WO2010028132A2 - Novel choline cocrystal of epalrestat - Google Patents
Novel choline cocrystal of epalrestat Download PDFInfo
- Publication number
- WO2010028132A2 WO2010028132A2 PCT/US2009/055868 US2009055868W WO2010028132A2 WO 2010028132 A2 WO2010028132 A2 WO 2010028132A2 US 2009055868 W US2009055868 W US 2009055868W WO 2010028132 A2 WO2010028132 A2 WO 2010028132A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cocrystal
- diabetic
- epalrestat
- oxo
- methyl
- Prior art date
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- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
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- 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
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/40—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton with quaternised nitrogen atoms bound to carbon atoms of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- the invention relates to a novel choline cocrystal of 5-[(l Z£E)-2-methyl-3- phenylpropenylidene]-4-oxo-2-thioxo-3-thiazolidineacetic acid, processes for making the novel cocrystal, pharmaceutical compositions comprising the novel choline cocrystal, and methods of treating and/or preventing various conditions by administering the novel choline cocrystal.
- 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 HI):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.
- each salt or each solid form of a drug 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. 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.
- crystalline forms are extremely useful in drug development. It may permit better characterization of the drug 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, for example, 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 drug by plastic deformation on storage (See, e.g., Gould, P. L. Int. J. Pharmaceutics 1986 33 201-217). It may be desirable in some cases for a solid form to melt above about 100 0 C.
- 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.; Kora, C. Int. J. Pharmaceutics 2004275 1-12).
- Active drug 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.
- Cocrystals are crystals that contain two or more non-identical molecules. Examples of cocrystals may be found in the Cambridge Structural Database. Examples of cocrystals may also be found at Etter, M.C., and Adsmond, D. A., J. Chem. Soc, Chem. Commun. 1990 589-591; Etter, M. C, MacDonald, J.C., and Bernstein, J., Acta Crystallogr., Sect. B, Struct. Sci.
- cocrystallizing an API or a salt of an API with a co-former (the other component of the cocrystal) one creates a new solid state form of the API which has unique properties compared with existing solid forms of the API or its salt.
- a cocrystal may have different dissolution and/or solubility properties than the active agent itself or its salt.
- Cocrystals containing APIs can be used to deliver APIs therapeutically.
- New drug formulations comprising cocrystals of APIs with pharmaceutically acceptable co-formers may, in some cases, have superior properties over existing drug formulations.
- cocrystal 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.
- the invention in various embodiments also relates to processes of preparing the novel choline cocrystal of epalrestat, pharmaceutical compositions containing the novel choline cocrystal of epalrestat, and its 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° 20.
- the tube voltage and amperage were set to 40 kV and 30 mA, 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. Each capillary was mounted onto a goniometer head that is motorized to permit spinning of the capillary during data acquisition. Instrument calibration was performed using a silicon reference standard.
- DSC differential scanning calorimetry
- DSC data disclosed herein were obtained using a TA Instruments differential scanning calorimeter Q2000. The sample was placed into an aluminum DSC pan, and the weight accurately recorded. The pan was crimped and the contents heated under nitrogen under the conditions given in the figures. Indium metal was used as the calibration standard.
- solubility data were collected in water at ambient temperature over approximately 24 hours using an orbital shaker. Samples were taken at approximately 1, 3, 6, and 24 hours, and analyzed by UV spectrophotometry using a SpectraMax M2 UV-VIS spectrophotometer. Wavelength calibration and photometric accuracy were performed using the SpectraMax Pro 5 software as an internal calibration of the instrument. The detector was zeroed with a reference well on a microplate filled with water on which data were obtained, and those data were subtracted from collected data. Samples were analyzed in the UV range at room temperature in the wells of a 96-well quartz plate.
- 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.
- choline hydrogen diepalrestat and “choline hydrogen diacid cocrystal of epalrestat,” including variations which use the chemical name “5- [(lZ,2E)-2-methyl-3-phenylpropenylidene]-4-oxo-2-thioxo-3-thiazolidineacetic acid” in place of the common name “epalrestat,” are used interchangeably to refer to the novel choline cocrystal of epalrestat described herein.
- FIG. 1 is an exemplary XRPD pattern of a choline hydrogen diacid cocrystal of epalrestat, according to one embodiment of the invention
- FIG. 2 is an exemplary DSC thermogram of a choline hydrogen diacid cocrystal of epalrestat, according to one embodiment of the invention
- FIG. 3A is an exemplary full 1 H-NMR spectrum of a choline hydrogen diacid cocrystal of epalrestat, according to one embodiment of the invention.
- FIG. 3B is an exemplary 1 H-NMR spectrum from 7.9 to 7.0 ppm of a choline hydrogen diacid cocrystal of epalrestat, according to one embodiment of the invention.
- FIG. 3C is an exemplary 1 H-NMR spectrum from 4.8 to 2.2 ppm of a choline hydrogen diacid cocrystal of epalrestat, according to one embodiment of the invention.
- FIG. 3D is an exemplary 1 H-NMR spectrum from 2.11 to 2.00 ppm of a choline hydrogen diacid cocrystal of epalrestat, according to one embodiment of the invention.
- FIG. 4 is an XRPD pattern of an intermediate product useful in an exemplary method of making a choline hydrogen diacid cocrystal of epalrestat according to one embodiment of the invention
- FIG. 5 A is a full 1 H-NMR spectrum of an intermediate product useful in an exemplary method of making a choline hydrogen diacid cocrystal of epalrestat according to one embodiment of the invention
- FIG. 5B is an 1 H-NMR spectrum from 8.0 to 5.4 ppm of an intermediate product useful in an exemplary method of making a choline hydrogen diacid cocrystal of epalrestat according to one embodiment of the invention
- FIG. SC is an 1 H-NMR spectrum from 4.6 to 2.2 ppm of an intermediate product useful in an exemplary method of making a choline hydrogen diacid cocrystal of epalrestat according to one embodiment of the invention.
- FIGS. 6A-6B show solubility data for a choline cocrystal of epalrestat, according to one exemplary embodiment of the invention.
- the invention relates to a novel choline cocrystal of epalrestat.
- the novel cocrystal which has been discovered is a choline hydrogen diacid cocrystal of epalrestat having two moles of epalrestat and one mole of choline.
- the novel cocrystal is anhydrous. At least one exemplary method of preparation of the novel choline cocrystal of epalrestat according to the invention is described below in the examples.
- the novel cocrystal described herein is obtained in a crystalline solid form, as seen by the high degree of crystallinity depicted in the XRPD pattern provided in FIG. 1.
- the cocrystal is shown to have distinct physicochemical properties.
- the cocrystal of epalrestat described herein is particularly suitable for the preparation of stable pharmaceutical preparations.
- the novel choline cocrystal of epalrestat is characterized by an XRPD pattern substantially as shown in FIG. 1, a DSC thermogram substantially as shown in FIG. 2, an 1 H- NMR spectrum substantially as shown in FIGS. 3 A-3D, and a solubility profile substantially as shown in FIG. 6A.
- An exemplary listing of representative XRPD peaks of the novel choline cocrystal of epalrestat according to an embodiment of the invention can be found in Table 1.
- An exemplary listing of representative NMR data can be found in Table 2.
- the novel choline cocrystal of epalrestat described herein possesses the same general pharmacological activity as epalrestat free acid, and is 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 a novel choline cocrystal of epalrestat as 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 a novel choline cocrystal 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 a novel choline cocrystal 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 a novel choline cocrystal 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 a novel choline cocrystal 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, diabetic retinopathy, 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.
- Further embodiments of the invention contemplate methods of treating and/or preventing homocystinuria, and/or reducing levels of homocysteine in the blood serum, for example in a patient with diabetes, by administering an effective amount of a novel choline cocrystal of epalrestat, or composition and/or formulation comprising an effective amount of a novel choline cocrystal of epalrestat, as described herein.
- choline is converted to betaine, also known as trimethylglycine or glycine betaine. Both choline and betaine are naturally occurring molecules found in dietary sources (Olthof MR, Curr Drug Metab 2005;6: 15- 22).
- betaine In biological systems, betaine is important in the metabolism of homocysteine, and functions as a methyl donor. Betaine is therefore used therapeutically to reduce elevated homocysteine concentrations (van Guldener C et al, Expert Opinion on Pharmacotherapy 2001 ;2: 1449- 1460), and is approved for use in the U.S. and Europe as a therapeutic agent to treat homocystinuria from genetic causes (Cystadane prescribing information, FDA; Cystadane product information, EMEA).
- Homocysteine is also elevated in patients with various non-cardiovascular diabetic complications, including diabetic nephropathy (Bostom AG et al, Arterioscler Thromb Vase Biol 1997; 17:2554-2558), diabetic retinopathy (Brazionis L et al, Diabetes Care 2OO8;31 :50-56), and diabetic neuropathy (Ambrosch A et al, Diabetic Medicine 2001 ; 18: 185- 192). Administration of a novel choline cocrystal of epalrestat may therefore have an additional beneficial therapeutic effect for treating these conditions.
- 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 developing disease.
- compositions comprising any amount, such as a therapeutically effective amount, of a novel choline cocrystal of epalrestat as described herein and a pharmaceutically acceptable carrier or excipient.
- the novel choline cocrystal of epalrestat according to the invention has 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 a novel choline cocrystal of epalrestat described herein, as appropriate, e.g. for treatment of a patient with the particular condition or disorder.
- the amount of the cocrystal 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" as described herein 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 a novel choline cocrystal of epalrestat as described herein.
- 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 cocrystal form. In other words, the carrier, in some embodiments, will not substantially alter the cocrystal form of epalrestat as described herein. In some embodiments, the carrier will similarly not be otherwise incompatible with epalrestat itself, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition.
- 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 a novel choline cocrystal of epalrestat described herein 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, carfooxymethylc ⁇ llulose, 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, alginic 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, ka
- 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.
- novel choline cocrystal of epalrestat described herein 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 novel choline cocrystal of epalrestat as described herein 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 cocrystal form may, in certain exemplary embodiments, not be maintained.
- the cocrystal may be dissolved in a liquid carrier.
- the novel cocrystal of epalrestat described herein may represent intermediate forms of epalrestat used in the preparation of the non-solid formulation.
- the novel choline cocrystal of epalrestat described herein 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 a novel choline cocrystal 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.
- novel choline cocrystal of epalrestat and pharmaceutical compositions containing the same 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 choline cocrystal of epalrestat according to the invention may be administered at dosage levels ranging from about 0.001 mg/kg to about 50 mg/kg, 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. It will also be appreciated that dosages smaller than about 0.001 mg/kg or greater than about 50 mg/kg (for example, ranging from about 50 mg/kg to about 100 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; 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 compositions comprising a novel choline cocrystal of epalrestat as described herein may be administered as a unit dosage form.
- Example 2 Preparation of a choline hydrogen diacid cocrvstal of epalrestat
- the dissolved concentration of epalrestat increased over time to 249 ⁇ g/mL after approximately 24 hours.
- the choline hydrogen diacid cocrystal of epalrestat appears to have a greater solubility in water than the free acid.
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Abstract
Description
Claims
Priority Applications (16)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
LTEP09812208.8T LT2326632T (en) | 2008-09-06 | 2009-09-03 | Novel choline cocrystal of epalrestat |
PL09812208T PL2326632T3 (en) | 2008-09-06 | 2009-09-03 | Novel choline cocrystal of epalrestat |
UAA201103353A UA106209C2 (en) | 2008-09-06 | 2009-09-03 | Choline cocrystal of 5-[(1z,2e)-2-methyl-3-phenylpropenylidene]-4-oxo-2-thioxo-3-thiazolidine acetic acid |
EP09812208.8A EP2326632B8 (en) | 2008-09-06 | 2009-09-03 | Novel choline cocrystal of epalrestat |
GB1105528.2A GB2476202B (en) | 2008-09-06 | 2009-09-03 | Novel choline cocrystal of epalrestat |
SI200931721T SI2326632T1 (en) | 2008-09-06 | 2009-09-03 | Novel choline cocrystal of epalrestat |
CN200980143667.4A CN102216281B (en) | 2008-09-06 | 2009-09-03 | Novel choline cocrystal of epalrestat |
DK09812208.8T DK2326632T3 (en) | 2008-09-06 | 2009-09-03 | New choline crystal of epalrestate |
ES09812208.8T ES2639019T3 (en) | 2008-09-06 | 2009-09-03 | New co-crystal of epalrestat hill |
US13/062,644 US8906948B2 (en) | 2008-09-06 | 2009-09-03 | Choline cocrystal of epalrestat |
EA201100245A EA016904B1 (en) | 2008-09-06 | 2009-09-03 | Novel choline cocrystal of epalrestat |
AU2009288037A AU2009288037B2 (en) | 2008-09-06 | 2009-09-03 | Novel choline cocrystal of epalrestat |
CA2738231A CA2738231C (en) | 2008-09-06 | 2009-09-03 | Novel choline cocrystal of epalrestat |
US14/532,517 US9611234B2 (en) | 2008-09-06 | 2014-11-04 | Choline cocrystal of epalrestat |
US15/449,723 US10464912B2 (en) | 2008-09-06 | 2017-03-03 | Choline cocrystal of epalrestat |
CY20171100917T CY1119752T1 (en) | 2008-09-06 | 2017-08-30 | HOLINESS CELLULAR CYLINDER OF EXALASTAT |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US9490408P | 2008-09-06 | 2008-09-06 | |
US61/094,904 | 2008-09-06 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
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US13/062,644 A-371-Of-International US8906948B2 (en) | 2008-09-06 | 2009-09-03 | Choline cocrystal of epalrestat |
US14/532,517 Division US9611234B2 (en) | 2008-09-06 | 2014-11-04 | Choline cocrystal of epalrestat |
Publications (2)
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WO2010028132A2 true WO2010028132A2 (en) | 2010-03-11 |
WO2010028132A3 WO2010028132A3 (en) | 2010-06-17 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/US2009/055868 WO2010028132A2 (en) | 2008-09-06 | 2009-09-03 | Novel choline cocrystal of epalrestat |
Country Status (17)
Country | Link |
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US (3) | US8906948B2 (en) |
EP (1) | EP2326632B8 (en) |
CN (1) | CN102216281B (en) |
AU (1) | AU2009288037B2 (en) |
CA (1) | CA2738231C (en) |
CY (1) | CY1119752T1 (en) |
DK (1) | DK2326632T3 (en) |
EA (2) | EA023435B1 (en) |
ES (1) | ES2639019T3 (en) |
GB (1) | GB2476202B (en) |
HU (1) | HUE034456T2 (en) |
LT (1) | LT2326632T (en) |
PL (1) | PL2326632T3 (en) |
PT (1) | PT2326632T (en) |
SI (1) | SI2326632T1 (en) |
UA (1) | UA106209C2 (en) |
WO (1) | WO2010028132A2 (en) |
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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 |
US10238668B2 (en) | 2008-10-17 | 2019-03-26 | Laboratorios Del Dr. Esteve, S.A. | Co-crystals of tramadol and coxibis |
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ITMI20120586A1 (en) | 2012-04-11 | 2013-10-12 | Milano Politecnico | CO-CRYSTALS OF 3-IODIOPROPINYL BUTYCARBAMMATE |
CN103951634B (en) * | 2014-05-07 | 2016-06-08 | 浙江东亚药业股份有限公司 | A kind of epalrestat crystal salt hydrate and hydroxy piperidine eutectic thing and its preparation method and application |
MX2016014863A (en) * | 2014-05-27 | 2017-06-21 | Artificial Cell Tech Inc | Automated layer by layer construction of multilayer coated cores by tff. |
KR20220003529A (en) | 2019-04-01 | 2022-01-10 | 어플라이드 테라퓨틱스 인크. | Inhibitors of aldose reductase |
AU2020268368A1 (en) * | 2019-05-07 | 2022-01-06 | Ucl Business Ltd | Treatment and detection of inherited neuropathies and associated disorders |
CN113336718B (en) * | 2021-06-01 | 2023-02-28 | 天津大学 | Epalrestat-metformin salt and preparation method and application thereof |
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CN113354596B (en) * | 2021-06-01 | 2022-11-29 | 天津大学 | Epalrestat-metformin salt acetone solvate, preparation method and application |
CN113292511B (en) * | 2021-06-01 | 2022-11-25 | 天津大学 | Epalrestat-metformin salt ethanol water double solvate, preparation method and application |
CN115947699B (en) * | 2023-01-16 | 2024-01-19 | 威海海洋职业学院 | Epalrestat eutectic crystal taking nicotinamide as precursor and preparation method thereof |
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- 2009-09-03 UA UAA201103353A patent/UA106209C2/en unknown
- 2009-09-03 EA EA201200489A patent/EA023435B1/en not_active IP Right Cessation
- 2009-09-03 EP EP09812208.8A patent/EP2326632B8/en not_active Not-in-force
- 2009-09-03 EA EA201100245A patent/EA016904B1/en not_active IP Right Cessation
- 2009-09-03 ES ES09812208.8T patent/ES2639019T3/en active Active
- 2009-09-03 PL PL09812208T patent/PL2326632T3/en unknown
- 2009-09-03 US US13/062,644 patent/US8906948B2/en active Active
- 2009-09-03 CA CA2738231A patent/CA2738231C/en not_active Expired - Fee Related
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- 2009-09-03 LT LTEP09812208.8T patent/LT2326632T/en unknown
- 2009-09-03 DK DK09812208.8T patent/DK2326632T3/en active
- 2009-09-03 PT PT98122088T patent/PT2326632T/en unknown
- 2009-09-03 AU AU2009288037A patent/AU2009288037B2/en not_active Ceased
- 2009-09-03 GB GB1105528.2A patent/GB2476202B/en not_active Expired - Fee Related
- 2009-09-03 HU HUE09812208A patent/HUE034456T2/en unknown
- 2009-09-03 CN CN200980143667.4A patent/CN102216281B/en not_active Expired - Fee Related
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Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
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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 |
US10245276B2 (en) | 2008-10-17 | 2019-04-02 | Laboratorios Del Dr. Esteve, S.A. | Co-crystals of tramadol and coxibs |
US10238668B2 (en) | 2008-10-17 | 2019-03-26 | Laboratorios Del Dr. Esteve, S.A. | Co-crystals of tramadol and coxibis |
US10548909B2 (en) | 2008-10-17 | 2020-02-04 | Esteve Pharmaceuticals, S.A. | Co-crystals of tramadol and coxibs |
US11478488B2 (en) | 2008-10-17 | 2022-10-25 | Esteve Pharmaceuticals, S.A. | Co-crystals of tramadol and coxibs |
EP3042654A1 (en) | 2011-01-20 | 2016-07-13 | Bionevia Pharmaceuticals Inc. | Modified release compositions of epalrestat or a derivative thereof and methods for using the same |
EP2665477A4 (en) * | 2011-01-20 | 2014-07-09 | Bionevia Pharmaceuticals Inc | Modified release compositions of epalrestat or a derivative thereof and methods for using the same |
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 |
WO2012100208A1 (en) * | 2011-01-20 | 2012-07-26 | Bionevia Pharmaceuticals Inc. | Modified release compositions of epalrestat or a derivative thereof and methods for using the same |
EP2665477A1 (en) * | 2011-01-20 | 2013-11-27 | Bionevia Pharmaceuticals Inc. | Modified release compositions of epalrestat or a derivative thereof and methods for using the same |
Also Published As
Publication number | Publication date |
---|---|
ES2639019T3 (en) | 2017-10-25 |
PL2326632T3 (en) | 2017-10-31 |
EA016904B1 (en) | 2012-08-30 |
CA2738231C (en) | 2015-04-07 |
EP2326632A2 (en) | 2011-06-01 |
UA106209C2 (en) | 2014-08-11 |
US9611234B2 (en) | 2017-04-04 |
SI2326632T1 (en) | 2017-11-30 |
US8906948B2 (en) | 2014-12-09 |
GB2476202B (en) | 2012-04-11 |
PT2326632T (en) | 2017-09-05 |
US10464912B2 (en) | 2019-11-05 |
AU2009288037B2 (en) | 2014-08-14 |
HUE034456T2 (en) | 2018-02-28 |
GB2476202A (en) | 2011-06-15 |
CY1119752T1 (en) | 2018-06-27 |
EP2326632B8 (en) | 2017-08-09 |
EA201200489A1 (en) | 2013-01-30 |
AU2009288037A1 (en) | 2010-03-11 |
EA023435B1 (en) | 2016-06-30 |
CN102216281B (en) | 2014-11-05 |
DK2326632T3 (en) | 2017-09-18 |
CN102216281A (en) | 2011-10-12 |
EP2326632A4 (en) | 2012-05-30 |
WO2010028132A3 (en) | 2010-06-17 |
EA201100245A1 (en) | 2011-08-30 |
LT2326632T (en) | 2017-09-25 |
US20150057319A1 (en) | 2015-02-26 |
US20110275682A1 (en) | 2011-11-10 |
CA2738231A1 (en) | 2010-03-11 |
GB201105528D0 (en) | 2011-05-18 |
US20170174643A1 (en) | 2017-06-22 |
EP2326632B1 (en) | 2017-05-31 |
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