WO2014057407A2 - Compositions et méthodes de traitement du diabète et du prédiabète - Google Patents

Compositions et méthodes de traitement du diabète et du prédiabète Download PDF

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Publication number
WO2014057407A2
WO2014057407A2 PCT/IB2013/059146 IB2013059146W WO2014057407A2 WO 2014057407 A2 WO2014057407 A2 WO 2014057407A2 IB 2013059146 W IB2013059146 W IB 2013059146W WO 2014057407 A2 WO2014057407 A2 WO 2014057407A2
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Prior art keywords
compositions
administration
diabetes
formula
acid
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PCT/IB2013/059146
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English (en)
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WO2014057407A3 (fr
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Mahesh Kandula
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Mahesh Kandula
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/207—Cyclohexane rings not substituted by nitrogen atoms, e.g. kasugamycins
    • 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

Definitions

  • This disclosure generally relates to compounds and compositions for the treatment of diabetes and pre-diabetes. More particularly, this invention relates to treating subjects with a pharmaceutically acceptable dose of compounds, crystals, solvates, enantiomer, stereoisomer, esters, salts, hydrates, prodrugs, or mixtures thereof,
  • the multifaceted 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 mellitus. It is also known as the insulin resistance syndrome, syndrome X, dysmetaboiic syndrome, or the deadly quartet, and is characterized by aberrations in a wide variety of metabolic risk markers such as hyperirtsulinemia, impaired glucose metabolism, elevated piasma levels of triglycerides, decreased levels of high-density lipoprotein cholesterol (HDL-C), raised blood pressure, centrally distributed obesity, impaired endothelial and haemostatic function, and a low-grade inflammatory state.
  • CVD cardiovascular disease
  • Type 2 Diabetes Mellitus is characterized by fasting and postprandial hyperglycemia and relative insulin insufficiency. f left untreated, then hyperglycemia may cause long term microvascular and roacrovascuSar 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 is now increasing at more rapid rates in Africa, Asia and South America than in Europe or the U.S. Thus, T2DM is now considered worldwide epidemic.
  • 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 dismuiase, glutathione peroxidase CiPx, glutathione reductase and catalase) and .no.aenzym.atic antioxidants (ex. glutathione G-SH, thioredoxin, Hpoic acid, ubiquinol, albumin, uric acid, flavonoids, vitamins A. C and E, etc.).
  • oxidative stress may determine the onset and progression of late-diabetes complications controversy exists about whether the increased oxidative stress is merely associative rather than causal in diabetes.
  • 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 diabetes and pre-diabetes.
  • jOOOSj The invention herein provides compositions comprising of formula ⁇ or pharmaceutical acceptable salts thereof.
  • the invention also provides pharmaceuticai compositions comprising one or more compounds of formul I or intermediates thereof and one or more of pharmaceutically acceptable carriers, vehicles or diluents. These compositions may be used in the treatment of diabetes and pre-diabetes and its associ a ted com plications.
  • the present invention relates to the compounds and compositions of formula L or pharmaceutically acceptable salts thereo
  • R l independently represents D, -CH 3 CO-, acetyl, CD3CO-, null,
  • a is independently 2,3 or 7;
  • each b is independently 3, 5 or 6;
  • e is independently L 2 or 6:
  • c and d are each independently H, D. -OH, -OD, Cj-tValkyl. - H-. or -COCH;.
  • kits comprising any of the pharmaceutical compositions disclosed herein.
  • the kit may comprise instructions for use in the treatment of diabetes and pre-diabetes or its related complications.
  • compositions herein 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, subdermal administration, or transdermal administration.
  • kits comprising the pharmaceutical compositions described herei
  • the kits may further comprise instructions for use in the treatment of diabetes and pre-diabetes or its related complications.
  • compositions described herein have several uses.
  • the present application provides, for example, methods of treating a patient suffering from diabetes and pre- diabetes or its related complications in an i tested from metabolic or genetic conditions or disorders, metaboiic diseases, chronic diseases or disorders; neurodegenerative disorders, metabolic condition, Hepatology, Cancer, Respiratory, Hematological, Orthopedic, Cardiovascular, Renal, Skin, Vascular or Ocular complications.
  • the compounds of the present invention can be present in the form of pharmaceuticall y 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 aci ds of formula ! 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 Irygroscoptc properties of an initially anhydrous compound of formula 1 (hydration).
  • An enanii onier can be characterized by the absolute configuration of its asymmetric center or centers and is described by the - and S-sequencing mles of Cahn, !ngold 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 (-)-isoraers 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".
  • metabolic condition refers to an inborn errors of metabolism (or genetic metabolic conditions) are genetic disorders that result from a defect in one or more metabolic pathways; specifically, the function of an enzyme is affected and is either deficient or completely absent.
  • polymorph as used herein is art-recognized and refers to one crystal structure of a given compound.
  • parenteral administration' ' and “administered parenterally” 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, intrapericardial, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, mtra-articular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.
  • a "patient,” “subject,” or “host-” to be treated b 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 forms 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.
  • the phrase ''pharmaceutically acceptable carrier is art- ecognized, and includes, for example, pharmaceutically acceptable materials, compositions or vehicles, such as a liquid or solid filler, diluent, solvent or encapsulating material involved in earning or transporting any subject composition, from one organ, or portion of the body, to another organ, or portion of the body.
  • 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 com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymeihyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (S) cocoa butter and suppository waxes, (9) oils, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; (.10) glycols, such as propylene glycol; (1.1.) polyols, such as glycerin, sorbitol, manmtol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) al
  • 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 hydrolyzed 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 com plications 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 invention.
  • treating 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 conditi n includes ameliorating at least one symptom of the particular disease or condition, even if the underlying pathophysiology is not affected, such as treating the hyperinsulenimia, diabetes mellitus, type 2 diabetes, beta cell apoptosis or degeneration, insulin resistance, glucose intolerance 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
  • therapeutically effective amount is an art-recognized term.
  • the term refers to an amount of a salt or compositio disclosed herein that, produces some desired effect at a reasonable benefit/risk ratio applicable to any medical treatment.
  • 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 particuiar 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 compositions 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 com posit on to be administered to a patient will depend on absorption, inactivation, and excretion rates of the drug as well as the deli ery rate of the salts and compositions from the subject compositions.
  • dosage values may also vary with the severity of the condition to be alleviated, ft is to be further understood that for any particular subject., specific dosage regimens should be adjusted over time according io 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 di sease or condition.
  • the dosage of the subject compositions 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 (Cmax) and the area under the plasma concentration-time curve from time 0 to infinity may be used.
  • Cmax maximum plasma concentration
  • 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 administrati n in which the entire amount of the substance is made biologically available at one time.
  • one or more of the pharmaceutically acceptable excipients may undergo gradual or delayed degradation (e.g., through hydrolysis) with concomitant release of any material incorporated therein, e.g., an therapeutic and/or biologically 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.
  • peripheral administration- and “admi istered peripherally” are art-recognized, and include the administration of a subject composition, therapeutic or other material at a site remote from the disease being treated.
  • 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.
  • 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.
  • compositions disclosed herein are contemplates prodrugs of the compositions disclosed herein, as well as pharmaceutically acceptable salts of said prodrugs.
  • compositions comprising a pharmaceutically acceptable carrier and the composition of a compound of Formula 1 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 ma 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 I) to be delivered in an amoun sufficient to deliver to a patient a therapeutically effective amount of a compound of formula 1 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 salt 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.
  • any particular " compound of formula I 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, b screening a range of concentration and/or amounts of the material in question using appropriate assays.
  • routine screening in animals e.g., rats, b screening a range of concentration and/or amounts of the material in question using appropriate assays.
  • methods are 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 microdialysis, as reviewed by T. E. Robinson et al., 1991, microdialysis in the neurosciences, Techniques, volume 7, Chapter 1.
  • 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.
  • the dosage of the subject compounds of formula ⁇ 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 1 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 I may also be administered to a huma patient at a dose of, for example, between 0.1 mg and 1000 nig, between 5 nig and 80 rag, 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, in certain embodiments, the compositions 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 1 required for the same therapeutic benefit.
  • An effective amount of the compounds of formula ⁇ described herei n refers to the amount of one of said salts or compositions which is capabl 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 deniyelization and/or elevated reactive oxidative- nitrosative species and/or abnormalities in physiological homeostasis' s, in patients who are at risk for such complications.
  • 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, parenteral! ⁇ ', e.g., intravenously, subcutaneously or intramedullary. Further, the compositions may be administered intranasally, as a rectal suppository, or using a "flash" formulation, i.e., allowing the medication to dissolve in the mouth without the need to use water. Furthermore, the compositions may be administered to a subject hi need of treatment by controlled release dosage forms, site specific drug delivery, transdermal drug de!ivery, patch ⁇ active/passive) mediated dasg 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 compositi ns 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-arginiiie, 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 lauryi sulfate and talc are often useful for Sab I el ting 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 essential 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 I 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 employee!.
  • aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • 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 .1 0, 50 to 250, 150 to 500 rng, or 350 to 800 nig e.g. 1(1 50, 100, 300, 500, 700, 800 mg of the compounds of formula I disclosed herein, for instance, compounds of formula I or pharmaceutical acceptable salts of a compounds of Formula I.
  • a composition as described herein may be administered orally, or parenteral I y (e.g., intravenous, intramuscular., subcutaneous or intramedullary). Topical administration may 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 tissue or organ as determined by the attending physician. Localized administration may also be indicated, for example, when a high dose- is desired at the target tissue or organ.
  • the active composition may take the form of tablets or lozenges formulated in a conventional manner.
  • he 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 1 00 mg/kg; and aerosol, 5 to about 1000 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, tntraoasally, pharyngolaryngeally, bronchially, intravaginally, rectaiiy, or ocularly in a concentration of from about 0.0 i to about 50% vv/w of the composition; preferably about i 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-parenteral 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-parenteral 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-parenteral solutions of suspensions, and oral solutions or suspensions and the like, containing suitable quantities of an active ingredient.
  • solid or .fluid unit dosage forms can be prepared.
  • the tablet core contains one or more hydrophiiic polymers.
  • Suitable hydrophiiic polymers include, but are not limited to, water sweilable cellulose derivatives, polyalkylene glycols, thermoplastic polyalkylene oxides, acrylic polymers, hydrocoMoids, clays, gelling starches, swelling cross-linked polymers, and mixtures thereof.
  • suitable water sweilable cellulose derivatives include, but are not limited to, sodium carboxymethylceliulose, cross- linked hydroxypropyl cellulose, hydroxypropyl cellulose (HPC), hydroxy propy 1 meth l eel 1 ul ose (HPMC), hydroxyi sopropy I cell ulose, hydroxy bury lcel lulose, hydroxyphenylceiSulose, hydroxyethy I cellulose (HEC), hydroxypentylcellulose, hydroxypropylethylcellulose, hydroxypropylbutylce!lulose, and hydroxypropylethylcellulose, and mixtures thereof
  • suitable polyalkylene glycols include, but are not limited to, polyethylene glycol.
  • thermoplastic polyalkylene oxides include, but are not limited to, polytethy!ene oxide).
  • suitable acrylic polymers include, but are no limited to, potassium methacrylatedivinyibenzene copolymer, polymethylmethacrylate, high-molecular weight cross! inked acrylic acid homopolymers and copolymers such as those commercially available from oveon Chemicals under the tradename CARBOPOL m .
  • hydrocolloids examples include, but are not limited to, alginates, agar, guar gum, locust bean gum, kappa carrageenan, iota carrageenan, tara, gum arable, tragacantli, pectin, xanthan gum, gellan gum, maitodextrin, galactomannan, pusstulan, laminarin, scleroglucan, gum arable, inulin, pectin, gelatin, whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin, chitosan, and mixtures thereof.
  • Suitable clays include, but are not limited to, smectites such as bentonUe, kaolin, and lap nite; magnesium irisilicate, magnesium aluminum siltoate; 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 pyrrolidorie, cross-linked agar, and cross-linked carboxymethylceiiulose sodium, and mixtures thereof.
  • the carrier may contain one or more suitable excipients for the formulation of tablets.
  • suitable excipients include, but are not limited to, fillers, adsorbents, binders, disintegrants, lubricants, glidants, release-modifying excipients, superdisintegrarits, antioxidants, and mixtures thereof.
  • Suitable binders include, but are not limited to, dry binders such as polyvinyl pyrrolidone and hydroxypropyl methy!cellulose; wet binders such as water-soluble polymers, including hydrocolloids such as acacia, alginates, agar, guar gum, locust- bean, carrageenan, carboxymethylceiiulose, tara, gum arabic, tragacaath, pectin, xanthan, gellan, gelatin, maitodextrin, galactomannan, pusstulan, !aminarin, scleroglucan, inulin, whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin, chitosan, polyvinyl pyrrolidone, cell losics, sucrose, and starches; and mixtures thereof.
  • dry binders such as polyvinyl pyrrolidone and hydroxyprop
  • Suitable disintegrants include, but are not limited to, sodium starch glycolate, cross-1 inked polyvin lpyrrolidone, cross-linked carboxymethylceiiulose, starches, microciystailine cellulose, and mixtures thereof.
  • j0 57J Suitabie 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.
  • Suitabie glidants include, but are not limited to, colloidal silicon, dioxide.
  • Suitabie release-modifying excipients include, but are not limited to, insoluble edible materials, pH-depetident polymers, and mixtures thereof.
  • jOOSSj Suitabie insoluble edible materials for use as rel ease-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, ethyl cellulose, polyvinyl alcohols, polyvinyl acetate, polycaprolactones, cellulose acetate and its derivatives, acrylates, rnethacrylat.es, acrylic acid copolymers, copolymers thereof, and mixtures thereof.
  • Suitable low-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.
  • Exampies of suitabie fatty acid esters include, but are not limited to, sucrose fatty acid esters, mono-, di ⁇ , and triglycerides, glyceryl behenate, glyceryl palmitostearate.
  • glyceryl monostearate glyceryl tri stearate, glyceryl trifatrrylate, glyceryl myristate, GlycoWax-932, lauroyi macrogol- 32 glycerides, stearoyl macrogoi-32 glycerides, and mixtures thereof.
  • suita.ble phospholipids include phosphotidvl choline, phosphotidvl serene, phosphotidvl enositol. phosphotidic acid, and mixtures thereof.
  • suitable waxes include, but are not limited to, carnauba wax, spermaceti wax, beeswax, candeliiJa wax, shellac wax, microcry stall ine wax, and paraffin wax; fat-containing mixtures such as chocolate, and mixtures thereof.
  • suitable waxes include, but are not limited to, carnauba wax, spermaceti wax, beeswax, candeliiJa wax, shellac wax, microcry stall ine wax, and paraffin wax; fat-containing mixtures such as chocolate, and mixtures thereof.
  • super disintegrants include, but are not limited to, croscarmellose sodium, sodium starch glycol ate and cross-linked povidone (crospovidone).
  • the tablet core contains up to about 5 percent by weight of such super dishitegrant.
  • antioxidants include, but are not limited to, tocopherols, ascorbic- acid, sodium pyrosulfite, butylhydroxytoluene, buty ' lated hydroxyanisole, edetic acid, and edetate salts, and mixtures thereof.
  • preservatives 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 immediate 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.
  • the immediate release coating is typically 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 a second portion, wherein at least one of the portions contains the second pharmaceutically active agent.
  • the portions contact each other a 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, in one embodiment, one of the portions contains a third phamiaceuticaiiy active agent, in one embodiment one of the portions contains a second immediate release portion of the same pharmaceuticall acti ve agent as that contained in the tabiet core.
  • 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 that 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 excipienis.
  • the immediate release dosage unit may or may not be coated, and ma o 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 "Remington The Science and Practice of
  • a diffusion system typically consists of one of two types of devices, reservoir and matrix, which are well known and described in die art.
  • the matrix devices are generally prepared by compressing the daig 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 o 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-containiiig 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 dosing frequency as compared to the drug presented as a conventional dosage form (e.g., as a solution or prompt drug-releasing, conventional solid dosage form).
  • a poised 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. %, preferably 60 wt. % to 40 wt. %, of the total amount of active agent in the dosage 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.
  • 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, in this dosage form, 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 delayed 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.
  • subject compositions of the present application maybe lyophi.liir.ed 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.
  • compositions or compositions include the step of bringing into association subject compositions with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimateiy bringing into association a subject composition with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • the compounds of formula ⁇ described herein may be administered in inhalant or aerosol formulations.
  • the inhalant or aerosol formulations may comprise one or more agents, such as adjuvants, diagnostic agents, imaging agents, or therapeutic agents useful in inhalation therapy.
  • the final aerosol formulation may for example contain 0.005-90% w/w, for instance 0.005-50%, 0,005-5% w/w, or 0.01- 1.0% w/w, of medicament relative to the total weight of the formulation.
  • the subject " composition is mixed with one or more pharmaceutically acceptable carriers and/or any of the following: (I) fillers or extenders, such as starches, lactose, sucrose, glucose, manmtol, and/or silicic acid; (2) binders, such as, for example, carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, a!ginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and gly
  • 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 administrati n include pharmaceutically acceptable emulsions, rnicroemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commoiiiy used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyi alcohol, ethyi 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 commoiiiy used in the art such as, for
  • Suspensions in addition to the subject compositions, may contain suspending agents such as, for example, ethoxylaied isostearyl alcohols, polyox ethylene sorbitol., and sorbitan esters, microcrystalline cellulose, aluminum metahydroside, bentonite, agar-agar and tragacaruh, and mi tures thereof.
  • suspending agents such as, for example, ethoxylaied isostearyl alcohols, polyox ethylene sorbitol., and sorbitan esters, microcrystalline cellulose, aluminum metahydroside, bentonite, agar-agar and tragacaruh, and mi tures 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 temperature, but liquid at body temperature and, therefore, will melt in the appropriate body cavity and release the encapsulated compound(s) and composition(s).
  • suitable non-irritating carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax, or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the appropriate body cavity and release the encapsulated compound(s) and composition(s).
  • Formulations which are suitable for vaginal administration 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 propel 1 ants that may be required.
  • the complexes may include lipophilic and hydrophilic groups to achieve the desired water solubility 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, taic and zinc oxide, or mixtures thereof.
  • Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and poiyamide powder, or mixtures of such substances.
  • Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile tin substituted 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 poly vinyl chioride-polyurethane composite and 2-10 parts by weight of a styrene-ethylene-butyiene-styrene copolymer, a first adhesive layer on the one side of the composite film, and a polyalkylene terephthalate 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 terephthalate film; and a second adhesive layer comprising a sty ene-diene-st ene 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 polyalkylene 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 polyalkylene terephthalate film.
  • Another type of patch comprises incorporating the datg 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 deli ver 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 drug Many of the newly developed proteins and peptide drugs are too large to be delivered through passive transdermal patches and may he delivered using technology such as electrical assist (iontophoresis) for large- molecule drues.
  • electrical assist iontophoresis
  • iontophoresis is a technique employed for enhancing the flux of ionized substances through membranes by application of electric current.
  • 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. Pal. 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) eiectroosmosis, 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 applicatio of electrical current.
  • kits may comprise a container for containing 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 form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage interval , or when titration of the indi vidual components of the combination is desired by the prescribing physicia
  • Blister packs are well known in the packaging industry and are widel used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist, of a sheet of relatively stiff material covered with a foil of a plastic material that may be transparent.
  • R 3 represents D, -C3 ⁇ 4CQ-, acetyl, CD3CO-, null.
  • a is independently 2,3 or 7;
  • each b is independently 3, 5 or 6;
  • e is independently i. 2 or 6:
  • c and d are each independently H, D, -OH, -OD, Cj-C «-alfcyl, - H :: or -COCH 3 .
  • the invention also includes methods for treating insulin resistance, hyperi nsul enemi a, glucose intolerance, type 2 diabetes, type 1 diabetes, diabetic complications, reduction of Hb l Ac leveis, hyperglycemia, microvascular and macrovascular diabetic complications.
  • sample refers to a sample of a body fluid, to a sample of separated cells 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, plasma, serum, or urine, more preferably, samples of blood, plasma or serum.
  • Tissue or organ samples may be obtained from any tissue or organ by, e.g., biopsy.
  • Separated cells may be obtained from the body fluids or the tissues or organs by separating techniques such as centrifugation or vacui sorting.
  • cell-, tissue- or organ samples are obtained from those ceils, tissues or organs which express or produce the peptides referred to herein.
  • compositions and methods for treating diabetes and pre-diabetes and their complications are provided among other things compositions and methods for treating diabetes and pre-diabetes and their complications. While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Man variations of the systems and methods herein will become apparent to those skilled in the art upon review of this specification. The full scope of the claimed systems and methods should be determined by reference to the claims, along with their full scope of equivalents, and the specificati n, along with such variations.

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Abstract

La présente invention concerne des composés de formule I ou leurs sels pharmaceutiquement acceptables, ainsi que leurs polymorphes, leurs solvates, énantiomères, stéréoisomères et hydrates. Elle concerne aussi des compositions pharmaceutiques comprenant une quantité efficace de composés de formule I et des méthodes de traitement ou de prévention du diabète. Lesdites compositions peuvent être formulées pour l'administration par voie orale, buccale, rectale, topique, transdermique, transmuqueuse, intraveineuse, parentérale, sous forme de sirop ou d'injection. Ces compositions peuvent être utilisées pour traiter le syndrome métabolique, la résistance à l'insuline, l'intolérance au glucose, l'hyperinsulinémie, le diabète sucré, le diabète insipide, l'hyperglycémie et les complications du diabète.
PCT/IB2013/059146 2012-10-12 2013-10-06 Compositions et méthodes de traitement du diabète et du prédiabète WO2014057407A2 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102140485A (zh) * 2010-12-25 2011-08-03 浙江工业大学 一种微生物发酵制备阿卡波糖的方法
WO2011117749A1 (fr) * 2010-03-23 2011-09-29 Mahesh Kandula Composé et procédé pour le traitement de la douleur
US20110300190A1 (en) * 2010-06-08 2011-12-08 Krisani Biosciences (P) Ltd Compound, composition and uses thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011117749A1 (fr) * 2010-03-23 2011-09-29 Mahesh Kandula Composé et procédé pour le traitement de la douleur
US20110300190A1 (en) * 2010-06-08 2011-12-08 Krisani Biosciences (P) Ltd Compound, composition and uses thereof
CN102140485A (zh) * 2010-12-25 2011-08-03 浙江工业大学 一种微生物发酵制备阿卡波糖的方法

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