WO2012167243A1 - Compositions et méthodes de traitement pour l'obésité - Google Patents

Compositions et méthodes de traitement pour l'obésité Download PDF

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Publication number
WO2012167243A1
WO2012167243A1 PCT/US2012/040726 US2012040726W WO2012167243A1 WO 2012167243 A1 WO2012167243 A1 WO 2012167243A1 US 2012040726 W US2012040726 W US 2012040726W WO 2012167243 A1 WO2012167243 A1 WO 2012167243A1
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Prior art keywords
pharmaceutical composition
pyridoxal
pharmaceutically acceptable
derivative
prodrug
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PCT/US2012/040726
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English (en)
Inventor
David I. CHAPNICK
James Leo WRIGHT
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B & P Company, Inc.
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Publication of WO2012167243A1 publication Critical patent/WO2012167243A1/fr

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    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4415—Pyridoxine, i.e. Vitamin B6
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • This invention relates to innovative pharmaceutical formulations, and methods for their use, to correct, to remove, or to neutralize biochemical and/or physiological abnormalities that cause, or contribute to the cause, of essential obesity.
  • the present invention provides for innovative pharmaceutical formulations directed to the termination of excessive secretion of hormones, etc., that enhance the intake and uptake of nutrient calories, and their conversion to triglyceride in the fat cells. More specifically, the compositions of this invention are directed to the prevention and treatment of the pathogenic activities (fasting hyperinsulinemia, hyperglucagonemia, and deficient growth hormone secretion) directly responsible for excessive accumulation of body fat.
  • Insulin is known to promote storage of body fat and to block the release of fat from storage.
  • Glucagon is known to stimulate insulin release and to elevate blood sugar by blocking glycogen formation and by inducing glucose synthesis from protein in the liver. Growth hormone is known to enhance the breakdown and release of stored fat.
  • Administration of insulin has been shown to cause increased body fat even when diet and activity are tightly controlled [Torbay, et al., 1985].
  • Pharmaceuticals directed to inhibition of insulin release for treatment of obesity include Ro 23-7637, an N-Substituted Diphenylpiperidine (See: U.S.
  • This invention provides a method for decreasing the secretion and/or availability of excessive quantities of insulin and glucagon in human beings, comprising administration. Included in the inventions are methods of treating a medical condition in a patient that involve administering a therapeutically effective amount of a pharmaceutical composition of the invention where the condition is amenable to treatment with the pharmaceutical composition.
  • compositions or pharmaceutical preparations of the invention are methods of using pharmaceutical compositions or pharmaceutical preparations of the invention in the manufacture of a medicament for the treatment of a medical condition, as defined herein, in a patient that involve administering a therapeutically effective amount of a pharmaceutical composition of the invention where the condition is amenable to treatment with the pharmaceutical composition.
  • compositions of the invention are in combination with one or more additional therapeutic agents where the additional agent is given prior, concurrently, or subsequent to the administration of the pharmaceutical composition of the invention.
  • compositions or solid oral dosage form may be employed in a monotherapy or in combination one or more additional therapeutic agents.
  • combination therapies include administration of the agents in a single dosage form or in multiple dosage forms administered at the same time or at different times.
  • the present invention further provides a method of treating a human in need of treatment utilizing the active agents, comprising administering a therapeutically effective amount of composition or solid oral dosage form according to the invention to provide administration of active ingredients.
  • Administration of the active agent may be carried out using any appropriate mode of administration.
  • administration can be, for example, oral, parenteral, transdermal, transmucosal (including rectal, vaginal, and transurethral), sublingual, by inhalation, or via an implanted reservoir in a dosage form.
  • active ingredient refers to the preparation accountable for the biological effect.
  • active agent refers to the preparation accountable for the biological effect.
  • pharmacologically active analogs including, but not limited to, salts, esters, amides, prodrugs, conjugates, active metabolites, and other such derivatives, analogs, and related compounds.
  • administration of the pharmaceutically active compounds and the pharmaceutical compositions defined herein includes systemic use, as by injection (especially parenterally), intravenous infusion, suppositories and oral administration thereof, as well as topical application of the compounds and compositions. Intravenous administration is particularly preferred in the present invention.
  • compositions which comprise the present invention are capable of being commingled without interacting in a manner which would substantially decrease the efficacy of the pharmaceutically active compound under ordinary use conditions.
  • an excipient means the substances used to formulate active pharmaceutical ingredients (API) into pharmaceutical formulations; in a preferred embodiment, an excipient does not lower or interfere with the primary therapeutic effect of the API. Preferably, an excipient is therapeutically inert.
  • excipient encompasses carriers, diluents, vehicles, solubilizers, stabilizers, bulking agents, acidic or basic pH-adjusting agents and binders. Excipients can also be those substances present in a pharmaceutical formulation as an indirect or unintended result of the manufacturing process. Preferably, excipients are approved for or considered to be safe for human and animal administration, i.e., GRAS substances (generally regarded as safe). GRAS substances are listed by the Food and Drug administration in the Code of Federal Regulations (CFR) at 21 CFR 182 and 21 CFR 184, incorporated herein by reference.
  • CFR Code of Federal Regulations
  • the excipients include, but are not limited to, hexitols, including mannitol and the like as well as sodium or potassium hydroxides (NaOH or KOH) and mixtures thereof.
  • Other examples include, without limitation, calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
  • Hyperinsulinemia or hyperinsulinaemia is a condition in which there are excess levels of insulin circulating in the blood than expected relative to the level of glucose. Hyperinsulinemia can result from a variety of metabolic diseases and conditions. While hyperinsulinemia is often seen in people with type two diabetes mellitus, it is not the cause of the condition and is only one symptom of the disease. Hyperinsulinemia is associated with hypertension, obesity, dyslipidemia, and glucose intolerance. These conditions are collectively known as metabolic syndrome. Hyperglucagonemia is a state of excess glucagon secretion. In healthy individuals, insulin has a suppressive effect on alpha-cell function and on glucagon secretion. The most common cause of hyperglucagonemia is an absence or deficiency of the restraining influence of insulin on glucagon production.
  • metabolic disease is understood as all types of disorders that lead to errors and imbalances in the metabolism as well as to metabolic processes taking place in a sub-optimal form.
  • the expression also relates to disorders that can be treated through metabolism modulation, although the disease in itself may not have been caused by a metabolic disorder.
  • the metabolic disease is selected from the set of obesity, hyperglycaemias, insulin resistance, type 2 diabetes, and dyslipemias.
  • the term "obesity”, as used in the present invention, relates to the definition of obesity provided by the WHO based on the body mass index (BMI), which consists of the ratio between the weight of a person (in kg) and the square of their height in metres.
  • BMI body mass index
  • a BMI lower than 18.5 kg/m2 is considered as insufficient weight or thinness
  • a BMI of 18.5-24.9 kg/m2 is considered a normal weight
  • a BMI of 25.0-29.9 kg/m2 is considered grade 1 of overweight
  • a BMI of 30.0-39.0 kg/m2 is considered a grade 2 of overweight
  • a BMI greater than or equal to 40.0 kg/m2 is considered morbid obesity.
  • an individual's degree of obesity such as the diameter of the waist measured at the midpoint between the lower limit of the ribs and the upper limit of the pelvis (in cm), the thickness of skin folds, and bioimpedance, based on the principle that a lean mass transmits electricity better than a fatty mass.
  • hyperglycaemia relates to a state where abnormally high blood glucose levels appear in relation to the fasting baseline levels.
  • hyperglycaemia is understood to take place when fasting blood glucose levels are consistently higher than 126 mg/dL, the postprandial glucose levels are higher than 140 mg/dL, and/or the glucose levels in venous plasma 2 hours after administration of a dose of glucose of 1.75 grams for each kilogram of body weight is over 200 mg/dL.
  • insulin resistance relates to a disorder wherein the cells do not respond correctly to insulin. As a result, the body produces more insulin in response to high blood glucose levels. Patients with insulin resistance frequently display high glucose levels and high circulating insulin levels. Insulin resistance is frequently linked to obesity, hypertension, and hyperlipidemia. Additionally, insulin resistance frequently appears in patients with type 2 diabetes.
  • type 2 diabetes relates to a disease characterized by an inappropriate increase in blood glucose levels, which generates chronic complications as it affects large and small vessels and nerves.
  • the underlying disorder in this disease is the difficulty for insulin action (in the form of a loss of tissue sensitivity to this hormone), which is called insulin resistance, and an inadequate secretion of insulin by the cells responsible for their production in the pancreas.
  • insulin resistance in the form of a loss of tissue sensitivity to this hormone
  • insulin resistance an inadequate secretion of insulin by the cells responsible for their production in the pancreas.
  • faulty insulin action frequently translates into an increase in cholesterol and/or triglyceride levels.
  • the term "dyslipemia”, as used in the present invention, relates to any pathological condition characterized by a disorder in the lipid metabolism, with a consequent disorder in lipid concentration (cholesterol, triglycerides and such like) and lipoproteins (high density lipoproteins) in the blood.
  • Dyslipemias that can be treated with the methods of the present invention include, without limitation, hypercholesterolemia, hypertriglyceridemia, hyperlipoproteinemia of type I, Ila, lib, III, IV, V, hyperchylomicronemia, combined hyperlipidemia, etc.
  • compositions of the invention are useful both for the treatment of morbid obesity and for the treatment of grade 1 or grade 2 of overweight, in which case the methods of the invention have a cosmetic purpose.
  • the patients with excess weight in the form of fat and who can be treated by the cosmetic method of the present invention are identified visually or by having a BMI higher than or equal to 25 kg/m2, preferably between 25 and 30. These individuals are considered obese, and needing weight control for cosmetic reasons.
  • pharmaceutically acceptable or “pharmacologically acceptable” is meant a material that is not biologically or otherwise undesirable, i.e., the material may be administered to an individual without causing any undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • a "pharmaceutically acceptable carrier” is a material that is nontoxic and generally inert and does not affect the functionality of the active ingredients adversely.
  • examples of pharmaceutically acceptable carriers are well known and they are sometimes referred to as diluents, vehicles or excipients.
  • the carriers may be organic or inorganic in nature.
  • Examples of pharmaceutically acceptable carriers that may be present in the present lyophilized formulations may be gelatin, lactose, starch, cocoa butter, dextrose, sucrose, sorbitol, mannitol, gum acacia, alginates, cellulose, talc, magnesium stearate, polyoxyethylene sorbitan monolaurate, polyvinylpyro-lidone (PVP) and other commonly used pharmaceutical carriers.
  • the pharmaceutical carrier comprises mannitol.
  • the formulation may contain minor amounts of pH adjusting agents such as sodium hydroxide (NaOH) additives such as flavoring agents, coloring agents, thickening or gelling agents, emulsifiers, wetting agents, buffers, stabilizers, and preservatives such as antioxidants.
  • pH adjusting agents such as sodium hydroxide (NaOH) additives such as flavoring agents, coloring agents, thickening or gelling agents, emulsifiers, wetting agents, buffers, stabilizers, and preservatives such as antioxidants.
  • physiological pH or a “pH in the physiological range” is meant a pH in the range of approximately 7.2 to 8.0 inclusive, more typically in the range of approximately 7.2 to 7.6 inclusive.
  • composition as used herein shall mean a composition that is made under conditions such that it is suitable for administration to humans, e.g., it is made under GMP conditions and contains pharmaceutically acceptable excipients, e.g., without limitation, stabilizers, pH adjusting agents such as NaOH, bulking agents, buffers, carriers, diluents, vehicles, solubilizers, and binders.
  • pharmaceutical composition includes but is not limited to a pre-lyophilization solution or dispersion as well as a liquid form ready for injection or infusion after reconstitution of a lyophilized preparation.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.
  • salts are meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like,
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galacturonic acids and the like (see, for example, Berge et al., 1977, J. Pharm. Sci. 66: 1-19).
  • Certain specific compounds of the invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the invention.
  • the invention provides compounds, which are in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not.
  • the prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug.
  • An example, without limitation, of a prodrug would be a compound of the invention, which is administered as an ester (the "prodrug"), but then is metabolically hydrolyzed to the carboxylic acid, the active entity.
  • Additional examples include peptidyl derivatives of a compound of the invention.
  • Certain compounds of the invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the invention. Certain compounds of the invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the invention and are intended to be within the scope of the invention.
  • Certain compounds of the invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, enantiomers, diastereomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of the invention.
  • These isomers can be resolved or asymmetrically synthesized using conventional methods to render the isomers "optically pure", i.e., substantially free of its other isomers. If, for instance, a particular enantiomer of a compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diasteromers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
  • substantially pure as used in connection with a isomer of a compound provided herein, such as, for example, a stereoisomer, enantiomer or diasteriomer, means that the compound comprises greater than about 70%, 75%, 80%, 85%, 90%, 93%, 95% or 97% by weight of one isomer.
  • isolated used in connection with a isomer of a compound provided herein, such as, for example, a stereoisomer, enantiomer or diasteriomer, means that the compound is in a form in which only one isomer is detectable using conventional techniques (e.g., NMR, polarimetry, chromatography, chiral resolution, etc.).
  • controlled release refers to a drug-containing formulation or fraction thereof in which release of the drug is not immediate, i.e., with a “controlled release” formulation, administration does not result in immediate release of the drug into an absorption pool.
  • controlled release includes sustained release and delayed release formulations.
  • sustained release (synonymous with “extended release”) is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that preferably, although not necessarily, results in substantially constant blood levels of a drug over an extended time period.
  • delayed release is also used in its conventional sense, to refer to a drug formulation which, following administration to a patient, provides a measurable time delay before drug is released from the formulation into the patient's body.
  • altering metabolism indicates an observable (i.e., measurable) change in at least one aspect of metabolism including, but not limited to, total blood glucose content, blood insulin, the blood insulin to blood glucose ratio, insulin sensitivity, or oxygen consumption.
  • mixture means a composition comprising two or more of compounds.
  • a mixture is a mixture of two or more distinct compounds.
  • a compound when referred to as a "mixture", this means that it can comprise two or more "forms" of the compounds, such as, salts, solvates, prodrugs or, where applicable, stereoisomers of the compound in any ratio.
  • forms such as, salts, solvates, prodrugs or, where applicable, stereoisomers of the compound in any ratio.
  • a compound in a mixture can also exist as a mixture of forms.
  • a compound may exist as a hydrate of a salt or as a hydrate of a salt of a prodrug of the compound.
  • CIs of ⁇ 0.3, 0.3-0.7, 0.7-0.85, 0.85-0.90, 0.90-1.10 or >1.10 indicate strong synergism, synergism, moderate synergism, slight synergism, additive effect or antagonism, respectively.
  • the CI is the statistical measure of synergy.
  • administered contemporaneously means that the active agent and additional active agent(s) are administered to a subject such that they are each biologically active in the subject at the same time.
  • the exact details of the administration will depend on the pharmacokinetics of the substances in the presence of each other, and can include administering one substance within 24 hours of administration of another, if the pharmacokinetics are suitable. Designs of suitable dosing regimens are routine for one skilled in the art.
  • two substances will be administered substantially simultaneously, i.e. within minutes of each other, or in a single composition that comprises both substances.
  • combination therapy means two or more substances, for example a 4-oxobutanoic acid compound and additional active agent(s), are administered to a subject over a period of time, contemporaneously or sequentially e.g. the substances are administered at the same time or at different times within the period of time in a regimen that will provide beneficial effects of the drug combination, at similar or different intervals.
  • the combination therapy is intended to embrace co-administration, in a substantially simultaneous manner such as in a single dosage form e.g. a capsule, having a fixed ratio of active ingredients or in multiple, separate dosage forms, e.g. capsules, for each substance.
  • the compounds may or may not be biologically active in the subject at the same time.
  • a first substance is administered weekly, and a second substance administered daily.
  • the exact details of the administration will depend on the pharmacokinetics of the two substances. Designs of suitable dosing regimens are routine for one skilled in the art.
  • the terms "treating" or "treatment” of a disease include preventing the disease, i.e. preventing clinical symptoms of the disease in a subject that may be exposed to, or predisposed to, the disease, but does not yet experience or display symptoms of the disease; inhibiting the disease, i.e., arresting the development of the disease or its clinical symptoms, such as by suppressing hyperthermia; or relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
  • LHA Hypothalamic areas
  • VMH Electrically stimulating the VMH triggers 'satiety,' enhancing the use of fat, and raising the metabolic rate before and during suppression of feeding [Ruffin & Nicolaidis, 1999] .
  • Chronic stimulation of the VMH causes a lasting change in metabolic rate that prevents weight gain independent of food intake [Stenger, Fournier, & Bielajew, 1990].
  • the terms "ventromedial nucleus” and “VMN” pertain to a nucleus of the hypothalamus.
  • the VMN is a medially located nucleus of the hypothalamus that is situated between the lateral wall of the third ventricle and the fornix and that is held to suppress the urge to eat when satiety is reached.
  • Neurons of the VMN can be glucose-responsive (GR) or non-responsive.
  • the present invention provides for compositions and methods for stimulating the glucose-responsive neurons that also respond to thermal stimulation via increased body temperature.
  • the present invention provides for compositions and methods for chemically stimulating neurons in the VMN to release neurotransmitter that is taken up by contiguous structures e.g., the lateral hypothalamic GABA-A receptors and arcuate nuclei GABA- A, B & C receptors, etc. This activity terminates the "preabsorptive" stimulation of insulin release and the autonomic, enteric, and central nervous impulses that trigger insulin and glucagon release, as well as initiating the synthesis, storage, and release of growth hormone and thyroid releasing hormone (TRH).
  • TRH growth hormone and thyroid releasing hormone
  • the present invention is directed to compositions and methods for restoring inhibition of LHA feeding-related activities, including increased insulin release; restoring inhibition of autonomic and enteric nervous system stimulation of excessive insulin and glucagon release by the endocrine pancreas; and restoring GABA-stimulated synthesis, storage, and release of growth hormone and TRH by the arcuate and anterior pituitary.
  • the present invention comprises a method for treating obesity by increasing GABA availability in the hypothalamus and the islets of Langerhans by administration, to a person in need thereof, of a pharmaceutical compound to enhance GABAergic activity sufficiently to reduce fasting insulin to normal levels in blood, and to terminate inappropriate secretion of glucagon.
  • the present invention provides for methods of treatment and prevention of obesity by restoring or replacing VMH control of pituitary, liver, thyroid, and endocrine pancreas responses.
  • the present invention also provides for methods of treatment and prevention by restoring or replacing VMH control of insulin, glucagon, and growth hormone secretion.
  • the invention encompasses compositions and methods that are useful in regulating, altering, treating, and preventing various disorders, particularly disorders of the metabolism as described herein.
  • the invention also provides for compositions and methods of treatment and prevention of obesity by activation of the receptors specific to the VMH glucose-responsive neurons.
  • inventions include methods of treating a medical condition in a patient that involve administering a therapeutically effective amount of a pharmaceutical composition of the invention where the condition is amenable to treatment with the pharmaceutical composition.
  • compositions or pharmaceutical preparations of the invention are the use of the pharmaceutical compositions or pharmaceutical preparations of the invention in the manufacture of a medicament for the treatment of a medical condition, as defined herein, in a patient that involve administering a therapeutically effective amount of a pharmaceutical composition of the invention where the condition is amenable to treatment with the pharmaceutical composition.
  • the present invention provides for pharmaceutical methods and compositions to chemically stimulate the glucose- responsive neurons in the ventromedial hypothalamus (VMH), initiating the satiety cascade. These responses terminate signals from the lateral hypothalamus (LHA) that increase insulin secretion, and inhibit impulses to the endocrine pancreas via the autonomic, enteric, and central nervous systems. They also trigger the synthesis and storage of thyroid releasing hormone (TRH) and human growth hormone (hGH) in the pituitary and arcuate nuclei.
  • VMH ventromedial hypothalamus
  • LHA lateral hypothalamus
  • TRH thyroid releasing hormone
  • hGH human growth hormone
  • GHB or one of its precursors, e.g., gamma- butyro lactone, can also give this response, but the adverse effects and the potential toxicity arising from doses required make such use impractical.
  • GABA Gamma-amino-beta-hydroxybutyric acid
  • the present invention provides for a method of treating obesity by administering pharmaceuticals that elicit a response from glucose/thermal-responsive neurons in the Ventromedial Hypothalamic Nuclei of human beings.
  • the formulations include phosphatidyl-4- oxobutanoate esterified one or more compounds selected from the group consisting of pyridoxal L-glutamic acid monophosphate, and phosphatidyl - N- succinyl-N-glutamic acid, pyridoxal ester.
  • the formulations include sources of succinate or 3 -hydroxybutyric acid.
  • the formulations include 4- oxobutanoate (succinic semialdehyde; SSA) as the source of succinate, including linear and cyclic derivatives.
  • the formulation further comprises one or more compounds selected from the group consisting of pyridoxal phosphate (PLP), hydroxy-L-threonine and pyridoxamine as desirable constituents to provide for modulating the activity of brain SSA reductase, inhibiting GDH in brain and in beta cells, and inhibiting acetyl CoA
  • the present invention provides for pharmaceutical methods and compositions to chemically stimulate the glucose- responsive neurons in the ventromedial hypothalamus (VMH), initiating the satiety cascade.
  • VMH ventromedial hypothalamus
  • compositions of the present invention comprise derivatives of 4-oxobutanoic acid, both linear and cyclic, and their pharmaceutically acceptable, pharmacologically active analogs, including, but not limited to, salts, esters, amides, prodrugs, conjugates, active metabolites, and other such derivatives, analogs, and related compounds.
  • the formulation is selected from the group consisting of phosphatidyl-N- succinylglutamate, sodium salt; and 4-oxobutanoic ester of N-pyridoxal- glutamic acid 5'-monophosphate.
  • compositions of the present invention comprise pyridoxal esters.
  • the pyridoxal ester is an ester of a compound selected from the group consisting of one or more of pyridoxal-5'- phosphate, pyridoxal, pyridoxine, pyridoxamine, 3-acylated analogues of pyridoxal, 3-acylated analogues of pyridoxal-4,5-aminal, pyridoxine phosphonate analogues, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof.
  • compositions of the present invention comprise esters and adducts of pyridoxal 5'-phosphate, an example of which is the imine pyridoxal-gamma-aminobutyric acid (which may be phosphatidylated, etc.), which can be made by adding 2 micromoles (mmol) of potassium hydroxide (KOH) to 5 milliliters (ml) of methanol.
  • KOH potassium hydroxide
  • the pyridoxal is esterified to a succinate including derivatives, and their pharmaceutically acceptable, pharmacologically active analogs, including, but not limited to, salts, esters, amides, prodrugs, conjugates, active metabolites, and other such derivatives, analogs, and related compounds.
  • the compositions of the present invention comprise pyridoxal esters of sodium succinic acid.
  • the compositions of the present invention comprise pyridoxal esters of succinic acid disodium salt.
  • the pyridoxal is esterified to a niacin derivative, including pharmaceutically acceptable, pharmacologically active analogs, including, but not limited to, salts, esters, amides, prodrugs, conjugates, active metabolites, and other such derivatives, analogs, and related compounds.
  • the compositions of the present invention comprise pyridoxal esters of nicotinyl and isonicotinyl derivatives. See, for example, Zhmurenko et al., Pharmaceutical Chemistry Journal Volume 14, Number 9 (1980), 612-617, DOI: 10.1007/BFO 1156373 and Kuznetsova, et al.,
  • compositions of the present invention comprise pyridoxal esters of a combination of GABA (gamma amino butyric acid) and niacin (or nicotinic acid, a B vitamin), and their pharmaceutically acceptable, pharmacologically active analogs, including, but not limited to, salts, esters, amides, prodrugs, conjugates, active metabolites, and other such derivatives, analogs, and related compounds.
  • the niacin derivative is selected from the group consisting of N-nicotinyl-gamma- aminobutyrate and isonicotinyl-gamma-aminobutyrate.
  • compositions of the present invention comprise sodium N-nicotinyl-gamma- aminobutyrate-pyridoxal and sodium isonicotinyl-gamma-aminobutyrate- pyridoxal.
  • the compositions of the present invention comprise pyridoxal esterified to a combination of GABA (gamma amino butyric acid) and pantoic acid (2,4-dihydroxy-3,3-dimethylbutyric acid), and pharmaceutically acceptable, pharmacologically active analogs, including, but not limited to, salts, esters, amides, prodrugs, conjugates, active metabolites, and other such derivatives, analogs, and related compounds.
  • the compositions of the present invention comprise pyridoxal esters of pantoyl derivatives.
  • the pantoyl derivative is pantoyl-gamma- aminobutyric acid (pantoyl-GABA).
  • compositions of the present invention comprise pyridoxal esters of succinic acid or succinate derivatives, and their pharmaceutically acceptable, pharmacologically active analogs, including, but not limited to, salts, esters, amides, prodrugs, conjugates, active metabolites, and other such derivatives, analogs, and related compounds.
  • the succinic acid to which pyridoxal is esterified is a disodium salt.
  • the composition is a succinate ester of pyridoxal 5'-phosphate, sodium salt.
  • compositions of the present invention comprise pyridoxal esters of succinic acid or succinate derivatives, and their pharmaceutically acceptable, pharmacologically active analogs, including, but not limited to, salts, esters, amides, prodrugs, conjugates, active metabolites, and other such derivatives, analogs, and related compounds.
  • compositions of the present invention comprise a succinate ester of pyridoxal 5'-phosphate, sodium salt.
  • compositions of the present invention are selected from the group consisting of N-nicotinyl-GABA-PLP, N-isonicotinyl-GABA-PLP and pantoyl-GABA-PLP.
  • compositions of the present invention comprise a combination of N-nicotinyl-GABA (or N-isonicotinyl-GABA), pyridoxal, and succinic acid disodium salt.
  • the pyridoxal is esterified to N-nicotinyl-GABA and then the pyridoxal-nicotinyl-GABA molecule is succinylated to form a pyridoxal-N— nicotinyl-GABA-sucinate molecule.
  • the pyridoxal is succinylated and then the succinate-pyridoxal molecule is then esterified to nicotinyl-GABA, creating the pyridoxal-N-nicotinyl-GABA-sucinate molecule.
  • the compositions of the present invention are selected from the group consisting of N-nicotinyl-GABA-PLP-succinate, N-isonicotinyl-GABA-PLP-succinate and pantoyl-GABA-PLP-succinate.
  • compositions of the present invention comprise pyridoxal esterified to a 4-hydroxybutyric acid-based molecule and their pharmaceutically acceptable, pharmacologically active analogs, including, but not limited to, salts, esters, amides, prodrugs, conjugates, active metabolites, and other such derivatives, analogs, and related compounds.
  • the 4-hydroxybutyric Acid-based molecule is selected from the group consisting of a 4-hydroxybutyric Acid ester of pyridoxal 5'-phosphate, sodium salt;
  • compositions of the present invention comprise linear and cyclic derivatives of 4-oxobutanoic acid formulated to enhance uptake from the small intestine and passage through the blood-brain barrier, such as phosphatidylation.
  • Penetration enhancement can be broadly divided into several categories: lipidization, structural modification to enhance stability, glycosylation, and use of nutrient transporters, prodrugs, vector-based, cationization, and polymer conjugation.
  • Lipid solubility is a key factor in determining the rate at which a drug passively crosses the BBB, the concept of lipidization focuses on this aspect.
  • the presence of terminal hydroxyl groups tends to promote hydrogen bonding with solvating water leading to a concomitant decrease in the partition coefficient (i.e. lipophilicity) with a resultant decrease in membrane permeability.
  • the removal of polar hydroxyl groups has been shown to increase lipid solubility with subsequent enhancement of brain entry.
  • Drugs containing only polar groups essential for pharmacological effect can be modified by addition of non-polar groups at sites that do not interfere with the appropriate receptor binding regions. Hydroxyl groups can be irreversibly blocked by methylation or reversibly blocked by esterification.
  • Methylation has been shown to increase lipophilicity and BBB permeability.
  • Halogenation (CI, Br, F, I) can also enhance lipophilicity and BBB
  • permeability Yet another method to increase lipophilicity is through acylation or alkylation of the N-terminal. Acylation has been proven to be an effective means to increase membrane permeability with limited interference in receptor binding.
  • Cyclization has been shown to increase lipophilicity and BBB permeability as well.
  • Glycosylation has proven to be a useful methodology for enhancing biodistribution to the brain.
  • a number of different sugar moieties have been investigated including glucose and xylose, with respective sugars exhibiting variations in BBB permeability.
  • the BBB expresses several transport systems for nutrients and endogenous compounds. Utilization of these transport systems is a potential strategy for controlling the delivery of drugs into the brain. Lipid-insoluble agents can compete for transport across the blood-brain barrier by the large neutral amino acid carrier.
  • Prodrugs contain a pharmacologically active moiety that is either conjugated to a molecule with a known transporter or to a lipophilicity enhancer, which is cleaved at or near the site of action, allowing drug to induce its effect.
  • the rationale for prodrug design is that the structural requirements needed to elicit a desired pharmacological action and those needed to provide optimal delivery to the target receptor site may not be the same.
  • Esterification or amidation of amino, hydroxyl, or carboxylic acid-containing drugs may greatly enhance lipid solubility, and thus brain entry. Once in the CNS, hydrolysis of the modifying group releases the active compound.
  • Pegylation the use of poly(ethylene glycol) linked to an active agent, will modify many of the pharmacokinetic features, while maintaining the primary biological activity.
  • PEG chains can contain linear and branched structures, which can be conjugated directly to the drug or linked in a prodrug manner.
  • the present invention provides for compositions and methods for stimulating the VMH glucose-responsive neurons that also respond to thermal stimulation by treating a subject with a therapeutic amount of one or more 4-oxobutanoic acid compound.
  • 4-oxobutanoic acid compound and “4-oxobutanoate” refer to a
  • pharmaceutically acceptable, pharmacologically active agents including, but not limited to, salts, esters, amides, prodrugs, conjugates, complexes, active metabolites, and other such derivatives, analogs, and related compounds of 4- oxobutanoic acid, including phosphatidylated, dyridoxylated and methylated derivatives (including methyl esters) as well as 4-oxobutanoic acid fusion compounds and 4-oxobutanoic acid compounds complexed with additional agents.
  • 4-oxobutanoic acid is also known in the art as 4-oxobutanoate, succinaldehydic acid, 4-oxobutanoic acid, butryaldehydic acid, succinate semialdehyde, 3-formylpropanoic acid, gamma-oxybutyric acid, 4-oxobutyric acid and beta-formylpropionic acid.
  • - a mono-, bi- or tricyclic aryl group containing 6 to 14 carbon atoms; . - a heteroaromatic group chosen from the groups pyridyl, pyrimidyl, pyrrolyl, furyl and thienyl;
  • aryl groups examples include phenyl, a-naphthyl, ⁇ -naphthyl and fluorenyl groups.
  • the x e alkyl groups may be linear or branched. Examples that may be mentioned include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert- butyl and pentyl groups.
  • the Ci-C(, alkoxy groups may similarly be linear or branched.
  • Examples that may be mentioned include methoxy, ethoxy, propoxy, isopropoxy, butoxy and isobutoxy groups.
  • the halogens can be chosen from fluorine, chlorine, bromine and iodine.
  • the present invention also encompasses the tautomeric forms of the compounds of the general formulas (II-IV), the enantiomers,
  • IV include pharmacologically acceptable salts, such as the sodium salts, potassium salts, magnesium salts, calcium salts, amine salts and other salts of the same type (aluminium, iron, bismuth, etc.).
  • pharmacologically acceptable salts such as the sodium salts, potassium salts, magnesium salts, calcium salts, amine salts and other salts of the same type (aluminium, iron, bismuth, etc.).
  • the 4-oxobutanoic acids are those of the formulas (II-IV) in which Ri ; R2, R 3 , and R4 are C2H 5 .
  • R2 and R 3 may be joined together with carbon atoms to make a 5 or 6 membered ring.
  • R4 H, CH 3 , C 2 H 5 , CH 3 CO.
  • the 4-oxobutanoic acids are chosen from one or more of the following:
  • 3,4-DBA or 3- hydroxybutyric acid stimulation of VMH triggers 'satiety' cascade thus decreasing the intake and storage of calories.
  • I3 ⁇ 4 and R3 may be joined together with carbon atoms to make a 5 or 6 membered ring.
  • succinic acid elicits the desired response from VMH once delivered across the BBB.
  • ketone body 3-hydroxybutyric acid also elicits the desired response once delivered across the BBB.
  • 3-hydroxybutyric acid is succinylated or glutamylated in a simple, one-pot synthesis.
  • the formulation further comprises phosphatidylserine as an additional agent.
  • the formulation further comprises phosphatidylserine as a constituent complexed to the active agent. In general, there is no need to encapsulate any of these compounds in liposomes since gradient, not lipophilicity, is the determining factor.
  • the formulation further comprises the committed precursor of pyridoxal, 4-Hydroxy-L-Threonine ⁇ also known as: (2S,3S)-2-amino-3,4-dihydroxybutanoic acid ⁇ .
  • compositions of the present invention additionally comprise one or more GABAergic compounds.
  • a first composition comprises one or more 4-oxobutanoic acid compound including pharmaceutically acceptable, pharmacologically active analogs, including, but not limited to, salts, esters, amides, prodrugs, conjugates, active metabolites, and other such derivatives, analogs, and related compounds
  • a second composition comprises one or more agents selected from a GABAergic compound, an inhibitor of glutamate dehydrogenase (GDH) enzyme activity, potassium channel activators and mixtures thereof.
  • GDH glutamate dehydrogenase
  • compositions of the present invention further comprise an active form of vitamin B6 including, for example, pyridoxine, pyridoxal and pyridoxamine.
  • B6 is a vitamin B6 related compound meaning any vitamin B6 related precursor, metabolite, derivative or analogue.
  • Methods of the invention include administration of a
  • the active agent along with a compound selected from the group consisting of one or more of pyridoxal-5 '-phosphate, pyridoxal, pyridoxine, pyridoxamine, 3-acylated analogues of pyridoxal, 3- acylated analogues of pyridoxal-4,5-aminal, pyridoxine phosphonate analogues, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof.
  • the vitamin B6 related compound is pyridoxamine 5'-phosphate, pyridoxal-5'-phosphate L-Glutamic Acid- pyridoxamine 5'-phosphate or L-Glutamic Acid-pyridoxal-5'-phosphate.
  • vitamin B6 related compounds which can also be used to practice the invention, include the 3-acylated analogues of pyridoxal, 3-acylated analogues of pyridoxal-4,5-aminal, and pyridoxine phosphate analogues.
  • the 3-acylated analogues of pyridoxal include wherein the pyridoxal is 3-acylated with an alkyl, alkenyl, in which alkyl can interrupted by nitrogen, oxygen, or sulfur, and can be unsubstituted or substituted at the terminal carbon with hydroxy, alkoxy, alkanoyloxy, alkoxyalkanoyl, alkoxycarbonyl, or wherein the pyridoxal is 3-acylated with
  • dialkylcarbamoyloxy alkoxy; dialkylamino; alkanoyloxy; alkanoyloxyaryl; alkoxyalkanoyl; alkoxycarbonyl; dialkylcarbamoyloxy; or wherein the pyridoxal is 3-acylated with aryl, aryloxy, arylthio, or aralkyl, in which aryl can be substituted by alkyl, alkoxy, amino, hydroxy, halo, nitro, or alkanoyloxy.
  • 3-acylated analogues of pyridoxal include, but are not limited to, 2- methyl-3-toluoyloxy-4-formyl-5-hydroxymethylpyridine and 2-methyl-.beta.- naphthoyloxy-4-formyl-5-hydroxymethylpyridine.
  • the 3-acylated analogues of pyridoxal-4,5-aminal include wherein the pyridoxal-4,5-aminal is 3-acylated with alkyl, alkenyl, in which alkyl can interrupted by nitrogen, oxygen, or sulfur, and can be unsubstituted or substituted at the terminal carbon with hydroxy, alkoxy, alkanoyloxy, alkoxyalkanoyl, alkoxycarbonyl, or the pyridoxal-4,5-aminal is 3-acylated with dialkylcarbamoyloxy; alkoxy; dialkylamino; alkanoyloxy; alkanoyloxyaryl; alkoxyalkanoyl; alkoxycarbonyl; dialkylcarbamoyloxy; or the pyridoxal-4,5- aminal is 3-acylated with aryl, aryloxy, arylthio, or aralkyl, in which aryl can be substituted by alkyl, alkoxy,
  • 3-acylated analogues of pyridoxal-4,5-aminal include, but are not limited to, 1-morpho lino- 1,3- dihydro-7-(p-toluoyloxy)-6-methylfuro(3,4-c)pyridine; 1 -morpholino- 1 ,3- dihydro-7-(naphthoyloxy)-6-methylfuro(3,4-c)pyridine; 1 -morpholino- 1,3- dihydro-7-pivaloyloxy-6-methylfuro(3,4-c)pyridine; 1 -morpholino- 1 ,3-dihydro- 7-carbamoyloxy-6-methylfuro(3,4-c)pyridine; and 1 -morpholino- 1 ,3-dihydro- acetylsalicyloxy-6-methylfuro(3,4-c)pyridine.
  • the pyridoxine phosphate analogues may be substituted at one or more positions with hydrogen, alkyl, aryl, -CHO— , -CH20H, -CH3, -C02;— CH2— O alkyl, hydroxy, halo, alkoxy, alkanoyloxy, alkylamino, or arylamino.
  • the medicament comprises between
  • the medicament comprises between 100-4000 mg of pyridoxal 5'-phosphate, for example, between 250-750 mg of pyridoxal 5'-phosphate, or about 250 mg of pyridoxal 5 '-phosphate.
  • the methods of the present invention also encompass treating the diseases or conditions described herein by the coadministration of two separate pharmaceutical compositions.
  • a first composition comprises a stimulant of VMH response and a second composition comprises an additional active agent.
  • first and second compositions are preferably co-administered either simultaneously, or in a specifically timed manner.
  • the VMH activator and additional active agent are separate molecules, comprised for example in a mixture or are fused together to form a single VMH- stimulant/additional active agent fusion molecule or variants or derivates thereof.
  • the said fusion molecule can be made using standard chemical synthesis methods, which are obvious to a person of skill in the art.
  • the composition comprises the 4- oxobutanoate ester of sodium Pyridoxal-5 '-Phosphate Glutamic acid.
  • the composition comprises sodium 4- oxobutanoate, a cofactor, and L-Glutamine.
  • the composition comprises 4-aminobutyraldehyde, a cofactor, and L-Glutamine.
  • the cofactor is pyridoxal 5'-phosphate.
  • the compositions of the present invention further comprise an inhibitor of glutamate dehydrogenase enzyme activity such as, for example, pyridoxal-5'- phosphate, 5-deoxypyridoxal, 2-oxoglutarate, and combinations thereof.
  • the composition comprises one or more compounds listed above wherein the active agent is combined structurally with one or more compounds selected from the group consisting of a glutamine, a pyroxidine, a 4-hydroxy-L-threonine and derivatives and lactones thereof.
  • the composition comprises an ester of 4- oxobutanoate and N-pyridoxyl-glutamic acid-5'-monophosphate.
  • equimolar amounts of 4-oxobutanoate and N-Pyridoxyl-glutamic acid-5 '-monophosphate are dissolved in a water-methanol [1 : 1] solution at pH 7, with sodium borohydride, and temperature of the solution is lowered by circulation of ice water around the outside of the reaction vessel until it has reached 10 °C, from which time the reaction is allowed to continue for one hour [1 hr.].
  • the compound is then acidified with sulphuric acid, then neutralized with sodium hydroxide, and evaporated [Rotavap].
  • the yellowish- white powder that remains is dissolved in methanol, which is evaporated in vaccuo.
  • the product is re-dissolved in methanol-water and chromatographed using water as the eluting solvent. The remaining product is washed in methanol, which is evaporated.
  • the composition comprises a 4- oxobutanoate ester of pyridoxal L-glutamic acid monophosphate.
  • the composition comprises a 4-oxobutanoate ester of pyridoxal L- glutamic acid monophosphate that has been phosphatidylated.
  • the composition comprises the phosphatidylated succinyl-L- glutamic acid, pyridoxal ester.
  • the composition comprises pyridoxylated derivatives of 4-oxobutanoate.
  • the composition comprises pyridoxylated derivatives of amino- succinate.
  • the composition comprises pyridoxylated derivatives of succinyl - hydroxy-L-threonine.
  • the composition comprises derivatives of succinic semialdehyde with magnesium pyridoxal 5'- phosphate glutamate as a mixture or complex.
  • the composition comprises 4-oxobutanoate and N-pyridoxyl-glutamic acid-5'- monophosphate as a mixture or complex.
  • the composition comprises the above active agents alone or in combination with diazoxide.
  • the composition comprises a pyridoxal derivative esterified to a pharmaceutically acceptable, pharmacologically active combination of gamma amino butyric acid and ascorbinate or analog, ester, amide, prodrug, conjugate, active metabolite, corresponding enantiomers, diastereoisomers or tautomers, or a pharmaceutically acceptable salt or prodrug thereof or derivative thereof.
  • the resulting ascorbinate composition is further succinylated or glutamylated.
  • the resulting composition further comprises one or more additional therapeutic agents selected from the group consisting of a phosphatidylserine, a GABAergic compound, an inhibitor of glutamate dehydrogenase enzyme activity, 4-hydroxy- L-threonine, and potassium channel activators.
  • a phosphatidylserine a GABAergic compound
  • an inhibitor of glutamate dehydrogenase enzyme activity 4-hydroxy- L-threonine
  • potassium channel activators potassium channel activators.
  • the composition comprises a pyridoxal derivative esterified to a pharmaceutically acceptable, pharmacologically active combination of gamma amino butyric acid and a vitamin complex (VC) or analog, ester, amide, prodrug, conjugate, active metabolite, corresponding enantiomers, diastereoisomers or tautomers, or a pharmaceutically acceptable salt or prodrug thereof or derivative thereof.
  • VC vitamin complex
  • the vitamin complex (VC) is selected from the group comprising vitamins A, B l, B2, B3, B5, B6, B7, choline, inositol, B8, biotin, B9, B 10, PABA, B 12, B 13, B 15, B17, C, P, D, E, K or analog, ester, amide, prodrug, conjugate, active metabolite, corresponding enantiomers, diastereoisomers or tautomers, or a
  • the composition comprises a pyridoxal derivative esterified to a pharmaceutically acceptable, pharmacologically active combination of gamma amino butyric acid and phthaloyl or analog, ester, amide, prodrug, conjugate, active metabolite, corresponding enantiomers,
  • the resulting phthaloyl composition is further succinylated or glutamylated.
  • the resulting composition further comprises one or more additional therapeutic agents selected from the group consisting of a phosphatidylserine, a GABAergic compound, an inhibitor of glutamate dehydrogenase enzyme activity, 4-hydroxy- L-threonine, and potassium channel activators.
  • P-GABA N-phthaloyl-GABA
  • 5-ethoxyoxolan-2-one (gamma- ethoxybutyrolactone) or 5-methoxy- oxolan-2-one (gamma- methoxybutyrolactone) may be used instead of 4-oxobutanoate (succinyl semialdehyde) as the starting active agent.
  • the composition comprises a pyridoxal derivative esterified to a pharmaceutically acceptable, pharmacologically active combination of gamma amino butyric acid and gamma-hydroxybutyrate or analog, ester, amide, prodrug, conjugate, active metabolite, corresponding enantiomers, diastereoisomers or tautomers, or a pharmaceutically acceptable salt or prodrug thereof or derivative thereof.
  • the resulting phthaloyl composition is further succinylated or glutamylated.
  • the gamma-hydroxybutyrate is selected from the group consisting of gamma-butyrolactone, gamma-crotonolactone, 5-ethoxyoxolan-2- one (gamma-ethoxybutyrolactone) and 5-methoxy- oxolan-2-one (gamma- methoxybutyro lactone) .
  • Both fasting and peak insulin release is lower within 30 minutes after the initial dose, and continues to drop for the next 150 minutes. Basal insulin level then stabilizes, remaining between 18 to 22% of pre-dose for another 90 minutes. If a second dose is not administered, plasma insulin returns to pre-treatment levels over the next 3 hours.
  • a fourth embodiment comprises lipophilic derivatives of GABA and 2-Pyrrolidinone, N-dodecanoyl-GABA and L-dodecanoyl-2-pyrrolidinone, respectively, showed anti-epileptic activity, but had no effect on energy homeostasis.
  • Addition of a succinic acid moiety, yielding succinyl-dodecanyl- GABA showed excellent efficacy on oral administration.
  • Doses of 150-350mg of the calcium salt of succinyl-dodecanyl-GABA three to four times a day, by mouth, corrected fasting insulin and paradoxical glucagon abnormalities within four days in two very obese subjects.
  • a fifth embodiment is beta-hydroxybutyrate esterified to 4- hydroxy-L-threonine and administering with phosphatidylserine.
  • a fifth embodiment is beta-hydroxybutyric acid ester of 2-pyrrolidone-5-carboxylate as an alternative medium, and 4-hydroxy-L-threonine, a substrate for pyridoxal.
  • Another exemplary embodiment is a formulation comprising succinyl-hydroxy-L-threonine.
  • Additional embodiments can combine Gamma-Glutamyl GABA, which provides a source for peripheral GABA with the 4-aminobutanoate ester of pyridoxamine;
  • agents utilized by the method of the present invention can be administered to an individual subject per se, or as part of a pharmaceutical composition where it is mixed with a pharmaceutically acceptable carrier.
  • Some of the compounds described herein contain one or more asymmetric centers and this may give raise to enantiomers, diasteriomers, and other stereoisomeric forms which may be defined in terms of absolute stereochemistry as (R)- or (S)-.
  • the present invention is meant to include all such possible diasteriomers and enantiomers as well as their racemic and optically pure forms.
  • Optically active (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the compounds described herein contain olefinic double bonds or other centers of geometric symmetry, and unless specified otherwise, it is intended that the compounds include both E and A geometric isomers. Likewise all tautomeric forms are intended to be included.
  • Suitable routes of administration of the pharmaceutical composition of the present invention may, for example, include oral, rectal, transmucosal, especially transnasal, intestinal or parenteral delivery, including intramuscular, subcutaneous and intramedullary injections as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal and intraocular injections.
  • a preparation in a local rather than systemic manner, for example, via injection of the preparation directly into a specific region of a patient's body or by direct administration to brain tissues (e.g. topical) during, for example, open brain surgery.
  • compositions of the present invention may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • compositions for use in accordance with the present invention may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active ingredients into preparations which, can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • the active ingredients of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological salt buffer.
  • physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological salt buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a patient.
  • Pharmacological preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carbomethylcellulose; and/or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings may be used which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions which can be used orally, include push- fit capsules made of gelatin as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push- fit capsules may contain the active ingredients in admixture with filler such as lactose, binders such as starches, lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active ingredients may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for the chosen route of administration.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the active ingredients for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or a nebulizer with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane or carbon dioxide.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane or carbon dioxide.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, e.g., gelatin for use in a dispenser may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • compositions described herein may be formulated for parenteral administration, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multidose containers with optionally, an added preservative.
  • the compositions may be suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active preparation in water-soluble form.
  • suspensions of the active ingredients may be prepared as appropriate oily or water based injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acids esters such as ethyl oleate, triglycerides or liposomes.
  • Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the active ingredients to allow for the preparation of highly concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. , sterile, pyrogen- free water based solution, before use.
  • a suitable vehicle e.g. , sterile, pyrogen- free water based solution
  • compositions of the present invention may also be formulated in rectal compositions such as suppositories or retention enemas, using, e.g., conventional suppository bases such as cocoa butter or other glycerides.
  • compositions suitable for use in context of the present invention include compositions wherein the active ingredients are contained in an amount effective to achieve the intended purpose. More specifically, a therapeutically effective amount means an amount of active ingredients effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
  • the therapeutically effective amount or dose can be estimated initially from in vitro assays.
  • a dose can be formulated in animal models and such information can be used to more accurately determine useful doses in humans.
  • Toxicity and therapeutic efficacy of the active ingredients described herein can be determined by standard pharmaceutical procedures in vitro, in cell cultures or experimental animals.
  • the data obtained from these in vitro and cell culture assays and animal studies can be used in formulating a range of dosage for use in human.
  • the dosage may vary depending upon the dosage form employed and the route of administration utilized.
  • the exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. (See e.g., Fingl, et al., 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p. 1).
  • the Examples section, which follows provides further guidance as to suitable dosages.
  • dosing can be of a single or a plurality of administrations, with course of treatment lasting from several days to several weeks or until cure is effected or diminution of the disease state or symptoms is achieved.
  • administered will, of course, be dependent on the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician, etc.
  • compositions including the preparation of the present invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • the CDC Disease Control and Prevention with respect to body mass index, or BMI, of a patient.
  • Factors such as weight and height are used to determine whether a person is underweight, normal, overweight or obese.
  • the CDC also notes other methods for analysis of amount and location of fat in a person by using measurements of skinfold thickness and waist circumference, waist-to-hip circumference ratios, and techniques such as ultrasound, computed tomography, and magnetic resonance imaging (MRI). Almost all aspects of a person are affected by overweight and obesity, from physical problems such as knee and ankle joint deterioration, to emotional problems due to society's rejection of overweight
  • Symptoms of overweight and obesity are usually quite obvious, as excess fat is often easy to see on individuals.
  • the medical problems caused by overweight and obesity can be serious and often life-threatening, and include diabetes, shortness of breath and other respiratory problems, gallbladder disease, hypertension, dyslipidemia (for example, high cholesterol or high levels of triglycerides), cancer, osteoarthritis, other orthopedic problems, reflux esophagitis (heartburn), snoring, sleep apnea, menstrual irregularities, infertility and heart trouble.
  • obesity and overweight substantially increase the risk of morbidity from hypertension, dyslipidemia, type 2 diabetes, coronary heart disease, stroke, gallbladder disease, osteoarthritis and endometrial, breast, prostate, and colon cancers.
  • Higher body weights are also associated with increases in all-cause mortality. Most or all of these problems are relieved or improved by permanent significant weight loss. Longevity is likewise significantly increased by permanent significant weight loss.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des méthodes de traitement de troubles du métabolisme, tels que l'obésité, par l'administration à une personne en ayant besoin de composés pharmaceutiques innovatifs qui corrigent, inversent ou neutralisent les anomalies biochimiques et/ou physiologiques responsables des manifestations caractéristiques de la maladie. Dans un mode de réalisation, la présente invention concerne des compositions et des procédés pour une stimulation des neurones sensibles au glucose qui sont également sensibles à la stimulation thermique par l'intermédiaire d'une température corporelle accrue. Dans un mode de réalisation, la présente invention concerne des compositions et des procédés pour la stimulation chimique de neurones dans le VMM pour libérer un neurotransmetteur qui est capté par des structures contiguës, par exemple les récepteurs hypothalamiques latéraux de GABA-A et les récepteurs A, B et C du noyau arqué, etc.
PCT/US2012/040726 2011-06-03 2012-06-04 Compositions et méthodes de traitement pour l'obésité WO2012167243A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2018218161A3 (fr) * 2017-05-26 2020-04-02 Arizona Board Of Regents On Behalf Of The University Of Arizona Méthodes et compositions pour régulariser l'homéostasie du glucose
CN113929762A (zh) * 2021-12-16 2022-01-14 清华大学 3-羟基丁酰化和/或3-羟基戊酰化修饰胰岛素及其应用
US11674953B2 (en) 2015-08-21 2023-06-13 Arizona Board Of Regents On Behalf Of The University Of Arizona Methods for measuring reducing equivalent production by tissues to determine metabolic rates and methods of use

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US5051448A (en) * 1984-07-24 1991-09-24 The Mclean Hospital Corporation GABA esters and GABA analog esters
US20030143167A1 (en) * 2000-06-20 2003-07-31 Astrid Kleen Vitamin B6 derivatives as protective components in the oxidative treatment of hair
US20060078627A1 (en) * 2004-10-08 2006-04-13 Dynapure Nutrition Inc Composition for treatment of obesity or generally aiding weight loss in pill, powder or liquid form, by appetite reduction and metabolism increase, comprising: L- phenylalanine, caffeine, and one or more of the group of all forms of 5-hydroxytryptophan and L-tryptophan, all from either natural or synthetic sources

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US5051448A (en) * 1984-07-24 1991-09-24 The Mclean Hospital Corporation GABA esters and GABA analog esters
US20030143167A1 (en) * 2000-06-20 2003-07-31 Astrid Kleen Vitamin B6 derivatives as protective components in the oxidative treatment of hair
US20060078627A1 (en) * 2004-10-08 2006-04-13 Dynapure Nutrition Inc Composition for treatment of obesity or generally aiding weight loss in pill, powder or liquid form, by appetite reduction and metabolism increase, comprising: L- phenylalanine, caffeine, and one or more of the group of all forms of 5-hydroxytryptophan and L-tryptophan, all from either natural or synthetic sources

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11674953B2 (en) 2015-08-21 2023-06-13 Arizona Board Of Regents On Behalf Of The University Of Arizona Methods for measuring reducing equivalent production by tissues to determine metabolic rates and methods of use
WO2018218161A3 (fr) * 2017-05-26 2020-04-02 Arizona Board Of Regents On Behalf Of The University Of Arizona Méthodes et compositions pour régulariser l'homéostasie du glucose
CN113929762A (zh) * 2021-12-16 2022-01-14 清华大学 3-羟基丁酰化和/或3-羟基戊酰化修饰胰岛素及其应用

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