US20120190817A2 - Romidepsin solid forms and uses thereof - Google Patents
Romidepsin solid forms and uses thereof Download PDFInfo
- Publication number
- US20120190817A2 US20120190817A2 US13/181,460 US201113181460A US2012190817A2 US 20120190817 A2 US20120190817 A2 US 20120190817A2 US 201113181460 A US201113181460 A US 201113181460A US 2012190817 A2 US2012190817 A2 US 2012190817A2
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- United States
- Prior art keywords
- compound
- xrpd
- solids
- peaks
- approximately
- 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.)
- Abandoned
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- 108010091666 romidepsin Proteins 0.000 title claims description 41
- OHRURASPPZQGQM-UHFFFAOYSA-N romidepsin Natural products O1C(=O)C(C(C)C)NC(=O)C(=CC)NC(=O)C2CSSCCC=CC1CC(=O)NC(C(C)C)C(=O)N2 OHRURASPPZQGQM-UHFFFAOYSA-N 0.000 title claims description 41
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- A61P31/04—Antibacterial agents
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- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1002—Tetrapeptides with the first amino acid being neutral
- C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
- C07K5/101—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- romidepsin solid forms of romidepsin and compositions comprising these forms.
- polymorphic forms of romidepsin In some embodiments, provided are solvate forms of romidepsin. In some embodiments, provided is amorphous romidepsin. Also provided are methods for producing such forms and compositions.
- Romidepsin is a natural product which was isolated from Chromobacterium violaceum by Fujisawa Pharmaceuticals. See Published Japanese Patent Application Hei 7 (1995)-64872; and U.S. Pat. No. 4,977,138, issued Dec. 11, 1990, each of which is incorporated herein by reference. Various preparations and purifications of romidepsin are described in PCT Publication WO 02/20817, which is incorporated herein by reference.
- Romidepsin is a depsipeptide which contains both amide and ester bonds.
- romidepsin can also be prepared by synthetic or semi-synthetic means. The total synthesis of romidepsin reported by Kahn et al. ( J. Am. Chem. Soc. 118:7237-7238, 1996) involves 14 steps and yields romidepsin in 18% overall yield. The structure of romidepsin is shown below and referred to hereinafter as “Compound I”:
- Compound I has been shown to have anti-microbial, immunosuppressive, and anti-tumor activities.
- Compound I is approved in the U.S. for treatment of cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL), and is currently being tested, for example, for use in treating patients with other hematological malignancies (e.g., multiple myeloma, etc.) and solid tumors (e.g., prostate cancer, pancreatic cancer, etc.).
- CTCL cutaneous T-cell lymphoma
- PTCL peripheral T-cell lymphoma
- solid tumors e.g., prostate cancer, pancreatic cancer, etc.
- HDAC histone deacetylase
- provided herein is a method of preparation of crystalline form C of Compound I and its characterization.
- provided herein is a method of preparation of crystalline form D of Compound I and its characterization.
- provided herein is a method of preparation of crystalline form E of Compound I and its characterization.
- provided herein is a method of preparation of crystalline form I of Compound I and its characterization.
- provided herein is a method of preparation of crystalline form J of Compound I and its characterization.
- provided herein is a method of preparation of crystalline form K of Compound I and its characterization.
- provided herein is a method of preparation of crystalline form L of Compound I and its characterization.
- provided herein is a method of preparation of crystalline form N of Compound I and its characterization.
- provided herein is a method of preparation of amorphous Compound I and its characterization.
- Compound I and solid forms thereof, are used for the preparation of pharmaceutical compositions.
- compositions and formulations e.g., pharmaceutical compositions and formulations
- comprising solid forms of Compound I are provided.
- cancers include, but are not limited to, carcinomas, sarcomas, leukemias, lymphomas and the like.
- cancer is a hematological malignancy.
- cancer is a solid tumor.
- provided herein are methods of electrolyte supplementation for patients receiving Compound I therapy.
- FIG. 1 ( a ) depicts a representative solution 1 HNMR spectrum obtained for Compound I.
- FIG. 1 ( b ) depicts a molecular structure for Compound I.
- FIG. 1 ( c ) depicts an XRPD for Compound I Form C collected at room temperature.
- FIG. 1 ( d ) tabulates observed peaks (part i); and prominent peaks (part ii) present in the XRPD of FIG. 1 ( c ).
- FIG. 1 ( e ) depicts a DSC thermogram obtained for Compound I Form C.
- FIG. 1 ( f ) depicts a TGA thermogram obtained for Compound I Form C.
- FIG. 1 ( g ) depicts an FT-IR spectrum obtained for Compound I Form C.
- FIG. 1 ( h ) tabulates peak positions of bands present in the FT-IR spectrum of FIG. 1 ( g ).
- FIG. 1 ( i ) depicts a calculated XRPD for Compound I Form C collected at subambient temperature.
- FIG. 1 ( j ) depicts theoretical observed peaks (part i); and representative peaks (part ii) present in the XRPD of FIG. 1 ( i ).
- FIG. 1 ( k ) depicts an ORTEP drawing of Compound I, Form C, water molecules not shown.
- FIG. 1 ( l ) depicts a packing diagram of Compound I, Form C viewed down the crystallographic a axis.
- FIG. 1 ( m ) depicts a packing diagram of Compound I, Form C viewed down the crystallographic b axis.
- FIG. 1 ( n ) depicts a packing diagram of Compound I, Form C viewed down the crystallographic c axis.
- FIG. 1 ( o ) tabulates positional parameters and estimated standard deviations for Compound I, Form C.
- FIG. 1 ( p ) tabulates bond distances (Angstroms) for Compound I, Form C.
- FIG. 1 ( q ) tabulates bond angles (degrees) for Compound I, Form C.
- FIG. 2 ( a ) depicts an XRPD for Compound I Form D collected at room temperature.
- FIG. 2 ( b ) tabulates observed peaks (part i); and prominent peaks (part ii) present in the XRPD of FIG. 2 ( a ).
- FIG. 2 ( c ) depicts a DSC thermogram obtained for Compound I Form D.
- FIG. 2 ( d ) depicts a TGA thermogram obtained for Compound I Form D.
- FIG. 2 ( e ) depicts an FT-IR spectrum obtained for Compound I Form D.
- FIG. 2 ( f ) tabulates peak positions of bands present in the FT-IR spectrum of FIG. 2 ( e ).
- FIG. 3 ( a ) depicts an XRPD for Compound I Form E collected at room temperature.
- FIG. 3 ( b ) tabulates observed peaks (part i); and prominent peaks (part ii) present in the XRPD of FIG. 3 ( a ).
- FIG. 3 ( c ) depicts a DSC thermogram obtained for Compound I Form E.
- FIG. 3 ( d ) depicts a TGA thermogram obtained for Compound I Form E.
- FIG. 3 ( e ) depicts an FT-IR spectrum obtained for Compound I Form E.
- FIG. 3 ( f ) tabulates peak positions of bands present in the FT-IR spectrum of FIG. 3 ( e ).
- FIG. 3 ( g ) depicts an FT-Raman spectrum for Compound I Form E.
- FIG. 3 ( h ) depicts a calculated XRPD for Compound I Form E collected at subambient temperature.
- FIG. 3 ( i ) depicts theoretical observed peaks (part i); and representative peaks (part ii) present in the XRPD of FIG. 3 ( h ).
- FIG. 3 ( j ) depicts an ORTEP drawing of Compound I, Form E.
- FIG. 3 ( k ) depicts a packing diagram of Compound I, Form E viewed down the crystallographic a axis.
- FIG. 3 ( l ) depicts a packing diagram of Compound I, Form E viewed down the crystallographic b axis.
- FIG. 3 ( m ) depicts a packing diagram of Compound I, Form E viewed down the crystallographic c axis.
- FIG. 3 ( n ) tabulates positional parameters and estimated standard deviations for Compound I, Form E.
- FIG. 3 ( o ) tabulates bond distances (Angstroms) for Compound I, Form E.
- FIG. 3 ( p ) tabulates bond angles (degrees) for Compound I, Form E.
- FIG. 4 ( a ) depicts an XRPD for Compound I Form H collected at room temperature.
- FIG. 4 ( b ) tabulates observed peaks (part i); and prominent peaks (part ii) present in the XRPD of FIG. 4 ( a ).
- FIG. 4 ( c ) depicts a DSC thermogram obtained for Compound I Form H.
- FIG. 4 ( d ) depicts a TGA thermogram obtained for Compound I Form H.
- FIG. 4 ( e ) depicts an FT-IR spectrum obtained for Compound I Form H.
- FIG. 4 ( f ) tabulates peak positions of bands present in the FT-IR spectrum of FIG. 4 ( e ).
- FIG. 5 ( a ) depicts an XRPD for Compound I Form I collected at room temperature.
- FIG. 5 ( b ) tabulates observed peaks present in the XRPD of FIG. 5 ( a ).
- FIG. 5 ( c ) depicts a DSC thermogram obtained for Compound I Form I.
- FIG. 5 ( d ) depicts a TGA thermogram obtained for Compound I Form I.
- FIG. 5 ( e ) depicts an FT-IR spectrum obtained for Compound I Form I.
- FIG. 5 ( f ) tabulates peak positions of bands present in the FT-IR spectrum of FIG. 5 ( e ).
- FIG. 5 ( g ) depicts a calculated XRPD for Compound I Form I collected at subambient temperature.
- FIG. 5 ( h ) depicts theoretical observed peaks (part i); and representative peaks (part ii) present in the XRPD of FIG. 5 ( g ).
- FIG. 5 ( i ) depicts an ORTEP drawing of Compound I, Form I, chloroform not shown.
- FIG. 5 ( j ) depicts a packing diagram of Compound I, Form I viewed down the crystallographic a axis.
- FIG. 5 ( k ) depicts a packing diagram of Compound I, Form I viewed down the crystallographic b axis.
- FIG. 5 ( l ) depicts a packing diagram of Compound I, Form I viewed down the crystallographic c axis.
- FIG. 5 ( m ) tabulates positional parameters and estimated standard deviations for Compound I, Form I.
- FIG. 5 ( n ) tabulates bond distances (Angstroms) for Compound I, Form I.
- FIG. 5 ( o ) tabulates bond angles (degrees) for Compound I, Form I.
- FIG. 5 ( p ) depicts an XRPD for Compound I Form I.
- FIG. 5 ( q ) tabulates observed peaks present in the XRPD of FIG. 5 ( p ).
- FIG. 5 ( r ) tabulates prominent peaks present in the XRPD of FIG. 5 ( p ).
- FIG. 5 ( s ) depicts an FT-IR spectrum obtained for Compound I Form I.
- FIG. 5 ( t ) tabulates peak positions of bands present in the FT-IR spectrum of FIG. 5 ( s ).
- FIG. 5 ( u ) depicts Panalytical X-Pert Pro MPD PW3040 data for Compound I Form I.
- FIG. 5 ( v ) depicts a DSC thermogram obtained for Compound I Form I.
- FIG. 5 ( w ) depicts a DSC thermogram obtained for Compound I Form I.
- FIG. 5 ( x ) depicts a TGA thermogram obtained for Compound I Form I.
- FIG. 5 ( y ) depicts an FT-IR spectrum obtained for Compound I Form I.
- FIG. 6 ( a ) depicts an X-ray diffraction pattern overlay of Compound I Form D and the calculated X-ray diffraction pattern of Compound I Form J.
- FIG. 6 ( b ) depicts an ORTEP drawing of the single crystal structure of Compound I Form J.
- FIG. 6 ( c ) depicts a calculated XRPD for Compound I Form J collected at subambient temperature.
- FIG. 6 ( d ) depicts theoretical observed peaks (part i); and prominent peaks (part ii) present in the XRPD of FIG. 6 ( c ).
- FIG. 6 ( e ) depicts a packing diagram of Compound I, Form J viewed down the crystallographic a axis.
- FIG. 6 ( f ) depicts a packing diagram of Compound I, Form J viewed down the crystallographic b axis.
- FIG. 6 ( g ) depicts a packing diagram of Compound I, Form J viewed down the crystallographic c axis.
- FIG. 6 ( h ) tabulates positional parameters and estimated standard deviations for Compound I, Form J.
- FIG. 6 ( i ) tabulates bond distances (Angstroms) for Compound I, Form J.
- FIG. 6 ( j ) tabulates bond angles (degrees) for Compound I, Form J.
- FIG. 6 ( k ) depicts an XRPD for Compound I Form J.
- FIG. 6 ( l ) tabulates observed peaks present in the XRPD of FIG. 6 ( k ).
- FIG. 6 ( m ) tabulates prominent peaks present in the XRPD of FIG. 6 ( k ).
- FIG. 6 ( n ) depicts an FT-IR spectrum obtained for Compound I Form J.
- FIG. 6 ( o ) tabulates peak positions of bands present in the FT-IR spectrum of FIG. 6 ( n ).
- FIG. 6 ( p ) depicts Panalytical X-Pert Pro MPD PW3040 data for Compound I Form J.
- FIG. 6 ( q ) depicts a DSC thermogram obtained for Compound I Form J.
- FIG. 6 ( r ) depicts a TGA thermogram obtained for Compound I Form J.
- FIG. 6 ( s ) depicts an FT-IR spectrum obtained for Compound I Form J.
- FIG. 7 ( a ) depicts an XRPD for amorphous Compound I collected at room temperature.
- FIG. 7 ( b ) depicts a modulated DSC thermogram obtained for amorphous Compound I.
- FIG. 7 ( c ) depicts a TGA thermogram obtained for amorphous Compound I.
- FIG. 7 ( d ) depicts an FT-IR spectrum obtained for amorphous Compound I.
- FIG. 7 ( e ) tabulates peak positions of bands present in the FT-IR spectrum of FIG. 7 ( d ).
- FIG. 7 ( f ) depicts an FT-Raman spectrum for amorphous Compound I.
- FIG. 8 ( a ) depicts an XRPD for Compound I, Form K collected at room temperature.
- FIG. 8 ( b ) tabulates observed peaks (part i); and prominent peaks (part ii); present in the XRPD of FIG. 8 ( a ).
- FIG. 8 ( c ) depicts an XRPD for Compound I, Form K.
- FIG. 8 ( d ) tabulates observed peaks present in the XRPD of FIG. 8 ( c ).
- FIG. 8 ( e ) tabulates prominent peaks present in the XRPD of FIG. 8 ( c ).
- FIG. 8 ( f ) depicts an FT-IR spectrum obtained for Compound I Form K.
- FIG. 8 ( g ) tabulates peak positions of bands present in the FT-IR spectrum of FIG. 8 ( f ).
- FIG. 8 ( h ) depicts Panalytical X-Pert Pro MPD PW3040 data for Compound I Form K.
- FIG. 8 ( i ) depicts a DSC thermogram obtained for Compound I Form K.
- FIG. 8 ( j ) depicts a DSC thermogram obtained for Compound I Form K.
- FIG. 8 ( k ) depicts a TGA thermogram obtained for Compound I Form K.
- FIG. 8 ( l ) depicts data for Compound I Form K.
- FIG. 9 ( a ) depicts an XRPD for Compound I Form F.
- FIG. 9 ( b ) tabulates observed peaks present in the XRPD of FIG. 9 ( a ).
- FIG. 9 ( c ) tabulates prominent peaks present in the XRPD of FIG. 9 ( a ).
- FIG. 9 ( d ) depicts an XRPD for Compound I Form F.
- FIG. 9 ( e ) tabulates observed peaks present in the XRPD of FIG. 9 ( d ).
- FIG. 9 ( o ) tabulates prominent peaks present in the XRPD of FIG. 9 ( d ).
- FIG. 9 ( g ) depicts an FT-IR spectrum obtained for Compound I Form F.
- FIG. 9 ( h ) tabulates peak positions of bands present in the FT-IR spectrum of FIG. 9 ( g ).
- FIG. 9 ( i ) depicts Panalytical X-Pert Pro MPD PW3040 data for Compound I Form F.
- FIG. 9 ( j ) depicts a DSC thermogram obtained for Compound I Form F.
- FIG. 9 ( k ) depicts a TGA thermogram obtained for Compound I Form F.
- FIG. 9 ( l ) depicts an FT-IR spectrum obtained for Compound I Form F.
- FIG. 10 ( a ) depicts an XRPD for Compound I Form L.
- FIG. 10 ( b ) tabulates observed peaks present in the XRPD of FIG. 10 ( a ).
- FIG. 10 ( c ) tabulates prominent peaks present in the XRPD of FIG. 10 ( a ).
- FIG. 10 ( d ) depicts an FT-IR spectrum obtained for Compound I Form L.
- FIG. 10 ( e ) tabulates peak positions of bands present in the FT-IR spectrum of FIG. 10 ( d ).
- FIG. 10 ( f ) depicts Panalytical X-Pert Pro MPD PW3040 data for Compound I Form L.
- FIG. 10 ( g ) depicts a DSC thermogram obtained for Compound I Form L.
- FIG. 10 ( h ) depicts a TGA thermogram obtained for Compound I Form L.
- FIG. 10 ( i ) depicts data for Compound I Form L.
- FIG. 11 ( a ) depicts an XRPD for Compound I Form N.
- FIG. 11 ( b ) depicts a DSC thermogram obtained for Compound I Form N.
- FIG. 11 ( c ) depicts a TGA thermogram obtained for Compound I Form N.
- FIG. 12 tabulates a single crystal structure summary for solid forms of Compound I.
- treat refers to a method of alleviating or abrogating a disease and/or its attendant symptoms.
- prevent refers to a method of barring a subject from acquiring a disease.
- terapéuticaally effective amount refers to that amount of the compound being administered sufficient to prevent development of or alleviate to some extent one or more of the symptoms of the condition or disorder being treated.
- subject is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In preferred embodiments, the subject is a human.
- salts are meant to include salts of active compounds which are prepared with relatively nontoxic acids. Acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
- Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
- inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like,
- salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge, et al. (1977) J. Pharm. Sci. 66:1-19).
- a pharmaceutically acceptable salt form of a compound can be prepared in situ during the final isolation and purification of the compound, or separately by reacting the free base functionality with a suitable organic or inorganic acid.
- suitable organic or inorganic acid examples include salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods used in the art such as ion exchange.
- salts can include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hernisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate
- alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
- Further pharmaceutically acceptable salts can include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate, and aryl sulfonate.
- the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
- the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
- polymorphs and “polymorphic forms” and related terms refer to one of a variety of different crystal structures that can be adopted by a particular compound.
- polymorphs occur when a particular chemical compound can crystallize in more than one structural arrangement.
- Different polymorphs may have different physical properties such as, for example, melting temperatures, heats of fusion, solubilities, dissolution rates and/or vibrational spectra as a result of the arrangement or conformation of the molecules in the crystal lattice.
- the differences in physical properties exhibited by polymorphs affect pharmaceutical parameters such as storage stability, compressibility and density (important in formulation and product manufacturing), and dissolution rates (an important factor in determining bioavailability).
- Differences in stability can result from changes in chemical reactivity (e.g., differential oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph) or mechanical changes (e.g., tablets crumble on storage as a kinetically favored polymorph converts to thermodynamically more stable polymorph) or both (e.g., tablets of one polymorph are more susceptible to breakdown at high humidity).
- changes in chemical reactivity e.g., differential oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph
- mechanical changes e.g., tablets crumble on storage as a kinetically favored polymorph converts to thermodynamically more stable polymorph
- both e.g., tablets of one polymorph are more susceptible to breakdown at high humidity.
- the physical properties of the crystal may be important in processing, for example, one polymorph might be more likely to form solvates or might be difficult to filter and wash free of impurities (i.e., particle shape and size distribution might be different between one polymorph relative to the other).
- Polymorphs of a molecule can be obtained by a number of methods, as known in the art. Such methods include, but are not limited to, melt recrystallization, melt cooling, solvent recrystallization, desolvation, rapid evaporation, rapid cooling, slow cooling, vapor diffusion and sublimation. Polymorphism can be detected using thermal analysis, e.g., differential scanning calorimetry (DSC) and thermogravimetry (TGA).
- DSC differential scanning calorimetry
- TGA thermogravimetry
- Techniques for characterizing polymorphs include, but are not limited to, differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), single crystal X-ray diffractometry, vibrational spectroscopy, e.g, IR and Raman spectroscopy, solution calorimetry, solid state NMR, hot stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis, particle size analysis (PSA), surface area analysis, solubility studies and dissolution studies.
- DSC differential scanning calorimetry
- XRPD X-ray powder diffractometry
- vibrational spectroscopy e.g, IR and Raman spectroscopy
- solution calorimetry e.g, solid state NMR, hot stage optical microscopy, scanning electron microscopy (SEM), electron crystallography and quantitative analysis
- particle size analysis PSA
- surface area analysis solubility studies and dissolution studies.
- solvate refers to a crystal form of a substance which contains solvent.
- hydrate refers to a solvate wherein the solvent is water.
- solvated solvate refers to a crystal form of a substance which can only be made by removing the solvent from a solvate.
- prodrug refers to structurally modified forms of the compound that readily undergo chemical changes under physiological conditions to provide the compound. Additionally, prodrugs can be converted to the compound by chemical or biochemical methods in an ex vivo environment. Prodrugs are often useful because, in some situations, they may be easier to administer than the compound, or parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. A wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. An example, without limitation, of a prodrug would be a compound which is administered as an ester (the “prodrug”), but then is metabolically hydrolyzed to the carboxylic acid, the active entity.
- anhydrous refers to a form of a compound that is substantially free of water.
- an anhydrous solid can contain various amounts of residual water wherein that water is not incorporated in the crystalline lattice. Such incorporation of residual water can depend upon a compound's hygroscopicity and storage conditions.
- hydrate refers to a crystal form adopted by a particular compound in which either a stoichiometric or non-stoichiometric amount of water is incorporated into the crystal lattice.
- carrier refers to any chemical (e.g., solvents, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, and the like, as suited to the particular dosage form desired, Remington's Pharmaceutical Sciences , Fifteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1975)) consistent with the stability of Compound I.
- the term “carrier” refers to a pharmaceutically acceptable carrier.
- An exemplary carrier herein is water.
- a crystalline form is associated with a particular data set (e.g., one or more XRPD peaks, melting point, DSC, TGA, DSC-TGA, and/or other characterization methods known to one of skill in the art, or combinations thereof).
- a solid form is “characterized by” a set of data when that set of data distinguishes the form from other known forms of the relevant compound and/or detects the presence of a particular form in a composition containing other entities (e.g., other forms of the compound and/or components that are not the compound).
- the present disclosure contains representative data obtained from a variety of different solid forms; comparison of provided data allows one of skill in the art to determine data sets that “characterize” any of the solid forms described herein.
- electrolyte supplementation refers to administration to a subject of a composition comprising one or more electrolytes in order to increase serum electrolyte levels in the subject.
- electrolyte supplementation when electrolyte supplementation is administered “prior to, during, or after” therapy, it may be administered prior to initiation of combination inhibitor therapy (i.e., prior to administration of any dose) or prior to, concurrently with, or after any particular dose or doses.
- formulation refers to a composition that includes at least one active compound (e.g., at least a provided form of Compound I) in combination with one or more excipients or other pharmaceutical additives for administration to a patient.
- active compound e.g., at least a provided form of Compound I
- excipients or other pharmaceutical additives for administration to a patient.
- particular excipients and/or other pharmaceutical additives are selected in accordance with knowledge in the art to achieve a desired stability, release, distribution and/or activity of active compound(s).
- in combination refers to administration of two or more agents to a subject. It will be appreciated that two or more agents are considered to be administered “in combination” whenever a subject is simultaneously exposed to both (or more) of the agents. Each of the two or more agents may be administered according to a different schedule; it is not required that individual doses of different agents be administered at the same time, or in the same composition. Rather, so long as both (or more) agents remain in the subject's body, they are considered to be administered “in combination”.
- isostructural refers to two or more solid forms of a compound containing essentially the same three-dimensional arrangement of geometrically similar structural units.
- “isostructural” forms show with similar or identical unit cell dimensions, the same space group, and similar or identical atomic coordinates for common atoms.
- “isostructural” forms have the same structure, but not the same cell dimensions nor the same chemical composition, and have comparable variability in their atomic coordinates to that of the cell dimensions and chemical composition.
- the present disclosure describes a set of isostructural forms of Compound I including, for example, taken from forms of Compound I described infra.
- the present disclosure describes a set of isostructural forms including, for example, Form J and/or Form D. In some embodiments, the present disclosure describes a set of isostructural forms including, for example, Form E and/or Form H. In some embodiments, the present disclosure describes a set of isostructural forms including, for example, Form C and/or the methanol solvate reported in Shigematsu et al., The Journal of Antibiotics, Vol. 47, No. 3, “FR901228, A Novel Antitumor Bicyclic Depsipeptide Produced by Chromobacterium violaceum No. 968, pp. 311-314 (March 1994).
- lyophilize refers to the process of isolating a solid substance from solution and/or removal of solvent. In some embodiments, this may be achieved by various techniques known to one of skill in the art, including, for example, evaporation (e.g., under vacuum, for example by rotary evaporation), freeze drying, and/or freezing the solution and vaporizing frozen solvent away under vacuum conditions, etc.
- parenteral includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
- XRPD X-ray powder diffraction
- composition or preparation is “substantially free of” a recited element if it contains less than 5%, 4%, 3%, 2%, or 1%, by weight of the element. In some embodiments, the composition or preparation contains less than 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1% or less of the recited element. In some embodiments, the composition or preparation contains an undetectable amount of the recited element.
- substantially similar refers to data sets (e.g., spectra/thermograms) that share similarities with each other and/or that differentiate them from one or more reference data sets.
- data sets are considered to be “substantially similar” to one another when their similarities to each other and differences from one or more reference data sets are sufficient to permit a conclusion that the two compared data sets are taken of the same form of a compound, whereas the reference data set is/are taken of a different form of the compound.
- two “substantially similar” data sets are the same (i.e., are identical within experimental error).
- presence in a data set of one or more data points characteristic of a particular form of a compound, but absence of some or all data points that are characteristic of a different form (e.g., data points that are usually present in reference data set) defines data sets as substantially similar to each other.
- unit dose refers to a physically discrete unit of a formulation appropriate for a subject to be treated (e.g., for a single dose); each unit containing a predetermined quantity of an active agent selected to produce a desired therapeutic effect (it being understood that multiple doses may be required to achieve a desired or optimum effect), optionally together with a pharmaceutically acceptable carrier, which may be provided in a predetermined amount.
- the unit dose may be, for example, a volume of liquid (e.g., an acceptable carrier) containing a predetermined quantity of one or more therapeutic agents, a predetermined amount of one or more therapeutic agents in solid form, a sustained release formulation or drug delivery device containing a predetermined amount of one or more therapeutic agents, etc.
- a unit dose may contain a variety of components in addition to the therapeutic agent(s).
- acceptable carriers e.g., pharmaceutically acceptable carriers
- diluents e.g., diluents, stabilizers, buffers, preservatives, etc.
- diluents e.g., diluents, stabilizers, buffers, preservatives, etc.
- the specific effective dose level for any particular subject or organism may depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of specific active compound employed; specific composition employed; age, body weight, general health, sex and diet of the subject; time of administration, and rate of excretion of the specific active compound employed; duration of the treatment; drugs and/or additional therapies used in combination or coincidental with specific compound(s) employed, and like factors well known in the medical arts.
- Compound I can exist in a variety of solid forms. Such solid forms include neat crystal forms. Such solid forms also include solvated forms and amorphous forms.
- the present disclosure provides certain such solid forms of Compound I.
- the present disclosure provides compositions comprising Compound I in a form described herein.
- Compound I is present as a mixture of one or more solid forms; in some embodiments of provided compositions, Compound I is present in only a single form.
- Compound I is provided as a crystalline solid. In certain embodiments, Compound I is provided as a crystalline solid substantially free of amorphous Compound I. In certain embodiments, Compound I is provided as an amorphous form. In certain embodiments, Compound I is provided as a solvated form.
- composition comprises a Compound I, present in a combination of different forms.
- the present disclosure provides a lyophilate of Compound I containing one or more solid forms described herein.
- a lyophilate comprises amorphous Compound I.
- a lyophilate comprises one or more crystalline forms.
- a lyophilate is substantially free of one or more crystalline forms.
- a lyophilate is substantially free of any crystalline form.
- the present disclosure provides one or more solid forms as described herein, in combination with one or more other components.
- other components are selected from the group consisting of, for example, buffers, carriers, crystallization inhibitors, diluents, excipients, pH adjustors, solvents, or other pharmaceutical additives for administration to a patient.
- compositions comprise one or more crystallization inhibitors.
- the present disclosure provides solid forms of Compound I.
- the present disclosure provides Compound I in a crystalline form.
- crystalline forms are substantially free of solvent.
- crystalline forms are a solvate.
- the present disclosure provides Compound I in an amorphous form.
- a summary table of the romidepsin solid forms (Table 1 is provided below.
- solid forms of Compound I provided herein possess improved properties. These properties include, but are not limited to, bioavailability, hydroscopicity, stability (including, without limitation, light and heat stability), solubility, compressability, flowability, electrostatic properties, bulk density, and rate of dissolution.
- Compound I is known to exist in different crystalline forms, known as Form A and Form B. These forms are described in PCT Publication No. WO02/020817, filed Aug. 22, 2001, which is incorporated herein by reference.
- the present disclosure provides Form C of Compound I, and compositions comprising Form C.
- a composition comprising Compound I contains at least some of Compound I in a crystalline form, which crystalline form comprises Form C.
- Compound I Form C is obtained from an acetone/water mixture.
- Compound I Form C is analyzed by one or more of optical microscropy, X-ray powder diffraction, differential scanning calorimetry, modulated differential scanning calorimetry, thermogravimetric analysis, infrared spectroscopy, nuclear magnetic resonance spectroscopy, and raman spectroscopy.
- crystalline Form C of Compound I is characterized by the presence of one or more, two or more, three or more, four or more, five or more, or six or more peaks from its XRPD pattern, which peaks, when taken alone or together with other characteristic data, distinguish Form C from other forms, as described infra.
- Compound I Form C shows an X-ray diffraction having peaks substantially similar to those in FIG. 1 ( c ).
- Form C is characterized by a peak in the XRPD at about 11.45 2 ⁇ . Other characteristic peaks include 8.28, 12.19, and 21.13 2 ⁇ .
- crystalline Form C of Compound I is characterized, for example, by some or all, of the exemplary data provided in FIGS. 1 ( c ) through 1 ( q ), infra (and discussed in Example 2).
- a DSC thermogram obtained for Compound I Form C exhibits broad endothermic events at ⁇ 140° C. (min); an endotherm at ⁇ 257° C. (min); and a minor exothermic event at approximately 177° C. (max).
- a TGA thermogram obtained for Compound I Form C exhibits a weight loss of ⁇ 5.3%.
- Form C is isostructural with the methanol solvate reported in Shigematsu et al., The Journal of Antibiotics , Vol. 47(3) “FR901228, A Novel Antitumor Bicyclic Depsipeptide Produced by Chromobacterium violaceum No. 968, pp. 311-314 (March 1994).
- the present disclosure provides a crystalline form obtained from acetone.
- the acetone is cold.
- the acetone has a temperature of ⁇ 15° C. or lower (e.g., ⁇ 25° C., ⁇ 35° C., ⁇ 50° C., ⁇ 70° C. or lower).
- such a crystalline form is a solvate.
- an acetone solvate is referred to as Form D of Compound I.
- Form D may be isostructural with Form J described infra.
- Compound I Form D is analyzed by one or more of optical microscopy, X-ray powder diffraction, differential scanning calorimetry, modulated differential scanning calorimetry, thermogravimetric analysis, infrared spectroscopy, nuclear magnetic resonance spectroscopy, and raman spectroscopy.
- the present disclosure provides Form D of Compound I, and compositions comprising Form D.
- a composition comprising Compound I contains at least some of Compound I in a crystalline form, which crystalline form comprises Form D.
- a composition comprising Compound I contains at least some of Compound I in a solvated crystalline form, which crystalline form comprises Form D.
- the solvated form is an acetone solvate.
- crystalline Form D of Compound I is characterized by the presence of one or more, two or more, three or more, four or more, five or more, or six or more peaks from its XRPD pattern, which peaks, when taken alone or together with other characteristic data, distinguish Form D from other forms, as described infra.
- Compound I Form D shows an X-ray diffraction having peaks substantially similar to those in FIG. 2 ( a ).
- Form D is characterized by a peak in the XRPD at about 7.54 2 ⁇ . Other characteristic peaks include 11.86 and 16.66 2 ⁇ .
- Compound I Form D is characterized by some or all of the exemplary data provided in 2 ( a ) through 2 ( f ), infra (and discussed in Example 3).
- a DSC thermogram obtained for Compound I Form D exhibits a small endothermic event at ⁇ 91° C. (min); and an endotherm at ⁇ 261° C. (min); followed by apparent decomposition.
- a TGA thermogram obtained for Compound I Form D exhibits a weight loss of ⁇ 10.9%.
- the present disclosure provides a crystalline form obtained from t-butanol. In some embodiments, the present disclosure provides a crystalline form obtained from a mixture of t-butanol and water. In some embodiments, such a crystalline form is a solvate. In some embodiments, a t-butanol solvate is referred to as Form E of Compound I. In some embodiments, Form E may be isostructural with Form H described infra.
- the present disclosure provides Form E of Compound I, and compositions comprising Form E.
- a composition comprising Compound I contains at least some of Compound I in a crystalline form, which crystalline form comprises Form E.
- a composition comprising Compound I contains at least some of Compound I in a solvated crystalline form, which crystalline form comprises Form E.
- the solvated form is a t-butanol solvate.
- Compound I Form E is analyzed by one or more of optical microscopy, X-ray powder diffraction, differential scanning calorimetry, modulated differential scanning calorimetry, thermogravimetric analysis, infrared spectroscopy, nuclear magnetic resonance spectroscopy, and raman spectroscopy.
- crystalline Form E of Compound I is characterized by the presence of one or more, two or more, three or more, four or more, five or more, or six or more peaks from its XRPD pattern, which peaks, when taken alone or together with other characteristic data, distinguish Form E from other forms, as described infra.
- Compound I Form E shows an X-ray diffraction having peaks substantially similar to those in FIG. 3 ( a ).
- Form E is characterized by a peak in the XRPD at about 10.3 2 ⁇ . Other characteristic peaks include 9.0, 11.7, and 20.04 2 ⁇ .
- Compound I Form E is characterized by some or all of the exemplary data provided in FIGS. 3 ( a ) through 3 ( p ), infra (and discussed in Example 4).
- a DSC thermogram obtained for Compound I Form E exhibits an endothermic event at ⁇ 158° C. (min); an endotherm at ⁇ 255° C. (min); followed by apparent decomposition.
- a TGA thermogram obtained for Compound I Form E exhibits a weight loss of ⁇ 10.9%.
- the present disclosure provides a crystalline form obtained from chloroform.
- the present disclosure provides Form F of Compound I, and compositions comprising Form F.
- a composition comprising Compound I contains at least some of Compound I in a crystalline form, which crystalline form comprises Form F. In some embodiments, such a crystalline form is a solvate.
- Compound I Form F is analyzed by one or more of optical microscopy, X-ray powder diffraction, differential scanning calorimetry, modulated differential scanning calorimetry, thermogravimetric analysis, infrared spectroscopy, nuclear magnetic resonance spectroscopy, and raman spectroscopy.
- crystalline Form F of Compound I is characterized by the presence of one or more, two or more, three or more, four or more, five or more, or six or more peaks from its XRPD pattern, which peaks, when taken alone or together with other characteristic data, distinguish Form F from other forms, as described infra.
- Compound I Form F shows an X-ray diffraction having peaks substantially similar to those in FIG. 9 ( a ) or 9 ( d ).
- Form F is characterized by a peak in the XRPD at about 20.28 2 ⁇ . Other characteristic peaks include 10.17, 17.8, 19.34, 20.04, and 22.63 2 ⁇ .
- Compound I Form F is characterized by some or all of the exemplary data provided in 9 ( a ) through ( 9 l ), infra (and discussed in Example 5).
- a DSC thermogram obtained for Compound I Form F exhibits a broad endothermic event at ⁇ 97° C. (min); and an endotherm at ⁇ 256° C. (min).
- a TGA thermogram obtained for Compound I Form F exhibits a weight loss of ⁇ 17%.
- Panalytical X-Pert Pro MPD PW3040 data for Compound I Form F obtained under the following conditions: X-ray Tube: Cu(1.54059 A°), Voltage: 45 kV; Amperage 40 mA; Scan range: 1.00-39.98 °2 ⁇ ; step size: 0.017 °2 ⁇ ; collection time: 721 sec.; scan speed: 3.2°/min; slit: DS: 1 ⁇ 2°; SS: null; revolution time: 1.0 sec., mode: transmission.
- the data for Compound I Form F obtained under the following conditions: detector: DTGS KBr; number of scans: 512; resolution: 2 cm ⁇ 1 .
- the present disclosure provides a crystalline form obtained from chloroform.
- a crystalline form is a solvate.
- a chloroform solvate is referred to as Form H of Compound I.
- Form H may be isostructural with Form E described infra.
- the present disclosure provides Form H of Compound I, and compositions comprising Form H.
- a composition comprising Compound I contains at least some of Compound I in a crystalline form, which crystalline form comprises Form H.
- a composition comprising Compound I contains at least some of Compound I in a solvated crystalline form, which crystalline form comprises Form H.
- the solvated form is a chloroform solvate.
- Compound I Form H is analyzed by one or more of optical microscopy, X-ray powder diffraction, differential scanning calorimetry, modulated differential scanning calorimetry, thermogravimetric analysis, infrared spectroscopy, nuclear magnetic resonance spectroscopy, and raman spectroscopy.
- crystalline Form H of Compound I is characterized by the presence of one or more, two or more, three or more, four or more, five or more, or six or more peaks from its XRPD pattern, which peaks, when taken alone or together with other characteristic data, distinguish Form H from other forms, as described infra.
- Compound I Form H shows an X-ray diffraction having peaks substantially similar to those in FIG. 4 ( a ).
- Form H is characterized by a peak in the XRPD at about 10.67 2 ⁇ . Other characteristic peaks include 8.94, 9.69, 10.51, 13.13, and 19.43 2 ⁇ .
- Compound I Form H is characterized by some or all of the exemplary data provided in 4 ( a ) through 4 ( f ), infra (and discussed in Example 6).
- a DSC thermogram obtained for Compound I Form H exhibits an endothermic event at ⁇ 96° C. (min); and an endotherm at ⁇ 257° C. (min).
- a TGA thermogram obtained for Compound I Form H exhibits a weight loss of ⁇ 10.1%.
- the present disclosure provides a crystalline form obtained from chloroform.
- a crystalline form is a solvate.
- a chloroform solvate is referred to as Form I of Compound 1.
- the present disclosure provides Form I of Compound I, and compositions comprising Form I.
- a composition comprising Compound I contains at least some of Compound I in a crystalline form, which crystalline form comprises Form I.
- a composition comprising Compound I contains at least some of Compound I in a solvated crystalline form, which crystalline form comprises Form I.
- the solvated form is a chloroform solvate.
- Compound I Form I is analyzed by one or more of optical microscopy, X-ray powder diffraction, differential scanning calorimetry, modulated differential scanning calorimetry, thermogravimetric analysis, infrared spectroscopy, nuclear magnetic resonance spectroscopy, and raman spectroscopy.
- crystalline Form I of Compound I is characterized by the presence of one or more, two or more, three or more, four or more, five or more, or six or more peaks from its XRPD pattern, which peaks, when taken alone or together with other characteristic data, distinguish Form I from other forms, as described infra.
- Compound I Form I shows an X-ray diffraction having peaks substantially similar to those in FIG. 5 ( a ) or 5 ( p ).
- Form I is characterized by a peak in the XRPD at about 20.96 2 ⁇ . Other characteristic peaks include 10.63, 17.97, 18.74, 19.12, and 23.18 2 ⁇ .
- crystalline Form I of Compound I is characterized by some or all of the exemplary data provided in 5 ( a ) through 5 ( y ), infra (and discussed in Example 7).
- a DSC thermogram obtained for Compound I Form I exhibits a broad endothermic event at ⁇ 74° C. (min); an endothermic event at ⁇ 100° C. (min); and an endotherm at ⁇ 256.4° C. (min) (10° C./min, C).
- a DSC thermogram obtained for Compound I Form I exhibits a broad endothermic event at ⁇ 88° C. (min); an endothermic event at ⁇ 113° C. (min); and an endotherm at ⁇ 256° C.
- a TGA thermogram obtained for Compound I Form I exhibits a weight loss of ⁇ 33%. In another embodiment, a TGA thermogram obtained for Compound I Form I exhibits a weight loss of ⁇ 27%.
- Panalytical X-Pert Pro MPD PW3040 data for Compound I Form I obtained under the following conditions: X-ray Tube: Cu(1.54059 A°), Voltage: 45 kV; Amperage 40 mA; Scan range: 1.00-39.99 °2 ⁇ ; step size: 0.017 °2 ⁇ ; collection time: 718 sec.; scan speed: 3.3°/min; slit: DS: 1 ⁇ 2°; SS: null; revolution time: 1.0 sec., mode: transmission.
- the data for Compound I Form I obtained under the following conditions: detector: DTGS KBr; number of scans: 512; resolution: 2 cm ⁇ 1 .
- the present disclosure provides a crystalline form obtained from methylethylketone.
- a crystalline form is a solvate.
- a methylethylketone solvate is referred to as Form J of Compound I.
- Form J may be isostructural with Form D described infra.
- the present disclosure provides Form J of Compound I, and compositions comprising Form J of Compound I.
- a composition comprising Compound I contains at least some of Compound I in a crystalline form, which crystalline form comprises Form J.
- a composition comprising Compound I contains at least some of Compound I in a solvated crystalline form, which crystalline form comprises Form J.
- the solvated form is a methylethylketone solvate.
- Compound I Form J is analyzed by one or more of optical microscopy, X-ray powder diffraction, differential scanning calorimetry, modulated differential scanning calorimetry, thermogravimetric analysis, infrared spectroscopy, nuclear magnetic resonance spectroscopy, and raman spectroscopy.
- crystalline Form J of Compound I is characterized by the presence of one or more, two or more, three or more, four or more, five or more, or six or more peaks from its XRPD pattern, which peaks, when taken alone or together with other characteristic data, distinguish Form J from other forms, as described infra.
- Compound I Form J shows an X-ray diffraction having peaks substantially similar to those in FIG. 6 ( k ).
- Form J is characterized by a peak in the XRPD at about 15.24 2 ⁇ . Other characteristic peaks include 7.44, 11.80, and 16.60 2 ⁇ .
- crystalline Compound I Form J is characterized by some or all of the exemplary data provided in 6 ( a ) through 6 ( u ), infra (and discussed in Example 8).
- a DSC thermogram obtained for Compound I Form J exhibits a broad endothermic event at ⁇ 130° C. (min); and an endotherm at ⁇ 260° C. (min).
- a TGA thermogram obtained for Compound I Form J exhibits a weight loss of ⁇ 12%.
- Panalytical X-Pert Pro MPD PW3040 data for Compound I Form J obtained under the following conditions: X-ray Tube: Cu(1.54059 A°), Voltage: 45 kV; Amperage 40 mA; Scan range: 1.00-39.99 °2 ⁇ ; step size: 0.017 °2 ⁇ ; collection time: 718 sec.; scan speed: 3.3°/min; slit: DS: 1 ⁇ 2°; SS: null; revolution time: 1.0 sec., mode: transmission.
- the data for Compound I Form J obtained under the following conditions: detector: DTGS KBr; number of scans: 512; resolution: 2 cm ⁇ 1 .
- the present disclosure provides Form K of Compound I, and compositions comprising Form K.
- a composition comprising Compound I contains at least some of Compound I in a crystalline form, which crystalline form comprises Form K.
- a composition comprising Compound I contains at least some of Compound I in a solvated crystalline form, which crystalline form comprises Form K.
- Compound I Form K is obtained from nitromethane.
- Compound I Form K is a nitromethane solvate.
- Compound I Form K is analyzed by one or more of optical microscopy, X-ray powder diffraction, differential scanning calorimetry, modulated differential scanning calorimetry, thermogravimetric analysis, infrared spectroscopy, nuclear magnetic resonance spectroscopy, and raman spectroscopy.
- crystalline Form K of Compound I is characterized by the presence of one or more, two or more, three or more, four or more, five or more, or six or more peaks from its XRPD pattern, which peaks, when taken alone or together with other characteristic data, distinguish Form K from other forms, as described infra.
- Compound I Form K shows an X-ray diffraction having peaks substantially similar to those in FIG. 8 ( c ).
- Form K is characterized by a peak in the XRPD at about 7.89 2 ⁇ . Other characteristic peaks include 11.25, 16.81, 19.40, and 20.96 2 ⁇ .
- Compound I Form K is characterized by some or all of the exemplary data provided in 8 ( a ) through 8 ( l ), infra (and discussed in Example 10).
- a DSC thermogram obtained for Compound I Form K exhibits a broad endothermic event at ⁇ 62° C. (min); another broad endothermic event at ⁇ 155° C. (min); and an endotherm at ⁇ 257° C. (min).
- a DSC thermogram obtained for Compound I Form K exhibits a broad endothermic event at ⁇ 69° C. and 81° C.; another broad endothermic event at ⁇ 146° C. (min); and an endotherm at ⁇ 257° C. (min).
- a TGA thermogram obtained for Compound I Form K exhibits a weight loss of ⁇ 9.5%.
- the Panalytical X-Pert Pro MPD PW3040 data for Compound I Form K obtained under the following conditions: X-ray Tube: Cu(1.54059 A°), Voltage: 45 kV; Amperage 40 mA; Scan range: 1.00-39.99 °2 ⁇ ; step size: 0.017 °2 ⁇ ; collection time: 717 sec.; scan speed: 3.3°/min; slit: DS: 1 ⁇ 2°; SS: null; revolution time: 1.0 sec., mode: transmission.
- the data for Compound I Form K obtained under the following conditions: detector: DTGS KBr; number of scans: 512; resolution: 2 cm ⁇ 1 .
- the present disclosure provides a crystalline form obtained from acetone and diffused with methanol.
- the present disclosure provides Form L of Compound I, and compositions comprising Form L.
- a composition comprising Compound I contains at least some of Compound I in a crystalline form, which crystalline form comprises Form L.
- Compound I Form L is a methanol solvate.
- Compound I Form L is analyzed by one or more of optical microscopy, X-ray powder diffraction, differential scanning calorimetry, modulated differential scanning calorimetry, thermogravimetric analysis, infrared spectroscopy, nuclear magnetic resonance spectroscopy, and raman spectroscopy.
- crystalline Form L of Compound I is characterized by the presence of one or more, two or more, three or more, four or more, five or more, or six or more peaks from its XRPD pattern, which peaks, when taken alone or together with other characteristic data, distinguish Form L from other forms, as described infra.
- Compound I Form L shows an X-ray diffraction having peaks substantially similar to those in FIG. 10 ( a ).
- Form L is characterized by a peak in the XRPD at about 21.46 2 ⁇ . Other characteristic peaks include 8.26, 10.05, 11.59, and 12.31 2 ⁇ .
- Compound I Form L is characterized by some or all of the exemplary data provided in 10 ( a ) through 10 ( i ), infra (and discussed in Example 11).
- a DSC thermogram obtained for Compound I Form L exhibits an endothermic event at ⁇ 168° C. (min); and an endotherm at ⁇ 259° C. (min).
- a TGA thermogram obtained for Compound I Form L exhibits a weight loss of ⁇ 6%.
- Panalytical X-Pert Pro MPD PW3040 data for Compound I Form L obtained under the following conditions: X-ray Tube: Cu(1.54059 A°), Voltage: 45 kV; Amperage 40 mA; Scan range: 1.00-39.98 °2 ⁇ ; step size: 0.017 °2 ⁇ ; collection time: 716 sec.; scan speed: 3.2°/min; slit: DS: 1 ⁇ 2°; SS: null; revolution time: 1.0 sec., mode: transmission.
- the data for Compound I Form L obtained under the following conditions: detector: DTGS KBr; number of scans: 512; resolution: 2 cm ⁇ 1 .
- the present disclosure provides a crystalline form obtained from nitromethane.
- the present disclosure provides Form N of Compound I, and compositions comprising Form N.
- a composition comprising Compound I contains at least some of Compound I in a crystalline form, which crystalline form comprises Form N.
- Form N of Compound I is a nitromethane solvate.
- Compound I Form N is analyzed by one or more of optical microscopy, X-ray powder diffraction, differential scanning calorimetry, modulated differential scanning calorimetry, thermogravimetric analysis, infrared spectroscopy, nuclear magnetic resonance spectroscopy, and raman spectroscopy.
- crystalline Form N of Compound I is characterized by the presence of one or more, two or more, three or more, four or more, five or more, or six or more peaks from its XRPD pattern, which peaks, when taken alone or together with other characteristic data, distinguish Form N from other forms, as described infra.
- Compound I Form N shows an X-ray diffraction having peaks substantially similar to those in FIG. 11 ( a ).
- Form N is characterized by a peak in the XRPD at about 8.92 2 ⁇ . Other characteristic peaks include 7.07, 9.76, 10.75, 11.22, 15.46, 20.37, and 21.31 2 ⁇ .
- Compound I Form N is characterized by some or all of the exemplary data provided in 11 ( a ) through 11 ( c ), infra (and discussed in Example 12).
- a DSC thermogram obtained for Compound I Form N exhibits an endotherm at ⁇ 150° C. (min).
- a TGA thermogram obtained for Compound I Form N exhibits a weight loss of ⁇ 5%.
- Panalytical X-Pert Pro MPD PW3040 data for Compound I Form N obtained under the following conditions: X-ray Tube: Cu(1.54059 A°), Voltage: 45 kV; Amperage 40 mA; Scan range: 1.00-39.99 °2 ⁇ ; step size: 0.017 °2 ⁇ ; collection time: 717 sec.; scan speed: 3.3°/min; slit: DS: 1 ⁇ 2°; SS: null; revolution time: 1.0
- the present disclosure provides amorphous Compound I, and compositions comprising amorphous Compound I.
- the present disclosure provides compositions comprising Compound I in which substantially all of Compound I is an amorphous form (i.e., the composition is substantially free of crystalline compound I).
- the present disclosure provides compositions containing Compound I in which at least some of the Compound I is in a form other than amorphous (e.g., is in a crystalline form such as, for example, Form A, Form B, Form C, Form D, Form E, Form F, Form H, Form I, Form J, Form K, Form L, Form N, and combinations thereof).
- amorphous Compound I is characterized by the absence of defined peaks above background in an XRPD pattern. In some embodiments, amorphous Compound I is characterized by the absence of characteristic peaks that may be present in Compound I Form A, Form B, Form C, Form D, Form E, Form F, Form H, Form I, Form J, Form K, Form L, Form N, and combinations thereof. In some embodiments, amorphous Compound I is characterized by having a powder X-ray diffraction pattern substantially similar to FIG. 7 ( a ). In some embodiments, amorphous Compound I is obtained from a water/dichloromethane mixture, or an isopropanol-trifluoroethanol/methanol mixture
- amorphous Compound I is characterized by the exemplary data provided in 7 ( a ) through 7 ( f ), infra (see Example 9).
- a DSC thermogram obtained for amorphous Compound I exhibits a glass transition temperature of ⁇ 91° C.
- a TGA thermogram obtained for amorphous Compound I exhibits a weight loss of ⁇ 3.5%.
- compositions Comprising Provided Forms of Compound I
- compositions that comprise and/or are prepared from solid forms of Compound I as described herein. Any of the forms provided herein of Compound I may be incorporated into a composition.
- the present disclosure provides pharmaceutical compositions that comprise and/or are prepared from solid forms of Compound I as described herein.
- a pharmaceutical composition comprises a therapeutically effective amount of Compound I and at least one pharmaceutically acceptable carrier or excipient.
- compositions comprising Compound I are provided as lyophilates.
- the present disclosure provides a lyophilate of Compound I comprising one or more solid forms described herein.
- a lyophilate comprises amorphous Compound I.
- a lyophilate comprises one or more crystalline forms.
- a lyophilate is substantially free of one or more crystalline forms.
- a lyophilate is substantially free of any crystalline form.
- compositions comprising or prepared from Compound I solid forms described herein, which compositions further comprise one or more additional components.
- compositions comprise, in addition to Compound I, at least one other component, such as a carrier (e.g., pharmaceutically acceptable carrier).
- a carrier e.g., pharmaceutically acceptable carrier
- materials which can serve as acceptable carriers include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; Cremophor; Solutol; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; sunflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphat
- compositions comprising Compound I as described herein may be formulated orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. In some embodiments, compositions are administered orally or parenterally.
- compositions are administered parenterally. In some embodiments, compositions are administered intraperitoneally or intravenously.
- injectable formulations are often provided as solutions or suspensions, e.g., aqueous or oleaginous suspension. Such solutions or suspensions may be formulated according to techniques known in the art, for example, using suitable dispersing or wetting agents and suspending agents. Injectable formulations are typically sterile. In some embodiments, an injectable solution or suspension comprises a non-toxic parenterally acceptable diluent or solvent.
- Exemplary vehicles and solvents typically employed include water, Ringer's solution, isotonic sodium chloride solution, acetone, chloroform, dichloromethane, isopropanol, methanol, methylethylketone, tert-butyl alcohol, trifluoroethanol and 1,3-butanediol, and combinations thereof.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are often useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, including their polyoxyethylated versions. In some embodiments, such oil solutions or suspensions contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
- a long-chain alcohol diluent or dispersant such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
- surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of acceptable (e.g., pharmaceutically acceptable) solid, liquid, or other dosage forms may also be used for the purposes of formulation.
- Orally acceptable dosage forms include, but are not limited to, capsules, tablets, aqueous suspensions or solutions.
- carriers commonly used include lactose and corn starch.
- Lubricating agents such as magnesium stearate, are also typically added.
- useful diluents commonly include lactose and dried cornstarch.
- aqueous suspensions are prepared for oral delivery, the active ingredient is typically combined with emulsifying and suspending agents, optionally much as discussed above with respect to parenteral formulations. If desired, certain sweetening, flavoring or coloring agents may also be added.
- oral compositions can be desirably linked to periods of food intake.
- oral compositions are administered with food; in some embodiments, oral compositions are administered without food, or within a particular time frame relative to consumption of food. In some embodiments, oral compositions are administered with little or no regard to the timing of food intake.
- compositions for oral administration can be formulated as solid or liquid preparation.
- a liquid formulation such as syrup, injection, eye drops or the like, is prepared with a pH adjustor (e.g., hydrochloric acid), solubilizer, isotonizing agent or the like, as well as a solubilizing aid, stabilizer, buffering agent, suspending agent, antioxidant, etc., if necessary.
- a liquid formulation is lyophilized, and an injection is administered intravenously, subcutaneously or intramuscularly.
- Suspending agents that can be used include, but not limited to, methyl cellulose, polysorbate 80, hydroxyethyl cellulose, gum arabic, tragacanth powder, sodium carboxymethylcellulose, polyoxyethylene sorbitan monolaurate and the like.
- Solubilizing aids that can be used include, but not limited to, polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate and the like.
- Stabilizing agents that can be used include, but not limited to, t sodium sulfite, sodium metasulfite, ether and the like.
- Preservatives that can be used include, but not limited to, methyl paraoxybenzoate, ethyl paraoxybenzoate, sorbic acid, phenol, cresol, chlorocresol, and the like.
- compositions may be formulated for rectal administration, e.g., as suppositories.
- rectally-appropriate forms can be prepared, for example, by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
- suitable non-irritating excipient include cocoa butter, beeswax and/or polyethylene glycols.
- compositions are formulated for topical administration, for example, the treatment site includes areas or organs readily accessible by topical application, for example, the eye, the skin, or the lower intestinal tract.
- Topical application to the lower intestinal tract can often be effected with a rectal suppository formulation (see above) or in a suitable enema formulation.
- topical or transdermal patches may be used.
- topical formulations are prepared in a suitable ointment containing an active component suspended or dissolved in one or more carriers.
- Carriers for topical administration typically include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
- Topical compositions can be formulated in a suitable lotion or cream, for example, containing one or more active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
- Suitable carriers may include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water, and combinations thereof.
- Formulations for ophthalmic delivery are often prepared as solutions or suspensions (e.g., isotonic, pH adjusted sterile saline).
- one or more preservatives e.g., benzylalkonium chloride
- Ophthalmic compositions may be formulated in an ointment such as petrolatum.
- compositions for nasal delivery are commonly formulated as aerosols.
- aerosol formulations may, for example, be or include solutions or suspensions (e.g., in saline), optionally containing one or more preservatives (e.g., benzyl alcohol), absorption promoters (e.g., to enhance bioavailability), and/or solubilizing or dispersing agents (e.g., fluorocarbons).
- preservatives e.g., benzyl alcohol
- absorption promoters e.g., to enhance bioavailability
- solubilizing or dispersing agents e.g., fluorocarbons
- compositions e.g., pharmaceutical compositions as described herein may include one or more processing agents and/or crystallization inhibitors, or combinations thereof.
- compositions contain one or more processing agents.
- the processing agent is water.
- the processing agent is tert-butyl alcohol.
- the processing agent is talc.
- the processing agent is lactose.
- the processing agent is precipitated calcium carbonate.
- the processing agent is titanium dioxide.
- the processing agent is silica.
- the processing agent is microcrystalline cellulose.
- provided compositions comprise one or more crystallization inhibitors.
- the crystallization inhibitor is water soluble. In certain embodiments, the crystallization inhibitor is water insoluble.
- Exemplary crystallization inhibitors include, but are not limited to, polyvinylpyrrolidone (PVP or povidone), including homo- and copolymers of polyvinylpyrrolidone and homopolymers or copolymers of N-vinylpyrrolidone; crospovidone; gums; cellulose derivatives (e.g., HPMC polymers, hydroxypropyl cellulose, ethyl cellulose, hydroxyethylcellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose); dextran; acacia; homo- and copolymers of vinyllactam, and mixtures thereof; cyclodextrins; gelatins; hypromellose phthalate; sugars; sugar alcohols including mannitol; polyhydric alcohols; polyethylene glycol (PEG); polyethylene oxides; polyoxyethylene derivatives; polyvinyl alcohol; propylene glycol derivatives and the like, SLS, Tweens, Eu
- the Compound I in the composition is amorphous.
- the crystallization inhibitor is polyvinylpyrrolidone (PVP or povidone).
- the crystallization inhibitor is povidone USP/NF, Ph. Eur, or JPE.
- the amount of Compound I and the amount of povidone is present in a composition in a ratio of about 1:2 (by weight).
- the amount of Compound I and the amount of povidone is present in a composition in a ratio of about 1:1 (by weight).
- the amount of Compound I and the amount of povidone is present in a composition in a ratio of about 2:1 (by weight).
- the amount of Compound I and the amount of povidone is present in a composition in a ratio of about 3:1 (by weight). In some embodiments, the amount of Compound I and the amount of povidone is present in a composition in a ratio of about 4:1 (by weight).). In some embodiments, the amount of Compound I and the amount of povidone is present in a composition in a ratio of about 5:1 (by weight).
- a crystallization inhibitor employed by the present disclosure is a PVP polymer.
- PVP polymers employed in the present disclosure have a molecular weight of about 2,000 to about 50,000 Daltons, about 2,000 to about 30,000 Daltons, about 2,000 to about 20,000 Daltons, about 2,500 to about 15,000 Daltons, about 2,500 to about 10,000 Daltons, or about 3,000 to about 10,000 Daltons.
- PVP polymers employed in the present disclosure have a dynamic viscosity (10% in water at 20° C.) of about 1.3 to about 700, about 1.5 to about 500, about 1.8 to about 300, about 2.0 to about 200, about 2.2 to about 150, about 2.5 to about 100, about 2.8 to about 70, about 3.0 to about 40, about 3.2 to about 25, or about 3.5 to about 8.5 mPas.
- povidone is selected from Plasdone® PVP polymers, which are synthetic, water-soluble homopolymers of N-vinyl-2-pyrrolidone.
- Plasdone polymers useful in the compositions provided herein include, but are not limited to, Plasdone C-12 and Plasdone C-17.
- povidone possesses K values between 12 and 17. In some embodiments, povidone possesses K values between 12 and 15.
- PVP polymers employed in the present disclosure are selected from Kollidon® PVP polymers (e.g., Kollidon® 12 PF, Kollidon® 17 PF).
- a crystallization inhibitor employed by the present disclosure is a PEG polymer.
- PEG polymers employed in the present disclosure have has an average molecular about 5,000-20,000 Dalton, about 5,000-15,000 Dalton, or about 5,000-10,000 Dalton.
- a crystallization inhibitor employed by the present disclosure is a surfactant.
- the crystallization inhibitor is a Tween® surfactant.
- Exemplary Tweens® include Tween® 20, Tween® 40, Tween®60, Tween® 65 and Tween® 80.
- a crystallization inhibitor employed by the present disclosure is an HPMC (hydroxypropylmethyl cellulose) polymer.
- HPMC polymers vary in the chain length of their cellulosic backbone and consequently in their viscosity as measured for example at a 2% (w/w) in water.
- the HPMC polymer has a viscosity in water (at a concentration of 2% (w/w)), of about 100 to about 100,000 cP, about 1000 to about 15,000 cP, for example about 4000 cP.
- the molecular weight of the HPMC polymer has greater than about 10,000, but not greater than about 1,500,000, not greater than about 1,000,000, not greater than about 500,000, or not greater than about 150,000.
- HPMC polymers also vary in the relative degree of substitution of available hydroxyl groups on the cellulosic backbone by methoxy and hydroxypropoxy groups. With increasing hydroxypropoxy substitution, the resulting HPMC polymer becomes more hydrophilic in nature. In certain embodiments, the HPMC polymer has about 15% to about 35%, about 19% to about 32%, or about 22% to about 30%, methoxy substitution, and having about 3% to about 15%, about 4% to about 12%, or about 7% to about 12%, hydroxypropoxy substitution.
- HPMC polymers include, but are not limited to, hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose acetate phthalate (HPMC-AP), hydroxypropylmethylcellulose acetate succinate (HPMC-AS), hydroxypropylmethylcellulose acetate trimellitate (HPMC-AT) and hydroxypropylmethylcellulose phthalate (HPMC-P).
- HPMC hydroxypropylmethylcellulose
- HPMC-AP hydroxypropylmethylcellulose
- HPMC-AP hydroxypropylmethylcellulose acetate phthalate
- HPMC-AS hydroxypropylmethylcellulose acetate succinate
- HPMC-AT hydroxypropylmethylcellulose acetate trimellitate
- HPMC-P hydroxypropylmethylcellulose phthalate
- HPMC hydroxypropylmethylcellulose
- HPMC-AS hydroxypropylmethylcellulose acetate succinate
- HPMC-P hydroxypropyl-methylcellulose phthalate
- HPMC polymers are available under the brand names MethocelTM of Dow Chemical Co. and MetoloseTM of Shin-Etsu Chemical Co.
- suitable HPMC polymers having medium viscosity include MethocelTM E4M, and MethocelTM K4M, both of which have a viscosity of about 4000 cP at 2% (w/w) water.
- suitable HPMC polymers having higher viscosity include MethocelTM E10M, MethocelTM K15M, and MethocelTM K100M, which have viscosities of about 10,000 cP, 15,000 cP, and 100,000 cP respectively viscosities at 2% (w/w) in water.
- provided formulation may include one or more crystallization inhibitors.
- the second crystallization inhibitor is a PVP polymer.
- the second crystallization inhibitor is a PEG polymer.
- the second crystallization inhibitor is a Tween® surfactant.
- the formulation or composition comprises an amount of one or more crystallization inhibitors of at least about 1%, 5%, 10%, 12%, 15%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 99% (w/w), based on the total weight of the formulation or composition.
- the composition is prepared by lyophilization from a solution.
- the composition is prepared by lyophilization from a solution of (60:40) (v/v) t-butanol/water.
- the solvent is tert-butanol.
- the solvent is a mixture of tert-butanol and water.
- the pH adjustor is hydrochloric acid.
- ISTODAX® is supplied as a kit which includes a sterile, lyophilized powder in a single-use vial containing 10 mg of Compound I and 20 mg of the bulking agent, povidone, USP. Additionally, each kit includes 1 sterile vial containing 2 mL of the Diluent composed of 80% propylene glycol, USP, and 20% dehydrated alcohol, USP.
- the K value of Povidone USP is 17.
- the molecular weight of povidone USP is about 10.000 Dalton.
- ISTODAX® is administered at a dose of 14 mg/m 2 intravenously over a 4-hour period on days 1, 8 and 15 of a 28-day cycle. Cycles are repeated every 28 days.
- Cell proliferative disorders, diseases or conditions include a variety of conditions characterized by aberrant cell growth, preferably abnormally increased cellular proliferation.
- Cell proliferative disorders, diseases, or conditions that can be treated using the provided compositions and methods include, but are not limited to, cancer, immune-mediated responses and diseases (e.g., transplant rejection, graft vs. host disease, immune reaction to gene therapy, autoimmune diseases, pathogen-induced immune dysregulation, etc.), certain circulatory diseases, and certain neurodegenerative diseases.
- Cancer is a group of diseases which are characterized by uncontrolled growth and spread of abnormal cells. Cancers include, but are not limited to, carcinomas, sarcomas, leukemias, lymphomas and the like. In certain embodiments, cancer is a hematological malignancy. In certain embodiments, cancer is a solid tumor.
- Hematological malignancies that may be treated using romidepsin include, but are not limited to: acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL), multiple myeloma, and myelodysplastic syndromes.
- ALL acute lymphoblastic leukemia
- AML acute myelogenous leukemia
- CML chronic myelogenous leukemia
- CLL chronic lymphocytic leukemia
- hairy cell leukemia Hodgkin's lymphoma
- non-Hodgkin's lymphoma non-Hodgkin's lymphoma
- CCL cutaneous T-cell lympho
- cancers treated include, but are not limited to, leukemias and lymphomas such as cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma, lymphomas associated with human T-cell lymphotrophic virus (HTLV) such as adult T-cell leukemia/lymphoma (ATLL), B-cell lymphomas, acute lymphocytic leukemia, acute nonlymphocytic leukemias, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, Hodgkin's disease, non-Hodgkin's lymphomas, multiple myeloma, myelodysplastic syndromes.
- CTCL cutaneous T-cell lymphoma
- HTLV human T-cell lymphotrophic virus
- ATLL adult T-cell leukemia/lymphoma
- B-cell lymphomas acute lymphocytic leukemia, acute nonlymphocytic leukemias, chronic lymphocytic
- the disclosure relates to treatment of solid tumors such as lung, breast, colon, liver, pancreas, renal, prostate, ovarian, and/or brain.
- the disclosure relates to treatment of pancreatic cancer.
- the disclosure relates to treatment of renal cancer.
- the disclosure relates to treatment of prostate cancer.
- the disclosure relates to treatment of sarcomas.
- the disclosure relates to treatment of soft tissue sarcomas.
- cancers that can be treated are solid cancers that include, but are not limited to, mesothelioma, common solid tumors of adults such as head and neck cancers (e.g., oral, laryngeal and esophageal), genitourinary cancers (e.g., prostate, bladder, renal, uterine, ovarian, testicular, rectal and colon), melanoma and other skin cancers, stomach cancer, brain tumors, liver cancer and thyroid cancer, and/or childhood solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilms' tumor, bone tumors, and soft-tissue sarcomas.
- the disclosure relates to treatment of solid tumors.
- Cancers that may be treated using the methods provided herein, including combination therapy, include but not limited to, colon cancer, lung cancer, bone cancer, pancreatic cancer, stomach cancer, esophageal cancer, skin cancer, brain cancer, liver cancer, ovarian cancer, cervical cancer, uterine cancer, testicular cancer, prostate cancer, bladder cancer, kidney cancer, and neuroendocrine cancer.
- cancer is pancreatic cancer. In certain embodiments, cancer is prostate cancer. In certain specific embodiments, the prostate cancer is hormone refractory prostate cancer.
- leukemia is chronic lymphocytic leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, acute myelogenous leukemia, or adult T cell leukemia/lymphoma.
- lymphoma is Hodgkin's or non-Hodgkin's (e.g., T-cell lymphomas such as peripheral T-cell lymphoma, cutaneous T-cell lymphoma, etc.) lymphoma.
- Hodgkin's or non-Hodgkin's e.g., T-cell lymphomas such as peripheral T-cell lymphoma, cutaneous T-cell lymphoma, etc.
- the disclosure relates to the treatment of multiple myeloma and/or myelodysplastic syndromes.
- Syndromes combining progressive dementia with other prominent neurologic abnormalities such as: A) syndromes appearing mainly in adults (e.g., Huntington's disease, Multiple system atrophy combining dementia with ataxia and/or manifestations of Parkinson's disease, Progressive supranuclear palsy (Steel-Richardson-Olszewski), diffuse Lewy body disease, and corticodentatonigral degeneration); and B) syndromes appearing mainly in children or young adults (e.g., Hallervorden-Spatz disease and progressive familial myoclonic epilepsy);
- A) syndromes appearing mainly in adults e.g., Huntington's disease, Multiple system atrophy combining dementia with ataxia and/or manifestations of Parkinson's disease, Progressive supranuclear palsy (Steel-Richardson-Olszewski), diffuse Lewy body disease, and corticodentatonigral degeneration
- B) syndromes appearing mainly in children or young adults e.g.
- cerebellar degenerations e.g., cerebellar cortical degeneration and olivopontocerebellar atrophy (OPCA)
- OPCA olivopontocerebellar atrophy
- spinocerebellar degeneration Friedreich's ataxia and related disorders
- VI. Syndromes of muscular weakness and wasting without sensory changes such as amyotrophic lateral sclerosis, spinal muscular atrophy (e.g., infantile spinal muscular atrophy (Werdnig-Hoffman), juvenile spinal muscular atrophy (Wohlfart-Kugelberg-Welander) and other forms of familial spinal muscular atrophy), primary lateral sclerosis, and hereditary spastic paraplegia;
- the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, and/or Huntington's disease.
- the diseases or conditions are associated with chromatin remodeling.
- unit doses of Compound I are within the range of about 0.5 mg/m 2 to about 28 mg/m 2 body surface area. In some embodiments, the range of about 6 to about 18 mg/m 2 is used. In some embodiments, the range is about 10 mg/m 2 to about 17 mg/m 2 . In some embodiments, particular unit doses are 10 mg/m 2 , 12 mg/m 2 , 13 mg/m 2 , 14 mg/m 2 , and 15 mg/m 2 .
- Compound I is administered intravenously.
- intravenous dosing regimens include daily dosing for 2 weeks, twice weekly dosing for 4 weeks, thrice weekly dosing for 4 weeks, and various other intermittent schedules (e.g., on days 1, 3, and 5; on days 4 and 10; on days 1, 8 and 15; on days 1 and 15; on days 5 and 12; or on days 5, 12, and 19 of 21 or 28 day cycles).
- Compound I is administered in individual unit doses over 4 hours on days 1, 8, and 15, with courses repeating every 28 days. Often, several courses (e.g., at least 4, at least 6, or more) are administered. Indeed, instances have been reported of as many as 72 courses being administered. In some embodiments, individual unit doses are administered by 4 hour infusion.
- Accelerated dosing regimens for Compound I may be utilized, in which one or more individual unit doses is administered intravenously over a period of time that is less than or equal to about one hour. In some embodiments, one or more individual doses are administered intravenously over a period of time that is less than about 50 minutes, 40 minutes, 30 minutes, 20 minutes, or less. Any regimen that includes at least one unit dose administered over a period of time that is less than about one hour (60 minutes) may be considered an accelerated dosing regimen in accordance with the present disclosure.
- all unit doses within a regimen are administered intravenously over a time period that is less than or equal to about one hour. In some embodiments, only some of the unit doses within a regimen are administered over a time period that is less than or equal to about one hour. In some embodiments, one or more unit doses within a regimen are administered by a route other than intravenous administration (e.g., oral, subcutaneous, nasal, topical, etc).
- Accelerated dosing regimens of Compound I can be administered without a significant increase in toxicity or adverse events, particularly in serious adverse events, as compared with a comparable regimen (e.g., an otherwise identical regimen) in which individual unit doses are administered intravenously over a 4-hour period. Accelerated dosing regimens can be administered without a significant increase in toxicity or adverse events, particularly in serious adverse events, as compared with a standard regimen of Compound I administered by 4-hour intravenous infusion of a dose of about 6-14 mg/m 2 on days 1, 8, and 15 of a 28 day cycle.
- Compound I is administered in an accelerated dosing regimen that is identical to a standard dosing regimen (see above) except that one or more unit doses is administered over a time period that is less than about 1 hour (e.g., rather than over a time period of about 4 hours).
- unit doses of Compound I are within the range of about 0.5 mg/m 2 to about 28 mg/m 2 . In certain embodiments, unit doses are in the range of about 1 mg/m 2 to about 25 mg/m 2 . In certain embodiments, unit doses are in the range of about 0.5 mg/m 2 to about 15 mg/m 2 . In certain embodiments, unit doses are the range of about 1 mg/m 2 to about 15 mg/m 2 . In certain embodiments, unit doses are in the range of about 1 mg/m 2 to about 8 mg/m 2 . In certain embodiments, unit doses are in the range of about 0.5 mg/m 2 to about 5 mg/m 2 .
- the unit doses are in the range of about 2 mg/m 2 to about 10 mg/m 2 . In some embodiments, unit doses are in the range of about 10 mg/m 2 to about 20 mg/m 2 . In certain embodiments, unit doses are in the range of about 5 mg/m 2 to about 10 mg/m 2 . In some embodiments, unit doses are in the range of about 10 mg/m 2 to about 15 mg/m 2 . In some embodiments, unit doses are in the range of about 6 to about 19 mg/m 2 . In some embodiments, unit doses are approximately 8 mg/m 2 . In still other embodiments, the unit doses are approximately 9 mg/m 2 . In still other embodiments, unit doses are approximately 10 mg/m 2 .
- unit doses are approximately 11 mg/m 2 . In still other embodiments, unit doses are approximately 12 mg/m 2 . In still other embodiments, unit doses are approximately 13 mg/m 2 . In still other embodiments, unit doses are approximately 14 mg/m 2 . In still other embodiments, unit doses are approximately 15 mg/m 2 . In still other embodiments, unit doses are approximately 30 mg/m 2 .
- different individual unit doses within a Compound I therapy regimen are different.
- increasing doses of Compound I are administered over the course of a cycle.
- a dose of approximately 8 mg/m 2 is administered, followed by a dose of approximately 10 mg/m 2 , followed by a dose of approximately 12 mg/m 2 may be administered over a cycle.
- An amount of Compound I administered in individual unit doses varies depending on the form of Compound I being administered.
- the dosages given herein are dose equivalents with respect to the active ingredient, Compound I.
- individual unit doses of Compound I are administered on one day followed by several days on which Compound I is not administered.
- Compound I is administered twice a week.
- Compound I is administered once a week.
- Compound I is administered every other week.
- Compound I is administered daily (for example for 2 weeks), twice weekly (for example for 4 weeks), thrice weekly (for example for 4 weeks), or on any of a variety of other intermittent schedules (e.g., on days 1, 3, and 5; on days 4 and 10; on days 1 and 15; on days 5 and 12; or on days 5, 12, and 19 of 21 or 28 day cycles).
- intermittent schedules e.g., on days 1, 3, and 5; on days 4 and 10; on days 1 and 15; on days 5 and 12; or on days 5, 12, and 19 of 21 or 28 day cycles.
- Compound I is administered on days 1, 8, and 15 of a 28 day cycle. In certain particular embodiments, an 8 mg/m 2 dose of Compound I is administered on day 1, a 10 mg/m 2 dose of Compound I is administered on day 8, and a 12 mg/m 2 dose of Compound I is administered on day 15. In certain embodiments, Compound I is administered on days 1 and 15 of a 28 day cycle with day 8 being skipped. A 28 day dosing cycle may be repeated. In certain embodiments, a 28 day cycle is repeated 2-10, 2-7, 2-5, or 3-10 times. In certain embodiments, the treatment includes 5 cycles. In certain embodiments, the treatment includes 6 cycles. In certain embodiments, the treatment includes 7 cycles. In certain embodiments, the treatment includes 8 cycles. In certain embodiments, 10 cycles are administered. In certain embodiments, greater than 10 cycles are administered.
- one or more unit doses within a Compound I dosing regimen may be administered via a route other than intravenous administration. In some embodiments, one or more doses may be administered orally. In certain embodiments, Compound I is dosed orally in the range of 10 mg/m 2 to 300 mg/m 2 . In certain embodiments, Compound I is dosed orally in the range of 25 mg/m 2 to 100 mg/m 2 . In certain embodiments, Compound I is dosed orally in the range of 100 mg/m 2 to 200 mg/m 2 . In certain embodiments, Compound I is dosed orally in the range of 200 mg/m 2 to 300 mg/m 2 .
- Compound I is dosed orally at greater than 300 mg/m 2 . In certain embodiments, Compound I is dosed orally in the range of 50 mg/m 2 to 150 mg/m 2 . In other embodiments, the oral dosage ranges from 25 mg/m 2 to 75 mg/m 2 .
- Compound I is administered orally on a daily basis. In some embodiments, Compound I is administered orally every other day. In still other embodiments, Compound I is administered orally every third, fourth, fifth, or sixth day. In certain embodiments, Compound I is administered orally every week. In certain embodiments, Compound I is administered orally every other week.
- one or more unit doses of Compound I is administered topically.
- the dosage, timing and/or routes of administration of particular unit doses of Compound I may vary depending on the patient and condition being treated.
- the cycles are continued as long as the patient is responding. Therapy may be terminated once there is disease progression, a cure or remission is achieved, or side effects become intolerable. Adverse side effects may also call for lowering the dosage of Compound I administered, or for adjusting the schedule by which doses are administered.
- Compound I has been administered to patients in a variety of different clinical contexts and studies. Observed toxicities include fatigue, nausea, vomiting, and myelosuppression (thrombocytopenia and/or neutropenia, e.g., Grade 3). Non-specific S-T segment changes on ECG and prolongation of QTc intervals occur in many patients. Observed toxicities were mild to moderate. Observed changes in ECGs did not correlate with elevated serial serum troponin levels and multiple gated acquisition (MUGA) scans, both of which were consistently normal.
- MUGA multiple gated acquisition
- Compound I may cause neutropenia and/or thrombocytopenia It is generally recommended that further treatment be withheld from patients with Grade 3 or Grade 4 neutropenia or thrombocytopenia, until their specific cytopenia returns to Grade 1 (i.e., ANC recovered to >1.9 ⁇ 10 9 /L and platelet count recovered to ⁇ 75 ⁇ 10 9 /L) or below, at which point therapy can be continued at full dose. If Grade 4 neutropenia or thrombocytopenia lasting more than 5 days or associated with bleeding, then it is generally recommended that treatment be withheld until specific cytopenia returns to Grade 1 or below, at which point therapy can continue, preferably at a reduced dose (e.g., 10 mg/m 2 ).
- a reduced dose e.g. 10 mg/m 2
- Grade 4 febrile ( ⁇ 38.5° C.) neutropenia or thrombocytopenia that requires platelet transfusion it is generally recommended that treatment be withheld until the specific cytopenia returns to Grade 1 or below, at which point therapy can continue, preferably at a reduced dose (e.g., 10 mg/m 2 ).
- Hematologic events are typically observed at a rate of about 21-52% with standard Compound I dosing regimens (National Cancer Institute IND 57,810 Annual Report, 2007).
- the NCI 2007 Annual Report provides the following rates for the following blood and bone marrow abnormalities: platelets (52%), hemoglobin/anemia (41%), abnormal white blood cell count (39%), abnormal ANC/AGC (37%), and lymphopenia (21%) (National Cancer Institute IND 57,810 Annual Report, 2007).
- Cardiac events observed with Compound I administration can include any or all of the following:
- the medical monitor and medical monitor should cardiologist evaluation is be notified and local complete cardiologist should be consulted A subsequent episode of any of the above, despite dose reduction Discontinue Compound I administration T-wave morphology Inversion of ⁇ 4 mm a Hold further dosing, If resolved, restart ST-segment Depression of ⁇ 2 mm b consult local treatment, preferably at a cardiologist, and treat reduced dose (e.g., 10 appropriately mg/m 2 ) In some patients, ST segment and T-wave morphology changes may recur despite a dose reduction. In such cases, further treatment should be withheld until the ECG changes resolve. If the patient experiences no concomitant clinical events, treatment may be resumed, preferably at the reduced dose level. If not resolved, discontinue therapy. a Measured from isoelectric line to peak of T-wave b Measured from isoelectric line to ST segment
- Cardiac events are typically observed at a rate of about 24% with standard Compound I dosing regimens (National Cancer Institute IND 57,810 Annual Report, 2007)
- Gastrointestinal events are typically observed at a rate of about 15-64% with standard Compound I dosing regimens (National Cancer Institute IND 57,810 Annual Report, 2007).
- NCI 2007 Annual Report provides the following rates for the following gastrointestinal events: nausea (64%), anorexia (39%), vomiting (39%), constipation (19%), dysguesia (18%), and diarrhea (15%) (National Cancer Institute IND 57,810 Annual Report, 2007).
- Compound I can be administered via accelerated dosing regimens without a clinically significant increase in relevant toxicities (e.g., in the rate and/or severity of one or more of dose limiting toxicities, serious adverse events, and/or adverse events).
- relevant toxicities e.g., in the rate and/or severity of one or more of dose limiting toxicities, serious adverse events, and/or adverse events.
- accelerated dosing regimens for Compound I in which the subject receiving Compound I does not suffer one or more particular adverse events, or serious adverse events, within a designated time period are provided.
- the designated time period is during administration of the accelerated dose.
- the designated time period is within about 2 to about 6 hours after the end of infusion of the accelerated dose.
- the designated time period is within about 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40 42, 44, 46, 48 or more hours after the end of infusion of the accelerated dose.
- any side effect, toxicity, or adverse event may be absent from the designated time period.
- the subject's QTc remains below about 500 msec during the designated time period; in some embodiments, the subject does not suffer a ventricular arrhythmia during the designated time period; in some embodiments, the subject does not suffer sinus tachycardia during the designated time period; in some embodiments, the subject does not suffer an atrial dysrhythmia during the designated time period; in some embodiments the subject does not suffer ST or T-wave changes indicative of repolarization during the designated time period.
- Compound I is administered in combination with one or more other pharmaceutical agents. In some embodiments, Compound I is administered in combination with one or more other chemotherapeutic agents and/or in combination with one or more other pharmaceutical agents (e.g., pain relievers, anti-inflammatories, antibiotics, steroidal agents, anti-folates, kinase inhibitors, methyl transferase inhibitors, antibodies, etc.).
- chemotherapeutic agents e.g., pain relievers, anti-inflammatories, antibiotics, steroidal agents, anti-folates, kinase inhibitors, methyl transferase inhibitors, antibodies, etc.
- Compound I is administered in combination with one or more cytotoxic agents.
- cytotoxic agents include, but are not limited to, gemcitabine, decitabine, and flavopiridol.
- Compound I is administered in combination with one or more taxanes and/or one or more proteasome inhibitors.
- proteasome inhibitors include, but are not limited to, bortezomib (VELCADE®), peptide boronates, salinosporamide A (NPI-0052), lactacystin, epoxomicin (Ac(Me)-Ile-Ile-Thr-Leu-EX), MG-132 (Z-Leu-Leu-Leu-al), PR-171, PS-519, eponemycin, aclacinomycin A, CEP-1612, CVT-63417, PS-341 (pyrazylcarbonyl-Phe-Leu-boronate), PSI (Z-Ile-Glu(OtBu)-Ala-Leu-al), MG-262 (Z-Leu-Leu-Leu-bor), PS-273 (MNLB), omuralide (clasto-lactacystin- ⁇ -lactone), NLVS (Nip-Leu-Leu-Leu-vinyl sulfone),
- Compound I is administered in combination with one or more anti-folates. In some such embodiments, Compound I is administered in combination with one or more of: folinic acid (leucovorin), methotrexate, pralatrexate, premextred, triazinate, or combinations thereof.
- Compound I is administered in combination with one or more kinase inhibitors (e.g., tyrosine kinase inhibitors). In some embodiments, Compound I is administered in combination with one or more antibodies that act as a kinase inhibitor.
- kinase inhibitors e.g., tyrosine kinase inhibitors
- antibodies that act as a kinase inhibitor.
- Compound I is administered in combination with one or more of ABT-869, AC220, AZD7762, BIBW 2992, BMS-690154, CDKIAT7519, CYC116, ISIS3521, GSK690693, GSK-461364, MK-0457, MLN8054, MLN8237, MP470, ON 01910.Na, OSI-930, PHA-739358, R935788, SNS-314, TLN-232, XL147, XL228, XL281, XL418, or XL765.
- Compound I is administered in combination with one or more methyl transferase inhibitors.
- Compound I is administered in combination with one or more therapeutic antibodies.
- Compound I is administered in combination with one or more of: bevacizumab, cetuximab, dasatinib, erlotinib, geftinib, imatinib, lapatinib, nilotinib, panitumumab, pegaptanib, ranibizumab, sorafenib, sunitinib, trastuzumab, or any antibody that binds to an antigen bound by one of these moieties.
- Compound I is administered in combination with an anti-inflammatory agent, pain reliever, anti-nausea medication, or anti-pyretic.
- Anti-inflammatory agents useful in the methods provided herein include, but are not limited to, aspirin, ibuprofen, and acetaminophen, etc.
- Compound I is administered in combination with a steroidal agent.
- Compound I is administered in combination with a steroidal agent selected from the group consisting of alclometasone diproprionate, amcinonide, beclomethasone diproprionate, betamethasone, betamethasone benzoate, betamethasone diproprionate, betamethasone sodium phosphate, betamethasone sodium phosphate and acetate, betamethasone valerate, clobetasol proprionate, clocortolone pivalate, cortisol (hydrocortisone), cortisol (hydrocortisone) acetate, cortisol (hydrocortisone) butyrate, cortisol (hydrocortisone) cypionate, cortisol (hydrocortisone) sodium phosphate, cortisol (hydrocortisone) sodium succinate, cortisol (hydrocortisone) valerate,
- Compound I is administered in combination with an agent to treat gastrointestinal disturbances such as nausea, vomiting, and diarrhea.
- agents may include anti-emetics, anti-diarrheals, fluid replacement, electrolyte replacement, etc.
- Compound I is administered in combination with electrolyte replacement or supplementation such as potassium, magnesium, and calcium. In certain embodiments, Compound I is administered in combination with electrolyte replacement or supplementation such as potassium, magnesium.
- Compound I is administered in combination with an anti-arrhythmic agent.
- Compound I is administered in combination with an agent that increases the production of platelets.
- Compound I is administered in combination with an agent to boost the production of blood cells.
- the agent is erythropoietin.
- Compound I is administered in combination with an agent to prevent hyperglycemia.
- Compound I is administered with another HDAC or DAC inhibitor.
- electrolyte supplementation is administered to subjects receiving Compound I therapy.
- Individuals with low electrolyte levels are susceptible to development of unwanted side effects if administered Compound I therapy (see, for example, published application No. US 2008/0124403, which is incorporated herein by reference).
- Such patients may be particularly susceptible to development of cardiac repolarization effects, including QTc prolongation (though potentially with no significant cardiac function changes), and/or cardiac dysrhythmias.
- Particular abnormalities that may be observed include an increase in QTc interval and/or abnormalities of the ST segment (e.g., ST segment depression) and/or the T-wave (e.g., T-wave flattening) on ECG.
- Serum concentrations of potassium are generally considered to be “normal” when they are within the range of about 3.5-5.5 mEq/L or about 3.5-5.0 mEq/L. It is often desirable to ensure that an individuals' serum potassium concentration is within these ranges prior to (and/or during) administration of Compound I therapy.
- Serum concentrations of magnesium are generally considered to be “normal” when they are within the range of about 1.5-2.5 mEq/L or about 1.5-2.2 mEq/L or about 1.25-2.5 mEq/L or about 1.25-2.2 mEq/L. It is often desirable to ensure that an individual's serum magnesium concentration is within these ranges prior to (and/or during) administration of Compound I therapy.
- an individual's serum potassium and/or magnesium concentration(s) is/are at the high end of the normal range prior to (and/or during) administration of Compound I therapy.
- an individual's serum potassium concentration is at least about 3.8 mEq/L, 3.9 mEq/L, 4.0 mEq/L, or more prior to and/or during administration of Compound I therapy.
- care is taken not to increase serum potassium concentration above about 5.0 mEq/L, 5.2 mEq/L, or 5.5 mEq/L.
- an individual's serum magnesium concentration is at least about 1.9 mEq/L or more prior to and/or during administration of Compound I therapy. In some embodiments, care is taken not to increase magnesium concentration above about 2.5 mEq/L.
- an individual's serum potassium concentration is at least about 3.5 mEq/L (in some embodiments at least about 3.8 mEq/L, 3.9 mEq/L, 4.0 mEq/L, or above) and the individual's serum magnesium concentration is at least about 1.85 mEq/L (in some embodiments at least about 1.25 mEq/L, 1.35 mEq/L, 1.45 mEq/L, 1.55 mEq/L, 1.65 mEq/L, 1.75 mEq/L, 1.85 mEq/L, 1.95 mEq/L, or above) prior to and/or during administration of Compound I therapy.
- electrolyte levels are assessed more than once during the course of Compound I therapy; in some embodiments, different assessments are separated by a regular interval (e.g., 0.5 days or less, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, etc.). In some embodiments, electrolyte levels are assessed prior to each administration of Compound I.
- a regular interval e.g., 0.5 days or less, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, etc.
- An individual's serum potassium and/or magnesium and/or other electrolyte concentration(s) may be assessed by any available means.
- samples may be collected from venous or arterial blood and processed for plasma or serum analysis.
- venous sampling is utilized. Any available assay may be utilized for assessment.
- potassium is measured by flame photometry, direct potentiometry (see, for example, Koch et al., Clin. Chem. 29:1090, 1983), enzymatic methods (e.g., by using tryptophanase; see, for example, Kimura et al., Clin. Chem. 38:44, 1992), calorimetric methods (e.g., using tetraphenyl borate), etc.
- magnesium is measured by complexometric titration, flame emission photometry, atomic absorption spectophotometry, other spectrophotometric techniques including enzymatic techniques and dye binding methods (e.g., Magnon dye binding and bichromatic absorbance; see, for example, Barbour et al., Clin. Chem. 34:2103, 1988; elimination of interference by bilirubin; see, for example, Rehak et al., Clin. Chem 35:1031, 1989; etc.).
- assays are performed in an automated clinical chemistry analyzer (e.g., the Abbott ARCHITECT®, etc.).
- potassium and magnesium levels are assessed, they may be assessed separately or together. Assessment of potassium and/or magnesium levels may be performed prior to, at the same time as, and/or after initiation of Compound I therapy.
- potassium and/or magnesium supplementation is administered prior to, at the same time as, or after initiation of Compound I therapy.
- Compound I therapy is suspended or delayed until serum potassium and/or magnesium levels are increased.
- Compound I therapy is suspended or delayed until serum potassium and/or magnesium levels are increased to within the normal range, or to within the upper end of the normal range.
- Compound I therapy is suspended or delayed until serum potassium concentration is above about 3.5 mEq/L; or is above about 3.8 mEq/L.
- Compound I therapy is suspended or delayed until serum magnesium concentration is above about 1.25 mEq/L; or is above about 1.8 mEq/L; or is above about 1.9 mEq/L. In some embodiments, Compound I therapy is suspended or delayed until both serum potassium and serum magnesium concentrations are increased as described.
- electrolyte supplementation may be administered prior to, concurrently with, and/or subsequent to initiation of Compound I therapy, and may include potassium and/or magnesium supplementation.
- electrolyte supplementation may include supplementation of one or more electrolytes selected from the group consisting of sodium, potassium, chloride, calcium, magnesium, bicarbonate, phosphate, sulfate, and combinations thereof.
- potassium supplemental forms are available (see, for example, the web page at the following world-wide-web address: pdrhealth.com).
- potassium supplements in the form of potassium chloride, potassium citrate, potassium gluconate, potassium bicarbonate, potassium aspartate and/or potassium orotate can readily be obtained.
- potassium supplemental forms is high-potassium (up to 800 milligrams per serving), low-sodium vegetable juices. Some soft drinks are rich in potassium. Some soft drinks contain potassium gluconate which has a less bitter taste than some other potassium supplements. Salt substitutes are high in potassium.
- Certain foods high in potassium such as raisins, figs, apricots, sardines, veal, bananas, avocado, and broccoli may be used as potassium supplements.
- Foods high in potassium may provide potassium that is easily bioavailable and/or may reduce gastrointestinal side effects associated with the administration of potassium salts.
- the potassium supplement may also be provided as part of a multivitamin.
- Potassium is typically supplemented orally or intravenously, though other modes of delivery are within the scope of the present disclosure.
- potassium acetate e.g., 2 mEq/mL or 4 mEq/mL for injection
- potassium acetate e.g., 75 mg, 95 mg, 99 mg, and 180 mg tablets and/or 2 mEq/mL, 10 mEq/50 mL, 20 mEq/50 mL, 10 mEq/100 mL, 20 mEq/100 mL, 30 mEq/100 mL, 40 mEq/100 mL for injection and/or 20 mEq/15 mL, 40 mEq/15 mL liquid and/or 20 mEq or 25 mEq powder for reconstitution, and/or 9 mEq, 10 mEq, or 20 mEq extended release tablets), and potassium gluconate (e.g., 486 mg, 500 mg, 550 mg, 595 mg, 610 mg, and 620 mg tablets).
- magnesium supplemental forms are also available.
- supplements in the form of magnesium chloride, magnesium gluconate, magnesium lactate, magnesium oxide and/or magnesium sulfate can readily be obtained.
- magnesium supplements Certain foods high in magnesium such as artichoke, banana, figs, almonds, cashews, pine nuts, brazil nuts, beans, spinach, and tomatoes may be used as magnesium supplements.
- the magnesium supplement may also be provided as part of a multivitamin.
- magnesium supplements include magnesium chloride (e.g., 200 mg/ml for injection, 535 mg extended release tablets), magnesium gluconate (3.25 mg/mL, 1000 mg/5 mL liquid; 500 mg tablet); magnesium lactate (84 mg extended release tablet); magnesium oxide (e.g., 140 mg, 600 mg capsules, powder, and/or 200 mg, 250 mg, 400 mg, 420 mg, and 500 mg tablets), magnesium sulfate (e.g., 40 mg/mL, 80 mg/mL, 125 mg/mL, 500 mg/mL, for injection).
- magnesium chloride e.g., 200 mg/ml for injection, 535 mg extended release tablets
- magnesium gluconate 3.25 mg/mL, 1000 mg/5 mL liquid; 500 mg tablet
- magnesium lactate 84 mg extended release tablet
- magnesium oxide e.g., 140 mg, 600 mg capsules, powder, and/or 200 mg, 250 mg, 400 mg, 420 mg, and 500 mg tablets
- magnesium sulfate e.
- electrolyte supplementation is administered in an amount sufficient to reduce or delay onset of one or more cardiac toxicities associated with Compound I therapy.
- the electrolyte administration may also reduce one or more of nausea, vomiting, fatigue (lethargy, malaise, asthenia), increased creatine phospho kinase (CPK), hyperuricemia, hypocalcemia, hyperglycemia, fever, gastritis, diarrhea, abdominal pain, dehydration, weight loss, hypophosphatemia, hyponatremia, hypokalemia, hypomagnesemia, syncope, hypoxia, pleural effusion, hypotension, myocardial ischemia, increased cardiac troponin I, confusion, and/or myelosuppression, and combinations thereof.
- nausea, vomiting, fatigue lethargy, malaise, asthenia
- CPK creatine phospho kinase
- hyperuricemia hypocalcemia
- hyperglycemia hyperglycemia
- fever fever
- gastritis diarrhea
- abdominal pain dehydration
- weight loss hypo
- cardiac toxicities are selected from the group consisting of heart-rate corrected QT (QTc) interval prolongation, supraventricular arrhythmias (supraventricular tachycardia (SVT)/atrial fibrillation/flutter), and combinations thereof.
- QTc prolongation and/or other electrophysiological changes are reduced to normal values or ranges after electrolyte supplementation.
- Solvents were either HPLC grade or ACS grade, unless stated otherwise. Samples were prepared from Compound I Form A solids or from samples generated from these solids. Form designation for the materials was based on X-ray powder diffraction (XRPD). Care was taken to protect samples from light, unless stated otherwise. Prior to characterization, solids were stored as follows: Form A and Form B (may have contained Form A solids as well) under ambient conditions, Form E and Form H over desiccant in a freezer, Form C in contact with mother liquor in a refrigerator, Form D in contact with mother liquor in a freezer, and Form I in contact with mother liquor under ambient conditions or in a freezer.
- Form A and Form B may have contained Form A solids as well
- Form E and Form H over desiccant in a freezer
- Form C in contact with mother liquor in a refrigerator
- Form D in contact with mother liquor in a freezer
- Form I in contact with mother liquor under ambient conditions or in a freezer.
- Optical microscopy was performed using a Leica MZ12.5 stereomicroscope. Samples were viewed in situ or on a glass slide (sometimes covered in Paratone-N oil) with crossed polarizers and a first order red compensator. Various objectives were used, ranging from 0.8-10 ⁇ .
- XRPD patterns were collected using an Inel XRG-3000 diffractometer equipped with a curved position sensitive detector with a 2 ⁇ range of 120°.
- An incident beam of Cu K ⁇ radiation (40 kV, 30 mA) was used to collect data in real time at a resolution of 0.03° 2 ⁇ .
- a silicon standard (NIST SRM 640c) was analyzed to verify the Si 111 peak position. Samples were prepared for analysis by packing them into thin-walled glass capillaries. Each capillary was mounted onto a goniometer head and rotated during data acquisition. The monochromator slit was set at 5 mm by 160 ⁇ m.
- XRPD patterns were collected using a PANalytical X'Pert Pro diffractometer. An incident beam of Cu K ⁇ radiation was produced using an Optix long, fine-focus source. An elliptically graded multilayer mirror was used to focus the Cu K ⁇ X-rays of the source through the specimen and onto the detector. Data were collected and analyzed using X'Pert Pro Data Collector software (v.2.2b). Prior to the analysis, a silicon specimen (NIST SRM 640c) was analyzed to verify the Si 111 peak position. The specimen was sandwiched between 3 ⁇ m thick films, analyzed in transmission geometry, and rotated to optimize orientation statistics. A beam-stop was used (sometimes with helium gas) to minimize the background generated by air scattering. Soller slits were used for the incident and diffracted beams to minimize axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) located 240 mm from the specimen.
- X'Celerator scanning position
- XRPD patterns were collected using a PANalytical X'Pert Pro diffractometer.
- An incident beam of Cu K ⁇ radiation was produced using a ceramic tube with a long, fine-focus source and a nickel filter.
- the diffractometer was configured using the symmetric Bragg-Brentano geometry with a reflection stage and a manually operated spinner. Data were collected and analyzed using X'Pert Pro Data Collector software (v. 2.2b).
- a silicon specimen NIST SRM 640c
- Anti-scatter slits were used to minimize the background generated by air scattering.
- Soller slits were used for the incident and diffracted beams to minimize axial divergence.
- Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) located 240 mm from the specimen.
- Peaks within the range of up to about 30° 2 ⁇ were selected. Different rounding algorithms were used to round each peak to the nearest 0.01° 2 ⁇ , depending upon the instrument used to collect the data and/or the inherent peak resolution. The location of the peaks along the x-axis (° 2 ⁇ ) in both the figures and the tables were automatically determined using proprietary software 1 and rounded to two significant figures after the decimal point based upon the above criteria. Peak position variabilities are given to within ⁇ 0.1° 2 ⁇ based upon recommendations outlined in the USP discussion of variability in x-ray powder diffraction 2 .
- the wavelength used to calculate d-spacings was 1.541874 ⁇ , a weighted average of the Cu—K ⁇ 1 and Cu—K ⁇ 2 wavelengths. Variability associated with d-spacing estimates was calculated from the USP recommendation, at each d-spacing, and provided in the respective data tables. 1 PatternMatchTM 3.0.4. 2 United States Pharmacopeia, USP 32, NF 27, Vol. 1, pg. 392, May 1, 2009 ⁇ 941> X-Ray Diffraction.
- peak tables contain data identified only as “Prominent Peaks”. These peaks are a subset of the entire observed peak list. Prominent peaks are selected from observed peaks by identifying preferably non-overlapping, low-angle peaks, with strong intensity.
- assessments of particle statistics (PS) and/or preferred orientation (PO) are possible. Reproducibility among XRPD patterns from multiple samples analyzed on a single diffractometer indicates that the particle statistics are adequate. Consistency of relative intensity among XRPD patterns from multiple diffractometers indicates good orientation statistics. Alternatively, the observed XRPD pattern may be compared with a calculated XRPD pattern based upon a single crystal structure, if available. Two-dimensional scattering patterns using area detectors can also be used to evaluate PS/PO. If the effects of both PS and PO are determined to be negligible, then the XRPD pattern is representative of the powder average intensity for the sample and prominent peaks may be identified as “Representative Peaks”.
- “Characteristic peaks” are a subset of Representative Peaks and are used to differentiate one crystalline polymorph from another crystalline polymorph. Characteristic peaks are determined by evaluating which representative peaks, if any, are present in one crystalline polymorph of a compound against all other known crystalline polymorphs of that compound to within +0.1° 2 ⁇ . Not all crystalline polymorphs of a compound necessarily have at least one characteristic peak.
- DSC Dynamic Sensor Analysis
- Temperature calibration was performed using NIST traceable indium metal.
- the sample was placed into an aluminum DSC pan, and the weight was accurately recorded.
- the pan was covered with a lid, and the lid was crimped.
- a weighed, crimped aluminum pan was placed on the reference side of the cell.
- the sample cell was equilibrated at the initial temperature and heated under a nitrogen purge. Reported temperatures are at the transition maxima, unless stated otherwise.
- MDSC Modulated Differential Scanning Calorimetry
- MDSC data were obtained on a TA Instruments Q2000 differential scanning calorimeter equipped with a refrigerated cooling system (RCS). Temperature calibration was performed using NIST traceable indium metal. The sample was placed into an aluminum DSC pan, and the weight was accurately recorded. The pan was covered with a lid perforated with a laser pinhole, and the lid was crimped or crimped then hermetically-sealed pan. A weighed, crimped aluminum pan was placed on the reference side of the cell. Data were obtained using a modulation amplitude of ⁇ 0.50° C. and a 60 second period with an underlying heating rate of 2.00° C./minute from ⁇ 50.00 to 200.00° C. The reported glass transition temperatures are obtained from the inflection point of the step change in the reversing heat flow versus temperature curve.
- TG analysis was performed using a TA Instruments 2050 thermogravimetric analyzer. Temperature calibration was performed using nickel and AlumelTM. The sample was placed in an aluminum pan and inserted into the TG furnace. In one embodiment, the pan was left open. The sample cell was equilibrated at the initial temperature and the furnace was heated under nitrogen. In another embodiment, the instrument was operated under a flow of helium at 10 and 90 cc/min for the purge and balance, respectively, and the furnace was heated under helium at a rate of 20° C./minute to a final temperature of 250° C.
- FT-IR spectra for solid forms described herein were acquired on Magna-IR 860® Fourier transform infrared (FT-IR) spectrophotometer (Thermo Nicolet) equipped with an Ever-Glo mid/far IR source, an extended range potassium bromide (KBr) beamsplitter, and a deuterated triglycine sulfate (DTGS) detector.
- FT-IR Fourier transform infrared
- DTGS deuterated triglycine sulfate
- Some amorphous solid form FT-IR spectra were acquired using Nexus 670®, equipped in the same way as described for Magna-IR 860® above. Wavelength verification for Magna-IR 860® and Nexus 670® were performed using NIST SRM 1921b (polystyrene).
- ATR attenuated total reflectance
- ThunderdomeTM Thermo Spectra-Tech
- Ge germanium
- ATR attenuated total reflectance
- Peak positions were determined using standard spectral software. Peak position variabilities are given to within ⁇ 2 cm ⁇ 1 , based on the observed sharpness of the peaks picked and acquisition of data using a 1 cm ⁇ 1 data point spacing (2 cm ⁇ 1 resolution). The accuracy and precision associated with any particular measurement reported herein has not been determined.
- Raman spectra were acquired on a FT-Raman 960 spectrometer (Thermo Nicolet) equipped with a germanium (Ge) detector. Wavelength verification was performed using sulfur and cyclohexane. Each sample was prepared for analysis by placing the sample into a 13 mm diameter gold-coated cup and leveling the material. Each spectrum represents 512 co-added scans collected at a spectral resolution of 2 cm ⁇ 1 .
- producing, purifying and/or storing Compound I at an apparent pH less than approximately 6.5 and/or at an apparent pH of about less than approximately 6.0 has been found to prevent the formation of dimerized, oligomerized or polymerized Compound I, as described in US Patent Application Publication No. US 20090186382, filed Dec. 28, 2007, which is incorporated herein by reference.
- one or more of the purification steps are performed at an apparent pH less than 6.5.
- one or more of the purification steps are performed at an apparent pH less than 6.0.
- one or more purification steps are performed at an apparent pH ranging from 4.0 to 6.0.
- all of the purification steps are carried out at an apparent pH ranging from approximately 4.0 to approximately 6.0.
- the apparent pH of a solution containing Compound I is not allowed to reach an apparent pH above approximately 7.0, or more preferably above approximately 6.0.
- the apparent pH of all purification processes is preferably monitored and subsequently adjusted, if need be, to an apparent pH below approximately 6.0. In certain embodiments, it is maintained within the apparent pH range of approximately 4.0 to approximately 6.0.
- the control of apparent pH in purification steps towards the end of the process or steps using aqueous solutions have been found to be particularly useful in diminishing or eliminating the formation of undesired contaminants.
- Any acid or buffer may be used to control pH.
- an organic acid such as acetic acid or formic acid is used to control pH in one of more of the purification steps.
- an inorganic acid such as phosphoric acid or hydrochloric acid is used.
- Any procedure for purifying Compound I, whether from fermentation, semi-synthesis, or total synthesis, can be modified based on the present disclosure to prevent the formation of undesired side products by monitoring apparent pH and reducing the apparent pH, if necessary.
- FIG. 1 ( a ) Exemplary data for Compound I in the form of 1 H-NMR in depicted in FIG. 1 ( a ) and a molecular structure of Compound I is depicted in FIG. 1 ( b ).
- the 1 H-NMR depicted in FIG. 1 ( a ) displays chemical shifts and integration consistent with Compound I, has residual acetone present (at approximately 2.08 ppm) and the water peak (occurring at 3.33 ppm) has been truncated.
- Compound I Form C was prepared via serial seeding of saturated solutions of romidepsin Form A with solids containing Compound I Form C, with the resulting X-ray powder diffraction (XRPD) pattern of each generated material exhibiting more reflections present in the Compound I Form C pattern than the last.
- the series included three experiments: (a) First Seeding Procedure; (b) Second Seeding Procedure; and (c) Final Preparation of Compound I Form C.
- An XRPD pattern collected for final product Compound I Form C does not appear to exhibit reflections from Compound I Form A. The experiments were conducted as follows:
- portion 1 A portion of the slurry (“portion 1”) was centrifuged in small aliquots at ambient temperature in a 1.0 mm glass capillary, for analysis by X-ray powder diffraction. Centrifugation was done in increments of several seconds to approximately 10 minutes, with total centrifugation more than 20 minutes. X-ray powder diffraction analysis showed evidence of reflections present in Compound I Form A and Compound I Form C, suggesting the recovered solids were a mixture of phases.
- portion 2 A second portion (“portion 2”) was left open in a vial at ambient temperature to partially dry the solids while a capillary was being prepared. Both capillary and bulk samples were stored in a refrigerator before and after the analysis. The capillary sample was analyzed shortly after preparation and the bulk sample was used as seed on the day of its isolation.
- the flask contained solids from “portion 2” (the amount approximately that of a spatula tip) as seed, to encourage formation of Compound I Form C. No precipitate was apparent but the seed solids remained. Additional solids from “portion 2” (the amount approximately that of a spatula tip) were added. No precipitate was apparent but the seed solids remained.
- portion 3 was centrifuged in small aliquots at ambient temperature in a 1.0 mm glass capillary, for analysis by X-ray powder diffraction. Centrifugation was done in increments of several seconds. X-ray powder diffraction analysis showed the recovered solids to consist mainly of Compound I Form C, and indications of presence of Compound I Form A.
- portion 4 The sample was stored in a refrigerator before and after the analysis but was not analyzed until the next day. Analysis occurred shortly after removal from the refrigerator (“portion 4”). “Portion 4” was left sealed at ambient temperature while the capillary was being prepared, returned to the ⁇ 5° C. bath for approximately 3 days and then stored in a refrigerator briefly before being used as seed.
- Exemplary data for Compound I Form C in the form of X-ray diffraction patterns (XRPD), differential scanning calorimeter thermograms (DSC), thermogravimetric analysis thermograms (TGA), infrared spectrums (FT-IR), and single crystal structure data are depicted in FIGS. 1 ( c ) through 1 ( q ), supra.
- XRPD X-ray diffraction patterns
- DSC differential scanning calorimeter thermograms
- TGA thermogravimetric analysis thermograms
- FT-IR infrared spectrums
- single crystal structure data e.g., ORTEP drawings, packing diagrams, positional parameters, bond distances and bond angles
- Form C is a crystalline non-stoichiometric hydrate of Compound I, as determined from single crystal data (see FIGS. 1 ( i ) through 1 ( q )).
- the crystal structure contains one fully occupied water molecule and a second water site with a refined occupancy of approximately 73%.
- the characterization of Compound I, Form C is summarized in Table 3. TABLE 3 Characterization of Compound I Form C Analysis Result Figure References XRPD Form C 1(c), 1(d), 1(i), 1(j) DSC 96.6° C. (broad endo, min) 1(e) 139.6° C. (broad endo, min) 177.2° C. (broad exo, max) 257.1° C. (endo, min) followed by decomp.
- the differential scanning calorimetry (DSC) thermogram for Compound I, Form C exhibits broad endothermic events at approximately 97° C. and 140° C. (min), ascribed to loss of solvent, based on the 5.3% weight loss observed in the thermogravimetric analysis (TGA) thermogram (see FIG. 1 ( f )).
- TGA thermogravimetric analysis
- This weight loss corresponds to approximately 1.7 moles of water, which is similar to the result obtained from the single crystal data. However, the loss may include acetone, since the sample was crystallized from an acetone/water mixture.
- the DSC thermogram also exhibits an endotherm at approximately 257° C. (min) (see FIG. 1 ( e )).
- Form C may be isostructural with the methanol solvate reported in Shigematsu et al., The Journal of Antibiotics, Vol. 47, No. 3, “FR901228, A Novel Antitumor Bicyclic Depsipeptide Produced by Chromobacterium violaceum No. 968, pp. 311-314 (March 1994).
- a summary of exemplary data presented in FIGS. 2 ( a ) through 2 ( f ) is as follows. As described in Example 8, one skilled in the art will be able to readily ascertain from the data presented herein that Compound I Form D may be isostructural with MEK solvate (Compound I Form J).
- Form D is an unstable crystalline acetone solvate of Compound I that converts to Form A under ambient conditions.
- a crystal prepared from cold acetone solution was indexed.
- the formula weight was determined to be 598.81 g/mol.
- the cell parameters are similar to the cell obtained from the Compound I Form J crystal structure. The similarity between the two unit cells and XRPD patterns of Compound I Form D and Compound I Form J suggest the two samples are related crystal forms.
- FIG. 2 ( a ) An experimental Compound I Form D pattern is provided in FIG. 2 ( a ) with an accompanying line list in FIG. 2 ( b ).
- the pattern is consistent with a pattern for Compound I Form D and similar to a pattern for Compound I Form J as observed in the XRPD overlay presented in FIG. 6 ( a ).
- This high resolution pattern of FIG. 2 ( a ) was collected after storage of the material in a freezer and displayed presence of Compound I Form D and Compound I Form A, suggesting a mixture of phases, so the pattern generated from the material after storage in the freezer was used to generate a corresponding peak list for Compound I Form D (see FIG. 2 ( b )).
- FIG. 2 ( e ) and FIG. 2 ( f ) An FT-IR spectrum of Compound I Form D and accompanying peak list is provided as FIG. 2 ( e ) and FIG. 2 ( f ). To avoid the potential for form conversion from solvent loss, the solids for the FT-IR data were collected immediately upon removal from the freezer.
- the TGA thermogram for Compound I Form D exhibits a weight loss of approximately 10.9% and the DSC thermogram (see FIG. 2 ( c )) exhibits a small exothermic event at approximately 91° C. These events appear to be mainly related to desolvation and recrystallization to Compound I Form A, respectively, based on the instability of Compound I Form D and tendency for conversion to Compound I Form A.
- the weight loss observed by TGA corresponds to slightly more than a mole of acetone. To avoid the potential for Form conversion from solvent loss, the solids were analyzed immediately upon removal from the freezer.
- a summary of exemplary data presented in FIGS. 3 ( a ) through 3 ( p ) is as follows.
- Compound I, Form E may be isostructural with Compound I, Form H (see Example 6).
- Compound I Form E is a crystalline mono-tert-butanol solvate of Compound I, as determined from single crystal data (see FIGS. 3 ( h ) through 3 ( p )).
- the characterization of Compound I Form E is summarized in Table 5.
- Table 5 Characterization of Compound I Form E Analysis Result Figure References XRPD Form E 3(a), 3(b), 3(h), 3(i) DSC 158.1° C. (broad endo, min) 3(c) 255.3° C. (endo, min) followed by apparent decomp. TGA 10.9 wt % loss to 200° C.
- the DSC thermogram for Compound I Form E exhibits an endothermic event at approximately 158° C. (min), ascribed to desolvation, based on the TGA thermogram (see FIG. 3 ( d )), and indicated by hot stage microscopy as partial loss of birefringence at approximately 157° C.
- Hot stage microscopy showed the specimen to melt at approximately 243° C., as indicated by an endotherm in the DSC at approximately 255° C. (min). Based on the melting temperature, it is believed that the sample desolvated to Compound I Form A prior to melt.
- the final weight loss from TGA suggests that decomposition is concurrent with the melt observed by hot stage microscopy, as it was for Compound I Form A.
- compound I Form A 105.9 mg, 0.2 mmol
- chloroform 4 mL
- XRPD X-ray powder diffraction
- Compound I Form A (740 mg, 1.4 mmol) and chloroform (30 mL) were charged to a glass vial and bath sonicated for a few minutes, producing a clear solution.
- Compound I Form A 750 mg, 1.4 mmol was added to ensure excess solids for slurry.
- the resulting sample was agitated for approximately 4 days on a rotating wheel. Remaining solids floated to the top upon standing, generating a clear solution at the bottom of the vial. Approximately 1 ⁇ 4 of the solution was drawn off to a clean glass vial and solids were precipitated via slow evaporation of the solvent (vial covered with perforated aluminum foil) in a laboratory fume hood. After approximately 2 days, no solvent was apparent.
- the solids consisting of Compound I Form F were left in a sealed vial at ambient temperature for approximately 1 day, and then stored in a freezer.
- Compound I Form F is a crystalline chloroform solvate of Compound I.
- the characterization of Compound I Form F is summarized in Table 6.
- Table 6 TABLE 6 Characterization of Compound I Form F Analysis Result Figure References XRPD Form F 9(a)-9(f), 9(h), 9(i) DSC 83.6° C. (minor endo) 9(j) 97.3° C. (endo) 256.4° C. (endo) FT-IR reference spectrum 9(g), 9(h) TGA Form F 9(k)
- a summary of exemplary data presented in FIGS. 4 ( a ) through 4 ( f ) is as follows.
- Compound I, Form H may be isostructural with Compound I, Form E (see Example 4).
- Compound I Form H is a crystalline chloroform solvate of Compound I. Characterization of Compound I Form H is summarized in Table 7. TABLE 7 Characterization of Compound I Form H Figure Analysis Result References XRPD Form H 4(a), 4(b) DSC 96.3° C. (broad endo, min) 4(c) 256.7° C. (endo, min) followed by apparent decomp TGA 10.1 wt % loss to 150° C. 4(d) FT-IR reference spectrum 4(e), 4(f)
- FIGS. 4 ( a ) and 4 ( b ) A high resolution XRPD pattern of Compound I Form H and an accompanying line list is provided in FIGS. 4 ( a ) and 4 ( b ).
- An FT-IR spectrum of Compound I Form H and an accompanying line list is provided in FIGS. 4 ( e ) and 4 ( f ).
- the DSC thermogram for Compound I Form H exhibits an endothermic event at approximately 96° C. (min). This event appears to be mainly related to desolvation, based on the weight loss of approximately 10.1% observed in the TGA thermogram for Compound I Form H (see FIG. 4 ( d )). This corresponds to more than 0.5 moles of chloroform.
- the solids were analyzed immediately upon removal from the freezer. Since no weight loss was observed prior to the start of the analysis, the weight loss observed is attributed to solvent loss from the crystal lattice, suggesting Compound I Form H is a solvate.
- the DSC thermogram see FIG.
- compound I Form A 500 mg, 0.9 mmol
- chloroform 5 mL
- XRPD X-ray powder diffraction
- compound I Form A (517 mg, 1.0 mmol) and chloroform (5 mL) were charged to a glass vial and bath sonicated for approximately 20 minutes, generating a clear solution, with a trace of solid.
- the resulting mixture was agitated on a rotating wheel for approximately 1 month at ambient temperature.
- the solids were stored in the mother liquor in a refrigerator.
- a portion of the solids (“portion 1”) was recovered for X-ray powder diffraction (XRPD) via filtration with a 0.22 ⁇ m nylon filter in a Swinnex Millipore filter body. The filter cake was not washed and the solids appeared dry upon recovery. The solids were gently crushed prior to XRPD analysis.
- XRPD X-ray powder diffraction
- portion 2 of the solids was recovered for solution proton nuclear magnetic resonance spectroscopy ( 1 H-NMR) by pipetting to a clean glass vial and decanting off the liquid.
- the XRPD and 1 H-NMR samples were stored at ambient temperature in sealed vials prior to analysis.
- Compound I Form A ( ⁇ 180 mg, 0.3 mmol) was charged to a glass vial.
- the vial was left uncapped in a glass jar containing chloroform ( ⁇ 10 mL), for vapor stress of the solids.
- the solids were stressed for approximately 7 days before transfer to a freezer, where they remained under chloroform vapor.
- a summary of exemplary data presented in FIGS. 5 ( a ) through 5 ( y ) is as follows.
- Compound I Form I is a crystalline chloroform solvate of Compound I that converts to Form H under ambient conditions.
- the structure was solved for a crystal prepared from chloroform slurry. Based on Compound I Form I XRPD pattern from a sub sample of the bulk solids, it is believed the crystal was of Compound I Form I.
- the single crystal data (see FIGS. 5 ( g ) through 5 ( o )) indicate chloroform solvate, the structure consisting of layers of Compound I molecules separated by residual electron density believed to be free chloroform and pockets containing refined chloroform molecules.
- the DSC thermogram for Compound I Form I exhibits a broad endothermic event at approximately 74° C. and an endothermic event at approximately 100° C. (min). These events appear to be mainly related to desolvation, based on the weight loss of approximately 33% from 19 to 102° C. observed in the TGA thermogram (see FIG. 5 ( d )). This corresponds to more than 2 moles of chloroform.
- the TGA thermogram also exhibits weight loss prior to 19° C., which is likely due to residual chloroform; however, there appears to be a clear transition into the main weight loss.
- the DSC thermogram (see FIG. 5 ( c )) also exhibits an endotherm at approximately 258° C. (min).
- Compound I (56.4 mg) Form J was dissolved in methyl ethyl ketone (4.5 mL). The solution was filtered through a 0.2- ⁇ m nylon filter. The sample was placed in a vial capped with perforated aluminum foil (single pinhole) in a laboratory fume hood and allowed to evaporate to dryness under ambient conditions. The sample was stored under ambient conditions until indexed by single crystal X-ray. Crystallization may be performed using methods known to one of skill in the art.
- Compound I Form A (Sandoz lot 49800203, 1.03 g, 1.9 mmol) and methyl ethyl ketone (80 mL) were charged to an Erlenmeyer flask, briefly swirled and bath sonicated for a few minutes, producing a clear solution. Approximately half of the solution was filtered through a 0.2 ⁇ m nylon filter to a clean glass vial. The vial was capped and placed into a freezer, in order to precipitate solids from the solution. After approximately 5 days, the sample was removed from the freezer and the precipitated solids were isolated by decanting off the clear supernatant. The solids were stored wet with solvent in a freezer.
- a summary of exemplary data presented in FIGS. 6 ( a ) through 6 ( j ) is as follows.
- the single crystal structure of Compound I Form J confirmed the molecular structure and the contents of the unit cell.
- MEK solvate methyl ethyl ketone
- the structure of Compound I Form J (MEK solvate) consists of layers of Compound I molecules hydrogen bonded to neighboring Compound I molecule running perpendicular to the crystallographic c axis.
- the reflections in the experimental pattern of the acetone solvate (Compound I Form D) are represented in the calculated XRPD pattern of the MEK solvate (Compound I Form J), suggesting that the two forms may be isostructural (see Example 3).
- Compound I Form J is a crystalline methyl ethyl ketone solvate of Compound I.
- the experimental data for Compound I Form J is provided in FIGS. 6 ( a ) to 6 ( s ).
- the characterization of Compound I Form J is summarized in Table 9. TABLE 9 Characterization of Compound I Form J Analysis Result Figure References XRPD Form J 6(a) 6(m) DSC 130.3° C. (endo) 6(q) 260.0° C. (endo) FT-IR reference spectrum 6(n), 6(o) TGA Form J 6(r)
- Compound I (1.0652 g) was dissolved in 9:1 dioxane/water (10 mL). The solution was filtered through a 0.2- ⁇ m nylon filter, and frozen in a 300 mL round-bottom flask immersed in a bath of dry ice and isopropanol. The flask containing the frozen sample was attached to a lyophilizer and dried for approximately 4 days. After drying, the solids were isolated and stored in the freezer over desiccant until used.
- Exemplary data for amorphous Compound I in the form of XRPD's, modulated DSC thermogram, TGA, FT-IR, FT-Raman spectroscopy and 1 HNMR are depicted in FIGS. 7 ( a ) through 7 ( f ), supra.
- a summary of exemplary data e.g., a summary of XRPD results in Table 10.
- FIG. 7 ( a ) A high resolution XRPD pattern of amorphous Compound I is provided in FIG. 7 ( a ).
- the modulated DSC thermogram for amorphous Compound I (see FIG. 7 ( b )) exhibits a glass transition temperature at approximately 91° C. Weight loss of approximately 3.5% was observed in the TGA thermogram (see FIG. 7 ( c )).
- An FT-IR spectrum of amorphous Compound I see FIGS. 7 ( d ) and 7 ( e )
- an FT-Raman spectrum see FIG. 7 ( f )
- Compound I Form A (410 mg, 0.8 mmol) and nitromethane (20 mL) were charged to a glass vial and bath sonicated for several minutes, producing a clear solution.
- the solution was filtered through a 0.2 ⁇ m nylon filter to a clean glass vial and allowed to evaporate slowly (vial covered with perforated aluminum foil) in a laboratory fume hood. After approximately 12 days, the sample was split into approximately four equal portions to speed up the evaporation. The sample was continued as a slow evaporation for an additional 7 days. Two of the four vials were uncapped (fast evaporation) and allowed to evaporate overnight. The next day, a small amount of solvent was visible in only one of the samples. After the majority of the solvent was removed by decantation, the precipitated solids from the other three samples were pooled into the original sample. The recombined solids were stored in a sealed vial in a freezer.
- solutions were prepared in various solvents at ambient temperature and passed through a 0.2- ⁇ m nylon filter into a glass vial.
- the filtered solution was allowed to evaporate at ambient in a vial covered with aluminum foil perforated with one or more pinholes. Any solids formed were isolated and analyzed. From nitromethane by slow evaporation, solids obtained display an XRPD pattern for Compound I, Form K ( FIG. 8 ( a ).
- solutions were prepared with various solvents at ambient temperature and passed through a 0.2- ⁇ m nylon filter into a glass vial. This filled vial was placed in a glass vial containing an antisolvent and capped. In general, the anti-solvent is miscible with and, typically, more volatile than the solvent. The experiment was left undisturbed at ambient temperature. Any solids formed were isolated and analyzed.
- Two scale-up lyophilization attempts (approx. 2-g scale using dioxane/water 9:1 v/v) were performed.
- the first attempt generated a disordered crystalline material with evidence of peaks also found in Form A and Form K as determined by visual comparison of XRPD.
- the second attempt generated a disordered crystalline material with evidence of peaks also found in Form K by visual comparison.
- Compound I Form K is a crystalline nitromethane solvate of Compound I.
- the experimental data for Compound I Form K is provided in FIGS. 8 ( a ) to 8 ( l ).
- the characterization of Compound I Form K is summarized in Table 11. TABLE 11 Characterization of Compound I Form K Analysis Result Figure References XRPD Form K 8(a)-8(e), DSC 155.3° C. (endo) 8(i) 257.3° C. (endo) FT-IR reference spectrum 8(f), 8(g) TGA Form K 8(k)
- Compound I Form L is a crystalline methanole solvate of Compound I.
- the experimental data for Compound I Form L is provided in FIGS. 10 ( a ) to 10 ( i ).
- the characterization of Compound I Form L is summarized in Table 12. TABLE 12 Characterization of Compound I Form L Analysis Result Figure References XRPD Form L 10(a)-10(c) DSC 168.2° C. (endo) 10(g) 259.2° C. (endo) FT-IR reference spectrum 10(d), 10(e) TGA Form L 10(h)
- Compound I, Form N was vacuum dried at ambient temperature for approximately 5 hours, at approximately 50 mTorr, losing approximately 12.4% of the initial weight.
- the resulting solids were characterized by proton NMR spectroscopy. The spectrum showed that the solids contained approximately 1 ⁇ 3 mole nitromethane.
- the dried sample was characterized by DSC. The observed results are subject to the conditions used at the time of analysis.
- the DSC data collected in a crimped pan exhibits a minor endothermic event at approximately 150° C., which may be related to volatiles loss on heating, and an intense endotherm at approximately 256° C. (onset).
- Form A (1.6 g, estimated) was slurried in nitromethane (9 mL) for approximately 5 days. Solids were recovered via vacuum filtration and washed with nitromethane (2 ⁇ 1 mL). The solids were left on the filter under vacuum for several minutes. Approximately 1.3 g of solid were recovered. The solids exhibited a mixture of rectangular plates and prisms by polarized light microscopy. The resulting high-resolution XRPD pattern was consistent with Form N.
- the sample was characterized by DSC and TGA in an open pan configuration to ensure that solvent could freely leave during analysis.
- the observed results are subject to the conditions used at the time of analysis.
- the resulting DSC thermogram exhibits a broad endothermic event at approximately 161° C., with a shoulder at approximately 148° C. This event appears to be concurrent with the weight loss of approximately 4.9% from 130-160° C. observed in the TGA thermogram, which correlates to approximately 1 ⁇ 2 mole of nitromethane, assuming the weight loss is attributed only to solvent loss.
- the thermogram exhibits an endotherm at approximately 256-259° C. (onset). The final weight loss from TGA suggests that decomposition is concurrent with this endotherm.
- the proton NMR data for Form N suggests the material contains approximately 1 ⁇ 3 mole of nitromethane.
- the space group of the Form N solution (P2 1 2 1 2) can only exhibit less than one molecule of solvent in the asymmetric unit if the solvent position is partially occupied, i.e. some of the asymmetric units contain solvent molecules and others do not.
- the ambient temperature solubility data for the Compound I Form A are summarized in Table 15.
- the solids exhibited apparent solubilities of well over 100 mg/ml for dimethylformamide (DMF), dichloromethane (DCM) and 2,2,2-trifluoroethanol (TFE).
- the material exhibited moderate solubility (e.g., >10 mg/ml) in the majority of solvent and solvent combinations tested. The only exception was isopropanol (IPA) at 4.6 mg/mL.
- This example illustrates various components present in a representative formulation containing Compound I according to the present disclosure, which was formulated as a bulk solution batch using the following steps: (a) preparing a Compound I solid form; (b) preparing a compounding solution comprising tert-butyl alcohol and water; (c) combining Compound I solid form and the compounding solution to form a mixture; (d) adding povidone to the mixture; (e) adjusting the pH of the mixture by adding hydrochloric acid solution, resulting in a formulated solution; (f) performing sterile filtration of the formulated solution; and (g) lyophilizing the formulated solution under aseptic conditions, to yield a final composition comprising Compound I.
- the steps are detailed in Table 18 below.
- Vessel 1 a 20 gallon, jacketed, stainless steel vessel, was purged with nitrogen NF/EP.
- the required amount of tert-butyl alcohol was added to Vessel 1.
- the temperature of the tert-butyl alcohol and compounding vessel were adjusted to 28 to 32° C. in advance to maintain this raw material as a free-flowing liquid.
- WFI water for injection
- a portion (25%) of the compounding solution was transferred to a second, smaller, jacketed, stainless steel vessel (Vessel 2) for use in subsequent compounding steps. Both vessels were temperature controlled at 28 to 32° C., and Vessel 1 was maintained with a nitrogen NF/EP overlay.
- Compound I solid form drug substance was weighed in an isolator and then transferred directly to the compounding solution tank (Vessel 1) by way of a single-use, disposable isolator transfer bag, to form a drug substance solution.
- the transfer bag was rinsed 3 times with a portion of the compounding solution from Vessel 2 and each rinse was added to the compounding solution tank.
- the drug substance solution was mixed for 30 ⁇ 5 minutes at 28 to 32° C. Following dissolution of amorphous Compound I, the specified amount of povidone, USP, was added to the compounding vessel. The weighing container was rinsed once with a portion of the compounding solution and the rinse was transferred to the compounding tank that was mixed for 20 ⁇ 5 minutes at 28 to 32° C. to dissolve the povidone.
- the pH of the bulk solution was adjusted with a predetermined amount of 0.1 N HCl solution and was mixed for 10 ⁇ 2 minutes at 28 to 32° C. to form a formulated bulk solution.
- the formulated bulk solution was sampled and the apparent pH was verified to be between 3.6 and 4.0.
- the QS volume of compounding solution required to achieve the calculated target weight was transferred from Vessel 2 to Vessel 1.
- the formulated bulk solution was mixed for 10 ⁇ 2 minutes at 28 to 32° C. and then sampled for quality control (QC) testing, including appearance, assay, density, pH, and bioburden.
- the compounding tank was sealed, and the temperature was maintained at 28 to 32° C. until sterile filtration.
- the compounding tank containing the formulated bulk solution was moved from the Class 100,000 compounding suite to an anteroom adjacent to the Class 10,000 filling suite.
- the formulated bulk solution was transferred via a 3 ⁇ 8′′ stainless-steel braided Teflon® hose passed through a port in the wall of the sterile filling suite to the filling suite by over pressurization with sterile nitrogen, NF/EP.
- the formulated bulk solution was first clarified through a Millipore Opticap® filter (0.22 ⁇ m Durapore® membrane) and then was sterilized by filtration through a filter assembly located within the aseptic core containing 2 Millipore Millipak® 0.22 ⁇ m Durapore® filters in series, into a sterile receiving vessel.
- the integrity of the product sterilizing filters was tested for pressure and flow pre- and post-filtration using Isopropyl Water (IPA)/Water (60%/40%) as the wetting solution.
- IPA Isopropyl Water
- the minimum pressure hold value was 10 psi prior to filtration, and the maximum flow is 1.3 mL/min at 12 psi after filtration.
- the sterile-filtered formulated bulk solution was sampled for QC testing, including appearance, assay, density, and pH.
- a sterile lyophilization stopper was partially seated in the vial and each tray of filled vials was moved to the loading area for the lyophilizer within the Class 100 aseptic area. Trays were immediately loaded onto precooled shelves in the lyophilizer.
- Vials containing compositions were lyophilized under aseptic conditions using a preprogrammed lyophilization cycle.
- a summary of the lyophilization cycle process and controls is provided in Table 19.
- Product thermocouples ⁇ 40° C.
- Ramp shelf temperature down to Chamber pressure 15 psia 5 ⁇ 3° C.
- Seat stoppers 13 Product unloading
- Ramp shelf temperature up to Product thermocouples ⁇ 15° C. 20 ⁇ 3° C.
- Chamber pressure 14 psia Open chamber and unload 1 Total terminal drying time, including initial 2 hour hold, is 18 ⁇ 1 hours 2
- the shelf is cooled to 5 ⁇ 3° C. only if it is necessary to hold the product for an extended time prior to unloading.
- an additional step after the secondary drying following step 11 includes drying the vials at the temperature of 50° C. up to 24 hours at the pressure of 50 ⁇ m Hg. In another embodiment, an additional step includes drying the vials at the temperature of 50° C. up to 48 hours at the pressure of 50 ⁇ m Hg.
- an additional step after the secondary drying following step 11 includes drying the vials at the temperature of 60° C. up to 3 hours at the pressure of 100 ⁇ m Hg. In yet another embodiment, an additional step includes drying the vials at the temperature of 60° C. up to 6 hours at the pressure of 100 ⁇ m Hg. In another embodiment, an additional step includes drying the vials at the temperature of 60° C. up to 12 hours at the pressure of 100 ⁇ m Hg. In another embodiment, an additional step includes drying the vials at the temperature of 60° C. up to 24 hours at the pressure of 100 ⁇ m Hg. In another embodiment, an additional step includes drying the vials at the temperature of 60° C. up to 48 hours at the pressure of 100 ⁇ m Hg.
- an additional step after the secondary drying following step 11 includes drying the vials at the temperature of 70° C. up to 24 hours at the pressure of 25 mm Hg. In another embodiment, an additional step includes drying the vials at the temperature of 70° C. up to 48 hours at the pressure of 25 mm Hg.
- Vials containing compositions were sealed immediately following unloading from the lyophilization chamber. Each seal was imprinted with the Composition lot number using a video jet printer incorporated into the automated sealing line. Seal inspection is performed every 15 minutes during the sealing operation.
- any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Since such embodiments are deemed to be known to one of skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the compositions of the disclosure (e.g., any targeting moiety, any disease, disorder, and/or condition, any linking agent, any method of administration, any therapeutic application, etc.) can be excluded from any one or more claims, for any reason, whether or not related to the existence of prior art.
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US20100093610A1 (en) * | 2006-12-29 | 2010-04-15 | Vrolijk Nicholas H | Romidepsin-based treatments for cancer |
Families Citing this family (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE102011090178A1 (de) * | 2011-12-30 | 2013-07-04 | Lts Lohmann Therapie-Systeme Ag | Transdermales therapeutisches System mit geringer Neigung zur Spontankristallisation |
MX2014008390A (es) | 2012-01-12 | 2014-09-22 | Celgene Corp | Formulaciones de romidepsina y sus usos. |
AU2013202506B2 (en) | 2012-09-07 | 2015-06-18 | Celgene Corporation | Resistance biomarkers for hdac inhibitors |
CN103877010B (zh) * | 2012-12-21 | 2018-06-01 | 正大天晴药业集团股份有限公司 | 一种罗米地辛溶液的制备方法 |
WO2014102731A1 (en) * | 2012-12-31 | 2014-07-03 | Leiutis Pharmaceuticals Pvt. Ltd | Novel pharmaceutical compositions of romidepsin |
ITMI20131856A1 (it) * | 2013-11-08 | 2015-05-09 | Gnosis Spa | Processo per la preparazione di differenti forme cristalline del s-acetil glutatione e loro utilizzi in formulazioni farmaceutiche e nutraceutiche |
CN103861084A (zh) * | 2014-02-12 | 2014-06-18 | 新乡医学院 | Romidepsin在治疗帕金森病中的应用 |
CN104262456B (zh) * | 2014-09-11 | 2018-01-09 | 浙江海正药业股份有限公司 | 一种罗米地辛的新晶型及其制备方法和用途 |
US10669528B2 (en) | 2015-06-25 | 2020-06-02 | Children's Medical Center Corporation | Methods and compositions relating to hematopoietic stem cell expansion, enrichment, and maintenance |
US20190119642A1 (en) | 2016-03-15 | 2019-04-25 | Children's Medical Center Corporation | Methods and compositions relating to hematopoietic stem cell expansion |
CN105801667B (zh) * | 2016-03-22 | 2019-04-09 | 浙江海正药业股份有限公司 | 一种制备无定型罗米地辛的方法 |
CA3044573A1 (en) * | 2016-11-22 | 2018-05-31 | Alkalidx, Inc. | Therapies for the treatment of lidocaine-ineffective and hypokalemic conditions |
CN109796521B (zh) * | 2017-11-17 | 2022-04-19 | 上海医药工业研究院 | 一种罗米地辛醋酸盐晶型及其制备方法 |
CN111187337B (zh) * | 2018-11-15 | 2023-01-24 | 上海医药工业研究院 | 罗米地辛一异丙醇溶剂合物及其晶型、制备方法和应用 |
US20220049213A1 (en) * | 2018-12-24 | 2022-02-17 | Marrone Bio Innovations, Inc. | A method for increasing romidepsin production from fermentation broth |
WO2021253338A1 (zh) * | 2020-06-18 | 2021-12-23 | 中国科学院深圳先进技术研究院 | 罗米地辛在预防和治疗冠状病毒相关疾病中的应用 |
CN113813366A (zh) * | 2020-06-18 | 2021-12-21 | 中国科学院深圳先进技术研究院 | 罗米地辛在制备预防和治疗抗新冠肺炎新型冠状病毒的药物中的应用 |
Family Cites Families (99)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8817743D0 (en) | 1988-07-26 | 1988-09-01 | Fujisawa Pharmaceutical Co | Fr901228 substance & preparation thereof |
US5143854A (en) | 1989-06-07 | 1992-09-01 | Affymax Technologies N.V. | Large scale photolithographic solid phase synthesis of polypeptides and receptor binding screening thereof |
US5545522A (en) | 1989-09-22 | 1996-08-13 | Van Gelder; Russell N. | Process for amplifying a target polynucleotide sequence using a single primer-promoter complex |
JPH0764872A (ja) | 1993-08-26 | 1995-03-10 | Fujitsu Ten Ltd | データ記憶制御装置 |
US5578832A (en) | 1994-09-02 | 1996-11-26 | Affymetrix, Inc. | Method and apparatus for imaging a sample on a device |
US5605793A (en) | 1994-02-17 | 1997-02-25 | Affymax Technologies N.V. | Methods for in vitro recombination |
US5837458A (en) | 1994-02-17 | 1998-11-17 | Maxygen, Inc. | Methods and compositions for cellular and metabolic engineering |
US6117679A (en) | 1994-02-17 | 2000-09-12 | Maxygen, Inc. | Methods for generating polynucleotides having desired characteristics by iterative selection and recombination |
US5556752A (en) | 1994-10-24 | 1996-09-17 | Affymetrix, Inc. | Surface-bound, unimolecular, double-stranded DNA |
US6777217B1 (en) | 1996-03-26 | 2004-08-17 | President And Fellows Of Harvard College | Histone deacetylases, and uses related thereto |
US5776905A (en) | 1996-08-08 | 1998-07-07 | The Board Of Trustees Of The Leland Stamford Junior University | Apoptotic regression of intimal vascular lesions |
US6124495A (en) | 1997-03-11 | 2000-09-26 | Beacon Laboratories, Inc. | Unsaturated oxyalkylene esters and uses thereof |
US6030961A (en) | 1997-03-11 | 2000-02-29 | Bar-Ilan Research & Development Co., Ltd. | Oxyalkylene phosphate compounds and uses thereof |
JP3494624B2 (ja) | 1997-09-02 | 2004-02-09 | 住友製薬株式会社 | 新規な環状テトラペプチド誘導体とその医薬用途 |
JPH11335375A (ja) | 1998-05-20 | 1999-12-07 | Mitsui Chem Inc | ヒストン脱アセチル化酵素阻害作用を有するベンズアミド誘導体 |
US6214986B1 (en) | 1998-10-07 | 2001-04-10 | Isis Pharmaceuticals, Inc. | Antisense modulation of bcl-x expression |
US20070148228A1 (en) | 1999-02-22 | 2007-06-28 | Merrion Research I Limited | Solid oral dosage form containing an enhancer |
US6723338B1 (en) | 1999-04-01 | 2004-04-20 | Inex Pharmaceuticals Corporation | Compositions and methods for treating lymphoma |
EA200601252A1 (ru) | 1999-09-08 | 2006-10-27 | Слоан-Кеттеринг Инститьют Фор Кэнсер Рисёч | Новый класс веществ, вызывающих дифференцировку клеток и являющихся ингибиторами гистондеацетилазы, и способы их применения |
US6828302B1 (en) | 1999-12-08 | 2004-12-07 | Xcyte Therapies, Inc. | Therapeutic uses of depsipeptides and congeners thereof |
ATE353663T1 (de) | 1999-12-08 | 2007-03-15 | Cyclacel Pharmaceuticals Inc | Verwendung von depsipeptide und deren analoge als immunosuppressiva zur behandlung von infektionskrankheiten, autoimmunerkrankungen, allergien und hyperproliferativer hautkrankheiten |
CA2317003A1 (en) | 2000-02-28 | 2001-08-28 | Hidenori Nakajima | Gene expression potentiator |
JP2001348340A (ja) | 2000-06-07 | 2001-12-18 | Yamanouchi Pharmaceut Co Ltd | ヒストン脱アセチル化酵素阻害剤 |
ATE425177T1 (de) | 2000-07-17 | 2009-03-15 | Astellas Pharma Inc | Reduziertes fk228 und seine verwendung |
WO2002015921A2 (en) * | 2000-08-18 | 2002-02-28 | The Governement Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Methods of treating cutaneous and peripheral t-cell lymphoma by a histone deacetylase inhibitor |
EP1313872A1 (en) * | 2000-09-01 | 2003-05-28 | Fujisawa Pharmaceutical Co., Ltd. | A method of producing fr901228 |
WO2002055017A2 (en) | 2000-11-21 | 2002-07-18 | Wake Forest University | Method of treating autoimmune diseases |
EP1356053A2 (en) | 2001-01-10 | 2003-10-29 | THE GOVERNMENT OF THE UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES | Histone deacetylase inhibitors in diagnosis and treatment of thyroid neoplasms |
EP1353693B1 (en) * | 2001-01-16 | 2005-03-16 | Glaxo Group Limited | Pharmaceutical combination containing a 4-quinazolineamine and paclitaxel, carboplatin or vinorelbine for the treatment of cancer |
US7219016B2 (en) | 2001-04-20 | 2007-05-15 | Yale University | Systems and methods for automated analysis of cells and tissues |
US6905669B2 (en) | 2001-04-24 | 2005-06-14 | Supergen, Inc. | Compositions and methods for reestablishing gene transcription through inhibition of DNA methylation and histone deacetylase |
ES2310213T3 (es) | 2001-05-02 | 2009-01-01 | The Regents Of The University Of California | Procedimiento para tratar trastornos neurodegenerativos, psiquiatricos y otros trastornos con inhibidores de desacetilasa. |
ES2349349T3 (es) | 2001-05-30 | 2010-12-30 | The Regents Of The University Of Michigan | Asociacion sinergica de (-)-gosipol con docetaxel o paclitaxel para el tratamiento de cancer. |
US7171311B2 (en) | 2001-06-18 | 2007-01-30 | Rosetta Inpharmatics Llc | Methods of assigning treatment to breast cancer patients |
PT1426054E (pt) | 2001-08-21 | 2011-12-06 | Astellas Pharma Inc | Utilização medicinal de inibidor da histona desacetilase e método de avaliação do seu efeito antitumoral |
US20040259772A1 (en) | 2001-08-24 | 2004-12-23 | Antonio Fojo | Use of a histone deacetylase inhibitor to increase the entry of an adenoviral agent into a cell |
EP1293205A1 (en) | 2001-09-18 | 2003-03-19 | G2M Cancer Drugs AG | Valproic acid and derivatives thereof for the combination therapy of human cancers, for the treatment of tumour metastasis and minimal residual disease |
US6706686B2 (en) | 2001-09-27 | 2004-03-16 | The Regents Of The University Of Colorado | Inhibition of histone deacetylase as a treatment for cardiac hypertrophy |
US20050123896A1 (en) | 2001-10-25 | 2005-06-09 | Benz Christopher C. | Screening system for modulators of her2 mediated transcription and her2 modulators identified thereby |
US7354928B2 (en) | 2001-11-01 | 2008-04-08 | The Regents Of The University Of Michigan | Small molecule inhibitors targeted at Bcl-2 |
AU2002351898A1 (en) | 2001-12-21 | 2003-07-09 | Universite Libre De Bruxelles | Method for obtaining the elimination of integrated and functional viruses from infected mammal cells |
US20030134423A1 (en) | 2002-01-04 | 2003-07-17 | Chu Yong Liang | Compounds for delivering substances into cells |
JP2005525345A (ja) | 2002-02-15 | 2005-08-25 | スローン−ケッタリング・インスティテュート・フォー・キャンサー・リサーチ | Trx媒介性疾患を処置する方法 |
AU2003211576A1 (en) | 2002-02-20 | 2003-09-09 | Sueharu Horinouchi | Histone deacetylase inhibitors and process for producing the same |
AU2003213684C1 (en) | 2002-03-04 | 2008-10-23 | Merck Hdac Research, Llc | Methods of inducing terminal differentiation |
AU2003226014A1 (en) | 2002-03-28 | 2003-10-13 | Brigham And Women's Hospital, Inc. | Histone deacetylase inhibitors for the treatment of multiple sclerosis, amyotrophic lateral sclerosis and alzheimer's disease |
CA2481466A1 (en) | 2002-04-05 | 2003-10-16 | Yoshinori Naoe | Depsipeptide for therapy of kidney cancer |
WO2003088954A1 (en) | 2002-04-15 | 2003-10-30 | Sloan-Kettering Institute For Cancer Research | Combination therapy for the treatment of cancer |
US6809118B2 (en) | 2002-07-25 | 2004-10-26 | Yih-Lin Chung | Methods for therapy of radiation cutaneous syndrome |
US20040002447A1 (en) | 2002-06-04 | 2004-01-01 | Regents Of The University Of California | Induction of insulin expression |
WO2004009771A2 (en) | 2002-07-24 | 2004-01-29 | Advanced Stent Technologies, Inc. | Stents capable of controllably releasing histone deacetylase inhibitors |
EP1547617B1 (en) | 2002-08-20 | 2010-04-28 | Astellas Pharma Inc. | Arthrodial cartilage extracellular matrix degradation inhibitor |
CA2498210C (en) | 2002-09-13 | 2011-10-18 | Virginia Commonwealth University | Combination of a) n-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine and b) a histone deacetylase inhibitor for the treatment of leukemia |
SE0300098D0 (sv) | 2003-01-15 | 2003-01-15 | Forskarpatent I Syd Ab | Use of cyclin D1 inhibitors |
WO2004064727A2 (en) | 2003-01-16 | 2004-08-05 | Georgetown University | Method of cancer treatment using hdac inhibitors |
EP1595952A4 (en) | 2003-02-19 | 2008-05-21 | Astellas Pharma Inc | METHOD FOR EVALUATING THE ANTITUMOR EFFECT OF A HISTONE DEACETYLASE INHIBITOR |
WO2004096289A1 (ja) | 2003-04-25 | 2004-11-11 | Fujisawa Pharmaceutical Co | 遺伝子導入効率増強剤 |
US20040213826A1 (en) | 2003-04-28 | 2004-10-28 | Marx Steven O. | Medical devices and methods for inhibiting proliferation of smooth muscle cells |
EP1491188A1 (en) | 2003-06-25 | 2004-12-29 | G2M Cancer Drugs AG | Topical use of valproic acid for the prevention or treatment of skin disorders |
CA2529840A1 (en) | 2003-06-27 | 2005-01-06 | Astellas Pharma Inc. | Therapeutic agent for soft tissue sarcoma |
ME00294B (me) | 2003-07-23 | 2011-05-10 | Bayer Pharmaceuticals Corp | Fluoro supstituisana omega-karaboksiaril difenil urea za liječenje i prevenciju bolesti i stanja bolesti |
EP1663194B1 (en) | 2003-08-26 | 2010-03-31 | Merck HDAC Research, LLC | Use of SAHA for treating mesothelioma |
CN102349927A (zh) | 2003-08-29 | 2012-02-15 | Hdac默克研究有限责任公司 | 联合治疗癌症的方法 |
US20050059682A1 (en) | 2003-09-12 | 2005-03-17 | Supergen, Inc., A Delaware Corporation | Compositions and methods for treatment of cancer |
BRPI0414568A (pt) | 2003-09-18 | 2006-11-07 | Combinatorx Inc | combinações de drogas para o tratamento de neoplasmas |
ES2344899T3 (es) | 2003-09-25 | 2010-09-09 | Astellas Pharma Inc. | Agente antitumoral que comprende un inhibidor de histona desacetilasa y un inhibidor de topoisomerasa ii. |
US8614318B2 (en) | 2003-11-13 | 2013-12-24 | Abbvie Inc. | Apoptosis promoters |
EP1689446B1 (de) | 2003-11-14 | 2015-01-07 | Per Sonne Holm | Neue adenoviren, dafür codierende nukleinsäuren und deren verwendung |
CA2546178A1 (en) | 2003-11-14 | 2005-06-09 | Per Sonne Holm | New use of adenovirus and nucleic acids coding therefor |
WO2005053609A2 (en) | 2003-11-26 | 2005-06-16 | Guilford Pharmaceuticals Inc. | Methods of nad+-dependent deacetylase inhibitors |
WO2005058298A2 (en) | 2003-12-10 | 2005-06-30 | Wisconsin Alumni Research Foundation | Fk228 analogs and their use as hdac-inhibitors |
US7951780B2 (en) | 2004-02-25 | 2011-05-31 | Astellas Pharma Inc. | Antitumor agent |
US20050187148A1 (en) | 2004-02-25 | 2005-08-25 | Yoshinori Naoe | Antitumor agent |
CA2557568C (en) | 2004-02-27 | 2014-05-27 | Jane Trepel | Pharmacodynamic assays using flow cytometry |
GB0405349D0 (en) | 2004-03-10 | 2004-04-21 | Univ Birmingham | Cancer therapy and medicaments therefor |
ES2308065T3 (es) | 2004-04-30 | 2008-12-01 | Topotarget Germany Ag | Formulacion que comprende un inhibidor de histona desacetilasa, que exhibe una liberacion bifasica. |
ITMI20040876A1 (it) | 2004-04-30 | 2004-07-30 | Univ Degli Studi Milano | Inibitori delle istone deacetilasi-hdac-quali agenti ipolipidemizzati per la terapia e la prevenzione dell'arteriosclerosi e malattie cardiovascolari |
US20050261174A1 (en) | 2004-05-20 | 2005-11-24 | Paul Lewer | Insecticidal activity of a cyclic peptide |
WO2005117930A2 (en) | 2004-06-04 | 2005-12-15 | Sloan-Kettering Institute For Cancer Research | Use of thioredoxin measurements for diagnostics and treatments |
US7470722B2 (en) | 2004-06-10 | 2008-12-30 | Kalypsys, Inc. | Multicyclic sulfonamide compounds as inhibitors of histone deacetylase for the treatment of disease |
US20060018921A1 (en) | 2004-07-16 | 2006-01-26 | Baylor College Of Medicine | Histone deacetylase inhibitors and cognitive applications |
WO2006027346A2 (en) | 2004-09-06 | 2006-03-16 | Altana Pharma Ag | Novel pyrazolopyrimidines |
EP1812036A2 (en) | 2004-11-17 | 2007-08-01 | The University Of Chicago | Histone deacetylase inhibitors and methods of use |
WO2006060382A2 (en) | 2004-11-30 | 2006-06-08 | Trustees Of The University Of Pennsylvania | Use of hdac and/or dnmt inhibitors for treatment of ischemic injury |
WO2006060429A2 (en) | 2004-12-03 | 2006-06-08 | Novartis Ag | Identification of variants in histone deacetylase 1 (hdac1) to predict drug response |
US20060128660A1 (en) | 2004-12-10 | 2006-06-15 | Wisconsin Alumni Research Foundation | FK228 analogs and methods of making and using the same |
GB0511266D0 (en) | 2005-06-02 | 2005-07-13 | Trust | Chemical compounds |
EP1743654A1 (en) | 2005-07-15 | 2007-01-17 | TopoTarget Germany AG | Use of inhibitors of histone deacetylases in combination with NSAID for the therapy of cancer and/or inflammatory diseases |
WO2007040522A1 (en) | 2005-09-30 | 2007-04-12 | The Ohio State Research Foundation | Antitumor agents |
TW200800354A (en) * | 2005-10-28 | 2008-01-01 | Kyowa Hakko Kogyo Kk | Concentration crystallizer and method |
WO2007058896A2 (en) | 2005-11-10 | 2007-05-24 | Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Materials and methods for abcb1 polymorphic variant screening, diagnosis, and treatment |
CA2630216A1 (en) | 2005-11-18 | 2007-05-31 | Gloucester Pharmaceuticals, Inc. | Metabolite derivatives of the hdac inhibitor fk228 |
CA2650520A1 (en) | 2006-04-24 | 2008-01-31 | Gloucester Pharmaceuticals | Treatment of ras-expressing tumors |
US8957027B2 (en) | 2006-06-08 | 2015-02-17 | Celgene Corporation | Deacetylase inhibitor therapy |
WO2007146234A2 (en) | 2006-06-09 | 2007-12-21 | Merrion Research Ii Limited | Solid oral dosage form containing an enhancer |
US7857804B2 (en) | 2006-09-01 | 2010-12-28 | Mccaffrey Timothy A | Use of Bcl inhibitors for the prevention of fibroproliferative reclosure of dilated blood vessels and other iatrogenic fibroproliferative disorders |
JP2010514801A (ja) * | 2006-12-29 | 2010-05-06 | グラスター ファーマシューティカルズ, インコーポレイテッド | ロミデプシンの精製 |
BRPI0720734A2 (pt) | 2006-12-29 | 2014-01-07 | Gloucester Pharmaceuticals Inc | Preparação da romidepsina |
CN102276689A (zh) | 2011-05-09 | 2011-12-14 | 中国药科大学 | 组蛋白去乙酰化酶抑制剂fk228的化学合成方法及其应用 |
-
2011
- 2011-07-12 CA CA2804795A patent/CA2804795A1/en not_active Abandoned
- 2011-07-12 CN CN2011800437821A patent/CN103108648A/zh active Pending
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- 2011-07-12 AU AU2011279303A patent/AU2011279303B2/en not_active Ceased
- 2011-07-12 UA UAA201301639A patent/UA114074C2/uk unknown
- 2011-07-12 SG SG2013002266A patent/SG187032A1/en unknown
- 2011-07-12 EP EP11739216.7A patent/EP2593123B1/en active Active
-
2014
- 2014-05-19 US US14/281,654 patent/US8980825B2/en active Active
- 2014-07-22 US US14/338,278 patent/US20140336132A1/en not_active Abandoned
-
2015
- 2015-02-05 US US14/615,384 patent/US9518094B2/en active Active
- 2015-11-10 US US14/937,804 patent/US9624271B2/en active Active
-
2016
- 2016-07-28 JP JP2016147920A patent/JP6490632B2/ja active Active
-
2018
- 2018-12-04 JP JP2018227150A patent/JP2019052177A/ja active Pending
Non-Patent Citations (3)
Title |
---|
Molife et al., "Phase II, two-stage, single-arm trial of the histone deacetylase inhibitor (HDACi) romidepsin in metastatic castration-resistant prostate cancer (CRPC)," Ann. Oncol. pp. 1-5 (epublished July 16, 2009) * |
Sheehan and Liapis, "Modeling of the Primary and Secondary Drying Stages of the Freeze Drying of Pharmaceutical Products in Vials: Numerical Results Obtained from the Solution of a Dynamic and Spatially Multi-Dimensional Lyophilization Model for Different Operational Policies", Biotech. Bioeng. 60: 712-728 (1998)) * |
Wang, "Lyophilization and development of solid protein pharmaceuticals", Int. J. Pharmaceut. 203:1-60 (2000) * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20100093610A1 (en) * | 2006-12-29 | 2010-04-15 | Vrolijk Nicholas H | Romidepsin-based treatments for cancer |
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