CN116964069A - Stabilized liquid compositions comprising levodopa-tyrosine conjugates and uses thereof - Google Patents

Stabilized liquid compositions comprising levodopa-tyrosine conjugates and uses thereof Download PDF

Info

Publication number
CN116964069A
CN116964069A CN202280019958.8A CN202280019958A CN116964069A CN 116964069 A CN116964069 A CN 116964069A CN 202280019958 A CN202280019958 A CN 202280019958A CN 116964069 A CN116964069 A CN 116964069A
Authority
CN
China
Prior art keywords
pharmaceutical composition
liquid pharmaceutical
amino
acid
tyr
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202280019958.8A
Other languages
Chinese (zh)
Inventor
阿维陶·莱瑟
E·加札
马茲·达甘-莱恩
艾琳娜·瓦因什多
亚拉·陶哈密
艾力克斯·曼菲德
E·札沃尼
诸熊贤治
中山和树
吉田瑛二
中尾朗
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Neuroderm Ltd
Original Assignee
Neuroderm Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Neuroderm Ltd filed Critical Neuroderm Ltd
Priority claimed from PCT/IL2022/050269 external-priority patent/WO2022190100A1/en
Publication of CN116964069A publication Critical patent/CN116964069A/en
Pending legal-status Critical Current

Links

Landscapes

  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Disclosed herein are levodopa prodrug compounds and methods of use thereof. Also disclosed herein are liquid pharmaceutical formulations comprising a levodopa-tyrosine conjugate and a stabilizer, wherein the liquid pharmaceutical formulations may further comprise a decarboxylase inhibitor such as carbidopa, an antioxidant, a solvent, or any other pharmaceutically acceptable excipient. Also disclosed are methods of treating neurodegenerative conditions and/or conditions characterized by reduced levels of dopamine in the brain, such as parkinson's disease, comprising administering the disclosed prodrugs and/or liquid pharmaceutical formulations.

Description

Stabilized liquid compositions comprising levodopa-tyrosine conjugates and uses thereof
Cross Reference to Related Applications
The present application claims the benefit and priority of U.S. provisional patent application No. 63/159,236 filed on 3 months 10 of 2021 and U.S. provisional patent application No. 63/296,032 filed on 1 month 3 of 2022, the entire disclosures of each of which are hereby incorporated by reference in their entireties.
Technical Field
The application relates to a levodopa prodrug compound and pharmaceutical application thereof. The application also relates to stabilized compositions comprising levodopa-tyrosine conjugates (LD-Tyr) and salts thereof, methods of making LD-Tyr compositions, and methods of using them, for example, in the treatment of conditions characterized by neurodegeneration and/or reduced dopamine levels in the brain (e.g., parkinson's disease).
Background
Parkinson's disease is a degenerative condition characterized by a decrease in the concentration of the neurotransmitter dopamine in the brain. Levodopa (L-dopa or L-3, 4-dihydroxyphenylalanine) is a direct metabolic precursor of dopamine, which, unlike dopamine, is able to cross the blood brain barrier and is most commonly used to restore dopamine concentration in the brain. Levodopa has been the most effective therapy for the treatment of parkinson's disease throughout the last 40 years.
However, conventional treatment of parkinson's disease with levodopa has proven inadequate for many reasons documented in the medical literature. For example, some patients eventually become less responsive to levodopa, such that previously effective doses eventually fail to produce any therapeutic benefit. Thus, systemic administration of levodopa, while initially producing a clinically beneficial effect, is complicated by the need to increase the dose to such high doses that may lead to adverse side effects. For this reason, the benefit of levodopa therapy typically begins to diminish after about 3 years or 4 years of therapy, regardless of the initial therapeutic response.
Peripheral administration of levodopa is further complicated by the fact that: about 1% -3% of the levodopa administered alone is able to enter the brain unchanged, with most of the levodopa being metabolized outside the brain, mainly by decarboxylation of levodopa to dopamine, which does not penetrate the blood brain barrier and is therefore ineffective in therapy. The metabolic conversion of levodopa to dopamine is catalyzed by aromatic L-amino acid decarboxylase, a ubiquitous enzyme with particularly high concentrations in intestinal mucosa, liver, brain and brain capillaries. Due to the possibility of the extracellular metabolism of levodopa, it is necessary to administer large doses of levodopa, resulting in high extracellular concentrations of dopamine. It has been found that co-administration of levodopa and a peripheral dopamine decarboxylase (aromatic L-amino acid decarboxylase) inhibitor such as carbidopa (carbidopa) or dopaminzide (benserazide) reduces the dose requirement of levodopa and reduces some side effects, respectively; however, in general, the reduction obtained is insufficient.
Finally, as treatment is prolonged, the clinical response of levodopa appears to fluctuate somewhat, with increasing frequency. In some patients, these fluctuations are correlated with the time of levodopa intake, known as "progressive-off reactions" or "end-of-dose akinesia". In other cases, fluctuations in clinical status are independent of the time of dosage and are commonly referred to as "on-off phenomenons". In the switching phenomenon, significant movement is not alternated with "off-period" of bradykinesia with "on-period" of improved mobility over the course of several hours, which is often associated with troublesome movement disorders.
In order to maintain the desired dopamine concentration in the brain, a method of continuously administering a formulation comprising levodopa with a pump has been developed. As an example, a gel for continuous intestinal delivery of L-dopa/carbidopa is known (under the trade name in europeAnd is tradename->Known) and has been used to treat parkinson's disease. However, because of the need for intestinal insertion, the burden on the patient is large, and thus less invasive and pharmacokinetic stable delivery systems are needed. An example of a less invasive delivery system is a method of subcutaneously administering a solution formulation with a pump. Such formulations are currently under investigation but have not yet been marketed.
As described above, when developing an optimal formulation for a continuous delivery system in the treatment of parkinson's disease, it is necessary that the active ingredient be soluble and stable in the formulation. Many different approaches can be considered; however, in order to improve the solubility of the active ingredient itself, one approach may be to produce novel prodrugs of levodopa. For example, it is known to add amino acids to prodrugs of levodopa molecules (U.S. patent No. 3803120). In addition, levodopa prodrug compounds with phosphate esters are also known (international patent publication No. WO 2017/184871).
Furthermore, it is recognized in the art that many of the drawbacks mentioned above are caused by the unfavorable pharmacokinetic properties of levodopa and, more particularly, by its poor aqueous solubility, bioavailability and rapid in vivo degradation. Another approach may be to develop an effective therapeutic formulation with improved stability for the treatment of disorders such as parkinson's disease.
Amino acids comprising an amino group and a carboxyl group are the basic units of proteins. Generally, amino acids are known to play an important role in the body, involved in tissue protein formation and enzyme hormone formation. Thus, any lack of amino acids affects protein synthesis. Amino acids are also known to regulate processes associated with gene expression, and in addition, amino acids also regulate protein functions involved in messenger RNA translation. Several amino acids, such as tyrosine, are synthesized in the human body, while others, known as essential amino acids, such as arginine and lysine, are consumed by the diet. Lanthionine (lanothionine) amino acid is a natural but non-proteinogenic diamino diacid and is structurally related to the amino acid cysteine. Lanthionine has a central mono-sulphur moiety (R/S configuration) bound to two alanine residues, allowing the possibility of different stereoisomeric forms of lanthionine.
The amino acid ionizes in aqueous solution, where the pH of the solution affects the ionic species of the amino acid and determines whether the amino acid will be in the form of a zwitterion, a cation, or an anion. The permeability coefficient of various compounds through the skin depends on their ionic form, with non-ionized substances generally having a higher permeability coefficient than ionized substances, and furthermore, cations generally having a higher permeability coefficient than anions.
U.S. patent No. 3,803,120, U.S. patent No. 4,035,507, U.S. patent No. 5,686,423, and U.S. patent application No. 2002/099013 disclose certain levodopa amino acid and levodopa peptide conjugates; however, details concerning formulations are not provided therein, and when provided, only solid oral formulations are contemplated. The theoretical options for preparing liquid compositions are briefly mentioned in U.S. Pat. No. 3,803,120 (U.S. Pat. No. 120, column 3, lines 49-53); however, no such compositions were prepared, and furthermore, it was erroneously disclosed that the conjugate was soluble (column 3, lines 65-66).
In addition, levodopa amino acid conjugates, such as LD-Tyr, may be unstable and/or form impurities over time. For example, LD-Tyr has a tendency to form Diketopiperazine (DKP) impurities, as shown in the schemes below.
As described in detail above, there remains a need for effective, stable formulations, and in particular liquid formulations, for the treatment of disorders such as parkinson's disease.
Summary of The Invention
The present disclosure intends to provide a novel compound having improved solubility and stability in solution compared to levodopa by generating a novel prodrug and allowing the compound to be converted into levodopa in vivo.
As a result of intensive studies to solve the above problems, the present inventors have found that a levodopa prodrug compound represented by general formula (I) or general formula (III) has high levodopa conversion efficiency and good solubility and stability in solution, and thus have achieved the present invention.
Thus, in one embodiment, the present disclosure relates to a levodopa amino acid complex represented by the following formula (I) or formula (III):
[ chemical formula 1]
Wherein R is an amino acid side chain which may be substituted;
R 1 and R is 2 C which may be the same or different and are each independently a hydrogen atom and may be substituted 1 -C 6 Alkyl, C 1 -C 6 Alkanoyl, phosphono, sulfinyl or glycosyl, provided that R 1 And R is 2 Not both hydrogen atoms;
R 3 and R is 4 May be the same or different and are each independently a hydrogen atom or C 1 -C 6 An alkyl group; and is also provided with
R 5 Is a hydrogen atom, or
[ chemical formula 3]
Wherein R is 11 And R is 12 Identical or different and are each hydrogen, alkyl which may be substituted, alkanoyl, P (=o) (OH) 2 S (=o) (OH) or glycosyl;
R 13 is alkyl which may be substituted, -R 15 -O-R 16 Or a 5-membered heterocyclic group containing at least one nitrogen atom, wherein R 15 Is alkylene, and R 16 Is hydrogen, optionally substituted alkyl, P (=O) (OH) 2 S (=o) (OH) or glycosyl; and is also provided with
R 14 Is hydrogen or an alkyl group, and is preferably a hydrogen atom,
provided that the following compounds are excluded;
(2S) -2- [ (2-Aminoacetyl) amino ] -3- (3, 4-diacetoxyphenyl) propionic acid,
(2S) -2- [ [ (2S) -2-amino-6- [ (2-chlorophenyl) methoxycarbonylamino ] hexanoyl ] amino ] -3- (3, 4-dimethoxyphenyl) propanoic acid,
(2S) -2- [ [ (2S) -2-amino-3- (3, 4-dihydroxyphenyl) propionyl ] amino ] -3- (4-hydroxy-3-methoxyphenyl) propanoic acid,
(2S) -2- [ [ (2S) -2-amino-3-phenylpropionyl ] amino ] -3- (3, 4-dimethoxyphenyl) propionic acid,
(2S) -2- [ [ (2R) -2-amino-3-phenylpropionyl ] amino ] -3- (3, 4-diacetoxyphenyl) propanoic acid, and
(2S) -2- [ [ (2S) -2-amino-5-methoxy-5-oxopentanoyl ] amino ] -3- (3, 4-dimethoxyphenyl) propanoic acid.
In certain embodiments, the disclosure further relates to a levodopa amino acid complex according to (1) above, or a pharmaceutically acceptable salt thereof, wherein R 3 、R 4 And R is 5 Is a hydrogen atom and is preferably a hydrogen atom,
R 1 and R is 2 Identical or different and are each a hydrogen atom, an acetyl group or a phosphono group, provided that R 1 And R is 2 Not both hydrogen atoms.
In certain embodiments, the disclosure further relates to a levodopa amino acid complex according to (1) or (2) above, or a pharmaceutically acceptable salt thereof, wherein R 3 、R 4 And R is 5 Is a hydrogen atom and is preferably a hydrogen atom,
R 1 is a hydrogen atom, and
R 2 is a phosphono group.
In certain embodiments, the present disclosure also relates to a levodopa amino acid complex according to any one of the above embodiments, or a pharmaceutically acceptable salt thereof, wherein the amino acid of the amino acid side chain is glutamic acid, valine, alanine, lysine, 3, 4-dihydroxyphenylalanine, or tyrosine.
In certain embodiments, the disclosure further relates to a levodopa amino acid complex selected from the group consisting of:
(2S) -2- [ [ (2S) -2-amino-3-phosphonooxypropionyl ] amino ] -3- (3, 4-dihydroxyphenyl) propanoic acid,
(2S) -2- [ [ (2S) -2-amino-3- (4-phosphonooxyphenyl) propionyl ] amino ] -3- (3, 4-dihydroxyphenyl) propanoic acid,
(2S) -2-amino-5- [ [ (1S) -1-carboxy-2- (3, 4-diacetoxyphenyl) ethyl ] amino ] -5-oxo-pentanoic acid,
(2S) -3- (3, 4-dihydroxyphenyl) -2- [ (2-methyl-2-phosphonooxypropionyl) amino ] propanoic acid, and
(2S) -2- [ [ (2S) -2-amino-3- [4- [ (2S, 3R,4S,5S, 6R) -3,4, 5-trihydroxy-6- (hydroxymethyl) oxacyclohex-2-yl ] oxyphenyl ] propionyl ] amino ] -3- (3, 4-dihydroxyphenyl) propanoic acid.
In certain embodiments, the present disclosure also relates to liquid pharmaceutical compositions comprising the levodopa amino acid complex according to any one of the above embodiments, or a pharmaceutically acceptable salt thereof, as an active ingredient.
In certain embodiments, the present disclosure also relates to a therapeutic agent for neurodegenerative diseases and/or diseases or symptoms caused by reduced dopamine concentration in the brain, comprising as an active ingredient a levodopa amino acid complex according to any one of the embodiments above or a pharmaceutically acceptable salt thereof. In certain embodiments, the neurodegenerative disease and/or the disease or condition caused by reduced dopamine concentration in the brain is parkinson's disease.
Also provided herein are, inter alia, compositions, e.g., pharmaceutically acceptable compositions, e.g., liquid pharmaceutical compositions, having improved stability, comprising a levodopa-tyrosine conjugate (LD-Tyr) or a salt thereof (e.g., a pharmaceutically acceptable salt thereof). Methods of preparing such compositions are also described herein. Also disclosed are methods of using compositions comprising LD-Tyr and pharmaceutically acceptable salts thereof, and compositions comprising LD-Tyr and pharmaceutically acceptable salts thereof, for example, in the treatment of conditions characterized by neurodegeneration and/or reduced dopamine levels in the brain (e.g., parkinson's disease).
Disclosed herein is a liquid pharmaceutical composition comprising:
a levodopa-tyrosine (LD-Tyr) conjugate of formula (II):
enantiomers, diastereomers, racemates, ions, zwitterionic, pharmaceutically acceptable salts thereof, or any combination thereof; and a stabilizer.
In some embodiments, the liquid pharmaceutical compositions disclosed herein comprise between about 10% w/v to about 45% w/v, at least about 30% w/v, or between about 30% w/v to about 45% w/v LD-Tyr, or an enantiomer, diastereomer, racemate, ion, zwitterionic, pharmaceutically acceptable salt thereof, or any combination thereof.
In some embodiments, the stabilizer is present in an amount of about 0.1% w/v to about 30% w/v.
In some embodiments, the stabilizer comprises a base. In some embodiments, the base is selected from the group consisting of: arginine, naOH, NH 4 OH, TRIS (hydroxymethyl) aminomethane (TRIS), ethylenediamine, diethylamine, ethanolamine, diethanolamine, meglumine, and any combination thereof. In some embodiments, the base is selected from the group consisting of: arginine, NH 4 OH, ethylenediamine, diethylamine, ethanolamine, diethanolamine, meglumine, and any combination thereof. In some embodiments, the base is selected from the group consisting of: L-Arg, diethylamine and combinations thereof. In some embodiments, the base is selected from the group consisting of: L-Arg, ethanolamine and combinations thereof.
In some embodiments, the liquid pharmaceutical composition comprises between about 0.1% w/v to about 30% w/v base. In some embodiments, the liquid pharmaceutical composition comprises between about 1.5% w/v to about 20% w/v base.
In some embodiments, the liquid pharmaceutical compositions disclosed herein have a pH in the range of between about 5 to about 10 at about 25 ℃. In some embodiments, the liquid pharmaceutical compositions disclosed herein have a pH in the range between about 8 to about 10. In some embodiments, the liquid pharmaceutical compositions disclosed herein have a pH in the range between about 8 to about 9.
In some embodiments, the liquid pharmaceutical compositions disclosed herein may comprise the free base and counter ion of the compound of formula II.
In some embodiments, the liquid pharmaceutical compositions disclosed herein may further comprise a decarboxylase inhibitor. For example, in some embodiments, the decarboxylase inhibitor is carbidopa. In some embodiments, the liquid pharmaceutical compositions disclosed herein may comprise between about 0.25% w/v to about 2.0% w/v of the decarboxylase inhibitor.
Any of the above-mentioned liquid pharmaceutical compositions described herein may further comprise an antioxidant or a combination of two or more antioxidants. For example, in some embodiments, the liquid pharmaceutical compositions described herein may comprise an antioxidant selected from the group consisting of: ascorbic acid or a salt thereof, cysteine, e.g. N-acetylcysteine (NAC), acid sulfite or a salt thereof, glutathione, tyrosinase inhibitors, cu 2+ Chelating agents, and any combination thereof. In some embodiments, the liquid pharmaceutical compositions described herein may comprise between about 0.05% w/v to about 1.5% w/v of an antioxidant or combination of antioxidants. In some embodiments, the liquid pharmaceutical composition comprises a combination of ascorbic acid and NAC.
Any of the above-mentioned liquid pharmaceutical compositions described herein may further comprise at least one of the following: catechol-O-methyltransferase (COMT) inhibitors, monoamine oxidase (MAO) inhibitors, surfactants, buffers, acids, bases, solvents, or any combination thereof. In some embodiments, the liquid pharmaceutical composition comprises between about 5.0% w/v to about 40.0% w/v buffer, base or solvent. For example, in some embodiments, the liquid pharmaceutical compositions described herein may comprise a solvent, wherein the solvent may be N-methylpyrrolidone (NMP), TRIS (hydroxymethyl) aminomethane (tromethamine, TRIS), ethers such as tetrahydrofuran and 1, 4-dioxane, amides such as N, N-dimethylformamide and N-methylpyrrolidone, nitriles such as acetonitrile, halogenated aliphatic hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as toluene, or any combination thereof. It should be noted that certain materials such as Tromethamine (TRIS) may be added to the composition and act as, for example, a base, buffer, solvent, or any combination thereof. In some embodiments, the liquid pharmaceutical compositions described herein may comprise a surfactant, wherein the surfactant is tween-80. In some embodiments, the liquid pharmaceutical compositions described herein may comprise a solvent and a surfactant, wherein the solvent is NMP and the surfactant is tween-80. In some embodiments, the liquid pharmaceutical composition may comprise between about 0.1% w/v to about 1.0% w/v surfactant, e.g., 0.1% w/v to about 1.0% w/v tween-80. In some embodiments, the liquid pharmaceutical composition may comprise between about 5.0% w/v to about 40.0% w/v solvent, e.g., between about 5.0% w/v to about 40.0% w/v NMP.
In certain embodiments, the solvent is TRIS. In certain embodiments, the stabilizer comprises polyethylene glycol.
In certain embodiments, the liquid pharmaceutical composition comprises less than about 1.5% w/v LD-Tyr-diketopiperazine after two weeks at 2 ℃ to 8 ℃. In certain embodiments, the liquid pharmaceutical composition comprises less than about 0.8% w/v LD-Tyr-diketopiperazine after two weeks at 2 ℃ to 8 ℃. In certain embodiments, the liquid pharmaceutical composition comprises less than about 5.0% w/v LD-Tyr-diketopiperazine after two weeks at 25 ℃. In certain embodiments, the liquid pharmaceutical composition comprises no more than about 4% w/v LD-Tyr-diketopiperazine after two weeks at 25 ℃.
Also disclosed herein is a method of treating a neurodegenerative condition and/or a condition characterized by reduced levels of dopamine in the brain, wherein the method comprises administering a liquid pharmaceutical composition as described herein.
For example, disclosed herein is a method of treating a neurodegenerative condition and/or a condition characterized by reduced levels of dopamine in the brain, wherein the method comprises administering a liquid pharmaceutical composition comprising LD-Tyr and a stabilizer.
Disclosed herein is a method of treating a neurodegenerative condition and/or a condition characterized by reduced levels of dopamine in the brain, wherein the neurodegenerative condition is parkinson's disease.
In some embodiments of the disclosed methods of treatment, the liquid pharmaceutical composition is administered concomitantly with the additional active ingredient. For example, in some embodiments, the additional active ingredient is a decarboxylase inhibitor, COMT inhibitor, MAO inhibitor, or any combination thereof.
In some embodiments of the methods of treatment disclosed herein, the liquid pharmaceutical composition is administered substantially continuously. In some embodiments, the liquid pharmaceutical composition is administered subcutaneously.
Also disclosed herein is a liquid pharmaceutical composition for treating a neurodegenerative condition and/or a condition characterized by reduced levels of dopamine in the brain.
Disclosed herein is a liquid pharmaceutical composition for treating a neurodegenerative condition and/or a condition characterized by reduced levels of dopamine in the brain, wherein the neurodegenerative condition is parkinson's disease.
According to some embodiments, the liquid pharmaceutical composition is administered to the patient concomitantly with additional active ingredients, such as decarboxylase inhibitors, COMT inhibitors, MAO inhibitors, and any combination thereof.
According to some embodiments, the liquid pharmaceutical composition is administered to the patient substantially continuously. According to further embodiments, the liquid pharmaceutical composition is administered subcutaneously.
Embodiments of the present invention also relate to a method of treating parkinson's disease in a patient in need thereof, the method comprising subcutaneously administering to the patient an effective amount of a liquid pharmaceutical formulation as disclosed herein. Further embodiments of the invention relate to the use of a liquid pharmaceutical formulation as disclosed herein for the treatment of neurodegenerative conditions and/or conditions characterized by reduced levels of dopamine in the brain, such as parkinson's disease.
Also disclosed herein is a process for preparing a liquid pharmaceutical composition, wherein the process comprises providing a pharmaceutically acceptable salt of LD-Tyr; combining a pharmaceutically acceptable salt with at least one solvent, thereby forming a solution, gel, cream, emulsion, or suspension; combining a solution, gel, cream, emulsion or suspension with a stabilizer; and adjusting the pH of the solution, gel, cream, emulsion or suspension to a physiologically acceptable pH value, thereby providing a liquid pharmaceutical composition.
In some embodiments, the process for preparing a liquid pharmaceutical composition described herein comprises providing LD-Tyr, an enantiomer, diastereomer, racemate, ion, zwitterionic, pharmaceutically acceptable salt thereof, or any combination thereof.
In some embodiments of the processes described herein, the LD-Tyr compound of formula (II) in the form of a pharmaceutically acceptable salt is mixed with at least one solvent and at least one stabilizer, thereby forming a solution. In some embodiments, the process includes a step of adjusting the pH, which step includes adding an alkaline solution. For example, in some embodiments, the process includes a step of adjusting the pH, the step including adding an alkaline solution, and the alkaline solution comprises NaOH. In some embodiments, the process does not include heating.
Brief Description of Drawings
FIG. 1 is a graph depicting the rate of formation of LD-Tyr-diketopiperazine (LD-Tyr-DKP) over time at 2℃to 8℃in an LD-Tyr formulation comprising the indicated base.
Fig. 2 is a graph depicting the rate of formation of LD-Tyr-diketopiperazine (LD-Tyr-DKP) over time at 25 ℃ in an LD-Tyr formulation comprising the indicated base.
FIG. 3 presents the K of LD-Tyr after incubation in rat blood RBC/PL 。
FIG. 4 presents KRBC/PL of LD-Tyr after incubation in small pig blood.
FIG. 5 presents KRBC/PL of LD-Tyr after incubation in human blood.
Figure 6 presents a summary of the integrated mean plasma LD-Tyr concentration versus time for pigs at home after 18 hours of continuous subcutaneous infusion.
FIG. 7 presents a summary of the integrated mean plasma LD concentration versus time in pigs at home after 18 hours of continuous subcutaneous infusion of LD-Tyr.
FIG. 8 presents a summary of the integrated mean plasma LD concentration versus time in pigs following continuous subcutaneous infusion of high concentrations of LD-Tyr and 1% CD for 18 hours.
FIG. 9 presents a summary of the integrated mean plasma LD concentration versus time in pigs following continuous subcutaneous infusion of high concentrations of LD-Tyr and 0.5% CD for 18 hours.
Figure 10 presents a summary of the integrated mean plasma LD concentration versus time for pigs at home after 18 hours of continuous subcutaneous infusion of LD-Tyr and varying amounts of CD.
Figure 11 presents a summary of the integrated mean normalized LD plasma concentrations versus time for pigs at home after 18 hours of continuous SC infusion of 30% LD-Tyr along with different CD concentrations.
FIG. 12 presents a summary of the combined mean plasma LD concentration versus time for pigs at home after bolus infusions of different volumes and 2 hours of continuous SC infusions of 30% LD-Tyr and 1% CD.
FIG. 13 shows a summary of the combined mean plasma LD-Tyr and LD concentrations versus time for a 2700mg dosing regimen. PK parameters are also shown.
FIG. 14 shows a summary of the integrated mean plasma LD-Tyr and LD concentrations versus time for a 5400mg dosing regimen. PK parameters are also shown.
Figure 15 shows a summary of integrated mean plasma LD concentrations versus time for 2700mg and 5400mg dosing regimens.
Detailed Description
Features and other details of the present disclosure will now be described more particularly. Certain terms used throughout the description, examples, and appended claims are collected here. These definitions should be read in light of the remainder of this disclosure and as understood by those skilled in the art. 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.
The terms "treatment", "treatment" and the like are generally used herein to refer to obtaining a desired pharmacological and/or physiological effect. The effect may be therapeutic in partially or completely curing the disease and/or adverse effects due to the disease. The term "treatment" as used herein includes any treatment of a disease in a mammal, particularly a human, and includes: (a) Inhibiting the disease, i.e., preventing an increase in the severity or extent of the disease; (b) Alleviating the disease, i.e. causing a partial or complete amelioration of the disease; or (c) preventing recurrence of the disease, i.e., preventing the disease from returning to an active state after previously successfully treating symptoms of the disease or treating the disease.
"preventing" includes delaying the onset of a clinical symptom, complication, or biochemical sign of a state, disorder, disease, or condition that develops in a subject who is likely to suffer from or is susceptible to the state, disorder, disease, or condition but has not experienced or exhibited a clinical or subclinical symptom of the state, disorder, disease, or condition. "preventing" includes the prophylactic treatment of a state, disorder, disease, or condition in or developing in a subject, including the prophylactic treatment of a clinical symptom, complication, or biochemical sign of a state, disorder, disease, or condition in or developing in a subject.
The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" as used herein interchangeably refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.
The terms "pharmaceutical composition" and "pharmaceutical formulation" as used herein refer to a composition or formulation comprising at least one biologically active compound as disclosed herein, e.g., a levodopa amino acid conjugate, or a pharmaceutically acceptable salt thereof, formulated with one or more pharmaceutically acceptable excipients. It should be noted that the terms "formulation" and "composition" are interchangeable unless specifically mentioned otherwise or unless understood otherwise by those skilled in the art.
The term "pharmaceutically acceptable salt" as used herein refers to salts of acidic groups or basic groups that may be formed with the conjugates used in the compositions disclosed herein.
"individual," "patient," or "subject" are used interchangeably and include any animal, including mammals, mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or non-human primates, and humans. In some embodiments, the mammal treated in the methods of the invention is a human suffering from a neurodegenerative condition such as parkinson's disease and/or a disease or symptom caused by reduced dopamine concentration in the brain.
The term "about" as used herein is considered to encompass a range of ±10% of the listed values unless specifically mentioned otherwise or unless the person skilled in the art would understand otherwise. It should also be noted that any value provided may be considered to encompass a range of + -10% of that value, even without the use of the term "about". This includes the values in the examples section, which may vary depending on the apparatus and machine used, the purity of the compound, etc.
The term "stable" as used herein refers to a state in which a substance is not or hardly decomposed in a solution unless specifically mentioned otherwise. Thus, the term "stable" as used herein means that no reduction in or a low degree of reduction in the peak area ratio is observed, for example, when a solution of the substance is prepared and the peak area ratio of the substance is to be measured immediately after preparation of the solution using the area percent method of High Performance Liquid Chromatography (HPLC) compared to the peak area ratio after the substance is left at 25 ℃ for about 1 day. In another embodiment, the term "stable" refers to a substance that is physically stable after the indicated period of time such that no precipitation is visible in a visual view of the substance (e.g., formulation) at a magnification of at least x 1.75.
Unless specifically mentioned otherwise or unless otherwise understood by those skilled in the art, the term "stabilizer" as used herein refers to a substance that prevents or slows the precipitation or development of impurities in the substance (e.g., a liquid pharmaceutical formulation). Thus, the term "stabilizer" as used herein refers to any excipient that provides enhanced stability, such as physical and/or chemical stability, to a liquid pharmaceutical composition. The stabilizing agent may be, for example, a solvent, a buffer, a base, an acid, or any combination thereof, and thus, any excipient referred to herein, e.g., as a solvent, a buffer, etc., may also be considered a stabilizing agent.
The term "liquid" as used herein refers to any type of fluid, including gels, aqueous compositions, non-aqueous compositions, and the like, unless specifically mentioned otherwise or unless otherwise understood by those skilled in the art.
The term "used in combination" as used herein means that two or more active ingredients are administered in combination, including simultaneously, individually or in the same composition, and also includes the continuous administration of two or more active ingredients on the same day, as well as the administration of active ingredients separately from each other for a predetermined period of time, and also includes the administration of two or more active ingredients on different days, unless specifically mentioned otherwise.
The term "concomitant" as used herein refers to any type of combined administration of two or more active ingredients, including simultaneous administration of the active ingredients in different or the same compositions, as well as sequential, consecutive administration of two or more active ingredients on the same day, wherein a predetermined period of time separates the administration of the active ingredients from each other, and the like, unless specifically mentioned otherwise or unless otherwise understood by those skilled in the art.
The terms "continuously" and "substantially continuously" as used herein refer to a period of time during which the composition is administered throughout the period of time, wherein the interval is less than about 24 hours, about 12 hours, about 5 hours, about 3 hours, about 1 hour, about 30 minutes, about 15 minutes, about 5 minutes, or about 1 minute, unless specifically mentioned otherwise or unless otherwise understood by those of skill in the art. The composition may be administered for a period of time of at least about 6 hours, about 8 hours, about 12 hours, about 15 hours, about 18 hours, about 21 hours, about 24 hours, three days, seven days, two weeks, one month, three months, six months, one year, two years, three years, five years, ten years, etc.
The term "physiologically acceptable pH" and similar terms as used herein refer to a pH in the range between about 4.5 to about 10 unless specifically mentioned otherwise or unless otherwise understood by those skilled in the art. It should also be noted that when pH values are provided, including in the examples, these values may be within about ± 0.1% and/or ± 10% of the listed values, such that if the measured pH is 8.1, the same formulation may be prepared to provide a pH of about 8.0 or 8.2. Such differences may be due to temperature variations, various measuring devices, etc.
I. Prodrugs
The compound of the present invention or a pharmaceutically acceptable salt thereof has a good conversion efficiency of levodopa and is useful as a prophylactic or therapeutic agent for neurodegenerative diseases and/or diseases or symptoms caused by a decrease in the concentration of dopamine in the brain (e.g., parkinson's disease).
Furthermore, the compounds of the present invention or pharmaceutically acceptable salts thereof are highly soluble and also highly stable in solution and easy to handle in solution state and are therefore highly suitable for use in the form of stable delivery systems.
In the present invention, alkyl means an alkyl group having 1 to 6 carbon atoms (C 1-6 ) Straight or branched saturated hydrocarbon groups of (a). In particular, having 1 to 4 carbon atoms (C 1-4 ) Is preferred. Specific examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl and the like. In particular, methyl is preferred.
Alkanoyl refers to a monovalent group in which the alkyl groups described above are bonded to a carbonyl group, and examples thereof include those having 1 to 6 carbon atoms (C 1-6 ) Straight or branched alkyl-CO-. Specific examples thereof include acetyl, propionyl, butyryl, pivaloyl, pentanoyl, hexanoyl, heptanoyl and the like. In particular, acetyl is preferred.
Amino acid side chains refer to amino acid side chains of natural amino acids, synthetic amino acids, unnatural amino acids or amino acids that do not produce proteins, and examples of the amino acid include arginine, histidine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, selenocysteine, glycine, proline, alanine, valine, isoleucine, leucine, methionine, phenylalanine, tyrosine, tryptophan, lanthionine, selenocysteine, pyrrolidine, ADDA amino acid ((2S, 3S,4E,6E,8S, 9S) -3-amino-9-methoxy-2, 6, 8-trimethyl-10-phenyldec-4, 6-dienoic acid), beta-alanine, 4-aminobenzoic acid, gamma-aminobutyric acid, S-aminoethyl-L-cysteine, 2-aminoisobutyric acid aminolevulinic acid, azetidine-2-carboxylic acid, canavanine, carboxyglutamic acid, chloroalanine, cystine, dehydroalanine, diaminopimelic acid (diaminopimelic acid), dihydroxyphenylglycine, enramycin (endin), homoserine, 4-phenylglycine, hydroxyproline, deoxyhypusine (hypusine), beta-leucine, norleucine, norvaline, ornithine, penicillamine, hypaphorine (plakohypaphorine), pyroglutamic acid, quisqualic acid, sarcosine, theanine, tranexamic acid (trichromatic acid), trichromatic acid, 3, 4-dihydroxyphenylalanine, and the like. In particular, glutamic acid, valine, alanine, lysine, 3, 4-dihydroxyphenylalanine or tyrosine is preferred.
Here, the amino acid side chain in the present invention may be substituted, and examples thereof include-P (O) (OR 6 ) 2 (wherein R is 6 Is hydrogen, alkyl, etc.), glucosyl groups (such as [ (2R, 3S,4R,5S, 6R) -3,4, 5-trihydroxy-6- (hydroxymethyl) tetrahydropyran-2-yl)]) A group bonded to another adjacent group to form an alkylene group which may be substituted (examples of the substituent group include an alkyl group, an alkoxy group, and the like), and the like. Examples of the substituted amino acid side chain include those in which a tyrosine side chain, a serine side chain, a threonine side chain or an amino acid side chain having a hydroxyl group such as (3, 4-dihydroxyphenyl) methyl group is substituted, and specific examples thereof include phosphonooxymethyl group, (4-phosphonooxyphenyl) methyl group, [4- [ (2S, 3R,4S,5S, 6R) -3,4, 5-trihydroxy-6- (hydroxymethyl) tetrahydropyran-2-yl group]Oxyphenyl radical]Methyl, (2, 2-dimethyl-1, 3-benzodioxol-5-yl) methyl, (2-ethoxy-2-methyl-1, 3-benzodioxol-5-yl) methyl, and the like.
In the present invention, monosaccharides as a source of glycosyl groups include aldoses such as glucose (dextrose), ribose, erythrose, xylose, arabinose, mannose and galactose, and ketoses such as ribulose, psicose, fructose, sorbose and tagatose. These monosaccharides may have the d-form, the l-form or the dl-form. Here, the monosaccharide in the present invention may be substituted, and examples of the substituent group include a carbonyl group, an acetamido group, a sulfinyloxy group, a phosphonooxy group, and the like. Specific examples of the substituted monosaccharides include glucuronic acid, N-acetylglucosamine, glucopyranoside-6- (bisulfate), and the like.
The present invention includes, as an embodiment, a levodopa amino acid complex represented by general formula (I) or general formula (III):
[ chemical formula 1]
Wherein R is an amino acid side chain which may be substituted;
R 1 and R is 2 C which may be the same or different and are each independently a hydrogen atom and may be substituted 1 -C 6 Alkyl, C 1 -C 6 Alkanoyl, phosphono, sulfinyl or glycosyl, provided that R 1 And R is 2 Not both hydrogen atoms;
R 3 and R is 4 May be the same or different and are each independently a hydrogen atom or C 1 -C 6 An alkyl group; and is also provided with
R 5 Is a hydrogen atom, or
[ chemical formula 3]
Wherein R is 11 And R is 12 Identical or different and are each hydrogen, alkyl which may be substituted, alkanoyl, P (=o) (OH) 2 S (=o) (OH) or glycosyl;
R 13 is alkyl which may be substituted, -R 15 -O-R 16 Or a 5-membered heterocyclic group containing at least one nitrogen atom, wherein R 15 Is alkylene, and R 16 Is hydrogen which can be substituted,Alkyl, P (=o) (OH) 2 S (=o) (OH) or glycosyl; and is also provided with
R 14 Is hydrogen or an alkyl group, and is preferably a hydrogen atom,
provided that the following compounds are excluded;
(2S) -2- [ (2-Aminoacetyl) amino ] -3- (3, 4-diacetoxyphenyl) propionic acid,
(2S) -2- [ [ (2S) -2-amino-6- [ (2-chlorophenyl) methoxycarbonylamino ] hexanoyl ] amino ] -3- (3, 4-dimethoxyphenyl) propanoic acid,
(2S) -2- [ [ (2S) -2-amino-3- (3, 4-dihydroxyphenyl) propionyl ] amino ] -3- (4-hydroxy-3-methoxyphenyl) propanoic acid,
(2S) -2- [ [ (2S) -2-amino-3-phenylpropionyl ] amino ] -3- (3, 4-dimethoxyphenyl) propionic acid,
(2S) -2- [ [ (2R) -2-amino-3-phenylpropionyl ] amino ] -3- (3, 4-diacetoxyphenyl) propanoic acid, and
(2S) -2- [ [ (2S) -2-amino-5-methoxy-5-oxopentanoyl ] amino ] -3- (3, 4-dimethoxyphenyl) propanoic acid.
When the compound (I) or the compound (III) of the present invention has an asymmetric carbon atom in its molecule, stereoisomers (optical isomers and diastereomers) based on the asymmetric carbon atom may exist. The compound (I) or compound (III) of the present invention includes any of these stereoisomers and mixtures thereof.
The compound (I) or compound (III) of the present invention includes compounds labeled with isotopes (e.g., 3H, 13C, 14C, 15N, 18F, 32P, 35S, 125I, etc.), and includes deuterium transformants.
The compound (I) or compound (III) of the present invention may be used for pharmaceutical purposes in free form or in the form of a pharmaceutically acceptable salt or in the form of a co-crystal. Examples of the pharmacologically acceptable salts of the compound (I) or the compound (III) of the present invention include inorganic acid addition salts (such as salts of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid and the like), organic acid addition salts (such as salts of methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, citric acid, malonic acid, fumaric acid, glutaric acid, adipic acid, maleic acid, tartaric acid, succinic acid, mandelic acid, malic acid, pantothenic acid, methylsulfuric acid and the like), inorganic base addition salts (such as salts of sodium, potassium, calcium, magnesium and the like), salts of amino acids (such as salts of glutamic acid, aspartic acid, arginine, lysine and the like), and the like.
The compound (I) or compound (III) of the present invention or a pharmacologically acceptable salt thereof includes any one of an intramolecular salt or adduct thereof, a solvate or hydrate thereof, and the like.
The compound (I) or compound (III) of the present invention or a pharmaceutically acceptable salt thereof may be administered orally or parenterally alone or as a pharmaceutical composition comprising compound (I) or compound (III) or a pharmaceutically acceptable salt thereof and a pharmacologically acceptable carrier. The pharmacologically acceptable carrier may be a carrier commonly used in the art, and examples thereof include diluents, binders (such as syrup, gum arabic, gelatin, sorbitol, tragacanth and polyvinylpyrrolidone), excipients (such as lactose, sucrose, corn starch, potassium phosphate, sorbitol and glycine), lubricants (such as magnesium stearate, talc, polyethylene glycol and silica), disintegrants (such as potassium starch), wetting agents (such as sodium lauryl sulfate), and the like. In addition, when producing a liquid pharmaceutical composition such as an injection or infusion, a carrier commonly used in the art may be used, and examples thereof include aqueous solvents (such as water for injection and purified water), isotonic agents (such as sodium chloride, potassium chloride, glycerin, mannitol, sorbitol, boric acid, borax, glucose, and propylene glycol), buffering agents (such as phosphoric acid buffer, acetic acid buffer, boric acid buffer, carbonic acid buffer, citric acid buffer, tris buffer, glutamic acid buffer, and epsilon aminocaproic acid buffer), preservatives (such as methylparaben, ethylparaben, propylparaben, chlorobutanol, benzyl alcohol, benzalkonium chloride, sodium dehydroacetate, sodium edetate, boric acid, and borax), soothing agents (such as lidocaine hydrochloride, procaine hydrochloride, benzyl alcohol, and chlorobutanol), viscous agents (such as hydroxyethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, and polyethylene glycol), stabilizers (such as acid, sodium thiosulfate, sodium edetate, sodium sulfite, ascorbic acid, and dibutylhydroxytoluene), pH adjusting agents (such as sodium hydroxide, sodium citrate, and acetic acid, and the like. Liquid pharmaceutical compositions may be produced by dissolving or dispersing the compounds of the invention described above in solutions with the appropriate addition of these carriers. Such pharmaceutically acceptable additives may be appropriately selected by those skilled in the art according to purposes, and conditions such as the amount of the additives may also be appropriately set. In addition, a solubilizing agent or the like may be used when necessary.
The dosage form of such a pharmaceutical composition is not particularly limited, and examples thereof include conventional pharmaceutical preparations such as tablets, granules, capsules, powders, injections, inhalants and suppositories. In particular, liquid pharmaceutical compositions comprising injectable formulations may be used.
Compound (I) or compound (III) of the present invention or a pharmaceutically acceptable salt thereof may be formulated in the form of a liquid pharmaceutical composition, for example, as a formulation suitable for all suitable routes of administration by parenteral administration, such as bolus administration, continuous administration or sustained administration. In particular, liquid pharmaceutical compositions comprising the compounds of the present invention may be formulated for subcutaneous administration, transdermal administration, intradermal administration, transmucosal administration, intravenous administration, intraarterial administration, intramuscular administration, intraperitoneal administration, intrathecal administration, intraduodenal administration, intrapleural administration, intranasal administration, sublingual administration, buccal administration, enteral administration, intraduodenal administration, rectal administration, intraocular administration, or oral administration. In addition, the compositions may also be formulated for inhalation or direct absorption through mucosal tissue.
The dosage amount of the compound (I) or the compound (III) of the present invention or a pharmaceutically acceptable salt thereof varies depending on the administration method and the age, weight, condition, etc. of the patient. However, when administered as a liquid pharmaceutical composition, it is typically 1mg/kg to 200mg/kg per day.
Depending on the disease to be treated (e.g., parkinson's disease), compound (I) or compound (III) of the invention or a pharmaceutically acceptable salt thereof may be used alone or in combination with one or more other therapeutic agents. As such a therapeutic agent, for example, one or more agents selected from the group consisting of: dopamine decarboxylase inhibitors (such as carbidopA and dopaminzide), catechol-O-methyltransferase ("COMT") inhibitors (such as entacapone and tolcapone), and monoamine oxidase A ("MAO-A") or monoamine oxidase B ("MAO-B") inhibitors (such as molobetaine, rasagiline, selegiline, and safinamide).
The compound (I) or compound (III) of the present invention or a pharmaceutically acceptable salt thereof may be administered simultaneously with the above-described therapeutic agents which may be used in combination, or may be administered separately. Furthermore, when the compounds of the present invention are used therapeutically with the above-described therapeutic agents that may be used in combination, the compounds of the present invention and therapeutic agents may be administered in the same dosage form, such as parenterally, and may be administered in different dosage forms, such as parenterally, and orally.
Preferred embodiments of the present invention are shown in the following table.
TABLE 1
The compound of the present invention or a pharmaceutically acceptable salt thereof can be produced, for example, as follows.
General synthetic method (A)
[ wherein Bn denotes benzyl, cbz denotes benzyloxycarbonyl, and the other symbols have the same meaning as above ]
In the object compound [ I ] of the present invention, the compound represented by the general formula [ Ia ] can be produced, for example, as follows. Subjecting the compound [ a-1] and the compound [ b-1] or the compound [ b-2] to a condensation reaction to obtain the compound [ c ], and then subjecting the compound [ c ] to phosphite esterification and oxidation, or to phosphate esterification, and thereby obtaining the compound [ f ]. In another aspect, compound [ f ] may also be obtained by condensing compound [ e ] with compound [ b-1] or compound [ b-2 ]. The compound [ Ia ] can be produced by subjecting the compound [ f ] thus obtained to deprotection or to hydrolysis and then deprotection.
Step 1
The condensation between the compound [ a-1] and the compound [ b-1] or a salt thereof or [ b-2] may be carried out according to a conventional method in a suitable solvent with or without a base, with or without a condensing agent, and with or without an activator. As the solvent, any solvent that does not affect the present reaction may be used. Examples of solvents include: ethers such as tetrahydrofuran and 1, 4-dioxane; amides such as N, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone; nitriles such as acetonitrile; halogenated aliphatic hydrocarbons such as chloroform and methylene chloride; aromatic hydrocarbons such as toluene; or a mixture of these compounds. Examples of the base include triethylamine, diisopropylethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene and the like. Examples of condensing agents include O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, and the like. Examples of the activator include 1-hydroxy-7-azabenzotriazole (HOAt), 1-hydroxybenzotriazole (HOBt), 4-dimethylaminopyridine and the like.
The amount of the compound [ b-1] or the compound [ b-2] to be used may be 1.0 equivalent to 5.0 equivalents, preferably 1.0 equivalent to 2.0 equivalents, in terms of a molar ratio relative to the compound [ a-1 ].
The amount of the base to be used may be 1.0 equivalent to 5.0 equivalents, preferably 1.0 equivalent to 2.0 equivalents, in terms of a molar ratio relative to the compound [ a-1 ].
The amount of the condensing agent to be used may be 1.0 equivalent to 5.0 equivalents, preferably 1.0 equivalent to 2.5 equivalents, in terms of a molar ratio relative to the compound [ a-1 ].
The amount of the activator to be used may be 1.0 equivalent to 5.0 equivalents, preferably 1.0 equivalent to 2.5 equivalents, in terms of a molar ratio relative to the compound [ a-1 ].
The reaction can be carried out at room temperature-heating, for example at room temperature-80 ℃, preferably at room temperature-50 ℃.
Step 2
The condensation of the compound [ c ] with the phosphite esterifying agent may be carried out according to conventional methods in a suitable solvent in the presence of an activator. As the solvent, any solvent that does not affect the present reaction may be used. Examples of solvents include: nitriles such as acetonitrile; halogenated aliphatic hydrocarbons such as chloroform and methylene chloride; or a mixture of these compounds. An example of a phosphite esterifying agent is dibenzyl N, N-diisopropylphosphoramidite. An example of an activator is 1-tetrazole.
The amount of phosphite esterifying agent to be used may be 1.0 equivalent to 5.0 equivalents, preferably 1.5 equivalents to 3.0 equivalents, based on the molar ratio with respect to compound [ c ].
The amount of the activator to be used may be 1.0 equivalent to 5.0 equivalents, preferably 1.5 equivalents to 3.0 equivalents, in terms of a molar ratio relative to the compound [ c ].
The reaction can be carried out under ice-cooling-heating, for example at 0℃to 80℃and preferably at room temperature to 50 ℃.
Step 3
The oxidation of the compound [ d ] can be carried out according to a conventional method in a suitable solvent in the presence of an oxidizing agent. As the solvent, any solvent that does not affect the present reaction may be used. Examples of solvents include: nitriles such as acetonitrile; halogenated aliphatic hydrocarbons such as chloroform and methylene chloride; or a mixture of these compounds. Examples of oxidizing agents include hydrogen peroxide solution, t-butyl hydroperoxide, m-chloroperoxybenzoic acid, and the like.
The amount of the oxidizing agent to be used may be 1.0 equivalent to 5.0 equivalents, preferably 1.5 equivalents to 3.0 equivalents, in terms of a molar ratio relative to the compound [ d ].
The reaction can be carried out under ice-cooling-heating, for example at 0℃to 80℃and preferably at room temperature to 50 ℃.
Step 4
The condensation of the compound [ c ] with the phosphate ester esterifying agent can be carried out according to conventional methods in a suitable solvent in the presence or absence of a base. As the solvent, any solvent that does not affect the present reaction may be used. Examples of solvents include: nitriles such as acetonitrile; halogenated aliphatic hydrocarbons such as chloroform and methylene chloride; or a mixture of these compounds. Examples of the phosphate ester esterifying agent include dibenzylphosphoryl chloride, tetrabenzyl pyrophosphate, and the like. Examples of bases include: alkali metal alkoxides such as sodium tert-butoxide and potassium tert-butoxide; alkylamines such as triethylamine, diisopropylethylamine and 1, 8-diazabicyclo [5.4.0] undec-7-ene; etc.
The amount of the phosphate ester esterifying agent to be used may be 1.0 equivalent to 5.0 equivalents, preferably 1.5 equivalents to 3.0 equivalents, in terms of a molar ratio relative to the compound [ c ].
The amount of the base to be used may be 1.0 equivalent to 5.0 equivalents, preferably 1.5 equivalents to 3.0 equivalents, in terms of a molar ratio relative to the compound [ c ].
The reaction can be carried out at room temperature-heating, for example at room temperature-100 ℃, preferably at room temperature-70 ℃.
Step 5
The condensation of the compound [ e ] and the compound [ b-1] or a salt thereof or [ b-2] can be carried out in the same manner as the condensation of the compound [ a-1] and the compound [ b-1] or a salt thereof or [ b-2] in the general synthetic method (A).
Step 6
Deprotection of compound [ f ] can be carried out according to conventional methods by treatment with a catalyst in a suitable solvent under a hydrogen atmosphere.
As the solvent, any solvent that does not affect the present reaction may be used. Examples of solvents include: ethers such as tetrahydrofuran and 1, 4-dioxane; alcohols such as methanol, ethanol, and isopropanol; water; or a mixture of these compounds; etc.
Examples of the catalyst include palladium on carbon and the like.
The reaction can be carried out at room temperature-heating, for example at room temperature-80 ℃, preferably at room temperature-50 ℃.
Step 7
The hydrolysis of the compound [ g ] can be carried out according to a conventional method in a suitable solvent in the presence of a base and water. As the solvent, any solvent that does not affect the present reaction may be used. Examples of solvents include: alcohols such as methanol, ethanol, and isopropanol; ethers such as tetrahydrofuran, 1, 4-dioxane and 1, 2-dimethoxyethane; water; or a mixture of these compounds; etc. Examples of bases include: alkali metal hydroxides such as sodium hydroxide and lithium hydroxide; etc.
The reaction can be carried out under ice-cooling-heating, for example at 0℃to 50℃and preferably at room temperature.
The amount of the base to be used may be 1.0 equivalent to 10.0 equivalents, preferably 1.0 equivalent to 4.0 equivalents, relative to the compound [ g ].
Step 8
Deprotection of compound [ g ] can be carried out in the same manner as in the deprotection of compound [ f ] in general synthetic method (A).
General synthetic method (B)
[ wherein the symbols have the same meanings as above ]
In the object compound [ I ] of the present invention, the compound represented by the general formula [ Ib ] can be produced, for example, as follows. The compound [ a-2] and the compound [ b-3] are subjected to a condensation reaction to obtain a compound [ h ], and then the compound [ h ] is subjected to phosphite esterification and oxidation, or to phosphate esterification, and thereby a compound [ j ] is obtained. Compound [ Ib ] can be produced by deprotecting compound [ j ].
Step 1
The condensation of the compound [ a-2] and the compound [ b-3] or a salt thereof can be carried out in the same manner as the condensation of the compound [ a-1] and the compound [ b-1] or a salt thereof in the general synthetic method (A).
Step 2
The condensation of the compound [ h ] with the phosphite esterifying agent may be carried out in the same manner as the condensation of the compound [ c ] with the phosphite esterifying agent in the general synthesis method (A).
Step 3
The oxidation of the compound [ i ] can be carried out in the same manner as the oxidation of the compound [ d ] in the general synthesis method (A).
Step 4
The condensation of the compound [ h ] and the phosphate ester esterifying agent can be carried out in the same manner as the condensation of the compound [ c ] and the phosphate ester esterifying agent in the general synthesis method (A).
Step 5
Deprotection of compound [ j ] can be carried out in the same manner as in the deprotection of compound [ f ] in general synthetic method (A).
General synthetic method (C)
[ wherein Ac indicates acetyl and the other symbols have the same meaning as above ]
In the target compound [ I ] of the present invention, the compound represented by the general formula [ Ic ] can be produced, for example, as follows. The compound [ a-3] and the compound [ b-1] are subjected to a condensation reaction to obtain the compound [ k ], and then the compound [ k ] is subjected to deprotection, and thereby the compound [ Ic ] can be produced.
Step 1
The condensation of the compound [ a-3] and the compound [ b-1] or a salt thereof can be carried out in the same manner as the condensation of the compound [ a-1] and the compound [ b-1] or a salt thereof in the general synthetic method (A).
Step 2
Deprotection of compound [ k ] can be carried out in the same manner as in the deprotection of compound [ f ] in general synthetic method (A).
General synthetic method (D)
[ wherein the symbols have the same meanings as above ]
In the target compound [ I ] of the present invention, the compound represented by the general formula [ Id ] can be produced, for example, as follows. Subjecting the compound [ a-2] and the compound [ b-1] to a condensation reaction to obtain the compound [ l ], and then, subjecting the compound [ l ] to deprotection, and thereby the compound [ Id ] can be produced.
Step 1
The condensation of the compound [ a-2] and the compound [ b-1] or a salt thereof can be carried out in the same manner as the condensation of the compound [ a-1] and the compound [ b-1] or a salt thereof in the general synthetic method (A).
Step 2
Deprotection of compound [ l ] can be carried out in the same manner as in the deprotection of compound [ f ] in general synthetic method (A).
The starting compounds in the above-described processes may be produced in the same manner as described in the known processes and/or in the examples described later.
The introduction of the protecting group into the functional group and the removal of the protecting group of the functional group can be performed with reference to a known method (PROTECTIVE GROUPS in ORGANIC SYNTHESIS (Theodora W.Greene, peter G.M.Wuts), etc.).
The compounds of the invention or starting compounds thereof produced as described above are isolated and purified in their free form or as salts thereof. Salts may be produced by conventional salt preparation processes. Isolation and purification can be performed by applying conventional chemical procedures such as extraction, concentration, crystallization, filtration, recrystallization, and various types of chromatography.
When the compound of the present invention or a pharmaceutically acceptable salt thereof exists as an optical isomer based on an asymmetric carbon atom, it can be separated into individual optical isomers by ordinary optical resolution means (e.g., fractional crystallization method and separation method using chiral column). In addition, optical isomers can also be synthesized using optically pure starting materials. In addition, optical isomers may also be synthesized by stereoselectively performing each reaction using an asymmetric auxiliary group or an asymmetric catalyst.
The compounds of the present invention or pharmaceutically acceptable salts thereof are useful for preventing or treating neurodegenerative diseases and/or diseases or symptoms caused by reduced concentration of dopamine in the brain. In particular, the compounds and combinations of the present invention are useful for preventing or treating parkinson's disease, secondary parkinsonism, huntington's disease, parkinsonism-like syndrome, progressive Supranuclear Palsy (PSP), multiple System Atrophy (MSA), amyotrophic Lateral Sclerosis (ALS), shay-Drager syndrome (Shy-Drager syndrome), dystonia, alzheimer's disease, lewy Body Dementia (LBD), akinesia, bradykinesia and hypokinesia, and are preferably useful for preventing or treating parkinson's disease. In addition, the compounds and combinations of the present invention are useful for preventing or treating diseases or symptoms caused by brain injury including carbon monoxide poisoning or manganese poisoning, or diseases or symptoms associated with neurological diseases or neurological disorders including alcoholism, drug addiction, or erectile dysfunction.
II, stabilized LD-Tyr formulations
Embodiments of the present invention relate to liquid pharmaceutical compositions comprising a levodopa-tyrosine conjugate of formula (II):
/>
an enantiomer, diastereomer, racemate, ion, zwitterionic, pharmaceutically acceptable salt thereof, or any combination thereof, and a stabilizer.
According to some embodiments, the liquid pharmaceutical composition comprises the LD-Tyr compound in the form of a pharmaceutically acceptable salt. According to some embodiments, the LD-Tyr salt is selected from the group consisting of trifluoroacetic acid (TFA) salt, HCl salt, fumaric acid salt, lactic acid salt, maleic acid salt, glucoheptonate, phosphoric acid salt, sulfuric acid salt, HBr salt, nitric acid salt, acetic acid salt, propionic acid salt, caproic acid salt, cyclopentanepropionic acid salt, glycolic acid salt, pyruvic acid salt, lactic acid salt, hippuric acid salt, methanesulfonic acid salt, ascorbic acid salt, malonic acid salt, oxalic acid salt, maleic acid salt, tartaric acid salt, citric acid salt, succinic acid salt, benzoic acid salt, cinnamic acid salt, sulfonic acid salt, lauryl sulfate, glucose salt, glutamic acid salt, hydroxynaphthalene formate, salicylic acid salt, stearic acid salt, muconate, alkali metal salts such as lithium, sodium or potassium salt, alkaline earth metal salts such as calcium or magnesium salt, aluminum salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, N-methylglucamine salt, dicyclohexylamine salt, adipic acid salt, alginic acid salt, ascorbate, aspartic acid salt, benzenesulfonate salt, bisulfate salt, borate salt, butyrate, camphorsulfonate, dibucate butyrate, dodecylsulfate butyrate, ethanesulfonate, glucoheptonate, glycerophosphate butyrate, gluconate butyrate, hemisulfate butyrate, heptanoate, hydroiodic acid butyrate, 2-hydroxy-ethanesulfonate, lactobionate, laurate butyrate, methanesulfonate butyrate, 2-naphthalenesulfonate butyrate, nicotinic acid butyrate, oleic acid butyrate, palmitic acid butyrate, pamoate butyrate, pectate butyrate, persulfate butyrate, 3-phenylpropionate butyrate, phosphobutyrate, picric acid butyrate, pivalic acid butyrate, tartaric acid butyrate, thiocyanate butyrate, paratoluenesulfonic acid butyrate, undecanoic acid butyrate, valerate, or any combination thereof.
The liquid pharmaceutical compositions of the present invention may comprise between about 2.5% w/v to about 70% w/v of the LD-Tyr compound, an enantiomer, diastereomer, racemate, ion, zwitterionic, pharmaceutically acceptable salt thereof, or any combination of two or more LD-Tyr compounds, enantiomers, diastereomers, racemates, ions, zwitterionic, pharmaceutically acceptable salts thereof. According to some embodiments of the present invention, the liquid pharmaceutical composition comprises between about 2.5% w/v and about 5% w/v, between about 5% w/v and about 10% w/v, between about 10% w/v and about 15% w/v, between about 15% w/v and about 20% w/v, between about 20% w/v and about 25% w/v, between about 25% w/v and about 30% w/v, at least about 30% w/v, between about 30% w/v and about 35% w/v, between about 35% w/v and about 40% w/v, between about 30% w/v and about 45% w/v, between about 30% w/v and about 50% w/v, between about 30% w/v and about 55% w/v, between about 30% w/v and about 60% w/v, between about 30% w/v and about 65% w/v, between about 30% w/v and about 70% w/v, between about 40% w/v, between about 30% w/v and about 40% w/v, between about 60% w/v and about 60% w/v, between about 40% w/v and about 60% w/v, between about 60% w/v and about 50% w/v, between about 50% w/v and about 50% w/v, between about 30% w and about 50% w/v, between about 22.5% w/v and about 27.5% w/v, between about 27.5% w/v and about 32.5% w/v, between about 32.5% w/v and about 37.5% w/v, between about 37.5% w/v and about 42.5% w/v, between about 42.5% w/v and about 45% w/v, about 10% w/v, about 12.5% w/v, about 15% w/v, about 17.5% w/v, about 20% w/v, about 22.5% w/v, about 25% w/v, about 27.5% w/v, about 30% w/v, about 32.5% w/v, about 35% w/v, about 37.5% w/v, about 40% w/v, about 42.5% w/v, about 45% w/v, about 47.5% w/v, about 50% w/v, about 52.5% w/v, about 55% w/v, about 67% of the enantiomer, about 60% w/v, about 65% of any combination thereof, or any enantiomer thereof, or any combination of two or more LD-Tyr compounds, enantiomers, diastereomers, racemates, ions, zwitterions, pharmaceutically acceptable salts thereof, or any combination thereof.
The liquid formulations as described herein comprise stabilizers that prevent or slow the precipitation of the formulation and/or prevent or slow the accumulation of impurities in the formulation. LD-Tyr has a propensity to form Diketopiperazine (DKP) impurities, as shown in the schemes below.
Thus, in certain embodiments, stabilizers as described herein are added to or included in liquid pharmaceutical compositions and prevent diketopiperazine formation. Thus, in certain embodiments, the liquid pharmaceutical composition comprises less than about 1.5% w/v LD-Tyr-diketopiperazine (LD-Tyr DKP) after two weeks at 2 ℃ -8 ℃. In certain embodiments, the liquid pharmaceutical composition comprises less than about 0.8% w/v LD-Tyr-diketopiperazine after two weeks at 2 ℃ -8 ℃. For example, after two weeks at 2 ℃ -8 ℃, the liquid pharmaceutical composition may comprise less than about 0.8% w/v, 0.7% w/v, 0.6% w/v, 0.5% w/v, 0.4% w/v, 0.3% w/v, 0.2% w/v, or 0.1% w/v LD-Tyr-diketopiperazine. In certain embodiments, the liquid pharmaceutical composition comprises less than about 4.0% w/v LD-Tyr-diketopiperazine after two weeks at 25 ℃. For example, after two weeks at 25 ℃, the liquid pharmaceutical composition may comprise less than about 5.0% w/v, 4.5% w/v, 4.0% w/v, 3.5% w/v, 3.0% w/v, 2.5% w/v, 2.0% w/v, 1.5% w/v, or 1.0% w/v LD-Tyr-diketopiperazine. In certain embodiments, the liquid pharmaceutical composition comprises no more than about 4.0% w/v LD-Tyr-diketopiperazine after two weeks at 25 ℃. Methods for measuring DKP are known in the art and include, for example, high Performance Liquid Chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS).
In certain embodiments, the liquid pharmaceutical composition comprises between about 0.1% w/v and about 30% w/v of the stabilizing agent. In certain embodiments, the liquid pharmaceutical composition comprises between about 1.5% w/v to about 20% w/v of the stabilizing agent. For example, the number of the cells to be processed, the liquid pharmaceutical composition may comprise between about 1.5% w/v and about 5.0% w/v, between about 1.5% w/v and about 10.0% w/v, between about 1.5% w/v and about 15.0% w/v, between about 1.5% w/v and about 20.0% w/v, between about 1.5% w/v and about 25.0% w/v, between about 3.0% w/v and about 5.0% w/v, between about 3.0% w/v and about 10.0% w/v, between about 3.0% w/v and about 15.0% w/v, between about 3.0% w/v and about 20.0% w/v, between about 3% w/v and about 25.0% w/v, between about 3.0% w/v and about 30.0% w/v, between about 5.0% w/v and about 10.0% w/v between about 5% w/v and about 15.0% w/v, between about 5.0% w/v and about 20.0% w/v, between about 5.0% w/v and about 25.0% w/v, between about 5.0% w/v and about 30.0% w/v, between about 7.0% w/v and about 10.0% w/v, between about 7.0% w/v and about 15.0% w/v, between about 7.0% w/v and about 20.0% w/v, between about 7.0% w/v and about 25.0% w/v, between about 7.0% w/v and about 30.0% w/v, between about 10.0% w/v and about 15.0% w/v, between about 10.0% w/v and about 20.0% w/v, between about 10% w/v and about 25.0% w/v, A stabilizer between about 10.0% w/v and about 30.0% w/v, between about 15.0% w/v and about 20.0% w/v, between about 15.0% w/v and about 25.0% w/v, between about 15.0% w/v and about 30.0% w/v. In certain embodiments, the liquid pharmaceutical composition comprises two, three, or four stabilizers in combination, wherein each individual stabilizer is present in an amount as described above, or the combination of stabilizers is present in an amount as described above.
According to certain embodiments, the stabilizer comprises a base. In other embodiments, the liquid pharmaceutical composition comprises a stabilizer and further comprises a base, e.g., to provide the composition with a predetermined pH. According to some embodiments, the base is selected from NaOH, NH 4 OH、Ca(OH) 2 Ammonium hydroxide, arginine, magnesium hydroxide, potassium hydroxide, meglumine, tromethamine (TRIS), triethylamine, ethylenediamine, diethylamine, ethanolamine, diisopropylethylamine, diazabicycloundecene, or any combination thereof. The liquid pharmaceutical composition may comprise between about 0.1% w/v to about 30.0% w/v of the base. According to some embodiments, the liquid pharmaceutical composition comprises between about 0.1% w/v and about 1.0% w/v, between about 1.0% w/v and about 2.0% w/v, between about 2.0% w/v and about 3.0% w/v, between about 3.0% w/v and about 4.0% w/v, between about 4.0% w/v and about 5.0% w/v, between about 5.0% w/v and about 6.0% w/v, between about 6.0% w/v and about 7.0% w/v, between about 8.0% w/v and about 9.0% w/v, between about 9.0% w/v and about 10.0% w/v, between about 10.0% w/v and about 11.0% w/v, between about 11.0% w/v and about 12.0% w/v, between about 12.0% w/v and about 12.0% w/v, between about 14.0% w/v and about 18.0% w/v, between about 16.0% w/v and about 10.0% w/v, between about 16.0% w/v and about 13.0% w/v Between about 19.0% w/v, between about 19.0% w/v and about 20.0% w/v, between about 20.0% w/v and about 21.0% w/v, between about 21.0% w/v and about 22.0% w/v, between about 22.0% w/v and about 23.0% w/v, between about 23.0% w/v and about 24.0% w/v, between about 24.0% w/v and about 25.0% w/v, between about 25.0% w/v and about 26.0% w/v, between about 26.0% w/v and about 27.0% w/v, between about 27.0% w/v and about 28.0% w/v, between about 28.0% w/v and about 29.0% w/v, between about 29.0% w/v and about 30.0% w/v.
In certain embodiments, the stabilizer comprises a base selected from the group consisting of: arginine, naOH, NH 4 OH, TRIS (hydroxymethyl) aminomethane (TRIS), ethylenediamine, diethylamine, ethanolamine, diethanolamine, meglumine, triethanolamine, and any combination thereof. In certain embodiments, the base is selected from the group consisting of: arginine, NH 4 OH, ethylenediamine, diethylamine, ethanolamine, diethanolamine, meglumine, and combinations thereof. In certain embodiments, the base is selected from the group consisting of: L-Arg, diethylamine and combinations thereof. In certain embodiments, the base is selected from the group consisting of: L-Arg, ethanolamine and combinations thereof. In certain embodiments, the liquid pharmaceutical composition comprises between about 0.1% w/v to about 30.0% w/v base. In certain embodiments, the liquid pharmaceutical composition comprises between about 1.5% w/v to about 20.0% w/v base. For example, the liquid pharmaceutical composition may comprise between about 1.5% w/v and about 5.0% w/v, between about 1.5% w/v and about 10.0% w/v, between about 1.5% w/v and about 15.0% w/v, between about 1.5% w/v and about 20.0% w/v, between about 1.5% w/v and about 25.0% w/v, between about 3.0% w/v and about 5.0% w/v, between about 3.0% w/v and about 10.0% w/v, between about 3.0% w/v and about 15.0% w/v, between about 3.0% w/v and about 20.0% w/v, between about 3.0% w/v and about 25.0% w/v, between about 3.0% w/v and about 30.0% w/v, between about 5.0% w/v and about 5.0% w/v, between about 3.0% w/v and about 10.0% w/v, between about 3.0% w/v and about 15.0% w/v, between about 3.0% w/v and about 20.0% w/v, between about 5.0% w/v and about 10.0% w/v, between about 5.0% w/v and about 0% w/v Between about 15.0% w/v, between about 7.0% w/v and about 20.0% w/v, between about 7.0% w/v and about 25.0% w/v, between about 7.0% w/v and about 30.0% w/v, between about 10.0% w/v and about 15.0% w/v, between about 10.0% w/v and about 20.0% w/v, between about 10.0% w/v and about 25.0% w/v, between about 10.0% w/v and about 30.0% w/v, between about 15.0% w/v and about 20.0% w/v, between about 15.0% w/v and about 25.0% w/v, between about 15.0% w/v and about 30.0% w/v. In certain embodiments, the liquid pharmaceutical composition comprises two, three, or four stabilizers in combination. For example, in certain embodiments, the liquid pharmaceutical composition comprises arginine and an additional base selected from the group consisting of: NH (NH) 4 OH, ethylenediamine, diethylamine, ethanolamine, diethanolamine, meglumine. In certain embodiments, each individual stabilizer is present in an amount as described above, or a combination of stabilizers is present in an amount as described above. In certain embodiments, arginine is present in an amount from about 7.0% w/v to about 8.0% w/v, and the additional base is present in an amount from about 3.0% w/v to about 8.0% w/v. In certain embodiments, the formulation comprises about 7.0% w/v to about 8.0% w/v (e.g., 7.2% w/v) L-Arg and about 3.0% w/v to about 8.0% w/v (e.g., about 5.4% w/v) diethylamine. In certain embodiments, the formulation comprises about 7.0% w/v to about 8.0% w/v (e.g., 7.2% w/v) L-Arg and about 2.0% w/v to about 7.0% w/v (e.g., about 4.5% w/v) ethanolamine.
In certain embodiments, the stabilizer comprises one or more of the following: polyethylene glycol (e.g., PEG-300, PEG-400, PEG-600), propylene glycol, choline, sodium or ammonium ions, amino acids (e.g., lys or His), benzyl alcohol, ethanol, group IIA metal complexes (e.g., ca) 2+ Salts such as CaCl 2 And Ca ascorbate), citric acid, lactic acid or acetic acid, electrophiles (e.g., lewis acids such as Na + 、K + 、Ca 2+ Boron compound, fe 3+ 、Al 3+ 、Cu 2+ And alpha-beta unsaturated carbonyl groups such as maleic acid), phosphate buffers, zn 2+ Ionic, reducing sugars such as glucose, sodium acetate, hydroxypropyl beta cyclodextrin, and soluble beta ringDextrin, medium chain triglycerides such as octanoic acid, mixed micelle glycocholate/lecithin, N-methylpyrrolidone, dimethylacetamide, soybean oil, sesame oil, castor oil, dimethylsulfoxide, glycerol, tris buffer, ammonium acetate or guanidine HCl. In certain embodiments, the stabilizing agent comprises a surfactant such as those described herein, e.g., poloxamer, tween-80, tween-20, and Kolliphor.
According to some embodiments, the liquid pharmaceutical composition further comprises an acid, e.g., to provide the composition with a predetermined pH. According to some embodiments, the acid is selected from HCl, HBr, methanesulfonic acid, ascorbic acid, acetic acid, citric acid, or any combination thereof. The liquid pharmaceutical composition may comprise between about 0.1% w/v to about 30.0% w/v of the acid. According to some embodiments, the liquid pharmaceutical composition comprises between about 0.1% w/v and about 1.0% w/v, between about 1.0% w/v and about 2.0% w/v, between about 2.0% w/v and about 3.0% w/v, between about 3.0% w/v and about 4.0% w/v, between about 4.0% w/v and about 5.0% w/v, between about 5.0% w/v and about 6.0% w/v, between about 6.0% w/v and about 9.0% w/v, between about 9.0% w/v and about 10.0% w/v, between about 10.0% w/v and about 11.0% w/v, between about 11.0% w/v and about 12.0% w/v, between about 4.0% w/v and about 5.0% w/v, between about 12.0% w/v and about 21.0% w/v, between about 18.0% w/v and about 18.0% w/v, between about 18.0% w/v and about 9.0% w/v, between about 9.0% w/v and about 10.0% w/v, between about 9.0% w/v and about 11.0% w/v, between about 11.0% w/v and about 11.0% w/v, between about 12.0% w/v and about, acids between about 25.0% w/v and about 26.0% w/v, between about 26.0% w/v and about 27.0% w/v, between about 27.0% w/v and about 28.0% w/v, between about 28.0% w/v and about 29.0% w/v, between about 29.0% w/v and about 30.0% w/v.
The pH of the liquid pharmaceutical composition of the present invention may be between about 4.5 and about 10 at about 25 ℃. According to some embodiments, the pH of the liquid pharmaceutical composition is between about 4.5 and about 5 at about 25 ℃. According to some embodiments, the pH of the liquid pharmaceutical composition is between about 5 and about 6 at about 25 ℃. According to some embodiments, the pH of the liquid pharmaceutical composition is between about 6 and about 7 at about 25 ℃. According to some embodiments, the pH of the liquid pharmaceutical composition is between about 7 and about 8 at about 25 ℃. According to some embodiments, the pH of the liquid pharmaceutical composition is between about 8 and about 9 at about 25 ℃. According to some embodiments, the pH of the liquid pharmaceutical composition is between about 9 and about 10 at about 25 ℃. According to some embodiments, the pH of the liquid pharmaceutical composition is between about 4.5 and about 5.5 at about 25 ℃. According to some embodiments, the pH of the liquid pharmaceutical composition is between about 5.5 and about 6.5 at about 25 ℃. According to some embodiments, the pH of the liquid pharmaceutical composition is between about 6.5 and about 7.5 at about 25 ℃. According to some embodiments, the pH of the liquid pharmaceutical composition is between about 7.5 and about 8.5 at about 25 ℃. According to some embodiments, the pH of the liquid pharmaceutical composition is between about 8.5 and about 9.5 at about 25 ℃. According to some embodiments, the pH of the liquid pharmaceutical composition is between about 9.5 and about 10 at about 25 ℃.
According to some embodiments, the liquid pharmaceutical composition further comprises a decarboxylase inhibitor. According to some embodiments, the decarboxylase inhibitor is selected from carbidopa, dopa hydrazine, methyldopa, 3',4',5, 7-tetrahydroxy-8-methoxyisoflavone, α -difluoromethyl-dopa, or any combination thereof. According to some embodiments, the decarboxylase inhibitor is carbidopa.
The liquid pharmaceutical composition of the invention may comprise between about 0.25% w/v to about 3.0% w/v of a decarboxylase inhibitor, e.g. carbidopa. According to some embodiments of the present invention, the liquid pharmaceutical composition comprises between about 0.25% w/v and about 0.5% w/v, between about 0.5% w/v and about 0.75% w/v, between about 0.75% w/v and about 1.0% w/v, between about 1.0% w/v and about 1.25% w/v, between about 1.25% w/v and about 1.5% w/v, between about 1.5% w/v and about 1.75% w/v, between about 1.75% w/v and about 2.0% w/v, between about 2.0% w/v and about 2.25% w/v, between about 2.25% w/v and about 2.5% w/v, between about 2.5% w/v and about 2.75% w/v, between about 2.75% w/v and about 3.0% w/v between about 0.5% w/v and about 1.0% w/v, between about 1.0% w/v and about 1.5% w/v, between about 0.75% w/v and about 1.4% w/v, between about 0.6% w/v and about 0.9% w/v, between about 0.7% w/v and about 0.8% w/v, about 0.5% w/v, about 0.55% w/v, about 0.6% w/v, about 0.65% w/v, about 0.7% w/v, about 0.75% w/v, about 0.8% w/v, about 0.85% w/v, about 0.9% w/v, about 0.95% w/v, about 1.0% w/v, about 1.05% w/v, about 1.1% w/v, about 1.15% w/v, about 1.2% w/v, about 1.7% w/v, about 25% w/v, about 1.3% w/v, about 1.4% w/v, about 1.45% w/v, about 1.5% w/v of a decarboxylase inhibitor, such as carbidopa.
According to some embodiments, the stabilizing agent comprises a buffer. According to some embodiments, the liquid pharmaceutical composition comprises a stabilizer, and further comprises a buffer. According to some embodiments, the buffer is selected from citrate buffer, sodium acetate buffer, tartrate buffer, phosphate buffer, succinate buffer, tris buffer, glycine buffer, hydrochloric acid buffer, potassium hydrogen phthalate buffer, sodium citrate tartrate buffer, sodium hydroxide buffer, sodium dihydrogen phosphate buffer, disodium hydrogen phosphate buffer, tromethamine (Tris), or any combination thereof. The liquid pharmaceutical composition may comprise between about 0.1% w/v to about 30.0% w/v buffer. According to some embodiments, the liquid pharmaceutical composition comprises between about 0.1% w/v and about 1.0% w/v, between about 1.0% w/v and about 2.0% w/v, between about 2.0% w/v and about 3.0% w/v, between about 3.0% w/v and about 4.0% w/v, between about 4.0% w/v and about 5.0% w/v, between about 5.0% w/v and about 6.0% w/v, between about 6.0% w/v and about 7.0% w/v, between about 8.0% w/v and about 9.0% w/v, between about 9.0% w/v and about 10.0% w/v, between about 10.0% w/v and about 15.0% w/v, between about 15.0% w/v and about 20.0% w/v, between about 20.0% w/v and about 25.0% w/v, between about 25.0% w/v.
According to some embodiments, the liquid pharmaceutical composition further comprises an antioxidant. According to some embodimentsThe antioxidant is selected from ascorbic acid or its salt, cysteine, acid sulfite or its salt, glutathione, tyrosinase inhibitor, and divalent cation (such as Cu) +2 ) Chelating agents, butylated Hydroxytoluene (BHT), beta Hydroxy Acid (BHA) tocopherols, gentisic acid, tocopherols, tocopherol derivatives such as tocopheryl acetate or tocopheryl succinate, thioglycerol or any combination thereof.
According to some embodiments, the antioxidant is an ascorbate selected from sodium ascorbate, calcium ascorbate, potassium ascorbate, or any combination thereof. According to some embodiments, the antioxidant is a cysteine selected from L-cysteine, N-acetylcysteine (NAC), or any combination thereof. According to some embodiments, the antioxidant is sodium metabisulfite, an acid sulfite. According to some embodiments, the antioxidant is the tyrosinase inhibitor captopril. According to some embodiments, the antioxidant is Cu +2 Chelating agent of Cu +2 The chelating agent is selected from Na 2 EDTA and Na 2 EDTA-Ca or any combination thereof.
According to some embodiments, the antioxidant is selected from methimazole, quercetin, arbutin (arbutin), aloesin (aloesin), N-acetylglucosamine, retinoic acid, ferulic acid alpha-tocopherol ester, magnesium Ascorbyl Phosphate (MAP), substrate analogs such as sodium benzoate, L-phenylalanine, dimercaptosuccinic acid, D-penicillamine, trientine-HCl, dimercaptopropanol (dimercaprol), clioquinol (clioquinol), sodium thiosulfate, triethylenetetramine, tetraethylenepentamine, curcumin (curcumin), neocuprines (neocuprines), tannins, cyclohexanone oxalyldihydrazone (cuprazone), sulfites such as sodium or sodium metabisulfite, lipoic acid, CB4 (N-acetylCysGlyProCys amide), CB3 (N-acetylCyCyCyCyCyCyCyCyCys amide), AD4 (N-acetylcysteine amide), AD6 (N-acetylGluCysGly amide), AD7 (N-acetylCysCysquinone), vitamin, D-tert-butyl phenol, tocopherol, or any combination thereof.
The liquid pharmaceutical composition of the present invention may comprise between about 0.05% w/v to about 2.0% w/v of an antioxidant or combination of antioxidants. According to some embodiments of the present invention, the liquid pharmaceutical composition comprises between about 0.05% w/v and about 0.1% w/v, between about 0.1% w/v and about 0.2% w/v, between about 0.2% w/v and about 0.3% w/v, between about 0.3% w/v and about 0.4% w/v, between about 0.4% w/v and about 0.5% w/v, between about 0.5% w/v and about 0.6% w/v, between about 0.7% w/v and about 0.8% w/v, between about 0.8% w/v and about 0.9% w/v, between about 0.9% w/v and about 1.0% w/v, between about 1.0% w/v and about 1.1% w/v, between about 1.1% w/v and about 1.2% w/v between about 1.2% w/v and about 1.3% w/v, between about 1.3% w/v and about 1.4% w/v, between about 1.4% w/v and about 1.5% w/v, between about 1.5% w/v and about 1.6% w/v, between about 1.6% w/v and about 1.7% w/v, between about 1.7% w/v and about 1.8% w/v, between about 1.8% w/v and about 1.9% w/v, between about 1.9% w/v and about 2.0% w/v, about 0.75% w/v, about 0.8% w/v, about 0.85% w/v, about 0.9% w/v, about 0.95% w/v, about 1.0% w/v, about 1.05% w/v, about 1.1% w/v, about 1.9% w/v, about 15% w/v, about 1.2% w/v antioxidant or combination of antioxidants.
According to some embodiments, the liquid pharmaceutical composition comprises a combination of two antioxidants, wherein each antioxidant is present in an amount between about 0% w/v and about 2% w/v, and wherein the total amount of antioxidants is present in an amount of about 0% w/v to about 2% w/v. According to some embodiments, the liquid pharmaceutical composition comprises between about 0.05% w/v and about 0.1% w/v, between about 0.1% w/v and about 0.2% w/v, between about 0.2% w/v and about 0.3% w/v, between about 0.3% w/v and about 0.4% w/v, between about 0.4% w/v and about 0.5% w/v, between about 0.5% w/v and about 0.6% w/v, between about 0.7% w/v and about 0.8% w/v, between about 0.8% w/v and about 0.9% w/v, between about 0.9% w/v and about 1.0% w/v, between about 1.0% w/v and about 1.1% w/v, between about 1.1% w/v and about 1.2% w/v, between about 0.5% w/v and about 0.6% w/v, between about 0.7% w/v and about 0.8% w/v, between about 0.8% w/v and about 0.9% w/v, between about 0.8% w/v and about 1.9% w/v, between about 0.9% w/v and about 1.0.9% w/v, between about 1.9% w/v and about 1.1% w/v, between about 1.1% w/v and about 1.2% w/v, between about 0.3% w/v and about 0.9% w/v, an antioxidant is present in an amount between about 0.5% w/v and about 0.6% w/v, between about 0.7% w/v and about 0.8% w/v, between about 0.8% w/v and about 0.9% w/v, between about 0.9% w/v and about 1.0% w/v, between about 1.0% w/v and about 1.1% w/v, between about 1.1% w/v and about 1.2% w/v, between about 1.2% w/v and about 1.3% w/v, between about 1.3% w/v and about 1.4% w/v, between about 1.4% w/v and about 1.5% w/v, between about 1.5% w/v and about 1.6% w/v, between about 1.6% w/v and about 1.7% w/v, between about 1.7% w/v and about 1.8% w/v, between about 1.9% w/v, between about 2% w/v and about 1.3% w/v, between the combination of antioxidants. In certain embodiments, the first antioxidant and the second antioxidant comprise N-acetylcysteine (NAC) and ascorbic acid or a salt thereof. In certain embodiments, the liquid pharmaceutical composition comprises 0%, about 0.25%, about 0.5%, about 0.75%, about 1%, about 1.25%, about 1.5%, about 1.75%, or about 2% NAC and 0%, about 0.25%, about 0.5%, about 0.75%, about 1%, about 1.25%, about 1.5%, about 1.75%, or about 2% ascorbic acid or a salt thereof, wherein the liquid pharmaceutical composition comprises no greater than 2% NAC and a combination of ascorbic acid or a salt thereof. In certain embodiments, the liquid pharmaceutical composition comprises about 1% NAC and no ascorbic acid, comprises about 1% NAC and about 1% ascorbic acid or a salt thereof, comprises about 2% NAC and no ascorbic acid, or comprises about 2% ascorbic acid or a salt thereof and no NAC.
According to some embodiments, the liquid pharmaceutical composition further comprises a catechol-O-methyltransferase (COMT) inhibitor. According to some embodiments, the COMT inhibitor is selected from entacapone, tolcapone, epicapone (opapone), or any combination thereof. According to some embodiments, the liquid pharmaceutical composition comprises between about 0.1% w/v to about 5.0% w/v COMT inhibitor. According to some embodiments, the liquid pharmaceutical composition comprises between about 0.1% w/v to about 1.0% w/v COMT inhibitor. According to some embodiments, the liquid pharmaceutical composition comprises between about 1.0% w/v to about 2.0% w/v COMT inhibitor. According to some embodiments, the liquid pharmaceutical composition comprises between about 2.0% w/v to about 3.0% w/v COMT inhibitor. According to some embodiments, the liquid pharmaceutical composition comprises between about 3.0% w/v to about 4.0% w/v COMT inhibitor.
According to some embodiments, the liquid pharmaceutical composition comprises between about 4.0% w/v to about 5.0% w/v COMT inhibitor.
According to some embodiments, the liquid pharmaceutical composition may be administered concomitantly with the COMT inhibitor.
According to some embodiments, the liquid pharmaceutical composition further comprises a monoamine oxidase (MAO) inhibitor. The MAO inhibitor may be A MAO-A inhibitor or A MAO-B inhibitor. According to some embodiments, the liquid pharmaceutical composition comprises between about 0.1% w/v to about 5.0% w/v of the MAO inhibitor. According to some embodiments, the liquid pharmaceutical composition comprises between about 0.1% w/v to about 1.0% w/v of the MAO inhibitor. According to some embodiments, the liquid pharmaceutical composition comprises between about 1.0% w/v to about 2.0% w/v of the MAO inhibitor. According to some embodiments, the liquid pharmaceutical composition comprises between about 2.0% w/v to about 3.0% w/v of the MAO inhibitor. According to some embodiments, the liquid pharmaceutical composition comprises between about 3.0% w/v to about 4.0% w/v of the MAO inhibitor. According to some embodiments, the liquid pharmaceutical composition comprises between about 4.0% w/v to about 5.0% w/v of the MAO inhibitor. According to some embodiments, the MAO inhibitor is selected from molobetaine, rasagiline, selegiline, salfenamide, or any combination thereof. According to some embodiments, the liquid pharmaceutical composition may be administered concomitantly with the MAO inhibitor.
According to some embodiments, the liquid pharmaceutical composition further comprises a surfactant. According to some embodiments, the surfactant is selected from the group consisting of Tween-80, tween-60, tween-40, tween-20, tween-65, tween-85, span 20, span 40,Span 60, span 80, span 85, polyoxyethylene 35 castor oil (Cremophor EL), polyoxyethylene 660-hydroxystearate (macrogol 660) or poloxamer 188F-68), or any combination thereof. The liquid pharmaceutical composition of the present invention may comprise between about 0.1% w/v to about 3.0% w/v surfactant or a combination of two or more surfactants. According to some embodiments, the liquid pharmaceutical composition comprises between about 0.1% w/v and about 0.2% w/v, between about 0.2% w/v and about 0.3% w/v, between about 0.3% w/v and about 0.4% w/v, between about 0.4% w/v and about 0.5% w/v, between about 0.5% w/v and about 0.6% w/v, between about 0.6% w/v and about 0.7% w/v, between about 0.7% w/v and about 0.8% w/v, between about 0.8% w/v and about 0.9% w/v, between about 0.9% w/v and about 1.0% w/v, between about 1.0% w/v and about 1.5% w/v, between about 1.5% w/v and about 2.0% w/v, between about 2.7% w/v and about 0.8% w/v, between about 0.9% w/v and about 1.0% w/v, between about 2.5% w/v, or more of the active agent.
The liquid pharmaceutical composition may further comprise additional pharmaceutically acceptable excipients, such as N-methyl pyrrolidone (NMP), polyvinylpyrrolidone (PVP), propylene glycol, preservatives, pharmaceutically acceptable vehicles, stabilizers, dispersants, suspending agents, amino sugars, calcium chelators, protease inhibitors, or any combination thereof. The liquid pharmaceutical composition of the invention may comprise between about 5.0% w/v to about 80.0% w/v of an additional pharmaceutically acceptable excipient, e.g., a solvent, buffer or any other co-solvent.
According to some embodiments, the liquid pharmaceutical compositions of the present invention comprise between about 5.0% w/v and about 10.0% w/v, between about 10.0% w/v and about 15.0% w/v, between about 15.0% w/v and about 20.0% w/v, between about 20.0% w/v and about 25.0% w/v, between about 25.0% w/v and about 30.0% w/v, between about 30.0% w/v and about 35.0% w/v, between about 35.0% w/v and about 40.0% w/v, between about 40.0% w/v and about 45.0% w/v, between about 45.0% w/v and about 50.0% w/v, between about 50.0% w/v and about 55.0% w/v, between about 55.0% w/v and about 60.0% w/v, between about 30.0% w/v and about 60.0% w/v, between about 60.0% w/v and about 70.0% w/v, between about 65% w/v, between any other solvents.
It should be noted that any one or any combination of any of the components disclosed herein may be added to the liquid pharmaceutical composition of the present invention.
The liquid pharmaceutical compositions of the present invention may be in the form of solutions, gels, creams, emulsions or suspensions. According to some embodiments, the liquid pharmaceutical composition of the invention may be dried to provide a solid, e.g. by lyophilization, wherein the dried material, e.g. a lyophilisate, may be constituted to provide a liquid composition, e.g. by adding a solvent, e.g. water. When the dry composition is constituted, an antioxidant, a surfactant, or the like may also be added. According to some embodiments, the dried composition is reconstituted using a dedicated solution comprising, for example, a solvent, an antioxidant, a surfactant, and any other desired excipients. According to some embodiments, the liquid pharmaceutical composition of the invention is an aqueous composition.
The liquid pharmaceutical compositions of the invention may be formulated for any suitable route of administration, for example for parenteral administration, for example by bolus administration or continuous administration. The liquid pharmaceutical compositions of the present invention may be formulated for subcutaneous administration, transdermal administration, intradermal administration, transmucosal administration, intravenous administration, intraarterial administration, intramuscular administration, intraperitoneal administration, intratracheal administration, intrathecal administration, intraduodenal administration (intraduodenal administration), intrapleural administration, intranasal administration, sublingual administration, buccal administration, enteral administration, intraduodenal administration (intraduodenally administration), rectal administration, intraocular administration, or oral administration. The composition may also be formulated for inhalation, or for direct absorption through mucosal tissue.
A further embodiment of the invention relates to a process for preparing a liquid pharmaceutical composition, wherein the process comprises:
a levodopa-tyrosine (LD-Tyr) conjugate of formula (II):
mixing with at least one solvent and/or stabilizer to form a solution, gel, cream, emulsion or suspension; and adjusting the pH of the solution, gel, cream, emulsion or suspension to a physiologically acceptable pH value, thereby providing a liquid pharmaceutical composition.
According to some embodiments, the process comprises mixing an LD-Tyr compound of formula (II) in the form of a pharmaceutically acceptable salt with at least one stabilizer, thereby forming a solution. According to some embodiments, the process comprises mixing an LD-Tyr compound of formula (II) in the form of a pharmaceutically acceptable solid salt with at least one stabilizer. According to some embodiments, the process of the present invention comprises further mixing the LD-Tyr compound of formula (II) with any additional active pharmaceutical ingredient and/or pharmaceutically acceptable excipients, as described in detail with respect to the liquid pharmaceutical composition of the present invention. In certain embodiments, the mixing is performed without heating. In certain embodiments, the mixing is performed at room temperature.
According to some embodiments, the process comprises mixing a salt form of LD-Tyr with at least one solvent and/or stabilizer, wherein the salt is TFA salt, HCl salt, fumarate, lactate salt, maleate, glucoheptonate, phosphate, sulfate, HBr salt, nitrate, acetate, propionate, hexanoate, cyclopentanepropionate, glycolate, pyruvate, lactate (lactic acid salt), hippurate, methanesulfonate, ascorbate, malonate, oxalate, maleate, tartrate, citrate, succinate, benzoate, cinnamate, sulfonate, lauryl sulfate, gluconate, glutamate, hydroxynaphthoate, salicylate, stearate, muconate, alkali metal salts such as lithium, sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, aluminum salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, N-methylglucamine salts, dicyclohexylamine salts, adipic acid salts, alginic acid salts, ascorbate salts, aspartic acid salts, benzenesulfonate salts, bisulfate salts, borate salts, butyric acid, camphoric acid butyrate, digluconic acid butyrate, dodecylsulfuric acid butyrate, ethanesulfonic acid butyrate, glucoheptonic acid butyrate, glycerophosphate butyrate, gluconic acid butyrate, hemisulfate butyrate, heptanoic acid butyrate, hydroiodic acid butyrate, 2-hydroxy-ethanesulfonic acid butyrate, lactobionic acid butyrate, lauric acid butyrate, methanesulfonic acid butyrate, 2-naphthalenesulfonic acid butyrate, nicotinic acid butyrate, oleic acid butyrate, palmitic acid butyrate, pamoic acid butyrate, pectic acid butyrate, persulfate butyrate, 3-phenylpropionate butyrate, phosphobutyrate, picrate butyrate, pivalate butyrate, tartrate butyrate, thiocyanate butyrate, paratoluenesulfonate butyrate, undecanoate butyrate, valerate, or any combination thereof.
A further embodiment of the invention relates to a liquid pharmaceutical composition prepared according to the process of the invention.
Some embodiments of the present invention relate to a liquid pharmaceutical composition wherein the LD-Tyr compound, enantiomer, diastereomer, racemate, ion, zwitterionic, pharmaceutically acceptable salt, or any combination thereof, has a solubility of between about 100mg/L and about 1000mg/L at a physiologically acceptable pH. According to some embodiments, the LD-Tyr compound, enantiomer, diastereomer, racemate, ion, zwitterionic, pharmaceutically acceptable salt, or any combination thereof, has a solubility at a physiologically acceptable pH of between about 100mg/L and about 200mg/L, between about 200mg/L and about 300mg/L, between about 300mg/L and about 400mg/L, between about 400mg/L and about 500mg/L, between about 500mg/L and about 600mg/L, between about 600mg/L and about 700mg/L, between about 700mg/L and about 800mg/L, between about 800mg/L and about 900mg/L, between about 900mg/L and about 1000 mg/L.
Further embodiments of the invention relate to a method of treating a neurodegenerative condition and/or a condition characterized by reduced levels of dopamine in the brain, wherein the method comprises administering a liquid pharmaceutical composition, wherein the liquid pharmaceutical composition comprises a stabilizer and a levodopa-tyrosine (LD-Tyr) conjugate of formula (II):
Enantiomers, diastereomers, racemates, ions, zwitterions, pharmaceutically acceptable salts thereof, or any combination thereof.
According to some embodiments, the neurodegenerative condition and/or condition characterized by reduced dopamine levels in the brain is selected from parkinson's disease, secondary parkinsonism, huntington's disease, parkinsonism, progressive Supranuclear Palsy (PSP), multiple System Atrophy (MSA), amyotrophic Lateral Sclerosis (ALS), chardel-crafts syndrome, dystonia, alzheimer's disease, lewy Body Dementia (LBD), akinesia, bradykinesia, hypokinesia, conditions resulting from brain damage including carbon monoxide poisoning or manganese poisoning, conditions associated with neurological diseases or disorders including alcoholism, opioid addiction, or erectile dysfunction. According to some embodiments, the neurodegenerative condition and/or the condition characterized by reduced levels of dopamine in the brain is parkinson's disease.
According to some embodiments, the methods of the present invention comprise administering a LD-Tyr compound of formula (II), an enantiomer, diastereomer, racemate, ion, zwitterionic, pharmaceutically acceptable salt, or any combination thereof, or any combination of two or more LD-Tyr compounds, enantiomers, diastereomers, racemates, ions, zwitterions, pharmaceutically acceptable salts, or any combination thereof, concomitantly with administration of an additional active ingredient, such as a decarboxylase inhibitor, e.g., carbidopa, COMT inhibitor, MAO inhibitor, or any combination thereof. According to some embodiments, the LD-Tyr compound is administered with a decarboxylase inhibitor, e.g., carbidopa, wherein the LD-Tyr compound and the decarboxylase inhibitor are administered in a single formulation.
According to some embodiments, the methods of the invention comprise substantially continuously administering the liquid pharmaceutical composition. According to some embodiments, the liquid pharmaceutical composition is administered subcutaneously. According to some embodiments, the liquid pharmaceutical composition is administered subcutaneously via a designated pump device.
The embodiments of the pumps specified may be any of the pump embodiments disclosed, for example, in US 62/529784, US 62/576362, PCT/IB2018/054962, US16/027804, US16/027710, US16/351072, US16/351076, US16/351061, US 29/655583, US 29/655587, US 29/655589, US 29/655591, US 29/655592, US 29/655594, US 29/655597, US 62/85903 and US29/723714, all of which are incorporated herein by reference in their entirety.
According to some embodiments, the methods of the invention comprise administering the liquid pharmaceutical composition at one site, two sites, or three or more sites, wherein the positions of the sites may be changed at any suitable, possibly predetermined, interval. According to some embodiments, once administered via a particular site, administration via the same site or in the vicinity of the site may be only after a possibly predetermined period of time. According to some embodiments, the location of any one of the sites is changed after 12 hours, 24 hours, 36 hours, 48 hours, 60 hours, or 72 hours. According to some embodiments, the location of the site is changed after 4 days, 5 days, 6 days, or 7 days. According to some embodiments, the location of the site is changed after two weeks, three weeks, or four weeks. According to some embodiments, the location of the site is changed when needed or desired, e.g., based on subjective data received from the patient and/or based on objective data received, e.g., from sensors located at or near the injection site.
According to some embodiments, the volume and/or rate of administration is the same in all or at least two sites. According to other embodiments, the rate of administration and/or the volume of administration varies from site to site. Each site may be controlled independently or otherwise, and all sites may be controlled dependent on each other.
According to some embodiments, the methods of the invention comprise subcutaneously administering between about 1ml to about 15ml of the liquid pharmaceutical composition of the invention over a 24 hour period. According to some embodiments, the methods of the invention comprise subcutaneously administering between about 1ml and about 2ml, between about 2ml and about 3ml, between about 3ml and about 4ml, between about 4ml and about 5ml, between about 5ml and about 6ml, between about 6ml and about 7ml, between about 7ml and about 8ml, between about 8ml and about 9ml, between about 9ml and about 10ml, between about 10ml and about 11ml, between about 11ml and about 12ml, between about 12ml and about 13ml, between about 13ml and about 14ml, and between about 14ml and about 15ml over a 24 hour course.
It should be noted that the rate of administration may remain unchanged over the course of 24 hours, or may change over the course of 24 hours. For example, according to some embodiments, there may be a certain rate for high activity/daytime hours and a different rate for low activity/nighttime hours. The high activity/daytime hours may be, for example, about 15 hours, about 16 hours, about 17 hours, about 18 hours, or about 19 hours, and the low activity nighttime hours may be about 9 hours, about 8 hours, about 7 hours, about 6 hours, or about 5 hours, respectively. According to some embodiments, the high activity/daytime rate is performed for about 18 hours, and the low activity/nighttime rate is performed for about 6 hours. According to some embodiments, the high activity/daytime rate is performed for about 16 hours, and the low activity/nighttime rate is performed for about 8 hours.
According to some embodiments, the rate of administration remains unchanged over the course of 24 hours. According to some embodiments, the liquid pharmaceutical formulation is administered every 24 hours for a period of time, e.g., 8 hours a day, 9 hours a day, 10 hours a day, 11 hours a day, 12 hours a day, 13 hours a day, 14 hours a day, 15 hours a day, 16 hours a day, 17 hours a day, 18 hours a day, 19 hours a day, 20 hours a day, 21 hours a day, 22 hours a day, or 23 hours a day. According to some embodiments, the number of hours administered per day may remain unchanged over a course of days, e.g., 7 days, 14 days, 21 days, 28 days, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, three years, four years, or more. According to some embodiments, the number of hours per day of administration may vary day to day, depending on the condition of the patient, the decision of the caregiver or doctor, input from the sensor, and the like. It should also be noted that although only the entire hour is specifically mentioned, any portion of the hour, day, month, etc. is possible for administration, e.g., 16.5 hours a day, 7.5 days, etc.
The rate of administration may be between about 0.01 mL/site/hour to about 1 mL/site/hour. According to some embodiments, the administration rate is between about 0.01 mL/site/hour and 0.02 mL/site/hour. According to some embodiments, the administration rate is between about 0.02 mL/site/hour and 0.03 mL/site/hour. According to some embodiments, the administration rate is between about 0.03 mL/site/hour and 0.04 mL/site/hour. According to some embodiments, the administration rate is between about 0.04 mL/site/hour and 0.05 mL/site/hour. According to some embodiments, the administration rate is between about 0.05 mL/site/hour and 0.06 mL/site/hour. According to some embodiments, the administration rate is between about 0.06 mL/site/hour and 0.07 mL/site/hour. According to some embodiments, the administration rate is between about 0.07 mL/site/hour and 0.08 mL/site/hour. According to some embodiments, the administration rate is between about 0.08 mL/site/hour and 0.09 mL/site/hour. According to some embodiments, the administration rate is between about 0.09 mL/site/hour and 0.1 mL/site/hour. According to some embodiments, the administration rate is between about 0.1 mL/site/hour and 0.15 mL/site/hour. According to some embodiments, the administration rate is between about 0.15 mL/site/hour and 0.2 mL/site/hour. According to some embodiments, the administration rate is between about 0.2 mL/site/hour and 0.25 mL/site/hour. According to some embodiments, the administration rate is between about 0.25 mL/site/hour and 0.3 mL/site/hour. According to some embodiments, the administration rate is between about 0.3 mL/site/hour and 0.35 mL/site/hour. According to some embodiments, the administration rate is between about 0.35 mL/site/hour and 0.4 mL/site/hour. According to some embodiments, the administration rate is between about 0.4 mL/site/hour and 0.45 mL/site/hour. According to some embodiments, the administration rate is between about 0.45 mL/site/hour and 0.5 mL/site/hour. According to some embodiments, the administration rate is between about 0.5 mL/site/hour and 0.55 mL/site/hour. According to some embodiments, the administration rate is between about 0.55 mL/site/hour and 0.6 mL/site/hour. According to some embodiments, the administration rate is between about 0.6 mL/site/hour and 0.65 mL/site/hour. According to some embodiments, the administration rate is between about 0.65 mL/site/hour and 0.7 mL/site/hour. According to some embodiments, the administration rate is between about 0.7 mL/site/hour and 0.75 mL/site/hour. According to some embodiments, the administration rate is between about 0.75 mL/site/hour and 0.8 mL/site/hour. According to some embodiments, the administration rate is between about 0.8 mL/site/hour and 0.85 mL/site/hour. According to some embodiments, the administration rate is between about 0.85 mL/site/hour and 0.9 mL/site/hour. According to some embodiments, the administration rate is between about 0.9 mL/site/hour and 0.95 mL/site/hour. According to some embodiments, the administration rate is between about 0.95 mL/site/hour and 1.0 mL/site/hour.
According to some embodiments, the rate of administration during low activity/night time is between about 0.01 mL/site/hour and 0.15 mL/site/hour. According to some embodiments, the rate of administration during low activity/night time is between about 0.01 mL/site/hour and 0.02 mL/site/hour. According to some embodiments, the rate of administration during low activity/night time is between about 0.02 mL/site/hour and 0.03 mL/site/hour. According to some embodiments, the rate of administration during low activity/night time is between about 0.03 mL/site/hour and 0.04 mL/site/hour. According to some embodiments, the rate of administration during low activity/night time is between about 0.04 mL/site/hour and 0.05 mL/site/hour. According to some embodiments, the rate of administration during low activity/night time is between about 0.05 mL/site/hour and 0.06 mL/site/hour. According to some embodiments, the rate of administration during low activity/night time is between about 0.06 mL/site/hour and 0.07 mL/site/hour. According to some embodiments, the rate of administration during low activity/night time is between about 0.07 mL/site/hour and 0.08 mL/site/hour. According to some embodiments, the rate of administration during low activity/night time is between about 0.08 mL/site/hour and 0.09 mL/site/hour. According to some embodiments, the rate of administration during low activity/night time is between about 0.09 mL/site/hour and 0.1 mL/site/hour. According to some embodiments, the rate of administration during low activity/night time is between about 0.1 mL/site/hour and 0.11 mL/site/hour. According to some embodiments, the rate of administration during low activity/night time is between about 0.11 mL/site/hour and 0.12 mL/site/hour. According to some embodiments, the rate of administration during low activity/night time is between about 0.12 mL/site/hour and 0.13 mL/site/hour. According to some embodiments, the rate of administration during low activity/night time is between about 0.13 mL/site/hour and 0.14 mL/site/hour. According to some embodiments, the rate of administration during low activity/night time is between about 0.14 mL/site/hour and 0.15 mL/site/hour. According to some embodiments, the rate of administration during low activity/night time is about 0.04 mL/site/hour.
According to some embodiments, the rate of administration during high activity/daytime is between about 0.15 mL/site/hour and 1.0 mL/site/hour. According to some embodiments, the rate of administration during high activity/daytime is between about 0.15 mL/site/hour and 0.2 mL/site/hour. According to some embodiments, the rate of administration during high activity/daytime is between about 0.2 mL/site/hour and 0.25 mL/site/hour. According to some embodiments, the rate of administration during high activity/daytime is between about 0.25 mL/site/hour and 0.3 mL/site/hour. According to some embodiments, the rate of administration during high activity/daytime is between about 0.3 mL/site/hour and 0.35 mL/site/hour. According to some embodiments, the rate of administration during high activity/daytime is between about 0.35 mL/site/hour and 0.4 mL/site/hour. According to some embodiments, the rate of administration during high activity/daytime is between about 0.4 mL/site/hour and 0.45 mL/site/hour. According to some embodiments, the rate of administration during high activity/daytime is between about 0.45 mL/site/hour and 0.5 mL/site/hour. According to some embodiments, the rate of administration during high activity/daytime is between about 0.5 mL/site/hour and 0.55 mL/site/hour. According to some embodiments, the rate of administration during high activity/daytime is between about 0.55 mL/site/hour and 0.6 mL/site/hour. According to some embodiments, the rate of administration during high activity/daytime is between about 0.6 mL/site/hour and 0.65 mL/site/hour. According to some embodiments, the rate of administration during high activity/daytime is between about 0.65 mL/site/hour and 0.7 mL/site/hour. According to some embodiments, the rate of administration during high activity/daytime is between about 0.7 mL/site/hour and 0.75 mL/site/hour. According to some embodiments, the rate of administration during high activity/daytime is between about 0.75 mL/site/hour and 0.8 mL/site/hour. According to some embodiments, the rate of administration during high activity/daytime is between about 0.8 mL/site/hour and 0.85 mL/site/hour. According to some embodiments, the rate of administration during high activity/daytime is between about 0.85 mL/site/hour and 0.9 mL/site/hour. According to some embodiments, the rate of administration during high activity/daytime is between about 0.9 mL/site/hour and 0.95 mL/site/hour. According to some embodiments, the rate of administration during high activity/daytime is between about 0.95 mL/site/hour and 1.0 mL/site/hour. According to some embodiments, the rate of administration during high activity/daytime hours is about 0.32 mL/site/hour.
It should also be noted that the volume and/or rate of administration may remain the same throughout the treatment, or may vary during different hours of the day, between different treatment days, weeks or months of treatment, etc. According to some embodiments, the patient is monitored, e.g., by an administrator independently, or electronically, e.g., by sensors, administration pumps, etc., that may be found in a dedicated device (e.g., a wristwatch-like device). According to such embodiments, the administration volume and/or the administration rate is determined from data received from such monitoring.
Some embodiments relate to methods for bolus subcutaneous injection of the liquid pharmaceutical compositions of the present invention. According to some embodiments, the bolus injection comprises between about 0.5mL/Kg to about 2.0mL/Kg of the liquid pharmaceutical composition. According to some embodiments, the bolus injection comprises between about 0.5mL/Kg to about 0.75mL/Kg of the liquid pharmaceutical composition. According to some embodiments, the bolus injection comprises between about 0.75mL/Kg to about 1.0mL/Kg of the liquid pharmaceutical composition. According to some embodiments, the bolus injection comprises between about 1.0mL/Kg to about 1.25mL/Kg of the liquid pharmaceutical composition. According to some embodiments, the bolus injection comprises between about 1.25mL/Kg to about 1.5mL/Kg of the liquid pharmaceutical composition. According to some embodiments, the bolus injection comprises between about 1.5mL/Kg to about 1.75mL/Kg of the liquid pharmaceutical composition. According to some embodiments, the bolus injection comprises between about 1.75mL/Kg to about 2.0mL/Kg of the liquid pharmaceutical composition.
According to some embodiments, the bolus injection comprises between about 0.75mL/Kg to about 1.25mL/Kg of the liquid pharmaceutical composition. According to some embodiments, the bolus injection comprises about 1.0mL/Kg of the liquid pharmaceutical composition.
Bolus subcutaneous injections may be administered at any point in time associated with any possible continuous subcutaneous administration, e.g., before, during, or after continuous administration.
According to some embodiments, the administered dose may be doubled, tripled, or more by using more than one pump, more than one injection site per pump, etc.
According to some embodiments, the liquid pharmaceutical composition is administered for a defined period of time, e.g., days, weeks, months or years. According to some embodiments, the liquid pharmaceutical composition is administered endlessly for the treatment of chronic conditions.
A further embodiment of the invention relates to a liquid pharmaceutical composition for use in the treatment of a neurodegenerative condition and/or a condition characterized by a reduced level of dopamine in the brain, wherein the liquid pharmaceutical composition comprises a stabilizer and a levodopa-tyrosine (LD-Tyr) conjugate of formula (II):
Enantiomers, diastereomers, racemates, ions, zwitterions, pharmaceutically acceptable salts thereof, or any combination thereof.
According to some embodiments, the liquid pharmaceutical composition is for use in the following treatments: parkinson's disease, secondary parkinsonism, huntington's disease, parkinsonism, progressive Supranuclear Palsy (PSP), multiple System Atrophy (MSA), amyotrophic Lateral Sclerosis (ALS), sham-de syndrome, dystonia, alzheimer's disease, lewy Body Dementia (LBD), akinesia, bradykinesia, hypokinesia, conditions caused by brain injury including carbon monoxide poisoning or manganese poisoning, conditions associated with neurological diseases or disorders including alcoholism, opioid addiction, or erectile dysfunction. Certain embodiments of the present invention relate to liquid pharmaceutical compositions of the present invention in the treatment of parkinson's disease.
The composition for use according to the present invention may comprise any additional material, in any amount, as described in detail herein with respect to embodiments of the composition of the present invention. Furthermore, the form, pH, etc. of the composition for use according to the present invention may be as described in detail herein with respect to embodiments of the composition of the present invention. Furthermore, the compositions of the present invention may be used with COMT inhibitors, MAO inhibitors or any other active ingredient, as described in detail herein.
Industry applicability: in the present invention, the levodopa prodrug compounds and stabilized formulations described herein are useful for preventing or treating neurodegenerative diseases and/or diseases or symptoms caused by reduced dopamine concentrations in the brain, such as parkinson's disease and related symptoms. Therefore, the invention has high practical value in the pharmaceutical industry.
Unless explicitly stated, the method embodiments described herein are not limited to a particular order or sequence. In addition, some of the described method embodiments or elements thereof may occur or be performed simultaneously, at the same point in time, or synchronously.
It is appreciated that certain features of the invention may also be provided in combination in a single embodiment. Conversely, various elements of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as appropriate in any other described embodiment of the invention. Furthermore, certain features described in the context of various embodiments should not be considered essential features of those embodiments unless the embodiments are not practical without those elements.
Various embodiments and aspects of the invention as described above and as claimed in the following claims section may be supported by the following examples; however, they are not limited by the examples.
Examples
Part I: prodrugs
Example 1: (2S) -2- [ [ (2S) -2-aminopropionyl]Amino group]-3- (3-hydroxy-4-phosphonooxyphenyl) propane Acid production
(2S) -3- [ 4-bis (phenylmethoxy) phosphoryloxy-3-phenylmethoxyphenyl ] -2- [ [ (2S) -2- (phenylmethoxycarbonylamino) propionyl ] amino ] benzyl propionate (551 mg) was dissolved in a mixed solvent of ethanol (2 mL) and tetrahydrofuran (2 mL), palladium on carbon (aqueous) (69 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 7 hours. The reaction mixture was filtered through a membrane filter (cellulose acetate) to remove insoluble materials. The insoluble matter was washed with water/ethanol (2:1, 12 mL), and the filtrate was distilled under reduced pressure until the filtrate was reduced to about 1mL, and freeze-drying was performed, and then, the title compound was obtained as a white powder (214 mg, yield: 100%).
MS(ESI)；m/z 349.1[M+H]+
Examples 2 to 19 and 120 to 131
The corresponding starting compounds were treated separately in the same manner as in example 1 to obtain the compounds shown in table 2 below. Some of the compounds shown in table 2 below can be obtained in the same manner as the above examples.
TABLE 2
/>
/>
/>
/>
/>
Example 20: (2S) -2- [ [ (2S) -2-amino-5-carbamazetidinyl pentanoyl]Amino group]-3-(3, 4-dihydroxybenzene) Radical) production of propionic acid hydrochloride
(2S) -3- [3, 4-bis (phenylmethoxy) phenyl ] -2- [ [ (2S) -5- [ (N-nitroformamidine) amino ] -2- (phenylmethoxycarbonylamino) pentanoyl ] amino ] benzyl propionate (257 mg) was dissolved in a mixed solvent of tetrahydrofuran (2 mL), 2-propanol (3 mL), and 2M hydrochloric acid (0.80 mL), and palladium on carbon (aqueous) (341 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 24 hours. 2-propanol (4 mL) and water (6 mL) were added to the reaction mixture, and insoluble materials were removed using a membrane filter. The insoluble material was washed with water (6 mL), 2-propanol (25 mL) was added, and the mixture was distilled under reduced pressure. Diisopropyl ether was added to the residue, and the precipitated solid was collected by filtration and dried under reduced pressure, and thus the title compound was obtained as a tan powder (144 mg, yield: 100%).
MS(ESI)；m/z 354.2[M+H]+
Examples 21 to 28
The compounds shown in table 3 below can be obtained in the same manner as in the above examples.
TABLE 3 Table 3
/>
Reference example 1: (2S) -3- [ 4-bis (phenylmethoxy) phosphoryloxy-3-phenylmethoxyphenyl ]-2- [ (2S) -3- (2-ethoxy-2-methyl-1, 3-benzodioxol-5) -yl) -2- (phenylmethoxycarbonylamino) Propionyl radical]Amino group]Production of propionic acid
(2S) -3- [ 4-bis (phenylmethoxy) phosphoryloxy-3-phenylmethoxyphenyl ] -2- [ [ (2S) -3- (2-ethoxy-2-methyl-1, 3-benzodioxol-5-yl) -2- (phenylmethoxycarbonylamino) propionyl ] amino ] benzyl propionate (208 mg) was dissolved in a mixed solvent of water (0.41 mL) and tetrahydrofuran (1.0 mL), and lithium hydroxide monohydrate (9.4 mg) was added under ice bath, and then the mixture was stirred at room temperature for 2 hours. After ethyl acetate was added to the reaction mixture, a saturated aqueous citric acid solution was added until the pH of the mixture reached 6, and extraction with ethyl acetate was performed. The organic layer was dried over magnesium sulfate, and insoluble matter was filtered, and then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) =70/30-0/100, (ethyl acetate)/methanol=100/0-85/15), and thereby the title compound (179 mg, yield: 94%) was obtained as a colorless viscous matter.
MS(ESI)；m/z 929.3[M-H]-
Reference example 2: (2S) -3- [ 4-bis (phenylmethoxy) phosphoryloxy-3-phenylmethoxyphenyl ]-2- [ [ (2S) -2- (Phenylmethoxycarbonylamino) propionyl]Amino group]Production of benzyl propionate
1H-tetrazole (72 mg) and dibenzyl N, N-diisopropylphosphoramidite (0.38 mL) were added to (2S) -3- (4-hydroxy-3-phenylmethoxyphenyl) -2- (phenylmethoxycarbonylamino) propionyl [ (2S) -2- (phenylmethoxycarbonylamino) under ice-cooling]Amino group]Benzyl propionate (387 mg), dichloromethane (4 mL) and acetonitrile (1.6 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was ice cooled, t-butyl hydrogen peroxide decane solution (5.5M) (0.18 mL) was added, and the mixture was stirred at room temperature for 1 hour. The solvent of the reaction mixture was distilled off under reduced pressure, and then toluene was added, and the reaction mixture was purified by Phase-Insoluble material is removed. The filtrate was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) =67/33-40/60), and the title compound (551 mg, yield: 90%) was obtained as a colorless viscous material.
MS(ESI)；m/z 843.7[M+H]+
Reference examples 3 to 16:
the corresponding starting compounds were treated separately in the same manner as in reference example 2 to obtain the compounds shown in table 4 below.
TABLE 4 Table 4
/>
/>
/>
Reference example 101:
(2S) -3- [ 4-bis (phenylmethoxy) phosphoryloxy-3-phenylmethoxyphenyl ]-2- [ [ (2S) -4-methyl-2 ] (Phenylmethoxycarbonyloxy) pentanoyl]Oxy group]Production of benzyl propionate
1, 8-diazabicyclo [5.4.0] undec-7-ene (223 μl) and tetrabenzyl pyrophosphate (805 mg) were added to a mixture of benzyl (2S) -3- (4-hydroxy-3-phenylmethoxyphenyl) -2- [ (2S) -4-methyl-2- (phenylmethoxycarbonylamino) pentanoyl ] amino ] propionate (623 mg) and acetonitrile (5 mL) under ice cooling, and the temperature was gradually raised to room temperature, and the mixture was stirred for 21 hours. 1, 8-diazabicyclo [5.4.0] undec-7-ene (74 μl) and tetrabenzyl pyrophosphate (266 mg) were added to the mixture, and the mixture was stirred for 3.5 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and extraction with ethyl acetate was performed. The organic layer was dried over magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) =67/33 to 40/60), and thereby the title compound was obtained as colorless mucus (702 mg,80% yield).
MS(ESI)；m/z 885.3[M+H]+
Reference examples 102 to 112:
the corresponding starting compounds were treated separately in the same manner as in reference example 101 to obtain the compounds shown in tables 8 to 5 below. Some of the compounds shown in tables 8-5 below can be obtained in the same manner as the above examples.
Tables 8 to 5
/>
/>
/>
Reference example 17: (2S) -3- (4-hydroxy-3-phenylmethoxyphenyl) -2- [ [ (2S) -2- (phenylmethoxy) Carbonylamino) propionyl]Amino group]Production of benzyl propionate
(2S) -2- (Benzyloxycarbonylamino) propionic acid (1.02 g), 1-hydroxy-7-azabenzotriazole (HOAt) (712 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCI) (1.03 g) and N, N-diisopropylethylamine (0.750 mL) were added to a mixture of (2S) -2-amino-3- (4-hydroxy-3-phenylmethoxyphenyl) benzyl propionate hydrochloride (1.87 g) and N, N-dimethylformamide (18 mL), and the mixture was stirred at room temperature for 18 hours. Saturated aqueous sodium bicarbonate and water were added to the reaction mixture, and extraction with ethyl acetate was performed. The organic layer was washed with water and saturated sodium chloride solution, and dried over magnesium sulfate. The insoluble material was filtered and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) =67/33-45/55), and the title compound (2.56 g, yield: 99%) was obtained as a white powder.
MS(ESI)；m/z 583.6[M+H]+
Reference examples 18 to 34:
the corresponding starting compounds were treated separately in the same manner as in reference example 17 to obtain the compounds shown in table 5 below.
TABLE 5
/>
/>
/>
/>
/>
Reference example 35: production of (2S) -2-acetamido-3- (3, 4-diacetoxyphenyl) benzyl propionate
Acetic anhydride (0.291 mL) was added to a mixture of (2S) -2-amino-3- (3, 4-dihydroxyphenyl) benzyl propionate hydrochloride (253 mg) and pyridine (1 mL) under ice cooling, and the mixture was stirred at room temperature for 18 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and extraction with chloroform was performed. The organic layer was washed with a saturated sodium chloride solution and dried over sodium sulfate, and insoluble matter was filtered, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) =80/20-0/100), and thereby the title compound (280 mg, yield: 72%) was obtained as a colorless viscous material.
MS(ESI)；m/z 414.2[M+H]+
Reference examples 36 and 37:
the corresponding starting compounds were treated separately in the same manner as in reference example 35 to obtain the compounds shown in table 6 below.
TABLE 6
Reference example 38: (2S) -2-amino-3- [3, 4-bis (phenylmethoxy) phenyl]Benzyl propionate hydrochloride Production of
A4M hydrogen chloride dioxane solution (43 mL) was added to (2S) -3- [3, 4-bis (phenylmethoxy) phenyl ] -2- [ (2-methylpropan-2-yl) oxycarbonylamino ] benzyl propionate (13.2 g) under ice cooling, and the mixture was stirred at room temperature for 3 hours. 4M ethyl hydrogen chloride solution (3 mL) was added and the mixture was stirred for 2 hours. The solvent of the reaction mixture was distilled off under reduced pressure. The residue was suspended in diisopropyl ether, and the precipitated solid was collected by filtration and dried under reduced pressure, and thus the title compound (10.4 mg, yield: 96%) was obtained as a white powder.
MS(ESI)；m/z 468.3[M+H]+
Reference example 39:
the corresponding starting compounds were treated separately in the same manner as in reference example 33 to obtain the compounds shown in table 7 below.
TABLE 7
Reference example 40: production of (2S) -2-amino-3- (3-benzyloxy-4-hydroxyphenyl) benzyl propionate hydrochloride Raw materials
(1) Trimethyl N- (tert-butoxycarbonyl) -phosphonoglycine (10 g) and 1, 3-tetramethylguanidine (5 mL) were added to a mixture of compound A-1 (8.31 g) and methylene chloride (90 mL) under ice-cooling, and the mixture was stirred at room temperature for 24 hours. Saturated aqueous sodium bicarbonate and water were added to the reaction mixture, and extraction with ethyl acetate was performed. The organic layer was subjected to silica gel column chromatography (solvent: ethyl acetate), and the solvent of the filtrate was distilled off under reduced pressure. The residue was suspended in ethanol, and the precipitated solid was collected by filtration and dried under reduced pressure, and Compound A-2 (10.7 g, yield: 79%) was obtained as a white powder.
MS(ESI)；m/z 440.3[M-H]-
(2) (+) -1, 2-bis ((2S, 5S) -2, 5-diethylphosphino) benzene (1, 5-cyclooctadiene) rhodium (I) tetrafluoroborate ((S, S) -Et-DUPHOS-Rh) (144 mg) was added to a mixture of compound A-2 (9.65 g) and tetrahydrofuran (80 mL), and the mixture was stirred under a pressurized hydrogen atmosphere (800 kPa) at 35℃for 3 hours. The reaction mixture was subjected to silica gel column chromatography (solvent: hexane/(ethyl acetate) =50/50), and the solvent of the filtrate was distilled off under reduced pressure. The residue was suspended in ethanol, and the precipitated solid was collected by filtration and dried under reduced pressure, and Compound A-3 (9.00 g, yield: 93%) was obtained as a white powder.
MS(ESI)；m/z 442.2[M-H]-
(3) Compound A-3 (7.52 g) was dissolved in a mixed solvent of tetrahydrofuran (40 mL), methanol (20 mL) and distilled water (15 mL), and a 4M aqueous lithium hydroxide solution (20 mL) was added under ice-cooling, and the mixture was stirred at 0℃for 7 hours. 1M hydrochloric acid (60 mL) was added to the reaction mixture, and extraction with ethyl acetate (100 mL) was performed. The organic layer was washed with a saturated sodium chloride solution and dried over magnesium sulfate, and insoluble matter was filtered, and the solvent was distilled off under reduced pressure, and thereby compound a-4 (7.52 g,88wt% yield: 100%) was obtained as a yellow viscous matter.
MS(ESI)；m/z386.2[M-H]-
(4) Cesium carbonate (3.97 g) and benzyl bromide (2.40 mL) were added to a mixture of compound a-4 (7.46 g,88 wt%) and N, N-dimethylformamide (4 mL) at room temperature, and the mixture was stirred at the same temperature for 4 hours. A saturated sodium chloride solution and water were added to the reaction mixture, and extraction with ethyl acetate was performed. The organic layer was washed with water and saturated sodium chloride solution, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) =80/20-67/33), and thereby compound a-5 (8.81 g,90wt%, 98%) was obtained as a white powder.
MS(ESI)；m/z476.2[M-H]-
(4) -2 (another synthetic method of compound a-5) iodine (153 mg) was added to a mixture of activated zinc (923 mg) and N, N-dimethylformamide (7 mL) at 5 ℃ under nitrogen atmosphere. The temperature was raised to 20 ℃ and the mixture was stirred for 10 minutes. The reaction mixture was cooled again to 6 ℃, and compound a-6 (1890 mg) was added in portions at 20 ℃ or lower, and the mixture was stirred at 20 ℃ for 30 minutes, and thereby a solution of compound a-7 was obtained.
Tris (dibenzylideneacetone) dipalladium (0) -chloroform adduct (31 mg), 2-dicyclohexylphosphino-2 ',6' -dimethoxybiphenyl dicyclohexyl (2 ',6' -dimethoxy- [1,1' -biphenyl ] -2-yl) phosphine (30 mg) and compound a-8 (1309 mg) were added in this order, and the mixture was stirred at room temperature for 16 hours. Hexane/(ethyl acetate) (1:1) was added to the reaction mixture, and insoluble matter was removed by filtration through celite. The insoluble matter was washed with hexane/(ethyl acetate) (1:1) and water, and the filtrate was washed with a saturated aqueous ammonium chloride solution and a saturated sodium chloride solution in this order. The organic layer was dried over anhydrous magnesium sulfate, and insoluble matter was filtered, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) =80/20-67/33), and thereby compound a-5 (1.84 g, yield: 90%) was obtained as a yellow viscous material.
MS(ESI)；m/z378.2[M+H-Boc]+
(5) A4M hydrogen chloride dioxane solution (6 mL) was added to a mixture of compound A-5 (1.63 g) and 1, 4-dioxane (15 mL) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. 4M hydrogen chloride dioxane solution (6 mL) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure until its volume was about 1/10. The residue was suspended in ethyl acetate, and the precipitated solid was collected by filtration and dried under reduced pressure, and thus the compound [ a-1] (1288 mg, yield: 90%) was obtained as a white powder.
MS(ESI)；m/z378.4[M+H]+
Reference example 41: production of (2S) -2-amino-3- (3, 4-diacetoxyphenyl) benzyl propionate hydrochloride
(1) Cesium carbonate (1.43 g) and benzyl bromide (0.58 mL) were added to a mixture of compound B-1 (2.0 g) and N, N-dimethylformamide (19 mL), and the mixture was stirred at room temperature for 2 hours. A saturated sodium chloride solution and water were added to the reaction mixture, and extraction with ethyl acetate was performed. The organic layer was washed with water and saturated sodium chloride solution, and dried over magnesium sulfate, and insoluble matter was filtered, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography, and thereby compound B-2 (1.68 g, yield: 75%) was obtained as a colorless viscous material.
MS(ESI)；m/z 372.1[M+H-Boc]+
(2) A4M ethyl hydrogen chloride solution (0.5 mL) was added to a solution of compound B-2 (515 mg) in ethyl acetate (5 mL) under ice-cooling, and the mixture was stirred at room temperature for 4 hours. 4M ethyl hydrogen chloride solution (3 mL) was added and the mixture was stirred at room temperature for 2.5 hours. The solvent of the reaction mixture was distilled off under reduced pressure. The residue was suspended in ethyl acetate, and the precipitated solid was collected by filtration and dried under reduced pressure, and thus compound B (409 mg, yield: 98%) was obtained as a white powder.
MS(ESI)；m/z 372.1[M+H]+
Reference example 42: (2S) -2- (Benzyloxycarbonylamino) -3- (2, 2-dimethyl-1, 3-benzodioxolan) Production of en-5-yl) propionic acid
Para-toluene sulfonic acid (175 mg) and 2, 2-dimethoxypropane (12.5 mL) were added to a mixture of compound C-1 (3.66 g) and toluene (102 mL), and the mixture was heated to reflux using a Dean-Stark apparatus for 14 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and extraction with ethyl acetate was performed. The organic layer was dried over magnesium sulfate, and insoluble matter was filtered, and then the solvent was distilled off under reduced pressure, and a crude product of compound C-2 was obtained as a yellow viscous matter.
The crude product of compound C-2 was dissolved in a mixed solvent of methanol (25 mL), water (20 mL) and tetrahydrofuran (51 mL), and lithium hydroxide monohydrate (855 mg) was added under an ice bath, and the mixture was stirred at the same temperature for 40 minutes, and then, the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and washed with diethyl ether. Ethyl acetate was added to the aqueous layer, and saturated aqueous citric acid was added until the pH of the mixture reached 6, and extraction with ethyl acetate was performed. The organic layer was dried over magnesium sulfate, and the insoluble matter was filtered, and then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (solvent: ethyl acetate), and thereby compound C (2.40 g, 2-step yield: 63%) was obtained as a yellow viscous material.
MS(ESI)；m/z 370.2[M-H]-
Reference example 43: (2S) -2- (benzyloxycarbonylamino) -3- (2-ethoxy-2-methyl-1, 3-benzodioxy) Production of cyclopenten-5-yl) propionic acid
(1) Compound D-1 (1.35 g) was dissolved in 1-butyl-3-methylimidazolium hexafluorophosphate (7.51 mL), and triethyl orthoacetate (1.38 mL) was added, and the mixture was stirred at 80℃for 3 hours. Water was added to the reaction mixture, and then, extraction with ethyl acetate was performed. The organic layer was dried over magnesium sulfate, and insoluble matter was filtered, and then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (solvent: hexane/(ethyl acetate) =85/15-70/30), and thereby compound D-2 (1.41 g, yield: 87%) was obtained as a colorless viscous substance.
MS(ESI)；m/z 430.0[M+H]+
(2) Compound D-2 (1.35 g) was dissolved in a mixed solvent of methanol (3.9 mL), water (6.3 mL) and tetrahydrofuran (6.3 mL), and lithium hydroxide monohydrate (264 mg) was added under an ice bath, and then the mixture was stirred at room temperature for 10 hours. After ethyl acetate was added to the reaction mixture, a saturated aqueous ammonium chloride solution was added until the pH of the mixture reached 6, and extraction with ethyl acetate was performed. The organic layer was dried over magnesium sulfate, and insoluble matter was filtered, and then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (solvent (ethyl acetate)/methanol=100/0-95/5), and thereby compound D (816 mg, yield: 65%) was obtained as a colorless solid.
MS(ESI)；m/z 400.2[M-H]-
Experimental example 1: evaluation of in vitro transformation efficiency Using human hepatocytes
The conversion efficiency of pro-drugs to levodopa was evaluated by metabolic studies using human hepatocytes. The prodrug was incubated with human hepatocytes for 4 hours at 37 ℃. A portion of the reaction solution was sampled at each predetermined time and mixed with an organic solvent to stop the reaction. The reaction stopped solution was centrifuged and the obtained supernatant was analyzed using liquid chromatography/tandem mass spectrometry. The conversion efficiency of levodopa was evaluated as the amount of levodopa produced after 4 hours of incubation. Table 8 shows the levodopa production of compounds as some examples of the invention.
TABLE 8
Examples Levodopa production (nmol/L)
1 862
2 1688
4 552
6 561
8 963
10 1083
17 574
As shown in the results of the above tests, it was confirmed that all compounds produced levodopa. Based on these results, efficient levodopa production in vivo is expected, and it is considered to be particularly useful as a therapeutic drug for parkinson's disease.
Experimental example 2-1: evaluation of solution stability
A phosphate buffer solution of pH 7.4 was added to each of the compounds to dissolve each of the compounds, and NaOH solution was added to adjust the pH of the mixture, as necessary, to prepare a solution of about 1 mg/mL. After storing the solution at 25 ℃ for about 1 day, HPLC purity (area percent,%) was measured. The HPLC purity of the solution immediately after preparation or the HPLC purity of the compound was subtracted from the HPLC purity after storage at 25 ℃ for about 1 day to obtain a HPLC purity difference. Table 9 shows the solution stability of the compounds of some of the examples of the invention. In tables 9-1 and 9-2, "LDP-Ala" represents L-tyrosine N-L-alanyl-3-hydroxy- (9 CI) and has the following structural formula:
TABLE 9-1
Experimental example 2-2: evaluation of solution stability
A phosphate buffer solution of pH 7.4 was added to each of the compounds to dissolve each of the compounds, and NaOH solution was added to adjust the pH of the mixture, as necessary, to prepare a solution of about 1 mg/mL. After storing the solution at 60 ℃ for about 1 day, HPLC purity (area percent,%) was measured. The HPLC purity of the solution immediately after preparation or the HPLC purity of the compound was subtracted from the HPLC purity after storage at 60 ℃ for about 1 day to obtain a HPLC purity difference. Table 9-2 shows the solution stability of the compounds of some of the examples of the present invention.
TABLE 9-2
As shown in the results of the above tests, it was confirmed that the compounds of the present invention were stable in a near neutral aqueous solution, and wherein the compounds of example 1 and example 8 were stable.
Based on the above results, the compounds of the present invention are expected to have high solution stability at pH 6 to 8 and are considered to be useful as solution formulations.
Experimental example 3: evaluation of solubility
Water was added to each of the compounds to prepare a suspension, the suspension was shaken at 25 ℃ for 24 hours, and then filtration through a filter was performed to obtain a filtrate. The concentration of the compound in the filtrate was quantified using HPLC to obtain solubility. In addition, the pH of the filtrate was measured. Table 10-1 shows the solubility of the compounds of some of the examples of the present invention.
TABLE 10-1
Examples Solubility (mg/mL) pH of the filtrate
1 15.6 2.6
2 ＞31.1 2.6
As shown in the results of the above tests, it was confirmed that all compounds showed good solubility at pH around the isoelectric point.
Based on the above results, the compounds are expected to have high solubility at pH 6-8 and are considered to be particularly useful as solution formulations.
(preparation method of the preparation)
Process for preparing LDP-Ala/CD preparation
The NaOH solution was added to LDP-Ala and stirred at room temperature to dissolve LDP-Ala. Carbidopa and antioxidants (N-acetylcysteine and ascorbic acid) are added to the mixture and dissolved while the pH is adjusted by adding NaOH solution as needed. Then, polysorbate 80 and NaOH solution were added to prepare formulation compositions in table 10-2, and the volume was adjusted with ultrapure water as appropriate. The above solution was filtered through a 0.22 μm filter and filled into vials while replacing the headspace with nitrogen.
TABLE 10-2
Component (%) LDP-Ala/CD formulations
LDP-AIa 40
Carbidopa 1.3
N-acetylcysteine 2.0
Ascorbic acid 2.0
NaOH q.s.
Polysorbate 80 0.3
pH 9.0
Preparation method of LDP-Lys/CD preparation
KOH solution and meglumine were added to LDP-Lys and stirred at room temperature to dissolve LDP-Lys. Carbidopa and antioxidants (N-acetylcysteine and ascorbic acid) are added to the mixture and dissolved while the pH is adjusted by adding KOH solution as needed. Then, polysorbate 80 and KOH solution were added to prepare the formulation compositions in table 10-3, and the volume was adjusted with ultrapure water as appropriate. The above solution was filtered through a 0.22 μm filter and filled into vials while replacing the headspace with nitrogen.
TABLE 10-3
Component (%) LDP-Lys/CD formulations
LDP-Lys 33
Carbidopa 1.3
N-acetylcysteine 2.0
Ascorbic acid 2.0
KOH q.s.
Meglumine (meglumine) q.s.
Polysorbate 80 0.3
pH 9.0
(results of stability evaluation of LDP-Ala and LDP-Lys formulations)
The formulations prepared as shown in tables 10-2 and 10-3 were kept refrigerated (2 ℃ C. -8 ℃ C.) for 2 weeks. Thereafter, the appearance of each of the formulations was visually inspected, and the presence of the precipitate was evaluated. HPLC was also used to determine the quantification and purity of LDP-Ala and LDP-Lys.
In both formulations shown in tables 10-2 and 10-3, no precipitation was observed after 2 weeks of cold storage, and no significant change in quantitative value was observed, indicating that the formulation was considered stable up to 2 weeks of cold storage. The results of evaluation of the stability of the formulations shown in tables 10-2 and 10-3 are shown in tables 10-4 and 10-5, respectively.
TABLE 10-4
Appearance of Initial initiation 5℃2W
LDP-Ala/CD formulations No precipitate No precipitate
LDP-Lys/CD formulations No precipitate No precipitate
TABLE 10-5
Quantitative value (purity%) Initial initiation 5℃2W
LDP-Ala/CD formulations 416.3(91.8％) 418.3(91.8％)
LDP-Lys/CD formulations 334.2(90.8％) 327.3(91.4％)
Part II: LD-Tyr formulations
Experimental examples 4-30% LD-tyrosine/0.75% carbidopa long-term stability at 2-8℃
A formulation containing 300mg/mL (30%) LD-tyrosine (LD-Tyr) and 7.5mg/mL (0.75%) carbidopa was prepared with 5.5% L-arginine and 11.5% Tris. The formulation also contained 0.5% ascorbic acid (Asc), 0.5% n-acetylcysteine (NAC) and 0.3% tween 80. The formulations were stored at 2 ℃ -8 ℃ for the indicated time and tested for% recovery and% LD-Tyr-DKP formation (impurities). The results are shown in table 11. The percent recovery is always high over time. DKP impurities accumulate over time.
TABLE 11 stability of LD-Tyr and carbidopa
Experimental example 5 solubility in Co-solvent
As indicated in Table 12, the solubility of LD-tyrosine (LD-Tyr) in a variety of co-solvents was tested. The formulations were stored at 2-8 ℃ or 25 ℃ for the indicated time and tested for stability (as measured by the presence of precipitate) and% DKP formation (impurities). As shown in table 12, the propylene glycol containing formulations were stable at 2 ℃ -8 ℃ for at least up to 1 month and at 25 ℃ for at least up to 2 weeks and showed less DKP accumulation than the formulation comprising 5.5% l-arginine and 11.5% tris shown in example 1. Formulations containing PEG 300 were unstable at 2-8 ℃ and showed more DKP accumulation than other formulations tested. Formulations comprising 5%, 10% and 15% DMA were also prepared. For all concentrations, significant levels of DKP were detected at t=0.
TABLE 12 Co-solvent
Experimental example 6-effect of various additives on stability of 30% ld-tyrosine-L-arginine based formulation
Formulations were prepared with 300mg/mL LD-Tyr, 5mg/mL (0.5%) NAC, 5mg/mL (0.5%) ascorbic acid, 18.1% L-Arg and the additives shown in Table 13. PVP K17 represents polyvinylpyrrolidone low molecular weight (PVP K17). All formulations were physically stable at 2 ℃ to 8 ℃ and 25 ℃ for at least two weeks. As shown in table 13, none of the tested additives showed the ability to inhibit or prevent DKP formation.
TABLE 13 additives
/>
Experimental example 7-solubility and physical stability in alkali (organic and inorganic)
In this example, LD-tyrosine was added in portions to a 0.8M solution of counterions and antioxidants while stirring. The L-arginine formulation was heated while stirring, while the other formulations were not heated. The pH was not adjusted. Solubility was confirmed after filtration by HPLC. Physical stability was measured after storage for 2 weeks and 1 month at 2-8 ℃ or 25 ℃. As shown in table 14, dissolution of LD-tyrosine in ethanolamine, diethylamine, and ammonium hydroxide resulted in physical stability (no sign of precipitation) at 2 ℃ -8 ℃ and 25 ℃ for at least one month. Solubility and stability depend on the particular base used and not only on pH.
TABLE 14 solubility and physical stability according to alkali modification
/>
In addition to stability, impurity (DKP) formation was measured in each formulation. As shown in table 15, DKP formation was minimal in the formulation using sodium hydroxide at 25 ℃. DKP formation in diethylamine, ethanolamine and ammonium hydroxide, respectively, was slightly higher.
TABLE 15 DKP formation according to alkali modification
Formulations were prepared with 300mg/mL LD-Tyr, 5mg/mL (0.5%) NAC, and 5mg/mL (0.5%) ascorbic acid, 17.2% meglumine or 18.1% L-Arg. All formulations were physically stable at 2 ℃ to 8 ℃ and 25 ℃ for at least two weeks. As shown in table 16, lower levels of DKP were observed when L-Arg was used relative to meglumine.
TABLE 16 meglumine
Experimental example 8-influence of various amines and inorganic bases on stability of 30% ld-tyrosine
In this example, 300mg/mL (30%) LD-tyrosine formulation was prepared with the ingredients indicated in Table 17, as well as the antioxidants ascorbic acid (0.5%) and N-acetylcysteine (NAC) (0.5%). No heating was used to prepare these formulations.
TABLE 17 effects of ethylenediamine, ethanolamine, diethanolamine, and diethylamine on DKP
As shown in table 17 and figures 1 and 2, the formulations comprising diethylamine and L-Arg resulted in the lowest DKP level formation, followed by diethanolamine and L-Arg and ethanolamine and L-Arg. Among the amines tested, the highest amount of DKP was observed in the formulation containing ethylenediamine and L-Arg, as well as ethylenediamine alone (without L-Arg). Relative DKP level formation was similar at 2 ℃ -8 ℃ and 25 ℃.
Formulations were prepared with a combination of 300mg/mL LD-Tyr, 5mg/mL (0.5%) NAC, and 5mg/mL (0.5%) ascorbic acid, and the bases indicated in Table 18. All formulations were physically stable at 2 ℃ to 8 ℃ for at least 70 days.
TABLE 18-Tris (tromethamine)
Formulations were prepared with 300mg/mL LD-Tyr, 5mg/mL (0.5%) NAC, 5mg/mL (0.5%) ascorbic acid, 7.2% L-Arg, and sodium hydroxide or ammonium hydroxide as indicated in Table 19. As shown in table 19, the formulations comprising sodium hydroxide exhibited physical instability.
TABLE 19 sodium hydroxide and ammonium hydroxide
Experimental example 9 Effect of ethanolamine on stability of 30% LD-tyrosine
In this example, 300mg/mL (30%) LD-tyrosine formulations were prepared with different concentrations of L-arginine and ethanolamine, alone and in combination, as shown in Table 20, along with the antioxidants ascorbic acid (0.5%) and N-acetylcysteine (NAC) (0.5%). During the preparation, only the preparation containing 18.1% L-Arg was heated.
TABLE 20 Ethanolamine
The formulations were then tested for DKP accumulation and physical stability over the course of 2 weeks at 2 ℃ -8 ℃ and 25 ℃. As shown in table 21, the formulations containing L-Arg alone had the lowest level of DKP accumulation, and the amount of DKP accumulation generally increased with increasing ratio of ethanolamine to L-Arg. No signs of precipitation were observed in any of the formulations tested. During the preparation, only the preparation containing 18.1% L-Arg was heated.
TABLE 21 DKP formation in ethanolamine
Table 22 presents additional 300mg/mL (30%) LD-tyrosine formulations prepared with L-arginine and ethanolamine or diethylamine, and the antioxidants ascorbic acid (0.5%) and N-acetylcysteine (NAC) (0.5%).
Table 22
Experimental example 10 blood/plasma ratio
The blood/plasma ratios (R) of LD-Tyr at concentrations of 50ng/mL, 150ng/mL and 2500ng/mL were studied ex vivo in rat, minipig and human blood B ) To understand the partition in Red Blood Cells (RBCs). In the blood of rats and small pigs, the partition coefficient between RBCs and plasma (K RBC/PL ) A value below 5 indicates limited RBC binding. In the blood of rats, K RBC/PL As incubation time increases (see fig. 3). K for the two highest concentrations (150 ng/mL and 2500 ng/mL) in the blood of small pigs RBC/PL Increasing with increasing incubation time, whereas K was reached at 1 for 15 and 30 minutes for the lowest concentration (50 ng/mL) RBC/PL Down to 0.0 (see fig. 4). In human blood, all measured K RBC/PL Are below 1 indicating no RBC binding (see fig. 5).
Experimental example 11 safety study of rats and piglets
In vivo non-clinical safety studies were performed in both rats and small pigs. In addition, as part of the PK study in pigs, an assessment of local infusion site response of LD-Tyr was performed. A summary of in vivo non-clinical safety results obtained in various non-clinical studies of LD-Tyr is presented in table 23.
TABLE 23 summary of in vivo non-clinical safety results
/>
Experimental example 12-effect of various additives on stability of 20% ld-tyrosine-L-arginine based formulations
Formulations were prepared with 200mg/mL LD-Tyr, 5mg/mL (0.5%) NAC, 5mg/mL (0.5%) ascorbic acid, 15.5% L-Arg and additives as shown in Table 24. As shown in table 24, the tested additives were able to limit DKP formation at 2 ℃ -8 ℃; however, the amount of DKP at room temperature is still large. It is also noted that MgCl is included 2 The formulation of (2) exhibits a relatively high viscosity. The solubility of LD-Tyr is DMA > ethanol > PEG 300, and the viscosity of the formulation is ethanol < DMA < PEG 300.
Table 24
Component (mg/mL) F1 F2 F3 F4 F5
LD-Tyr 200 200 200 200 200
Arg 155 155 155 155 155
NAC 5 5 5 5 5
Ascorbic acid 5 5 5 5 5
Hydroxypropyl beta cyclodextrin (HPBCD) 200
Sulfobutyl ether beta cyclodextrin (SBECD) 200
Lysine 200
Ethanol 155.5
PEG 300 226
MgCl 2 100
pH 8.77 8.98 9.76 8.84 7.88
DKP increases by 1M2-8 ℃ (area percent) 0.15 0.15 0.16 0.21 0.12
DKP increased by 1M25 ℃ (% area) 2.93 3 2.33 2.7 1.5
Experimental example 13 Effect of ethanol and/or PEG 300 on formulation Properties
The stability and saturation of the formulations in table 25 were evaluated. F1 proved to be stable at 5℃for 1 week even when the amount of LD-Tyr was increased to 400 mg/ml. On the other hand, F2-F4 did not remain stable when the amount of LD-Tyr was increased to 400 mg/ml. To maintain physical stability, L-arginine was added to formulations F2-F4, and the pH was adjusted to the original level. After doing so, F2-F4 was able to remain stable at 5℃for 1 week, even when the amount of LD-Tyr was increased to 400 mg/ml.
Table 25
Component (mg/mL) Action F1 F2 F3 F4
Levodopa-Tyr API 300 300 300 300
Carbidopa API 13 13 13 13
L-arginine pH adjustment/counter ion 240 200 200 200
Ethanol Co-solvent 155.5 116.6 0 116.6
PEG 300 Co-solvent 0 0 100 50
N-acetylcysteine Antioxidant agent 10 10 10 10
WFI Solvent(s) QS QS QS QS
pH 9.0 8.7 8.7 8.7
Visual inspection after one month also confirmed the physical stability of the formulations in table 25 (the formulations remained clear and no apparent precipitation). Stability was also tested by HPLC and the results showed 100% recovery after 5 days. Furthermore, one month stability HPLC tests on formulations maintained at 2-8 ℃ or 25 ℃ for one month showed that stability was maintained under both conditions. The main difference between the formulations is the amount of DKP formed over time, wherein the formation of DKP is inhibited at 2-8 ℃ and not at 25 ℃. In this regard, it is noted that the amount of DKP formed in F1 is lower than the amount of DKP formed in any of F2-F4.
Experimental example 14-LD-Tyr pharmacokinetics in domestic pigs
A series of PK studies were completed in pigs using several LD-Tyr formulations as detailed in table 26 and dosing regimens as detailed in table 27. After 18 hours of continuous SC infusion into female pigs, the LD-Tyr and thus the PK profile of LD was determined. Using a connection to an infusion device (Accu-FlexLink, roche) Crono-ND infusion pump (canre SpA Medical Technology, riveli, italy) each formulation was administered at one infusion site per animal.
Blood samples for determining LD-Tyr and LD plasma levels were collected from pigs at the following time points:
0 (pre-dose), 30min after starting infusion, 1h, 2h, 6h, 8h, 9h, 10h, 12h, 14h, 18h, 18.5h, 19h, 21h, 23h and 26h.
Table 26
A summary of PK parameters and dosing regimens for each study are detailed in table 27.
TABLE 27 summary of dosing regimen and PK profile of LD-Tyr and LD following continuous subcutaneous infusion in pigs
/>
The LD-Tyr and the resulting integrated average concentration of LD from the study described in detail above are depicted in FIGS. 6 and 7, respectively.
Experimental example 15-pharmacokinetic and local site reaction Studies of high concentration LD-Tyr formulation containing TRIS in pigs
Experimental example 15A-1% CD
A series of PK and local toxicity studies were completed in pigs using several high concentration LD-Tyr formulations comprising 1% cd and varying amounts of TRIS as detailed in table 28, and dosing regimens as detailed in table 29. After 18 hours of continuous SC infusion into female pigs, the LD-Tyr and thus the PK profile of LD was determined. Using a connection to an infusion device (Accu-FlexLink, roche) Crono-ND infusion pump (canre SpA Medical Technology, riveli, italy) each formulation was administered at one infusion site per animal.
Blood samples for determining LD-Tyr and LD plasma levels were collected from pigs at the following time points:
0 (pre-dose), 30min after starting infusion, 1h, 2h, 6h, 8h, 9h, 10h, 12h, 14h, 18h, 18.5h, 19h, 21h, 23h and 26h.
Table 28
/>
Table 29
PK results
A summary of the PK parameters obtained is provided in table 30.
Table 30
The integrated mean concentrations of LD resulting from the study described in detail above are depicted in fig. 8.
Based on the results of this study and under the conditions of this study, it can be concluded that no significant difference in systemic exposure to LD was observed after infusion of 9mL LD-Tyr 30%, 7.5mL LD-Tyr 37% or 6mL LD-Tyr 44%.
Local site reaction
Immediately after pump removal, any local reaction at the infusion site was checked. Any skin reactions (e.g., erythema, edema/swelling) were recorded and scored according to the 5-point Draize scale for scoring skin irritation as provided in table 31.
Table 31
The results show that none of the test formulations induced significant local skin reactions. As shown in table 32, very slight to well-defined erythema and edema (grade 1-2) were observed immediately after pump removal.
Table 32
Experimental example 15B-0.5% CD
A series of PK and local toxicity studies were completed in pigs using several high concentration LD-Tyr formulations comprising 0.5% cd and varying amounts of TRIS as detailed in table 33 and dosing regimens as detailed in table 34. After 18 hours of continuous SC infusion into female pigs, the LD-Tyr and thus the PK profile of LD was determined. Using a connection to an infusion device (Accu-FlexLink, roche) Crono-ND infusion pump (canre SpA Medical Technology, riveli, italy) each formulation was administered at one infusion site per animal.
Blood samples for determining LD-Tyr and LD plasma levels were collected from pigs at the following time points:
0 (pre-dose), 30min after starting infusion, 1h, 2h, 6h, 8h, 9h, 10h, 12h, 14h, 18h, 18.5h, 19h, 21h, 23h and 26h.
Table 33
Test item (w/v%) LD-Tyr 30％ LD-Tyr 37％ LD-Tyr 44％
LD-tyrosine 30 37 44
Carbidopa 0.50 0.50 0.50
Polysorbate 80 0.30 0.30 0.30
Ascorbic acid 0.50 0.50 0.50
N-acetylcysteine (NAC) 0.50 0.50 0.50
L-arginine 5.50 6.50 8.00
Tromethamine (TRIS) 11.50 13.00 15.00
WFI 69.25 61.50 53.00
Final pH 8.25 8.13 8.17
Watch 34
PK results
A summary of the PK parameters obtained is provided in table 35.
Table 35
The integrated mean concentrations of LD resulting from the study described in detail above are depicted in fig. 9.
Based on the results of this study and under the conditions of this study, it can be concluded that no significant difference in systemic exposure to LD was observed after infusion of 9mL LD-Tyr 30%, 7.5mL LD-Tyr 37% or 6mL LD-Tyr 44%.
Local site reaction
Immediately after pump removal, any local reaction at the infusion site was checked. Any skin reactions (e.g., erythema, edema/swelling) were recorded and scored according to the 5-point Draize scale for scoring skin irritation as provided in table 31.
No significant local skin reactions were observed at most of the treated sites. As shown in table 36, the reaction observed immediately after pump removal was very slight to moderate (grade 1-3) erythema and edema.
Table 36
Experimental example 16-pharmacokinetic and local site-response Studies in domestic pigs administered formulations with different concentrations of LD-Tyr and CD
Using the details as in table 37Several concentrations of LD-Tyr formulations containing varying amounts of CD are described, along with dosing regimens as detailed in table 38, a series of PK and local site response studies were completed in pigs. After 18 hours of continuous SC infusion into female pigs, the LD-Tyr and thus the PK profile of LD was determined. Using a connection to an infusion device (Accu-FlexLink, roche) Crono-ND infusion pump (canre SpA Medical Technology, riveli, italy) each formulation was administered at one infusion site per animal.
Blood samples for determining LD-Tyr and LD plasma levels were collected from pigs at the following time points:
0 (pre-dose), 30min after starting infusion, 1h, 2h, 6h, 8h, 9h, 10h, 12h, 14h, 18h, 18.5h, 19h, 21h, 23h and 26h.
Table 37
Test item (w/v%) LD-Tyr 30％ LD-Tyr 30％ LD-Tyr 44％
LD-tyrosine alkali 30 30 44
Carbidopa 0.50 1.50 1.0
Polysorbate 80 0.30 0.30 0.30
Ascorbic acid 0.50 0.50 0.50
N-acetylcysteine (NAC) 0.50 0.50 0.50
L-arginine 18.10 18.10 25.70
WFI 65.33 65.14 53.51
Final pH 8.4 8.42 8.35
Table 38
PK results
A summary of the PK parameters obtained is provided in table 39.
Table 39
The integrated mean concentrations of LD resulting from the study described in detail above are depicted in fig. 10.
Local site reaction
Immediately after pump removal, any local reaction at the infusion site was checked. Any skin reactions (e.g., erythema, edema/swelling) were recorded and scored according to the 5-point Draize scale for scoring skin irritation as provided in table 31.
No significant local skin reactions were observed at all treated sites. As shown in table 40, the reaction observed immediately after pump removal was very mild to well-defined erythema (grade 1-2).
Table 40
Experimental example 17-CD titration
The effect of CD dose on LD systemic exposure was assessed by comparing plasma concentrations of LD after continuous SC infusion of LD-Tyr 30% and combinations of different concentrations of CD (0.5% -1.5%). These data were obtained from various preclinical studies (see table 41) and normalized to animal body weight. The integrated mean normalized plasma concentrations for LD are shown in figure 11.
TABLE 41 LD-Tyr/CD dose for evaluation of CD titration
It should be noted that the results show that the LD plasma concentrations after infusion of LD-Tyr 30% with various CD concentrations are similar to each other, independent of CD dose.
Experimental example 18-PK and local site response studies after bolus and subcutaneous administration of 30% ld-Tyr formulation
A series of PK and local toxicity studies were completed in pigs using several concentrations of LD-Tyr formulations containing varying amounts of CD as detailed in table 42, and dosing regimens as detailed in table 43. After 18 hours of continuous SC infusion into female pigs, the LD-Tyr and thus the PK profile of LD was determined. Using a connection to an infusion device (Accu-FlexLink, roche) Crono-ND infusion pump (canre SpA Medical Technology, riveli, italy) each formulation was administered at one infusion site per animal.
Blood samples for determining LD-Tyr and LD plasma levels were collected from pigs at the following time points:
0 (before administration), 10min after starting bolus administration (end of bolus), 15min, 30min, 45min, 60min, 75min, 90min, 120min and 240min.
Table 42
Table 43
PK results
The LD-Tyr of the pigs and the resulting overall average PK parameters of the LD are shown in table 44. The combined mean plasma concentrations of LD-Tyr and the resulting LD are depicted in FIG. 12.
TABLE 44 comprehensive PK parameters after bolus infusion and 2 hour continuous SC administration of LD-Tyr for pigs
Based on the results of this study and under the conditions of this study, it can be concluded that increasing bolus injection volume from 0.7mL to 1.2mL, and then to 1.7mL, followed by 2 hours continuous infusion at the same LD-Tyr/CD concentration (30%/1%) resulted in a proportional increase in dose of systemic exposure to LD.
The results also show that bolus injection of LD-Tyr prior to continuous SC infusion can reduce LD tmax as compared to continuous SC infusion of LD-Tyr without bolus injection.
Local infusion site reaction
Immediately after pump removal, any local reaction at the infusion site was checked. Any skin reactions (e.g., erythema, edema/swelling) were recorded and scored according to the 5-point Draize scale for scoring skin irritation as provided in table 31.
No significant local skin reactions were observed at all treated sites. As shown in table 45, the reaction observed immediately after pump removal was very slight to well-defined edema (grade 1-2).
Table 45
Experimental example 19-local tolerability and pathological Studies of multiple formulations after 24h SC administration in pigs
The local tolerability and pathology of the injection site after SC administration for 24 hours in pigs were tested according to the formulations and vehicles detailed in dosing regimen table 46 as detailed in table 47.
Watch 46
Table 47
Results
Based on histopathological results, it was concluded that ethanolamine, diethanolamine and diethylamine based formulations (F2-F5 and V2-V5) were intolerant after 24 hour SC infusion in a volume of 9 mL. In contrast, F1/V1 formulations that are not amine-based are tolerated.
Experimental example 20-local tolerability and pathological Studies of additional formulations after 24h SC administration in pigs
The local tolerability and pathology of the injection site after SC administration for 24 hours in pigs were tested according to the formulations and vehicles detailed in dosing regimen table 48 as detailed in table 49.
Table 48
Table 49
Results
Based on histopathological results, it can be concluded that all formulations tested were well tolerated after 24 hours SC infusion at a volume of 9 mL. In view of additional chemical experiments (stability etc.), the decision was focused on formulation F1 and formulation F4, wherein it was noted that F4 exhibited better local tolerability than F1.
Experimental example 21-local tolerability study of formulations comprising PEG 300 and/or ethanol after 24h SC administration in pigs
The local tolerability and pathology of the injection site after SC administration for 24h in pigs were tested according to the formulations and vehicles detailed in dosing regimen table 50 as detailed in table 51.
Table 50
Table 51
Results
Immediately after pump removal, any local reaction at the infusion site was checked. Any skin reactions (e.g., erythema, edema/swelling) were recorded and scored according to the 5-point Draize scale for scoring skin irritation as provided in table 31.
No significant local skin reactions were observed at all treated sites. As shown in table 52, the reaction observed immediately after pump removal was very slight to moderate (grade 1-3) erythema or edema.
Table 52-incidence of local reactions at infusion sites immediately after pump removal
Furthermore, based on histopathological results and under the conditions of the present study, it can be concluded that all three formulations (F1-F3) were well tolerated after 24 hour SC infusion at a volume of 9 mL.
Experimental example 22-SC Pharmacokinetic (PK) of L-dopa (LD) after LD-Tyr administration in ethanol-containing formulations
The purpose of this study was to determine the Pharmacokinetics (PK) of LD-Tyr after 18 hours of continuous Subcutaneous (SC) administration of a formulation comprising 30% LD-Tyr and ethanol in domestic pigs. Table 53 provides LD-Tyr formulations tested in this study.
Table 53
Formulation composition Nominal concentration (mg/ml)
LD-tyrosine 300.00
Carbidopa 13.00
L-arginine 240.00
EtOH 155.50
NAC 10.00
WFI q.s
2700mg or 5400mg of LD-Tyr in the formulation of Table 53 was administered to animals in 18 hours continuous subcutaneous administration at infusion volumes of 9mL or 18mL (9 mL. Times.2 sites).
FIG. 13 shows a summary of the combined mean plasma LD-Tyr and LD concentrations versus time for a 2700mg dosing regimen. PK parameters are also shown.
FIG. 14 shows a summary of the integrated mean plasma LD-Tyr and LD concentrations versus time for a 5400mg dosing regimen. PK parameters are also shown.
Figure 15 shows a summary of integrated mean plasma LD concentrations versus time for 2700mg and 5400mg dosing regimens.
Table 54 provides a summary of PK results. The results presented in FIG. 15 and Table 54 show the dosage ratio of LD-Tyr.
Watch 54
/>
Experimental example 23
To optimize the antioxidants in the LD-Tyr formulation, the following formulations were prepared and analyzed and evaluated.
TABLE 55 preliminary preparation
TABLE 56 analysis results
/>
The results presented in table 56 show that none of the antioxidants alone prevented impurities, and that their combination prevented impurities. Thus, the final amount of each of ascorbic acid and NAC will be between about 0.1% and about 1%.
The following additional formulations described in detail in table 57 were also prepared and their analytical values at time 0 were measured using two analytical methods as described in detail in tables 58a and 58 b.
Table 57
Table 58a
Table 58b
Once the amount of ascorbic acid is optimized, the amount of NAC will also be optimized. Contemplated formulations for optimizing the amount of NAC are provided in table 59 below:
component (mg/ml) F1 F2 F3 F4 F5
LD-tyrosine 300 300 300 300 300
Carbidopa 13 13 13 13 13
NAC 0 2.5 5 7.5 10
Ascorbic acid 0-10* 0-10* 0-10* 0-10* 0-10*
L-arginine 240 240 240 240 240
Ethanol 155.5 155.5 155.5 155.5 155.5
* To be set according to the optimization of the amount of ascorbic acid
Equivalent(s)
Although certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those skilled in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention. All numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification are to be understood as being modified in all instances by the term "about", even though the term "about" is not specifically recited for any disclosed embodiment.
Incorporated by reference
The entire contents of all patents, published patent applications, websites, and other references mentioned herein are hereby expressly incorporated by reference in their entirety.

Claims (51)

1. A levodopa amino acid complex represented by the following formula (I) or formula (III):
[ chemical formula 1]
Wherein R is an amino acid side chain that can be substituted;
R 1 and R is 2 C which can be identical or different and are each independently a hydrogen atom and can be substituted 1 -C 6 Alkyl, C 1 -C 6 Alkanoyl, phosphono, sulfinyl or glycosyl, provided that R 1 And R is 2 Not both hydrogen atoms;
R 3 and R is 4 Can be the same or differentAnd are each independently a hydrogen atom or C 1 -C 6 An alkyl group; and is also provided with
R 5 Is a hydrogen atom; or (b)
[ chemical formula 3]
Wherein R is 11 And R is 12 Identical or different and are each hydrogen, alkyl which can be substituted, alkanoyl, P (=o) (OH) 2 S (=o) (OH) or glycosyl;
R 13 is alkyl which can be substituted, -R 15 -O-R 16 Or a 5-membered heterocyclic group containing at least one nitrogen atom, wherein R 15 Is alkylene, and R 16 Is hydrogen, alkyl which can be substituted, P (=O) (OH) 2 S (=o) (OH) or glycosyl; and is also provided with
R 14 Is hydrogen or alkyl;
provided that the following compounds are excluded;
(2S) -2- [ (2-Aminoacetyl) amino ] -3- (3, 4-diacetoxyphenyl) propionic acid,
(2S) -2- [ [ (2S) -2-amino-6- [ (2-chlorophenyl) methoxycarbonylamino ] hexanoyl ] amino ] -3- (3, 4-dimethoxyphenyl) propanoic acid,
(2S) -2- [ [ (2S) -2-amino-3- (3, 4-dihydroxyphenyl) propionyl ] amino ] -3- (4-hydroxy-3-methoxyphenyl) propanoic acid,
(2S) -2- [ [ (2S) -2-amino-3-phenylpropionyl ] amino ] -3- (3, 4-dimethoxyphenyl) propionic acid,
(2S) -2- [ [ (2R) -2-amino-3-phenylpropionyl ] amino ] -3- (3, 4-diacetoxyphenyl) propanoic acid, and
(2S) -2- [ [ (2S) -2-amino-5-methoxy-5-oxopentanoyl ] amino ] -3- (3, 4-dimethoxyphenyl) propanoic acid.
2. The levodopa amino acid complex or pharmaceutically acceptable salt thereof according to claim 1, wherein
R 3 、R 4 And R is 5 Is a hydrogen atom, and
R 1 and R is 2 Identical or different and are each a hydrogen atom, an acetyl group or a phosphono group, provided that R 1 And R is 2 Not both hydrogen atoms.
3. The levodopa amino acid complex or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein
R 3 、R 4 And R is 5 Is a hydrogen atom and is preferably a hydrogen atom,
R 1 is a hydrogen atom, and
R 2 is a phosphono group.
4. A levodopa amino acid complex according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein
The amino acid of the amino acid side chain is glutamic acid, valine, alanine, lysine, 3, 4-dihydroxyphenylalanine or tyrosine.
5. A levodopa amino acid complex selected from the group consisting of:
(2S) -2- [ [ (2S) -2-amino-3-phosphonooxypropionyl ] amino ] -3- (3, 4-dihydroxyphenyl) propanoic acid,
(2S) -2- [ [ (2S) -2-amino-3- (4-phosphonooxyphenyl) propionyl ] amino ] -3- (3, 4-dihydroxyphenyl) propanoic acid,
(2S) -2-amino-5- [ [ (1S) -1-carboxy-2- (3, 4-diacetoxyphenyl) ethyl ] amino ] -5-oxo-pentanoic acid,
(2S) -3- (3, 4-dihydroxyphenyl) -2- [ (2-methyl-2-phosphonooxypropionyl) amino ] propanoic acid,
And
(2S) -2- [ [ (2S) -2-amino-3- [4- [ (2S, 3R,4S,5S, 6R) -3,4, 5-trihydroxy-6- (hydroxymethyl) oxacyclohex-2-yl ] oxyphenyl ] propionyl ] amino ] -3- (3, 4-dihydroxyphenyl) propanoic acid.
6. A liquid pharmaceutical composition comprising the levodopa amino acid complex according to any one of claims 1-5 or a pharmaceutically acceptable salt thereof as an active ingredient.
7. A therapeutic agent for neurodegenerative diseases and/or diseases or symptoms caused by a decrease in the concentration of dopamine in the brain, which comprises the levodopa amino acid complex according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient.
8. The therapeutic agent according to claim 7, wherein
The neurodegenerative disease and/or the disease or condition caused by a decrease in the concentration of dopamine in the brain is parkinson's disease.
9. A liquid pharmaceutical composition comprising:
levodopa-tyrosine conjugate (LD-Tyr) of formula (II):
enantiomers, diastereomers, racemates, ions, zwitterionic, pharmaceutically acceptable salts thereof, or any combination thereof; and
a stabilizer.
10. The liquid pharmaceutical composition of claim 9, comprising between about 10% w/v to about 45% w/v LD-Tyr, an enantiomer, diastereomer, racemate, ion, zwitterionic, pharmaceutically acceptable salt thereof, or any combination thereof.
11. The liquid pharmaceutical composition of claim 9, comprising at least about 30% w/v LD-Tyr, an enantiomer, diastereomer, racemate, ion, zwitterionic, pharmaceutically acceptable salt thereof, or any combination thereof.
12. The liquid pharmaceutical composition of claim 10 or claim 11, comprising between about 30% w/v and about 45% w/v LD-Tyr, an enantiomer, diastereomer, racemate, ion, zwitterionic, pharmaceutically acceptable salt thereof, or any combination thereof.
13. The liquid pharmaceutical composition of any one of claims 9-12, wherein the stabilizer is present in an amount of about 0.1% w/v to about 30% w/v.
14. The liquid pharmaceutical composition of any one of claims 9-13, wherein the stabilizer comprises a base.
15. The liquid pharmaceutical composition of claim 14, wherein the base is selected from the group consisting of: arginine, naOH, NH 4 OH, TRIS (hydroxymethyl) aminomethane (TRIS), ethylenediamine, diethylamine, ethanolamine, diethanolamine, meglumine, and any combination thereof.
16. The liquid pharmaceutical composition of claim 15, wherein the base is selected from the group consisting of: arginine, NH 4 OH, ethylenediamine, diethylamine, ethanolamine, diethanolamine, meglumine, and any combination thereof.
17. The liquid pharmaceutical composition of claim 16, wherein the base is selected from the group consisting of: L-Arg, diethylamine and combinations thereof.
18. The liquid pharmaceutical composition of claim 17, wherein the base is selected from the group consisting of: L-Arg, ethanolamine and combinations thereof.
19. The liquid pharmaceutical composition of any one of claims 14-18, wherein the liquid pharmaceutical composition comprises between about 0.1% w/v to about 30% w/v base.
20. The liquid pharmaceutical composition of claim 19, wherein the liquid pharmaceutical composition comprises between about 1.5% w/v to about 20% w/v base.
21. The liquid pharmaceutical composition of any one of claims 9-20, wherein the liquid pharmaceutical composition has a pH in the range of between about 5 to about 10 at about 25 ℃.
22. The liquid pharmaceutical composition of claim 21, wherein the liquid pharmaceutical composition has a pH in the range of between about 8 to about 10 at about 25 ℃.
23. The liquid pharmaceutical composition of claim 22, wherein the liquid pharmaceutical composition has a pH in the range of between about 8 to about 9 at about 25 ℃.
24. The liquid pharmaceutical composition of any one of claims 9-23, further comprising a decarboxylase inhibitor.
25. The liquid pharmaceutical composition of claim 24, wherein the decarboxylase inhibitor is carbidopa.
26. The liquid pharmaceutical composition of any one of claims 24 or 25, wherein the liquid pharmaceutical composition comprises between about 0.25% w/v to about 1.5% w/v of the decarboxylase inhibitor.
27. The liquid pharmaceutical composition of any one of claims 9-26, further comprising an antioxidant or a combination of two or more antioxidants.
28. The liquid pharmaceutical composition of claim 27, wherein the antioxidants are each independently selected from the group consisting of: ascorbic acid or a salt thereof, cysteine, acid sulfite or a salt thereof, glutathioneTyrosinase inhibitor, cu 2+ Chelating agents, and any combination thereof.
29. The liquid pharmaceutical composition of claim 28, wherein the cysteine is N-acetylcysteine (NAC).
30. The liquid pharmaceutical composition of any one of claims 27-29, wherein the antioxidant is a combination of ascorbic acid and NAC.
31. The liquid pharmaceutical composition of any one of claims 27-30, wherein the liquid pharmaceutical composition comprises between about 0.05% w/v to about 1.5% w/v of the antioxidant or combination of antioxidants.
32. The liquid pharmaceutical composition of any one of claims 1-31, further comprising at least one of: catechol-O-methyltransferase (COMT) inhibitors, monoamine oxidase (MAO) inhibitors, surfactants, buffers, acids, solvents, and any combination thereof.
33. The liquid pharmaceutical composition of claim 32, wherein the buffer is TRIS.
34. The liquid pharmaceutical composition of any one of claims 32-33, wherein the liquid pharmaceutical composition comprises between about 5.0% w/v to about 40.0% w/v of the buffer.
35. The liquid pharmaceutical composition of any one of claims 1-34, wherein the stabilizer comprises polyethylene glycol.
36. The liquid pharmaceutical composition of any one of claims 1-35, wherein the liquid pharmaceutical composition comprises less than about 1.5% w/v LD-Tyr-diketopiperazine after two weeks at 2 ℃ -8 ℃.
37. The liquid pharmaceutical composition of claim 36, wherein the liquid pharmaceutical composition comprises less than about 0.8% w/v LD-Tyr-diketopiperazine after two weeks at 2 ℃ -8 ℃.
38. The liquid pharmaceutical composition of any one of claims 1-36, wherein the liquid pharmaceutical composition comprises less than about 5.0% w/v LD-Tyr-diketopiperazine after two weeks at 25 ℃.
39. The liquid pharmaceutical composition of claim 38, wherein the liquid pharmaceutical composition comprises no more than about 4.0% w/v LD-Tyr-diketopiperazine after two weeks at 25 ℃.
40. A method of treating a neurodegenerative condition and/or a condition characterized by reduced levels of dopamine in the brain, wherein the method comprises administering an effective amount of the liquid pharmaceutical composition according to any one of claims 1-39.
41. The method of claim 40, wherein the neurodegenerative condition is parkinson's disease.
42. The method of claim 40 or claim 41, wherein the liquid pharmaceutical composition is administered to the patient concomitantly with an additional active ingredient.
43. The method of claim 42, wherein the additional active ingredient is selected from the group consisting of: decarboxylase inhibitors, COMT inhibitors, MAO inhibitors, and any combination thereof.
44. The method of any one of claims 40-43, wherein the liquid pharmaceutical composition is administered to the patient substantially continuously.
45. The method of any one of claims 40-44, wherein the liquid pharmaceutical composition is administered subcutaneously.
46. The liquid pharmaceutical composition according to any one of claims 1-39, for use in the treatment of neurodegenerative conditions and/or conditions characterized by reduced levels of dopamine in the brain.
47. The liquid pharmaceutical composition according to claim 46, wherein the neurodegenerative condition is parkinson's disease.
48. The liquid pharmaceutical composition of claim 46 or claim 47, wherein the liquid pharmaceutical composition is administered to a patient concomitantly with an additional active ingredient.
49. The liquid pharmaceutical composition according to claim 48, wherein the additional active ingredient is selected from the group consisting of: decarboxylase inhibitors, COMT inhibitors, MAO inhibitors, and any combination thereof.
50. The liquid pharmaceutical composition of any one of claims 46-49, wherein the liquid pharmaceutical composition is administered to the patient substantially continuously.
51. The liquid pharmaceutical composition of any one of claims 46-50, wherein the liquid pharmaceutical composition is administered subcutaneously.
CN202280019958.8A 2021-03-10 2022-03-09 Stabilized liquid compositions comprising levodopa-tyrosine conjugates and uses thereof Pending CN116964069A (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US63/159,236 2021-03-10
US202263296032P 2022-01-03 2022-01-03
US63/296,032 2022-01-03
PCT/IL2022/050269 WO2022190100A1 (en) 2021-03-10 2022-03-09 Stabilized liquid compositions comprising a levodopa-tyrosine conjugate and uses thereof

Publications (1)

Publication Number Publication Date
CN116964069A true CN116964069A (en) 2023-10-27

Family

ID=88447774

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202280019958.8A Pending CN116964069A (en) 2021-03-10 2022-03-09 Stabilized liquid compositions comprising levodopa-tyrosine conjugates and uses thereof

Country Status (1)

Country Link
CN (1) CN116964069A (en)

Similar Documents

Publication Publication Date Title
KR101072339B1 (en) Compounds and methods for delivery of prostacyclin analogs
US11046640B2 (en) Water-soluble L-DOPA esters
ES2942468T3 (en) Deuterium-containing compounds
US20130253056A1 (en) Continuous Administration of Levodopa and/or Dopa Decarboxylase Inhibitors and Compositions for Same
JP6906047B2 (en) Compositions and Methods Related to Salts of Specific Inflammatory Convergent Mediators
WO2019038638A1 (en) Process for preparing purified levodopa amide
US5359128A (en) Malic acid derivatives and compositions for the treatment of psoriasis
CN116964069A (en) Stabilized liquid compositions comprising levodopa-tyrosine conjugates and uses thereof
AU2006330655A1 (en) Compounds for delivering amino acids or peptides with antioxidant activity into mitochondria and use thereof
WO2022190100A1 (en) Stabilized liquid compositions comprising a levodopa-tyrosine conjugate and uses thereof
US20220016253A1 (en) L-dopa and/or dopa decarboxylse inhibitors conjugated to sugar for the treatment of dopamine-responsive disorders
US20220362386A1 (en) Liquid compositions comprising a levodopa amino acid conjugate and uses thereof
JP2024010252A (en) Combination medicament for treatment of parkinson&#39;s disease
US11844754B2 (en) Methods for treatment of Parkinson&#39;s disease
WO2012129680A1 (en) Prodrugs of d-gamma-glutamyl-d-tryptophan and d-gamma- glutamyl-l-tryptophan
TWI826795B (en) Novel analogs of pterostilbene amino acid bearing carbonates for treating a non-alcoholic fatty liver disease and nonalcoholic steatohepatitis
TW202339710A (en) Methods and compositions for treating parkinson&#39;s disease
CN117769541A (en) protease inhibitors as antiviral agents

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination