JPWO2019182506A5 - - Google Patents

Description

BACKGROUND OF THE INVENTION Neurodegenerative disorders occur when neurons do not normally regenerate or replace themselves, and therefore when damaged neurons cannot be replaced. Progressive degeneration and/or death of neuronal cells often results in motor problems (eg, ataxia) or mental function problems (eg, dementia). Many neurodegenerative disorders are currently considered incurable. Examples of neurodegenerative disorders include Parkinson's disease ("PD"), Alzheimer's disease ("AD") and Huntington's disease ("HD").

Parkinson's disease is characterized by a progressive degeneration of dopaminergic pathways, which itself manifests in patients as symptoms of bradykinesia (e.g., bradykinesia), rigidity, tremors, and imbalances in the brain. resulting in a reduction in the concentration of the neurotransmitter dopamine.

Biochemically, dopamine (3,4-dihydroxyphenethylamine) is formed by the metabolism of dopamine precursors. For example, dopamine is produced in both the brain and peripheral circulation by the precursor levodopa (L-dopa; L- It is formed by decarboxylation of 3,4-dihydroxyphenylalanine). Levodopa, in turn, is produced from the amino acid L-tyrosine by the enzyme tyrosine hydroxylase (TH).

Dopamine is primarily synthesized by two metabolic pathways: (i) through 3,4-dihydroxyphenylacetic acid (DOPAC) by the enzymes monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT); and (ii) metabolized to homovanillic acid (HVA) via 3-methoxytyramine by the enzymes catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO).

The most common treatments for PD aim to restore dopamine levels in the brain. Administration of dopamine is not effective because dopamine does not cross the blood-brain barrier. However, because the precursor levodopa crosses the blood-brain barrier and is converted to dopamine in the brain, administration of levodopa has long been, and still is, the drug of choice for the treatment of PD.

It is well established that fluctuations in plasma concentrations of levodopa correlate with fluctuations in PD symptoms. The therapeutic window varies between individual patients, and every patient has an individual pharmacokinetic (PK) profile. The majority of patients with Parkinson's disease exhibit what is known as "afternoon wearing off." These patients require increased plasma concentrations of levodopa in the afternoon following their usual morning dosing.

SUMMARY The present invention provides methods for treating and/or administering agents useful for the treatment of certain dopamine-related diseases, disorders, and conditions, including certain neurodegenerative disorders (e.g., Parkinson's disease (PD)). A method or regimen for administering an active agent or pharmaceutical composition is provided. Administration is carried out by administering a once daily dose, a first dose, followed by sequential administration of a second dose.

The present invention reduces the patient's total daily dose and facilitates titration of dopamine replacement agents in the patient. The latter has been shown to be important for patients suffering from PD, as many patients require higher doses later in the day or in the evening. The first dose should also be high, 20-35% of the total daily dose. By using a high first dose, the present invention is able to maintain the bioavailability of the dopamine replenisher at a sufficiently high level even when the continuing dose is significantly reduced. Shown.

In a first aspect, the present invention provides a pharmaceutical composition comprising a dopamine supplement, a dopamine decarboxylase inhibitor (DDI), and a catechol-O-methyltransferase (COMT) inhibitor for use as a medicament. the total daily dose of the dopamine supplement,
a. administering a first dose of the pharmaceutical composition that is 20-35% of the total daily dose of dopamine supplement; and b. The present invention relates to a pharmaceutical composition that is administered by sequentially administering second doses of the pharmaceutical composition that add up to a total daily dose of dopamine replenisher.

In a second aspect, the invention provides a kit comprising a first container and at least one further container, wherein the first and at least one further container are each for use as a medicament. comprising first and second doses of a pharmaceutical composition according to any one of 1 to 22;
a. the first dose comprises 20-35% of the total daily dose of the dopamine supplement;
b. the second doses add up to a total daily dose of dopamine supplement;
At least the second dose relates to a kit that is a liquid pharmaceutical composition, suspension or gel.

In a third aspect, the invention provides a pharmaceutical composition comprising a dopamine supplement, a dopamine decarboxylase inhibitor (DDI) and a catechol-O-methyltransferase (COMT) inhibitor, and optionally a suitable adjuvant. A method for administering a total daily dose of a dopamine supplement to a patient in need thereof, comprising:
a. administering a first dose of a pharmaceutical composition comprising 20-35% of the total daily dose of dopamine supplement; and b. The method includes sequentially administering second doses of the pharmaceutical composition that add up to a total daily dose of dopamine replenisher.

All embodiments described herein are applicable to all aspects unless stated otherwise.

In some embodiments, the present disclosure provides for administering to a subject a combination of agents comprising each of (i) a dopamine replenisher, (ii) a dopamine decarboxylase inhibitor (DDI), and (iii) a COMT inhibitor. provides certain unexpected advantages, particularly when the drug or agents are delivered enterally, subcutaneously, transdermally or intravenously, or by pharmaceutical gels, solutions or suspensions, and/or Includes insights that solve one or more problems associated with previous plans to treat neurodegenerative disorders (eg, PD).

In many embodiments, enteral administration is typically into the duodenum and/or jejunum via an external access point.

In certain embodiments, the invention comprises at least about 10 mg/ml levodopa and at least about 1 mg/ml or 2.5 mg/ml of a dopamine decarboxylase inhibitor, including at least about 5 mg/ml or 10 mg/ml. ml of a COMT inhibitor is provided.

In certain embodiments, the invention comprises at least about 10 mg/ml of levodopa and at least about 1 mg/ml or 2.5 mg/ml of a dopamine decarboxylase inhibitor, and the gel composition comprises at least about 10 mg/ml of a dopamine decarboxylase inhibitor. A pharmaceutical liquid composition for intravenous or subcutaneous administration is provided, further comprising ml of a COMT inhibitor.

In certain compositions and/or methods, one or more active agents (e.g., levodopa and/or one or more DDIs [e.g., carbidopa] and/or one or more COMT inhibitors [e.g., entacapone]) may be provided and/or utilized in the form of their pharmaceutically acceptable salts, and/or their hydrates or solvates. In certain embodiments, certain compositions and/or methods may utilize one or more active compounds that may be provided and/or utilized in solid form; In embodiments, the solid form may be or include a crystalline form, and in some such embodiments, the solid form may be or include an amorphous form. In some embodiments, the solid form comprises or consists of an amorphous form or certain single crystal forms.

In some embodiments, compositions according to the invention include at most 200 mg/ml levodopa, at most 50 mg/ml dopamine decarboxylase inhibitor, and at most 200 mg/ml COMT inhibitor.

Exemplary dopamine decarboxylase inhibitors include carbidopa, benserazide, α-difluoromethyldopa [(2S)-2-amino-2-[3,4-dihydroxyphenyl)-methyl]-3,3-difluoropropanoic acid ] and α-methyldopa [(S)-2-amino-3-[3,4-dihydroxyphenyl)-2-methyl-propanoic acid].

In some embodiments, the dopamine decarboxylase inhibitor is carbidopa, benserazide, or any combination thereof.

In some embodiments, the dopamine decarboxylase inhibitor is carbidopa.
In some embodiments, the COMT inhibitor is selected from the group consisting of entacapone, tolcapone, opicapone, and any combination thereof.

In some embodiments, the COMT inhibitor is entacapone.
In some embodiments, the dopamine replenisher is levodopa, a pharmaceutically acceptable salt or derivative thereof, such as levodopa methyl ester.

In some embodiments, the pharmaceutical composition includes a DDI, such as carbidopa, and further includes an agent capable of inhibiting the degradation of carbidopa to hydrazine.

In some embodiments, the agent capable of inhibiting the breakdown of carbidopa to hydrazine includes entacapone.

In some embodiments, the pharmaceutical composition comprises about 20 mg/ml levodopa, 5 mg/ml carbidopa, and 20 mg/ml entacapone.

In some embodiments, the weight ratio between the dopamine replenisher and the DDI is approximately 1/10. In another embodiment, the ratio is approximately 1/4.

In some embodiments, a pharmaceutical composition as described herein comprising one or more COMT inhibitors and at least one additional active compound, e.g., has no (or only one) COMT inhibitor. In some embodiments, the stability of the at least one additional active compound is increased (e.g., degradation is reduced) relative to that observed in other comparable compositions (containing different absolute or relative amounts). It has the following characteristics. In some such embodiments, stability is assessed over time (eg, after a certain period of time) and/or under certain storage conditions. For example, in some embodiments, such increased stability is achieved, for example, under refrigerated conditions (e.g., when the composition is at a temperature below about 15°C, and preferably from about 0°C to about 15°C, from about 0°C to about 12°C). °C, about 0 °C to about 10 °C, about 0 °C to about 8 °C, or about 2 °C to about 8 °C) for at least 1 week, 2 weeks, 5 weeks, 7 weeks, 10 Observations may be made over an extended period of 1 week, 15 weeks, 20 weeks or more.

In some embodiments, provided compositions include and/or are prepared from and/or are maintained at a pH of about 5.7 or less. In some embodiments, such provided compositions comprising one or more active agents (e.g., levodopa, DDI, COMT inhibitors, etc.) are different from related reference compositions, e.g., at different pH values. In comparison, the stability of one or more such active agents is characterized by improved stability.

In some embodiments, the composition is deoxygenated (eg, via nitrogen purge). In some embodiments, such provided compositions comprising one or more active agents are compared to related reference compositions that differ, for example, in the presence and/or duration of such deoxygenation. characterized by improved stability of one or more such active agents.

In some embodiments, the pharmaceutical composition includes an antioxidant (eg, ascorbic acid or citric acid). In some embodiments, such provided compositions comprising one or more active agents may differ, e.g., in the presence and/or amount (e.g., absolute or relative) of such antioxidants. Characterized by improved stability of one or more such active agents compared to a reference composition.

In some embodiments, deoxygenation is combined with reduced pH or antioxidants.
In some embodiments, provided compositions are substantially free (e.g., lack detectable and/or material levels) of metal chelating agents, such as EDTA, and in some embodiments, The compositions provided are substantially free of any metal chelating agents.

In some embodiments, the pharmaceutical composition is provided in a light-protected container.

In some embodiments, the one or more active agents (e.g., levodopa, dopamine decarboxylase inhibitors (e.g., carbidopa), and COMT inhibitors (e.g., entacapone)) are in the form of particles, e.g., about 80 μm or less. The particles may, in some embodiments, be suspended in a carrier (e.g., an aqueous carrier), and in some such embodiments, the carrier may be suspended at a moderate shear rate. It has a viscosity of at least 300 mPas when measured at .

In some embodiments, the viscosity of the gel composition is at least 1800 mPas. In another embodiment, the viscosity ranges from 2200 to 4500 mPas.

The carrier may typically be of the polysaccharide type and may be selected from, for example, cellulose, methylcellulose (MC), ethylcellulose, carboxymethylcellulose (CMC) and salts thereof, xanthan gum, carrageenan and combinations thereof, but the carrier may also be It may also be a synthetic polymer such as polyvinylpyrrolidone (PVP; povidone) or polyacrylic acid (PAA; carbomer). An exemplary carrier is the sodium salt of carboxymethyl cellulose (NaCMC).

In some embodiments, the pharmaceutical composition comprises about 2% (w/w) micronized levodopa, about 0.5% (w/w) micronized carbidopa, about 2% (w/w) of micronized entacapone, and about 2.92% (w/w) sodium carboxymethylcellulose.

In some embodiments, the pH value of the pharmaceutical composition is selected to be a minimum pH value equal to or greater than about 5.0 to about 5.5, and after 12 days at 25°C. The viscosity of is at least 300 mPas at moderate shear rates.

In some embodiments, the carrier of the pharmaceutical composition is NaCMC and the pH value is 5.5±0.2.

Some embodiments of the invention provide pharmaceutical compositions for the treatment of neurodegenerative disorders (eg, Parkinson's disease).

In some aspects of the invention there is provided a method of treating Parkinson's disease comprising enterally administering a pharmaceutical composition according to certain aspects of the invention as described above.

In some embodiments, the pharmaceutical composition is administered continuously for a period of less than about 16 hours per day.

In some embodiments, the pharmaceutical composition is administered continuously for a period of more than about 16 hours, such as 24 hours, per day.

In some embodiments, the pharmaceutical composition is administered continuously for more than one day as a chronic treatment.
In some embodiments, the pharmaceutical composition comprises levodopa, a dopamine decarboxylase inhibitor, and a COMT inhibitor, and the weight ratio of COMT inhibitor to dopamine decarboxylase inhibitor is about 10:1 to about 2. :1, or about 5:1 to about 3:1.

In some embodiments, the pharmaceutical composition comprises levodopa, a dopamine decarboxylase inhibitor, and a COMT inhibitor, and the weight ratio of dopamine decarboxylase inhibitor to levodopa is at least about 1:10.

In some embodiments, the pharmaceutical composition comprises levodopa, a dopamine decarboxylase inhibitor, and a COMT inhibitor, and the levodopa, dopamine decarboxylase inhibitor, and COMT inhibitor are in the form of particles, and the particles are aqueous. The particles are suspended in a carrier and have a particle size of about 80 μm or less.

Some embodiments are described in the dependent claims.
A more complete understanding of the invention, as well as further characteristics and advantages thereof, may be obtained by reference to the following detailed description, read in conjunction with the accompanying drawings.

FIG. 3 shows simulated plasma concentrations of levodopa following doses of Trigel from 400 mg/day to 2000 mg/day. The morning dose was 25% of the total daily dose. The gradual increase is more evident at higher doses. FIG. 3 shows simulated plasma concentrations of levodopa following doses of Trigel from 800 mg/day to 2000 mg/day. The morning dose was 20% of the total daily dose, and the continuing dose was reduced by 20% after 5 hours (noon). A linear trend (μg/h) indicates a flat (steady state) plasma concentration of levodopa. Figure 2 shows simulated plasma concentrations of levodopa following doses of Trigel from 400 mg/day to 1200 mg/day. The morning dose was 25% of the total daily dose and was followed by one continuous flow rate. A linear trend indicates a slight gradual increase. The titration is similar to that seen with Duodopa treatment for lower doses. Simulations following a 1200 mg Trigel dose with one continuous flow rate (open square) and with two flow rates (solid line) pasted on top of the Duodopa PK profile (black dots adapted from Nyholm 2013). FIG. 2 is a diagram showing the plasma concentration of levodopa. Both simulations mimic Duodopa's profile well.

DEFINITIONS As used herein, the term "activator" means that the presence or level of the drug is at the level of the target compared to that observed when the drug is not present (or the drug is used at a different level). or represents a drug that correlates with increased activity. In some embodiments, the activator is one whose presence or level is observed under suitable reference conditions, such as the presence of a particular reference level or activity (e.g., a well-known activator, e.g., a positive control). ) that correlates with target levels or activity equal to or greater than .

As used herein, the term "administration" refers to the administration of a composition to a subject or system. Administration to an animal subject (eg, a human) can be by any suitable route. For example, in some embodiments, administration is bronchial (including intrabronchial instillation), buccal, enteral, interdermal, intraarterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal. Intraspinal, intravenous, intraventricular, intraventricular, specific organs (e.g. intrahepatic), mucous membranes, nasal cavity, oral, rectal, subcutaneous, sublingual, topical, tracheal (including intratracheal injection), intravenous It may be dermal, intravaginal and intravitreal. In some embodiments, administration may involve intermittent dosing. In some embodiments, administration may involve continuous dosing (eg, perfusion) for at least a selected period of time. As is well known in the art, antibody therapies are generally administered parenterally (eg, by intravenous or subcutaneous injection).

As used herein, the term "approximately" or "about" when applied to one or more values of interest refers to a value similar to the stated reference value. In certain embodiments, the term "approximately" or "about" refers to the term "approximately" or "approximately," unless otherwise stated or clear from the context (when such number exceeds 100% of the possible values). 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9% of the stated reference value , 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% in any direction (above or below).

As the term "related" is used herein, two events or entities are "associated" with each other if the presence, level and/or form of one is correlated with that of the other. For example, certain entities (e.g., polypeptides, gene signatures, metabolites, etc.) whose presence, levels, and/or form may be associated with the incidence and/or susceptibility of a disease, disorder, or condition (e.g., across a relevant population) If correlated, it is considered to be associated with a particular disease, disorder or condition. In some embodiments, two or more entities are physically "associated" with each other if they are and/or interact directly or indirectly such that they are in and/or remain in physical proximity to each other. In some embodiments, two or more entities that are physically related to each other are covalently bonded to each other, and in some embodiments, two or more entities that are physically related to each other are They are not covalently bonded, but are non-covalently associated, for example by means of hydrogen bonds, van der Waals interactions, hydrophobic interactions, magnetic forces and combinations thereof.

As used herein, the term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the composition is administered. In some exemplary embodiments, carriers include sterile, e.g. water or oils, including oils of petroleum, animal, vegetable or synthetic origin, e.g. peanut oil, soybean oil, mineral oil, sesame oil, etc. Examples include liquids. In some embodiments, the carrier is or includes one or more solid components.

As used herein, the term "combination therapy" refers to situations in which a subject is exposed to two or more treatment regimens (eg, two or more therapeutic agents) at the same time. In some embodiments, two or more agents may be administered simultaneously; in some embodiments, such agents may be administered sequentially; and in some embodiments, such agents may be administered sequentially; The drugs are administered in overlapping dosing regimens.

A "composition" or "pharmaceutical composition" according to the present invention refers to a combination of two or more agents as described herein for simultaneous administration or administration as part of the same regimen. It is not required in all embodiments that the drug combination be a physical mixture, i.e. each of the components of the composition can be administered as a separate co-agent. However, many patients or practitioners in the art find it advantageous to prepare compositions that are mixtures of two or more components in a pharmaceutically acceptable carrier, diluent, or excipient. , it will be found possible to administer the components of the combination simultaneously.

As used herein, the term "equivalent" refers to comparisons that cannot be identical to each other, but so that conclusions can reasonably be drawn based on observed differences and similarities. Represents two or more drugs, entities, situations, sets of conditions, etc. that are sufficiently similar to be tolerated. In some embodiments, a set of equivalent conditions, situations, individuals or populations is characterized by a plurality of substantially identical characteristics and one or a small number of different characteristics. Those skilled in the art will understand from the context what degree of identity is required for two or more such agents, entities, situations, sets of conditions, etc. to be considered equivalent in any given situation. It will be understood in For example, a person skilled in the art can reasonably assume that differences in results obtained or observed phenomena under or with different sets of situations, individuals or populations are caused by or exhibit variations in these different characteristics. One will recognize that a set of situations, individuals, or populations are equivalent to each other when they are characterized by a sufficient number and kind of substantially identical characteristics to warrant a conclusion.

As used herein, the term "dopamine replacement agent" means that administration to humans increases the Represents a drug that correlates with increased dopamine levels. In some embodiments, the dopamine supplement is characterized by the ability to cross the blood-brain barrier. In some embodiments, dopamine supplements include metabolic precursors of dopamine (e.g., levodopa, melevodopa, etilevodopa, etc. and combinations thereof), dopamine agonists (e.g., apomorphine, bromocriptine, cabergoline, dihydroergocristine mesylate, pergolide, etc.), drugs that block the breakdown of dopamine (e.g. MAO-B inhibitors such as selegiline, rasagiline, etc. and combinations thereof) and/or others that stimulate dopamine production. selected from the group consisting of drugs (e.g. vudipine) that A variety of commercially available formulations and preparations of these agents are well known in the art, including certain oral (e.g. capsules or tablets), transdermal (e.g. patches), parenteral (e.g. especially for injection) subcutaneous, intravenous, intraspinal, etc.), and/or other (eg gels and especially enteral gels) formulations.

As used herein, the term "dosage form" refers to a physically discrete unit of an active agent (eg, a therapeutic or diagnostic agent) for administration to a subject. Each unit contains a predetermined amount of active agent. In some embodiments, such amount is according to a dosing regimen that has been determined to be correlated with a desired or beneficial outcome when administered to an appropriate population (i.e., according to a therapeutic dosing regimen). A unit dose (or a whole fraction thereof) suitable for administration. Those skilled in the art will recognize that the total amount of therapeutic composition or agent administered to a particular subject will be determined by one or more attending physicians and may involve administration of multiple dosage forms.

As used herein, the term "dosage regimen" refers to a set of unit doses (typically more than one), typically separated by time period, and administered individually to a subject. In some embodiments, a given therapeutic agent has a recommended dosing regimen that may involve one or more doses. In some embodiments, the dosing regimen comprises a plurality of doses, each of which is separated from each other by a period of the same length, and in some embodiments, the dosing regimen comprises a plurality of doses, at least The individual doses are separated in two different time periods. In some embodiments, all doses within a dosing regimen are the same unit dose. In some embodiments, different doses within a dosing regimen are different amounts. In some embodiments, the dosing regimen comprises a first dose at a first dose followed by one or more additional doses at a second dose different from the first dose. In some embodiments, the dosing regimen comprises a first dose at a first dose followed by one or more additional doses at a second dose that is the same as the first dose. In some embodiments, the dosing regimen correlates with a desired or beneficial outcome when administered to an appropriate population (ie, is a therapeutic dosing regimen).

As used herein, the term "excipient" refers to a non-therapeutic agent that may be included in a pharmaceutical composition, for example, to provide or contribute to a desired consistency or stability effect. Suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerin, Examples include propylene, glycol, water, ethanol, and the like.

As used herein, the term "gel" refers to a viscoelastic material whose rheological properties distinguish it from, for example, solutions, solids, and the like. In some embodiments, a material or composition is considered a gel if its storage modulus (G') is greater than its elastic modulus (G''). In some embodiments, the composition is A gel is considered a gel when there is a chemically or physically cross-linked network in the solution, as distinguished, for example, from entangled molecules in a viscous solution. In some embodiments, a gel composition is Can be or include particles of the first material suspended or otherwise distributed within the matrix. In some embodiments, the matrix is of or includes polysaccharide type. , for example selected from cellulose, methylcellulose (MC), ethylcellulose, carboxymethylcellulose (CMC) and their salts, xanthan gum, carrageenan and combinations thereof; the carrier may also be polyvinylpyrrolidone (PVP; povidone) or polyacrylic acid (PAA; An exemplary carrier is the sodium salt of carboxymethyl cellulose (NaCMC).

As used herein, the term "patient" refers to the patient to whom the provided composition is administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and/or therapeutic purposes; or represents any organism that may be administered. Typical patients include animals, such as mammals such as mice, rats, rabbits, non-human primates, and/or humans. In some embodiments, the patient is a human. In some embodiments, the patient suffers from or is susceptible to one or more disorders or conditions (eg, dopamine-related diseases, disorders or conditions, eg, neurodegenerative disorders such as PD). In some embodiments, the patient exhibits one or more symptoms of a disease, disorder or condition. In some embodiments, the patient has been diagnosed with one or more diseases, disorders or conditions. In some embodiments, the patient is undergoing or has undergone certain therapy for diagnosing and/or treating a disease, disorder or condition.

As used herein, the term "pharmaceutical composition" refers to a composition in which an active agent is optionally formulated with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is in unit doses suitable for administration in a therapeutic regimen that exhibits a statistically significant probability of achieving a predetermined therapeutic effect when administered to an appropriate population. Exist in quantity. In some embodiments, the pharmaceutical compositions are intended for: oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., buccal, sublingual, and systemic absorption. , boluses, powders, granules, pastes for application to the tongue; parenteral administration, e.g. by subcutaneous, intramuscular, intravenous or epidural injection, e.g. in sterile solutions or suspensions, or sustained release. As a formulation; for topical application, e.g. as a cream, ointment, or controlled release patch or spray applied to the skin, lungs or oral cavity; intravaginally or rectally, e.g. as a pessary, cream or foam; sublingually; ocularly; They may be specifically formulated for administration in solid or liquid forms, including; transdermally; or applied nasally, pulmonaryly and other mucosal surfaces.

As used herein, the term "shear rate" refers to the rate at which progressive deformation of the material mass, in which parallel interior surfaces are displaced from each other, is applied to some materials. As used herein, "moderate shear rate" is the shear rate at which the aqueous carrier is moderately agitated, typically less than about 500 s ^-1 but about 20 s ^-1 Corresponding to higher shear rates, where the support is almost stationary.

The term "stable" as applied to the compositions herein means that the compositions exhibit one or more of their physical structures and/or activities over a period of time under a specified set of conditions. It means to maintain the aspect. In some embodiments, the period of time is at least about 1 hour, and in some embodiments, the period of time is about 5 hours, about 10 hours, about 1 (1) day, about 1 (1) week, about 2 (2) weeks, about 1 (1) month, about 2 (2) months, about 3 (3) months, about 4 (4) months, about 5 (5) months, about 6 (6) months, about 8 (8) months, about 10 (10) months, about 12 (12) months, about 24 (24) months, about 36 (36) months or more. In some embodiments, the period of time is from about one (1) day to about twenty-four (24) months, from about two (2) weeks to about twelve (12) months, from about two (2) months to about five (5) It is within the range of months, etc. In some embodiments, the specified conditions are ambient conditions (eg, room temperature and atmospheric pressure). In some embodiments, the specified conditions are physiological conditions (eg, in vivo or at about 37°C, eg, in serum or phosphate buffered saline). In some embodiments, the specified conditions are under refrigeration (eg, at or below about 4°C, -20°C or -70°C). In some embodiments, the specified condition is darkness.

As used herein, the term "substantially" refers to the qualitative state of exhibiting the full or nearly complete range or extent of the characteristic or property in question. Those skilled in the field of biology understand that biological and chemical phenomena rarely, if ever, progress to completion and/or perfection or achieve or avoid absolute results. You will understand that. The term "substantially" is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.

As used herein, the phrase "therapeutic agent" or "active agent" (e.g., "active compound") generally refers to any agent that, when administered to an organism, elicits a desired pharmaceutical effect. represents. In some embodiments, an agent is considered a therapeutic agent if it exhibits a statistically significant effect across the appropriate population. In some embodiments, a suitable population may be a population of model organisms. In some embodiments, appropriate populations may be defined by various criteria, such as certain age groups, gender, genetic background, pre-existing clinical conditions, and the like. In some embodiments, the therapeutic agent alleviates, ameliorates, reduces, inhibits, prevents, delays the onset of, or reduces the severity of one or more symptoms or characteristics of a disease, disorder, and/or condition. substances that can be used to reduce the severity and/or reduce the incidence. In some embodiments, a "therapeutic agent" is an agent that has been approved or requires approval by a governmental agency before it can be marketed for administration to humans. In some embodiments, a "therapeutic agent" is a drug that requires a prescription for administration to humans.

As used herein, the term "therapeutically effective amount" means an amount that produces the desired effect on those administered. In some embodiments, the term refers to the treatment of a disease, disorder, and/or condition when administered according to a therapeutic dosing regimen to a population suffering from or susceptible to the disease, disorder, and/or condition. Represents sufficient quantity. In some embodiments, a therapeutically effective amount is one that reduces the incidence and/or severity and/or delays the onset of one or more symptoms of a disease, disorder, and/or condition. Those skilled in the art will recognize that the term "therapeutically effective amount" does not require that actual successful treatment be achieved in a particular individual. Rather, a therapeutically effective amount may be an amount that, when administered to a patient in need of such treatment, produces a particular desired pharmaceutical response in a large number of subjects. In some embodiments, reference to a therapeutically effective amount refers to one or more specific tissues (e.g., tissues affected by a disease, disorder, or condition) or body fluids (e.g., blood, saliva, serum, sweat, tears). , urine, etc.). Those skilled in the art will recognize that in some embodiments, a therapeutically effective amount of a particular agent or treatment can be combined and/or administered in a single dose. In some embodiments, a therapeutically effective amount can be formulated and/or administered in multiple doses, eg, as part of a dosing regimen.

As used herein, the term "therapy" (also "treating" or "treating") refers to the treatment of one or more of a particular disease, disorder and/or condition (e.g. cancer). Substances that partially or completely alleviate, ameliorate, alleviate, inhibit, delay the onset of, reduce the severity of, and/or reduce the incidence of symptoms, properties, and/or causes (e.g. Represents any administration of an anti-receptor tyrosine kinase antibody or receptor tyrosine kinase antagonist). Such treatment may be to subjects who do not exhibit symptoms of the disease, disorder, and/or condition involved, and/or who exhibit only early signs of the disease, disorder, and/or condition. Alternatively or additionally, such treatment may be to a subject exhibiting one or more proven symptoms of the disease, disorder and/or condition involved. In some embodiments, treatment may be to a subject diagnosed with a related disease, disorder, and/or condition. In some embodiments, the treatment is to a subject known to have one or more susceptibility factors that are statistically correlated with an increased risk of developing the disease, disorder, and/or condition of interest. It is.

As used herein, the expression "unit dose" refers to an amount administered as a single dose and/or in physically separate units of pharmaceutical composition. In many embodiments, a unit dose contains a predetermined amount of active agent. In some embodiments, the unit dose is
Contains an entire single dose of drug. In some embodiments, more than one unit dose is administered to achieve a total single dose. In some embodiments, administration of multiple unit doses is required, or expected to be required, to achieve the intended effect. A unit dose is, for example, a volume of a liquid (e.g., an acceptable carrier) containing a predetermined amount of one or more therapeutic agents, a predetermined amount of one or more therapeutic agents in solid form. , a sustained release formulation or drug delivery device containing predetermined amounts of one or more therapeutic agents. It will be appreciated that unit doses may be presented in formulations containing any of a variety of ingredients in addition to the therapeutic agent. For example, acceptable carriers (eg, pharmaceutically acceptable carriers), diluents, stabilizers, buffers, preservatives, and the like may be included as described below. Those skilled in the art will appreciate that in many embodiments, an appropriate total daily dose of a particular therapeutic agent may include several or more unit doses, e.g., within the scope of sound medical judgment. You will recognize that this can be determined by your doctor. In some embodiments, the particular effective dose level for any particular subject or organism depends on the disorder being treated and the severity of the disorder; the activity of the particular active compound employed; the particular composition employed. the age, weight, general health, sex and diet of the subject; the time of administration and excretion rate of the particular active compound employed; the duration of the treatment; the drugs used in combination with or simultaneously with the particular active compound employed; and/or further treatment, and may depend on a variety of factors, including similar factors known in the medical art.

The term "continuously administered" can mean that the pharmaceutical composition is administered continuously , but also includes frequent microdosing using a dosing pump. A typical example of the latter is administering dopamine decarboxylase inhibitors (DDIs), such as levodopa, up to 5 mg per dose by continuous flow microdosing using a dosing pump.

DETAILED DESCRIPTION The following description is intended to be exemplary and illustrative of the invention only and is not intended to limit the invention to the particular embodiments described.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

All references cited herein, including patent applications and publications, are incorporated by reference in their entirety.

As mentioned above, the present invention relates to novel methods or regimens and kits for administering compositions to treat certain dopamine-related diseases, disorders and conditions. In many embodiments, the invention relates to compositions and/or methodologies for treating neurodegenerative diseases (eg, Parkinson's disease, often referred to hereinafter as PD). In particular, the present invention provides dopamine replenishers, COMT inhibitors (e.g., entacapone, opicapone, tolcapone, etc. and combinations thereof), dopamine replenishers (e.g., levodopa, melevodopa, etilevodopa, vudipine and combinations thereof) and dopamine decarboxylases. (eg , carbidopa, benserazide, and combinations thereof) in the context of a pharmaceutical composition. In many embodiments, all three components are administered enterally, intravenously, subcutaneously or orally, often in the same composition (ie, in the same unit dosage form). However, the components of the composition may be administered separately or in any combination.

(Method of daily administration)
The present invention relates to a method of administering a total daily dose of dopamine replacement to a patient. Dopamine supplements are administered together with dopamine decarboxylase inhibitors (DDIs) and catechol-O-methyltransferase (COMT) inhibitors in pharmaceutical compositions in which the different compounds may be administered individually or in combination. , the method is:
a. administering a first dose of the pharmaceutical composition that is 20-35% of the total daily dose of dopamine supplement; and b. sequentially administering second doses of the pharmaceutical composition that add up to a total daily dose of dopamine replenisher.

The first administration is administered as one dose, even though the individual components may be administered separately or in combination. Patients suffering from neurodegenerative diseases such as PD usually have more obvious symptoms in the morning, therefore the first dose is aimed at increasing the dopamine supplement above clinical levels as soon as possible. and thus the first dose is rich in dopamine replenisher. The first dose should be 20-35% of the total daily dose, preferably 25-30%. The effect of the first dose of levodopa on plasma concentrations is shown in Figure 1, where the initial concentration peak is shown. The first dose should have a dose of dopamine replacement agent high enough to increase the dopamine replacement agent beyond the lower clinical value, but not above the level of hyperkinesia. These two levels, the lower clinical level and the hyperkinesia level, are patient dependent and therefore the first dose should be adjusted to suit the individual patient.

The second dose is then administered continuously to the patient for a suitable period of time. This period may be 12-18 hours, such as 13-17 hours or 14-16 hours. In one embodiment, the second dose is administered for more than 18 hours, such as 24 hours. The second doses add up to a total daily dose, and the second dose may therefore be 65-80% of the total daily dose. The dosage of the second dose is much lower. Overall, this results in a 30-40% reduction in the total daily dose of dopamine supplements, with sufficient therapeutic effect.

The second dose composition may be a gel, liquid or suspension to facilitate continuous administration, and the rate of administration may be 15-100 mg/h. We observed a gradual increase in the plasma concentration of levodopa during administration of the second dose. This is shown in FIG.

Without wishing to be bound by theory, the reason for this phenomenon is that, unlike DDIs, COMT inhibitors bind more tightly to COMT, resulting in the accumulation of inhibited COMT for a longer period of time. It is believed that. Therefore, the inhibitory effect increases over time, resulting in increased levodopa or dopamine supplementation. This phenomenon has two favorable effects. The first is that increasing and accumulating concentrations of dopamine replacement agents are helpful to patients, as many patients require higher or complementary doses later in the day or in the evening. This method eliminates the need for temporary dose escalations or supplementary doses. The second effect is that the total daily dose may be reduced.

Dopamine supplements, dopamine decarboxylase inhibitors (DDIs) and catechol-O-methyltransferase (COMT) inhibitors may each be administered separately, in combination, or together. When administered separately or in combination of the two, the time between administration of the separate parts should not be so substantial that the preventive effect of the inhibitor is lost. Typically, the time difference should not be more than a few minutes, for example not more than 5 minutes. In one embodiment, a dopamine decarboxylase inhibitor (DDI) and a catechol-O-methyltransferase (COMT) inhibitor are administered together. In another embodiment, the dopamine decarboxylase inhibitor (DDI) and the dopamine decarboxylase inhibitor (DDI) are administered together and the catechol-O-methyltransferase (COMT) ) The inhibitors are administered separately but within minutes.

In one embodiment, the second dose may be given or administered in two or more parts, a first part and a second part. The first portion of the second dose may initially be administered continuously for a suitable period of time, such as 3 to 8 hours, such as 4 to 6 hours. After the period, the continuing dose is reduced and a second portion of the second dose is administered continuously until the total daily dose is achieved. For the second portion, a lower amount of dopamine replenisher is administered per hour, such as at least 10% lower than the first portion, such as a 20-30% reduction of the first portion. This, of course, depends on the patient. Plasma concentrations of levodopa over time for such a dosing regimen are shown in FIG. 2. This type of administration is particularly suitable for PD patients suffering from or susceptible to hyperkinesia. Furthermore, this method lowers the total daily dose even further.

The first and second dose compositions may both be gels, liquids or suspensions and may be administered using a suitable pump, wherein the dose is regulated by the pump. Ru.

The composition or method is suitable for any total daily dose, such as 200 to 3500 mg or 400 to 3000 mg. An even more pronounced gradual increase in dopamine supplementation is seen for higher doses, such as 800 mg and above and 1000 mg and above.

The method is preferably suitable for patients suffering from PD and also for PD patients who also suffer from a susceptibility to or have a tendency to become hyperkinetic.

Patients suffering from neurodegenerative diseases such as PD usually have low levels of dopamine or dopamine supplements in the morning. The first dose is therefore usually administered in the morning, which may be defined in a non-limiting manner as sometime between 5am and 10am, or 6am and 9am.

The composition according to the invention may be in the form of a solid, liquid, solution, gel or suspension. The solid form may be, for example, a tablet or a powder, which tablet or powder is preferably for oral administration. The first dose composition may be in the form of a solid, liquid, suspension or gel. In one embodiment, the first dose composition is a liquid, solution, suspension or gel. The first dose may be administered orally, intravenously, subcutaneously, enterally or transdermally, preferably orally or enterally.

In order to more easily administer the second dose sequentially , the composition of the second dose should be in the form of a liquid, solution, gel or suspension. The second dose may be intravenous, subcutaneous, enteral or transdermal.

An advantage of this method is that it allows the total daily dose to be reduced by at least 30% on average. Additionally, the method adapts the method to patients and patients susceptible to hyperkinesia, resulting in a natural or natural increase in dopamine replacement.

(24-hour administration method)
An alternative treatment regimen involves continuous 24-hour administration. The treatment regimen is suitable for patients who suffer from overt parkinsonian symptoms at night and require constant dopamine supplementation. A composition of the invention comprising a dopamine replacement agent, a DDI and a COMT inhibitor is administered continuously , with the first dose starting when the patient wakes up. The dose is then changed to a second, lower dose that is administered sequentially . The second dose is maintained until the patient goes to bed, and the dose is reduced yet again to the third dose, which is maintained while the patient sleeps. The third dose is significantly lower because the need for dopamine supplements is significantly lower during sleep. In one embodiment, the first dose may be 10-25% of the total daily dose of the dopamine replacement agent, the second dose may be 50-70% of the total daily dose, and the third dose may be 10-25% of the total daily dose of the dopamine supplement. Doses are 10-40% and the three doses add up to a total 24 hour dose.

(kit for administration)
A kit comprising a first container and at least one further container, the first and at least one further container containing a first and a second container, respectively, of a pharmaceutical composition according to the invention for use as a medicament. containing a dosage of
a. the first dose comprises 20-35% of the total daily dose of the dopamine supplement;
b. the second doses add up to a total daily dose of dopamine supplement;
The kit, wherein at least the second dose is a liquid pharmaceutical composition, suspension or gel.

In a further embodiment of the kit, both the first and second doses are in the form of a liquid pharmaceutical composition, solution, suspension or gel. In another, the second dose is divided into two containers, a second and a third container, the third of which contains a pharmaceutical composition having a lower concentration of dopamine replenisher. Including things. The pharmaceutical composition of the third container is intended to provide a lower dose of dopamine replenisher per unit of time.

(Dopamine related disease, disorder or condition)
In many embodiments, the present disclosure relates to treatment of one or more dopamine-related diseases, disorders or conditions. In some embodiments, the present disclosure relates specifically to the treatment of levodopa-responsive patients.

As mentioned above, dopamine is a neurotransmitter. Dopamine plays several important roles in the nervous system, and several important diseases, disorders or conditions are associated with dysfunction of the dopamine system. In some embodiments, the dopamine-related disease, disorder, or condition affects one or more involved nervous system regions or tissues (e.g., in the brain) relative to what is observed in the absence of the disease, disorder, or condition. or specific regions thereof) may be associated with changes in dopamine levels and/or activity. In many embodiments, such changed levels are decreased levels.

Exemplary dopamine-related diseases, disorders or conditions include albinism, Alzheimer's disease, amblyopia, Angelman syndrome, anterior ischemic optic neuropathy, aphasia, back pain, depression, dopamine beta-hydroxylase deficiency, drug ( (e.g. alcohol, cocaine, opiate) dependence/abuse, dyslexia, dystonic cerebral palsy, Huntington's disease, hypotensive syncope, impulse control disorder, medullary carcinoma, motor neuron disease, movement disorders, multiple system atrophy, orthostatic hypostasis. Blood pressure, orthostatic intolerance, Parkinson's disease, prion disease, restless legs syndrome, retinal disease, schizophrenia, spinal cord injury, spinal muscular atrophy, spinocerebellar ataxia, stroke, thyroid cancer, thyroid neoplasm, Tourette's syndrome, etc. can be mentioned.

In some embodiments, the dopamine-related disease, disorder or condition can be or include one or more proliferative disorders (e.g. cancer), inflammatory conditions, neurodegenerative diseases, etc., and combinations thereof. .

In many embodiments, the dopamine-related disease, disorder or condition is a neurodegenerative disorder (eg, PD, AD, HD).

Embodiments of the present disclosure are particularly relevant to the treatment of PD. Generally, patients receiving treatment as described herein may be at any stage of PD. However, in many embodiments, the PD patient is at a moderate to advanced stage, eg, consistent with Horn and Yahr (H&Y) stage II or higher. In some embodiments, the PD patient experiences fluctuations in mobility and hyperkinesia/dyskinesia. In some embodiments, the PD patient has used one or more conventional treatments as described herein (e.g., those involving intermittent dosing and/or exposing the patient to active agents). Have received prior treatment. In certain embodiments, the PD patient may have previously received oral levodopa therapy and experienced fluctuations in mobility. In some embodiments, the present disclosure provides that such motility fluctuations may be due, at least in part, to undulatory dopaminergic stimulation and, in some circumstances, to the short half-life of oral levodopa therapy. and/or is proposed to be exacerbated by erratic absorption (such as may result from gastric emptying). In some aspects, the disclosure provides that each of certain compositions provided herein (specifically, (a) a dopamine replenisher; (b) a DDI; and (c) a COMT inhibitor) (including as active agents) may provide multiple benefits in the treatment of such patients. Without being bound by any particular theory, such compositions can achieve substantially continuous dopaminergic stimulation in these (or other patients), thereby improving therapeutic outcome. It has been proposed that the risk of developing or worsening motility fluctuations may be reduced.

Patients typically receive a mixture of anti-Parkinson's medications, although they can be treated with a small number of tablets per day. Patients may also be treated with more continuous dopaminergic stimulation such as levodopa carbidopa enteral gel (DUODOPA®, DUOPA®), apomorphine, DBS and/or patches or combinations thereof. can be done.

Current recommended treatments for dopamine-related diseases, disorders, or conditions often include dopamine, a precursor that is metabolically converted to dopamine after administration (e.g., levodopa, melevodopa, etylevodopa), or another type of dopamine. Includes administration of supplements. In particular, the metabolic precursor levodopa is commonly administered, particularly in the treatment of neurodegenerative dopamine-related diseases, disorders or conditions, such as PD.

(Dopamine supplement)
As mentioned above, many dopamine-related diseases, disorders or conditions are associated with decreased levels of dopamine in one or more involved tissues or sites. Recommended therapies often include administration of dopamine or a precursor compound that is metabolically converted to dopamine after administration. In particular, given that dopamine does not cross the blood-brain barrier, alternative agents that cross the blood-brain barrier are particularly desirable for the treatment of neurodegenerative dopamine-related diseases, disorders or conditions such as PD. Such agents are referred to herein as "dopamine supplements" and include, for example, metabolic precursors of dopamine (e.g., levodopa, melevodopa, etilevodopa, etc. and combinations thereof), dopamine agonists (e.g., apomorphine, bromocriptine, cabergoline, dihydro- ergocristine mesylate, pergolide, piribedyl pramipexole, ropinirole, rotigotine, etc., and combinations thereof), agents that block the breakdown of dopamine (e.g. MAO-B inhibitors, e.g. selegiline, rasagiline, etc., and combinations thereof); and/or other agents that stimulate dopamine production (eg, vudipine). A variety of commercially available formulations and preparations of these agents are well known in the art, including certain oral (e.g. capsules or tablets), transdermal (e.g. patches), parenteral (e.g. especially for injection) subcutaneous, intravenous, intraspinal, etc.), and/or other (eg, gels, and especially enteral gels) formulations.

Levodopa therapy is currently the standard of care for the treatment of PD.
Levodopa, an aromatic amino acid, is a white crystalline compound that is sparingly soluble in water and has a molecular weight of 197.2. Levodopa is chemically called (-)-L-α-amino-β-(3,4-dihydroxybenzene)propanoic acid. The empirical formula of levodopa is C ₉ H ₁₁ NO ₄ and its structural formula is:

Levodopa is a metabolic precursor to dopamine as well as other neurotransmitters such as norepinephrine (noradrenaline) and epinephrine (adrenaline), both of which, like dopamine, are members of the catecholamine class. It is.

Dosing and administration of levodopa can pose challenges, particularly for patients suffering from PD. Before an individual develops clinical symptoms of PD, the individual has already lost 50 to 60% of dopamine neurons in the brain, resulting in a corresponding decrease in dopamine levels by approximately 70 to 80%. In early disease, surviving neurons still take up levodopa and transfer it to dopamine, despite fluctuating plasma levels of levodopa due to its short half-life and frequent and unpredictable enteral absorption of oral medications. It is possible to store dopamine as a drug and release dopamine slowly over time in a continuous and relatively constant manner. However, in progressive disease, more dopamine neurons die and this buffering capacity is lost.

Thus, over time, patients begin to notice a phenomenon known as motility fluctuations, in which the beneficial effects of levodopa last for several hours and then diminish or fade. As more dopamine neurons are lost, the patient's clinical response will more closely reflect fluctuations in levodopa blood concentrations, and ultimately the levodopa response may last only 1 or 2 hours and then wane. be. By losing buffering capacity, dopamine receptors are exposed to fluctuations in dopamine concentration due to fluctuations in plasma levels of levodopa. When dopamine levels from levodopa in the brain are very high, patients experience dyskinesia (orientation movements), and when brain dopamine levels are very low, PD symptoms recur. This creates a therapeutic concentration window that becomes progressively narrower over time. Once a patient exhibits dyskinesia, adding more dopamine medication will increase the dyskinesia, while decreasing dopamine medication will increase the off time during which PD symptoms recur.

The undulating dopamine stimulation obtained with oral levodopa formulations is only somewhat reduced over conventional sustained release oral levodopa formulations. Alternative formulations and dosing regimens continue to be explored in hopes of improving effective levodopa administration. The present disclosure describes techniques for achieving improved levodopa administration, particularly in combination with DDI and COMT inhibitors, and specifically provides improved control over each of these agents with surprising benefits to the subject. The present invention provides techniques by providing compositions and methods for achieving such exposures. Additionally, in some embodiments, the present disclosure provides a combination composition (e.g., a composition comprising each of levodopa, a DDI, and a COMT inhibitor [particularly entacapone]), wherein one Some embodiments provide combination compositions that greatly improve the stability of levodopa even when compared to alternative formulations of the same three drugs.

In some embodiments, in accordance with the present invention, levodopa may be administered orally. In some embodiments, in accordance with the present invention, levodopa may be administered enterally.

In some embodiments, in accordance with the present invention, levodopa may be administered in tablet form. In some embodiments, in accordance with the present invention, levodopa may be administered in gel form. In certain embodiments, levodopa may be administered enterally in gel form.

Various forms for administration of levodopa and its compositions are well known in the art. Some such compositions include specific inhibitors of enzymes involved in the metabolic breakdown of levodopa. For example, PARCOPA® tablets contain both levodopa and carbidopa and have the characteristic of quickly disintegrating on the tongue without the need for water to aid in dissolution and swallowing; SINEMET® and SINEMET® CR are sustained release tablets containing levodopa and carbidopa; KINSON® tablets contain both levodopa and carbidopa; MADOPAR® tablets contain levodopa and benserazide hydrochloride STALEVO® is a tablet containing levodopa, carbidopa and entacapone.

Additionally, DUODOPA® is an enteral gel containing a combination of levodopa and carbidopa in a 4:1 ratio that is described to provide a continuous enema of levodopa. Use of this gel form has been reported to reduce motility fluctuations and increase "on" time for patients (eg, with advanced PD) relative to that observed with oral formulations. Because the plasma concentration of levodopa is maintained at a constant level within the therapeutic range, fluctuations in motility and hyperkinesia-dyskinesia are less likely to occur in patients receiving DUODOPA® (in patients receiving oral therapy). ). DUODOPA® is administered directly into the duodenum via an inserted tube. Levodopa is rapidly and efficiently absorbed from the intestine through a high capacity transport system for amino acids. Levodopa has the same bioavailability (81-98%) when administered via DUODOPA® gel as when administered in tablets. However, the variation in plasma concentrations of levodopa/dopamine within an individual is considerably smaller when levodopa is administered via DUODOPA® gel (compared to via tablets), and such reduced It has been proposed that this variation may contribute to the continuous enteral administration achieved with the DUODOPA® gel, avoiding the influence of gastric emptying rate on the absorption rate. With the first morning high dose of DUODOPA® enteral gel, therapeutic plasma levels of levodopa/dopamine are achieved within 10-30 minutes.

Particularly available pharmaceutical compositions of levodopa, including STALEVO® tablets, are described, for example, in US Pat. No. 6,500,867 (B1) and No. 6,797,732 (B2). Oral pharmaceutical compositions comprising levodopa, carbidopa and entacapone are described in WO2008/053297, WO2012/147099, US2006/0222703 and WO2009/098661. Certain gel compositions of levodopa, and in particular enteric gel forms such as DUODOPA®, are described, for example, in US 5,635,213 and EP 0670713 B1.

Prescribing information for PARCOPA® is available in three strengths: PARCOPA® 25/100 containing carbidopa 25 mg and levodopa 100 mg; PARCOPA® containing carbidopa 10 mg and levodopa 100 mg; Trademark) 10/100; and PARCOPA® 25/250 containing 25mg of carbidopa and 250mg of levodopa. Inactive ingredients are aspartame, citric acid, crospovidone, magnesium stearate, mannitol, microcrystalline cellulose, natural and artificial mint flavors and sodium bicarbonate. PARCOPA® 10/100 and 25/250 also contain FD&C blue #2 HT aluminum lake. PARCOPA® 25/100 also contains yellow 10 iron oxide. PARCOPA® is used to treat symptoms of idiopathic Parkinson's disease (tremor paralysis), postencephalitic parkinsonism, and secondary parkinsonism that can follow damage to the nervous system due to carbon monoxide and/or manganese poisoning. There are adaptations. PARCOPA® has been shown to reduce nausea and vomiting in these conditions, has a more rapid dose titration, is somewhat milder in response, and can be used as a substitute for lower doses of levodopa with additional pyridoxine (vitamin B6). It has been shown that administration is possible. Recommended dosing involves starting with one tablet of PARCOPA® 25/100 three times daily. This dosing schedule provides 75 mg of carbidopa per day. The dosage may be increased if necessary, one tablet per day or per day, until a dosage of 8 tablets of PARCOPA® 25/100 is reached per day. When using PARCOPA® 10/100, dosage may start with one tablet three or four times a day. However, this will not provide sufficient amounts of carbidopa for many patients. The dosage may be increased, one tablet each day or every other day, until a total of eight tablets (two tablets, four times a day) are reached.

Prescribing information provided with the SINEMET® tablets describes the SINEMET® tablets as a "combination of carbidopa and levodopa" and is indicated for "the treatment of Parkinson's disease." SINEMET® tablets contain 25 mg of carbidopa and 100 mg of levodopa and are administered three times a day. The dosage may be increased, if necessary, by 1 tablet daily or per day, up to a maximum daily dose of 8 tablets. SINEMET® should not be administered to subjects who have other exposures to levodopa, and dosing of SINEMET® should not be started until at least 12 hours after other doses of levodopa have been discontinued. do not have.

Prescribing information for KINSON® tablets indicates that KINSON® tablets contain 100 mg of levodopa and 25 mg of anhydrous carbidopa. The tablets also contain the following inactive ingredients: microcrystalline cellulose, corn starch, sodium starch glycolate, refined talcum, povidone, magnesium stearate, Quinoline Yellow CI 47005. KINSON® tablets are approved for the treatment of PD and Parkinsonism. KINSON® tablets are said to be useful in reducing many of the symptoms of parkinsonism, particularly rigidity and bradykinesia, as well as tremors, dysphagia, and salivation associated with Parkinson's disease and syndromes. (sialorrhoea), and are also frequently reported to be useful in the management of postural sway. Like many other levodopa/carbidopa combination products, KINSON® is not recommended for administration to patients receiving other levodopa therapy and levodopa administration is not recommended for treatment with KINSON®. should be discontinued at least 12 hours before the start of treatment. Titrated dosing is recommended to tailor the dose to each individual patient, but note that peripheral dopamine decarboxylase is saturated by carbidopa to approximately 70-100 mg per day, and patients receiving less than this amount Note that patients are more likely to experience nausea and vomiting.

MADOPAR® is described in its prescribing information as a "drug used in Parkinson's disease" containing "benserazide hydrochloride/levodopa." MADOPAR® tablets contain 50 mg of levodopa and 12.5 mg of benserazide hydrochloride, and the recommended dosage is 4 to 8 capsules per day.

The prescribing information provided with the STALEVO® tablets describes the STALEVO® tablets as a "combination of carbidopa, levodopa and entacapone" and that they are for use in the "treatment of Parkinson's disease." It shows that it is a thing. STALEVO® tablets contain 50 mg carbidopa, 200 mg levodopa and 200 mg entacapone, and the maximum recommended dosage is 6 tablets within 24 hours.

The prescribing information provided with DUOPOPA® indicates that the gel contains 20 mg of levodopa and 5 mg of carbidopa monohydrate per mL of gel. Inactive ingredients include carmellose sodium and purified water. DUOPOPA® is approved in the United States for the treatment of advanced idiopathic Parkinson's disease with severe motor fluctuations despite optimized oral therapy. Prior to inserting a permanent percutaneous endoscopic gastrostomy (PEG) tube, it is recommended to confirm a favorable clinical response to DUOPOPA® administered via a temporary nasoduodenal tube. Ru. DUOPOPA® may also be delivered directly to the patient's small intestine. DUOPOPA® is intended for continuous daytime enteral administration. Percutaneous endoscopic gastrostomy (PEG) with an outer transabdominal tube and an inner intestinal tube, a permanent tube, a portable pump (specifically Direct administration into the duodenum using the CADD-legacy DUOPOPA® pump (CE 0473) is recommended, especially for long-term administration. If PEG is not suitable for any reason, radiological gastrojejunostomy may be considered instead. Before starting treatment with a permanent tube, it is recommended to use a temporary nasoduodenal tube to see if the patient responds favorably to this method of treatment and to adjust the dose. . Doses are typically adjusted for the individual patient to the optimal clinical response, which minimizes the number of off episodes and off times (bradykinesia) and on times with disabling dyskinesias. This means maximizing functional on-time during the day. At least initially, it is recommended that DUOPOPA® be initially given as monotherapy (ie, administered to patients who are not receiving other treatments concurrently).

In some embodiments, the present disclosure provides and/or utilizes pharmaceutical gel compositions for enteral administration of levodopa. In some embodiments, such compositions include about 10 mg/ml, about 15 mg/ml, about 20 mg/ml, about 25 mg/ml, about 30 mg/ml, about 35 mg/ml, about 40 mg/ml, about 45mg/ml, about 50mg/ml, about 55mg/ml, about 60mg/ml, about 65mg/ml, about 70mg/ml, about 75mg/ml, about 80mg/ml, about 85mg/ml, about 90mg/ml, about 95mg/ml, about 100mg/ml, about 105mg/ml, about 110mg/ml, about 115mg/ml, about 120mg/ml, about 125mg/ml, about 130mg/ml, about 135mg/ml, about 140mg/ml, about Contains 145 mg/ml, or about 150 mg/ml of levodopa. In some embodiments, such compositions are about 10 mg/ml to about 150 mg/ml, 10 mg/ml to about 140 mg/ml, 10 mg/ml to about 130 mg/ml, 10 mg/ml to about 120 mg/ml. , 10 mg/ml to about 110 mg/ml, 10 mg/ml to about 100 mg/ml, about 10 mg/ml to about 90 mg/ml, about 10 mg/ml to about 85 mg/ml, about 10 mg/ml to about 80 mg/ml, about 10 mg/ml to about 75 mg/ml, about 10 mg/ml to about 70 mg/ml, about 10 mg/ml to about 65 mg/ml, about 10 mg/ml to about 60 mg/ml, about 10 mg/ml to about 55 mg/ml, about 10 mg/ml to about 50 mg/ml, or about 20 mg/ml to about 50 mg/ml levodopa.

In some embodiments, the present disclosure can provide or utilize pharmaceutical compositions for oral administration of levodopa. In some embodiments, such compositions include about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg of levodopa. include.

(Dopamine decarboxylase inhibitor (DDI))
Levodopa has a short half-life in the body of 30 to 60 minutes, and when taken alone, over 90% of the levodopa is metabolized to dopamine before it reaches the brain. Thus, many protocols for administering levodopa involve administering large doses, which in turn leads to high dopamine concentrations outside the brain, which can often be accompanied by nausea and other harmful side effects. bring. In order to increase the bioavailability of levodopa and reduce its side effects, levodopa is therefore usually treated with a dopamine decarboxylase inhibitor (DDI), typically carbidopa (L-2-hydrazino-3-(3,4-dihydroxy (phenyl)-2-methylpropanoic acid) or benserazide (DL-2'-(2,3,4-trihydroxybenzyl)serine hydrazide), which inhibits the conversion of levodopa to dopamine outside the brain. , does not cross the blood-brain barrier.

(carbidopa)
Carbidopa, an inhibitor of decarboxylation of aromatic amino acids, is a white crystalline compound that is sparingly soluble in water and has a molecular weight of 244.2. Carbidopa is chemically called (-)-L-α-hydrazino-α-methyl-β-(3,4-dihydroxybenzene)propanoic acid monohydrate.

Carbidopa is often present and/or utilized in monohydrate form with a molecular weight of 226.3. The empirical formula of carbidopa is C ₁₀ H ₁₄ N ₂ O ₄ ×H ₂ O, and its structural formula is:

In many embodiments, a reference to an amount by weight or weight percent of carbidopa can be understood as an amount found by weight (or weight percent) of carbidopa monohydrate (i.e., a listed amount of carbidopa monohydrate). (can be understood or understood as an amount equal to the weight)

Carbidopa is available in a variety of forms for administration to patients. For example, carbidopa is commercially available as an oral tablet under the name Lodosyn. Lodosyn tablets contain 25 mg of carbidopa and are used to treat symptoms of idiopathic Parkinson's disease (tremor paralysis), postencephalitic parkinsonism, and secondary parkinsonism that can follow damage to the nervous system due to carbon monoxide and/or manganese poisoning. It is indicated for use with carbidopa-levodopa or levodopa in the treatment of. In particular, Lodosyn is for use with carbidopa-levodopa in patients where the dose of carbidopa-levodopa provides less than a sufficient daily dose of carbidopa (usually 70 mg daily). Lodosyn is said to be for use with levodopa, particularly in occasional patients where the required doses of carbidopa and levodopa require separate titration of each drug. The use of Lodosyn with carbidopa-levodopa or levodopa results in reduced nausea and vomiting, more rapid titration of doses, and a somewhat milder response than that observed with administration of the related levodopa forms/regimens. , has been shown to allow administration of lower doses of levodopa. However, it is noted that patients with markedly abnormal ("on-off") responses to levodopa do not show benefit from the addition of carbidopa. Lodosyn should be administered by titration. Most patients are said to respond to a 1:10 ratio of carbidopa and levodopa, provided the daily dose of carbidopa is 70 mg or more per day. The maximum daily dose to be administered to subjects receiving Lodosyn (either as the sole source of carbidopa or in combination with a levodopa/carbidopa product) should not exceed 200 mg.

As mentioned above, carbidopa is also available in certain forms (eg, oral form and enteral gel form) provided in combination with levodopa.

In some embodiments, the present disclosure provides and/or utilizes a pharmaceutical composition (eg, for enteral administration) comprising a pharmaceutically active agent comprising or consisting of carbidopa. In some embodiments, the present disclosure provides and/or utilizes pharmaceutical compositions. In certain embodiments, the present disclosure provides compositions comprising pharmaceutically active agents comprising or consisting of carbidopa in combination with dopamine supplements (e.g. levodopa), COMT inhibitors (e.g. entacapone), or both for administration).

In some embodiments, the present disclosure provides about 0.5 mg/ml, about 1.0 mg/ml, about 1.5 mg/ml, about 2.0 mg/mg, 2.5 mg/ml, about 3.0 mg/ml. mg, about 3.5 mg/mg, about 4.0 mg/mg, about 4.5 mg/mg, about 5 mg/ml, about 5.5 mg/mg, about 6.0 mg/mg, about 6.5 mg/mg, about 7.0mg/mg, about 7.5mg/ml, about 8.0mg/mg, about 8.5mg/mg, about 9.0mg/mg, about 9.5mg/mg, about 10mg/ml, about 12.5mg Compositions (eg, for enteral administration) are provided and/or utilized that include carbidopa/ml, about 15 mg/ml, about 17.5 mg/ml, or about 20 mg/ml. In some embodiments, such compositions are about 2.5 mg/ml to about 25 mg/ml, about 2.5 mg/ml to 22.5 mg/ml, about 2.5 mg/ml to about 20 mg/ml. , about 2.5 mg/ml to about 17.5 mg/ml, about 2.5 mg/ml to about 15 mg/ml, about 2.5 mg/ml to about 12.5 mg/ml, or about 2.5 mg/ml to about Contains 10 mg/ml carbidopa.

(benserazide)
Benserazide is an inhibitor of aromatic amino acid decarboxylation and has a molecular weight of 257.2. Benserazide is chemically called (RS)-2-amino-3-hydroxy-N'-(2,3,4-trihydroxybenzyl)propane hydrazide. The empirical formula of benserazide is C ₁₀ H ₁₅ N ₃ O ₅ and its structural formula is:

As noted above, benserazide is available in certain commercially available pharmaceutical products, and in particular in combination products with levodopa (specifically MADOPAR®, mentioned above, and in certain jurisdictions as PROLOPA®). (also commercially available).

In some embodiments, the invention can utilize one or more available pharmaceutical products containing benserazide. However, in certain embodiments, the present disclosure provides and/or utilizes benserazide in novel compositions. In certain embodiments, the present disclosure contemplates enteral administration of benserazide, such as via an enteral gel. In some embodiments, the present disclosure provides compositions (eg, for enteral administration) comprising a pharmaceutically active agent comprising or consisting of benserazide. In certain embodiments, the present disclosure provides compositions (e.g., intestinal for internal administration).

In some embodiments, the present disclosure provides and/or utilizes pharmaceutical compositions for enteral administration of benserazide. In some embodiments, such compositions contain about 2.5 mg/ml, about 5.0 mg/ml, about 7.5 mg/ml, about 10 mg/ml, about 12.5 mg/ml, about 15 mg/ml. ml, about 17.5 mg/ml, or about 20 mg/ml benserazide. In some embodiments, such compositions are about 2.5 mg/ml to about 25 mg/ml, about 2.5 mg/ml to 22.5 mg/ml, about 2.5 mg/ml to about 20 mg/ml. , about 2.5 mg/ml to about 17.5 mg/ml, about 2.5 mg/ml to about 15 mg/ml, about 2.5 mg/ml to about 12.5 mg/ml, or about 2.5 mg/ml to about Contains 10 mg/ml benserazide.

In some embodiments, the present disclosure provides and/or utilizes pharmaceutical compositions for enteral administration of dopamine decarboxylase inhibitors. In some embodiments, such compositions contain about 2.5 mg/ml, about 5.0 mg/ml, about 7.5 mg/ml, about 10 mg/ml, about 12.5 mg/ml, about 15 mg/ml. ml, about 17.5 mg/ml, or about 20 mg/ml of one or more dopamine decarboxylase inhibitors. In some embodiments, such compositions are about 2.5 mg/ml to about 25 mg/ml, about 2.5 mg/ml to 22.5 mg/ml, about 2.5 mg/ml to about 20 mg/ml. , about 2.5 mg/ml to about 17.5 mg/ml, about 2.5 mg/ml to about 15 mg/ml, about 2.5 mg/ml to about 12.5 mg/ml, or about 2.5 mg/ml to about 10.0 mg/ml of one or more dopamine decarboxylase inhibitors.

In some embodiments, the present disclosure can provide or utilize pharmaceutical compositions for oral administration of DDIs. Some compositions contain from about 12.5 mg to about 75 mg of one or more DDIs.

(Catechol-O-methyltransferase (COMT) inhibitor)
In some embodiments, the properties of the invention include enteral gels in the composition, and in particular, optionally in combination with one or more other active agents (e.g., with levodopa and/or DDI). It includes the recognition that certain beneficial effects may be achieved and/or problems may be avoided through administration of a COMT inhibitor in a composition. The present disclosure shows that enteral administration of COMT inhibitors, eg, in pharmaceutical compositions, has particular benefits for subjects undergoing treatment with dopamine precursors, and especially with levodopa.

In some embodiments, such administration is required in conjunction with other forms and/or regimens for the administration of levodopa (e.g., alone, in combination with a DDI (e.g., carbidopa), and/or in a different form). levodopa can reduce a patient's exposure to levodopa.

Alternatively or additionally, such administration can reduce negative effects (eg, hydrazine levels) in subjects undergoing treatment with levodopa and DDIs (eg, carbidopa). Still further, the present disclosure specifically demonstrates improved storage stability characteristics for certain compositions when a COMT inhibitor (eg, entacapone) is included in the composition.

In some aspects, the present disclosure demonstrates such improved storage stability characteristics for pharmaceutical compositions containing levodopa and carbidopa, i.e., the present disclosure provides that COMT inhibitors (e.g., entacapone) When included in a composition comprising levodopa and carbidopa, it exhibits such improved storage stability characteristics compared to other comparable compositions without a COMT inhibitor. As will be appreciated by those skilled in the art upon reading this disclosure, the findings illustrated herein can be reasonably generalized to other combinations of COMT inhibitors, DDI inhibitors and/or dopamine precursors. .

Still further, the present disclosure provides that certain compositions comprising dopamine precursors (e.g., levodopa), DDIs (e.g., carbidopa), and COMT inhibitors (e.g., entacapone) may be administered enterally in other forms. describes surprising properties in that it enhances the bioavailability of dopamine precursors to a greater extent than that observed with comparable combinations.

In PD patients, levodopa is directly converted to 3-O-methyldopa (3-OMD; 3-methoxy-4-hydroxy-L-phenylalanine) by the enzyme catechol-O-methyltransferase (COMT) after peripheral administration. It may also be metabolized. To further increase the half-life of levodopa in the body, catechol-O-methyltransferase inhibitors, typically entacapone ((2E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl )-N,N-diethyl-prop-2-enamide) has been administered in conjunction with levodopa and carbidopa. Entacapone as a catechol-O-methyltransferase (COMT) inhibitor is described in European Patent No. 0444899 (B1). Another COMT inhibitor used as an adjunct to levodopa/carbidopa medications is tolcapone (3-dihydroxy-4'-methyl-5-nitrobenzophenone). A COMT inhibitor recently developed for add-on therapy to levodopa is opicapone (2,5-dichloro-3-[5-(3,4-dihydroxy-5-nitrophenyl]-1,2,4-oxa diazol-3-yl)-4,6-dimethylpyridine-1-oxide).

Entacapone, an inhibitor of catechol-O-methyltransferase (COMT), is a compound with a nitro-catechol structure and a molecular weight of 305.3. The chemical name of entacapone is (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide. The empirical formula of entacapone is C ₁₄ H ₁₅ N ₃ O ₅ and its structural formula is:

In some embodiments, the present disclosure provides and/or utilizes pharmaceutical compositions of entacapone. In some embodiments, such compositions are about 5.0 mg/ml, about 10 mg/ml, about 15 mg/ml, about 20 mg/ml, about 25 mg/ml, about 30 mg/ml, about 35 mg/ml. , about 40 mg/ml, about 45 mg/ml, about 50 mg/ml, about 55 mg/ml, about 60 mg/ml, about 65 mg/ml, about 70 mg/ml, or about 75 mg/ml of entacapone. In some embodiments, such compositions are about 5.0 mg/ml to about 100 mg/ml, about 5.0 mg/ml to about 90 mg/ml, about 5.0 mg/ml to about 85 mg/ml, about 5.0 mg/ml to about 80 mg/ml, about 5.0 mg/ml to about 75 mg/ml, about 5.0 mg/ml to about 70 mg/ml, about 5.0 mg/ml to about 65 mg/ml, about 5 .0 mg/ml to about 60 mg/ml, about 5.0 mg/ml to about 55 mg/ml, about 5.0 mg/ml to about 50 mg/ml, about 5.0 mg to about 45 mg/ml, about 5.0 mg/ml Contains about 40 mg/ml of entacapone.

In some embodiments, the present disclosure can provide or utilize pharmaceutical compositions for oral administration of entacapone. In some embodiments, such compositions include about 12.5 mg to about 250 mg of entacapone.

Opicapone is an inhibitor of catechol-O-methyltransferase (COMT) and has a molecular weight of 413.17. The chemical name of opicapone is (4Z)-4-[3-(2,5-dichloro-4,6-dimethyl-1-oxidopyridin-1-ium-3-yl)-2H-1,2,4- Oxadiazol-5-ylidene]-2-hydroxy-6-nitrocyclohex-2,5-dien-1-one. The empirical formula of opicapone is C ₁₅ H ₁₀ C ₁₂ N ₄ O ₆ and its structural formula is:

In some embodiments, the present disclosure provides and/or utilizes pharmaceutical compositions of opicapone. In some embodiments, such compositions include about 0.5 mg/ml, about 1.0 mg/ml, about 1.5 mg/ml, about 2.0 mg/ml, about 2.5 mg/ml, about 3.0 mg/ml, about 4.0 mg/ml, about 5.0 mg/ml, about 6.0 mg/ml, about 7.0 mg/ml, about 8.0 mg/ml, about 9.0 mg/ml, or about Contains 10 mg/ml opicapone. In some embodiments, such compositions are about 0.5 mg/ml to about 10 mg/ml, about 0.5 mg/ml to about 9.0 mg/ml, about 0.5 mg/ml to about 8.0 mg/ml. 5 mg/ml, about 0.5 mg/ml to about 8.0 mg/ml, about 0.5 mg/ml to about 7.5 mg/ml, about 0.5 mg/ml to about 7.0 mg/ml, about 0.5 mg /ml to about 6.5 mg/ml, about 0.5 mg/ml to about 6.0 mg/ml, about 0.5 mg/ml to about 5.5 mg/ml, or about 0.5 mg/ml to about 5.0 mg Contains opicapone/ml.

In some embodiments, the present disclosure can provide or utilize pharmaceutical compositions for oral administration of opicapone. In some embodiments, such compositions include about 10 mg to about 100 mg of opicapone.

Tolcapone is an inhibitor of catechol-O-methyltransferase (COMT) and has a molecular weight of 273.2. The chemical name of opicapone is (3,4-dihydroxy-5-nitrophenyl)(4-methylphenyl)methanone. The empirical formula of opicapone is C ₁₄ H ₁₁ NO ₅ and its structural formula is:

In some embodiments, the present disclosure provides and/or utilizes pharmaceutical compositions of tolcapone. In some embodiments, such compositions include about 5.0 mg/ml, about 10 mg/ml, about 15 mg/ml, about 20 mg/ml, about 25 mg/ml, about 30 mg/ml, about 35 mg/ml, about 40 mg/ml, about 45 mg/ml, about 50 mg/ml, about 55 mg/ml, about 60 mg/ml, about 65 mg/ml, about 70 mg/ml, or about 75 mg/ml tolcapone. In some embodiments, such compositions are about 10 mg/ml to about 100 mg/ml, about 10 mg/ml to about 90 mg/ml, about 10 mg/ml to about 85 mg/ml, about 10 mg/ml to about 80 mg/ml, about 10 mg/ml to about 75 mg/ml, about 10 mg/ml to about 70 mg/ml, about 10 mg/ml to about 65 mg/ml, about 10 mg/ml to about 60 mg/ml, about 10 mg/ml to about 55 mg/ml, about 10 mg/ml to about 50 mg/ml, or about 5.0 mg/ml to about 40 mg/ml of tolcapone.

In some embodiments, the present disclosure can provide or utilize pharmaceutical compositions for oral administration of tolcapone. In some embodiments, such compositions include about 12 mg to about 75 mg tolcapone.

Addition of a COMT inhibitor to levodopa/carbidopa treatment provides the following additional benefits:
i) expected prolongation of the elimination half-life of levodopa, allowing for prolongation of various daily activities;
ii) Reduction in plasma levels of 3-O-methyldopa (3-OMD), an inactive levodopa metabolite, causing reduction in plasma levels of homocysteine. Despite being a problematic risk factor for vascular events, non-motor symptoms (NMS) such as cognitive dysfunction and peripheral neuropathy, elevated levels of homocysteine have been proposed;
iii) The gradual increase in plasma levels of levodopa obtained over the day with Lecigon is compatible with the exacerbation of parkinsonian symptoms frequently observed during the second half of the day.

(Intestinal composition)
to improve the stability of levodopa in pharmaceutical compositions and/or to improve the consistency of its delivery, e.g. to reduce one or more side effects of levodopa administration (e.g. dyskinesia), and/or Certain attempts have been made in hopes of reducing the frequency and/or length of "off periods."

For example, as mentioned above, depending on which levodopa is administered continuously through infusion via an external pump directly into the site of the small intestine (e.g. duodenum or jejunum) where the majority of levodopa is absorbed (especially , for the treatment of late-stage PD patients) injection techniques have been developed. Such an approach is believed to result in more sustained plasma levels, which in turn is intended to achieve a reduction in both off-periods and dyskinesias. It is also well known that continuous delivery can reduce motor complications since they are due to non-physiological and intermittent drug administration. (Olanow et al., www.thelancet.com/neurology, vol. 13, p. 141-149, 2014). However, due to the low water solubility of levodopa and carbidopa, large doses of Levodopa/carbidopa solution had to be used.

Other technologies that have been developed include liquid compositions of levodopa and carbidopa stabilized by citric acid and EDTA, as described, for example, in EP 1 670 450 B1.

Additionally, as mentioned above, enteral gel technology has been developed in which micronized levodopa and carbidopa are suspended in a methylcellulose thickener gel and the composition is delivered directly to the duodenum by intraduodenal injection. . Specifically, an enteral gel for intraduodenal infusion containing 20 mg/ml levodopa and 5 mg/ml carbidopa is commercially available under the trade name DUODOPA®. Such pharmaceutical formulations for intraduodenal injection are disclosed in US 5,635,213 and EP0670713 B1. Long-term 24-hour enteral administration of levodopa/carbidopa is disclosed in WO2007/138086 A1. DUODOPA® is reported to exhibit/achieve improvements in the chemical stability of levodopa in aqueous media compared to that observed for other forms of levodopa. DUODOPA® has also been reported to have beneficial particle distribution (eg, absence of precipitates) properties and to be useful in the treatment of PD.

The present disclosure provides certain compositions and treatment regimens that exhibit improvements even over DUODOPA®. In some embodiments, e.g., provided compositions (particularly including pharmaceutical gel compositions such as DUODOPA®) include both levodopa and carbidopa, and a COMT inhibitor (e.g., entacapone) further including. Thus, in some embodiments, the present disclosure includes pharmaceutical active agents that include or consist of a COMT inhibitor (e.g., entacapone) in combination with a dopamine replenisher (e.g., levodopa), a DDI (e.g., carbidopa), or both. , provides gel compositions (eg, for enteral administration).

Among other things, the present disclosure identifies the source of problems with DUODOPA® as a pharmaceutical form for storage and/or administration of levodopa. Specifically, the present disclosure recognizes that DUODOPA® has a relatively short shelf life (e.g., 15 weeks in the refrigerator (e.g., 2-8°C), 16 hours at room temperature (e.g., 25°C)). do. It is even recommended that DUODOPA® be stored frozen to extend its shelf life. For example, one drug cassette can only be used for up to 16 hours.

It has been reported that intraduodenal administration of DUODOPA®, sometimes combined with oral administration of entacapone, can increase the bioavailability of levodopa. (https://www.medicines.org.uk/emc/medicine/20786, 3rd September, last visit 2015) However, the present disclosure does not allow for the unpredictable enteral absorption of oral drugs as described above. Identify the cause of problems in such a plan, taking into account fluctuations in plasma levels of drugs. Thus, the present disclosure recognizes that it can be difficult to produce consistent results using oral administration of entacapone, and therefore provides an improved regimen for the administration of the triple combination of levodopa, DDI, and entacapone. further recognize that it is desirable and that it can be developed.

A stable liquid composition, inter alia for intraduodenal administration, comprising levodopa, carbidopa and entacapone together with arginine and optionally meglumine is disclosed in WO2012/0666538.

The present disclosure provides the insight that certain beneficial effects may be achieved by providing and utilizing certain gel compositions (e.g., for enteral administration) that include COMT inhibitors (e.g., entacapone). and further includes, for example, certain of those in which the pharmaceutically active agent contained in the composition comprises or consists of a combination of a dopamine replenisher (e.g., levodopa), a DDI (e.g., carbidopa), and a COMT inhibitor (e.g., entacapone). The present invention encompasses the insight that such gel compositions have certain unexpected and valuable properties compared to other available forms containing some or all of these agents. For example, the present disclosure shows, among other things, that the provided three-part gel compositions can provide stable drug plasma levels and long shelf life compared to other forms.

In some embodiments, the compositions provided by the present invention are comprised of previously known levodopa/carbidopa enteral gels such as DUODOPA® (hereinafter referred to for brevity as "LCIGG"), such as DUODOPA®. ”). Among other things, in some embodiments, the provided compositions have improved stability of the included active agent, e.g., compared to other compositions containing such agents (e.g., DUODOPA®). It has the characteristic of being In some embodiments, the provided compositions provide a patient with one or more It may be included and/or administered to receive lower or less frequent doses of the included active agent.

In certain embodiments, the provided composition is or includes an enteral gel and includes levodopa, a DDI, and a COMT inhibitor. In certain embodiments, the provided compositions are one or more of the reference compositions described in one or more of the enteral gels and/or commercially available as DUODOPA®. Enteral gel compositions that are substantially similar to, but differ from such reference compositions in that they contain within them a COMT inhibitor such as entacapone.

Compared to LCIG, according to certain embodiments of the invention, including a COMT inhibitor (e.g., entacapone, opicapone, tolcapone) can reduce the daily levodopa dose by about 10-30%; This may reduce the risk of patients developing levodopa-related side effects such as dyskinesia or fluctuations in movement.

Reducing levodopa doses is also highly desirable. More severe neurographic abnormalities have been reported in patients treated with LCIG infusion than in orally treated patients. The degree of severity of neuropathic changes correlates with increasing doses of levodopa.

In some embodiments, administration of a COMT inhibitor (eg, entacapone, tolcapone) via an enteral gel composition can result in controlled delivery of entacapone or tolcapone. In some embodiments, separate oral administration of entacapone or tolcapone may be combined with LCIG administration.

In some embodiments, the present disclosure can provide or utilize pharmaceutical compositions of DDI and levodopa. In some embodiments, the weight ratio of DDI to levodopa in such compositions is about 1:20 to about 1:2, about 1:15 to about 1:2, about 1:10 to about 1 :2, about 1:8 to about 1:4, about 1:5 to about 1:3, about 1:15 to about 1:8, or about 1:12 to about 1:0. In some embodiments, the weight ratio of DDI to levodopa in such compositions is about 1:12, about 1:11, about 1:10, about 1:9, about 1:8, about 1 :7, about 1:6, about 1:5, about 1:4, about 1:3, or about 1:2.

In some embodiments, the present disclosure can provide or utilize pharmaceutical compositions of a COMT inhibitor and levodopa. In some embodiments, the weight ratio of COMT inhibitor to levodopa in such compositions is about 10:1 to about 0.5:1, about 8:1 to about 4:1, about 5:1. 1 to about 3:1, about 5:1 to about 0.5:1, about 3:1 to about 0.5:1, or about 2:1 to about 0.5:1. In some embodiments, the weight ratio of COMT inhibitor to levodopa in such compositions is about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, about 2:1, about 1:1, or about 0.5:1.

In some embodiments, the provided gel form is a semi-solid composition, and the pharmaceutically active ingredients (e.g., levodopa, DDI and COMT inhibitors) are present at moderate shear rates as defined herein. The present invention is in the form of particles suspended in an aqueous carrier having a viscosity of at least about 300 mPas.

In some embodiments, the particles of active ingredient in the enteral gel composition may have a maximum particle size of no more than about 80 μm, about 60 μm, about 40 μm, or about 20 μm. The particles may be micronized. Furthermore, the aqueous carrier has a viscosity at moderate shear rates (between 20 and 500 s ⁻¹ ) of at least 300 mPas, usually in the range from 300 to 5000 Pas.

In some embodiments, the carrier may have plastic or pseudoplastic properties such that the viscosity decreases during agitation, thereby making it easier to pump the liquid aqueous carrier.

In some embodiments, the aqueous carrier is typically polysaccharide types, including, for example, cellulose, methylcellulose, ethylcellulose, carboxymethylcellulose and their salts, xanthan gum, carrageenan, or synthetic polymers, such as polyvinylpyrrolidone or polyacrylic acid, combinations thereof. A pharmaceutically acceptable colloid, a dispersion or solution of a water-soluble or water-swellable colloid.

In some embodiments, the viscosity of the gel composition can be high enough to have a drug loading of the active ingredient without a tendency to sediment. In some embodiments, the viscosity may not be too high such that the gel can be pumped, eg, with a mobile pump (eg, with reasonable battery consumption).

In certain embodiments, a suitable viscosity can be obtained by adjusting the molecular weight of the colloid used within a suitable range, for example by adjusting the degree of polymerization. In some embodiments, viscosity can be adjusted by selecting a suitable concentration of colloid in the aqueous system.

In some embodiments, the viscosity of the enteral gel composition may be at least about 1800 mPas, or within the range of about 2200 to about 4500 mPas.

In some embodiments, the enteral gel composition further comprises other ingredients. For example, in some embodiments, such compositions may include one or more pharmaceutically inactive ingredients. In some embodiments, other ingredients may be selected from the group consisting of metal chelators, preservatives, excipients, surfactants, emollients, buffers, and combinations thereof.

In some embodiments, the enteral gel composition further comprises one or more dopamine agonists (e.g., bromocriptine, cabergoline, pergolide, pramipexole, ropinirole, rotigotine, apomorphine, dihydroergocristine mesylate, piribedil). . Dopamine agonists activate dopamine receptors in the absence of dopamine, mimicking the function of dopamine in the brain.

In some embodiments, the enteral gel composition further comprises one or more monoamine oxidase type B (MAO-B) inhibitors (eg, rasagiline, selegiline). Monoamine oxidase type B (MAO-B) degrades dopamine in the brain and catalyzes the oxidative deamination of biogenic and xenobiotic amines.

In some embodiments, the enteral gel composition further comprises one or more anticholinergic agents (eg, antihistamines, tropins, tropin derivatives (eg, ethers of tropin)). Anticholinergic drugs block the binding of acetylcholine to its receptors within nerve cells, thus inhibiting acetylcholine in the nervous system.

In some embodiments, the enteral gel composition further comprises one or more glutamate antagonists.

In some embodiments, the enteral gel composition further comprises one or more amantadine or amantadine derivatives.

Enteral gel compositions are prepared by mixing the carrier with water to form a gel, and then combining the active compounds (e.g., levodopa, DDI and COMT inhibitors) with the aqueous carrier using methods and equipment known to those skilled in the art. It can be prepared by finely dispersing it in a liquid. The prepared formulation is then dispensed, eg, into a suitable container, for enteral administration, such as into the duodenum.

The enteral gel compositions are administered via enteral administration (e.g., directly into the intestine (e.g., duodenum or jejunum)) by direct jejunostomy or via percutaneous endoscopic gastrostomy. It's okay.

In some embodiments, the gel is administered using a handheld pump (eg, peristaltic or syringe type). An exemplary peristaltic pump is one sold under the trade name CADD-Legacy DUODOPA® Pump (Smiths Medical, MN, USA). The gel may be contained in a cassette, pouch or vial that is attached to a pump to create a delivery system. The delivery system is connected to the duodenal or jejunal tube for enteral administration. An example of a syringe-type delivery system is a portable pump sold under the trade name Cane Crono Infusion Pump (Applied Medical Technology Ltd., Cambridge, United Kingdom).

In some embodiments, the enteral gels of the invention may be administered continuously for a period of up to about 16 hours, about 18 hours, about 20 hours, about 22 hours, up to about 24 hours per day. good. In some embodiments, the enteral gels of the invention may be administered continuously for more than one day, one week, or one month.

In some embodiments, the enteral gel composition is administered to deliver the desired amount of one or more of the active agents in a single day (eg, over a 24 hour period).

(Stability)
One characteristic of certain embodiments of the invention relates to the storage stability or shelf life of pharmaceutical compositions, and particularly enteral gel compositions.

The shelf life of prior art enteral gels LCIG (e.g. DUODOPA®) under refrigerated conditions is primarily due to the degradation of carbidopa and, more specifically, is believed to be genotoxic. determined by the level of the decomposition product hydrazine.

Although levodopa has been found to be relatively stable in prior art LCIG as well as in the enteral gel compositions of the present invention, carbidopa has been found to be relatively stable in the enteral gel compositions of the present invention as well as in the corresponding enteral gel compositions further containing entacapone. It has been found to degrade approximately 50 percent faster.

In some embodiments, the levodopa/carbidopa/entacapone gel compositions of the present invention provide the surprising property of preventing the formation of final carbidopa degradation products (eg, hydrazine). In some embodiments, the compositions of the present invention have advantageously reduced hydrazine levels ( for example, less than about 20 ppm, or less than about 30 ppm). In some embodiments, compositions of the present invention can have about 50% lower hydrazine levels compared to prior art enteral gels LCIG (eg, DUODOPA®).

In some embodiments, in such gel compositions, entacapone will function not only as a COMT inhibitor, but also as a hydrazine formation inhibitor in the degradation of carbidopa.

The increased stability of the levodopa/carbidopa/entacapone compositions of the present invention, which have a stability of about 10 weeks, about 15 weeks, about 20 weeks, or about 25 weeks under refrigerated conditions, can be achieved, for example, if the active ingredient is still meaningful. When having a therapeutic effect, it can be achieved by different means separately or optionally by a combination of two or more thereof. In some embodiments, the present invention has a stability of about 18 hours, about 20 hours, about 22 hours, about 24 hours, about 26 hours, about 28 hours, or about 30 hours, e.g., at room temperature (e.g., 25° C.). Increased stability of the levodopa/carbidopa/entacapone compositions of the invention.

According to some embodiments of the invention, the stability of the enteral gel composition is such that the pH of the gel composition is adjusted to be less than or equal to about 5.7. It can be increased by

Generally, the stability of the active agent (mainly carbidopa) in the gel composition increases as the pH decreases. However, on the other hand, the stability of the gel itself decreases as the pH decreases (it becomes unstable as the viscosity weakens). Furthermore, the very low pH value of the gel composition is harmful to the patient's intestines.

According to some embodiments of the present invention, increased storage stability with respect to the active agent and gel structure and patient intestinal sensitivities lowers the pH from about 4.5 to about 5.7, preferably from 4.5 to 5. It has been found that this can be achieved by careful selection within the optimal range of .5, for example about 5.0.

In some embodiments, acidic adjustment of pH may be performed with a mineral acid, such as hydrochloric acid, or an organic acid, such as citric acid or citrate buffer.

Alternatively or in addition to pH stabilization, stabilization of the gel composition may be performed by oxygen removal, typically by purging with nitrogen gas, by known methods.

A further alternative method of stabilizing enteral gel compositions is to introduce one or more antioxidants, such as ascorbic acid or citric acid, into the gel. Other antioxidants that can be used can be readily selected from commonly known antioxidants by those skilled in the art.

It has also been found that storage of gel compositions in light-attenuating containers such as aluminum bags has some favorable effects on the degradation of carbidopa and entacapone.

In some embodiments, the enteral gel compositions of the present invention have a pH of about 5, are deoxygenated with nitrogen gas, and are preferably provided in a light-tight container.

Heavy metals are well known to catalyze the decomposition of carbidopa. Although prior art levodopa/carbidopa formulations have been shown to be stabilized by EDTA, which has excellent chelating properties, the stability of the enteral gel compositions of the present invention is surprisingly It has been found that there are negative effects. In some embodiments, the gel compositions provided by the present invention are therefore preferably free of any chelating agent.

Those skilled in the art upon reading this disclosure will appreciate its inclusion regarding the increased stability of carbidopa in the presence of entacapone (and specifically in the presence of entacapone in gel compositions for enteral administration). It will be appreciated that the demonstration may be well generalized to the presence of other COMT inhibitors and/or to contexts other than the combination in gel form as described herein. Dew. Thus, in some embodiments, the present disclosure provides gel compositions (e.g., for enteral administration) comprising pharmaceutically active agents comprising or consisting of carbidopa and a COMT inhibitor, and optionally further comprising levodopa. I will provide a. Additionally, in some embodiments, the present disclosure provides that the administration of carbidopa is performed in an optionally separate composition from the administration of entacapone (e.g., in the context of a gel composition for enteral administration) or other COMT inhibitors. therapeutic regimens that are combined in a clinical setting and capable of reducing hydrazine levels with beneficial effects for the patient (compared to those observed under comparable conditions in the absence of a COMT inhibitor, e.g. entacapone). I will provide a.

(Combination therapy)
As described herein, the invention involves combination therapy with (a) a dopamine replacement agent; (b) one or more DDIs and (c) one or more COMT inhibitors. and/or provide technology to achieve it. As described herein, in many embodiments, the present disclosure relates to the administration of individual agents or combinations of agents for which certain therapeutic regimens and forms are already well known. In some embodiments, the insights embodied in this disclosure may result in reduced dosing (e.g., daily dose, total amount over a selected period of time, and/or compositions and/or dosing regimens containing or including (in a frequency of dosing).

In certain embodiments, each of (a) a dopamine replenisher, (b) a DDI; and (c) a COMT inhibitor, as described herein, are administered simultaneously and in a single composition ( It may even be administered in enteral gel compositions, such as those described herein. The teachings contained herein provide those skilled in the art with insight and techniques (eg, compositions and methods) that are not limited to the particular illustrative embodiments.

For example, the teachings provided herein will teach those skilled in the art that, for example, (a) a dopamine replenisher, (b) a DDI; and (c) a COMT inhibitor are administered in separate compositions in certain embodiments. indicates what will be done. In some embodiments, each may be in separate compositions. In some embodiments, the two may be together in a single composition while the third is in a separate composition. To give just one specific example, one of ordinary skill in the art upon reading this disclosure will appreciate that co-administration of DUODOPA® and separate enteric gel compositions containing entacapone and/or another COMT inhibitor is You will realize that it would be desirable.

Of course, those skilled in the art will readily appreciate that not all advantages described herein may be achieved in all such forms or to the same level. . That is, certain advantages may be due, at least in part, to the co-localization of all three agents in a single composition. However, those skilled in the art will also appreciate that significant benefits may be achieved even without such co-localization. For example, simultaneous administration (substantially simultaneously or at different times) of separate gels, but nevertheless, to all three of the same site [e.g., duodenum] of the patient and optionally within the patient. (either of which achieves exposure to one drug) may well provide significant benefit over other available treatment regimens.

One skilled in the art upon reading this disclosure will appreciate that, in some embodiments, depending on the particular properties of (a) the dopamine replenisher (b) the DDI; and (c) the COMT inhibitor utilized, It will be particularly appreciated that separate dosing patterns may be beneficial in some contexts. For example, different drugs within a particular class may have different half-lives and/or other pharmaceutical properties such that the timing of their administration relative to other drugs is desirably staggered. To give just one specific example, different pharmacokinetic and pharmacodynamic properties for different COMT inhibitors have been reported in studies (e.g. Forsberg et al., JPET 304:498, 2003). For example, tolcapone has been reported to have a longer duration of action and better brain penetration than entacapone. Specifically, Forsberg et al.
“After intravenous administration (3 mg/kg), the elimination half-life (t _1/2β ) of entacapone (0.8 h) was clearly shorter than that of tolcapone (2.9 h). Tolcapone The striatal/serum ratio of was three times higher than that of entacapone. After a single oral dose (10 mg/kg), both entacapone and tolcapone produced an equal maximal degree of COMT inhibition in peripheral tissues. However, tolcapone inhibited COMT in the striatum more effectively than entacapone. After 7 days of treatment (10 mg/kg twice daily), COMT activity decreased 8 hours after the final dose of entacapone. within, levels recovered from 67 to 101% of controls. In animals treated with tolcapone, there was still greater COMT inhibition in the peripheral tissues, and the degree of inhibition was greater than that achieved after a single dose. Pharmacokinetic and pharmacodynamic modeling showed that for both entacapone and tolcapone, a plateau of COMT inhibition close to the maximal achievable inhibition was already achieved with plasma concentrations below 2000 ng/ml. We found that entacapone and tolcapone equally inhibited rat liver COMT in vitro with K _i values of 10.7 and 10.0 nM, respectively.
reported that these results "suggest that peripheral COMT inhibitors are continuously inhibited when tolcapone is administered at 12-hour intervals, but this is not seen with entacapone." concludes.

A person of ordinary skill in the art who is aware of these differences and who reads this disclosure will recognize that, for example, it may be desirable to administer tolcapone less frequently than entacapone. The present disclosure shows, among other things, the particular utility of administering enteral gels of COMT inhibitors, including compositions containing each of (a) a dopamine supplement, (b) a DDI; and (c) a COMT inhibitor. Given that the present disclosure also exhibits certain advantages, one skilled in the art will appreciate that the present disclosure provides a method for preparing combination compositions comprising tolcapone (e.g., compositions comprising each of levodopa, carbidopa, and tolcapone), optionally in gel form. For example, it will be appreciated that providing for enteral administration, in some embodiments, when the COMT inhibitor is tolcapone, a lower amount of It will also be appreciated that it may be desirable to include a COMT inhibitor. Alternatively, comparable ratios would be maintained, but less frequent dosing would be utilized, optionally with intervals for further dosing of the composition containing, for example, (a) the dopamine replacement agent and (b) the DDI. will be opened.

Alternatively or additionally, one of ordinary skill in the art upon reading this disclosure will appreciate that in the context that the teachings are in already available form (e.g., as described herein), (a) dopamine replenishers (b) DDI and (c) will appreciate the extent to which administration of one or more COMT inhibitors may be applied and/or combined. Thus, for example, in some embodiments, therapeutic regimens provided by the present disclosure include combining a COMT inhibitor (e.g., entacapone) with (a) a dopamine replacement agent (e.g., levodopa), e.g., in the context of an available commercially available form; ) and/or (b) in combination with a DDI (eg carbidopa) can be utilized. In some such embodiments, the route, timing and/or amount of any individual dose (and/or total dose) of a commercially available form includes a COMT inhibitor as provided herein. When combined with enteral administration of the gel composition, it may be different.

Still further, those skilled in the art will appreciate that in some embodiments, combination therapy as described herein allows a patient to receive (a) a dopamine replacement agent; (b) one or more DDIs and (c) It will be readily appreciated that depending on which treatment is received with each of the one or more COMT inhibitors, it may be further combined with one or more other treatments/therapy modalities. In some embodiments, the treatments provided include one or more anticholinergic agents (e.g., antihistamines, tropins and/or esters thereof, etc., and combinations thereof), to name a few or in combination with multiple glutamate antagonists and/or one or more amantadine derivatives. In some embodiments, one or more such agents are included in an enteral gel as described herein.

(bioavailability)
In some embodiments, the invention provides for administering to a subject a combination of levodopa, a DDI, and a COMT inhibitor, wherein one or more agents in the combination are administered by enteral administration of a pharmaceutical gel. , an unexpected change in one or more pharmacokinetic properties (e.g. area under the curve (AUC), bioavailability (e.g. absolute bioavailability, relative bioavailability), half-life, etc.) of one or more active agents; Contains insights that lead to improvements.

Among other things, the present disclosure presents the surprising discovery that the provided compositions and/or methods can achieve significant improvements in the bioavailability of dopamine supplements (eg, levodopa). Specifically, previous reports of combination therapy using a three-component combination of (a) levodopa, (b) carbidopa, and (c) entacapone in a single tablet indicated that (a) levodopa and (b) The bioavailability of levodopa can be increased by about 10% to about 30% compared to other comparable tablets containing carbidopa but without (c) entacapone. (For example, an overview of the product characteristics of STALEVO (registered trademark), http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000511/WC5000574 85.pdf, September 3, 2015 Table 1 below outlines certain literature reports that observed increased bioavailability of levodopa when combined with COMT inhibitors.

As seen with reference to the Examples section below, the present disclosure provides pharmaceutically active agents comprising or consisting of each of: (a) a dopamine replenisher; (b) a DDI; and (a) a COMT inhibitor. Certain inventive gel compositions (e.g., formulated for enteral administration) containing an average increase of 55% (1.5 to 3.0 The surprising finding is that dramatically greater increases in levodopa availability can be achieved, even by as much as 40%, 45%, 50%, and even more than 55%, as observed (in the range of 2-fold improvement). Describe.

In the following, non-limiting embodiments of the enteral gel compositions of the present invention and their equivalent experiments are described.

Example 1
A PK model was developed to simulate the concentration time curve of levodopa for total daily doses of levodopa from 400 mg to 2000 mg. The simulation results are shown in Figure 1. Assume that 25% of the total daily dose of levodopa is given as the morning dose. Simulations show that the gradual increase in plasma levels of levodopa is more pronounced at higher doses.

The gradual increase in plasma levels of levodopa obtained over the course of a day with the composition according to the invention (Lecigon®) is beneficial and reduces the parkinsonian symptoms frequently observed during the second half of the day. Fits worse. For patients who exhibit a tendency to become hyperkinetic in the afternoon, titration can be reduced using a second reduced continuous flow rate during the day. The continuing dose was reduced by 20% 5 hours after treatment. The simulation results show a very flat concentration, see FIG. 2.

The linear trend in the simulations indicates that a flat profile can be obtained for patients requiring higher levodopa doses when applying a second lower continuous flow rate 5 hours after the start of treatment (noon). Show clearly. This is of particular interest for patients with a tendency to bothersome hyperkinesia in the afternoon. The characteristics of the Crono Lecig pump by Cane easily allow for a second continuous flow rate program that can be selected by the patient when needed.

To input the expected plasma profile and daily variation in context, construct plots and simulate Lecigon with one or two continuous flow rates using Duodopa according to Nyholm et al., 2013. Figure 3 compares with the profile of levodopa published in

In general, the plasma concentration profile of levodopa can be individualized and optimized to meet patient requirements over the entire dose range. The gradual increase in plasma levels of levodopa obtained over the day with Lecigon is beneficial and compatible with the exacerbation of parkinsonian symptoms frequently observed during the second half of the day. For patients who exhibit a tendency to become hyperkinetic in the afternoon, titration can be reduced using a second reduced continuous flow rate during the day.

Claims (17)

A pharmaceutical composition comprising a dopamine replenisher, a dopamine decarboxylase inhibitor (DDI), and a catechol-O-methyltransferase (COMT) inhibitor for use as a medicine, wherein the dopamine replenisher is levodopa, a pharmaceutically acceptable salt thereof, melevodopa or etilevodopa, the dopamine decarboxylase inhibitor is selected from the group consisting of carbidopa, benserazide and combinations thereof, and the COMT inhibitor is entacapone, tolcapone, opicapone and the like. selected from the group consisting of a combination of :
a. administering a first dose of the pharmaceutical composition that is 20-35% of the total daily dose of the dopamine supplement; and b. sequentially administering second doses of the pharmaceutical composition that add up to the total daily dose of the dopamine replenisher , wherein the second doses of the pharmaceutical composition are in a liquid form; a pharmaceutical composition, suspension or gel of
A pharmaceutical composition administered by. The method is
a. administering a first dose of the pharmaceutical composition that is 20-35% of the total daily dose of the dopamine supplement;
b. successively administering second doses of the pharmaceutical composition that add up to the total daily dose of the dopamine replenisher, the first portion of the second dose being initially for a predetermined period of time, after which a second portion of said second dose is sequentially administered, the sum of said first and second portions adding up to said second dose. 2. The pharmaceutical composition of claim 1, comprising the step of continuous administration, wherein for the second portion, a lower amount of the dopamine replenisher is administered per time unit. The pharmaceutical composition according to claim 1 , wherein the dopamine decarboxylase inhibitor is carbidopa. The dopamine supplement, the dopamine decarboxylase inhibitor (DDI) and the catechol-O-methyltransferase (COMT) inhibitor, and optionally a suitable adjuvant are contained in a single pharmaceutical composition. The pharmaceutical composition according to claim 1. the pharmaceutical composition comprises first, second and third parts, the first part comprising the dopamine replenisher and the second part comprising the dopamine decarboxylase inhibitor (DDI); The third part comprises the catechol-O-methyltransferase (COMT) inhibitor, each part optionally comprising a suitable adjuvant, or the pharmaceutical composition comprises the dopamine supplement and the dopamine depletion agent. 2. The pharmaceutical composition of claim 1, comprising a first part comprising a carbonic acid enzyme inhibitor (DDI) and a second part comprising said COMT inhibitor, each part optionally comprising a suitable adjuvant. The first dose of the dopamine supplement, the dopamine decarboxylase inhibitor (DDI) and the catechol-O-methyltransferase (COMT) inhibitor, and optionally a suitable adjuvant are administered individually. or said dopamine supplement and said dopamine decarboxylase inhibitor (DDI) are administered simultaneously, said COMT inhibitor being administered essentially simultaneously with said dopamine supplement and said dopamine decarboxylase inhibitor (DDI). A pharmaceutical composition according to claim 1, which is administered. A pharmaceutical composition according to claim 1, wherein the total daily dose of the dopamine supplement is from 200 to 3500 mg, such as from 400 to 3000 mg. A pharmaceutical composition according to claim 1, which is administered to a patient suffering from Parkinson's disease. 9. A pharmaceutical composition according to claim 8 , wherein the patient suffers from a susceptibility to hyperkinesia or has a tendency to develop hyperkinesia. 2. The pharmaceutical composition according to claim 1, wherein the administration of the second dose of the pharmaceutical composition is carried out continuously for 24 hours. A pharmaceutical composition according to claim 1, wherein the administration of the second dose of the pharmaceutical composition is carried out continuously for 12 to 18 hours, such as 13 to 17 hours or 14 to 16 hours. 2. The pharmaceutical composition of claim 1, wherein the first dose is administered in the morning, such as between 5am and 10am. 2. The pharmaceutical composition of claim 1, wherein the first dose of the pharmaceutical composition is an oral pharmaceutical composition, a liquid pharmaceutical composition, a suspension or a gel. 14. The pharmaceutical composition of claim 13 , wherein the first dose is administered orally, intravenously, subcutaneously, enterally or transdermally. 2. The pharmaceutical composition of claim 1, wherein the second dose is administered intravenously, subcutaneously, enterally or transdermally. 16. A kit according to any one of claims 1 to 15 , comprising a first container and at least one further container, wherein the first and at least one further container are each for use as a medicament. comprising first and second doses of a pharmaceutical composition according to
a. said first dose comprises 20-35% of said total daily dose of said dopamine supplement;
b. The second doses sum to the total daily dose of the dopamine supplement; at least the second dose is a liquid pharmaceutical composition, suspension or gel. 17. The kit of claim 16 , wherein both the first and second doses are in the form of a liquid pharmaceutical composition, suspension or gel.