WO2022266311A1 - PARPi-FL FORMULATIONS - Google Patents

PARPi-FL FORMULATIONS Download PDF

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Publication number
WO2022266311A1
WO2022266311A1 PCT/US2022/033772 US2022033772W WO2022266311A1 WO 2022266311 A1 WO2022266311 A1 WO 2022266311A1 US 2022033772 W US2022033772 W US 2022033772W WO 2022266311 A1 WO2022266311 A1 WO 2022266311A1
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formulation
pharmaceutically acceptable
forming
parp inhibitor
pharmaceutical composition
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PCT/US2022/033772
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French (fr)
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Christian Brand
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Summit Biomedical Imaging
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/22—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
    • A61K49/0052—Small organic molecules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
    • A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
    • A61K49/0076—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form dispersion, suspension, e.g. particles in a liquid, colloid, emulsion
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
    • G01N33/582—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances with fluorescent label
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/91—Transferases (2.)
    • G01N2333/912—Transferases (2.) transferring phosphorus containing groups, e.g. kinases (2.7)
    • G01N2333/91205—Phosphotransferases in general
    • G01N2333/91245—Nucleotidyltransferases (2.7.7)

Definitions

  • the technology relates to stable formulations of PARPi-FL that show enhanced properties for use in the detection of cancers, including cancer of the oral cavity.
  • Cancer is a set of disease that are marked by abnormal cell growth. Cancer affects millions of people and results in millions of deaths annually. Early detection of cancer is critical to enabling better patient outcomes. Later diagnosis allows cancer more time to grow and potentially metastasize, leading to worse patient outcomes.
  • PARP inhibitors include several commercial drugs, including olaparib.
  • U.S. Patent No. 7,151,102 describes phthalazinone derivatives that can be PARP inhibitors.
  • U.S. Patent No. 7,449,464 describes phthalazinone derivatives that can be PARP inhibitors.
  • U.S. Patent No. 7,981,889 describes phthalazinone derivatives that can be PARP inhibitors.
  • PARP inhibitors are known to treat certain cancers.
  • phthalazinone derivatives that can be used to treat certain cancers.
  • U.S. Patent No. 8,247,416 describes phthalazinone derivatives that can be used to treat certain cancers.
  • U.S. Patent No. 8,475,842 describes phthalazinone derivatives that can be used to treat certain cancers.
  • U.S. Patent No. 8,859,562 describes phthalazinone derivatives that can be used to treat certain cancers.
  • U.S. Patent No. 8,912,187 describes phthalazinone derivatives that can be used to treat certain cancers.
  • Modified PARP inhibitors including PARP inhibitors that have been modified with fluorescence tags, can be used to detect cancer.
  • U.S. Patent No. 9,649,394 describes modified PARP inhibitors that can be used to detect cancer.
  • U.S. Patent No. 10,117,954 describes modified PARP inhibitors that can be used to detect cancer.
  • PCT Publication No. WO2016164771 describes modified PARP inhibitors that can be used to detect cancer.
  • Modified PARP inhibitors including PARP inhibitors that have been modified with fluorescence tags, have been formulated for use in detecting cancer.
  • PCT Publication No. WO2016164771 describes formulations of modified PARP inhibitors, including PARPi-FL (75nmol) in phosphate buffered saline (167 m ⁇ ) with 30% PEG300 by volume.
  • compositions are described as having, including, or comprising specific components, or where methods are described as having, including, or comprising specific steps, it is contemplated that there are also compositions of the present invention that consist essentially of, or consist of the recited components, and that there are methods according to the present invention that consist essentially of, or consist of the recited steps.
  • the present invention uses a PARP inhibitor molecule with a fluorescent tag to detect the presence of cancer either in vivo or ex vivo.
  • the PARP inhibitors selected from the group comprising AZD2281, AG014699 (rucaparib), ABT888 (veliparib), BSI201 (iniparib), BSI101, DR2313, FR 247304, GPH15427, GPI16539, M 4827, NU1025, NU1064, NU1085, PD128763, PARP Inhibitor II (INH2BP), PARP Inhibitor m (DPQ), PARP Inhibitor VHI (PJ34), PARP Inhibitor IX (EB-47), and TIQ-A.
  • the PARP inhibitor molecule is a derivative of olaparib that has been modified to have a fluorescence tag, where a fluorescence tag is a moiety that fluoresces.
  • the molecule is PARPi-FL, the molecule in Fig. 1.
  • PARPi-FL can also be referred to as (T-4)-[4-[[3-[[4-[3-[5-[(3,5-Dimethyl- 2H-pyrrol-2-ylidene-KN)methyl]-lH-pyrrol-2-yl-KN-l-oxopropyl]-l-piperazinyl]carbonyl]-4- fluorophenyl]methyl]-l(2H)-phthalazinonato]difluoroboron.
  • a person of ordinary skill in the art will appreciate that many PARP inhibitors exist and that many fluorescence tags exist and may combine them to make a PARP inhibitor molecule with a fluorescence tag as contemplated by this invention.
  • the PARP inhibitor with a fluorescence tag binds to cancers that overexpress PARP, including but not limited to oral, cervical, esophageal, lung, skin, colorectal, and breast.
  • the PARP inhibitor molecule with a fluorescence tag may be administered topically, intravenously, orally, or applied to liquid or solid samples outside of a patient's body.
  • the PARP inhibitor molecule is delivered in a formulation.
  • the formulation is either a liquid or a solid.
  • the formulation is a liquid, gel, paste, spray, cream, lozenge, rinse, sachet, film, tablet, pill, aerosol, emulsion, or other pharmaceutically acceptable delivery system.
  • the formulation may be immediate, extended, or modified release.
  • the formulation may contain an excipient.
  • excipients include: surfactants, buffering agents, disintegrants (including super disintegrants), bulking agents, solubilizing agents, flavoring agents, diluents, binders, granulating agents, compression aides, glidants, lubricants, coloring agents, coating agents, agents controlling release, anti-caking agents, pH modifiers, free radical scavengers, and stabilizers.
  • the formulation is a liquid.
  • the liquid formulation contains a solvent, which may be any pharmacologically acceptable solvent liquid, including: water, ethanol, glycerol or mixtures thereof.
  • the liquid formulation contains an excipient. If an excipient is present in the formulation it may be selected from pharmacologically acceptable excipients.
  • the excipient is a pharmacologically acceptable polyethylene glycol.
  • Polyethylene glycols are a class of hydrophilic polyether that are commonly used as excipients in pharmaceutical formulations.
  • the excipient is PEG3350, a polyethylene glycol with an average M n of 3,350 g/mol.
  • M n number average molecular weight
  • the formulation is a solid.
  • the solid formulation is prepared either by lyophilization, spray drying, or evaporation.
  • the solid formulation contains an excipient. If an excipient is present in the formulation it may be selected from pharmacologically acceptable excipients.
  • the excipient is a pharmacologically acceptable polyethylene glycol.
  • the excipient is PEG3350.
  • a liquid formulation is made by reconstituting a solid formulation. Such reconstitution may comprise combining a solid formulation with a liquid formulation to dissolve or suspend the solid in the liquid.
  • a solid formulation containing the PARP inhibitor molecule is reconstituted by adding a liquid to the solid, which can be followed by agitation to ensure dissolution of the solid.
  • a liquid formulation containing the PARP inhibitor molecule may contain excipients, including PEG3350.
  • Headers are provided for convenience and are not intended to limit the content or applicability of the material contained therein.
  • Figure 1 shows a fluorescent biomarker molecule, PARPi-FL.
  • Figure 2 shows white light illumination of FaDu cells in phosphate buffered saline.
  • the image was collected with a Dino-Lite GFBW using LED based white light illumination.
  • All three vials which contain a control of cells in phosphate buffered saline, cells incubated in phosphate buffered saline with PARPi-FL and PEG3350, and cells incubated in phosphate buffered saline with PARPi-FL and PEG300, show solutions that contain FaDu cells.
  • Figure 3 shows fluorescence imaging of FaDu cells in phosphate buffered saline.
  • the image was collected with a Dino-Lite GFBW collecting fluorescence from the illuminated samples.
  • the vial that contains a control of cells in phosphate buffered saline does not show any appreciable fluorescence.
  • Figure 4 tabulates fluorescence intensity from the three samples - a control of cells in phosphate buffered saline, cells incubated in phosphate buffered saline with PARPi-FL and PEG3350, and cells incubated in phosphate buffered saline with PARPi-FL and PEG300.
  • control is labelled "PBS”
  • the cells incubated in phosphate buffered saline with PARPi-FL and PEG3350 is labelled “PEG3350”
  • the cells incubated in phosphate buffered saline with PARPi-FL and PEG300 are labelled "PEG300”.
  • Example 1 - FaDu cells were prepared in 900 m ⁇ of phosphate buffered saline. FaDu cells (P-4, 95% confluent) were prepared in 6 mL of phosphate buffered saline (250 m ⁇ were replated for additional experiments). 1.5 mL Eppendorf vials were charged with FaDu solution (900 m ⁇ in phosphate buffered saline) to prepare a control, a sample with PARPi-FL (1000 nM) in 30% by weight PEG3350 in phosphate buffered saline, and a sample with PARPi-FL (1000 nM) in 30% by weight PEG300 in PBS.
  • FaDu solution 900 m ⁇ in phosphate buffered saline
  • the PARPi-FL containing solutions were diluted to 100 nM of PARPi-FL in 1.0 mL. Samples were incubated for 5 min at room temperature and then spun at 1,400 RPM for 3 min. The supernatants were removed. 900 m ⁇ of phosphate buffered saline was added to break up the cell pellet. The samples were then centrifuged at 1,400 RPM for 3 min and the supernatants were removed. 900 m ⁇ . of phosphate buffered saline was again added to break up the cell pellet. The samples were then centrifuged at 1,400 RPM for 3 min and the supernatants were removed. Imaging of the cells was performed with a Dino-Lite GFBW. The PEG3350 formulation showed higher fluorescence intensity than the PEG300 formulation, both of which showed higher fluorescence intensity than the PBS control.

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Abstract

The present invention provides stable formulations of fluorescence labelled PARR inhibitors, including PARPi-FL, that exhibit favorable properties, for use in the detection of cancers, including cancer of the oral cavity.

Description

PARPi-FL Formulations
Claim of Priority
This application claims priority under 35 U.S.C. §119(e) to U.S. Patent Application Serial No. 63/211,049, filed on June 16, 2021, which is incorporated herein by reference in its entirety.
Technical Field
The technology relates to stable formulations of PARPi-FL that show enhanced properties for use in the detection of cancers, including cancer of the oral cavity.
Statement Regarding Federally Sponsored Research or Development
The present invention was made with U.S. government support under Grant No. 1R42CA254776-01A1 awarded by the National Cancer Institute. The Government has certain rights in the invention.
Background Art
Cancer is a set of disease that are marked by abnormal cell growth. Cancer affects millions of people and results in millions of deaths annually. Early detection of cancer is critical to enabling better patient outcomes. Later diagnosis allows cancer more time to grow and potentially metastasize, leading to worse patient outcomes.
Some cancers, including many solid tumors, overexpress Poly-ADP Ribose Polymerase (PARP), a DNA-repair enzyme. Inhibition of PARP has been used as a therapeutic modality for treating various cancers. PARP inhibitors include several commercial drugs, including olaparib. U.S. Patent No. 7,151,102 describes phthalazinone derivatives that can be PARP inhibitors. U.S. Patent No. 7,449,464 describes phthalazinone derivatives that can be PARP inhibitors. U.S. Patent No. 7,981,889 describes phthalazinone derivatives that can be PARP inhibitors. PARP inhibitors are known to treat certain cancers. U.S. Patent No. 8,143,241 describes phthalazinone derivatives that can be used to treat certain cancers. U.S. Patent No. 8,247,416 describes phthalazinone derivatives that can be used to treat certain cancers. U.S. Patent No. 8,475,842 describes phthalazinone derivatives that can be used to treat certain cancers. U.S. Patent No. 8,859,562 describes phthalazinone derivatives that can be used to treat certain cancers. U.S. Patent No. 8,912,187 describes phthalazinone derivatives that can be used to treat certain cancers.
Modified PARP inhibitors, including PARP inhibitors that have been modified with fluorescence tags, can be used to detect cancer. U.S. Patent No. 9,649,394 describes modified PARP inhibitors that can be used to detect cancer. U.S. Patent No. 10,117,954 describes modified PARP inhibitors that can be used to detect cancer. PCT Publication No. WO2016164771 describes modified PARP inhibitors that can be used to detect cancer.
Modified PARP inhibitors, including PARP inhibitors that have been modified with fluorescence tags, have been formulated for use in detecting cancer. PCT Publication No. WO2016164771 describes formulations of modified PARP inhibitors, including PARPi-FL (75nmol) in phosphate buffered saline (167 mί) with 30% PEG300 by volume.
The mention herein of any publication, is not an admission that the publication serves as prior art with respect to any of the claims herein. The Background section is presented for purposes of clarity and is not meant as a description of prior art with respect to any claim. Summary of Invention
Herein, where compositions are described as having, including, or comprising specific components, or where methods are described as having, including, or comprising specific steps, it is contemplated that there are also compositions of the present invention that consist essentially of, or consist of the recited components, and that there are methods according to the present invention that consist essentially of, or consist of the recited steps.
It should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable.
It should be understood that two or more steps or actions in a method may be performed simultaneously.
The present invention uses a PARP inhibitor molecule with a fluorescent tag to detect the presence of cancer either in vivo or ex vivo.
In a preferred embodiment, the PARP inhibitors selected from the group comprising AZD2281, AG014699 (rucaparib), ABT888 (veliparib), BSI201 (iniparib), BSI101, DR2313, FR 247304, GPH15427, GPI16539, M 4827, NU1025, NU1064, NU1085, PD128763, PARP Inhibitor II (INH2BP), PARP Inhibitor m (DPQ), PARP Inhibitor VHI (PJ34), PARP Inhibitor IX (EB-47), and TIQ-A. In a preferred embodiment, the PARP inhibitor molecule is a derivative of olaparib that has been modified to have a fluorescence tag, where a fluorescence tag is a moiety that fluoresces. In a more preferred embodiment, the molecule is PARPi-FL, the molecule in Fig. 1. PARPi-FL can also be referred to as (T-4)-[4-[[3-[[4-[3-[5-[(3,5-Dimethyl- 2H-pyrrol-2-ylidene-KN)methyl]-lH-pyrrol-2-yl-KN-l-oxopropyl]-l-piperazinyl]carbonyl]-4- fluorophenyl]methyl]-l(2H)-phthalazinonato]difluoroboron. A person of ordinary skill in the art will appreciate that many PARP inhibitors exist and that many fluorescence tags exist and may combine them to make a PARP inhibitor molecule with a fluorescence tag as contemplated by this invention.
In a preferred embodiment the PARP inhibitor with a fluorescence tag binds to cancers that overexpress PARP, including but not limited to oral, cervical, esophageal, lung, skin, colorectal, and breast.
In a preferred embodiment, the PARP inhibitor molecule with a fluorescence tag may be administered topically, intravenously, orally, or applied to liquid or solid samples outside of a patient's body. In a preferred embodiment, the PARP inhibitor molecule is delivered in a formulation.
In a preferred embodiment, the formulation is either a liquid or a solid.
In a preferred embodiment, the formulation is a liquid, gel, paste, spray, cream, lozenge, rinse, sachet, film, tablet, pill, aerosol, emulsion, or other pharmaceutically acceptable delivery system.
In a preferred embodiment, the formulation may be immediate, extended, or modified release.
In a preferred embodiment, the formulation may contain an excipient. Some pharmaceutically acceptable excipients include: surfactants, buffering agents, disintegrants (including super disintegrants), bulking agents, solubilizing agents, flavoring agents, diluents, binders, granulating agents, compression aides, glidants, lubricants, coloring agents, coating agents, agents controlling release, anti-caking agents, pH modifiers, free radical scavengers, and stabilizers.
In a preferred embodiment, the formulation is a liquid. In another preferred embodiment, the liquid formulation contains a solvent, which may be any pharmacologically acceptable solvent liquid, including: water, ethanol, glycerol or mixtures thereof.
In another preferred embodiment, the liquid formulation contains an excipient. If an excipient is present in the formulation it may be selected from pharmacologically acceptable excipients.
In another preferred embodiment, the excipient is a pharmacologically acceptable polyethylene glycol. Polyethylene glycols are a class of hydrophilic polyether that are commonly used as excipients in pharmaceutical formulations. In a further preferred embodiment, the excipient is PEG3350, a polyethylene glycol with an average Mn of 3,350 g/mol. A person of ordinary skill in the art will appreciate the different methods of characterizing the molecular weight of a polymer, including number average molecular weight (Mn), the average of molecular masses of individual macromolecules in a polymer sample.
In another preferred embodiment, the formulation is a solid.
In another preferred embodiment, the solid formulation is prepared either by lyophilization, spray drying, or evaporation.
In another preferred embodiment, the solid formulation contains an excipient. If an excipient is present in the formulation it may be selected from pharmacologically acceptable excipients.
In another preferred embodiment, the excipient is a pharmacologically acceptable polyethylene glycol. In a further preferred embodiment, the excipient is PEG3350. In another preferred embodiment, a liquid formulation is made by reconstituting a solid formulation. Such reconstitution may comprise combining a solid formulation with a liquid formulation to dissolve or suspend the solid in the liquid.
In another preferred embodiment, a solid formulation containing the PARP inhibitor molecule is reconstituted by adding a liquid to the solid, which can be followed by agitation to ensure dissolution of the solid. In such an embodiment, either or both of the solid and liquid formulations may contain excipients, including PEG3350.
For understanding, certain terms are defined below. Additional definitions for the following and other terms are set forth throughout the specification.
Headers are provided for convenience and are not intended to limit the content or applicability of the material contained therein.
As used in this application, the terms "about" and "approximately" are used as equivalents.
As used in this application, any number used with or without "about" or "approximately" is meant to cover normal fluctuations appreciated by one of ordinary skill in the relevant art.
As used in this application, "or" means "and/or" unless stated otherwise.
Drawings are presented herein for illustration purposes, not for limitation.
Brief Description of the Drawings:
Figure 1 shows a fluorescent biomarker molecule, PARPi-FL.
Figure 2 shows white light illumination of FaDu cells in phosphate buffered saline. The image was collected with a Dino-Lite GFBW using LED based white light illumination. All three vials, which contain a control of cells in phosphate buffered saline, cells incubated in phosphate buffered saline with PARPi-FL and PEG3350, and cells incubated in phosphate buffered saline with PARPi-FL and PEG300, show solutions that contain FaDu cells.
Figure 3 shows fluorescence imaging of FaDu cells in phosphate buffered saline. The image was collected with a Dino-Lite GFBW collecting fluorescence from the illuminated samples. The vial that contains a control of cells in phosphate buffered saline does not show any appreciable fluorescence. Cells incubated in phosphate buffered saline with PARPi-FL and PEG3350 for 5 minutes, and cells incubated in phosphate buffered saline with PARPi-FL and PEG300 for 5 minutes, fluoresce.
Figure 4 tabulates fluorescence intensity from the three samples - a control of cells in phosphate buffered saline, cells incubated in phosphate buffered saline with PARPi-FL and PEG3350, and cells incubated in phosphate buffered saline with PARPi-FL and PEG300.
In Figure 4, the control is labelled "PBS", the cells incubated in phosphate buffered saline with PARPi-FL and PEG3350 is labelled "PEG3350", and the cells incubated in phosphate buffered saline with PARPi-FL and PEG300 are labelled "PEG300".
EXAMPLES:
Example 1 - FaDu cells were prepared in 900 mί of phosphate buffered saline. FaDu cells (P-4, 95% confluent) were prepared in 6 mL of phosphate buffered saline (250 mί were replated for additional experiments). 1.5 mL Eppendorf vials were charged with FaDu solution (900 mί in phosphate buffered saline) to prepare a control, a sample with PARPi-FL (1000 nM) in 30% by weight PEG3350 in phosphate buffered saline, and a sample with PARPi-FL (1000 nM) in 30% by weight PEG300 in PBS. The PARPi-FL containing solutions were diluted to 100 nM of PARPi-FL in 1.0 mL. Samples were incubated for 5 min at room temperature and then spun at 1,400 RPM for 3 min. The supernatants were removed. 900 mΐ of phosphate buffered saline was added to break up the cell pellet. The samples were then centrifuged at 1,400 RPM for 3 min and the supernatants were removed. 900 mί. of phosphate buffered saline was again added to break up the cell pellet. The samples were then centrifuged at 1,400 RPM for 3 min and the supernatants were removed. Imaging of the cells was performed with a Dino-Lite GFBW. The PEG3350 formulation showed higher fluorescence intensity than the PEG300 formulation, both of which showed higher fluorescence intensity than the PBS control.

Claims

Claims:
1. A pharmaceutical composition comprising a fluorescence labelled PARP inhibitor in a formulation. 2. The pharmaceutical composition of claim 1, wherein the fluorescence labelled PARP inhibitor comprises (T-4)-[4-[[3-[[4-[3-[5-[(3,5-Dimethyl-2H-pyrrol-2-ylidene-KN)methyl]-lH- pyrrol-2-yl-KN-l-oxopropyl]-l-piperazinyl]carbonyl]-4-fluorophenyl]methyl]-l(2H)- phthalazinonato]difluoroboron.
3. The pharmaceutical composition of claim 1, wherein the formulation comprises a solid or liquid.
4. The pharmaceutical composition of claim 1, wherein the formulation is formed by mixing a solid composition and a liquid composition.
5. The pharmaceutical composition of claim 1, wherein the formulation comprises a fluorescence labelled PARP inhibitor and an excipient. 6. The pharmaceutical composition of claim 1, wherein the formulation comprises a fluorescence labelled PARP inhibitor, water, and a polyethylene glycol.
7. The pharmaceutical composition of claim 6, wherein the polyethylene glycol comprises PEG3350.
8. A method for forming a pharmaceutically acceptable formulation, comprising dissolving a solid fluorescence labelled PARP inhibitor and PEG3350 in a liquid.
9. The method for forming a pharmaceutically acceptable formulation of claim 8, wherein the liquid comprises water.
10. The method for forming a pharmaceutically acceptable formulation of claim 9, wherein the liquid comprises 30% by weight of polyethylene glycol in water.
11. The method for forming a pharmaceutically acceptable formulation of claim 10, wherein the polyethylene glycol comprises PEG3350.
12. The method for forming a pharmaceutically acceptable formulation of claim 8, wherein the formulation is formed by mixing two containers, one containing the solid fluorescence labelled PARP inhibitor and PEG3350 and the other containing water, and then agitating the combined mixture.
13. A kit for forming a pharmaceutically acceptable formulation, comprised of a first container that contains a fluorescence labelled PARP inhibitor and polyethylene glycol, and a second container that contains a liquid.
14. The kit for forming a pharmaceutically acceptable formulation of claim 13, wherein the fluorescence labelled PARP inhibitor comprises (T-4)-[4-[[3-[[4-[3-[5-[(3,5-Dimethyl-2H- pyrrol-2-ylidene-KN)methyl]-lH-pyrrol-2-yl-KN-l-oxopropyl]-l-piperazinyl]carbonyl]-4- fluorophenyl]methyl]-l(2H)-phthalazinonato]difluoroboron.
15. The kit for forming a pharmaceutically acceptable formulation of claim 13, wherein the polyethylene glycol is PEG3350.
16. The kit for forming a pharmaceutically acceptable formulation of claim 13, wherein the liquid comprises water.
17. The kit for forming a pharmaceutically acceptable formulation of claim 13, wherein the final formulation comprises 30% by weight polyethylene glycol in water.
19. A pharmaceutical composition comprising a rinsing solution for use with a PARP inhibitor.
20. The pharmaceutical composition of claim 19, wherein the composition is 30% by weight polyethylene glycol in water.
PCT/US2022/033772 2021-06-16 2022-06-16 PARPi-FL FORMULATIONS WO2022266311A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060275367A1 (en) * 2005-04-25 2006-12-07 Shubha Chungi Extended release formulations
US20200360538A1 (en) * 2015-04-10 2020-11-19 Memorial Sloan Kettering Cancer Center Methods of cancer detection using parpi-fl

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060275367A1 (en) * 2005-04-25 2006-12-07 Shubha Chungi Extended release formulations
US20200360538A1 (en) * 2015-04-10 2020-11-19 Memorial Sloan Kettering Cancer Center Methods of cancer detection using parpi-fl

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DEMÉTRIO DE SOUZA FRANÇA PAULA, DEMÉTRIO DE SOUZA FRANÇA PAULA, VIRAY TARA, ROBERTS SHERYL, MICHEL ALEXA, ABRAHÃO MARCIO, PATEL SN: "Polyethylene Glycol 3350 (PEG 3350) as a Practical Vehicle for Rapid Reconstitution of PARPi-FL Formulations for Clinical Use", MOLECULAR IMAGING & BIOLOGY, ELSEVIER, BOSTON, 26 July 2022 (2022-07-26), Boston , XP093017019, ISSN: 1536-1632, DOI: 10.1007/s11307-022-01756-8 *

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