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WO2021097228A1 - Compositions et sels pour améliorer la biodisponibilité de la l-arginine - Google Patents

Compositions et sels pour améliorer la biodisponibilité de la l-arginine Download PDF

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Publication number
WO2021097228A1
WO2021097228A1 PCT/US2020/060441 US2020060441W WO2021097228A1 WO 2021097228 A1 WO2021097228 A1 WO 2021097228A1 US 2020060441 W US2020060441 W US 2020060441W WO 2021097228 A1 WO2021097228 A1 WO 2021097228A1
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Prior art keywords
agmatine
arginine
salt
disorder
disease
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Inventor
Maurizio Fava
Xudong Huang
James R. Komorowski
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General Hospital Corp
JDS Therapeutics LLC
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General Hospital Corp
JDS Therapeutics LLC
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Publication of WO2021097228A1 publication Critical patent/WO2021097228A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Preparation or treatment thereof
    • A23L2/52—Adding ingredients
    • A23L2/56—Flavouring or bittering agents
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Preparation or treatment thereof
    • A23L2/52—Adding ingredients
    • A23L2/60—Sweeteners
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/501—Inorganic compounds

Definitions

  • compositions and salts which may be useful for mediating NO production and improving L-arginine bioavailability in a subject.
  • L-arginine is one of the essential amino acids for human health, and nitric oxide (NO) is an important cellular signaling molecule involved in many physiological and pathophysiological processes.
  • L-arginine is a substrate for different forms of NO synthase (NOS) that catalyze NO production in the L-arginine-to-NO metabolic pathway. It has been used as a natural supplement for boosting NO production.
  • NOS NO synthase
  • the present application provides, inter alia , a pharmaceutical composition comprising L-arginine, agmatine, and silica.
  • the composition is a silica encapsulated form of the L- arginine and agmatine.
  • the L-arginine and agmatine are in the form of an L- arginine agmatine salt. In some embodiments, the L-arginine and agmatine are in the form of an L-arginine agmatine hydrochloride salt.
  • the composition further comprises a sugar.
  • the sugar is inositol.
  • the present application further provides a process of preparing the pharmaceutical composition provided herein, comprising: i) heating a silicate salt in a solvent to form a silicate solution; ii) adding L-arginine and agmatine to the silicate solution to form an L- arginine agmatine silicate solution; and iii) isolating the composition from L-arginine agmatine silicate solution.
  • the silicate salt is heated at a temperature of about 45°C to about 55°C.
  • step i) further comprises heating the silicate salt in the presence of a solvent and a sugar.
  • the sugar is inositol.
  • inositol is used based on 1 molar equivalent of the silicate salt.
  • the solvent comprises water.
  • the silicate salt is potassium silicate.
  • the isolating comprises precipitating the composition from the L-arginine agmatine silicate solution. In some embodiments, the precipitating comprises cooling the L-arginine agmatine silicate solution and adding a second solvent to the L-arginine agmatine silicate solution, thereby precipitating the composition from the solution. In some embodiments, the L-arginine agmatine silicate solution is cooled to about room temperature. In some embodiments, the second solvent is methanol. In some embodiments, the isolating comprises spray drying the L-arginine agmatine silicate solution.
  • the process further comprises filtering the isolated composition.
  • the present application further provides a pharmaceutical composition comprising L-arginine, agmatine, and silica, which is prepared according to a process provided herein.
  • the present application further provides a salt, which is an arginine agmatine salt.
  • the salt is an arginine agmatine hydrochloride salt.
  • the arginine is L-arginine.
  • the present application further provides a process of preparing an arginine agmatine salt, comprising: i) reacting a first agmatine salt, with a strong base in the presence of a first solvent to form a second agmatine salt; and ii) reacting the second agmatine salt with arginine, or a salt thereof, in the presence of a second solvent to form the arginine agmatine salt.
  • the first agmatine salt is agmatine trifluoroacetate or agmatine sulfate.
  • the strong base is an alkali metal hydroxide base. In some embodiments, the strong base is sodium hydroxide.
  • the first solvent comprises water.
  • the second agmatine salt is agmatine hydroxide.
  • the second solvent comprises water.
  • the process further comprises reacting the arginine agmatine salt in with a strong acid in the presence of a third solvent to afford a second arginine agmatine salt.
  • the strong acid is hydrochloric acid.
  • the third solvent comprises dioxane.
  • the second arginine agmatine salt is arginine agmatine hydrochloride.
  • the present application further provides a salt comprising arginine and agmatine, which is prepared according a process provided herein.
  • the present application further provides a composition comprising L-arginine, agmatine, and silica nanoparticles.
  • the silica nanoparticles comprise tetraethylorthosilicate.
  • the composition consists of the L-arginine, agmatine, and silica nanoparticles.
  • the composition further comprises an ionic liquid.
  • the ionic liquid is an organic molten salt at about room temperature.
  • the ionic liquid is 1 -butyl-3 -methylimidazolium tetrafluorob orate.
  • the composition consists of the L-arginine, agmatine, silica nanoparticles, and ionic liquid.
  • the present application further provides a method of increasing the global arginine bioavailability ratio (GABR) in a subject, comprising administering to the subject an effective amount of a composition provided herein.
  • GBR global arginine bioavailability ratio
  • the present application further provides a method of treating or preventing a disease or disorder in a subject, comprising administering to the subject an effective amount of a composition provided herein.
  • the disease or disorder is associated with abnormal levels of L-arginine, abnormal levels of agmatine, or a combination thereof, in the subject, compared to a normal subject.
  • the disease or disorder is selected from a neurological disorder, a psychiatric disorder, a neurodegenerative disease, a cardiovascular disease, a renal disease, a urological or sexual disorder, cancer, and a genetic disorder.
  • the disease or disorder is a neurological disorder.
  • the treating comprises reducing brain oxidative stress in the subject, reducing neuroinflammation in the subject, reducing proapoptotic signaling in the subject, mediating NO production in the subject, or any combination thereof.
  • the psychiatric disorder is major depressive disorder (MDD) or an anxiety disorder.
  • MDD major depressive disorder
  • anxiety disorder an anxiety disorder
  • the disease or disorder is a cardiovascular or renal disease.
  • the cardiovascular or renal disease comprises hypertension.
  • the treating comprises improving postprandial endothelial dysfunction in the subject.
  • the disease or disorder is a urological disorder or a sexual disorder.
  • the urological or sexual disorder is erectile dysfunction.
  • the disease or disorder is a neurodegenerative disease.
  • the neurodegenerative disease is Alzheimer’s disease.
  • the disease or disorder is cancer.
  • the treating comprises slowing tumor growth, inhibiting tumor metastases, improving immune function, or any combination thereof.
  • the cancer is selected from the group consisting of breast cancer, sarcoma, and lung cancer.
  • the disease or disorder is a genetic disorder.
  • the genetic disorder is Duchenne Muscular Dystrophy (DMD) or autism spectrum disorder.
  • the method provided herein is a method of treating the disease or disorder in the subject. In some embodiments, the method provided herein is a method of preventing the disease or disorder in the subject.
  • compositions provided herein is administered as an adjunctive therapy in combination with one or more additional therapeutic agents, compared to a normal subject.
  • the disease or disorder is associated with abnormal levels of L-arginine in the subject, compared to a normal subject. In some embodiments, the disease or disorder is associated with abnormal levels of agmatine in the subject, compared to a normal subject. In some embodiments, the disease or disorder is associated with abnormal levels of L-arginine and abnormal levels of agmatine in the subject, compared to a normal subject.
  • FIG. 1. shows a representative schematic of the L-arginine/NO/agmatine pathway.
  • AD Alzheimer's disease
  • psychiatric disorders such as depression (e.g, major depressive disorder; see e.g, Ali- Sisto et al, J. Affect. Disord. 2018, 229:145-151, schizophrenia, and the like (see e.g., Ali-Sisto et al., J. Affective Disorders, 2018, 229; 145-151), anxiety disorders (see e.g., Smriga et al, Biomed. Res. 2007, 28:85-90; Jezova et al, Prog.
  • DMD Duchenne Muscular Dystrophy
  • Cr cerebral creatine
  • L-arginine supplementation enhances both innate and adaptive immunity and slows down cancer cell growth (see e.g, Cao et al, BMC Cancer, 2016, 16:343). It has been shown that L-arginine may improve immune function of cancer patients when administered in high doses, as it has several immunomodulatory effects such as stimulating T- and natural killer cell activity and influencing pro- inflammatory cytokine levels. Without being bound by theory, it is believed that the compositions of the present application may perform the same function as L-arginine at lower doses.
  • Oral supplementation with L-arginine has been administered to subjects in doses ranging from 1-20 g/day for a variety of clinical indications, including hypertension, hypercholesterolemia, coronary artery disease, congestive heart failure, peripheral arterial disease, sexual dysfunction, major depressive disorder, sickle cell disease, and in elderly humans, in attempts to improve NO-mediated vascular function (see e.g., McRae, J. Chiropr. Med. 2016, 15(3): 184-189).
  • Metabolic data from experimental and human studies suggest that after oral administration, L- arginine is extensively metabolized by arginase in the gut wall and liver (see e.g, Castillo et al, Proc. Natl. Acad. Sci.
  • the absolute bioavailability of a single oral 10 g dose of L-arginine is about 20%, with the baseline plasma concentration of L-arginine on a normal diet over 8 hours being about 15.1 ⁇ 2.6 pg/mL (-86.7 mM ⁇ 14.9 pM), with peak concentration at 50.0 pg/mL ⁇ 13.4 pg/mL (-287.0 pM ⁇ 76.9 pM), occurring 1 h after administration.
  • therapeutic agents that mitigate the above medical conditions are available, having more effective drugs or even nutraceuticals with fewer side effects and higher bioavailability is still an unmet medical need.
  • agmatine A metabolite from L-arginine metabolic pathway, agmatine (see e.g, FIG. 1), has been proposed as a neuroprotectant for treating brain disorders by suppressing oxidative stress, neuroinflammation, pro-apoptotic signaling, and NO production (see e.g, Neis et al., Neurochemistry International, 2017, 108:318-331) and to serve as a treatment for major depressive disorder (see e.g, Freitas et al Eur. Neuropsychopharmacol. 2016, 26(12): 1885-1899).
  • decreased agmatine levels have been shown in autism (see e.g, Esnafoglu E, & Irende L J. Neural.
  • compositions and salts comprising L-arginine and agmatine, which are believed to dissolve in vivo into L- arginine and agmatine.
  • the compositions and salts provided herein are expected to be attacked by arginase more slowly than L-arginine, and agmatine can preserve physiological stores of L-arginine by mediating NO production.
  • the compositions and salts provided herein will increase bioavailability of L-arginine, and consequential efficacy, by slowing down pre-systemic elimination by arginase as it is not an immediate substrate for the enzyme.
  • the compositions and salts of the present application are not expected to exhibit toxicity and/or immunogenecity in view of the chemical structure/composition and predictable major in vivo break-down products, L-arginine and agmatine.
  • compositions e.g ., pharmaceutical compositions
  • salts comprising arginine and agmatine.
  • the present application further provides a pharmaceutical composition comprising arginine and agmatine, and one or more pharmaceutically acceptable carriers.
  • the arginine is ionically bonded to the agmatate.
  • the arginine is L-arginine.
  • the composition comprises an arginine agmatate salt.
  • the composition comprises an L- arginine agmatate salt.
  • the composition comprises an L- arginine agmatate hydrochloride salt.
  • the present application further provides a composition (e.g., a pharmaceutical composition), comprising arginine, agmatine, and silica.
  • a pharmaceutical composition comprising arginine, agmatine, and silica, and one or more pharmaceutically acceptable carriers.
  • the composition is a silica encapsulated form of the arginine and agmatine.
  • the arginine and agmatine are in the form of an arginine agmatine salt.
  • the arginine and agmatine are in the form of an arginine agmatine hydrochloride salt.
  • the arginine is L-arginine.
  • the composition provided herein further comprises a sugar.
  • the sugar is a carbocyclic sugar comprising 6 to 10 carbon atoms.
  • the sugar is inositol.
  • the present application further provides processes of preparing a composition described herein (e.g, a pharmaceutical composition described herein).
  • the process comprises: i) heating a silicate salt in a solvent to form a silicate solution; ii) adding arginine (e.g, L-arginine) and agmatine to the silicate solution to form an arginine agmatine silicate solution; and iii) isolating the composition from arginine agmatine silicate solution.
  • arginine e.g, L-arginine
  • the silicate salt is heated at a temperature sufficient to dissolve the silicate salt in the solvent. In some embodiments, the silicate salt is heated at a temperature of about 35°C to about 65°C. In some embodiments, the silicate salt is heated at a temperature of about 45°C to about 55°C. In some embodiments, the silicate salt is heated at a temperature of about 50°C.
  • step i) further comprises heating the silicate salt in the presence of a solvent and a sugar.
  • the sugar is a carbocyclic sugar comprising 6 to 10 carbon atoms. In some embodiments, the sugar is inositol.
  • less than 1 molar equivalent of inositol is used based on 1 molar equivalent of the silicate salt. In some embodiments, about 0.1 to about 0.5 molar equivalents of inositol is used based on 1 molar equivalent of the silicate salt. In some embodiments, about 0.2 to about 0.4 molar equivalents of inositol is used based on 1 molar equivalent of the silicate salt. In some embodiments, about 0.3 molar equivalents of inositol is used based on 1 molar equivalent of the silicate salt.
  • the solvent comprises water.
  • the silicate salt is an alkali metal silicate. In some embodiments, the silicate salt is potassium silicate.
  • the isolating comprises precipitating the composition from the arginine agmatine silicate solution.
  • the precipitating comprises cooling the arginine agmatine silicate solution and adding a second solvent to the arginine agmatine silicate solution, thereby precipitating the composition from the solution.
  • the arginine agmatine silicate solution is cooled to a temperature of from about 0°C to about 35°C. In some embodiments, the arginine agmatine silicate solution is cooled to about room temperature.
  • the second solvent comprises Ci-4 alcohol (e.g, methanol, ethanol, isopropanol, and the like). In some embodiments, the second solvent comprises methanol.
  • the isolating comprises spray drying the L-arginine agmatine silicate solution.
  • the processes provided herein further comprise filtering the isolated composition.
  • the filtering comprises isolating the composition, wherein the isolated composition has an average diameter than is less than about 10 mm (e.g, less than about 9 mm, less than about 8 mm, less than about 7 mm, less than about 6 mm, less than about 5 mm, and the like).
  • the present application provides compositions comprising arginine, agmatine, and silica nanoparticles.
  • the present application further provides a pharmaceutical composition comprising arginine, agmatine, and silica nanoparticles, and one or more pharmaceutically acceptable carriers.
  • the arginine is L-arginine.
  • silica e.g ., the silica nanoparticles
  • exemplary silica sources include, but are not limited to, organic silicates (e.g., tetraethylorthosilicate (TEOS)), potassium silicates, magnesium silicates, or other pharmaceutically acceptable fillers, excipients, and glidants such as colloidal silicon (e.g, colloidal anhydrous silicon) and other silica compounds.
  • TEOS tetraethylorthosilicate
  • the silica nanoparticles comprise tetraethylorthosilicate (TEOS).
  • the silica source is potassium silicate.
  • the composition consists of the arginine (e.g, L- arginine), agmatine, and silica nanoparticles.
  • the composition provided herein further comprises an ionic liquid.
  • the ionic liquid is an organic molten salt at about room temperature (e.g, at a temperature of from about 20°C to about 30°C).
  • the ionic liquid is 1 -butyl-3 -methylimidazolium tetrafluorob orate ([BMIM]BF ).
  • the composition consists of the arginine (e.g, L- arginine), agmatine, silica, and ionic liquid. In some embodiments, the composition consists of the arginine (e.g, L-arginine), agmatine, silica nanoparticles, and ionic liquid.
  • composition provided herein e.g., the pharmaceutical composition
  • the composition provided herein is prepared according to one or more of the processes described herein.
  • the present application further provides salt forms comprising arginine and agmatine.
  • the salt is an arginine agmatine salt.
  • the salt is an arginine agmatine hydrochloride salt.
  • the arginine is L-arginine.
  • the present application further provides a pharmaceutical composition comprising a salt form comprising arginine and agmatine, and one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition comprises an arginine agmatine salt, and one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition comprises an arginine agmatine hydrochloride salt, and one or more pharmaceutically acceptable carriers.
  • the present application further provides processes of preparing a salt form described herein (e.g ., an arginine agmatine salt form).
  • the process comprises: i) reacting agmatine, or a salt thereof, with a strong base in the presence of a first solvent to form an agmatine salt; and ii) reacting the agmatine salt with arginine, or a salt thereof, in the presence of a second solvent to form the arginine agmatine salt.
  • the process comprises: i) reacting a first agmatine salt, with a strong base in the presence of a first solvent to form a second agmatine salt; and ii) reacting the second agmatine salt with arginine, or a salt thereof, in the presence of a second solvent to form the arginine agmatine salt.
  • the first agmatine salt is agmatine trifluoroacetate or agmatine sulfate. In some embodiments, the first agmatine salt is agmatine trifluoroacetate. In some embodiments, the first agmatine salt is agmatine sulfate.
  • the strong base is an alkali metal hydroxide base. In some embodiments, the strong base is sodium hydroxide. In some embodiments, the second agmatine salt is agmatine hydroxide.
  • the first solvent comprises water. In some embodiments, the second solvent comprises water. In some embodiments, the first and second solvents are each water.
  • the process further comprises reacting the arginine agmatine salt in with a strong acid in the presence of a third solvent to afford a second arginine agmatine salt.
  • the strong acid is a mineral acid. In some embodiments, the strong acid is hydrochloric acid.
  • the third solvent comprises dioxane.
  • the second arginine agmatine salt is arginine agmatine hydrochloride.
  • the salt form provided herein is prepared according to one or more processes described herein.
  • the reactions for preparing compositions described herein can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis.
  • suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, (e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature).
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected by the skilled artisan.
  • Preparation of salts described herein can involve the protection and deprotection of various chemical groups.
  • the need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art.
  • the chemistry of protecting groups can be found, for example, in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., Wiley & Sons, Inc., New York (1999).
  • Reactions can be monitored according to any suitable method known in the art.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 'H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectroscopy (LC/MS), or thin layer chromatography (TLC).
  • HPLC high performance liquid chromatography
  • LC/MS liquid chromatography-mass spectroscopy
  • TLC thin layer chromatography
  • the compositions can be purified by those skilled in the art by a variety of methods, including high performance liquid chromatography (HPLC) and normal phase silica chromatography.
  • room temperature is understood in the art and refer generally to a temperature, e.g. a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a temperature from about 20°C to about 30°C.
  • compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the present application also includes pharmaceutically acceptable salts of the compounds described herein.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present disclosure include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (ACN) are preferred.
  • non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (ACN) are preferred.
  • ACN acetonitrile
  • composition and salts provided herein are substantially isolated.
  • substantially isolated is meant that the composition or salt is at least partially or substantially separated from the environment in which it was formed or detected.
  • Partial separation can include, for example, a composition enriched in a salt form provided herein.
  • Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the salt form provided herein.
  • the salts provided herein may be crystalline.
  • crystalline or “crystalline form” refers to a certain lattice configuration of a crystalline substance. Different crystalline forms of the same substance typically have different crystalline lattices (e.g, unit cells) which are attributed to different physical properties that are characteristic of each of the crystalline forms. In some instances, different lattice configurations have different water or solvent content.
  • Different salt forms can be identified, e.g, by solid state characterization methods such as by X-ray powder diffraction (XRPD). Other characterization methods such as differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), and the like further help identify the form as well as help determine stability and solvent/water content.
  • XRPD X-ray powder diffraction
  • Other characterization methods such as differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), and the like further help identify the form as well as help determine stability and solvent/water content.
  • the present application further provides methods of treating a disease in a subject in need thereof.
  • the term “subject,” refers to any animal, including mammals. Exemplary subjects include, but are not limited to, mice, rats, other rodents, guinea pigs, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the subject is a human.
  • the present application provides a method of increasing the global arginine bioavailability ratio (GABR) in a subject, comprising administering to the subject an effective amount of a composition or salt provided herein.
  • GABR global arginine bioavailability ratio
  • Equation 1 units based on concentration of each component in the equation:
  • GABR L-arginine / (L-ornitine + L-citrulline)
  • the present application provides a method of treating or preventing a disease or disorder in a subject, comprising administering to the subject an effective amount (e.g ., a therapeutically effective amount) of a composition or salt provided herein.
  • an effective amount e.g ., a therapeutically effective amount
  • the disease or disorder is associated with abnormal levels of L-arginine, abnormal levels of agmatine, or a combination thereof, in the subject, compared to a normal subject.
  • the disease or disorder is associated with abnormal levels of L-arginine in the subject, compared to a normal subject. In some embodiments, the disease or disorder is associated with abnormally low levels of L- arginine in the subject, compared to a normal subject.
  • the disease or disorder is associated with abnormal levels of agmatine in the subject, compared to a normal subject. In some embodiments, the disease or disorder is associated with abnormally low levels of agmatine in the subject, compared to a normal subject. In some embodiments, the disease or disorder is associated with abnormal levels of L-arginine and agmatine in the subject, compared to a normal subject. In some embodiments, the disease or disorder is associated with abnormally low levels of L-arginine and agmatine in the subject, compared to a normal subject.
  • the disease or disorder is selected from a psychiatric disorder, a neurological disorder, a neurodegenerative disease, a cardiovascular disease, a renal disease, a urological or sexual disorder, cancer, and a genetic disorder.
  • the treating comprises mediating NO production in the subject.
  • the mediating comprises inhibiting NO production.
  • administration of the composition provided herein results in about equivalent reduced NO production in the subject compared to administration of L-arginine to a subject at the same concentration (e.g ., administration of 100 nM to a subject results in about equivalent NO production in the subject compared to administering about 100 nM L-arginine to the subject).
  • the disease or disorder is a neurological disorder.
  • the treating comprises reducing brain oxidative stress in the subject, reducing neuroinflammation in the subject, reducing proapoptotic signaling in the subject, mediating NO production in the subject, or any combination thereof.
  • the psychiatric disorder is major depressive disorder (MDD) or an anxiety disorder.
  • the psychiatric disorder is major depressive disorder (MDD).
  • the psychiatric disorder is an anxiety disorder.
  • the mediating comprises inhibiting.
  • the disease or disorder is a cardiovascular or renal disease.
  • the cardiovascular or renal disease comprises hypertension.
  • the disease or disorder is postprandial endothelial dysfunction.
  • the disease or disorder is a urological or sexual disorder.
  • the urological or sexual disorder is erectile dysfunction.
  • the disease or disorder is a neurodegenerative disease.
  • the neurodegenerative disease is Alzheimer’s disease.
  • the disease or disorder is cancer.
  • treating a cancer comprises slowing tumor growth and inhibiting tumor metastases, improving immune function of cancer patients.
  • the cancer is selected from the group consisting of breast cancer, sarcoma, and lung cancer, etc.
  • the disease or disorder is a genetic disorder.
  • the genetic disorder is Duchenne Muscular Dystrophy (DMD) or autism spectrum disorder.
  • the genetic disorder is Duchenne Muscular Dystrophy (DMD).
  • the genetic disorder is autism spectrum disorder.
  • the method provided herein is a method of treating the disease or disorder in the subject.
  • the phrase “therapeutically effective amount” refers to the amount of the composition or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician.
  • the dosage of the composition, administered to a subject is about 1 mg to about 10 g, about 1 mg to about 1000 mg, about 1 mg to about 500 mg, about 1 mg to about 100 mg, about 1 mg to 50 mg, or about 50 mg to about 500 mg.
  • treating refers to one or more of (1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (/. ., arresting further development of the pathology and/or symptomatology); and (2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (/. ., reversing the pathology and/or symptomatology) such as decreasing the severity of disease or reducing or alleviating one or more symptoms of the disease.
  • the method provided herein is a method of preventing the disease or disorder in the subject.
  • the term “preventing” refers to preventing a disease, condition, or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.
  • the method provided herein is an in vivo method. In some embodiments, the method provided herein is an in vitro method.
  • the present application provides a method of monitoring NO production in a subject, comprising: i) administering to the subject an effective amount of a composition or salt provided herein; and ii) measuring the NO concentrations in the subject.
  • the method further comprises obtaining a first biological sample from the subject (e.g., a blood sample) before the administering of step i). In some embodiments, the method further comprises measuring the NO levels in the first biological sample. In some embodiments, the method further comprises obtaining a second biological sample from the subject after the administering of step i). In some embodiments, the measuring of step ii) is performed on the second biological sample obtained from the subject. In some embodiments, the method is performed one or more times over a period of time (e.g., over a period of 1 week, 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 52 weeks, etc).
  • a period of time e.g., over a period of 1 week, 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 52 weeks, etc.
  • the present application provides a method of monitoring L-arginine levels in a subject, comprising: i) administering to the subject an effective amount of a composition or salt provided herein; and ii) measuring the L-arginine concentrations in the subject.
  • the method further comprises obtaining a first biological sample from the subject (e.g., a blood sample) before the administering of step i). In some embodiments, the method further comprises measuring the L-arginine levels in the first biological sample. In some embodiments, the method further comprises obtaining a second biological sample from the subject after the administering of step i). In some embodiments, the measuring of step ii) is performed on the second biological sample obtained from the subject. In some embodiments, the method is performed one or more times over a period of time (e.g, over a period of 1 week, 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 52 weeks, etc).
  • the present application provides a method of monitoring agmatine levels in a subject, comprising: i) administering to the subject an effective amount of a composition or salt provided herein; and ii) measuring the agmatine concentrations in the subject.
  • the method further comprises obtaining a first biological sample from the subject (e.g., a blood sample) before the administering of step i). In some embodiments, the method further comprises measuring the agmatine levels in the first biological sample. In some embodiments, the method further comprises obtaining a second biological sample from the subject after the administering of step i). In some embodiments, the measuring of step ii) is performed on the second biological sample obtained from the subject. In some embodiments, the method is performed one or more times over a period of time (e.g., over a period of 1 week, 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 52 weeks, etc).
  • a period of time e.g., over a period of 1 week, 4 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 52 weeks, etc.
  • One or more additional therapeutic agents e.g, one, two, three, four, or more additional therapeutic agents
  • a therapeutic agent provided herein can be used in combination with the compositions or salts provided herein for treatment of the diseases or disorders provided herein.
  • the additional therapeutic agent is selected from an anti-inflammatory agent, chemotherapeutic agent, a steroid, a PDE5 inhibitor, an antidepressant agent, a selective serotonin reuptake inhibitor (SSRI), a serotonin- norepinephrine reuptake inhibitor (SNRI), and an anesthetic (e.g, for use in combination with a surgical procedure).
  • an anti-inflammatory agent chemotherapeutic agent
  • a steroid e.g., a selective serotonin reuptake inhibitor (SSRI), a serotonin- norepinephrine reuptake inhibitor (SNRI), and an anesthetic (e.g, for use in combination with a surgical procedure).
  • SSRI selective serotonin reuptake inhibitor
  • SNRI serotonin- norepinephrine reuptake inhibitor
  • an anesthetic e.g, for use in combination with a surgical procedure.
  • anti-inflammatory agents include, but are not limited to, aspirin, choline salicylates, celecoxib, diclofenac potassium, diclofenac sodium, diclofenac sodium with misoprostol, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, meclofenamate sodium, mefenamic acid, nabumetone, naproxen, naproxen sodium, oxaprozin, piroxican, rofecoxib, salsalate, sodium salicylate, sulindac, tolmetin sodium, and valdecoxib.
  • Exemplary steroids include, but are not limited to, corticosteroids such as cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, and prednisone.
  • Exemplary PDE5 inhibitors include, but are not limited to, sildenafil (Viagra®), tadalafil (Cialis®), vardenafil (Levitra®), avanafil, lodenafil, mirodenafil, udenafil, and zaprinast.
  • antidepressant agents include, but are not limited to, tricyclic antidepressant agents, Desyrel (trazodone), Serzone (nefazodone), Wellbutrin (bupropion), Remeron (mirtazapine), Valdoxan (agomelatine), Stablon (tianeptine), Edronax (reboxetine), Bolvidon/Depnon, Norval/Tolvon (mianserin), Insidon (opipramol), Spravato (esketamine), and ketamine.
  • tricyclic antidepressant agents Desyrel (trazodone), Serzone (nefazodone), Wellbutrin (bupropion), Remeron (mirtazapine), Valdoxan (agomelatine), Stablon (tianeptine), Edronax (reboxetine), Bolvidon/Depnon, Norval/Tolvon (mianserin), Insidon (opipramol), Spravato (esketamine), and ket
  • Example tricyclic antidepressant agents include, but are not limited to, Adapin (doxepin), Anafranil (clomipramine), Asendin (amoxapine), Endep/Elavil (amitriptyline), Ludiomil (maprotiline), Norpramin (desipramine), Pamelor (nortriptyline), Sinequan (doxepin), Surmontil (trimipramine), Tofranil (imipramine), Vivactil (protriptyline), Azafen (pipof ezine), and Agedal/Elronon (noxiptiline).
  • Exemplary Selective Serotonin Reuptake Inhibitors include, but are not limited to, Luvox (fluvoxamine), Paxil (paroxetine), Prozac (fluoxetine), Zoloft (sertraline), Celexa (citalopram), Lexapro (escitalopram), Viibryd (vilazodone), and Brintellix (vortioxetine).
  • Serotonin-Norepinephrine Reuptake Inhibitors include, but are not limited to, Effexor (venlafaxine), Cymbalta (duloxetine), Pristiq (desvenlafaxine), Savella (milnacipran), Fetzima (levomilnacipran).
  • anesthetics include, but are not limited to, local anesthetics (e.g ., lidocaine, procain, ropivacaine) and general anesthetics (e.g., desflurane, enflurane, halothane, isoflurane, methoxyflurane, nitrous oxide, sevoflurane, mmobarbital, methohexital, thiamylal, thiopental, diazepam, lorazepam, midazolam, etomidate, ketamine, propofol, alfentanil, fentanyl, remifentanil, buprenorphine, butorphanol, hydromorphone levorphanol, meperidine, methadone, morphine, nalbuphine, oxymorphone, pentazocine).
  • local anesthetics e.g ., lidocaine, procain, ropivacaine
  • chemotherapeutic agents include, but are not limited to, alkylating agents, antimetabolites, anti-tumor antibiotics, topoisomerase inhibitors, mitotic inhibitors, kinase inhibitors, and hormone receptor inhibitors.
  • the composition or salt provided herein is administered as an adjunctive therapy in combination with one or more additional therapeutic agents, compared to a normal subject.
  • the additional therapeutic agent is administered simultaneously with the composition or salt provided herein.
  • the additional therapeutic agent is administered after administration of the composition or salt provided herein.
  • the additional therapeutic agent is administered prior to administration of the composition or salt herein.
  • the composition or salt provided herein is administered during a surgical procedure.
  • the composition or salt provided herein is administered in combination with an additional therapeutic agent during a surgical procedure.
  • the additional therapeutic agents provided herein can be effective over a wide dosage range and are generally administered in an effective amount. It will be understood, however, that the amount of the therapeutic agent actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be imaged, the chosen route of administration, the actual compound or composition or salt administered, the age, weight, and response of the individual subject, the severity of the subject’s symptoms, and the like.
  • compositions e.g ., the pharmaceutical compositions
  • salts provided herein can be administered in the form of pharmaceutical formulations.
  • These formulations can be prepared as described herein or elsewhere, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated.
  • the administration is selected from the group consisting of pulmonary administration (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer, intratracheal administration, or intranasal administration), oral administration, or parenteral administration (e.g, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or injection or infusion, intracranial, intrathecal, intraventricular administration, and the like).
  • the administration is intravenous or nasal administration.
  • Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump. Conventional pharmaceutical carriers, aqueous, powder, or oily bases, thickeners and the like, may be necessary or desirable.
  • compositions which contain, as the active ingredient, a composition or salt provided herein in combination with one or more pharmaceutically acceptable carriers (excipients).
  • excipients may be, for example, mixed with an excipient or diluted by an excipient.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier, or medium for the nanoparticle composition.
  • the pharmaceutical formulations can be in the form of powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), sterile injectable solutions, sterile packaged powders, and the like.
  • An ionic liquid (IL) which is an organic molten salt at room temperature, such as l-butyl-3-methylimidazolium tetrafluorob orate [BMIMJBF4 (see e.g. , Shaikh,
  • the resulting reaction volume of 1 mL contains a final TEOS concentration of 1 mM and final L-arginine and agmatine concentrations of 1 mM and 0.2 mM, respectively. Water and TEOS volumes are maintained at the minimum possible levels to avoid a change in the properties of ILs.
  • the resulting products in IL are centrifuged (e.g, at 8,000 rpm for 10 min) and thoroughly washed with an organic solvent (e.g, acetonitrile) to remove viscous IL.
  • an organic solvent e.g, acetonitrile
  • the synthetic process for preparing cationic L-arginine and agmatine specific biomimetic silicification in IL may be performed at an industrial scale for making L- arginine/agmatine/biosilica nanocomposites that may be used potentially as a health supplement.
  • these nanocomposites with co-assembly of L- arginine, agmatine, and silica may overcome the limitation on the overall drug payload, concentration uniformity, drug release control, and blood-brain barrier (BBB) penetration.
  • BBB blood-brain barrier
  • the plate is prepared for passage.
  • the plate is transferred to sterile conditions and 2 mL of EndoGro Basal Media is added to inhibit Trypsin reaction.
  • Cells are pipetted 20x and thoroughly mixed before transferring into 25 mL of EndoGro Basal Media.
  • CellToxTM Green Cytotoxicity Assay Promega Corporation. See also CellToxTM Green Cytotoxicity Assay, Instructions for Use of Products G8741, G8742, G8743, and G8731, revised 5/2015, the disclosure of which is incorporated herein by reference in its entirety.
  • Samples containing 1:1000 L-Arginine (L-Arg; 100 nM, 10 mM, 100 mM, or 0.5 mL) or 1:1000 of Composition A (Example 1; 100 nM, 10 pM, 100 pM, or 0.5 mL) are prepared with EndoGro Basal Media without supplements (MWOS) into sterile 10 x 1 mL microcentrifuge tubes. For concentrations of 0, 1:1000 PBS to MWOS are made. Exemplary samples are shown in Table 1.
  • composition A will be found to be non-toxic in the cellular model at the administered doses, and that no significant difference in toxicity will be observed for Composition A in comparison to L- arginine.
  • Example 4 In vitro NO Detection Assay
  • Master mix 3 pL dye to 1.5 mL of Assay buffer for at least 60 wells.
  • Standard curve master mix 5 pL NO stock solution to 95 pL NO Buffer for at least 60 wells.
  • Composition A and L- arginine will exhibit at least similar or even enhanced capacity for mediating NO production.
  • Agmatine trifluoroacetate salt (see Example 5) or agmatine sulfate (commercial source) was mixed with an appropriate amount of strongly basic anion exchange resin in the hydroxyl form (e.g. , Amberlite IRN78) and water, and the mixture was stirred. Periodically, an aliquot was removed and added to saturated barium chloride to determine if exchange of trifluoroacetate or sulfate was complete. If trifluoroacetate or sulfate was present, the resin was removed by filtration and an appropriate amount of fresh resin was added. The procedure was repeated until a negative test for trifluoroacetate or sulfate was obtained. A solution of agmatine hydroxide was thus obtained and the resin removed by filtration.
  • strongly basic anion exchange resin in the hydroxyl form e.g. , Amberlite IRN78
  • Potassium silicate solution was added to deionised water in a kettle and stirred.
  • the resulting solution was heated to approximately 50°C, and inositol was added to the kettle while stirring (molar ratio of silicate to inositol is 1 :0.3).
  • a clear and colourless solution resulted.
  • 1 mole of L- arginine and 1 mole of agmatine were slowly added to the kettle, while continuing to stir, to dissolve components in the solution. While stirring, the solution was heated to 90 to 95°C and maintained for a maximum of 5 minutes.
  • the encapsulated product was collected in either of two ways.
  • methanol was added in a volume sufficient to induce precipitation of encapsulated arginine agmatate.
  • the hot solution was transferred to a spray drier and spray-dried under an inert gas atmosphere. With each procedure, the final encapsulated product was passed through a 20-mesh sifter screen to remove any solids > 7 mm.

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Abstract

La présente invention concerne des compositions et des sels qui peuvent être utiles pour médier la production de NO et améliorer la biodisponibilité de la L-arginine chez un sujet. L'invention concerne également des procédés d'utilisation desdites compositions et desdits sels.
PCT/US2020/060441 2019-11-13 2020-11-13 Compositions et sels pour améliorer la biodisponibilité de la l-arginine Ceased WO2021097228A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080213883A1 (en) * 2006-10-26 2008-09-04 Davis Tracy M Silica nanoparticles in basic amino acid-silica sols
US8952045B1 (en) * 2007-09-18 2015-02-10 Thermolife International, Llc Amino acid compositions
WO2016054259A1 (fr) * 2014-10-01 2016-04-07 Arsia Therapeutics, Inc. Formulations de polysaccharides et d'acides nucléiques contenant des agents réducteurs de viscosité
US20170071883A1 (en) * 2015-09-14 2017-03-16 JW Nutritional, LLC Systems and Methods for Increasing Agmatine Cellular Uptake by Oral Administration

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080213883A1 (en) * 2006-10-26 2008-09-04 Davis Tracy M Silica nanoparticles in basic amino acid-silica sols
US8952045B1 (en) * 2007-09-18 2015-02-10 Thermolife International, Llc Amino acid compositions
WO2016054259A1 (fr) * 2014-10-01 2016-04-07 Arsia Therapeutics, Inc. Formulations de polysaccharides et d'acides nucléiques contenant des agents réducteurs de viscosité
US20170071883A1 (en) * 2015-09-14 2017-03-16 JW Nutritional, LLC Systems and Methods for Increasing Agmatine Cellular Uptake by Oral Administration

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