WO2013167995A2 - Compositions et méthodes de traitement de l'hyperglycémie - Google Patents

Compositions et méthodes de traitement de l'hyperglycémie Download PDF

Info

Publication number
WO2013167995A2
WO2013167995A2 PCT/IB2013/050903 IB2013050903W WO2013167995A2 WO 2013167995 A2 WO2013167995 A2 WO 2013167995A2 IB 2013050903 W IB2013050903 W IB 2013050903W WO 2013167995 A2 WO2013167995 A2 WO 2013167995A2
Authority
WO
WIPO (PCT)
Prior art keywords
compositions
administration
independently
diabetes
complications
Prior art date
Application number
PCT/IB2013/050903
Other languages
English (en)
Other versions
WO2013167995A3 (fr
Inventor
Mahesh Kandula
Original Assignee
Mahesh Kandula
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mahesh Kandula filed Critical Mahesh Kandula
Priority to CN201380030654.2A priority Critical patent/CN104812737A/zh
Priority to SG11201407316QA priority patent/SG11201407316QA/en
Priority to AU2013257716A priority patent/AU2013257716A1/en
Priority to CA2873087A priority patent/CA2873087A1/fr
Priority to JP2015510897A priority patent/JP2016510306A/ja
Publication of WO2013167995A2 publication Critical patent/WO2013167995A2/fr
Publication of WO2013167995A3 publication Critical patent/WO2013167995A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • This disclosure generally relates to compounds and compositions for the treatment of hyperglycemia, diabetes and insulin resistance More particularly, this invention relates to treating subjects with a pharmaceutically acceptable dose of compounds, crystals, esters, stereoisomers, enantiomers, salts, hydrates, prodrugs, or mixtures thereof.
  • the muitifaceted metabolic syndrome is defined as a number of major metabolic disorders that enhances the risk of cardiovascular disease (CVD) - still the most important cause of death in the Western world -- and type 2 diabetes melHtus. It is also known as the insulin resistance syndrome, syndrome X, dysmetabolic syndrome, or the deadly quartet, and is characterized by aberrations in a wide variety of metabolic risk markers such as hyperinsulinemia, impaired glucose metabolism., elevated plasma leveis of triglycerides, decreased levels of high-density lipoprotein cholesteroi (HDL-C), raised blood pressure, centrally distributed obesity, impaired endothelial and haemostatic function, and a low-grade inflammatory state.
  • CVD cardiovascular disease
  • HDL-C high-density lipoprotein cholesteroi
  • Type 2 Diabetes Mellitus is characterized by fasting and postprandial hyperglycemia and relative insulin insufficiency. If left untreated, then hyperglycemia may cause long term microvascular and macrovascular complications, such as nephropathy, neuropathy, retinopathy, and atherosclerosis. This disease causes significant morbidity and mortality at considerable expense to patients, their families and society.
  • T2DM Type 2 Diabetes Mellitus
  • Oxidative stress has long been associated with the late complications of diabetes, and has been implicated in their etiology.
  • the reactive oxygen intermediates, produced in mitochondria, peroxisomes, and the cytosol, are scavenged by cellular defending systems, including enzymatic (ex. superoxide dismutase, glutathione peroxidase GPx, glutathione reductase and cataJase) and nonenzymatic antioxidants (ex. glutathione G-SH, thioredoxin, lipoic acid, ubiquinol, albumin, uric acid, flavonoids, vitamins A, C and E, etc.).
  • enzymatic ex. superoxide dismutase, glutathione peroxidase GPx, glutathione reductase and cataJase
  • nonenzymatic antioxidants ex. glutathione G-SH, thioredoxin, lipoic acid, ubiquinol, albumin,
  • oxidative stress may determine the onset and progression of late-diabetic complications controversy exists about whether the increased oxidative stress is merely associative rather than causal in hyperglycemia.
  • the present invention provides compounds, compositions containing these compounds and methods for using the same to treat, prevent and/or ameliorate the effects of the conditions such as hyperglycemia.
  • the invention herein provides compositions comprising of formula I or pharmaceutical acceptable salts thereof.
  • the invention also provides pharmaceutical compositions comprising one or more compounds of formul ⁇ or intermediates thereof and one or more of pharmaceutically acceptable carriers, vehicles or diluents. These compositions may be used in the treatment of hyperglycemia and its associated complications.
  • the present invention relates to the compounds and compositions of formula I, or pharmaceutically acceptable salts thereof,
  • R independently represents D, H, methyl, ethyl, C3 ⁇ 4CO- or each n is independently 0, 1 , 2, or 3; independently represents H, D, ⁇
  • a is independently 2,3 or 7;
  • each b is independently 3, 5 or 6;
  • e is independently 1 , 2 or 6;
  • e and d are each independently H, D, -OH, -OD, d-CV.-a kyi, - H? or -COCH,,;
  • ⁇ R' , R' ⁇ R' each independentl are selected from the groups consisting of H, D, -OH, -01 methyl, ethyl, -0C3 ⁇ 4, -OCI3 ⁇ 4 or acetyl .
  • kits comprising any of the pharmaceutical compositions disclosed herein.
  • the kit may comprise instructions for use in the treatment of hyperglycemia or its related complications.
  • the application also discloses a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the compositions herein.
  • the pharmaceutical composition is formulated for systemic administration, oral administration, sustained release, parenteral administration, injection, subdemsal administration, or transdermal administration.
  • kits comprising the pharmaceutical compositions described herein.
  • the kits may further comprise instructions for use in the treatment of hyperglycemia or its related complications.
  • compositions described herein have several uses.
  • the present application provides, for example, methods of treating a patient suffering from hyperglycemia or its related complications manifested from metabolic conditions or disorders, metabolic syndrome, chronic diseases or disorders; HypermsuUnemia, Insulin resistance, Glucose intolerance,. Hepatology, Cancer, Respiratory, Hematological, Orthopedic, Cardiovascular, Renal, Skin, Vascular or Ocular complications. DETAI LED DESCRIPTION OF THE ' INVENTION
  • the compounds of the present invention can be present in the form of pharmaceutically acceptable salts.
  • the compounds of the present invention can also be present in the form of pharmaceutically acceptable esters (i.e., the methyl and ethyl esters of the acids of formula I to be used as prodrugs).
  • the compounds of the present invention can also be solvated, i.e. hydrated. The solvation can be affected in the course of the manufacturing process or can take place i .e. as a consequence of hygroscopic properties of an initially anhydrous compound of formula 1 (hydration).
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center or centers and. is described by the - and S-sequencing rules of Calm, Ingold and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as ⁇ +) or ( ⁇ ) ⁇ Isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture" .
  • a molecular conjugate comprises of compounds selected from the group consisting of R-iipoie acid (CAS No, 1200-22-2), salsalate (CAS No. 552-94-3). acetylcysteine (CAS No. 61 -91-.1 ), Eieosapentaenoic acid (CAS No. 10417- 94-4), Docosahexaenoic acid (CAS No. 6217-54-5).
  • polymorph as used herein is art-recognized and refers to one crystal structure of a given compound.
  • parenteral administration and “administered parenteral! " as used herein refer to modes of administration other than enteral and topical administration, such as injections, and include without limitation intravenous, intramuscular, intrapleural, intravascular, intrapericardiai, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intrademial, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intra sternal injection and infusion.
  • a "patient,' " " "subject,” or “host” to be treated by the subject method may mean either a human or non-human animal, such as primates, mammals, and vertebrates.
  • compositions, polymers and other materials and/or dosage fonns which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of mammals, human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier is art-recognized, and includes, for example, pharmaceutically acceptable materials, compositions or vehicles, such as a. liquid or solid .filler, diluent, so!
  • a pharmaceutically acceptable carrier is non-pyrogenic.
  • materials which may serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carhoxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com oil and soybean oil; ( 10) glycols, such as propylene glycol; (11) polyols.
  • sugars such as lactose, glucose and sucrose
  • starches such as corn starch and potato starch
  • cellulose, and its derivatives such as sodium carhoxymethyl cellulose, ethyl cellulose and cellulose acetate
  • (4) powdered tragacanth (5) malt; (6) gelatin; (7)
  • esters such as ethyl oleate and ethyi lattrate
  • agar such as glycerin, sorbitol, mannitol and polyethylene glycol
  • esters such as ethyl oleate and ethyi lattrate
  • agar such as agar
  • buffering agents such as magnesium hydroxide and aluminum hydroxide
  • prodrug is intended to encompass compounds that, under physiological conditions, are converted into the therapeutically active agents of the present invention.
  • a common method for making a prodrug is to include selected moieties that are hydro!yzed under physiological conditions to reveal the desired molecule.
  • the prodrug is converted by an enzymatic activity of the host animal .
  • prophylactic or therapeutic treatment is art-recognized and includes administration to the host of one or more of the subject compositions, if it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, i.e., it protects the host against developing the unwanted condition, whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i .e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).
  • the unwanted condition e.g., disease or other unwanted state of the host animal
  • the term "predicting" as used herein refers to assessing the probability related diseases patient will suffer from abnormalities or complication and/or terminal platelet aggregation or failure and/or death (i.e. mortality) within a defined time window (predictive window) in the future.
  • the mortality may be caused by the central nervous system or complication.
  • the predictive window is an interval in which the subject will develop one or more of the said complications according to the predicted probability.
  • the predictive window may be the entire remaining lifespan of the subject upon analysis by the method of the present i nvention.
  • treating is art -recognized and includes preventing a disease, disorder or condition from occurring in an animal which may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it; inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and/or condition.
  • Treating the disease or condition includes ameliorating at least one symptom of the particular disease or condition, even if the underlying pathophysiology is not affected, such as treating the hyperglycemia, insulin resistance, diabetes mellitus, diabetes insipidus, type 1 diabetes, type 2 diabetes, microvascular complications, macrovascular complications, lipid disorders, hypertriglyceridemia, cardiovascular complications, and post prandsal hyperglycemia of a subject by administration of an agent even though such agent does not treat the cause of the condition.
  • the term "treating”, “treat” or “treatment” as used herein includes curative, preventative (e.g., prophylactic), adjunct and palliative treatment.
  • 0029 The phrase "therapeutically effective amount" is an art-recognized term.
  • the term refers to an amount of a salt or composition disclosed herei that produces some desired effect at a reasonable benefit/risk ratio applicable to any medical treatment, in certain embodiments, the term refers to that amount necessary or sufficient to eliminate or reduce medical symptoms for a period of time
  • the effective amount may vary depending on such factors as the disease or condition being treated, the particular targeted constructs being administered, the size of the subject, or the severity of the disease or condition.
  • One of ordinary skill in the art may empirically determine the effective amount of a particular composition without necessitating undue experimentation.
  • the pharmaceutical composition described herein are formulated in a manner such that said compositions will be delivered to a patient in a therapeutically effective amount, as part of a prophylactic or therapeutic treatment.
  • the desired amount of the composition to be administered to a patient will depend on absorption, inactivation, and excretion rates of the drug as well as the delivery rate of the salts and compositions from the subject compositions. It is to be noted that dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions. Typically, dosing will be determined using techniques known to one skilled in the art.
  • the optimal concentration and/or quantities or amounts of any particular salt or composition may be adjusted to accommodate variations in the treatment parameters.
  • treatment parameters include the clinical use to which the preparation is put, e.g., the site treated, the type of patient, e.g., human or non-human, adult or child, and the nature of the disease or condition.
  • the dosage of the subject compositi ns provided herein may be determined by reference to the plasma concentrations of the therapeutic composition or other encapsulated materials. For example, the maximum plasma concentration (Crnax) and the area under the plasma conce tration-time curve from time 0 to infinity may he used.
  • sustained release When used with respect to a pharmaceutical composition or other material, the term "sustained release" is art-recognized.
  • a subject composition which releases a substance over time may exhibit sustained release characteristics, in contrast to a bolus type administration in which the entire amount of the substance is made biologically available at one time.
  • one or more of the pharmaceutically acceptable excspients may undergo gradual or delayed degradation (e.g., through hydrolysis) with concomitant release of any material incorporated therein, e.g., an therapeutic and/or biologicall active salt and/or composition, for a sustained or extended period (as compared to the release from a bolus).
  • This release may result in prolonged delivery of therapeutically effective amounts of any of the therapeutic agents disclosed herein.
  • systemic administration means administration of a subject composition, therapeutic or other material at a site remote from the disease being treated.
  • Administration of an agent for the disease being treated may be termed “local” or “topical” or “regional” administration, other than directly into the central nervous system, e.g., by subcutaneous administration, such that it enters the patient's system and, thus, i subject to metabolism and other like processes.
  • the phrase "therapeutically effective amount" is an art-recognized term.
  • the term refers to an amount of a salt or composition disclosed herein that produces some desired effect at a reasonable benefit/risk ratio applicable to any medical treatment, in certain embodiments, the term refers to that amount necessary or sufficient to eliminate or reduce medical symptoms for a period of time.
  • the effective amount may vary depending on such factors as the disease or condition being treated, the particular targeted constructs being admi n stered, the size of the subject, or the severity of the disease or condition.
  • One of ordinary skill in the art may empirically determine the effective amount of a particular composition without necessitating undue experimentation.
  • fOO j The present disclosure also contemplates prodrugs of the compositions disclosed herein, as wel l as pharmaceuticall acceptable salts of said prodrugs.
  • compositions comprising a pharmaceutically acceptable carrier and the composition of a compound of Formula.
  • I may be formulated for systemic or topical or oral administration.
  • the pharmaceutical composition may be also formulated for oral administration, oral solution, injection, subdermal administration, or transdermal administration.
  • the pharmaceutical composition may further comprise at least one of a pharmaceutically acceptable stabilizer, diluent, surfactant, filler, binder, and lubricant.
  • the pharmaceutical compositions described herein will incorporate the disclosed compounds and compositions (Formula 1) to be delivered in an amount sufficient to deliver to a patient a therapeutically effective amount of a compound of formula I or composition as part of a prophylactic or therapeutic treatment.
  • the desired concentration of formula I or its pharmaceutical acceptable salts will depend on absorption, inactivation, and excretion rates of the drug as well as the delivery rate of the salts and compositions from the subject, compositions. It is to be noted that dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions. Typically, dosing will be determined using techniques known to one skilled in the art.
  • the optimal concentration and/or quantities or amounts of any particular compoimd of formul ⁇ may be adjusted to accommodate variations in the treatment parameters.
  • treatment parameters include the clinical use to which the preparation is put, e.g., the site treated, the type of patient, e.g., human or non-human, adult or child, and the nature of the disease or condition.
  • concentration and/or amount of any compound of formula ⁇ may be readily identified by routine screening in animals, e.g., rats, by screening a range of concentration and/or amounts of the materia! in question using appropriate assays.
  • Known methods axe also available to assay local tissue concentrations, diffusion rates of the salts or compositions, and local blood flow before and after administration of therapeutic formulations disclosed herein.
  • One such method is niicrodialysss, as reviewed by T. E, Robinson et al., 1 91 , microdtaiysis in the oeurosctences, Techniques, volume 7, Chapter .
  • the methods reviewed by Robinson may be applied, in brief as follows. A microdialysis loop is placed in situ in a test animal.
  • Dialysis fluid is pumped through the loop.
  • compounds with formula 1 suc as those disclosed herein are injected adjacent to the loop, released drugs are collected in the dialysate in proportion, to their local tissue concentrations.
  • the progress of diffusion of the salts or compositions may be determined thereby with suitable calibration procedures using known concentrations of salts or compositions.
  • the dosage of the subject compounds of formula 1 provided herein may be determined by reference to the plasma concentrations of the therapeutic composition or other encapsulated materials.
  • the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to infinity may be used.
  • an effective dosage for the compounds of Formulas I is in the range of about 0.01 mg kg day to about 100 mg/kg/day in single or divided doses, for instance 0.01 mg kg day to about 50 mg kg day in single or divided doses.
  • the compounds of Formulas I may be administered at a dose of, for example, less than 0.2 mg kg day, 0.5 mg kg/day, 1.0 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day, 20 mg/kg/day, 30 mg kg/day, or 40 mg kg day.
  • Compounds of Formula ⁇ may also be administered to a human patient at a dose of, for example, between 0.1 mg and 1000 mg, between 5 mg and 80 mg, or less than .1.0, 9.0. 12.0, 20.0, 50.0, 75.0, 100, 300, 400, 500, 800, 1000, 2000, 5000 mg per day.
  • the composiiions herein are administered at an amount that is less than 95%, 90%, 80% 70%, 60%, 50%, 40%, 30%, 20%, or 10% of the compound of formula I required for the same therapeutic benefit.
  • An effective amount of the compounds of formula 1 described herein refers to the amount of one of said salts or compositions which is capable of inhibiting or preventing a disease.
  • An effective amount may be sufficient to prohibit, treat, alleviate, ameliorate, halt, restrain, slow or reverse the progression, or reduce the severity of a complication resulting from, nerve damage or demyeiization and/or elevated reactive oxidative- nitrosative species and/or abnormalities in physiological homeostasis' s, in patients who are at risk for such complicati ns.
  • these methods include both medical therapeutic (acute) and/or prophylactic (prevention) administration as appropriate
  • the amount and timing of compositions administered will, of course, be dependent on the subject being treated, on the severity of the affliction, on the manner of administration and on the judgment of the prescribing physician.
  • the dosages given above are a guideline and the physician may titrate doses of the drug to achieve the treatment that the physician considers appropriate for the patient.
  • the physician must balance a variety of factors such as age of the patient, presence of preexisting disease, as well as presence of other diseases.
  • compositions provided by this application may be administered to a subject in need of treatment by a variety of conventional routes of administration, including orally, topically, parenteraiiy, e.g., intravenously, subcutaneously or intramedullary. Further, the compositions may be administered intranasal! y, as a rectal suppository, or using a "flash" formulation, i.e., allowing the medication to dissolve i the mouth without the need to use water Furthermore, the compositions may be administered to a subject in need of treatment by controlled release dosage forms, site specific drug delivery, transdermal drug delivery, patch (active/passive) mediated drug delivery, by stereotactic injection, or in nanoparticles.
  • compositions may be administered alone or in combination with pharmaceutically acceptable carriers, vehicles or diluents, in either single or multiple doses.
  • suitable pharmaceutical carriers, vehicles and diluents include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
  • the pharmaceutical compositions formed by combining the compositions and the pharmaceutically acceptable carriers, vehicles or diluents are then readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions and the like.
  • These pharmaceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, excipients and the like.
  • tablets containing various excipients such as L-arginine, sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrates such as starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium iauryl sulfate and talc are often useful for tahletting purposes.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules. Appropriate materials for this include lactose or milk sugar and high molecular weight polyethylene glycols.
  • the essentia! active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and. if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and combinations thereof.
  • the compounds of formula 1 may also comprise enterically coated comprising of various excipients, as is well known in the pharmaceutical art.
  • solutions of the compositions may be prepared in (for example) sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solutions may be employed.
  • aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • these particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
  • the formulations for instance tablets, may contain e.g. 10 to 100, 50 to 250, 150 to 500 mg, or 350 to 800 mg e.g. 10, 50, 100, 300, 500, 700, 800 nig of the compounds of formula 1 disclosed herein, for instance, compounds of formula 1 or pharmaceutical acceptable salts of a compounds of Formula 1
  • a composition as described herein may be administered orally, or parenierally (e.g., intravenous, intramuscular, subcutaneous or intramedullary). Topical administration ma also be indicated, for example, where the patient is suffering from gastrointestinal disorder that prevent oral administration., or whenever the medication is best applied to the surface of a tissue or organ as determined by the attending physician. Localized administration may also he indicated, for example, when a high dose is desired at the target tissue or organ.
  • the active composition may take the form of tabl ets or lozenges formulated in a conventional manner.
  • 0050 The dosage administered will be dependent upon the identity of the metabolic disease; the type of .host involved, including its age, health and weight; the kind of concurrent treatment, if any, the frequency of treatment, and therapeutic ratio.
  • dosage levels of the administered active ingredients are: intravenous, 0.1 to about 200 mg kg; .intramuscular, 1 to about 500 mg kg; orally, 5 to about 1000 mg/kg; intranasal instillation, 5 to about 1000 mg/kg; and aerosol, 5 to about 1 00 mg/kg of host body weight.
  • an active ingredient can be present in the compositions of the present invention for localized use about the cutis, intranasaiiy, pharyngolaryngeaily, bronchi ally, intra vaginally, rectaliy, or ocularly in a concentration of from about 0.01 to about 50% w/w of the composition; preferably about 1 to about 20% w/w of the composition; and for parenteral use in a concentration of from about 0.05 to about 50% w/v of the composition and preferably from about 5 to about 20% w/v.
  • compositions of the present invention are preferably presented for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, suppositories, sterile parenteral solutions or suspensions, sterile non-parenterai solutions of suspensions, and oral solutions or suspensions and the like, containing suitable quantities of an active ingredient.
  • unit dosage forms such as tablets, capsules, pills, powders, granules, suppositories, sterile parenteral solutions or suspensions, sterile non-parenterai solutions of suspensions, and oral solutions or suspensions and the like, containing suitable quantities of an active ingredient.
  • unit dosage forms such as tablets, capsules, pills, powders, granules, suppositories, sterile parenteral solutions or suspensions, sterile non-parenterai solutions of suspensions, and oral solutions or suspensions and the like, containing suitable quantities of an active ingredient.
  • the tablet core contains one or more I dropliilic polymers.
  • Suitable hydrophilic polymers include, but are not limited to, water swellable cellulose derivatives, poly alky lene glycols, thermoplastic polyalkylene oxides, acrylic polymers, hydrocolloids., clays, gelling starches, swelling cross-linked polymers, and mixtures thereof.
  • suitable water swellable cellulose derivatives include, but are not limited to, sodium carboxymethylcellulose, cross-linked hydroxypropylcellulose, hydroxy propyl eel lul ose (HPC), h droxypropy Imethylcel 1 ul ose (HP C), h droxy isopropylcellul ose, hy droxy buty !
  • Suitable polyalkylene glycols include, but are not limited to, polyethylene glycol.
  • suitable thermoplastic polyalkylene oxides include, but are not. limited to, fx>Sy(ethylerie oxide).
  • acrylic polymers include, but are not limited to, potassium methacrylatedi vinylbenzene copolymer, polymethylmethacrylate, high-molecular weight crossl inked acrylic acid homopolymers and copolymers such as those commercially available from Noveon Chemicals under the tradename CARBOPOL tM .
  • hydrocolloids include, but are not limited to, alginates, agar, guar gum, locust bean gum, kappa carrageenan, iota carrageenan, tara, gum arabic, tragacanth, pectin, xanthan gum, gel I an gum, maltodextrin, galactomannan, pusstulan, laminarin, sclerogiucan, gum arabic, inulin, pectin, gelatin, whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin, chitosan, and mixtures thereof.
  • Suitable clays include, but are not limited to, smectites such as bentonite, kaolin, and laponite; magnesium trisilicate; magnesium aluminum silicate; and mixtures thereof.
  • suitable gelling starches include, but are not limited to, acid hydrolyzed starches, swelling starches such as sodium starch glycolate and derivatives thereof and mixtures thereof.
  • suitable swelling cross-linked polymers include, but are not limited to, cross-linked polyvinyl pyrrol idone, cross-linked agar, and cross-linked carboxymethylcellu!ose sodium, and mixtures thereof.
  • the carrier may contain one or more suitable excipients for ihe formulation of tablets.
  • suitable excipients include, but are not limited to, fillers, adsorbents, binders, disintegrants, lubricants, giidanis, release-modifying excipients, superdisintegrants, antioxidants, and mixtures thereof.
  • Suitable binders include, but are not limited to, dry binders such as polyvinyl pyrroli done and hydroxypropylmethylcellulose; wet binders such as water-soluble polymers, including hydrocolloids such as acacia, alginates, agar, guar gum, locust bean, carrageenan, carboxymethyicellulose, tara, gum arabic, tragacanth. pectin, xanthan. gellan, gelatin, maltodextrin, galactomannao, pusstulan, laminarin, scleroglucari., inuHn, whelan, rhamsan, zooglan, methylan.
  • dry binders such as polyvinyl pyrroli done and hydroxypropylmethylcellulose
  • wet binders such as water-soluble polymers, including hydrocolloids such as acacia, alginates, agar, guar gum, locust bean, carrageenan,
  • chitin cyclodextrin. chiiosan, polyvinyl pyrrolidone, cellulosics, sucrose, and starches; and mixtures thereof.
  • Suitable disintegrants include, but are not limited to, sodium starch gl col ate, cross-linked poly vin l pyrrolidone, cross-linked carboxymethyleellulose, starches, macrocrystalline cellulose, and mixtures thereof.
  • Suitable lubricants include, but are not limited to. long chain fatty acids and their salts, such as magnesium stearate and stearic acid, talc, glycerides waxes, and mixtures thereof.
  • Suitable gli.dan.ts include, but are not limited to, colloidal silicon dioxide.
  • Suitable release-modifying excipients include, but are not limited to, insoluble edible materials, pH-dependent polymers, and mixtures thereof,
  • Suitable insoluble edible materials for use as release-modifying excipients include, but are not limited to, water-insoluble polymers and low-melting hydrophobic materials, copolymers thereof ' and mixtures thereof.
  • suitable water- insoluble polymers include, but are not limited to, efhylceilulose, polyvinyl alcohols, polyvinyl acetate, polycaprolactones, cellulose acetate and its derivatives, acrylates, methacryiat.es, acrylic acid copolymers, copolymers thereof and mixtures thereof.
  • Suitable l w-melting hydrophobic materials include, but are not limited to, fats, fatty acid esters, phospholipids, waxes, and mixtures thereof.
  • suitable fats include, but are not limited to, hydrogenated vegetable oils such as for example cocoa butter, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated sunflower oil, and hydrogenated soybean oil, free fatty acids and their salts, and mixtures thereof.
  • suitable fatty acid esters include, but are not limited to, sucrose fatty acid esters, mono-, di ⁇ , and triglycerides, glyceryl behenate, glyceryl pa!mitostearate, glyceryl moiiosiearate, glyceryl tri stearate, glyceryl trilaur late, glyceryl myiistate, GlycoWax- 932, lauroyl macrogol-32 glycerides, stearoyl macrogol-32 glycerides, and mixtures thereof.
  • Suitable phospholipids include phosphatidyl choline, phosphotidyl serene, phosphotidyl enositoi, phosphotidic acid, and mixtures thereof.
  • suitable waxes include, but are not limited to, carnauba wax, spermaceti wax, beeswax, candeJilla wax, shellac wax, macrocrystalline wax, and paraffin wax; fat-containing mixtures such as chocolate, and mixtures thereof.
  • super disintegrates include, but are not limited to, croscarmeilose sodium, sodium starch glycolate and cross- linked povidone (erospovidone). in one embodiment the tablet, core contains up to abou 5 percent by weight of such super disi tegrant.
  • antioxidants include, but are not limited to, tocopherols, ascorbic acid, sodium pyrosulfite, butylhydroxytoluene, buiylated hydroxyanisole, edetic acid, and edetate salts, and mixtures thereof.
  • preservati ves include, but are not limited to, citric acid, tartaric acid, lactic acid, malic acid, acetic acid, benzoic acid, and sorbic acid, and mixtures thereof.
  • the immedi ate release coating has an average thickness of at least 50 microns, such as from about 50 microns to about 2500 microns, e.g., from about 250 microns to about 1000 microns, in embodiment, the immediate release coating is typicall compressed at a density of more than about 0.9 g/cc, as measured by the weight and volume of that specific layer.
  • the immediate release coating contains a first portion and second portion, wherein at least one of the portions contains the second pharmaceutically active agent.
  • the portions contact each other at a center axis of the tablet.
  • the first portion includes the first pharmaceutically active agent and the second portion includes the second pharmaceutically active agent
  • the first portion contains the first pharmaceutically active agent and the second portion contains the second pharmaceutically active agent.
  • one of the portions contains a third pharmaceutically active agent.
  • one of the portions contains a second immediate release portion of the same pharmaceutically active agent as that contained in the tablet core.
  • 0O63J in one embodiment, the outer coating portion is prepared as a dry blend of materials prior to addition to the coated tablet core. In another embodiment the outer coating portion is included of a dried granulation including the pharmaceutically active agent,
  • Formulations with different drug release mechanisms described above could be combined in a final dosage form containing single or multiple units.
  • Examples of multiple units include multilayer tablets, capsules containing tablets, beads, or granules in a solid or liquid form.
  • Typical, immediate release formulations include compressed tablets, gels, films, coatings, liquids and particles thai can be encapsulated, for example, in a gelatin capsule, Many methods for preparing coatings, covering or incorporating drugs, are known in the art
  • the immediate release dosage, unit of the dosage form i.e., a tablet, a plurality of drug-containing beads, granules or particles, or an outer layer of a coated core dosage form, contains a therapeutically effective quantity of the active agent with conventional pharmaceutical excipients.
  • the immediate release dosage unit may or may not be coated, and may or may not be admixed with the delayed release dosage unit or units (as in an encapsulated mixture of immediate release drug-containing granules, particles or beads and delayed release drug-containing granules or beads).
  • Extended release formulations are generally prepared as diffusion or osmotic systems, for example, as described in "Remingto— The Science and Practice of Pharmacy * ⁇ 20th. Ed.. Lippiiicott Williams & Wilkins, Baltimore, Md., 2000).
  • A. diffusion system typically consists of one of two types o devices, reservoir and matrix, which are wellknown and described in die art.
  • the matrix devices are generally prepared by compressing the drug with a slowly dissolving polymer carrier into a tablet form.
  • An immediate release portion can be added to the extended release system by means of either applying an immediate release layer on top of the extended release core; using coating or compression processes or in a multiple unit system such as a capsule containing extended and immediate release beads.
  • Delayed release dosage formulations are created by coating a solid dosage form with a film of a polymer which is insoluble in the acid environment of the stomach, but soluble in the neutral environment of small intestines.
  • the delayed release dosage units can be prepared, for example, by coating a drug or a drug-containing composition with a selected coating material .
  • the drug-containing composition may be a tablet for incorporation into a capsule, a tablet for use as an inner core in a "coated core" dosage form, or a plurality of drug-containing beads, particles or granules, for incorporation into either a tablet or capsule.
  • a pulsed release dosage form is one that mimics a multiple dosing profile without repeated dosing and typically allows at least a twofold reduction in dosi ng frequency as compared to the drug presented as a conventional dosag form (e.g., as a solution or prompt drug-releasing, conventional solid dosage form).
  • a pulsed release profile is characterized by a time period of no release (lag time) or reduced release followed by rapid drug release.
  • Each dosage form contains a therapeutically effective amount of active agent.
  • approximately 30 wt. % to 70 wt. %, preferably 40 wt. % to 60 wt. %., of the total amount of active agent in the dosage form is released in the initial pulse, and., correspondingly approximately 70 wt. % to 3.0 wt % depict preferably 60 wt. % to 40 wt. %, of the total amount of active agent in the dosase form is released in the second pulse.
  • the second pulse is preferably released approximately 3 hours to less than 14 hours, and more preferably approximately 5 hours to 12 hours, following administration.
  • 0071 J Another dosage form contains a compressed tablet or a capsule having a drug- containing immediate release dosage unit, a delayed release dosage unit and an optional second delayed release dosage unit.
  • the immediate release dosage unit contains a plurality of beads, granules particles that release drug substantially immediately following oral administration to provide an initial dose.
  • the deiayed release dosage unit contains a plurality of coated beads or granules, which release drug approximately 3 hours to 14 hours following oral administration to provide a second dose.
  • dilute sterile, aqueous or partially aqueous solutions (usually in about 0.1% to 5% concentration), otherwise similar to the above parenteral solutions, may be prepared,
  • compositions of the present application maybe lyophilized or subjected to another appropriate drying technique such as spray drying.
  • the subject compositions may be administered once, or may be divided into a number of smaller doses to be administered at varying intervals of time, depending in part on the release rate of the compositions and the desired dosage.
  • Formulations useful in the methods provided herein include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, aerosol and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of a subject composition which may be combined with a carrier material to produce a single dose may vary depending upon the subject being treated, and the particular mode of administration.
  • Methods of preparing these formulations or compositions include the step of bringing into association subject compositions with the carrier and, optionally, one or more accessory ingredients in general , the formulations are prepared by uniformly and intimately bringing into association a subject composition with liquid carriers, or finely di vided solid carriers, or both, and then, if necessary, shaping the product.
  • the compounds of formula .1 described herein may be administered in inhalant or aerosol formulations.
  • the inhalant or aerosoi formulations may comprise one or more agents, such as adjuvants, diagnostic agents, imaging agents, or therapeutic agents useful in inhalatio iherapy.
  • the final aerosol formulation may for example contain 0.005-90% w/w, for instance 0.005-50%, 0.005-5% w/w, or 0.0 ⁇ - 1.0% w/w, of medicament relative to the total weight of the formul tion.
  • the subject composition is mixed with one or more pharmaceutically acceptable carriers and/or an of the following: (I) fillers or extenders, such as starches, lactose, sucrose, glucose, rnannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethyiceliulose, alginates, gelatin, polyvinyl pyrroiidone, sucrose and or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (?) wetting agents, such as, for example, acetyl
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft, and hard-filled gelatin capsules using lactose or milk sugars, as well as .high molecular weight polyethylene glycols and the like.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsioris, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example,, water or other solvents, solubilizing agents and ernuis.ifse.rs, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, corn, peanut, sunflower, soybean, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solub
  • Suspensions in addition to the subject compositions, may contain suspending agents such as, for example, ethoxy Sated isostearyl alcohols, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar- agar and tragacanth, and mixtures thereof.
  • suspending agents such as, for example, ethoxy Sated isostearyl alcohols, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar- agar and tragacanth, and mixtures thereof.
  • Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or .more suitable non-irritating carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax, or a salicylate, and which is solid at room tem erature, but liquid at bod temperature and, therefore, will melt in the appropriate body cavity and release the encapsulated corapound(s) and composition ⁇ ).
  • Formulations which are suitable for vaginal admini tration also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing such carriers as are known in the art to be appropriate.
  • Dosage forms for transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants.
  • a subject composition may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.
  • the complexes may include lipophilic and hydrophilic groups to achieve the desired water solubilit and transport properties.
  • the ointments, pastes, creams and gels may contain, in addition to subject compositions, other carriers, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and spra s may contain, in addition to a subject composition, exci ients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and po!yamide powder, or mixtures of such substances.
  • Sprays may additionally contain customary propellants, such as chiorofluorohydrocarbons arid volatile unsubstituted hydrocarbons, such as butane and propane.
  • a transdermal patch may comprise: a substrate sheet comprising a composite film formed of a resin composition comprising 100 parts by weight of a polyvinyl chlonde-po!yurethane composite and 2-10 parts by weight, of a styrene-ethylene-butylene-styrene copolymer, a first adhesive layer on the one side of the composite film, and a polyalkylene terephthaiaie film adhered to the one side of the composite film by means of the first adhesive layer, a primer layer which comprises a saturated polyester resin and is formed on the surface of the polyalkylene tereph thai ate film; and a second adhesive Iayer comprising a siyrene-diene-styrene block copolymer containing a pharmaceutical agent layered on the primer layer.
  • a method for the manufacture of the above-mentioned substrate sheet comprises preparing the above resin composition molding the resin composition into a composite film by a calendar process, and then adhering a polyalkyiene terephthalate film on one side of the composite Film by means of an adhesive layer thereby forming the substrate sheet, and forming a primer layer comprising a saturated polyester resin on the outer surface of the polyalkyiene terephthalate film.
  • Another type of patch comprises incorporating the drug directly in a pharmaceutically acceptable adhesive and laminating the drug-containing adhesive onto a suitable backing member, e.g. a polyester backing membrane.
  • the drug should be present at a concentration which will not affect the adhesive properties, and at the same time deliver the required clinical dose.
  • Transdermal patches may be passive or active. Passive transdermal drug delivery systems currently available, such as the nicotine, estrogen and nitroglycerine patches, deliver small -molecule drugs. Many of the newly developed proteins and peptide drugs are too large to be delivered through passive transdermal patches and may be delivered using technology such as electrical assist (iontophoresis) for large-molecule drugs.
  • Iontophoresis is a technique employed for enhancing the .flux of ionized substances through membranes by application, of electric current.
  • An iontophoretic membrane is given, in U.S. Pat. No. 5,080,646 to Theeuwes.
  • the principal mechanisms by which iontophoresis enhances molecular transport across the skin are (a) repelling a charged ion from an electrode of the same charge, (b) electroos.mos.is, the convective movement of solvent that occurs through a charged pore in response the preferential passage of counter-ions when an electric Field is applied or (c) increase skin permeability due to application of electrical current.
  • kits it may be desirable to administer in the form of a kit, it may comprise a container for containin the separate compositions such as a divided bottle or a divided foil packet
  • the kit comprises directions for the administration of the separate components.
  • the kit farm is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.
  • kits are so-called blister pack.
  • Blister packs are well known in the packaging industry and are widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively sti f material covered with a foil of a plastic material that may be transparent.
  • Methods and compositions for the treatment of hyperglycemia comprising administering to a patient in need thereof a therapeutically effective amount of compound of Formula I:
  • R independently represents D, H, methyl, ethyl, C3 ⁇ 4CO- or each n is independently 0,1, 2, or 3;
  • R" independently represents H, D, 33
  • R independently represents ⁇
  • a is independently 2,3 or 7;
  • each b is independentl 3, 5 or 6;
  • e is independently 1, 2 or 6;
  • c and d are each independently H, D, -OH, -OD, CpCc-alkyl, - H 2 or -COC3 ⁇ 4;
  • ⁇ R', R' ⁇ R' each i dependentl are selected from the groups consisti g of H, D, -OH, -OD, methyl, ethyl, -OC3 ⁇ 4, -OCD 3 or acetyl.
  • the invention also includes methods for treating hyperglycemia, insulin resistance, diabetes mellitus, diabetes insipidus, type i diabetes, type 2 diabetes, microvascular complications, macrovascular complications, lipid disorders, prediabetes, obesity, arrhythmia, myocardial infarction, stroke, neuropathy, renal complications, hypertriglyceridemi , cardiovascular complications, and post prandial hyperglycemia.
  • the compound of Formula I (1-3) is therefore, at least 260 times more soluble in water than EPA itself. This is a clear indication of an unexpectedly high degree of bioavailability of the compositions of the invention. Highly water soluble medicinal preparations, when administered orally, result in efficient absorption from the gastrointestinal tract in to systemic circulation. Furthermore, water soluble preparations are especially suitable for parenteral administration.
  • sample refers to a sample of a body fluid, to a sample of separated cel ls or to a sample from a tissue or an organ.
  • Samples of body fluids can be obtained by well known techniques and include, preferably, samples of blood, piasma, serum, or urine, more preferably, samples of blood, plasma or serum.
  • compositions and methods for treating hyperglycemia and their complications are provided among other things compositions and methods for treating hyperglycemia and their complications. While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not. .restrictive.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Endocrinology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Emergency Medicine (AREA)
  • Child & Adolescent Psychology (AREA)
  • Nutrition Science (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

La présente invention concerne des composés de formule I ou leurs sels pharmaceutiquement acceptables, ainsi que leurs formes polymorphes, leurs solvates, leurs énantiomères, leurs stéréoisomères et leurs hydrates. Elle concerne des compositions pharmaceutiques comprenant une quantité efficace de composés de formule I; et des méthodes de traitement de l'hyperglycémie. Ces compositions peuvent être formulées pour administration par voie orale, buccale, rectale, topique, transdermique, muqueuse, intraveineuse, parentérale, sous forme de sirop ou d'injection. Ces compositions peuvent être utilisées pour traiter la résistance à l'insuline, le diabète sucré, le diabète insipide, le diabète de type 1, le diabète de type 2, les complications microvasculaires, les complications macrovasculaires, les troubles lipidiques, le prédiabète, l'obésité, l'arythmie, l'infarctus du myocarde, l'accident vasculaire cérébral, la neuropathie, les complications rénales, l'hypertriglycéridémie, les complications cardiovasculaires, et l'hyperglycémie post-prandiale.
PCT/IB2013/050903 2012-05-08 2013-02-03 Compositions et méthodes de traitement de l'hyperglycémie WO2013167995A2 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
CN201380030654.2A CN104812737A (zh) 2012-05-08 2013-02-03 用于治疗高血糖症的组合物和方法
SG11201407316QA SG11201407316QA (en) 2012-05-08 2013-02-03 Compositions and methods for the treatment of hyperglycemia
AU2013257716A AU2013257716A1 (en) 2012-05-08 2013-02-03 Compositions and methods for the treatment of hyperglycemia
CA2873087A CA2873087A1 (fr) 2012-05-08 2013-02-03 Compositions et methodes de traitement de l'hyperglycemie
JP2015510897A JP2016510306A (ja) 2012-05-08 2013-02-03 高血糖の治療のための組成物及び方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1811/CHE/2012 2012-05-08
IN1811CH2012 2012-05-08

Publications (2)

Publication Number Publication Date
WO2013167995A2 true WO2013167995A2 (fr) 2013-11-14
WO2013167995A3 WO2013167995A3 (fr) 2016-09-01

Family

ID=54193690

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2013/050903 WO2013167995A2 (fr) 2012-05-08 2013-02-03 Compositions et méthodes de traitement de l'hyperglycémie

Country Status (6)

Country Link
JP (1) JP2016510306A (fr)
CN (1) CN104812737A (fr)
AU (1) AU2013257716A1 (fr)
CA (1) CA2873087A1 (fr)
SG (1) SG11201407316QA (fr)
WO (1) WO2013167995A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016198971A1 (fr) * 2015-06-08 2016-12-15 Mohan M Alapati Compositions et méthodes de traitement de l'hyperglycémie et du syndrome métabolique

Family Cites Families (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3992441A (en) * 1972-12-26 1976-11-16 Pfizer Inc. Sulfamylbenzoic acids
JPS5283951A (en) * 1976-01-01 1977-07-13 Nippon Shinyaku Co Ltd Remedy for hyperglycemia and depressant for lipid-biosythesis
JPS5943946B2 (ja) * 1978-04-28 1984-10-25 日本新薬株式会社 Ｎ−アルケニルモラノリン誘導体
DE3737523A1 (de) * 1987-11-05 1989-05-18 Bayer Ag Verwendung von substituierten hydroxypiperidinen als antivirale mittel
JPH01308229A (ja) * 1988-02-23 1989-12-12 Glaxo Group Ltd 複素環誘導体
JPH06329671A (ja) * 1993-05-21 1994-11-29 Tsumura & Co 新規アルカロイド及びその用途
TW381025B (en) * 1993-08-05 2000-02-01 Hoffmann La Roche Pharmaceutical composition containing a glucosidase inhibitor and a lipase inhibitor
WO2004007524A2 (fr) * 2002-07-17 2004-01-22 Boehringer Ingelheim Pharma Gmbh & Co. Kg Oligopeptides bicycliques
CA2646729A1 (fr) * 2005-03-21 2006-09-28 Dov Pharmaceutical, Inc. Methodes et compositions destinees au traitement de l'incontinence urinaire
CN101129476B (zh) * 2006-08-21 2013-07-24 中国医学科学院药物研究所 桑枝生物碱有效部位在制备降血糖药物中的应用
EP1903034A1 (fr) * 2006-09-19 2008-03-26 Technische Universität Graz Iminosucres glycoconjugués
US20110009351A1 (en) * 2007-05-09 2011-01-13 Traffick Therepeutics Inc. Screening assay to identify correctors of protein trafficking defects
GB0809360D0 (en) * 2008-05-22 2008-07-02 Isis Innovation Calcium modulation
WO2010015816A2 (fr) * 2008-08-06 2010-02-11 Summit Corporation Plc Traitement de troubles de stockage lysosomal et autres maladies protéostatiques
BR112012016879A2 (pt) * 2010-01-08 2015-09-01 Catabasis Pharmaceuticals Inc Derivados de fumarato de acido graxo e seus usos

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016198971A1 (fr) * 2015-06-08 2016-12-15 Mohan M Alapati Compositions et méthodes de traitement de l'hyperglycémie et du syndrome métabolique

Also Published As

Publication number Publication date
AU2013257716A1 (en) 2014-11-27
WO2013167995A3 (fr) 2016-09-01
CA2873087A1 (fr) 2013-11-14
CN104812737A (zh) 2015-07-29
JP2016510306A (ja) 2016-04-07
SG11201407316QA (en) 2014-12-30

Similar Documents

Publication Publication Date Title
EP2847152A1 (fr) Compositions et méthodes de traitement du syndrome métabolique
WO2013167993A1 (fr) Compositions et méthodes de traitement de troubles neurologiques dégénératifs
WO2013168014A1 (fr) Compositions et méthodes de traitement de la polyneuropathie amyloïde familiale
US9403826B2 (en) Compositions and methods for the treatment of inflammatory disorders
US9738631B2 (en) Compositions and methods for the treatment of neurological disorders
WO2014080307A2 (fr) Compositions et procédés pour le traitement du diabète et du pré-diabète
WO2014006529A2 (fr) Compositions et méthodes de traitement de la douleur modérée à aiguë
WO2013167998A2 (fr) Compositions et méthodes de traitement de troubles autonomiques et autres troubles neurologiques
AU2013257710B2 (en) Compositions and methods for the treatment of neurological disorders
WO2013175344A2 (fr) Compositions et méthodes pour le traitement de la parodontite et de la polyarthrite rhumatoïde
US9403857B2 (en) Compositions and methods for the treatment of metabolic syndrome
EP2846795A2 (fr) Compositions et méthodes de traitement de l'épilepsie
US9315478B2 (en) Compositions and methods for the treatment of metabolic syndrome
WO2013167987A1 (fr) Compositions et méthodes de traitement du diabète
WO2013167995A2 (fr) Compositions et méthodes de traitement de l'hyperglycémie
WO2014053962A2 (fr) Compositions et méthodes de traitement du diabète et du prédiabète
WO2013167984A2 (fr) Compositions et méthodes de traitement de la douleur musculaire
US9150557B1 (en) Compositions and methods for the treatment of hyperglycemia
WO2013167999A2 (fr) Compositions et méthodes de traitement d'affections neurologiques
US9187427B2 (en) N-substituted nicotinamide compounds and compositions for the treatment migraine and neurologic diseases
WO2013168012A1 (fr) Compositions et méthodes de traitement de troubles respiratoires
US20150141384A1 (en) Compositions and methods for the treatment of neurological degenerative disorders
WO2014060925A2 (fr) Compositions et méthodes de traitement de maladies neurologiques et neurodégénératives
WO2014057407A2 (fr) Compositions et méthodes de traitement du diabète et du prédiabète
WO2014060941A2 (fr) Compositions d'agents neuroprotecteurs et procédés correspondants destinés au traitement de maladies neurologiques et neurodégénératives

Legal Events

Date Code Title Description
ENP Entry into the national phase in:

Ref document number: 2873087

Country of ref document: CA

Ref document number: 2015510897

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2013787060

Country of ref document: EP

NENP Non-entry into the national phase in:

Ref country code: DE

ENP Entry into the national phase in:

Ref document number: 2013257716

Country of ref document: AU

Date of ref document: 20130203

Kind code of ref document: A