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WO2010011922A2 - Nouveaux sels cristallins d’epalrestat - Google Patents

Nouveaux sels cristallins d’epalrestat Download PDF

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Publication number
WO2010011922A2
WO2010011922A2 PCT/US2009/051687 US2009051687W WO2010011922A2 WO 2010011922 A2 WO2010011922 A2 WO 2010011922A2 US 2009051687 W US2009051687 W US 2009051687W WO 2010011922 A2 WO2010011922 A2 WO 2010011922A2
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WO
WIPO (PCT)
Prior art keywords
diabetic
crystalline
thioxo
oxo
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/US2009/051687
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English (en)
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WO2010011922A3 (fr
Inventor
Isabel Kalofonos
G. Patrick Stahly
William Martin-Doyle
Dimitris Kalofonos
Jeffrey S. Stults
Travis L. Houston
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Bionevia Pharmaceuticals Inc
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Bionevia Pharmaceuticals Inc
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Publication date
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Priority to EA201100244A priority Critical patent/EA018600B1/ru
Publication of WO2010011922A2 publication Critical patent/WO2010011922A2/fr
Publication of WO2010011922A3 publication Critical patent/WO2010011922A3/fr
Priority to US13/013,786 priority patent/US8697735B2/en
Anticipated expiration legal-status Critical
Priority to US14/251,039 priority patent/US9447056B2/en
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/36—Sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the invention relates to novel crystalline salts of 5-[(lZ,2E)-2-methyl-3- phenylpropenylidene]-4-oxo-2-thioxo-3-thiazolidineacetic acid, processes for making those novel crystalline salts, pharmaceutical compositions comprising those novel crystalline salts, and methods of treating and/or preventing various conditions by administering those novel crystalline salts.
  • Epalrestat is useful in treating and/or preventing various conditions such as, for example, complications of diabetes, as well as affording cardioprotection in non-diabetic patients.
  • epalrestat has a positive indication for the treatment and/or prevention of diabetic neuropathy, and is useful for the treatment and/or prevention of various other diabetic complications including, for example, diabetic retinopathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic gastroparesis, diabetic microangiopathy, and diabetic macroangiopathy in mammals.
  • Epalrestat is also useful in affording cardioprotection to subjects who may not be suffering from diabetes, and as a neuroprotectant or treatment for neurological or neurodegenerative disorders.
  • Therapeutic activity of epalrestat in various conditions has been demonstrated in the clinical literature, including but not limited to Machii H. et al., Gendai Iryo, 1996;28:1273; Miyamoto S. et al., Gendai Iryo, 1986;18 (Extra Issue III):82: Goto Y. et al., Journal of Clinical and Experimental Medicine, 1990;152:405; Nakano K. et al., Journal of Clinical and Experimental Medicine, 1990; 152: 137; Okamoto H.
  • the salt and solid state form (e.g. crystalline or amorphous forms) of a drug candidate can be important to its pharmacological properties and to its development as a viable API.
  • each salt or each crystalline form of a drag candidate can have different solid state (physical and chemical) properties.
  • the differences in physical properties exhibited by a particular solid form of an API, such as a cocrystal, salt, or polymorph of the original compound, can affect pharmaceutical parameters of the API.
  • storage stability For example, storage stability, compressibility and density, all of which can be important in formulation and product manufacturing, and solubility and dissolution rates, which may be important factors in determining bioavailability, may be affected. Because these physical properties are often influenced by the solid state form of the API, they can significantly impact a number of factors, including the selection of a compound as an API, the ultimate pharmaceutical dosage form, the optimization of manufacturing processes, and absorption in the body. Moreover, finding the most adequate form for further drug development can reduce the time and the cost of that development.
  • crystalline forms are extremely useful in drug development. It may permit better characterization of the drag candidate's chemical and physical properties. For example, crystalline forms often have better chemical and physical properties than amorphous forms. As a further example, a crystalline form may possess more favorable pharmacology than an amorphous form, or may be easier to process. It may also have better storage stability.
  • Flowability affects the ease with which the material is handled during processing into a pharmaceutical composition.
  • a formulation specialist must take that fact into account in developing a tablet or capsule formulation, which may necessitate the use of additional components such as glidants, including colloidal silicon dioxide, talc, starch, or tribasic calcium phosphate.
  • Another solid state property of a pharmaceutical compound that may be important is its dissolution rate in aqueous fluid.
  • the rate of dissolution of an active ingredient in a patient's stomach fluid may have therapeutic consequences since it can impact the rate at which an orally administered active ingredient may reach the patient's bloodstream.
  • Another solid state property of a pharmaceutical compound that may be important is its thermal behavior, including its melting point.
  • the melting point of the solid form of a drug is optionally high enough to avoid melting or plastic deformation during standard processing operations, as well as concretion of the drag by plastic deformation on storage ⁇ See, e.g., Gould, P. L. Int. J. Pharmaceutics 198653 201-217). It may be desirable in some cases for a solid form to melt above about 100 0 C, For example, melting point categories used by one pharmaceutical company are, in order of preference, + (mp > 120 0 C), 0 (mp 80-120 0 C), and - (mp ⁇ 80 0 C) (Balbach, S.; Kom, C. Int.
  • Active drag molecules may be made into pharmaceutically acceptable salts for therapeutic administration to the patient.
  • Crystalline salts of a drug may offer advantages over the free form of the compound, such as improved solubility, stability, processing improvements, etc., and different crystalline salt forms may offer greater or lesser advantages over one another.
  • crystalline salt formation is not predictable, and in fact is not always possible.
  • a crystalline form of a compound, a crystalline salt of the compound, or a cocrystal containing the compound or its salt form generally possesses distinct crystallographic and spectroscopic properties when compared to other crystalline forms having the same chemical composition. Crystallographic and spectroscopic properties of a particular form may be measured by XRPD, single crystal X-ray crystallography, solid state NMR spectroscopy, e.g. 13 C CP/MAS NMR, or Raman spectrometry, among other techniques.
  • a particular crystalline form of a compound, of its salt, or of a cocrystal often also exhibits distinct thermal behavior. Thermal behavior can be measured in the laboratory by such techniques as, for example, capillary melting point, TGA, and DSC.
  • novel crystalline salt forms of epalrestat including a potassium anhydrate salt, a sodium anhydrate salt, and a l-(2-hydroxyethyl)- pyrrolidine anhydrate salt.
  • the invention in various embodiments also relates to processes of preparing those crystalline salts of epalrestat, pharmaceutical compositions containing them, and their use in the treatment and/or prevention of various conditions such as diabetic complications, and also to afford cardioprotection in patients who may be non-diabetic.
  • XRPD refers to x-ray powder diffraction.
  • the XRPD data disclosed herein were obtained using an Inel XRG-3000 diffractometer equipped with a CPS (Curved Position Sensitive) detector with a 2 ⁇ range of 120°.
  • Real time data were collected using Cu-Ka radiation at a resolution of 0.03° 2ft
  • the tube voltage and amperage were set to 40 kV and 30 niA, respectively.
  • the monochromator slit was set at 5 mm by 160 ⁇ m. Samples were prepared for analysis by packing them into thin-walled glass capillaries.
  • DSC differential scanning calorimetry
  • DSC data disclosed herein were obtained using a TA Instruments differential scanning calorimeter 2920.
  • the sample was placed into an aluminum DSC pan, and the weight accurately recorded.
  • the pan was crimped with manual pin hole.
  • the sample cell was equilibrated at 25 0 C then heated under a nitrogen purge at a rate of 10 °C/min, up to a final temperature of 300 or 325 0C.
  • Indium metal was used as the calibration standard.
  • 1 H-NMR proton nuclear magnetic resonance spectroscopy.
  • FID free induction decay
  • TGA refers to thermogravimetric analysis. TGA data disclosed herein were obtained using a TA Instruments 2950 thermogravimetric analyzer. Each sample was placed in an aluminum sample pan and inserted into the TG furnace. The furnace was first equilibrated at 25 0 C and then heated under nitrogen at a rate of 10 °C/min, up to a fina 1 temperature of 350 0 C. Nickel and AlumelTM were used as the calibration standards.
  • hep means hydroxyethylpyrrolidone
  • peak locations, intensities, and/or presence may vary slightly from sample to sample, despite the fact that the samples are, within accepted scientific principles, the same form, and this may be due to, for example, preferred orientation or varying solvent or water content. It is well within the ability of those skilled in the art, looking at the data as a whole, to appreciate whether such differences indicate a different form, and thus determine whether analytical data being compared to those disclosed herein are substantially similar.
  • FlG. 1 is an XRPD pattern of a crystalline potassium anliydrate salt of epalrestat, according to one embodiment of the invention
  • FIG. 2 is an XRPD pattern of a crystalline sodium anliydrate salt of epalrestat, according to one embodiment of the invention.
  • FlG. 3 is an XRPD pattern of a crystalline 1 -(2-hydroxyethyl)-pyrrolidine anhydrate salt of epalrestat, according to one embodiment of the invention
  • FIG. 4 is a DSC thermogram of a crystalline potassium anhydrate salt of epalrestat, according to one embodiment of the invention.
  • FIG. 5 is a DSC thermogram of a crystalline sodium anhydrate salt of epalrestat, according to one embodiment of the invention.
  • FIG. 6 is a DSC thermogram of a crystalline l-(2-hydroxyethyl)-pyrrolidine anhydrate salt of epalrestat, according to one embodiment of the invention.
  • FIG. 7 A is a full 1 H-NMR spectrum of a crystalline potassium anhydrate salt of epalrestat, according to one embodiment of the invention.
  • FIG. 7B is an 1 H-NMR spectrum from 8.1 to 6.8 ppm of a crystalline potassium anhydrate salt of epalrestat, according to one embodiment of the invention.
  • FIG. 7C is an 1 H-NMR spectrum from 4.6 to 2.1 ppm of a crystalline potassium anhydrate salt of epalrestat, according to one embodiment of the invention
  • FIG. 7D is an 1 H-NMR spectrum from 1.9 to 1.0 ppm of a crystalline potassium anhydrate salt of epalrestat, according to one embodiment of the invention
  • FIG. 8 A is a fell 1 H-NMR spectrum of a crystalline sodium anhydrate salt of epalrestat, according to one embodiment of the invention.
  • FIG. 8B is an 1 H-NMR spectrum from 10.25 to 9.95 ppm of a crystalline sodium anhydrate salt of epalrestat, according to one embodiment of the invention;
  • FIG. 8C is an 1 H-NMR spectrum from 8.0 to 7.14 ppm of a crystalline sodium anhydrate salt of epalrestat, according to one embodiment of the invention.
  • FIG. 8D is an 1 H-NMR spectrum from 4.5 to 1.5 ppm of a crystalline sodium anhydrate salt of epalrestat, according to one embodiment of the invention.
  • FIG. 9A is a full 1 H-NMR spectrum of a crystalline l-(2-hydroxyethyl)- pyrrolidine anhydrate salt of epalrestat, according to one embodiment of the invention.
  • FIG. 9B is an 1 H-NMR spectrum from 8.0 to 7.2 ppm of a crystalline l-(2- hydroxyethyl)-pyrrolidine anhydrate salt of epalrestat, according to one embodiment of the invention.
  • FIG. 9C is an 1 H-NMR spectrum from 4.8 to 2.8 ppm of a crystalline l-(2- hydroxyethyl)-pyrrolidine anhydrate salt of epalrestat, according to one embodiment of the invention.
  • FIG. 9D is an 1 H-NMR spectrum from 3.0 to 1.4 ppm of a crystalline l-(2- hydroxyethyl)-pyrrolidine anhydrate salt of epalrestat, according to one embodiment of the invention.
  • FIG. 10 is TGA profile of a crystalline potassium anhydrate salt of epalrestat, according to one embodiment of the invention.
  • FIG. 11 is TGA profile of a crystalline sodium anhydrate salt of epalrestat, according to one embodiment of the invention:
  • FIG. 12 is TGA profile of a crystalline 1 -(2-hydroxyethyl)-pyrrolidine anhydrate salt of epalrestat, according to one embodiment of the invention. DESCRIPTION OF EXEMPLAEY EMBODIMENTS
  • the invention relates to novel crystalline salt forms of epalrestat.
  • novel crystalline salts which have been discovered include a potassium anhydrate salt, a sodium anhydrate salt, and a l-(2-hydroxyethyl)- ⁇ yrrolidine anhydrate salt of epalrestat. Exemplary methods of preparation of the crystalline salt forms of epalrestat according to various embodiments of the invention are described below in the examples.
  • All of the inventive salts of epalrestat as described herein can be obtained in a crystalline solid form.
  • the salts of the invention are described as crystalline because of the high degree of crystallinity of the forms as depicted by the XRPD patterns provided in FIGS. 1-3.
  • the forms are shown to have distinct physicochemical properties.
  • the crystalline salt forms of epalrestat according to various embodiments of the invention are particularly suitable for the preparation of stable pharmaceutical preparations,
  • the crystalline potassium anhydrate salt of epalrestat is characterized by an XRPD pattern substantially as shown in FIG. 1, a DSC thermogram substantially as shown in FIG. 4, 1 H-NMR spectra substantially as shown in FIGS. 7A-7D, and a TGA profile substantially as shown in FIG. 10.
  • An exemplary listing of representative XRPD peaks of a crystalline potassium anhydrate salt of epalrestat according to the invention can be found in Table 1.
  • Prominent XRPD peaks may include, in one exemplary embodiment, peaks at 3,8, 15.4, and 15.7 °2 ⁇ ⁇ 0,2.
  • An exemplary listing of representative NMR data can be found in Table 2. Table 1
  • the crystalline sodium anhydrate salt of epalrestat is characterized by an XRPD pattern substantially as shown in FIG. 2, a DSC thermogram substantially as shown in FIG.5, 1 H -NMR spectra substantially as shown in FIGS.8A-8D, and a TGA profile substantially as shown in FIG.11.
  • An exemplary listing of representative XRPD peaks of a crystalline sodium anhydrate salt of epalrestat according to the invention can be found in Table 3.
  • Prominent XRPD peaks may include, in one exemplary embodiment, peaks at 3.7, 17.3, and 18.2 °2 ⁇ ⁇ 0.2.
  • An exemplary listing of representative NMR data can be found in Table 4.
  • the crystalline l-(2-hydroxyethyl)-pyrrolidine anhydrate salt of epalrestat is characterized by an XRPD pattern substantially as shown in FIG. 3, a DSC thermogram substantially as shown in FIG. 6, H -NMR spectra substantially as shown in FIGS. 9A-9D, and a TGA profile substantially as shown in FIG. 12.
  • An exemplary listing of representative XRPD peaks of a crystalline l-(2-hydroxyethyl)-pyrrolidine anhydrate salt of epalrestat according to the invention can be found in Table 5.
  • Prominent XRPD peaks may include, in one exemplary embodiment, peaks at 6.7, 10.5, 1 1.5, and 14.2 °2 ⁇ ⁇ 0.2.
  • An exemplary listing of representative NMR data can be found in Table 6.
  • epalrestat possess the same general pharmacological activity as epalrestat free acid, and are useful for treating and/or preventing diabetic complications such as those discussed above, including, for example, diabetic neuropathy, diabetic retinopathy, and diabetic nephropathy.
  • diabetic complications such as those discussed above, including, for example, diabetic neuropathy, diabetic retinopathy, and diabetic nephropathy.
  • treating or “alleviating” it is meant decreasing the symptoms, markers, or any negative effects of a condition in any appreciable degree in a patient who currently has the condition
  • preventing it is meant preventing entirely or preventing to some extent, such as, for example, by delaying the onset or lessening the degree to which a patient develops the condition.
  • various embodiments of the invention include methods for preventing and/or treating cardiac tissue ischemia in a mammal comprising administering to said mammal an effective amount of one or more of the crystalline salt forms of epalrestat described herein.
  • Various embodiments of the invention also include methods for treating and'or preventing cardiac tissue ischemia in a mammal comprising administering to said mammal a pharmaceutical composition comprising at least one crystalline salt form of epalrestat and a pharmaceutically acceptable vehicle, carrier, and/or diluent.
  • said mammal may be suffering from cardiac tissue ischemia or may be at risk of suffering from cardiac tissue ischemia.
  • a mammal at risk may be awaiting or undergoing cardiac, cardiovascular, or other major surgery.
  • various embodiments of the invention include methods for providing myocardial protection during surgery or myocardial protection in patients presenting with ongoing cardiac or cerebral ischemic events or chronic cardioprotection in patients diagnosed with, or at risk for, coronary heart disease, cardiac dysfunction or myocardial stunning.
  • "mammal" is intended to include humans.
  • Various embodiments of the invention include methods of inhibiting aldose reductase in a mammal in need of inhibition of aldose reductase comprising administering an aldose reductase inhibiting amount of at least one of the crystalline salt forms of epalrestat as described herein.
  • Various embodiments of the invention also include methods of inhibiting aldose reductase in a mammal in need of inhibition of aldose reductase comprising administering a pharmaceutical composition comprising at least one crystalline salt form of epalrestat as described herein, and a pharmaceutically acceptable vehicle, carrier, and/or diluent,
  • Additional embodiments of the invention include methods of treating and/or preventing one or more diabetic complications in a mammal suffering from one or more diabetic complications comprising administering to said mammal an effective amount of at least one crystalline salt form of epalrestat as described herein.
  • Diabetic complications which may be treated and/or prevented by exemplary methods of the invention include, but are not limited to, diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, cardiac autonomic neuropathy, diabetic retinopathy, diabetic macular edema, diabetic gastroparesis, cataracts, foot ulcers, diabetic macroangiopathy, and diabetic microangiopathy.
  • Various embodiments of the invention are also directed to methods of treating and/or preventing one or more diabetic complications in a mammal suffering from one or more diabetic complications comprising administering to said mammal an effective amount of a pharmaceutical composition as set forth herein.
  • Various additional embodiments of the invention include methods of palliating neurological disorders and delaying development of neurological disorders using aldose reductase inhibitors, in order to modulate neurotrophic factor-associated activity, especially CNTF-associated levels and activity, for example as disclosed in U.S. Pat. No. 6,696,407. These methods are useful, for example, for a condition or circumstance in which neurotrophic factor-associated activity is indicated, such as neurological disorders, including neurodegenerative disorders.
  • a “neurological disorder” as used herein means an aberration from clinically normal neural cell activity (i.e., compromised neural cell activity) and includes, by way of example only, neurodegenerative disease (of the CNS and/or PNS), neuropathies associated with toxicity (neurotoxicity) such as chemotherapy (i.e., vincristine or cisplatin-induced motor neuropathy) and alcohol consumption, immune-mediated neurodiseases such as multiple sclerosis (MS) and Guillain-Barre syndrome, hereditary neuropathies such as Charcot-Marie- Tooth neuropathies [see Lebo et al. (1992) Am. J. Hum. Genet. 50:42-55], injury due to trauma, and compromised function due to senescence.
  • neurodegenerative disease of the CNS and/or PNS
  • neuropathies associated with toxicity neuropathies associated with toxicity
  • chemotherapy i.e., vincristine or cisplatin-induced motor neuropathy
  • alcohol consumption i.e., vincri
  • neurodegenerative disorders include but are not limited to, Huntington's disease, amyotrophic lateral sclerosis (ALS). Alzheimer's disease, Parkinson's disease, and Shy-Drager syndrome.
  • the methods may also be useful in delaying development of a neurological disorder, and thus may be used in individuals who show no overt signs of disease but are, for example, at risk of de ⁇ el ⁇ ping disease.
  • additional embodiments of the invention relate to pharmaceutical compositions comprising a therapeutically effective amount of one or more crystalline salts of epalrestat according to various embodiments of the invention and a pharmaceutically acceptable carrier or excipient.
  • the crystalline salts of epalrestat according to various embodiments of the invention have the same or similar pharmaceutical activity as previously reported for epalrestat free acid.
  • Pharmaceutical compositions for the treatment and/or prevention of those conditions or disorders may contain some amount, for example a therapeutically effective amount, of one or more of the crystalline salts of epalrestat described herein, as appropriate, e.g.
  • the amount of the one or more of the crystalline salts of epalrestat in the pharmaceutical compositions may likewise be lower than a therapeutically effective amount, and may, for example, be in the composition in conjunction with another compound or form of epalrestat which, when combined, are present in a therapeutically effective amount
  • a 'therapeutically effective amount refers to an amount of a therapeutic agent sufficient to treat, alleviate, and/or prevent a condition treatable and/or preventable by administration of a composition of the invention, in any degree. That amount can be an amount sufficient to exhibit a detectable therapeutic or preventative or ameliorative effect, and can be determined by routine experimentation by those of skill in the art.
  • the effect may include, for example, treatment, alleviation, and/or prevention of the conditions listed herein,
  • the actual amount required, e.g. for treatment of any particular patient will depend upon a variety of factors including the disorder being treated and/or prevented; its severity; the specific pharmaceutical composition employed; the age, body weight, general health, gender, and diet of the patient; the mode of administration; the time of administration; the route of administration; the rate of excretion of epalrestat; the duration of the treatment; any drugs used in combination or coincidental with the specific compound employed; and other such factors well known in the medical arts. These factors are discussed in Goodman and Gilman's "The Pharmacological Basis of Therapeutics", Tenth Edition, A. Gilman, J.Hardman and L. Limbird, eds., McGraw- Hill Press, 155-173, 2001.
  • a pharmaceutical composition according to various embodiments of the invention may be any pharmaceutical form which contains one or more crystalline salts of epalrestat according to various embodiments of the invention.
  • the pharmaceutically acceptable carrier may be chosen from any one or a combination of carriers known in the art. The choice of the pharmaceutically acceptable carrier depends upon the pharmaceutical form and the desired method of administration to be used.
  • a carrier may be chosen that maintains the crystalline salt form. In other words, the carrier, in some embodiments, will not substantially alter the crystalline form of the crystalline salts of epalrestat as described herein.
  • the carrier will similarly not be otherwise incompatible with epalrestat itself or crystalline salts of epalrestat according to various embodiments of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition.
  • the pharmaceutical compositions according to various embodiments of the invention are optionally formulated in unit dosage form for ease of administration and uniformity of dosage.
  • a "unit dosage form" refers to a physically discrete unit of therapeutic agent appropriate for the patient to be treated. It will be understood, however, that the total daily dosage of the crystalline salts of epalrestat according to various embodiments of the invention and pharmaceutical compositions thereof will be decided by the attending physician within the scope of sound medical judgment using known methods.
  • Solid dosage forms are a preferred form for the pharmaceutical composition of the invention.
  • Solid dosage forms for oral administration may include, for example, capsules, tablets, pills, powders, and granules.
  • the solid dosage form is a tablet.
  • the active ingredient may be contained in a solid dosage form formulation that provides quick release, sustained release, or delayed release after administration to the patient.
  • the active compound may be mixed with at least one inert, pharmaceutically acceptable carrier, such as, for example, sodium citrate or dicalcium phosphate.
  • the solid dosage form may also include one or more of various additional ingredients, including, for example: a) fillers or extenders such as, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as, for example, glycerol; d) disintegrating agents such as, for example, agar, calcium carbonate, potato or tapioca starch, alg ⁇ nfc acid, certain silicates, and sodium carbonate; e) dissolution retarding agents such as, for example, paraffin; f) absorption accelerators such as, for example, quaternary ammonium compounds; g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate; h) absorbents such as, for example, kaolin and benton
  • the solid dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof.
  • Solid dosage forms of pharmaceutical compositions according to various embodiments of the invention can also be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art.
  • the crystalline salts of epalrestat according to various embodiments of the invention can be, in one exemplary embodiment, administered in a solid micro-encapsulated form with one or more carriers as discussed above.
  • Microencapsulated forms may also be used in soft and hard-filled gelatin capsules with carriers such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the crystalline salts of epalrestat according to various embodiments of the invention may also be used in the preparation of non-solid formulations, e.g., injectables and patches, of epalrestat.
  • non-solid formulations are known in the art.
  • the crystalline salt form may, in certain exemplary embodiments, not be maintained.
  • the crystalline salt form may be dissolved in a liquid carrier.
  • the crystalline salts of epalrestat according to various embodiments of the invention may represent intermediate forms of epalrestat used in the preparation of the non-solid formulation.
  • the crystalline salts of epalrestat according to various embodiments of the invention may provide advantages of handling stability and purity to the process of making such formulations.
  • the invention also relates to the treatment and/or prevention of diabetes- associated disorders such as those discussed above.
  • the invention provides a method for treating and/or preventing diabetes-associated disorders by administering to mammals one or more of the novel crystalline salt forms of epalrestat as described herein, or a pharmaceutical composition containing the same, in an amount sufficient to treat and/or prevent a condition treatable and/or preventable by administration of a composition of the invention. That amount is the amount sufficient to exhibit any detectable therapeutic and/or preventative or ameliorative effect.
  • the effect may include, for example, treatment and/or prevention of the conditions listed herein.
  • crystalline salt forms of epalrestat and pharmaceutical compositions containing them may, according to various embodiments of the invention, be administered using any amount, any form of pharmaceutical composition, and any route of administration effective, e.g. for treatment, all of which are easily determined by those of skill in the art through routine experimentation.
  • the pharmaceutical compositions can be administered to humans and other mammals by any known method, such as, for example, orally, rectally, or topically (such as by powders or other solid form-based topical formulations).
  • the novel crystalline salt forms of epalrestat according to various embodiments of the invention may be administered at dosage levels ranging from about 0.001 mg/kg to about 50 ing/Teg, from about 0.01 mg/kg to about 25 mg/kg, or from about 0.1 mg/kg to about 10 mg/kg of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect
  • dosages smaller than about 0.001 mg/kg or greater than about 50 mg/kg can also be administered to a subject in certain embodiments of the invention.
  • the amount required for a particular patient will depend upon a variety of factors including the disorder being treated and/or prevented; its severity; the specific pharmaceutical composition employed; the age, body weight, general health, gender, and diet of the patient; the mode of administration; the time of administration; the route of administration; and the rate of excretion of epalrestat; the duration of the treatment; any drugs used in combination or coincidental with the specific compound employed; and other such factors well known in the medical arts.
  • the pharmaceutical composition of the crystalline salts of epalrestat as described herein may be administered as a unit dosage form.
  • Example 2 Preparation of a crystalline sodium anhydrate salt of epalrestat
  • Analytical data were obtained on the final product: the XRPD pattern was as shown in FIG.
  • Example 3 Preparation of a crystalline sodium anhydrate salt of epalrestat [0068J A mixture of solution containing 3.08 g (9.64 mmol) of epalrestat free acid, 50 niL of methanol, and 3.75 mL of a solution of 516 mg of sodium hydroxide in 5 mL of water (387 mg, 9.68 mmol of sodium hydroxide) was briefly placed in an ultrasonic bath and stirred for 10 minutes.
  • Example 4 Preparation of a crystalline 1 -(2-hydroxyethyl)-pyrrolidine anhydrate salt of epalrestat

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Endocrinology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)

Abstract

Cette invention concerne de nouveaux sels cristallins de l’acide 5-[(lZ,2E)-2-méthyl-3-phénylpropénylidène]-4-oxo-2-thioxo-3-thiazolidine acétique. L’invention concerne aussi la préparation et la caractérisation des sels cristallins selon les différents modes de réalisation de l’invention. L’invention concerne par ailleurs des compositions pharmaceutiques contenant les nouveaux sels cristallins et leur utilisation thérapeutique pour traiter et/ou prévenir différentes pathologies, notamment les complications diabétiques, l’inhibition de l’aldose réductase et la cardioprotection chez les patients éventuellement non diabétiques.
PCT/US2009/051687 2008-07-25 2009-07-24 Nouveaux sels cristallins d’epalrestat Ceased WO2010011922A2 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EA201100244A EA018600B1 (ru) 2008-07-25 2009-07-24 Новые кристаллические соли эпалрестата
US13/013,786 US8697735B2 (en) 2008-07-25 2011-01-25 Solid forms of epalrestat
US14/251,039 US9447056B2 (en) 2008-07-25 2014-04-11 Solid forms of epalrestat

Applications Claiming Priority (2)

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US8361108P 2008-07-25 2008-07-25
US61/083,611 2008-07-25

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PCT/US2009/051693 Continuation-In-Part WO2010011926A2 (fr) 2008-07-25 2009-07-24 Nouveau co-cristal de bétaïne d'épalrestat

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US13/013,786 Continuation-In-Part US8697735B2 (en) 2008-07-25 2011-01-25 Solid forms of epalrestat
US13/013,786 Continuation US8697735B2 (en) 2008-07-25 2011-01-25 Solid forms of epalrestat

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8697735B2 (en) 2008-07-25 2014-04-15 Bionevia Pharmaceuticals, Inc. Solid forms of epalrestat
US8906948B2 (en) 2008-09-06 2014-12-09 Bionevia, LLC Choline cocrystal of epalrestat
EP3042654A1 (fr) 2011-01-20 2016-07-13 Bionevia Pharmaceuticals Inc. Compositions à libération modifiée d'epalrestat ou d'un dérivé de celui-ci et leurs procédés d'utilisation
JP2017043605A (ja) * 2015-08-28 2017-03-02 エーザイ・アール・アンド・ディー・マネジメント株式会社 エパルレスタットを調製する方法
CN113336718A (zh) * 2021-06-01 2021-09-03 天津大学 依帕司他-二甲双胍盐及其制备方法和应用

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5740478A (en) * 1980-08-22 1982-03-06 Ono Pharmaceut Co Ltd Rhodanine derivative, its preparation and aldose reductase inhibitor containing rhodanine derivative
EP1106210A3 (fr) * 1999-12-07 2003-12-03 Pfizer Products Inc. Combinaisons pour le traitement de complications diabétiques, comprenant un inhibiteur de reductase d'aldose et un agents antihypertensif
JP4892915B2 (ja) * 2005-10-04 2012-03-07 大日本印刷株式会社 エパルレスタット製造法

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8697735B2 (en) 2008-07-25 2014-04-15 Bionevia Pharmaceuticals, Inc. Solid forms of epalrestat
US9447056B2 (en) 2008-07-25 2016-09-20 Bionevia Pharmaceuticals, Inc. Solid forms of epalrestat
US8906948B2 (en) 2008-09-06 2014-12-09 Bionevia, LLC Choline cocrystal of epalrestat
US10464912B2 (en) 2008-09-06 2019-11-05 Bionevia Pharmaceuticals, Inc. Choline cocrystal of epalrestat
EP3042654A1 (fr) 2011-01-20 2016-07-13 Bionevia Pharmaceuticals Inc. Compositions à libération modifiée d'epalrestat ou d'un dérivé de celui-ci et leurs procédés d'utilisation
US9566269B2 (en) 2011-01-20 2017-02-14 Bionevia Pharmaceuticals Inc. Modified release compositions of epalrestat or a derivative thereof and methods for using the same
JP2017043605A (ja) * 2015-08-28 2017-03-02 エーザイ・アール・アンド・ディー・マネジメント株式会社 エパルレスタットを調製する方法
JP2022000462A (ja) * 2015-08-28 2022-01-04 エーザイ・アール・アンド・ディー・マネジメント株式会社 エパルレスタットを調製する方法
CN113336718A (zh) * 2021-06-01 2021-09-03 天津大学 依帕司他-二甲双胍盐及其制备方法和应用
CN113336718B (zh) * 2021-06-01 2023-02-28 天津大学 依帕司他-二甲双胍盐及其制备方法和应用

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EA201100244A1 (ru) 2011-08-30
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