010] Other embodiments of the present invention relate to a method for treating a patient with Parkinson's disease who is currently receiving levodopa and carbidopa in the form of oral direct release alone and requires further treatment. The method comprises: administering to the patient subcutaneously, over a 24-hour subcutaneous infusion schedule, a first pharmaceutically acceptable liquid composition comprising levodopa, carbidopa, arginine, and an antioxidant, in an amount of approximately 720 mg of levodopa and approximately 90 mg of carbidopa to the patient over the at least approximately 24-hour period; and administering to the patient orally daily, before or during the subcutaneous infusion schedule, at least one tablet or capsule comprising 100 mg of levodopa and 25 mg of carbidopa.

[0011] This article discloses a method for treating neurological or motor disorders in patients in need, the method comprising: administering to the patient, non-enterally, a first pharmaceutical composition comprising: a) levodopa, levodopa salt, levodopa prodrug or any combination thereof; and b) dopa decarboxylase inhibitor (DDCI), DDCI salt, DDCI prodrug or any combination thereof; and concurrently, administering to the patient, orally, a second pharmaceutical composition comprising an active agent selected from the group consisting of: levodopa, levodopa salt, levodopa prodrug, dopa decarboxylase inhibitor (DDCI), DDCI salt, DDCI prodrug or any combination thereof.

[0012] In some embodiments, the method described herein includes DDCI, which comprises, consists of, or is substantially composed of carbidopa, benserazide, or any combination thereof.

[0013] In some embodiments, the method described herein includes a DDCI in a first pharmaceutical composition identical to that of a DDCI in a second pharmaceutical composition.

[0014] In some embodiments, the method described herein includes a DDCI in a first pharmaceutical composition that is different from a DDCI in a second pharmaceutical composition.

[0015] In some embodiments, the methods described herein include levodopa and DDCI as a second pharmaceutical composition.

[0016] In some embodiments, the methods described herein include DDCI carbidopa.

[0017] In some embodiments, methods described herein include subcutaneous, percutaneous, intradermal, intravenous, intramuscular, endotracheal, intranasal, intrathecal, intragastric, or intraduodenal administration of a first pharmaceutical composition.

[0018] In some embodiments, the methods described herein include subcutaneous administration with a first pharmaceutical composition.

[0019] In some embodiments, the method described herein comprises administering a pharmaceutical composition to a patient in need via one or more sites.

[0020] In some embodiments, neurological or motor disorders concerning the methods described herein include Parkinson's disease; syndrome, postencephalitis Parkinson’s and vascular Parkinson’s;fluctuating drug efficacy;neurodegenerative conditions;motor difficulties;reduced dopamine content in the brain;levodopa-induced dyskinesia;rapid eye movement sleep behavior disorder (RBD ); disease);

[0021] Generally, physicians use various scales, such as those for assessing the severity of Parkinson's disease based on objective and subjective signs and symptoms, and thus prescribe levodopa administration. One of the well-known and widely used scales for diagnosing Parkinson's disease and determining its severity is the Unified Parkinson's Disease Rating Scale (UPDRS). Variations of the UPDRS can also be used to classify Parkinson's patients. Another known method for measuring the severity of Parkinson's disease is based on the Hoehn and Yahr (H&Y) staging system, which includes a 5-stage scale. Stages 1 and 2 are considered mild or early-stage Parkinson's disease, stage 3 is considered moderate or intermediate-stage Parkinson's disease, and stages 4 and 5 are considered late-stage Parkinson's disease. The daily levodopa dosage can be determined and changed periodically by the physician based on factors such as clinical findings and trial-and-error methods, taking into account the specific patient's condition, response to treatment, and similar cases. Furthermore, patients can receive different daily doses on different days based on their symptoms, with the range of daily doses set by the physician, thus providing flexibility in treatment. It should be noted that physicians typically refer to symptoms as objective measurements and signs as subjective measurements.

[0022] According to some embodiments, this document provides a method for treating patients with advanced Parkinson's disease. According to some embodiments, this document provides a method for treating patients with advanced and / or moderate Parkinson's disease. According to some embodiments, this document provides a method for treating patients with fluctuating drug efficacy. According to some embodiments, this document provides a method for treating patients with Parkinson's disease who have fluctuating drug efficacy.

[0023] According to some embodiments, this article provides a method for treating patients with Parkinson's disease who require doses higher than about 300 mg levodopa / day, higher than about 400 mg levodopa / day, higher than about 500 mg levodopa / day, higher than about 600 mg levodopa / day, higher than about 700 mg levodopa / day, higher than about 800 mg levodopa / day, higher than about 900 mg levodopa / day, and higher than about 1000 mg levodopa / day.

[0024] According to some embodiments, this document provides a method for treating patients with Parkinson's disease in which a higher dose of levodopa is required at specific time points, such as in the morning, near the end of a low-activity / nighttime period (approximately the last hour), or at the beginning of a high-activity / daytime period (approximately the first hour). For example, according to some embodiments, the high-activity / daytime period may have one rate and the low-activity / nighttime period may have a different rate, wherein a higher dose of levodopa may be administered near the end of the low-activity / nighttime period, at the end of the low-activity / nighttime period, and at the beginning of the high-activity / daytime period. Such a higher dose may be provided by oral administration of a second pharmaceutical composition, for example, at the times mentioned above, which is provided concurrently with a substantially continuous first pharmaceutical composition.

[0025] According to some embodiments, this article provides a method for treating patients with Parkinson's disease for a period of time that lasts for more than about 4 years, more than about 5 years, more than about 6 years, more than about 7 years, more than about 8 years, more than about 9 years, or more than about 10 years.

[0026] According to some embodiments, this article provides a method for treating patients with Parkinson's disease who suffer from "off time" of at least 1 hour, at least 1.5 hours, at least 2 hours, at least 2.5 hours, or at least 3 hours per day, wherein "off time" refers to the recurrence of Parkinson's symptoms between drug administrations.

[0027] In some embodiments, the method described herein includes substantially continuous dosing of a first pharmaceutical composition.

[0028] In some embodiments, the method described herein includes administering the second pharmaceutical composition 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 times per day.

[0029] In some embodiments, the method described herein includes administering a second pharmaceutical composition when the administration is required for symptoms arising from the neurological or motor disorder.

[0030] In some embodiments, the methods described herein include administering a second pharmaceutical composition at a predetermined time, a predetermined interval, or both.

[0031] In some embodiments, the method described herein includes administering a second pharmaceutical composition more than once, wherein the dosage administered is the same in all administrations.

[0032] In some embodiments, the method described herein includes administering a second pharmaceutical composition more than once, wherein the dosage administered differs in at least two administrations.

[0033] In some embodiments, the method described herein includes administering a second pharmaceutical composition in each administration at a dose between about 25 mg and about 400 mg of levodopa or its salt or its prodrug.

[0034] In some embodiments, the methods described herein include levodopa, carbidopa and arginine or any salt thereof or a prodrug thereof as a first pharmaceutical composition.

[0035] In some embodiments, the methods described herein include levodopa, carbidopa and arginine or any salt thereof or a prodrug thereof as a first pharmaceutical composition, and at least one antioxidant.

[0036] In some embodiments, the methods described herein include levodopa, carbidopa and arginine or any salt thereof or a prodrug thereof as a first pharmaceutical composition, and at least two antioxidants.

[0037] In some embodiments, the methods described herein include a composition as a first pharmaceutical composition comprising levodopa, carbidopa and arginine or any salt thereof or a prodrug thereof, and a base selected from the group consisting of arginine, NaOH, tris(hydroxymethyl)aminomethane (TRIS) and any combination thereof.

[0038] In some embodiments, the methods described herein include a composition as a first pharmaceutical composition having a pH in the range of about 6 to about 10, about 8 to about 10, about 9 to about 10, about 9.1 to about 9.8, or about 9.5.

[0039] In some embodiments, the methods described herein include a composition as a first pharmaceutical composition comprising levodopa, a levodopa prodrug, a levodopa salt, or any combination thereof, at a rate of about 1% w / v to about 40% w / v, about 1% w / v to about 20% w / v, about 1% w / v to about 10% w / v, about 2% w / v to about 8% w / v, about 4% w / v to about 8% w / v, about 5% w / v to about 7% w / v, or about 6% w / v.

[0040] In some embodiments, the methods described herein include a composition as a first pharmaceutical composition comprising carbidopa, carbidopa salt, carbidopa prodrug, or any combination thereof at about 0.5% w / v to about 10% w / v, about 0.5% w / v to about 6% w / v, about 0.5% w / v to about 4% w / v, about 0.5% w / v to about 2% w / v, about 0.5% w / v to about 1% w / v, or about 0.75% w / v.

[0041] In some embodiments, the methods described herein include antioxidants selected from the group consisting of: ascorbic acid or a salt thereof; cysteine, such as N-acetylcysteine; bisulfite or a salt thereof; glutathione; tyrosinase inhibitors; divalent cations; butylated hydroxytoluene (BHT); β-hydroxy acid (BHA) tocopherol; gentian acid; tocopherol; tocopherol derivatives; thioglycerol; and any combination thereof.

[0042] In some embodiments, the method described herein includes a composition as a first pharmaceutical composition comprising an antioxidant or combination of antioxidants at a concentration of between about 0.05% w / v and about 2.0% w / v, between about 0.5% w / v and about 1.5% w / v, about 0.75% w / v, about 0.9% w / v, about 1.0% w / v, about 1.1% w / v, or about 1.25% w / v.

[0043] In some embodiments, the method described herein includes a composition as a first pharmaceutical composition comprising an alkali between about 5% w / v and about 30% w / v, between about 10% w / v and 20% w / v, between about 12.5% ​​w / v and 17.5% w / v, about 15% w / v, or about 15.2% w / v.

[0044] In some embodiments, the method described herein includes administering a first pharmaceutical composition via one or two sites.

[0045] In some embodiments, the method described herein includes administering a first pharmaceutical composition to a volume of about 1 ml to about 30 ml per day, about 2 ml to about 20 ml per day, about 3 ml to about 10 ml per day, about 5 ml to about 7 ml per day, or about 6 ml per day per point.

[0046] This article also discloses a first pharmaceutical composition comprising: levodopa, levodopa salt, levodopa prodrug, or any combination thereof; and dopa decarboxylase inhibitor (DDCI), DDCI salt, DDCI prodrug, or any combination thereof; and a second pharmaceutical composition comprising: levodopa, levodopa salt, levodopa prodrug, dopa decarboxylase inhibitor (DDCI), DDCI salt, DDCI prodrug; or any combination thereof, for use in combination to treat neurological or motor disorders, wherein the first pharmaceutical composition is formulated as a non-enteric composition and the second pharmaceutical composition is formulated as an oral composition.

[0047] This document also discloses a kit comprising: a first pharmaceutical composition in a non-enteral form comprising: levodopa, levodopa salt, levodopa prodrug or any combination thereof; and a dopa decarboxylase inhibitor (DDCI), DDCI salt, DDCI prodrug or any combination thereof; a second pharmaceutical composition in an oral form comprising: levodopa, levodopa salt, levodopa prodrug, dopa decarboxylase inhibitor (DDCI), DDCI salt, DDCI prodrug or any combination thereof; and instructions for use in conjunction with the administration of the first pharmaceutical composition and the second pharmaceutical composition for the treatment of neurological or motor disorders.

[0048] In other embodiments, this document discloses a method for treating neurological or motor disorders in a patient in need, the method comprising: subcutaneously administering to a patient a first pharmaceutically acceptable liquid composition comprising levodopa and carbidopa over a subcutaneous infusion course of about 7 hours to about 10 hours or longer (e.g., about 8 hours), wherein the amount delivered to the patient is about 100 mg to 200 mg of levodopa and about 12 mg to about 50 mg of carbidopa; and orally administering to the patient a direct-release tablet or capsule comprising levodopa and carbidopa before or during the subcutaneous infusion course. The direct-release tablets may include, for example, 50 mg, 75 mg, 100 mg, 125 mg or 150 mg of levodopa, and / or may include 2.5 mg, 18.57 mg, 25 mg, 31.25 mg, 37.5 mg or 50 mg of carbidopa. In some embodiments, the methods described herein include initial and / or simultaneous oral administration of a direct-release tablet or capsule at the start of an infusion schedule. For example, the oral administration of the direct-release tablet or capsule may be performed substantially at the same time as the start of the infusion, and / or approximately 1, 2, 3, 4, or 5 hours after the start of the infusion schedule (e.g., approximately 0 hours or approximately 4 hours after the start of the infusion schedule), and / or approximately 1, 2, 3, 4, or 5 hours before the start of the infusion schedule (e.g., approximately 0 hours or approximately 4 hours before the start of the infusion schedule).

[0049] In some embodiments, the methods described herein include direct release tablets or capsules containing 100 mg of levodopa and 25 mg of carbidopa.

[0050] The methods described herein may include subcutaneous administration of a first-medical-acceptable liquid composition comprising levodopa and carbidopa, wherein an amount of about 140 mg to 170 mg of levodopa and about 16 mg to about 24 mg of carbidopa is delivered to the patient. The first-medical-acceptable liquid composition covered may include a liquid composition comprising about 6 wt% levodopa, about 0.75 wt% carbidopa, and about 10 wt% to about 20 wt% arginine.

[0051] For example, the method described herein may include subcutaneous administration of the first composition and oral administration of tablets or capsules, wherein the area under the curve (AUC) of levodopa in the patient from time 0 to the end of the infusion time is higher than the following combinations: the levodopa AUC of the patient who received the first composition subcutaneously from time 0 to the end of the infusion time and the levodopa AUC of the patient who received tablets or capsules alone, wherein the amount of levodopa administered subcutaneously and orally is approximately the same as the amount of levodopa administered subcutaneously and orally alone.

[0052] This article also discloses a method for treating neurological or motor disorders in patients in need, comprising: administering subcutaneously to a patient a first medically acceptable liquid composition comprising about 6 wt% levodopa and about 0.75 wt% carbidopa over a subcutaneous infusion course of about 7 hours to about 10 hours or longer; and administering orally to the patient a direct-release tablet or capsule comprising 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 200 mg or 250 mg levodopa before or during the subcutaneous infusion course, wherein the direct-release tablet or capsule further comprises carbidopa as appropriate.

[0053] This article also discloses a method for treating neurological or motor disorders in patients in need, comprising: administering subcutaneously to a patient a first medically acceptable liquid composition comprising levodopa and carbidopa over a subcutaneous infusion course of about 24 hours or longer, wherein the amount of about 720 mg of levodopa and about 90 mg of carbidopa is delivered to the patient over a course of about 24 hours; and administering orally to the patient, before or during the subcutaneous infusion course, a tablet or capsule comprising levodopa and carbidopa, such as a direct-release or modified-release tablet or capsule, such as a extended-release tablet or capsule.

[0054] In some embodiments, the method disclosed herein includes administering subcutaneous infusion at a high activity rate over a time span of about 18 hours and at a low activity rate over a time span of about 6 hours, wherein about 691.2 mg of levodopa and about 86.4 mg of carbidopa are administered during the 18-hour high activity period and about 28.8 mg of levodopa and 3.6 mg of carbidopa are administered during the 6-hour low activity period.

[0055] According to some embodiments, the tablets or capsules are administered orally substantially simultaneously at the start of the infusion course. The tablets or capsules may be administered at predetermined intervals during the infusion, or as needed or requested, based on feedback from, for example, the patient, caregiver, physician, sensor, or similar source. The intervals at which the tablets or capsules are administered may be substantially the same or different from each other. According to some embodiments, the tablets or capsules are administered orally approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours after the start of the infusion course, wherein any number of tablets or capsules may be administered, as detailed herein. According to some embodiments, the tablets or capsules contain 100 mg of levodopa and 25 mg of carbidopa.

[0056] According to some embodiments, a first pharmaceutically acceptable liquid composition comprising about 6 wt% levodopa, about 0.75 wt% carbidopa and about 10 wt% to about 20 wt% arginine is administered by the method of the present invention for a duration of 24 hours or longer.

[0057] According to some embodiments, regardless of the administration of a first pharmaceutically acceptable liquid composition for 24 hours or longer according to the method of the invention, accompanied by oral administration of tablets or capsules, as detailed herein, when the amount of levodopa administered subcutaneously and orally is approximately the same as the combined amount of levodopa administered subcutaneously and orally alone, the area under the curve (AUC) of levodopa in the patient from time 0 to the end of the infusion time is higher than the combination of: the levodopa AUC in the patient from time 0 to the end of the infusion time when the first composition is administered subcutaneously alone and the levodopa AUC in the patient when tablets or capsules are administered alone.

Implementation Method

[0058] Cross-reference to related applications

[0059] This application claims the benefit and priority of U.S. Provisional Patent Application No. 63 / 114,688, filed November 17, 2020, and U.S. Patent Application No. 17 / 334,554, filed May 28, 2021, the disclosures of each of which are incorporated herein by reference in their entirety.

[0060] The features and other details of the invention will now be described more precisely. Certain terms used in this specification, examples, and appended claims are compiled herein. These definitions should be read in light of the remainder of the invention and as understood by one skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one skilled in the art to which this invention pertains.

[0061] The terms “treat” and similar terms are used herein to generally refer to the attainment of desired pharmacological and / or physiological effects. Such effects may be therapeutic in relation to the partial or complete cure of a disease and / or adverse effects attributable to the disease. As used herein, the term “treat” covers any treatment of a disease in mammals (particularly humans) and includes: (a) suppressing the disease, i.e., preventing an increase in the severity or extent of the disease; (b) alleviating the disease, i.e., causing partial or complete improvement of the disease; or (c) preventing the recurrence of the disease, i.e., preventing the disease from returning to an active state after previously successfully treating the symptoms of the disease or after treating the disease.

[0062] "Prevention" includes delaying the onset of clinical symptoms, complications, or biochemical markers of a condition, symptom, disease, or illness that develops in an individual who may have or be susceptible to the condition, symptom, disease, or illness but has not yet experienced or displayed clinical or subclinical symptoms of the condition, symptom, disease, or illness. "Prevention" also includes preventive treatment of a condition, symptom, disease, or illness that is present in or develops in an individual, including preventive treatment of clinical symptoms, complications, or biochemical markers of a condition, symptom, disease, or illness that is present in or develops in an individual.

[0063] As used herein, the terms “medically acceptable carrier” or “medically acceptable excipient” may be used interchangeably to refer to any and all solvents, dispersion media, coatings, isotonics and absorption delay agents and the like that are compatible with pharmaceutical administration.

[0064] As used herein, the terms “pharmaceutical composition” and “pharmaceutical formulation” refer to a composition or formulation comprising at least one bioactive compound (e.g., levodopa or carbidopa) or a pharmaceutically acceptable salt thereof or a prodrug thereof formulated together with one or more pharmaceutically acceptable excipients.

[0065] As used herein, the term "medically acceptable salt" means a salt of an acidic or basic group that can be formed by the combination used in the compositions disclosed herein.

[0066] The terms "individual," "patient," or "subject" are used interchangeably and include any animal, including mammals, mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or non-human primates and humans. In some embodiments, the mammal treated in the method of the present invention is a human suffering from a neurodegenerative condition (such as Parkinson's disease).

[0067] Unless otherwise specifically mentioned, or unless understood otherwise by one skilled in the art, the term "about" as used herein shall be deemed to cover a range of ±10% of the listed values. It should be further noted that any value provided may also be deemed to cover a range of ±10% of that value, even if the term "about" is not used. This includes the values ​​in the examples section, which may vary depending on the apparatus and machinery used, the purity of the compound, etc.

[0068] Unless otherwise specifically mentioned, or unless understood by one of those skilled in the art, the term "liquid" as used herein means any type of fluid, including gels, aqueous and non-aqueous compositions and the like.

[0069] Unless otherwise specifically mentioned, or unless understood by one skilled in the art, the term "concomitant" as used herein means any type of combined administration of two or more active ingredients in the same composition, simultaneous administration of such active ingredients in separate compositions, and sequential administration of two or more active ingredients on the same day, wherein the administration of the active ingredients is separated from each other at predetermined time intervals, and the like. The term "concomitant" may also be used herein to refer to any type of combined administration of two separate pharmaceutical compositions, wherein the compositions may be administered via different routes of administration, at different intervals, at different doses, etc. For example, as detailed herein, a composition may be administered non-enterally, such as subcutaneously, substantially sequentially, while a second composition is administered concurrently with the first composition by oral administration in a non-sequential manner. Furthermore, the concomitant administration of two or more separate compositions may be dependent on or independent of each other.

[0070] Unless otherwise specifically mentioned, or unless understood otherwise by one skilled in the art, the terms "continuous" and "substantially continuous" as used herein mean a period of time during which the composition is administered, with interruptions of less than about 24 hours, about 12 hours, about five hours, about three hours, about one hour, about 30 minutes, about 15 minutes, about five minutes, or about one minute. The period of administration of the composition may be at least about six hours, about eight hours, about 12 hours, about 15 hours, about 18 hours, about 21 hours, about 24 hours, three days, seven days, two weeks, one month, three months, six months, one year, two years, three years, five years, ten years, etc.

[0071] Unless otherwise specifically mentioned, or unless otherwise understood by those familiar with the technology, the term "physiologically acceptable pH" and its analogues as used herein refer to pH values ​​in the range between about 4.5 and about 10. It should be further noted that when pH values ​​are provided, included in instances, the values ​​may be in the range of about ±0.1 and / or ±10% of the listed values ​​such that the same formulation can be prepared to provide a pH of about 8.0 or 8.2 if the measured pH is 8.1. These differences can be attributed to temperature changes, various measuring devices, and so on.

[0072] Nervous disorder is a condition of the nervous system of the body, and as used herein the term "motor disorder" refers to a condition of the nervous system that causes abnormal autonomic or involuntary movement or slow, reduced movement. According to some embodiments, the neurological or motor disorder is Parkinson's disease; symptoms;fluctuations in drug efficacy;neurodegenerative conditions;movement difficulties;reduced dopamine content in the brain;levodopa-induced motor difficulties;rapid eye movement sleep behavior disorder (RBD);muscular insufficiency;inability to exercise in the morning;concussion symptoms, etc such as idiopathic tremor and drug-induced tremor;myoclonus;chorea, such as drug-induced chorea;convulsions, such as drug-induced convulsions and organic convulsions;drug-induced dyskinesia;drug-induced restlessness;restless leg syndrome (RLS);zombie syndrome;benign tremor seizures;malignant antipsychotic syndrome;Hangdington's chorea;Chey-Delger's disease-induced oxidative carbohydrate syndrome, any combination of manganese-damaging or oxidative carbohydrates;

[0073] As used herein, the term "dopa decarboxylase inhibitor" refers to an agent capable of inhibiting the peripheral metabolism of levodopa to dopamine by aromatic L-amino acid decarboxylase, such as carbidopa and benzyl hydrazine.

[0074] Unless otherwise specifically mentioned, or unless otherwise understood by those familiar with the technology, the terms "morning dose" and "morning oral dose" as used herein are interchangeable and refer to oral dosage forms containing levodopa, which are administered especially in the morning hours, such as 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 30 minutes, 2 hours, 45 hours of the patient's awakening time. According to some embodiments, the morning dose refers to an oral dosage form comprising levodopa, which is administered within 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, or 30 minutes of the patient's waking time.

[0075] According to some embodiments, the morning oral dose includes one of the following: 25 mg levodopa, 50 mg levodopa, 75 mg levodopa, 95 mg levodopa, 100 mg levodopa, 125 mg levodopa, 145 mg levodopa, 150 mg levodopa, 195 mg levodopa, 200 mg levodopa, 245 mg levodopa, or 250 mg levodopa.

[0076] An embodiment of the present invention relates to a method for treating neurological or motor disorders (such as Parkinson's disease) in patients in need, wherein the method comprises: administering, non-enterally, a first pharmaceutical composition comprising: levodopa, levodopa salt, levodopa prodrug, or any combination thereof; and a dopa decarboxylase inhibitor (DDCI), DDCI salt, DDCI prodrug, or any combination thereof; and concurrently, administering, orally, a second pharmaceutical composition comprising: levodopa, levodopa salt, levodopa prodrug; a dopa decarboxylase inhibitor (DDCI), DDCI salt, DDCI prodrug, or any combination thereof.

[0077] According to some embodiments, the accompanying administration of the first pharmaceutical composition and the second pharmaceutical composition provides a synergistic effect, such that the levodopa blood level obtained by the accompanying administration is higher than the expected additive effect when the first and second pharmaceutical compositions are not administered. According to some embodiments, the synergistic effect between the first and second pharmaceutical compositions provides an increase in levodopa blood level of about 5% to about 50% compared to the expected additive effect. According to some embodiments, the synergistic effect between the first and second pharmaceutical compositions provides an increase in levodopa blood level of about 10% to 40%, about 15% to 35%, about 20% to 40%, about 25% to 35%, or about 30% compared to the expected additive value.

[0078] According to some embodiments, the first pharmaceutical composition comprises levodopa and carbidopa. According to some embodiments, the second pharmaceutical composition comprises levodopa and carbidopa. According to some embodiments, the second pharmaceutical composition comprises only levodopa.

[0079] According to some embodiments, the first pharmaceutical composition and / or the second pharmaceutical composition comprises (1) levodopa, levodopa salt and / or levodopa prodrug, and / or (2) carbidopa, carbidopa salt and / or carbidopa prodrug. According to some embodiments, the levodopa prodrug is any of the prodrugs disclosed in PCT / IL2020 / 050960 or US 63 / 159,236, which are incorporated herein by reference in their entirety. According to some embodiments, the carbidopa prodrug is any prodrug disclosed in JP 2021-037959.

[0080] According to some embodiments, DDCI is carbidopa, a carbidopa prodrug, a carbidopa salt, benserazide, a benserazide prodrug, a benserazide salt, or any combination thereof. According to some embodiments, DDCI is carbidopa. The DDCI in the first pharmaceutical composition may be the same as or different from the DDCI in the second pharmaceutical composition. Furthermore, the levodopa component in each of the first and second pharmaceutical compositions may be the same or different. That is, according to some embodiments, both the first and second pharmaceutical compositions contain levodopa, while according to other embodiments, the first pharmaceutical composition may contain one type of levodopa component, such as a levodopa prodrug and / or a levodopa salt, while the second pharmaceutical composition contains a different type of levodopa component, such as levodopa. It should be further noted that the concentration or amount of each component in the first pharmaceutical composition may differ from the concentration or amount of that component in the second pharmaceutical composition.

[0081] According to some embodiments, the first pharmaceutical composition can be administered via any non-enteric route, such as subcutaneously, percutaneously, intradermally, intravenously, intramuscularly, intratracheally, intranasally, intrathecally, intragastrically, or intraduodenally. According to some embodiments, the first pharmaceutical composition is administered subcutaneously. According to some embodiments, the first pharmaceutical composition is a liquid. According to some embodiments, the first pharmaceutical composition is aqueous.

[0082] According to some embodiments, the first pharmaceutical composition is substantially continuously administered. According to some embodiments, the first pharmaceutical composition is administered subcutaneously via a designated pump device.

[0083] Embodiments of the specified pump may be, for example, disclosed in US 62 / 529,784, US 62 / 576,362, PCT / IB2018 / 054962, US 16 / 027,804, US 16 / 027,710, US 10,463,787, US 10,463,572, US 10,603,430, US 16 / 685,364, US 2020 / 0093984, USD 29 / 655,583, USD 29 / 655,587, USD 29 / 655,589, USD 29 / 655,591, USD 29 / 655,592, USD 29 / 655,594, USD 29 / 655,597, USD Any pump embodiments described in US 29 / 723,714 and US 62 / 851,903 are incorporated herein by reference in their entirety.

[0084] According to some embodiments, the method of the present invention includes administering a first pharmaceutical composition at one, two, or three or more sites, wherein the location of the sites may be changed at any suitable, possibly predetermined interval. Once administered via a specific site, according to some embodiments, administration may only be performed via the same site or near that site after a possibly predetermined period of time. According to some embodiments, the location of any of the sites may be changed after 12, 24, 36, 48, 60, or 72 hours. According to some embodiments, the site location may be changed after 4, 5, 6, or 7 days. According to some embodiments, the site location may be changed after two, three, or four weeks. According to some embodiments, the site location may be changed upon request or need, for example, based on subjective data received from the patient and / or objective data received, for example, from a sensor located at or near the injection site.

[0085] According to some embodiments, the dosage volume and / or dosage rate are consistent across all or at least two sites. According to other embodiments, the dosage rate and / or dosage volume differ between sites. Each site may be controlled independently or otherwise, and all sites may be controlled dependently on each other.

[0086] According to some embodiments, the method of the present invention includes subcutaneous administration of the first pharmaceutical composition of the present invention over a time period of about 5 to about 24 hours or longer, for example about 5 to about 12 hours or longer, about 7 to about 10 hours or longer, or for example about 8 hours or about 24 hours.

[0087] According to some embodiments, the dose of the carbidopa component in the first pharmaceutical composition is between about 10 mg and about 25 mg per dose, between about 10 mg and about 50 mg per dose, between about 10 mg and about 75 mg per dose, between about 12 mg and about 25 mg per dose, between about 12 mg and about 50 mg per dose, between about 12 mg and about 75 mg per dose, between about 15 mg and about 25 mg per dose, between about 15 mg and about 50 mg per dose, between about 15 mg and about 75 mg per dose, between about 25 mg and about 50 mg per dose, between about 25 mg and about 75 mg per dose, and between about 50 mg and about 75 mg per dose. According to some embodiments, the dose of the carbidopa component in the first pharmaceutical composition is about 90 mg, for example, administered over a time interval of about 5 to about 24 hours or longer. According to some embodiments, the dose of the carbidopa component in the first pharmaceutical composition is between about 46 mg and about 90 mg per administration. According to some embodiments, the dose of the carbidopa component in the first pharmaceutical composition is about 90 mg, for example, administered over a time interval of about 24 hours. According to some embodiments, the dose of the carbidopa component in the first pharmaceutical composition is between about 46 mg and about 90 mg, for example, administered over a time interval of about 24 hours.

[0088] According to some embodiments, the dosage of the levodopa component in the first pharmaceutical composition is between about 10 mg and about 800 mg per dose, between about 10 mg and about 25 mg per dose, between about 25 mg and about 50 mg per dose, between about 50 mg and about 75 mg per dose, between about 75 mg and about 100 mg per dose, between about 100 mg and about 150 mg per dose, between about 150 mg and about 200 mg per dose, between about 200 mg and about 250 mg per dose, between about 250 mg and about 300 mg per dose, between about 300 mg and about 350 mg per dose, between about 350 mg and about 400 mg per dose, between about 400 mg and about 450 mg per dose, between about 450 mg and about 500 mg per dose, between about 500 mg and about 800 mg per dose, and about 600 mg per dose. Between approximately 370 mg and about 800 mg, between approximately 700 mg and about 800 mg, or about 720 mg. In some embodiments, the dose of the levodopa component in the first pharmaceutical composition is between approximately 370 mg and about 720 mg. In some embodiments, the dose is administered over a time interval of about 5 to about 24 hours (e.g., about 7 to about 10 hours, or about 8 hours, or about 24 hours) or longer. According to some embodiments, the dose of the levodopa component in the first pharmaceutical composition is about 720 mg, for example, administered over a time interval of about 24 hours. According to some embodiments, the dose of the levodopa component in the first pharmaceutical composition is between approximately 370 mg and about 720 mg, for example, administered over a time interval of about 24 hours. According to some embodiments, the dose of the levodopa component in the first pharmaceutical composition is between approximately 360 mg and about 720 mg, for example, administered over a time interval of about 24 hours. According to some embodiments, the dose of the levodopa component in the first pharmaceutical composition is at most about 720 mg.

[0089] In some embodiments, the first pharmaceutical composition is administered to the patient in an amount of about 100 mg to about 200 mg of levodopa and about 12 mg to about 50 mg of carbidopa. In some embodiments, the first pharmaceutical composition is administered to the patient in an amount of about 140 mg to about 170 mg of levodopa and about 16 mg to about 24 mg of carbidopa. In some embodiments, the dose is administered over a time interval of about 5 to about 24 hours (e.g., about 7 to about 10 hours) or longer. In some embodiments, the first pharmaceutical composition is administered to the patient over a time interval of about 24 hours in an amount of about 650 mg to about 800 mg, for example about 720 mg of levodopa and about 80 mg to about 100 mg, for example about 90 mg of carbidopa. According to some embodiments, the dose of the carbidopa component in the first pharmaceutical composition is between about 46 mg and about 90 mg, for example, over a time interval of about 24 hours. According to some embodiments, the dose of the carbidopa component in the first pharmaceutical composition is between about 45 mg and about 90 mg, for example, administered over a time interval of about 24 hours. According to some embodiments, the dose of the carbidopa component in the first pharmaceutical composition is at most about 90 mg.

[0090] According to some embodiments, the method of the present invention comprises subcutaneously administering between about 1 and about 30 ml of the first pharmaceutical composition of the present invention over a 24-hour time course. According to some embodiments, the method of the present invention includes subcutaneous administration over a time course of approximately 24 hours in amounts between approximately 1 ml and approximately 2 ml, between approximately 2 ml and approximately 3 ml, between approximately 3 ml and approximately 4 ml, between approximately 4 ml and approximately 5 ml, between approximately 5 ml and approximately 6 ml, between approximately 6 ml and approximately 7 ml, between approximately 7 ml and approximately 8 ml, between approximately 8 ml and approximately 9 ml, between approximately 9 ml and approximately 10 ml, between approximately 10 ml and approximately 11 ml, between approximately 11 ml and approximately 12 ml, between approximately 12 ml and approximately 13 ml, between approximately 13 ml and approximately 14 ml, between approximately 14 ml and approximately 15 ml, between approximately 15 ml and approximately 16 ml, between approximately 16 ml and approximately 17 ml, between approximately 17 ml and approximately 18 ml, between approximately 18 ml and approximately 19 ml, between approximately 19 ml and approximately 20 ml, between approximately 20 ml and approximately 21 ml, between approximately 21 ml and approximately 22 ml, and between approximately 22 ml and approximately 23 ml. A first pharmaceutical composition is administered in the range of approximately 23 ml to approximately 24 ml, approximately 24 ml to approximately 25 ml, approximately 25 ml to approximately 26 ml, approximately 26 ml to approximately 27 ml, approximately 27 ml to approximately 28 ml, approximately 28 ml to approximately 29 ml, and approximately 29 ml to approximately 30 ml. According to some embodiments, the method of the present invention comprises subcutaneously administering approximately 12 ml of the first pharmaceutical composition of the present invention over a time interval of approximately 24 hours.

[0091] According to some embodiments, the first pharmaceutical composition is administered at a volume of about 1 ml to about 30 ml per day per dose, about 2 ml to about 20 ml per day per dose, about 3 ml to about 10 ml per day per dose, about 5 ml to about 7 ml per day per dose, or about 6 ml per day per dose. According to some embodiments, the first pharmaceutical composition is administered at a volume of about 1 ml to about 2.5 ml per day, at a volume of about 2.5 ml to about 5.0 ml per day, at a volume of about 5.0 ml to about 7.5 ml per day, at a volume of about 7.5 ml to about 10 ml per day, at a volume of about 10 ml to about 12.5 ml per day, at a volume of about 12.5 ml to about 15 ml per day, at a volume of about 15 ml to about 17.5 ml per day, at a volume of about 17.5 ml to about 20 ml per day, at a volume of about 20 ml to about 22.5 ml per day, at a volume of about 22.5 ml to about 25 ml per day, at a volume of about 25 ml to about 27.5 ml per day, and at a volume of about 27.5 ml to about 30 ml per day. According to some embodiments, the first pharmaceutical composition is administered at a volume of about 6 ml per day.

[0092] It should be noted that the application rate may be constant over a 24-hour timeframe or may vary over a 24-hour timeframe. For example, according to some embodiments, there may be a certain rate for high activity / daytime hours and different rates for low activity / nighttime hours. High activity / daytime hours may be, for example, about 15 hours, about 16 hours, about 17 hours, about 18 hours, or about 19 hours, while low activity / nighttime hours may correspond to about 9 hours, about 8 hours, about 7 hours, about 6 hours, or about 5 hours. According to some embodiments, the high activity / daytime rate is implemented for about 18 hours, while the low activity / nighttime rate is implemented for about 6 hours. According to some embodiments, the high activity / daytime rate is implemented for about 16 hours, while the low activity / nighttime rate is implemented for about 8 hours. According to some embodiments, the application rate is determined at least in part by input received from the patient, caregiver, at least one sensor, and the like. According to some embodiments, the application rate may be increased or decreased as needed according to a predetermined pattern, which may be set periodically, for example, by the caregiver or patient. According to other embodiments, the delivery rate can be changed online, for example, increased or decreased, such as by instructing a change in delivery rate to be necessary or beneficial based on input received from the patient, caregiver, or at least one sensor. For example, if a patient wishes to rest at a certain point during the day, the rate can be reduced from a daytime rate to a nighttime rate, for example, by a command provided by the patient. Furthermore, a caregiver can provide the system with commands about the patient, such as resting during the day. Additionally, sensors can alert the system that the patient has fallen asleep (or asleep) and thus reduce the delivery rate. Sensors can also provide sleep pattern data, allowing the system to be notified and responded to before the patient wakes up from sleep, for example, by increasing the delivery rate. Monitored patient conditions can also cause changes in the delivery rate; for example, entering a "shutdown period" or similar conditions can cause the delivery rate to increase.

[0093] The dosing rate can be between about 0.01 mL / site / hour and about 1 mL / site / hour. According to some embodiments, the dosing rate is between about 0.01 and 0.02 mL / site / hour. According to some embodiments, the dosing rate is between about 0.02 and 0.03 mL / site / hour. According to some embodiments, the dosing rate is between about 0.03 and 0.04 mL / site / hour. According to some embodiments, the dosing rate is between about 0.04 and 0.05 mL / site / hour. According to some embodiments, the dosing rate is between about 0.05 and 0.06 mL / site / hour. According to some embodiments, the dosing rate is between about 0.06 and 0.07 mL / site / hour. According to some embodiments, the dosing rate is between about 0.07 and 0.08 mL / site / hour. According to some embodiments, the dosing rate is between about 0.08 and 0.09 mL / site / hour. According to some embodiments, the dosing rate is between about 0.09 and 0.1 mL / site / hour. According to some embodiments, the dosing rate is between about 0.1 and 0.15 mL / site / hour. According to some embodiments, the dosing rate is between about 0.15 and 0.2 mL / site / hour. According to some embodiments, the dosing rate is between about 0.2 and 0.25 mL / site / hour. According to some embodiments, the dosing rate is between about 0.25 and 0.3 mL / site / hour. According to some embodiments, the dosing rate is between about 0.3 and 0.35 mL / site / hour. According to some embodiments, the dosing rate is between about 0.35 and 0.4 mL / site / hour. According to some embodiments, the dosing rate is between about 0.4 and 0.45 mL / site / hour. According to some embodiments, the dosing rate is between about 0.45 and 0.5 mL / site / hour. According to some embodiments, the dosing rate is between about 0.5 and 0.55 mL / site / hour. According to some embodiments, the dosing rate is between about 0.55 and 0.6 mL / site / hour. According to some embodiments, the dosing rate is between about 0.6 and 0.65 mL / site / hour. According to some embodiments, the dosing rate is between about 0.65 and 0.7 mL / site / hour. According to some embodiments, the dosing rate is between about 0.7 and 0.75 mL / site / hour. According to some embodiments, the dosing rate is between about 0.75 and 0.8 mL / site / hour. According to some embodiments, the dosing rate is between about 0.8 and 0.85 mL / site / hour. According to some embodiments, the dosing rate is between about 0.85 and 0.9 mL / site / hour. According to some embodiments, the dosing rate is between about 0.9 and 0.95 mL / site / hour. According to some embodiments, the dosing rate is between about 0.95 and 1.0 mL / site / hour.

[0094] According to some embodiments, the dosing rate during low activity / nighttime is between about 0.01 and 0.15 mL / site / hour. According to some embodiments, the dosing rate during low activity / nighttime is between about 0.01 and 0.02 mL / site / hour. According to some embodiments, the dosing rate during low activity / nighttime is between about 0.02 and 0.03 mL / site / hour. According to some embodiments, the dosing rate during low activity / nighttime is between about 0.03 and 0.04 mL / site / hour. According to some embodiments, the dosing rate during low activity / nighttime is between about 0.04 and 0.05 mL / site / hour. According to some embodiments, the dosing rate during low activity / nighttime is between about 0.05 and 0.06 mL / site / hour. According to some embodiments, the dosing rate during low activity / nighttime is between about 0.06 and 0.07 mL / site / hour. According to some embodiments, the dosing rate during periods of low activity / nighttime is between approximately 0.07 and 0.08 mL / site / hour. According to some embodiments, the dosing rate during periods of low activity / nighttime is between approximately 0.08 and 0.09 mL / site / hour. According to some embodiments, the dosing rate during periods of low activity / nighttime is between approximately 0.09 and 0.1 mL / site / hour. According to some embodiments, the dosing rate during periods of low activity / nighttime is between approximately 0.1 and 0.11 mL / site / hour. According to some embodiments, the dosing rate during periods of low activity / nighttime is between approximately 0.11 and 0.12 mL / site / hour. According to some embodiments, the dosing rate during periods of low activity / nighttime is between approximately 0.12 and 0.13 mL / site / hour. According to some embodiments, the dosing rate during periods of low activity / nighttime is between approximately 0.13 and 0.14 mL / site / hour. According to some embodiments, the dosing rate during periods of low activity / nighttime is between approximately 0.14 and 0.15 mL / site / hour. According to some embodiments, the dosing rate during periods of low activity / nighttime is approximately 0.04 mL / site / hour. According to some embodiments, the dosing rate during periods of low activity / nighttime is approximately 0.08 mL / site / hour.

[0095] According to some embodiments, the dosing rate during high activity / daytime periods is between about 0.15 and 1.0 mL / site / hour. According to some embodiments, the dosing rate during high activity / daytime periods is between about 0.15 and 0.2 mL / site / hour. According to some embodiments, the dosing rate during high activity / daytime periods is between about 0.2 and 0.25 mL / site / hour. According to some embodiments, the dosing rate during high activity / daytime periods is between about 0.25 and 0.3 mL / site / hour. According to some embodiments, the dosing rate during high activity / daytime periods is between about 0.3 and 0.35 mL / site / hour. According to some embodiments, the dosing rate during high activity / daytime periods is between about 0.35 and 0.4 mL / site / hour. According to some embodiments, the dosing rate during high activity / daytime periods is between about 0.4 and 0.45 mL / site / hour. According to some embodiments, the dosing rate during high activity / daytime periods is between about 0.45 and 0.5 mL / site / hour. According to some embodiments, the dosing rate during high activity / daytime periods is between about 0.5 and 0.55 mL / site / hour. According to some embodiments, the dosing rate during high activity / daytime periods is between about 0.55 and 0.6 mL / site / hour. According to some embodiments, the dosing rate during high activity / daytime periods is between about 0.6 and 0.65 mL / site / hour. According to some embodiments, the dosing rate during high activity / daytime periods is between about 0.65 and 0.7 mL / site / hour. According to some embodiments, the dosing rate during high activity / daytime periods is between about 0.7 and 0.75 mL / site / hour. According to some embodiments, the dosing rate during high activity / daytime periods is between about 0.75 and 0.8 mL / site / hour. According to some embodiments, the dosing rate during high activity / daytime periods is between about 0.8 and 0.85 mL / site / hour. According to some embodiments, the dosing rate during high activity / daytime periods is between about 0.85 and 0.9 mL / site / hour. According to some embodiments, the dosing rate during periods of high activity / daytime is between about 0.9 and 0.95 mL / site / hour. According to some embodiments, the dosing rate during periods of high activity / daytime is between about 0.95 and 1.0 mL / site / hour. According to some embodiments, the dosing rate during periods of high activity / daytime is about 0.32 mL / site / hour. According to some embodiments, the dosing rate during periods of high activity / daytime is between about 0.32 mL / hour and about 0.64 mL / hour.

[0096] As mentioned above, although the low rate and high rate are referred to as the night rate and day rate respectively, they can be used regardless of the time of day; instead, they are used in relation to the patient's condition and similar conditions, such as low activity and high activity. Furthermore, the rate can be gradually changed and can be set to any appropriate value, and is not necessarily tied to a specific high rate and a specific low rate.

[0097] According to some embodiments, the first composition is administered at a high activity rate for about 12 to about 20 hours (e.g., about 18 hours) and at a low activity rate for about 4 to about 12 hours (e.g., about 6 hours), wherein about 500 mg to about 800 mg (e.g., about 700 mg or about 691.2 mg) of levodopa and about 60 mg to about 100 mg (e.g., about 80 mg or about 86.4 mg) of carbidopa are administered during the high activity period, and about 20 mg to about 40 mg (e.g., about 30 mg or about 28.8 mg) of levodopa and about 2 mg to about 5 mg (e.g., about 3 mg or about 3.6 mg) of carbidopa are administered during the low activity period. According to some embodiments, the high activity rate and / or low activity rate may be continuous periods within a 24-hour timeframe. According to other embodiments, the high activity rate and / or low activity rate may be administered over a 24-hour timeframe in several discontinuous periods.

[0098] It should be further noted that the volume and / or rate of administration may be constant throughout the treatment, or may vary at different times of day, different days of treatment, different weeks, or different months, and similar periods. According to some embodiments, the patient is monitored, for example, independently by a caregiver, or electronically by sensors that may be present in a dedicated device, such as a watch-like device, a patch-like sensor, an administration pump, or the like. According to such embodiments, the volume and / or rate of administration are determined based on data received from such monitoring.

[0099] Some embodiments relate to a method of subcutaneous bolus injection for administering the first pharmaceutical composition of the present invention. According to some embodiments, the bolus injection comprises a first pharmaceutical composition at a concentration between about 0.5 and about 2.0 mL / kg. According to some embodiments, the bolus injection comprises a first pharmaceutical composition at a concentration between about 0.5 and about 0.75 mL / kg. According to some embodiments, the bolus injection comprises a first pharmaceutical composition at a concentration between about 0.75 and about 1.0 mL / kg. According to some embodiments, the bolus injection comprises a first pharmaceutical composition at a concentration between about 1.0 and about 1.25 mL / kg. According to some embodiments, the bolus injection comprises a first pharmaceutical composition at a concentration between about 1.25 and about 1.5 mL / kg. According to some embodiments, the bolus injection comprises a first pharmaceutical composition at a concentration between about 1.5 and about 1.75 mL / kg. According to some embodiments, the bolus injection comprises a first pharmaceutical composition at a concentration between about 1.75 and about 2.0 mL / kg. According to some embodiments, the bolus injection comprises a first pharmaceutical composition at a concentration between about 0.75 and about 1.25 mL / kg. According to some embodiments, the pellet injection contains about 1.0 mL / Kg of a first pharmaceutical composition.

[0100] Subcutaneous bolus injections can be administered at any time relative to any possible consecutive subcutaneous administration, such as before, during, or after consecutive administrations. Subcutaneous bolus injections can be administered at any time of day. Subcutaneous bolus injections can be administered once a day, once every two, three, four, five, or six days, once a week, or at longer intervals. When requested / needed, subcutaneous bolus injections can be administered based on feedback received from the patient, caregiver, physician, sensor, and similar individuals and / or according to a predetermined protocol. Subcutaneous bolus injections can be administered between approximately five minutes and approximately 40 minutes, between approximately five minutes and approximately 10 minutes, between approximately 10 minutes and 15 minutes, between approximately 15 minutes and 20 minutes, between approximately 20 minutes and 25 minutes, between approximately 25 minutes and 30 minutes, between approximately 30 minutes and 35 minutes, or between approximately 35 minutes and 40 minutes.

[0101] According to some embodiments, the dosage can be doubled, tripled or more by using more than one pump, each pump having more than one injection site and the like.

[0102] According to some embodiments, the first pharmaceutical composition is administered for a determined period of time, such as several days, weeks, months, or years. According to some embodiments, the first pharmaceutical composition is administered indefinitely for the treatment of chronic symptoms.

[0103] According to some embodiments, the first pharmaceutical composition comprises levodopa, levodopa prodrug, levodopa salt, or any combination thereof, between about 1% w / v and about 40% w / v. According to some embodiments, the first pharmaceutical composition comprises levodopa, levodopa prodrug, levodopa salt, or any combination thereof at about 1% w / v to about 5% w / v, about 5% w / v to about 10% w / v, about 10% w / v to about 15% w / v, about 15% w / v to about 20% w / v, about 20% w / v to about 25% w / v, about 25% w / v to about 30% w / v, about 30% w / v to about 35% w / v, about 35% w / v to about 40% w / v, about 2% w / v to about 10% w / v, about 4% w / v to about 8% w / v, about 5% w / v to about 7% w / v, or about 6% w / v.

[0104] According to some embodiments, the first pharmaceutical composition comprises carbidopa, carbidopa salt, carbidopa prodrug, or any combination thereof, between about 0.5% w / v and about 10% w / v. According to some embodiments, the first pharmaceutical composition comprises approximately 0.5% w / v to approximately 1% w / v, approximately 1% w / v to approximately 1.5% w / v, approximately 1.5% w / v to approximately 2% w / v, approximately 2% w / v to approximately 2.5% w / v, approximately 2.5% w / v to approximately 3% w / v, approximately 3% w / v to approximately 3.5% w / v, approximately 3.5% w / v to approximately 4% w / v, approximately 4% w / v to approximately 4.5% w / v, approximately 4.5% w / v to approximately 5% w / v, approximately 5% w / v to approximately 5.5% w / v, approximately 5.5% w / v to approximately 6% w / v, approximately 6% w / v to approximately 6.5% w / v, approximately 6.5% w / v to approximately 7% w / v, and approximately 7% w / v to approximately 7.5%. Carbidopa, carbidopa salts, carbidopa prodrugs, or any combination thereof, at a dose between approximately 7.5% w / v and approximately 8% w / v, between approximately 8% w / v and approximately 8.5% w / v, between approximately 8.5% w / v and approximately 9% w / v, between approximately 9% w / v and approximately 9.5% w / v, between approximately 9.5% w / v and approximately 10% w / v, or at a dose of approximately 0.75% w / v.

[0105] For example, this document provides a first pharmaceutical composition suitable for administration non-intestinal (e.g., subcutaneously) to the patient, comprising about 4 to 10 wt% levodopa, about 0.5 to about 2 wt% carbidopa, and about 10 to about 20 wt% arginine. Another exemplary first pharmaceutical composition provided herein comprises about 6 wt% levodopa, about 0.75 wt% carbidopa, and about 10 to about 20 wt% arginine.

[0106] According to some embodiments, the first pharmaceutical composition comprises approximately 0.05% w / v to approximately 2.0% w / v, approximately 0.05% w / v to approximately 0.1% w / v, approximately 0.1% w / v to approximately 0.2% w / v, approximately 0.2% w / v to approximately 0.3% w / v, approximately 0.3% w / v to approximately 0.4% w / v, approximately 0.4% w / v to approximately 0.5% w / v, approximately 0.5% w / v to approximately 0.6% w / v, approximately 0.6% w / v to approximately 0.7% w / v, approximately 0.7% w / v to approximately 0.8% w / v, approximately 0.8% w / v to approximately 0.9% w / v, approximately 0.9% w / v to approximately 1.0% w / v, approximately 1% w / v to approximately 1.1% w / v, and approximately 1.1% w / v. w / v between approximately 1.2% w / v, approximately 1.2% w / v between approximately 1.3% w / v, approximately 1.3% w / v between approximately 1.4% w / v, approximately 1.4% w / v between approximately 1.5% w / v, approximately 1.5% w / v between approximately 1.6% w / v, approximately 1.6% w / v between approximately 1.7% w / v, approximately 1.7% w / v between approximately 1.8% w / v, approximately 1.8% w / v between approximately 1.9% w / v, approximately 1.9% w / v between approximately 2.0% w / v, approximately 0.75% w / v between approximately 1.25% w / v, approximately 0.75% w / v, approximately 0.8% w / v, approximately 0.85% w / v, approximately 0.9% w / v, approximately 0.95% w / v, approximately 1.0% w / v w / v antioxidants or combinations of antioxidants.

[0107] According to some embodiments, the antioxidant is selected from the group consisting of: ascorbic acid or a salt thereof; cysteine, such as N-acetylcysteine; bisulfite or a salt thereof; glutathione; tyrosinase inhibitors; divalent cations; butylated hydroxytoluene (BHT); β-hydroxy acid (BHA) tocopherol; gentian acid; tocopherol; tocopherol derivatives; thioglycerol; and any combination thereof. According to some embodiments, the antioxidant is ascorbic acid. According to some embodiments, the antioxidant is N-acetylcysteine ​​(NAC). According to some embodiments, the first pharmaceutical composition comprises a combination of ascorbic acid and NAC. For example, this article provides a first pharmaceutical composition suitable for subcutaneous administration, comprising about 0.1 to about 10 wt% ascorbic acid or a pharmaceutically acceptable salt thereof, about 0.01 to about 1 wt% of a component selected from the group consisting of: NAC, L-cysteine ​​and a pharmaceutically acceptable salt thereof; about 2 to about 16 wt% levodopa or an ester thereof; and about 0.6 to about 2 wt% carbidopa or an ester thereof.

[0108] According to some embodiments, the first pharmaceutical composition comprises a base. According to some embodiments, the base is selected from the group consisting of: arginine, NaOH, trimethylolpropane (TRIS), NH4OH, ethylenediamine, diethylamine, ethanolamine, diethanolamine, meglumine, and any combination thereof. According to some embodiments, the base is arginine.

[0109] According to some embodiments, the first pharmaceutical composition comprises an base between about 5% w / v and about 30% w / v. According to some embodiments, the first pharmaceutical composition comprises an base between about 5% w / v and about 10% w / v, between about 10% w / v and about 15% w / v, between about 15% w / v and about 20% w / v, between about 20% w / v and about 25% w / v, between about 25% w / v and about 30% w / v, between about 12.5% ​​w / v and about 17.5% w / v, or about 15% w / v, or about 15.2% w / v.

[0110] According to some embodiments, the first pharmaceutical composition comprises a surfactant. According to some embodiments, the surfactant is selected from Tween-80, Tween-60, Tween-40, Tween-20, Tween-65, Tween-85, Span 20, Span 40, Span 60, Span 80, Span 85, polyoxyethylene 35 castor oil (Cremophor EL), polyethylene oxide-660-hydroxystearate (Macrogo l660), or poloxamer 188 (Pluronic® F-68), or any combination thereof. The first pharmaceutical composition of the present invention may comprise about 0.1 to about 3.0% w / v of a surfactant or a combination of two or more surfactants. According to some embodiments, the first pharmaceutical composition comprises a surfactant or a combination of two or more surfactants in amounts ranging from about 0.1 to about 0.2% w / v, about 0.2 to about 0.3% w / v, about 0.3 to about 0.4% w / v, about 0.4 to about 0.5% w / v, about 0.5 to about 0.6% w / v, about 0.6 to about 0.7% w / v, about 0.7 to about 0.8% w / v, about 0.8 to about 0.9% w / v, about 0.9 to about 1.0% w / v, about 1.0 to about 1.5% w / v, about 1.5 to about 2.0% w / v, about 2.0 to about 2.5% w / v, or about 2.5 to about 3.0% w / v.

[0111] The first pharmaceutical composition may further comprise additional pharmaceutically acceptable excipients, such as N-methylpyrrolidone (NMP), polyvinylpyrrolidone (PVP), propylene glycol, preservatives, pharmaceutically acceptable mediators, stabilizers, dispersants, suspending agents, sucraloses, calcium chelators, protease inhibitors, or any combination thereof. The first pharmaceutical composition of the present invention may comprise between about 5.0% and about 80.0% w / v of additional pharmaceutically acceptable excipients, such as solvents, such as NMP or buffers or any other co-solvents. For example, a pharmaceutically acceptable first composition is provided herein comprising about 6 wt% levodopa, about 0.75 wt% carbidopa, about 10 to about 20 wt% arginine, about 0.5 wt% L-cysteine ​​or NAC, and / or about 0.5 wt% ascorbic acid or a salt thereof. An exemplary first pharmaceutical composition (e.g., formulation A) may include about 6 wt% levodopa, about 0.75 wt% carbidopa, and about 14 to about 16 wt% arginine. Another exemplary pharmaceutical composition may include about 6 wt% levodopa, about 0.75 wt% carbidopa, about 14 to about 16 wt% arginine, about 0.5 wt% ascorbic acid, and about 0.5 wt% NAC.

[0112] According to some embodiments, the first pharmaceutical composition of the present invention comprises approximately 5.0 to approximately 10.0% w / v, approximately 10.0 to approximately 15.0% w / v, approximately 15.0 to approximately 20.0% w / v, approximately 20.0 to approximately 25.0% w / v, approximately 25.0 to approximately 30.0% w / v, approximately 30.0 to approximately 35.0 w / v, approximately 35.0 to approximately 40.0% w / v, approximately 40.0 to approximately 45.0% w / v, approximately 45.0 to approximately 50.0% w / v, approximately 50.0 to approximately 55.0% w / v, approximately 55.0 to approximately 60.0% w / v, approximately 60.0 to approximately 65.0% w / v, approximately 65.0 to approximately 70.0% w / v, and approximately 70.0 to approximately 75.0%. Solvents between w / v and approximately 75.0% to 80.0% w / v, such as NMP, buffers, or any other co-solvent.

[0113] According to some embodiments, the first pharmaceutical composition further comprises a buffer solution. According to some embodiments, the buffer solution is selected from citrate buffer, citrate buffer, sodium acetate buffer, acetate buffer, tartrate buffer, phosphate buffer, succinate buffer, Tris buffer, glycine buffer, hydrochloric acid buffer, potassium hydrogen phthalate buffer, sodium citrate buffer, sodium tartrate buffer, sodium hydroxide buffer, sodium dihydrogen phosphate buffer, disodium hydrogen phosphate buffer, triammonium phosphate (TRIS), or any combination thereof. The first pharmaceutical composition may contain a buffer solution between about 0.1% and about 30.0% w / v. According to some embodiments, the first pharmaceutical composition comprises a buffer solution between about 0.1 and about 1.0% w / v, between about 1.0 and about 2.0% w / v, between about 2.0 and about 3.0% w / v, between about 3.0 and about 4.0% w / v, between about 4.0 and about 5.0% w / v, between about 5.0 and about 6.0% w / v, between about 6.0 and about 7.0% w / v, between about 8.0 and about 9.0% w / v, between about 9.0 and about 10.0% w / v, between about 10.0 and about 15.0% w / v, between about 15.0 and about 20.0% w / v, between about 20.0 and about 25.0% w / v, and between about 25.0 and about 30.0% w / v.

[0114] According to some embodiments, the first pharmaceutical composition further comprises an acid or base, for example, to provide a composition having a predetermined pH value. According to some embodiments, the acid is selected from HCl, HBr, methanesulfonic acid, ascorbic acid, acetic acid, citric acid, or any combination thereof. According to some embodiments, the base is selected from NaOH, Ca(OH)2, ammonium hydroxide, arginine, magnesium hydroxide, potassium hydroxide, meglumine, trimethylolamine (TRIS), triethylamine, diisopropylethylamine, diazabicycloundecene, or any combination thereof. The first pharmaceutical composition may contain a base or acid at a rate of about 0.1% to about 30.0% w / v. According to some embodiments, the first pharmaceutical composition comprises about 0.1 to about 1.0% w / v, about 1.0 to about 2.0% w / v, about 2.0 to about 3.0% w / v, about 3.0 to about 4.0% w / v, about 4.0 to about 5.0% w / v, about 5.0 to about 6.0% w / v, about 6.0 to about 7.0% w / v, about 8.0 to about 9.0% w / v, about 9.0 to about 10.0% w / v, about 10.0 to about 11.0% w / v, about 11.0 to about 12.0% w / v, about 12.0 to about 13.0% w / v, about 13.0 to about 14.0% w / v, about 14.0 to about 15.0% w / v, about 15.0 to about 16.0% w / v, about 16.0 to about 17.0% w / v, and about 17.0 to about 18.0%. Approximately 18.0% to 19.0% w / v, approximately 19.0% to 20.0% w / v, approximately 20.0% to 21.0% w / v, approximately 21.0% to 22.0% w / v, approximately 22.0% to 23.0% w / v, approximately 23.0% to 24.0% w / v, approximately 24.0% to 25.0% w / v, approximately 25.0% to 26.0% w / v, approximately 26.0% to 27.0% w / v, approximately 27.0% to 28.0% w / v, approximately 28.0% to 29.0% w / v, and approximately 29.0% to 30.0% w / v of base or acid.

[0115] The pH of the first pharmaceutical composition of the present invention at about 25°C may be between about 4.5 and about 10. According to some embodiments, the pH of the first pharmaceutical composition at about 25°C is between about 4.5 and about 5. According to some embodiments, the pH of the first pharmaceutical composition at about 25°C is between about 5 and about 6. According to some embodiments, the pH of the first pharmaceutical composition at about 25°C is between about 6 and about 7. According to some embodiments, the pH of the first pharmaceutical composition at about 25°C is between about 7 and about 8. According to some embodiments, the pH of the first pharmaceutical composition at about 25°C is between about 8 and about 9. According to some embodiments, the pH of the first pharmaceutical composition at about 25°C is between about 9 and about 10. According to some embodiments, the pH of the first pharmaceutical composition at about 25°C is between about 4.5 and about 5.5. According to some embodiments, the pH of the first pharmaceutical composition at about 25°C is between about 5.5 and about 6.5. According to some embodiments, the pH of the first pharmaceutical composition at about 25°C is between about 6.5 and about 7.5. According to some embodiments, the pH of the first pharmaceutical composition at about 25°C is between about 7.5 and about 8.5. According to some embodiments, the pH of the first pharmaceutical composition at about 25°C is between about 8.5 and about 9.5. According to some embodiments, the pH of the first pharmaceutical composition at about 25°C is between about 9.5 and about 10. According to some embodiments, the pH of the first pharmaceutical composition at about 25°C is about 9.5. According to some embodiments, an acid or base is added to the first pharmaceutical composition to provide a composition having a predetermined pH value. According to some embodiments, the acid is selected from HCl, HBr, methanesulfonic acid, ascorbic acid, acetic acid, citric acid, or any combination thereof. According to some embodiments, the base is selected from NaOH, arginine, amine bases, any of the bases mentioned herein, or any combination thereof.

[0116] According to some embodiments, a second medical composition is administered when needed and / or required, such as when symptoms from the neurological or motor disorder require such administration, or according to a predetermined treatment plan. The timing assessment of the administration of the second medical composition can be performed by a caregiver, physician, the patient to whom the composition is administered, or any combination thereof, and this assessment arises from consultation and / or joint decision-making and the like. According to some embodiments, a system supported by any type of sensor can provide information for determining the need to administer the second medical composition. Such information can be delivered to the caregiver, physician, patient, or any combination thereof by any means, such as via electronic devices, for example, smartphones, dedicated consoles, tablets, email, dedicated or known applications, and the like.

[0117] According to some embodiments, the second pharmaceutical composition is administered at a predetermined time, a predetermined interval, or both, for example, based on a treatment plan or based on data received from the patient, caregiver, physician, sensor, and the like. The predetermined time and / or interval can be reset at any point in time, for example, taking into account data received from the patient, caregiver, sensor, physician assessment, and the like.

[0118] According to some embodiments, the second pharmaceutical composition is administered orally substantially simultaneously with the start of the infusion schedule. According to some embodiments, the second pharmaceutical composition is administered orally approximately 1, 2, 3, 4, or 5 hours after the start of the infusion schedule. It should be noted that "the start of the infusion schedule" can be a time of day, including infusion cycles such as when a new vial is introduced into the system, when the cartridge is changed, when the infusion kit is replaced, and similar situations.

[0119] According to some embodiments, the oral administration of the second pharmaceutical composition is a morning oral dose. According to some embodiments, the morning oral dose comprises levodopa, levodopa salt, levodopa prodrug, or any combination thereof. According to some embodiments, the morning oral dose comprises one of the following: 25 mg levodopa, 50 mg levodopa, 75 mg levodopa, 95 mg levodopa, 100 mg levodopa, 125 mg levodopa, 145 mg levodopa, 150 mg levodopa, 195 mg levodopa, 200 mg levodopa, 245 mg levodopa, or 250 mg levodopa.

[0120] According to some embodiments, the morning oral dose comprises (a) levodopa, levodopa salt, levodopa prodrug; (b) dopa decarboxylase inhibitor (DDCI), DDCI salt, DDCI prodrug, or (c) any combination thereof.

[0121] According to some embodiments, the second pharmaceutical composition is administered up to 20 times per day. According to some embodiments, the second pharmaceutical composition is administered about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times per day. According to some embodiments, the second pharmaceutical composition is administered between about 3 and 7 times per day. According to some embodiments, the second pharmaceutical composition is administered between about 4 and 6 times per day. According to some embodiments, the second pharmaceutical composition is administered at a frequency between about 30 minutes and about 24 hours. According to some embodiments, the second pharmaceutical composition is administered at a frequency between about 30 minutes and about one hour, about one hour and about two hours, about two hours and about three hours, about three hours and about four hours and about five hours, about five hours and about six hours, about six hours and about seven hours, about seven hours and about eight hours, about eight hours and about nine hours, about nine hours and about ten hours, about ten hours and about eleven hours, about eleven hours and about twelve hours, about twelve hours and about thirteen hours, about thirteen hours and about fourteen hours, about fourteen hours and about fifteen hours, about fifteen hours and about sixteen hours and about sixteen hours, about seventeen hours and about eighteen hours, about eighteen hours and about nineteen hours and about twenty hours, about twenty hours and ...

[0122] The interval between one administration and the next administration may also vary, depending on, for example, the patient / caregiver / physician’s observations and assessments, data received from any type of appropriate sensor, the planned treatment plan, any combination thereof, and the like.

[0123] According to some embodiments, the dosage of the levodopa component in the second pharmaceutical composition is the same in each administration. According to some embodiments, the dosage of the levodopa component in the second pharmaceutical composition may differ between different administrations. According to some embodiments, the dosage of the levodopa component in the second pharmaceutical composition is between about 10 mg and about 3000 mg per day, between about 10 mg and about 50 mg per day, between about 50 mg and about 100 mg per day, between about 100 mg and about 150 mg per day, between about 150 mg and about 250 mg per day, between about 250 mg and about 350 mg per day, between about 350 mg and about 500 mg per day, between about 500 mg and about 750 mg per day, between about 750 mg and about 1000 mg per day, between about 1000 mg and about 1250 mg per day, between about 1250 mg and about 1500 mg per day, between about 1500 mg and about 1750 mg per day, between about 1750 mg and about 2000 mg per day, and between about 2000 mg per day. The dosage of levodopa in the second pharmaceutical composition is between approximately 100 mg and approximately 1800 mg per day. According to some embodiments, the dosage of levodopa in the second pharmaceutical composition is between approximately 350 mg and approximately 700 mg per day.

[0124] It should be noted that the dosage is determined based on the time of administration of the composition to the patient, and therefore, if several tablets, such as four tablets, each containing 100 mg of levodopa, are administered to the patient almost simultaneously, the dosage of levodopa in the second pharmaceutical composition is considered to be 400 mg. Furthermore, the daily dose may consist of several doses that may not be consistent with each other; for example, the patient may take 100 mg at 8:00 AM, 200 mg at 10:00 AM, 100 mg at 3:00 PM, and 75 mg at 7:00 PM, so that the dosage of the levodopa component in the second pharmaceutical composition is considered to be 475 mg per day.

[0125] According to some embodiments, the dosage of the levodopa component in the second pharmaceutical composition is between about 10 mg and about 500 mg per dose, between about 10 mg and about 25 mg per dose, between about 25 mg and about 50 mg per dose, between about 50 mg and about 75 mg per dose, between about 75 mg and about 100 mg per dose, between about 100 mg and about 150 mg per dose, between about 150 mg and about 200 mg per dose, between about 200 mg and about 250 mg per dose, between about 250 mg and about 300 mg per dose, between about 300 mg and about 350 mg per dose, between about 350 mg and about 400 mg per dose, between about 400 mg and about 450 mg per dose, and between about 450 mg and about 500 mg per dose. According to some embodiments, the dosage varies between different doses. According to other embodiments, the dose is kept constant and administered at least twice, for example, within a timeframe of 24 hours, three days, one week, or similar.

[0126] In some embodiments, the dosage of the levodopa component in the second pharmaceutical composition is, for example, about 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 200 mg, or 250 mg of levodopa in a direct-release tablet or capsule. According to some embodiments, the dosage of the levodopa component in the second pharmaceutical composition is about 95 mg, about 145 mg, about 195 mg, or about 245 mg of levodopa, for example, in a sustained-release form, such as tablets or capsules.

[0127] As mentioned above, the levodopa component may be levodopa, levodopa salt, levodopa prodrug, or any combination thereof. According to some embodiments, the levodopa component is levodopa.

[0128] According to some embodiments, the dosage of the carbidopa component in the second pharmaceutical composition is between about 2.5 mg and about 50 mg per dose, between about 2.5 mg and about 20 mg per dose, between about 2.5 mg and about 25 mg per dose, between about 2.5 mg and about 35 mg per dose, between about 2.5 mg and about 40 mg per dose, between about 15 mg and about 20 mg per dose, between about 15 mg and about 25 mg per dose, between about 15 mg and about 35 mg per dose, between about 15 mg and about 40 mg per dose, between about 15 mg and about 50 mg per dose, between about 20 mg and about 25 mg per dose, between about 20 mg and about 35 mg per dose, between about 20 mg and about 40 mg per dose, between about 20 mg and about 50 mg per dose, between about 25 mg and about 35 mg per dose, between about 25 mg and about 25 ... The dosage of the carbidopa component in the second pharmaceutical composition is between 2.5 mg and about 40 mg, between 25 mg and about 50 mg per dose, between 35 mg and about 40 mg per dose, between 35 mg and about 50 mg per dose, and between 40 mg and about 50 mg per dose. According to some embodiments, the dosage of the carbidopa component in the second pharmaceutical composition comprises 2.5 mg, 18.57 mg, 25 mg, 31.25 mg, 37.5 mg, or 50 mg of carbidopa.

[0129] The second pharmaceutical composition may be in any suitable oral form, such as pills, hard or soft capsules, tablets, sugar-coated tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, syrups, or elixirs. The second pharmaceutical composition may be in a direct-release form or any type of controlled-release form, such as sustained release, extended release, delayed release, prolonged release, and the like. As noted above, the second pharmaceutical composition may contain at least two active ingredients, such as levodopa and carbidopa. It should be noted that each of the active ingredients in the second pharmaceutical composition may be formulated with different release forms; for example, levodopa may be in a controlled-release form while carbidopa is in a direct-release form, or vice versa.

[0130] According to some embodiments, the second pharmaceutical preparation is administered only during periods of high activity / wakefulness (e.g., during daytime), such that the dosing intervals during high activity / wakefulness are shorter than during other parts of the day (e.g., low activity / nighttime). According to other embodiments, the dose of the second pharmaceutical preparation administered during high activity / wakefulness is higher than the dose administered during other parts of the day, such as low activity / nighttime. According to some embodiments, a 24-hour dosing regimen is designed, and this dosing regimen can remain constant over a specific number of days, while within the same day, the regimen can vary based on wakefulness, activity, and the like. According to some embodiments, the dosing regimen can vary between different days and within the same day.

[0131] An embodiment of the present invention further relates to a method for treating neurological or motor disorders (such as Parkinson's disease) in patients in need, wherein the method comprises: administering, non-enterally, a first pharmaceutical composition comprising: levodopa, levodopa salt, levodopa prodrug, or any combination thereof; and a dopa decarboxylase inhibitor (DDCI), DDCI salt, DDCI prodrug, or any combination thereof; and concurrently, administering, orally, a morning oral dose composition comprising: levodopa, levodopa salt, levodopa prodrug; a dopa decarboxylase inhibitor (DDCI), DDCI salt, DDCI prodrug; or any combination thereof.

[0132] Other embodiments of the present invention relate to a first pharmaceutical composition comprising: levodopa, levodopa salt, levodopa prodrug, or any combination thereof; and dopa decarboxylase inhibitor (DDCI), DDCI salt, DDCI prodrug, or any combination thereof; and a second pharmaceutical composition comprising: levodopa, levodopa salt, levodopa prodrug; dopa decarboxylase inhibitor (DDCI), DDCI salt, DDCI prodrug; or any combination thereof, for use in combination to treat neurological or motor disorders, such as Parkinson's disease, wherein the first pharmaceutical composition is formulated as a non-enteric composition and the second pharmaceutical composition is formulated as an oral composition.

[0133] Other embodiments of the present invention relate to a kit comprising: a first pharmaceutical composition in a non-enteral form comprising: levodopa, levodopa salt, levodopa prodrug, or any combination thereof; and a dopa decarboxylase inhibitor (DDCI), DDCI salt, DDCI prodrug, or any combination thereof; a second pharmaceutical composition in an oral form comprising: levodopa, levodopa salt, levodopa prodrug; a dopa decarboxylase inhibitor (DDCI), DDCI salt, DDCI prodrug, or any combination thereof; and instructions for use with the first and second pharmaceutical compositions for the treatment of neurological or motor disorders (such as Parkinson's disease).

[0134] Other embodiments of the present invention relate to a kit comprising: a first pharmaceutical composition in a non-enteric form comprising: levodopa, levodopa salt, levodopa prodrug or any combination thereof; and a dopa decarboxylase inhibitor (DDCI), DDCI salt, DDCI prodrug or any combination thereof; and instructions for use with the administration of the first pharmaceutical composition and the second pharmaceutical composition for the treatment of neurological or motor disorders (such as Parkinson's disease), wherein the second pharmaceutical composition is provided separately.

[0135] Other embodiments of the present invention relate to a method for treating Parkinson's disease in a patient in need, wherein the patient has previously been administered levodopa in a prior form other than a direct-release carbidopa-levodopa tablet in a 1:4 ratio, and wherein the method comprises: converting the patient from the prior form of levodopa to an orally administered direct-release levodopa-carbidopa 100 / 25 mg tablet; administering subcutaneously to the patient a first pharmaceutically acceptable liquid composition containing levodopa over a subcutaneous infusion course of at least about 24 hours or longer; and administering orally to the patient at least one oral formulation containing levodopa before or during the subcutaneous infusion course.

[0136] Other embodiments of the present invention relate to a method for treating a patient with Parkinson's disease in need, wherein the patient has previously been administered levodopa in a prior form, and wherein the method comprises: converting the patient from the prior form of levodopa to an orally direct-release levodopa-carbidopa form; after the conversion, administering subcutaneously to the patient, over a subcutaneous infusion course of at least about 24 hours or longer, a first pharmaceutically acceptable liquid composition containing levodopa; and administering orally to the patient, before or during the subcutaneous infusion course, at least one orally administered oral dosage form containing levodopa.

[0137] Other embodiments of the present invention relate to a method for treating a patient with Parkinson's disease who has previously been given a previous form of levodopa, and the method comprises: converting the patient from the previous form of levodopa to an orally direct-release form of levodopa, and thus administering a certain amount of orally direct-release levodopa to the patient. Following this conversion, after a subcutaneous infusion course of at least approximately 24 hours, the patient is subcutaneously administered a first medically acceptable liquid composition containing a subcutaneous amount of levodopa, wherein if the amount of the orally released form of levodopa is higher than the subcutaneous amount of levodopa, the amount of the orally released form of levodopa is reduced by approximately the amount of the subcutaneous amount of levodopa, and the remaining amount of orally released levodopa is administered to the patient; and if the amount of the orally released form of levodopa is lower than the subcutaneous amount of levodopa, then the orally released form of levodopa is not administered to the patient except as a morning dose of orally released levodopa administered before or during the subcutaneous infusion course.

[0138] Other embodiments of the present invention relate to a method for treating Parkinson's disease in a patient in need, wherein the patient has previously been administered a prior form of levodopa, and wherein the method comprises: converting the patient from the prior form of levodopa to an orally direct-release form of levodopa, thereby administering to the patient an initial daily dose of orally direct-release levodopa; following this conversion, administering to the patient subcutaneously, over a subcutaneous infusion period of at least about 24 hours or longer, a first pharmaceutically acceptable liquid composition, the amount of which delivers about 720 mg of levodopa to the patient over a period of at least about 24 hours, wherein if the initial daily dose of the orally direct-release form of levodopa is higher than about 700 mg, the dose of the orally direct-release form of levodopa is reduced by about 700 mg, and the patient is administered the remaining dose of orally direct-release levodopa, the remaining dose being equal to the initial daily dose of orally direct-release levodopa minus 700 mg. mg; and if the initial daily dose of levodopa in the oral direct-release form is less than about 700 mg, then only the morning dose of oral direct-release levodopa shall be administered to the patient before or during the subcutaneous infusion schedule.

[0139] In some embodiments of the methods described herein, administration of a first composition (non-enteral, e.g., subcutaneous) and a second composition (e.g., oral tablets) to a patient causes the area under the curve (AUC) of levodopa from time 0 to the end of the non-enteral (e.g., subcutaneous) infusion to be higher than the combined AUC of levodopa in the patient when the first and second compositions are not administered, wherein the total amount of levodopa administered is the same regardless of whether it is administered concurrently or not.

[0140] Unless expressly stated otherwise, the method embodiments described herein are not limited to a particular order or sequence. Furthermore, some of the described method embodiments or elements thereof may occur or be performed simultaneously, at the same point in time, or synchronously.

[0141] It should be understood that certain features of the present invention may also be provided in combination in a single embodiment. Conversely, for the sake of brevity, various elements of the present invention described in the context of a single embodiment may also be provided individually or in any suitable sub-combination, or provided as suitable for any other described embodiment of the present invention. Furthermore, certain features described in the context of various embodiments are not considered essential features of those embodiments unless the embodiment does not function without those elements.

[0142] As described above and claimed in the following claims section, various embodiments and aspects of the present invention can be supported by the following examples; however, it is not limited to these examples. Example 1

[0143] To assess plasma exposure to LD, tests were performed after co-administration of levodopa (LD) and carbidopa (CD) via subcutaneous (SC) and oral administration. Therefore, results obtained from the combined SC + oral administration were compared with results obtained from SC administration alone and oral administration alone. An additive plasma exposure and pharmacokinetic (PK) curve was expected; that is, the combined SC + oral administration was expected to provide results equal to the sum of the results obtained from SC and oral administration alone when administered separately. Methods

[0144] Sixteen healthy subjects (aged 18 to 50) were treated in a crossover manner, i.e., sequentially, with a 6-day clearance period between the following two treatments:

[0145] Treatment A: Administer a total dose of 180 / 22.5 mg LD / CD via SC infusion at a stable infusion rate over an 8-hour timeframe (Formulation A).

[0146] Treatment B: Administer 100 / 25 mg LD / CD direct release (IR) tablets orally at time 0 hours.

[0147] Following a 32-hour clearance period, LC / CD was administered orally and subcutaneously to the same 16 healthy subjects according to the following treatment:

[0148] Treatment C: Administer a dose of 153.6 / 19.2 LD / CD (composition A) via SC infusion at a stable infusion rate over an 8-hour timeframe, combined with a single oral IR LD / CD tablet of 100 / 25 mg four hours after the start of infusion. Total LD / CD dose: 253.6 / 44.2 mg.

[0149] Blood samples were collected at the following time points:

[0150] Treatment A: 0 (before treatment begins), 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 5.5 hours, 6 hours, 7 hours, 8 hours (before the end of infusion).

[0151] Treatment B: 0 (before treatment begins), 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours.

[0152] Treatment C: 0 (before treatment begins), 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 7 hours, 8 hours (before the end of infusion). Results

[0153] As described above, the standardized AUC0-8 of LD and CD produced by treatment C from the combination of SC and oral therapy was calculated and compared with the sum of the AUC of standardized LD and CD obtained from treatment A (AUC0-8 produced by 8 hours of SC infusion) and the AUC of standardized LD and CD obtained from treatment B (AUC0-4 produced by an IR oral tablet). The results are presented in Tables 1 and 2 below. Table 1 Ratio of observed to calculated LD AUC produced by SC, oral therapy and SC + oral therapy Observation (C) ID 1. Treatment A AUC (0-8)×0.853* 2. Treatment of B AUC (0-4) 3. Combination 1+2 [Estimated Value] 4. Treatment AUC (0-8) [Observed Values] Addition ratio 1001 2266 + 1327 = 3593 4092 vs. 1.139 1002 2218 + 1434 = 3652 3961 vs. 1.085 1003 2620 + 1752 = 4372 5136 vs. 1.175 1004 1729 + 919 = 2648 3508 vs. 1.325 1005 2031 + 969 = 3000 4105 vs. 1.368 1006 2693 + 1885 = 4578 6325 vs. 1.382 1008 2603 + 986 = 3589 5031 vs. 1.402 1009 1920 + 1167 = 3087 3889 vs. 1.260 1010 2575 + 1375 = 3950 4175 vs. 1.057 1011 3686 + 2658 = 6344 7678 vs. 1.210 1012 2310 + 1419 = 3729 4772 vs. 1.280 1013 3087 + 1799 = 4886 5620 vs. 1.150 1014 2196 + 1426 = 3622 5059 vs. 1.397 1015 2629 + 1812 = 4441 5861 vs. 1.320 1016 2236 + 1837 = 4073 4610 vs. 1.132 Geometric Mean 1.240 geometric mean group 2412 + 1458 = 3870 4817 vs. 1.245 *The AUC of treatment A is multiplied by 0.853 to provide a dose equal to the subcutaneous dose of treatment C. In this regard, it should be noted that previous studies (not shown) demonstrated the dosage ratio of subcutaneous levodopa and carbidopa, and therefore comparisons between these doses are performed using linear normalization. Table 2: Ratio of observed to calculated CD AUCs from SC, oral, and SC + oral treatments. Observation (C) ID 1. Treatment A AUC (0-8)×0.853* 2. Treatment of B AUC (0-4) 3. Combination 1+2 [Estimated Value] 4. Treatment AUC (0-8) [Observed Values] Addition ratio 1001 850 + 256 = 1106 917 vs. 0.829 1002 827 + 290 = 1117 973 vs. 0.871 1003 925 + 266 = 1191 1086 vs. 0.912 1004 773 + 219 = 992 1000 vs. 1.008 1005 942 + 246 = 1188 1181 vs. 0.994 1006 955 + 322 = 1277 1218 vs. 0.954 1008 988 + 349 = 1337 1047 vs. 0.783 1009 657 + 318 = 975 754 vs. 0.773 1010 880 + 322 = 1202 995 vs. 0.828 1011 1231 + 513 = 1744 1358 vs. 0.779 1012 855 + 300 = 1155 868 vs. 0.752 1013 1017 + 459 = 1476 1200 vs. 0.813 1014 770 + 297 = 1067 1152 vs. 1.080 1015 1120 + 252 = 1372 1255 vs. 0.915 1016 859 + 351 = 1210 936 vs. 0.774 Geometric Mean 0.866 geometric mean group 900 + 309 = 1209 1051 vs. 0.869 *The AUC of treatment A is multiplied by 0.853 to provide a dose equal to the subcutaneous dose of treatment C. In this regard, it should be noted that previous studies (not shown) demonstrated the dosage ratio of subcutaneous levodopa and carbidopa, and therefore comparisons between these doses are performed using linear normalization.

[0154] The expected combined / additive results of treatments A and B (combination, i.e., adding them together) are almost identical to the results obtained from self-treatment C, which is essentially a combination of treatments A and B within its treatment regimen.

[0155] Surprisingly, as presented in the results above, the comparison of the standardized AUC0-8 of treatment C with the sum of the standardized AUCs of treatments A and B, as described above, showed a higher LD AUC than expected, while the CD AUC of treatment C was lower than expected.

[0156] Specifically, as shown in Table 1, the ratio of the LD-standardized AUC of each individual obtained from treatment C to the equivalent AUC obtained from treatment A+B (which, together, simulates the SC in treatment C plus oral administration) is greater than 1.0, with an average ratio of 1.245 and a range of 1.057 to 1.402. Furthermore, as shown in Table 2, the ratio of the CD-standardized AUC of most individuals obtained from treatment C to the equivalent AUC obtained from treatment A+B is less than 1.0, with an average ratio of 0.869 and a range of 0.773 to 1.080.

[0157] Therefore, unexpectedly, the combination of SC and oral therapy provided a higher LD level than would have been expected if the two types of drugs were administered separately. In contrast, the CD level obtained from the combination of SC and oral therapy was lower than would have been expected if the two types of drugs were administered separately. The low CD result obtained in the combination therapy made the higher-than-expected LD level even more unexpected; even with the reduced CD level, the LD level actually increased, contrary to what was expected, because generally, CD inhibits peripheral metabolism of LD, and therefore the lower the CD level, the lower the expected LD level. Equivalent

[0158] Although specific embodiments of the invention have been discussed, the above description is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this description. The full scope of the invention, as well as its equivalents, the description, and such variations, should be determined with reference to the claims.

[0159] Unless otherwise indicated, all numbers representing quantities of ingredients, reaction conditions, etc., as used in this specification and the claims shall be understood to be modified by the term "about" in all cases. It should be noted that, unless otherwise stated, when a specific value is described in the specification and the claims, the term "about" means that an acceptable margin of error should be assumed for that specific value, for example, at most 5% or 10%. (Incorporated by reference)

[0160] All patents, published patent applications, websites and other references cited herein are hereby expressly incorporated herein by way of full citation.

Claims

1. The use of a levodopa, carbidopa, or combination thereof for the preparation of a medicament for the treatment of Parkinson's disease in a patient in need, the treatment comprising: administering subcutaneously to the patient a pharmaceutically acceptable liquid composition comprising levodopa and carbidopa over a subcutaneous infusion course of approximately 24 hours, the amount being approximately 720 mg of levodopa and approximately 90 mg of carbidopa delivered to the patient over the approximately 24-hour course; and administering orally to the patient 1 to 10 direct-release tablets or capsules comprising 100 mg of levodopa before or during the subcutaneous infusion course.

2. As claimed in claim 1, wherein the pharmaceutically acceptable liquid composition further comprises arginine.

3. As claimed in claim 1, wherein the pharmaceutically acceptable liquid composition further comprises at least one antioxidant.

4. As claimed in claim 1, wherein the direct-release tablet or capsule further comprises carbidopa.

5. As claimed in claim 1, wherein the area under the curve (AUC) of plasma levodopa in the patient from time 0 to the end of the infusion course after the subcutaneous administration and the oral administration is higher than the combination of: i) plasma levodopa AUC from time 0 to the end of the infusion course when the patient is given the pharmaceutically acceptable liquid composition subcutaneously for about 24 hours alone; and ii) plasma levodopa AUC in patients given levodopa orally alone.

6. Use of a levodopa, carbidopa, or combination thereof for the preparation of a medicament for the treatment of Parkinson's disease in a patient in need, the treatment comprising: administering subcutaneously to the patient, over a subcutaneous infusion period of approximately 24 hours, a first pharmaceutically acceptable liquid composition comprising levodopa, carbidopa, arginine, and an antioxidant, in an amount of approximately 720 mg of levodopa and approximately 90 mg of carbidopa to the patient over the approximately 24-hour period; and administering orally to the patient, before or during the subcutaneous infusion period, a tablet or capsule comprising levodopa.

7. As claimed in claim 6, wherein the tablet or capsule comprises one of the following: 50 mg levodopa, 75 mg levodopa, 95 mg levodopa, 100 mg levodopa, 125 mg levodopa, 145 mg levodopa, 150 mg levodopa, 195 mg levodopa, 200 mg levodopa, 245 mg levodopa, or 250 mg levodopa.

8. As claimed in item 6, wherein the tablet or capsule is an oral dose taken in the morning.

9. As requested in item 6, where the patient experiences fluctuations in drug efficacy.

10. Use of a levodopa, carbidopa, or combination thereof in the preparation of a medicament for treating a patient with Parkinson's disease who is currently receiving levodopa and carbidopa in the form of directly released levodopa and carbidopa alone and requires further treatment comprising: administering to the patient subcutaneously, over a subcutaneous infusion period of approximately 24 hours, a first pharmaceutically acceptable liquid composition comprising levodopa, carbidopa, arginine, and an antioxidant, in an amount of approximately 720 mg of levodopa and approximately 90 mg of carbidopa delivered to the patient over the approximately 24-hour period; and administering to the patient daily, before or during the subcutaneous infusion period, a tablet or capsule comprising 100 mg of levodopa and 25 mg of carbidopa.

11. The use of a levodopa, carbidopa, or combination thereof in the preparation of a medicament for treating Parkinson's disease in a patient in need, the treatment comprising: administering subcutaneously to the patient, during a subcutaneous infusion course of about 24 hours, a pharmaceutically acceptable liquid composition comprising levodopa, carbidopa, arginine, and an antioxidant, in an amount of about 370 mg to about 720 mg of levodopa and about 46 mg to about 90 mg of carbidopa to the patient during the about 24-hour course; and administering orally to the patient, before or during the subcutaneous infusion course, a tablet or capsule comprising levodopa.

12. For the purposes of claim 11, wherein the tablet or capsule comprises one of the following: 50 mg levodopa, 75 mg levodopa, 95 mg levodopa, 100 mg levodopa, 125 mg levodopa, 145 mg levodopa, 150 mg levodopa, 195 mg levodopa, 200 mg levodopa, 245 mg levodopa, or 250 mg levodopa.

13. As claimed in claim 11, wherein the tablet or capsule is an oral dose taken in the morning.

14. As requested in item 11, where the patient experiences fluctuations in drug efficacy.

15. As claimed in claim 11, wherein the area under the curve (AUC) of plasma levodopa in the patient from time 0 to the end of the infusion course after the subcutaneous administration and the oral administration is higher than the combination of: i) plasma levodopa AUC from time 0 to the end of the infusion course when the patient is given the pharmaceutically acceptable liquid composition subcutaneously for about 24 hours alone; and ii) plasma levodopa AUC in patients given levodopa orally alone.