Co-crystals of Ovixibabet

Abstract

The present invention relates to co-crystals of 1, 1-dioxo-3, 3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-alpha-[N-((S)-1-carboxylpropyl) carbamoyl]-4-hydroxybenzyl} carbamoylmethoxy)-2, 3, 4, 5-tetrahydro-1, 2, 5-benzothiadiazepine (Ovicobatide) and a pyridoxine, in particular to co-crystals of 1, 1-dioxo-3, 3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-alpha-[N-((S)-1-carboxylpropyl) carbamoyl]-4-hydroxybenzyl} carbamoylmethoxy)-2, 3, 4, 5-tetrahydro-1, 2, 5-benzothiadiazepine (Ovicobatide). The invention also relates to pharmaceutical compositions comprising said co-crystals, and their use in the treatment of various conditions as described herein.

Description

[0001] The present invention relates to a co-crystal of 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine (odevixibat) and pyridoxine having high chemical and physical stability. The present invention also relates to a pharmaceutical composition comprising the co-crystal, and its use in the treatment of various conditions as described herein. Background Art

[0002] WO 03 / 022286 discloses the compound 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine (odevixibat). As an ileal bile acid transporter (IBAT) inhibitor, odevixibat prevents the natural reabsorption of bile acids from the ileum into the hepatic portal circulation, resulting in the excretion of unabsorbed bile acids through feces. This leads to a decrease in bile acid levels in serum and liver. Thus, odevixibat can be used to treat or prevent diseases such as dyslipidemia, constipation, diabetes, and liver diseases, especially liver diseases associated with elevated bile acid levels.

[0003] According to the experimental section of WO 03 / 022286, the last step in the preparation of odevixibat involves hydrolysis of the tert-butyl ester under acidic conditions. The crude compound is obtained by evaporating the solvent under reduced pressure and then purifying the residue by preparative HPLC (Example 29). No crystalline material was identified. The amorphous material may contain residual solvent, which is highly undesirable for a material intended for pharmaceutical use. In addition, due to the low chemical and physical stability of the amorphous material, the amorphous material may exhibit faster decomposition and may spontaneously form crystals with variable crystallinity compared to crystalline material. This may lead to non-reproducible dissolution rates and difficulties in storing and handling the material. In pharmaceutical formulations, for this reason, the active pharmaceutical ingredient (API) is preferably used in a highly crystalline state.

[0004] WO 2019 / 245448 discloses a crystalline sesquihydrate of odevixibat, and its preparation from certain solvents or solvent mixtures.

[0005] Nevertheless, there remains a need for additional crystal forms of odevixibat having improved properties in terms of stability, batch processing, and solubility. Accordingly, it is an object of the present invention to provide a stable crystal form of odevixibat having good crystallinity and good formulation properties. Description of the Drawings

[0006] Figure 1 Displays the X-ray powder diffraction pattern of the eutectic of obeticholic acid and pyridoxine.

[0007] Figure 2 Displays the DSC thermogram of the eutectic.

[0008] Figure 3 Displays the TG-FTIR thermogram of the eutectic.

[0009] Figure 4 Displays the DVS isotherm of the eutectic, where the change in water content is a function of time.

[0010] Figure 5 Displays the DVS isotherm of the eutectic, where the change in water content is a function of relative humidity.

[0011] Figure 6 Displays the superimposed X-ray powder diffraction patterns of the eutectic before (bottom) and after (top) the dynamic vapor sorption experiment. Detailed Description of the Invention

[0012] It has been found that stable crystalline forms of obeticholic acid can be obtained by crystallizing obeticholic acid with certain eutectic formers. Thus, in a first aspect, the present invention relates to a eutectic of obeticholic acid and pyridoxine. As described in the experimental section, the eutectic can be obtained, for example, from an isopropanol solution of obeticholic acid and pyridoxine. It has been determined by 1 1H NMR that the eutectic contains obeticholic acid and pyridoxine in a 2:1 molar ratio (data not shown). In one embodiment, the present invention relates to a eutectic of obeticholic acid and pyridoxine, wherein obeticholic acid and pyridoxine are present in a 2:1 molar ratio.

[0013] It has been observed that the eutectic retains water in a reversible and continuous manner. At 95% relative humidity, approximately 2.5% water is retained. By reducing the humidity to zero, the eutectic loses all of its water. The expected water content of the monohydrate is 2.1%, and thus the eutectic is considered to be a non-stoichiometric hydrate that typically contains approximately 1% water under ambient storage conditions.

[0014] In some embodiments, the present invention relates to a eutectic of obeticholic acid and pyridoxine having an X-ray powder diffraction (XRPD) pattern obtained with CuKα1 radiation, said XRPD pattern having at least three specific peaks at °2θ positions selected from: 4.70 ±0.2, 6.13 ±0.2, 8.02 ±0.2, 9.22 ±0.2, 11.32 ±0.2, 11.52 ±0.2, 12.92±0.2, 15.93 ±0.2, 16.76 ±0.2 and 24.12 ±0.2.

[0015] In some embodiments, the present invention relates to a cocrystal of obeticholic acid and pyridoxine having an XRPD pattern obtained with CuKα1 radiation, said XRPD pattern having at least three specific peaks at °2θ positions selected from: 4.70 ±0.2, 6.13 ±0.2, 8.02 ±0.2, and 11.52 ±0.2.

[0016] In some embodiments, the present invention relates to a cocrystal of obeticholic acid and pyridoxine having an XRPD pattern obtained with CuKα1 radiation, said XRPD pattern having specific peaks at °2θ positions 4.70 ±0.2, 6.13 ±0.2, 8.02 ±0.2, and 11.52±0.2, and at one or more of 12.92 ±0.2, 15.93 ±0.2, and 16.76 ±0.2.

[0017] In some embodiments, the present invention relates to a cocrystal of obeticholic acid and pyridoxine having an XRPD pattern obtained with CuKα1 radiation, said XRPD pattern having specific peaks at °2θ positions 4.70 ±0.2, 6.13 ±0.2, 8.02 ±0.2, 11.52 ±0.2, 12.92 ±0.2, and 16.76 ±0.2.

[0018] In some embodiments, the cocrystal of obeticholic acid and pyridoxine has an XRPD pattern obtained with CuKα1 radiation, said XRPD pattern having specific peaks at °2θ positions 4.70 ±0.2, 6.13 ±0.2, 8.02 ±0.2, 9.22 ±0.2, 11.32 ±0.2, 11.52 ±0.2, 12.92 ±0.2, 15.93 ±0.2, 16.76 ±0.2, and 24.12 ±0.2.

[0019] In some embodiments, the cocrystal of obeticholic acid and pyridoxine has an XRPD pattern obtained with CuKα1 radiation, said XRPD pattern having specific peaks at °2θ positions 4.70 ±0.2, 6.13 ±0.2, 8.02 ±0.2, 9.22 ±0.2, 11.32 ±0.2, 11.52 ±0.2, 12.92 ±0.2, 15.93 ±0.2, 16.76 ±0.2, and 24.15 ±0.2, and at one or more of 8.28 ±0.2, 10.17 ±0.2, 13.32 ±0.2, 14.07 ±0.2, 14.62 ±0.2, 16.44 ±0.2, 18.13±0.2, 18.73 ±0.2, 19.29 ±0.2, 24.48 ±0.2, and 25.45 ±0.2.

[0020] In some embodiments, the eutectic of obeticholic acid and pyridoxine has an XRPD pattern obtained with CuKα1 radiation, the XRPD pattern having specific peaks at 2θ positions of 4.70 ±0.2, 6.13 ±0.2, 8.02 ±0.2, 8.28 ±0.2, 9.22 ±0.2, 10.17 ±0.2, 11.32 ±0.2, 11.52 ±0.2, 12.92 ±0.2, 13.32 ±0.2, 14.07 ±0.2, 14.62 ±0.2, 15.93 ±0.2, 16.44 ±0.2, 16.76 ±0.2, 18.13 ±0.2, 18.73 ±0.2, 19.29±0.2, 24.15 ±0.2, 24.48 ±0.2 and 25.45 ±0.2.

[0021] In some embodiments, the present invention relates to a eutectic of obeticholic acid and pyridoxine, which has an XRPD pattern obtained with CuKα1 radiation, the XRPD pattern having specific peaks as disclosed in Table 1.

[0022] In some embodiments, the present invention relates to a eutectic of obeticholic acid and pyridoxine, which has an XRPD pattern obtained with CuKα1 radiation, the XRPD pattern being substantially as Figure 1 shown.

[0023] In some embodiments, the present invention relates to a eutectic of obeticholic acid and pyridoxine, wherein the DSC curve of the eutectic comprises an endothermic peak between about 143 °C and about 160 °C, such as at about 145.7 °C.

[0024] In some embodiments, the present invention relates to a eutectic of obeticholic acid and pyridoxine, wherein the crystallinity is greater than 99%.

[0025] In a second aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a eutectic as disclosed herein and one or more pharmaceutically acceptable excipients. Excipients may include fillers, binders, surfactants, disintegrants, glidants and lubricants. The pharmaceutical composition may further comprise at least one other active substance, such as an active substance selected from the following: an IBAT inhibitor; an enteroendocrine peptide or an enhancer thereof; a dipeptidyl peptidase IV inhibitor; a biguanide; an incretin mimetic; a thiazolidinedione; a PPAR agonist; an HMG Co-A reductase inhibitor; a bile acid binder; a TGR5 receptor modulator; a member of the prostone class of compounds; a guanylate cyclase C agonist; a 5-HT4 serotonin agonist; or a pharmaceutically acceptable salt of any of these active substances. Examples of such combinations are disclosed in WO2012 / 064268.

[0026] In one embodiment, the present invention relates to a pharmaceutical composition as disclosed herein, wherein the polymorphic purity of the cocrystal is at least about 90%. In some embodiments, the polymorphic purity is at least about 95%. In some embodiments, the polymorphic purity is at least about 98%. For example, the polymorphic purity can be at least about 98.5%, such as at least about 99%, such as at least about 99.5%, such as at least about 99.8%, or such as at least about 99.9%.

[0027] Generally, the pharmaceutical composition can be prepared in a conventional manner using conventional excipients. In some embodiments, the ingredients of the formulation are mixed into a homogeneous mixture and then formulated into tablets or capsules. The homogeneous mixture of ingredients can be compressed into tablets using conventional techniques (such as rotary tablet pressing techniques). The mixture of ingredients can also be granulated. For example, the mixture of ingredients can be wetted by adding a liquid (such as water and / or a suitable organic solvent (such as ethanol or isopropanol)), and then granulated and dried. Alternatively, the granules can be prepared by dry granulation (such as by roller compaction). The obtained granules can be compressed into tablets using conventional techniques. The capsules can contain a powder mixture of the ingredients or small multi-particulates (such as granules, extruded pellets or mini-tablets). If desired, any of the above tablets, capsules, granules, extruded pellets and mini-tablets can be coated with one or more coating layers. Such coating layers can be applied by methods known in the art, such as film coating involving a perforated disk and a fluidized bed. In some embodiments, the formulation is in the form of a tablet.

[0028] In a further aspect, the present invention relates to a cocrystal of obeticholic acid and pyridoxine as disclosed herein, which is used in therapy.

[0029] Obeticholic acid is an inhibitor of ileal bile acid transporter (IBAT). Ileal bile acid transporter (IBAT) is the main mechanism for the reabsorption of bile acids from the gastrointestinal tract. Partial or complete blockade of this IBAT mechanism will result in a decrease in the bile acid concentration in the small intestinal wall, portal vein, hepatic parenchyma, intrahepatic bile duct tree and extrahepatic bile duct tree (including the gallbladder). Diseases that may be caused by partial or complete blockade of the IBAT mechanism may be those diseases with symptoms of excessive bile acid concentration in the serum and the above organs as the main pathophysiological defect. Therefore, the cocrystals as described herein can be used to treat or prevent conditions, disorders and diseases in which inhibition of the bile acid cycle is desired, such as cardiovascular diseases or disorders, fatty acid metabolism and glucose utilization disorders, gastrointestinal diseases and disorders, liver diseases and disorders, and hyperabsorption syndromes.

[0030] Cardiovascular disorders or diseases, or disorders of fatty acid metabolism, or disorders of glucose utilization including hypercholesterolemia; disorders involving insulin resistance; disorders of fatty acid metabolism; type 1 and type 2 diabetes; diabetic complications including cataracts, microvascular and macrovascular diseases, retinopathy, neuropathy, nephropathy and delayed wound healing, tissue ischemia, diabetic foot; atherosclerosis; myocardial infarction; acute coronary syndrome; unstable angina; stable angina; stroke; peripheral arterial occlusive disease; cardiomyopathy; heart failure; cardiac arrhythmias and restenosis; diabetes-related diseases such as insulin resistance (impaired glucose homeostasis), hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, obesity, dyslipidemia, hyperlipidemia including hypertriglyceridemia, metabolic syndrome (syndrome X), atherosclerosis and hypertension; and elevated high density lipoprotein levels.

[0031] Gastrointestinal diseases or disorders including constipation; chronic constipation; functional constipation; chronic idiopathic constipation (CIC); intermittent / sporadic constipation; constipation secondary to diabetes; constipation secondary to stroke; constipation secondary to chronic kidney disease; constipation secondary to multiple sclerosis; constipation secondary to Parkinson's disease; constipation secondary to systemic sclerosis; drug-induced constipation; irritable bowel syndrome with constipation (IBS-C); mixed irritable bowel syndrome (IBS-M); pediatric functional constipation and opioid-induced constipation; Crohn's disease; primary bile acid malabsorption; irritable bowel syndrome (IBS); inflammatory bowel disease (IBD); ileitis; and reflux diseases and their complications such as Barrett's esophagus, bile reflux esophagitis and bile reflux gastritis.

[0032] Liver diseases or disorders are defined herein as genetic metabolic disorders of the liver; congenital defects in bile acid synthesis; congenital biliary anomalies; biliary atresia; biliary atresia after Kasai; biliary atresia after liver transplantation; neonatal hepatitis; neonatal cholestasis; hereditary forms of cholestasis; cerebrotendinous xanthomatosis; secondary defects in bile acid (BA) synthesis; Zellweger syndrome; cystic fibrosis-related liver disease; α1-antitrypsin deficiency; Alagilles syndrome (ALGS); Byler syndrome; primary defects in bile acid (BA) synthesis; progressive familial intrahepatic cholestasis (PFIC), including PFIC-1, PFIC-2, PFIC-3, and PFIC, unspecified, PFIC after biliary shunt, and PFIC after liver transplantation; benign recurrent intrahepatic cholestasis (BRIC), including BRIC1, BRIC2, and BRIC, unspecified, BRIC after biliary shunt, and BRIC after liver transplantation; autoimmune hepatitis; primary biliary cirrhosis (PBC); liver fibrosis; non-alcoholic fatty liver disease (NAFLD); non-alcoholic steatohepatitis (NASH); portal hypertension; cholestasis; cholestasis in Down syndrome; drug-induced cholestasis; intrahepatic cholestasis of pregnancy; jaundice during pregnancy; intrahepatic cholestasis; extrahepatic cholestasis; parenteral nutrition-associated cholestasis (PNAC); low phospholipid-associated cholestasis; lymphedema cholestasis syndrome 1 (LSC1); primary sclerosing cholangitis (PSC); immunoglobulin G4-related cholangitis; primary biliary cholangitis; cholelithiasis (gallstones); biliary stones; common bile duct stones; gallstone pancreatitis; Caroli disease; malignant tumors of the bile ducts; malignant tumors causing obstruction of the biliary tree; biliary stricture; AIDS cholangiopathy; ischemic cholangiopathy; pruritus due to cholestasis or jaundice; pancreatitis; chronic autoimmune liver diseases leading to progressive cholestasis; hepatic steatosis; alcoholic hepatitis; acute fatty liver; fatty liver of pregnancy; drug-induced hepatitis; iron overload disorders; congenital bile acid synthesis defect type 1 (BAS type 1); drug-induced liver injury (DILI); liver fibrosis; congenital hepatic fibrosis; cirrhosis; Langerhans cell histiocytosis (LCH); neonatal ichthyosis sclerosing cholangitis (NISCH); erythropoietic protoporphyria (EPP); idiopathic adulthood ductopenia (IAD); idiopathic neonatal hepatitis (INH); non-syndromic intrahepatic bile ductopenia (NS PILBD); North American Indian childhood cirrhosis (NAIC); hepatic sarcoidosis; amyloidosis; necrotizing enterocolitis; toxicity caused by serum bile acids, including cardiac arrhythmias (e.g., atrial fibrillation) in the case of abnormal serum bile acid profiles, cardiomyopathy associated with cirrhosis ("cholecardia"), and skeletal muscle wasting associated with cholestatic liver diseases;Viral hepatitis (including hepatitis A, hepatitis B, hepatitis C, hepatitis D, and hepatitis E); hepatocellular carcinoma (hepatoma); cholangiocarcinoma; bile acid-related gastrointestinal cancer; and cholestasis caused by tumors and neoplasms of the liver, bile duct, and pancreas. The eutectic can also be used to enhance corticosteroid therapy for liver diseases.;

[0033] Malabsorption syndromes include abetalipoproteinemia, familial hypobetalipoproteinemia (FHBL), chylomicron retention disease (CRD), and sitosterolemia; hypervitaminosis and osteosclerosis; hypertension; glomerular hyperfiltration; and pruritus in renal failure. The eutectic can also be used to prevent kidney damage associated with liver or metabolic diseases.

[0034] In one embodiment, the present invention relates to a eutectic of obeticholic acid and pyridoxine as described herein for treating or preventing the diseases or disorders listed above.

[0035] In another embodiment, the present invention relates to the use of a eutectic of obeticholic acid and pyridoxine as described herein in the preparation of a medicament for treating or preventing the diseases or disorders listed above.

[0036] The crystalline form of obeticholic acid will generally be administered to warm-blooded animals in unit doses in the range of about 0.01 to about 1.0 mg / kg, such as about 0.01 to about 0.5 mg / kg, or such as about 0.01 to about 0.2 mg / kg, and this generally provides a therapeutically effective dose. Unit dosage forms (such as tablets or capsules) will generally contain about 0.1 to about 20 mg, such as about 0.1 to about 10 mg, or such as about 0.2 to about 5 mg, or such as about 0.2 to about 1.0 mg of the active ingredient. For example, the unit dosage form may contain about 0.2 mg, about 0.4 mg, about 0.6 mg, or about 1.2 mg of the active ingredient. The daily dose can be administered as a single dose or divided into two, three, or more unit doses. The daily dose for oral administration of an IBAT inhibitor is preferably within about 0.1 to about 50 mg, more preferably within about 0.1 to about 20 mg, such as within about 0.2 to about 10 mg, or such as within about 0.2 to about 5.0 mg.

[0037] The dosage required for therapeutic or prophylactic treatment will depend on the route of administration, the severity of the disease, the age and weight of the patient, and other factors that a treating physician normally considers in determining an individual regimen and dosage level suitable for a particular patient.

[0038] Definition

[0039] As used herein, the term "eutectic" refers to a crystalline form (or polymorph) that contains at least two components (such as at least two molecules).

[0040] As used herein, the term "polymorph" refers to crystals of the same molecule (or at least the same combination of two or more molecules) that have different physical properties due to the order of the molecules in the crystal lattice. Polymorphs of a single compound have one or more chemical, physical, mechanical, electrical, thermodynamic, and / or biological properties that differ from one another. Differences in the physical properties exhibited by polymorphs can affect pharmaceutical parameters such as storage stability, compressibility, density (important in the manufacture of compositions and products), dissolution rate (an important factor determining bioavailability), solubility, melting point, chemical stability, physical stability, powder flowability, water uptake, compaction, and particle morphology. Differences in stability can result from changes in chemical reactivity (e.g., differences in oxidation such that a dosage form discolors more rapidly when containing one polymorph than when containing another) or mechanical changes (e.g., changes in the crystal upon storage when the kinetically favored polymorph converts to the thermodynamically more stable polymorph) or both (e.g., one polymorph is more hygroscopic than another). Some transformations can affect potency and / or toxicity due to solubility / dissolution differences. In addition, the physical properties of the crystals can be important in processing; for example, one polymorph may be more likely to form a solvate or may be difficult to filter and wash to remove impurities (i.e., the particle shape and size distribution may differ between one polymorph and another). "Polymorph" does not include the amorphous form of a compound.

[0041] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder or one or more symptoms thereof as described herein. In some embodiments, treatment can be administered after one or more symptoms have developed. In other embodiments, treatment can be administered in the absence of symptoms. For example, treatment can be administered to a susceptible individual prior to the onset of symptoms (e.g., based on a symptom history and / or based on genetic or other predisposing factors). Treatment can also continue after symptoms have resolved, for example, to prevent or delay their recurrence.

[0042] As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are suitable for use in human pharmaceutical applications and are generally safe, non-toxic, and without biological or other adverse effects.

[0043] As used herein, the term "about" refers to a value or parameter herein that includes (and describes) embodiments for that value or parameter itself. For example, a description that refers to "about 20" includes a description of "20". A numerical range includes the numbers that define the range. Generally, the term "about" refers to the indicated value of a variable and all variable values within the experimental error of the indicated value (e.g., within the 95% confidence interval of the mean) or within 10% of the indicated value, whichever is greater.

[0044] The crystallinity of the eutectic of obeticholic acid and pyridoxine can be measured, for example, by X-ray powder diffraction (XRPD) method or by differential scanning calorimetry (DSC) method. When referring to a crystalline compound herein, the crystallinity is preferably greater than about 70%, such as greater than about 80%, particularly greater than about 90%, and more particularly greater than about 95%. In some embodiments of the present invention, the crystallinity is greater than about 98%, preferably greater than about 99%. In one embodiment, the crystallinity is between about 0 and about 100%, preferably between about 50 and about 100%, more preferably between about 90 and about 100%, and even more preferably between about 95 and about 100%. The crystallinity % refers to the weight percentage of the total sample material that is crystalline.

[0045] As used herein, the term "polymorph purity", when used in reference to a composition comprising a polymorph of obeticholic acid, refers to the percentage of a particular polymorph relative to another polymorph or the amorphous form of obeticholic acid in the composition in question. For example, a composition comprising a eutectic of obeticholic acid and pyridoxine having a polymorph purity of 90% will contain 90 parts by weight of the eutectic and 10 parts by weight of other crystalline and / or amorphous forms of obeticholic acid. Preferably, the described eutectic of obeticholic acid and pyridoxine contains less than, for example, 20%, 15%, 10%, 5%, 3%, or particularly less than 1% by weight of other polymorphs of obeticholic acid. Thus, preferably, the polymorph purity of the described eutectic of obeticholic acid is >80%, >85%, >90%, >95%, >97%, or particularly >99%.

[0046] The examples of the present invention described below do not limit the present invention in any way. All cited literature and references are incorporated by reference.

[0047] Abbreviation

[0048] DMSO dimethylformamide

[0049] TMS trimethylsilane

[0050] RH relative humidity

[0051] NMR nuclear magnetic resonance

[0052] equiv equivalent

[0053] General experimental methods

[0054] Powder X-ray diffraction (XRPD) analysis

[0055] These analyses were performed on a Stoe Stadi P diffractometer equipped with a Mythen1K detector operating with Cu - Kα1 radiation. A curved Ge monochromator allows testing with Cu - Kα1 radiation. For typical sample preparation, approximately 10 mg of the sample was placed between two pieces of acetate foil and mounted in a Stoe transmission sample holder.

[0056] The sample was rotated during analysis to increase sample randomness. The following experimental settings were used:

[0057] Ambient air atmosphere

[0058] Tube voltage and power: 40 kV, 40 mA

[0059] 0.02° 2θ step size

[0060] 12 s step time

[0061] 1.5 - 50.5° 2θ scan range

[0062] 1° 2θ detector step

[0063] It is known in the art that X - ray powder diffraction patterns with one or more measurement errors can be obtained depending on the measurement conditions (such as the equipment used, sample preparation, or machine). Specifically, it is generally known that the intensities in XRPD patterns can fluctuate depending on the measurement conditions and sample preparation. For example, those skilled in the art of XRPD will recognize that the relative intensities of the peaks can vary depending on the orientation of the sample under test and the type and settings of the instrument used. Those skilled in the art will also recognize that the position of the reflections can be affected by the exact height of the sample in the diffractometer and the zero calibration of the diffractometer. The surface flatness of the sample may also have a small effect. Thus, those skilled in the art will understand that the diffraction patterns presented herein should not be construed as absolute, and any crystalline form that provides a powder diffraction pattern substantially the same as those disclosed herein falls within the scope of this disclosure (for more information, see R. Jenkins and R.L. Snyder, “Introduction to X - ray powder diffractometry”, John Wiley & Sons, 1996).

[0064] Thermogravimetric analysis coupled with Fourier transform infrared spectroscopy (TG-FTIR)

[0065] Thermogravimetric analysis measurements were performed using a Netzsch Thermo-Microbalance TG209 coupled with a Bruker FTIR spectrometer Vector 22, with a sample pan having a pinhole, N2 atmosphere, and a heating rate of 10 °C / min up to 300 °C.

[0066] Dynamic vapor sorption (DVS)

[0067] DVS measurements were carried out using an SPS11-100n “Sorptions Prüfsystem” from ProUmid (formerly “Projekt Messtechnik”), August-Nagel-Str. 23, 89079 Ulm (Germany).

[0068] Approximately 5 - 20 mg of the sample was placed into an aluminum sample pan. A humidity change rate of 5% per hour was used.

[0069] The sample was placed on an aluminum or platinum holder on top of a microbalance and allowed to equilibrate at 50% RH, then the predefined humidity program was started:

[0070] (1) At 50% RH for 2 h

[0071] (2) 50 → 0% RH (5% / h); at 0% RH for 5 h

[0072] (3) 0 → 95% RH (5% / h); at 95% RH for 5 h

[0073] (4) 95 → 0% RH (5% / h); at 0% RH for 5 h

[0074] (5) 0 → 95% RH (5% / h); at 95% RH for 5 h

[0075] (6) 95% RH → 50% RH (5% / h); at 50% RH for 2 h

[0076] Differential scanning calorimetry (DSC)

[0077] DSC measurements were performed using a TA Q2000 instrument (closed aluminum sample pan with or without a pinhole in the lid, heating rate 10 °C / min). The melting point was understood as the peak maximum.

[0078] Examples

[0079] Example 1

[0080] Preparation of obeticholic acid / pyridoxine cocrystal

[0081] At 40 °C, 515.9 mg of obeticholic acid (0.67 mmol) was dissolved in 5 mL of 1-propanol. At 40 °C, 113.7 mg of pyridoxine (1 equiv.) was added to the clear solution. The heating was stopped, and the temperature was allowed to cool to room temperature, and the mixture was stirred for one day. After shaking, a turbid solution was obtained and a fine suspension was formed. After stirring for another day, a suspension was obtained. Then, the vial was opened to allow the solvent to evaporate and stirring was continued for an additional 5 days. Then, optical microscopy revealed crystalline material, and the suspension was filtered through a fritted glass filter with a porosity of 4. The filter cake was dried on the filter in air for 40 minutes and then submitted for XPRD (Table 1, Figure 1 ). 284 mg of powder was recovered. 1 1H NMR data showed that the crystalline material consisted of obeticholic acid and pyridoxine in a 2:1 molar ratio (data not shown).

[0082] Table 1. XRPD peaks of the co-crystal

[0083] Position [°2-θ] d-spacing [Å] Relative intensity [%] 4.7 19.0 54 6.13 14.42 100 8.02 11.02 61 8.28 10.67 16 9.22 9.58 28 10.17 8.69 18 11.32 7.81 24 11.52 7.68 47 12.92 6.85 38 13.32 6.64 18 14.07 6.29 16 14.62 6.05 17 15.27 5.80 15 15.93 5.56 30 16.44 5.39 18 16.76 5.29 39 17.08 5.19 13 18.13 4.89 17 18.73 4.74 20 19.29 4.60 18 19.99 4.44 12 20.56 4.32 13 21.47 4.14 12 22.38 3.97 11 22.91 3.88 12 23.19 3.83 11 23.53 3.78 12 24.12 3.69 24 24.48 3.63 17 24.91 3.57 12 25.45 3.50 20 26.28 3.39 11 27.06 3.29 11 27.33 3.26 8 29.50 3.03 7 29.92 2.98 7 30.36 2.94 8 33.63 2.66 7

[0084] *Relative intensity depends on particle orientation, grain size / shape, strain, and sample thickness

[0085] Differential scanning calorimetry (DSC) analysis

[0086] The measured melting point was 145.7 °C, onset 143 °C, as Figure 2 shown.

[0087] Thermogravimetric analysis

[0088] Thermogravimetric analysis showed that between 25 °C and 140 °C, there was a 1.4% loss of water, which corresponded to the evaporation of surface water. Decomposition was observed above 170 °C, as shown in the TG-FTIR thermogram in Figure 3 .

[0089] Dynamic vapor sorption (DVS) analysis

[0090] The behavior of the co-crystal was investigated using DVS measurements in the presence of variable water vapor pressures. At the start of the measurement, the sample contained approximately 1.5% water at 50% relative humidity; this observation was consistent with the TG-FTIR results. When the relative humidity was decreased to 0%, the sample lost all of its water. When stored at 95% relative humidity, the sample absorbed almost 2.5% water. The results of the DVS tests are presented in Figure 4 and Figure 5 .

[0091] Water sorption appears to be reversible and continuous. Since the monohydrate has an expected water content of 2.1%, the pyridoxine eutectic is considered a non-stoichiometric hydrate that typically contains approximately 1% water under ambient storage conditions, but the water content can vary between 0 and approximately 2.5%. After DVS testing, the samples were recovered and subjected to XPRD, and no change in the solid form was observed ( Figure 6 ).

Claims

1. Co-crystal of obeticholic acid and pyridoxine.

2. The co-crystal according to claim 1, wherein obeticholic acid and pyridoxine are present in a molar ratio of 2:

1.

3. The co-crystal according to any one of claims 1 or 2, which has an XRPD pattern obtained with CuKα1 radiation, the XRPD pattern having at least three specific peaks at °2θ positions selected from: 4.70 ± 0.2, 6.13 ± 0.2, 8.02 ± 0.2, 9.22 ± 0.2, 11.32 ± 0.2, 11.52 ± 0.2, 12.92 ± 0.2, 15.93 ± 0.2, 16.76 ± 0.2, and 24.12 ± 0.

2.

4. The co-crystal according to any one of the preceding claims, which has an XRPD pattern obtained with CuKα1 radiation, the XRPD pattern having at least three specific peaks at °2θ positions selected from: 4.70 ± 0.2, 6.13 ± 0.2, 8.02 ± 0.2, and 11.52 ± 0.

2.

5. The co-crystal according to any one of the preceding claims, which has an XRPD pattern obtained with CuKα1 radiation, the XRPD pattern having specific peaks at °2θ positions 4.70 ± 0.2, 6.13 ± 0.2, 8.02 ± 0.2, and 11.52 ± 0.2, and having one or more additional specific peaks at 12.92 ± 0.2, 15.93 ± 0.2, or 16.76 ± 0.

2.

6. The co-crystal according to any one of the preceding claims, which has an XRPD pattern obtained with CuKα1 radiation, the XRPD pattern being substantially as shown in Figure 1.

7. The co-crystal according to any one of the preceding claims, wherein the DSC curve of the co-crystal includes an endotherm between about 143 °C and about 160 °C, for example at about 145.7 °C.

8. The co-crystal according to any one of the preceding claims, wherein the crystallinity is greater than 99%.

9. A pharmaceutical composition comprising a therapeutically effective amount of the co-crystal according to any one of claims 1 - 8, and one or more pharmaceutically acceptable excipients.

10. The pharmaceutical composition according to claim 9, wherein the polymorphic purity of the co-crystal is at least about 99%.

11. The co-crystal according to any one of claims 1 - 8, for use in therapy.

12. The eutectic according to any one of claims 1 - 8, which is used for treating or preventing cardiovascular diseases or fatty acid metabolism disorders or glucose utilization disorders, such as hypercholesterolemia; disorders involving insulin resistance; type 1 and type 2 diabetes; diabetic complications, including cataracts, microvascular diseases and macrovascular diseases, retinopathy, neuropathy, nephropathy and delayed wound healing, tissue ischemia, diabetic foot; atherosclerosis, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, stroke, peripheral arterial occlusive disease, cardiomyopathy, heart failure, cardiac arrhythmia and restenosis; diabetes - related diseases, such as insulin resistance (impaired glucose homeostasis), hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, obesity, dyslipidemia, hyperlipidemia including hypertriglyceridemia, metabolic syndrome (syndrome X), atherosclerosis and hypertension; and elevated high - density lipoprotein levels.

13. The eutectic according to any one of claims 1 - 8, which is used for treating or preventing gastrointestinal diseases or disorders, such as constipation, chronic constipation, functional constipation, chronic idiopathic constipation (CIC), intermittent / sporadic constipation, constipation secondary to diabetes, constipation secondary to stroke, constipation secondary to chronic kidney disease, constipation secondary to multiple sclerosis, constipation secondary to Parkinson's disease, constipation secondary to systemic sclerosis, drug - induced constipation, irritable bowel syndrome with constipation (IBS - C), mixed irritable bowel syndrome (IBS - M), pediatric functional constipation and opioid - induced constipation; Crohn's disease; primary bile acid malabsorption; irritable bowel syndrome (IBS); inflammatory bowel disease (IBD); ileitis; and reflux diseases and their complications, such as Barrett's esophagus, bile reflux esophagitis and bile reflux gastritis.

14. The eutectic according to any one of claims 1-8, which is used for treating or preventing liver diseases or disorders, such as hereditary metabolic disorders of the liver; congenital defects in bile acid synthesis; congenital biliary anomalies; biliary atresia; biliary atresia after Kasai; biliary atresia after liver transplantation; neonatal hepatitis; neonatal cholestasis; hereditary forms of cholestasis; cerebrotendinous xanthomatosis; secondary defects in BA synthesis; Zellweger syndrome; cystic fibrosis-related liver disease; α1-antitrypsin deficiency; Alagilles syndrome (ALGS); Byler syndrome; primary defects in bile acid (BA) synthesis; progressive familial intrahepatic cholestasis (PFIC), including PFIC-1, PFIC-2, PFIC-3 and unspecified PFIC, PFIC after biliary shunt and PFIC after liver transplantation; benign recurrent intrahepatic cholestasis (BRIC), including BRIC1, BRIC2 and unspecified BRIC, BRIC after biliary shunt and BRIC after liver transplantation; autoimmune hepatitis; primary biliary cirrhosis (PBC); liver fibrosis; non-alcoholic fatty liver disease (NAFLD); non-alcoholic steatohepatitis (NASH); portal hypertension; cholestasis; cholestasis in Down syndrome; drug-induced cholestasis; intrahepatic cholestasis of pregnancy (jaundice during pregnancy); intrahepatic cholestasis; extrahepatic cholestasis; parenteral nutrition-associated cholestasis (PNAC); low phospholipid-associated cholestasis; lymphedema cholestasis syndrome 1 (LSC1); primary sclerosing cholangitis (PSC); immunoglobulin G4-related cholangitis; primary biliary cholangitis; cholelithiasis (gallstones); biliary tract stones; common bile duct stones; gallstone pancreatitis; Caroli disease; malignant tumors of the bile duct; malignant tumors causing obstruction of the biliary tree; biliary stricture; AIDS cholangiopathy; ischemic cholangiopathy; pruritus due to cholestasis or jaundice; pancreatitis; chronic autoimmune liver disease leading to progressive cholestasis; hepatic steatosis; alcoholic hepatitis; acute fatty liver; fatty liver of pregnancy; drug-induced hepatitis; iron overload disorders; congenital bile acid synthesis defect type 1 (BAS type 1); drug-induced liver injury (DILI); liver fibrosis; congenital hepatic fibrosis; cirrhosis; Langerhans cell histiocytosis (LCH); neonatal ichthyosis sclerosing cholangitis (NISCH); erythropoietic protoporphyria (EPP); idiopathic adulthood ductopenia (IAD); idiopathic neonatal hepatitis (INH); non-syndromic intrahepatic bile ductopenia (NSPILBD); North American Indian childhood cirrhosis (NAIC); hepatic sarcoidosis; amyloidosis; necrotizing enterocolitis; toxicity caused by serum bile acids, including cardiac arrhythmias (e.g., atrial fibrillation) in the case of abnormal serum bile acid profiles, cardiomyopathy associated with cirrhosis ("cholecardia") and skeletal muscle wasting associated with cholestatic liver disease;Viral hepatitis (including hepatitis A, hepatitis B, hepatitis C, hepatitis D, and hepatitis E); hepatocellular carcinoma (hepatoma); cholangiocarcinoma; bile acid-related gastrointestinal cancer; and cholestasis caused by tumors and neoplasms of the liver, bile duct, and pancreas; or corticosteroid therapy for enhancing liver disease.; 15. The eutectic according to any one of claims 1 - 8, which is used for treating or preventing hyperabsorption syndromes (including abetalipoproteinemia, familial hypobetalipoproteinemia (FHBL), chylomicron retention disease (CRD) and sitosterolemia); vitamin excess and osteosclerosis; hypertension; glomerular hyperfiltration; and pruritus in renal failure; or for preventing liver - or metabolism - related kidney injury.

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