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WO2016023911A1 - Utilisation de l'acide 1,3-propane disulfonique ou de sels de celui-ci pour empêcher l'apparition de l'amyloïdose chez certaines populations - Google Patents

Utilisation de l'acide 1,3-propane disulfonique ou de sels de celui-ci pour empêcher l'apparition de l'amyloïdose chez certaines populations Download PDF

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Publication number
WO2016023911A1
WO2016023911A1 PCT/EP2015/068486 EP2015068486W WO2016023911A1 WO 2016023911 A1 WO2016023911 A1 WO 2016023911A1 EP 2015068486 W EP2015068486 W EP 2015068486W WO 2016023911 A1 WO2016023911 A1 WO 2016023911A1
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pharmaceutically acceptable
subject
acceptable salt
propanedisulfonic acid
composition
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Denis Garceau
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Kiacta Sarl
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Kiacta Sarl
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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

  • the present disclosure relates to methods for the treatment of amyloidosis.
  • the disclosure relates to treatment of subjects identified as obese to prevent the onset of amyloidosis.
  • Amyloidosis is a disease associated with extracellular deposition of insoluble fibrillar proteins in tissues and organs. Amyloidosis can affect different organs in different people, and there are different types of amyloidosis.
  • Amyloidosis is rare, and the exact cause is often unknown. Treatments are available to help patients manage the symptoms thereof and limit the production of amyloid protein.
  • PCT patent application publication no. WO 2007/004072 discloses methods of treating AA amyloidosis by administering 1 ,3 propanedisulfonic acid.
  • PCT patent application publication no. WO 2007/0238788 discloses methods of treating diabetic neuropathy by administering 1 ,3 propanedisulfonic acid.
  • a method for treating an obese subject to prevent the onset of amyloidosis including administering to the subject an effective amount of 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof.
  • methods which comprise identifying a subject as obese, and treating said subject so as to prevent the onset of amyloidosis.
  • Such methods include (a) identifying and/or diagnosing a subject as obese, and (b) prophylactically administering to said obese subject an amount of 1,3-propanedisulfonic acid (or a pharmaceutically acceptable salt thereof) effective to prevent the onset or progression of amyloidosis.
  • 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof
  • pharmaceutically acceptable salt thereof is 1,3-propanedisulfonic acid.
  • the 1,3-propanedisulfonic acid or pharmaceutically acceptable salt thereof is the disodium salt of 1,3-propanedisulfonic acid.
  • a method for treating an obese subject so as to prevent the onset of amyloidosis include administering to an obese subject an effective amount of 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof as well as relevant compositions for use in such methods.
  • the 1,3-propanedisulfonic acid or pharmaceutically acceptable salt thereof is 1,3- propanedisulfonic acid.
  • the 1,3- propanedisulfonic acid or pharmaceutically acceptable salt thereof is the disodium salt of 1,3-propanedisulfonic acid.
  • amyloidosis may refer to the extracellular deposition of insoluble fibrillar proteins in tissues and organs.
  • amyloidosis may be one or more types selected from the list consisting of Primary Amyloidosis (AL), Secondary Amyloidosis (AA), Familial Amyloidosis (ATTR), Beta-2 Microglobulin Amyloidosis (Abeta2m), and Localized Amyloidosis (ALoc).
  • AL Primary Amyloidosis
  • AA Secondary Amyloidosis
  • ARR Familial Amyloidosis
  • BRR Beta-2 Microglobulin Amyloidosis
  • Abeta2m Beta-2 Microglobulin Amyloidosis
  • ALoc Localized Amyloidosis
  • the term "obesity” refers to a medical condition in which excess body fat has accumulated to the extent that it may have a negative effect on health, leading to reduced life expectancy and/or increased health problems. People are considered obese when their body mass index (BMI), a measurement obtained by dividing a person's weight by the square of the person's height, exceeds 30 kg/m 2 .
  • BMI body mass index
  • the term "morbidly obese” refers to individuals who are 100 pounds or more over his/her ideal body weight, have a BMI of 40 or more, or a BMI of 35 or more and experiencing obesity-related health conditions, such as high blood pressure or diabetes.
  • Morbid obesity is a serious health condition that can interfere with basic physical functions such as breathing or walking. Those who are morbidly obese are at greater risk for illnesses including diabetes, high blood pressure, sleep apnea, gastroesophageal reflux disease (GERD), gallstones, osteoarthritis, heart disease, cancer, and the like.
  • GFD gastroesophageal reflux disease
  • identifying and the like in the context of the body weight of a subject refers, in the usual and customary sense, to physical observation of weight and height of a subject and subsequent diagnosis of obesity, as well known in the medical arts.
  • identifying a subject as underweight means that the subject exhibits a BMI below 18.5.
  • Identifying a subject as normal weight means that the subject exhibits a BMI in the range 18.5 to 24.9.
  • Identifying a subject as overweight means that the subject exhibits a BMI in the range 25.0 to 29.9.
  • Identifying a subject as obese means that a subject exhibits a BMI in excess of 30 kg/m 2 .
  • Identifying a subject as morbidly obese means that the subject exhibits at least 100 pounds over his/her ideal body weight, has a BMI of 40 or more, or a BMI of 35 or more in combination with obesity-related health conditions, such as high blood pressure or diabetes. Accordingly, a morbidly obese subject is also an obese subject, based on the BMI criteria set forth above.
  • diagnosis refers, in the usual and customary sense, to determination of the nature of an illness or disorder for a subject by examination of the symptoms exhibited by the subject. Accordingly, “diagnosing a subject with respect to obesity” refers to physical observation of the height and weight of the subject, calculation of the BMI exhibited by the subject, and identification of whether or not the subject is obese (e.g., underweight, normal, overweight, obese, morbidly obese) based on the BMI exhibited by the subject. Accordingly, the term “diagnosing a subject as obese” means diagnosing a subject with respect to obesity and concluding that the subject is obese.
  • the subject is prone to obesity yet not exhibiting a BMI classification of obese.
  • prone to obesity refers to a dispensation of a subject to develop obesity in the future as understood by those of skill in the medical arts, such dispensation related to genetic, behavioral, and/or environmental factors.
  • obesity induced chronic inflammation has been determined to be a risk factor for the onset of amyloidosis
  • subjects prone to obesity are correspondingly prone to development of amyloidosis.
  • Such subjects can benefit from embodiments disclosed herein for the treatment, including prevention, of amyloidosis.
  • the administration of 1,3-propanedisulfonic acid or pharmaceutically acceptable salt thereof results in the reduction in one or more inflammatory mediators selected from the group consisting of IL-18, IL-10 and TNF.
  • the administration of 1,3-propanedisulfonic acid or pharmaceutically acceptable salt thereof prevents the onset of amyloidosis symptoms in the subject (e.g., granuloma formation, granulomatous inflammation, and the like).
  • the effective amount of 1,3-propanedisulfonic acid or pharmaceutically acceptable salt thereof comprises administration of at least lmg/kg thereof to said subject per dose.
  • the effective amount of 1,3-propanedisulfonic acid or pharmaceutically acceptable salt thereof is administered more than once daily.
  • Exemplary administration protocols contemplate administration of 1,3-propanedisulfonic acid or pharmaceutically acceptable salt thereof at least 2 times daily; at least 3 times daily; at least 4 times daily; at least 5 times daily; at least 6 times daily; or even more frequently, including continuous administration thereof.
  • the 1,3-propanedisulfonic acid is administered to a subject (for example orally) in a dose of 400 mg, or 800 mg, or 1,200 mg per administration.
  • the 1,3-propanedisulfonic acid is administered to a subject in a dose of 400 mg QID, or 600 mg QID, or 800 mg QID, or 1000 mg QID, or 1,200 mg QID per administration.
  • no more than 20mg/kg of 1,3-propanedisulfonic acid or pharmaceutically acceptable salt thereof is administered to said subject per dose.
  • 1,3-propanedisulfonic acid or pharmaceutically acceptable salts thereof can be administered in a variety of ways, e.g., by oral, parenteral, intraperitoneal, intraspinal, intracerebral, nasal, mucosal, transdermal, intravascular, intraarterial, intramuscular, subcutaneous delivery, or the like.
  • 1,3- propanedisulfonic acid or pharmaceutically acceptable salts thereof are administered by oral delivery.
  • compositions for the treatment of obese subjects to prevent the onset of amyloidosis comprising 1,3- propanedisulfonic acid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier therefor.
  • compositions may further comprise a second agent traditionally employed for the prevention and/or treatment of amyloidosis.
  • a second agent is a corticosteroid.
  • obesity induced chronic inflammation has been determined to be a risk factor for the onset of amyloidosis.
  • methods for treating an obese subject to prevent the onset of amyloidosis including prophylactically administering to the subject an effective amount of 1,3 -propanedisulfonic acid or a pharmaceutically acceptable salt thereof.
  • methods comprising:
  • methods for treating an obese subject comprising administering to said subject an effective amount of 1,3- propanedisulfonic acid or a pharmaceutically acceptable salt thereof so as to prevent the onset of amyloidosis.
  • subject includes living organisms in which obesity or a related condition can occur, or which are susceptible to obesity or related diseases.
  • the term “subject” includes humans.
  • subject includes a subject (i.e., a human) specifically chosen to receive 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof, or a composition containing same.
  • subjects include subjects who are at risk of becoming obese, or have been diagnosed as being obese.
  • Subjects at risk of becoming obese include those with an underlying disease, such as a metabolic disorder, an inflammatory disease, infection, hereditary fever or neoplasm.
  • a preferred subject is a human.
  • treatment includes the application or administration of 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof, or a composition containing same to a subject (or application or administration of 1,3- propanedisulfonic acid or a pharmaceutically acceptable salt thereof to a cell or tissue from a subject) with the purpose of stabilizing, curing, healing, alleviating, relieving, altering, remedying, less worsening, ameliorating, improving, or affecting the disease or condition, the symptom of the disease or condition, or the risk of (or susceptibility to) the disease or condition.
  • treating refers to any indicia of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission; lessening of the rate of worsening; stabilization, diminishing of symptoms or making the injury, pathology or condition more tolerable to the subject; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; or improving a subject's physical or mental well-being.
  • the term “treating” can include increasing a subject's life expectancy. It is understood that treating further contemplates prevention of a disease (e.g., amyloidosis).
  • prophylactically administering means, in the usual and customary sense, administration of an agent (e.g., 1,3-propanedisulfonic acid or pharmaceutically acceptable salt thereof) to prevent onset of a disease or disorder (e.g., amyloidosis).
  • agent e.g., 1,3-propanedisulfonic acid or pharmaceutically acceptable salt thereof
  • the term "therapeutically effective amount” and the like refer to the amount of a compound which is effective to treat a subject, e.g., treat an obese subject or a subject having an underlying disease, such as, but not limited to, a metabolic disorder, an inflammatory disorder, a malignant neoplasm, or chronic microbial infection.
  • the therapeutically effective amount may vary based on the particular disorder(s) the subject is suffering from, the age, weight, and lifestyle of a particular subject. In addition, the therapeutically effective amount may depend on the severity of the disease state, organ function, kidney function, or underlying disease (e.g., the subject may be suffering from an inflammatory disease, a malignant neoplasm, a chronic infection, or the like).
  • the dosage administered in the methods of the present disclosure may be selected such that desired pharmacokinetic parameters and/or biologically favorable parameters are obtained after administration of the compound of the disclosure to the subject.
  • the dosage is selected such that the subject receives at least lmg/kg of 1,3- propanedisulfonic acid or a pharmaceutically acceptable salt thereof per dose; in another embodiment, the dosage is selected such that the subject receives at least 2mg/kg of 1,3- propanedisulfonic acid or a pharmaceutically acceptable salt thereof per dose; in still another embodiment, the dosage is selected such that the subject receives at least 3mg/kg of 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof per dose; in yet another embodiment, the dosage is selected such that the subject receives at least 4mg/kg of 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof per dose; in a still further embodiment, the dosage is selected such that the subject receives at least 5mg/kg of 1,3-propan
  • the disclosure also pertains, at least in part, to a pharmaceutical formulation.
  • the formulation comprises an active agent which is 1,3- propane disulfonic acid or a pharmaceutically acceptable salt thereof in an amount effective to prevent the onset of amyloidosis in a subject diagnosed as being obese, and a pharmaceutically acceptable carrier.
  • the formulation is orally administered to a subject diagnosed as being obese in a dose of 400 mg of 1,3- propanedisulfonic acid or a pharmaceutically acceptable salt thereof.
  • the formulation is orally administered to a subject diagnosed as being obese in a dose of 800 mg of 1,3-propane disulfonic acid or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the formulation is orally administered to a subject diagnosed as being obese in a dose of 1200 mg of 1,3-propane disulfonic acid or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the disclosure pertains to a pharmaceutical formulation comprising 1,3-propane disulfonic acid or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier for oral administration to a subject diagnosed as being obese for twenty-four months in a dose of 400 mg of the active agent; or in a dose of 800 mg of the active agent; or in a dose of 1200 mg of the active agent.
  • the disclosure also pertains to a pharmaceutical formulation, comprising 1,3-propane disulfonic acid or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein the formulation is orally administered for seven days in a dose of 400 mg QID of the active agent; or in a dose of 800 mg QID of the active agent; or in a dose of 1200 mg QID of the active agent; or in a dose of 1600 mg QID of the active agent; or in a dose of 2000 mg QID of the active agent.
  • the disclosure also pertains to a method of stabilizing or improving renal function or delaying progression of renal disease in a subject diagnosed as being obese.
  • the method includes orally administering an effective amount of a formulation comprising 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.
  • the disclosure pertains to a method of preventing the onset of amyloidosis in a subject, especially in a subject diagnosed as being obese.
  • the method includes administering to a subject in need thereof (e.g., a subject diagnosed as being obese), a therapeutically effective amount of 1,3-propanedisulfonic acid or a
  • the term "in combination with” refers to the concurrent administration of 1,3- propanedisulfonic acid or a pharmaceutically acceptable salt thereof and a second agent; the administration of 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof can be carried out prior to administration of the second agent; or administration of the second agent can be carried out prior to administration of 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof.
  • the compounds of the present disclosure contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases.
  • pharmaceutically acceptable salts in these instances refers to the relatively non-toxic, inorganic and organic base addition salts of 1,3-propanedisulfonic acid.
  • salts can likewise be prepared in situ during the final isolation and purification of the agents, or by separately reacting the purified agent in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine.
  • a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine.
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like.
  • “Pharmaceutically acceptable salts” also includes, for example, derivatives of agents modified by making base salts thereof, as described further below and elsewhere in the present application.
  • Examples of pharmaceutically acceptable salts include alkali or organic salts of acidic residues such as sulfonates.
  • Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent agent formed, for example, from non-toxic inorganic or organic acids.
  • Such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acid; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmoic, maleic, hydroxymaleic, phenylacetic, glutamic, mesylate, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic acid, and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acid
  • organic acids such as acetic, propionic, succinic, glycolic, stearic
  • salts may be synthesized from the parent agent which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts may be prepared by reacting the free acid or base forms of these agents with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two.
  • All acid, salt, base, and other ionic and non-ionic forms of the compounds described are included as compounds of the disclosure.
  • the salt forms of the compound are also included.
  • the acid and/or basic forms are also included.
  • the disclosure pertains to a pharmaceutical formulation for preventing the onset of amyloidosis, comprising a therapeutically effective amount of 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof in a formulation such that the formulation has at least one favorable biological property (FBP) upon administration to a subject.
  • FBP biological property
  • pharmaceutical formulation includes pharmaceutical compositions as described below.
  • the pharmaceutical formulations are designed to have favorable biological properties which enhance the ability of the compounds of the disclosure to prevent the onset of amyloidosis and/or related diseases. The favorable biological properties of the formulation were discovered by administering the compounds of the disclosure to subjects during clinical trials.
  • the disclosure also pertains, at least in part, to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof and second agent.
  • the therapeutically effective amount is effective to prevent the onset of amyloidosis.
  • the disclosure pertains to a packaged pharmaceutical composition.
  • the packaged pharmaceutical composition includes a therapeutically effective amount of 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof packaged in combination with a label or insert advising that the composition be administered in combination with a second agent.
  • the therapeutically effective amount is effective to prevent the onset of amyloidosis in a subject diagnosed as being obese.
  • the disclosure pertains to a packaged pharmaceutical composition, which includes a therapeutically effective amount of a second agent packaged in combination with a label or insert advising that the composition be administered in combination with 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof.
  • label or insert includes, but is not limited to all written, electronic, or spoken communication with the subject, or with any person substantially responsible for the care of the subject, regarding the administration of the compositions of the present disclosure.
  • An insert may further include information regarding coadministration of the compositions of the present disclosure with other compounds or compositions, e.g., second agents. Additionally, an insert may include instructions regarding administration of the compositions of the present disclosure with (or without) food.
  • the disclosure pertains to a packaged pharmaceutical composition, which includes a container holding a pharmaceutical composition comprising a therapeutically effective amount of 1 ,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof in combination with a label or insert advising that the composition be administered with (or without) food.
  • 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof may be supplied in a solution with an appropriate solvent or in a solvent-free form (e.g., lyophilized).
  • the agents and buffers necessary for carrying out the methods of the disclosure may be packaged as a kit.
  • the kit may be commercially used according to the methods described herein and may include instructions for use in a method of the disclosure.
  • Additional kit components may include acids, bases, buffering agents, inorganic salts, solvents, antioxidants, preservatives, or metal chelators.
  • the additional kit components are present as pure compositions, or as aqueous or organic solutions that incorporate one or more additional kit components. Any or all of the kit components may optionally further comprise buffers.
  • 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof may also be administered in a variety of ways, e.g., parenterally, intraperitoneally, intraspinally, intracerebrally, and the like.
  • Dispersions can be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.
  • 1 ,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof may be administered to a subject in an appropriate carrier, for example, liposomes, or a diluent.
  • Pharmaceutically acceptable diluents include saline and aqueous buffer solutions.
  • Liposomes include water-in-oil-in-water CGF emulsions as well as conventional liposomes (Strejan et al., J. Neuroimmunol. 7, 27 (1984)). It should be noted that the term "pharmaceutical composition” includes the "pharmaceutical formulations" described above.
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the composition must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • Suitable pharmaceutically acceptable vehicles include, without limitation, any non-immunogenic pharmaceutical adjuvants suitable for oral, parenteral, nasal, mucosal, transdermal, intravascular (IV), intraarterial (IA), intramuscular (IM), and subcutaneous (SC) administration routes, such as phosphate buffer saline (PBS).
  • IV intravascular
  • IA intraarterial
  • IM intramuscular
  • SC subcutaneous
  • PBS phosphate buffer saline
  • the vehicle can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents are included, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.
  • Sterile injectable solutions can be prepared by incorporating the therapeutic agent in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the therapeutic agent into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient (i.e., the compound of the disclosure) plus any additional desired ingredient from a previously sterile- filtered solution thereof.
  • 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof can be orally administered, for example, with an inert diluent or an assimilable edible carrier.
  • 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof and other ingredients may also be enclosed in a hard or soft shell gelatin capsule, compressed into tablets, or incorporated directly into the subject's diet.
  • 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • compositions and preparations may, of course, be varied.
  • therapeutically useful compositions is such that a suitable dosage will be obtained.
  • the present disclosure therefore includes pharmaceutical formulations comprising 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof, in
  • compositions for aerosol, oral and parenteral administration include such compounds, or salts thereof, which have been lyophilized and which may be reconstituted to form pharmaceutically acceptable formulations for administration, as by intravenous, intramuscular, or subcutaneous injection. Administration may also be intradermal or transdermal.
  • 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof may be administered orally or through inhalation as a solid, or may be administered intramuscularly or intravenously as a solution, suspension or emulsion.
  • the agents or salts may also be administered by inhalation, intravenously or intramuscularly as a liposomal suspension.
  • compositions or formulations are also provided which are suitable for administration as an aerosol, by inhalation. These formulations comprise a solution or suspension of 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof, or a plurality of solid particles of the agent or salt.
  • the desired formulation may be placed in a small chamber and nebulized. Nebulization may be accomplished by compressed air or by ultrasonic energy to form a plurality of liquid droplets or solid particles comprising the agents or salts.
  • the liquid droplets or solid particles should have a particle size in the range of about 0.5 to about 5 microns.
  • the solid particles can be obtained by processing the solid agent of 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof, in any appropriate manner known in the art, such as by micronization.
  • the size of the solid particles or droplets will be, for example, from about 1 to about 2 microns. In this respect, commercial nebulizers are available to achieve this purpose.
  • a pharmaceutical formulation suitable for administration as an aerosol may be in the form of a liquid, the formulation will comprise a water-soluble form of 1,3- propanedisulfonic acid or a pharmaceutically acceptable salt thereof, in a carrier which comprises water.
  • a surfactant may be present which lowers the surface tension of the formulation sufficiently to result in the formation of droplets within the desired size range when subjected to nebulization.
  • Peroral compositions also include liquid solutions, emulsions, suspensions, and the like.
  • the pharmaceutically acceptable vehicles suitable for preparation of such compositions are well known in the art.
  • Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water.
  • typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, tragacanth, and sodium alginate;
  • typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate.
  • Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above.
  • compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the subject agent is released in the gastrointestinal tract in the vicinity of the desired topical application, or at various times to extend the desired action.
  • dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, waxes, shellac, and the like.
  • compositions useful for attaining systemic delivery of 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof include sublingual, buccal and nasal dosage forms.
  • Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia,
  • microcrystalline cellulose carboxymethyl cellulose and hydroxypropyl methyl cellulose.
  • Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.
  • 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof can also be administered topically to a subject, e.g., by the direct laying on or spreading of a composition containing same on the epidermal or epithelial tissue of the subject, or transdermally via a "patch".
  • a composition containing same on the epidermal or epithelial tissue of the subject, or transdermally via a "patch".
  • Such compositions include, for example, lotions, creams, solutions, gels and solids.
  • These topical compositions may comprise an effective amount, usually at least about 0.1 wt , or even from about 1 wt % to about 5 wt , of 1,3- propanedisulfonic acid or a pharmaceutically acceptable salt thereof.
  • Suitable carriers for topical administration typically remain in place on the skin as a continuous film, and resist being removed by perspiration or immersion in water.
  • the carrier is organic in nature and capable of having dispersed or dissolved therein the therapeutic agent.
  • the carrier may include pharmaceutically acceptable emollients, emulsifiers, thickening agents, solvents, and the like.
  • Toxicity and therapeutic efficacy of such agents can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio LD50/ED50; usually a larger therapeutic index is more efficacious. While compounds that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such agents to the site of affected tissue in order to minimize potential damage to unaffected cells and, thereby, reduce side effects.
  • 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof will vary, for example, depending upon the identity, size, and condition of the subject or sample being treated, further depending upon the route by which the composition is to be administered, if applicable, and the effect which the practitioner desires the 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof to have upon the subject.
  • Exemplary doses include milligram or microgram amounts of 1 ,3- propanedisulfonic acid or a pharmaceutically acceptable salt thereof per kilogram of subject or sample weight (e.g. , about 1 microgram per kilogram to about 500 milligrams per kilogram, about 100 micrograms per kilogram to about 5 milligrams per kilogram, or about 1 microgram per kilogram to about 50 micrograms per kilogram). It is furthermore understood that appropriate doses depend upon the potency. Such appropriate doses may be determined using assays known in the art. When 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof is to be administered to an animal (e.g.
  • a human a physician, veterinarian, or researcher may, for example, prescribe a relatively low dose at first, subsequently increasing the dose until an appropriate response is obtained.
  • the specific dose level for any particular animal subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, gender, and diet of the subject, the time of administration, the route of administration, the rate of excretion, and any drug combination.
  • doses may depend on the state of renal function in the subject, as measured, for example, by the rate of creatinine clearance, which may affect the rate of clearance of the compound from the subject.
  • rate of creatinine clearance which may affect the rate of clearance of the compound from the subject.
  • subjects with a lower rate of creatinine clearance would be expected to achieve a particular plasma concentration at a lower dose than those with a higher rate of creatinine clearance.
  • compositions may be formulated in dosage unit form for ease of administration and uniformity of dosage.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit containing a predetermined quantity of 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle.
  • the specifications for the dosage unit forms of the disclosure are dictated by and directly dependent on (a) the unique characteristics of the therapeutic agent and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding 1,3-propanedisulfonic acid or a pharmaceutically acceptable salt thereof for the prevention of the onset of amyloidosis or related disease.
  • THP-1 cells were subjected to PMA (phorbol 12-myristate 13-acetate (EMD Cat.# 524400)), SAA (serum amyloid A (PeroTech Cat.#300-13)), and 1,3-propanedisulfonic acid (KIACTA C933 (NRA610-01-CF)).
  • PMA phorbol 12-myristate 13-acetate
  • SAA serum amyloid A
  • KIACTA C933 N933 (NRA610-01-CF)
  • the SAA treated cells were used as a positive control, with the SAA increasing the inflammatory mediators, TNF, IL-18 and IL-10.
  • 1,3- propanedisulfonic acid is added to the cell cultures and the effect on TNF, IL- 18 and IL- 10 levels is measured.
  • a patient is diagnosed as being obese. 1,3-propane disulfonic acid is then administered to said patient. The treatment prevents the onset of amyloidosis symptoms in the patient.
  • Patents and publications mentioned in the specification are indicative of the levels of those skilled in the art to which the disclosure pertains. These patents and publications are incorporated herein by reference to the same extent as if each individual application or publication was specifically and individually incorporated herein by reference.

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  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne des méthodes de traitement d'un sujet diagnostiqué comme étant obèse visant à empêcher l'apparition de l'amyloïdose. Selon certains aspects et modes de réalisation, l'invention concerne des compositions contenant de l'acide 1,3-propane disulfonique ou un sel pharmaceutiquement acceptable de celui-ci, et/ou l'utilisation de telles compositions destinées au traitement d'un sujet diagnostiqué comme étant obèse visant à empêcher l'apparition de l'amyloïdose. Selon un autre aspect, l'invention concerne des compositions contenant de l'acide 1,3-propane disulfonique ou un sel pharmaceutiquement acceptable de celui-ci ainsi qu'un second principe actif. Selon encore un autre aspect, l'invention concerne des kits contenant des agents utilisables pour le traitement de l'amyloïdose.
PCT/EP2015/068486 2014-08-11 2015-08-11 Utilisation de l'acide 1,3-propane disulfonique ou de sels de celui-ci pour empêcher l'apparition de l'amyloïdose chez certaines populations Ceased WO2016023911A1 (fr)

Applications Claiming Priority (2)

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US201462035883P 2014-08-11 2014-08-11
US62/035,883 2014-08-11

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WO2016023911A1 true WO2016023911A1 (fr) 2016-02-18

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3137071A4 (fr) * 2014-04-30 2017-11-01 Icahn School of Medicine at Mount Sinai Utilisation d'acide 1,3-propane disulfonique ou de sels pharmaceutiquement acceptable de celui-ci pour le traitement de la sarcoïdose

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007004072A2 (fr) * 2005-04-15 2007-01-11 Neurochem (International) Limited Formulations et methodes de traitement de l'amylose

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007004072A2 (fr) * 2005-04-15 2007-01-11 Neurochem (International) Limited Formulations et methodes de traitement de l'amylose

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
ALSINA E ET AL: "Renal AA amyloidosis secondary to morbid obesity?", CLINICAL NEPHROLOGY, DUSTRI VERLAG, NUENCHEN-DEISENHOFEN, DE, vol. 72, no. 4, 1 October 2009 (2009-10-01), pages 312 - 314, XP009186433, ISSN: 0301-0430 *
LAURA OBICI ET AL: "AA amyloidosis: basic knowledge, unmet needs and future treatments", SWISS MEDICAL WEEKLY, 1 January 2012 (2012-01-01), Switzerland, pages w13580, XP055217959, Retrieved from the Internet <URL:http://www.ncbi.nlm.nih.gov/pubmed/22653707> [retrieved on 20151005], DOI: 10.4414/smw.2012.13580 *
LIDIA USNARSKA-ZUBKIEWICZ ET AL: "AL Amyloidosis (Amyloidosis Antibody Light). Part 2 - Epidemiology, Clinical Symptoms, Diagnosis and Treatment of Amyloidosis AL", 1 January 2011 (2011-01-01), XP055217965, Retrieved from the Internet <URL:http://www.advances.am.wroc.pl/pdf/2011/20/6/771.pdf> [retrieved on 20151002] *
P. REVILL ET AL: "Eprodisate Sodium", DRUGS OF THE FUTURE, vol. 31, no. 7, 1 January 2006 (2006-01-01), pages 576, XP055217942, ISSN: 0377-8282, DOI: 10.1358/dof.2006.031.07.1012786 *
POITOU C ET AL: "Serum amyloid A: production by human white adipocyte and regulation by obesity and nutrition", DIABETOLOGIA ; CLINICAL AND EXPERIMENTAL DIABETES AND METABOLISM, SPRINGER, BERLIN, DE, vol. 48, no. 3, 1 March 2005 (2005-03-01), pages 519 - 528, XP019322465, ISSN: 1432-0428, DOI: 10.1007/S00125-004-1654-6 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3137071A4 (fr) * 2014-04-30 2017-11-01 Icahn School of Medicine at Mount Sinai Utilisation d'acide 1,3-propane disulfonique ou de sels pharmaceutiquement acceptable de celui-ci pour le traitement de la sarcoïdose
US10682321B2 (en) 2014-04-30 2020-06-16 Icahn School Of Medicine At Mount Sinai Use of 1,3-propanedisulfonic acid or pharmaceutically acceptable salts thereof for the treatment of sarcoidosis
US11413260B2 (en) 2014-04-30 2022-08-16 Icahn School Of Medicine At Mount Sinai Use of 1,3-propanedisulfonic acid or pharmaceutically acceptable salts thereof for the treatment of sarcoidosis

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